U.S. patent application number 10/986230 was filed with the patent office on 2005-07-07 for medical implants and fibrosis-inducing agents.
This patent application is currently assigned to Angiotech International AG. Invention is credited to Gravett, David M., Hunter, William L., Liggins, Richard T., Maiti, Arpita, Signore, Pierre E., Toleikis, Philip M..
Application Number | 20050148512 10/986230 |
Document ID | / |
Family ID | 34596199 |
Filed Date | 2005-07-07 |
United States Patent
Application |
20050148512 |
Kind Code |
A1 |
Hunter, William L. ; et
al. |
July 7, 2005 |
Medical implants and fibrosis-inducing agents
Abstract
Implants are used in combination with a fibrosis-inducing agent
in order to induce fibrosis that may otherwise not occur when the
implant is placed within an animal or increase fibrosis between the
implant and the host tissue.
Inventors: |
Hunter, William L.;
(Vancouver, CA) ; Gravett, David M.; (Vancouver,
CA) ; Toleikis, Philip M.; (Vancouver, CA) ;
Maiti, Arpita; (Vancouver, CA) ; Signore, Pierre
E.; (Vancouver, CA) ; Liggins, Richard T.;
(Coquitlam, CA) |
Correspondence
Address: |
SEED INTELLECTUAL PROPERTY LAW GROUP PLLC
701 FIFTH AVENYUE, SUITE 6300
SEATTLE
WA
98104-7092
US
|
Assignee: |
Angiotech International AG
Zug
CH
|
Family ID: |
34596199 |
Appl. No.: |
10/986230 |
Filed: |
November 10, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60518785 |
Nov 10, 2003 |
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60523908 |
Nov 20, 2003 |
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60524023 |
Nov 20, 2003 |
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60586861 |
Jul 9, 2004 |
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60578471 |
Jun 9, 2004 |
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Current U.S.
Class: |
424/85.2 ;
424/680; 424/85.1; 514/11.3; 514/13.3; 514/154; 514/2.9; 514/23;
514/53; 514/55; 514/724; 514/8.1; 514/8.2; 514/8.5; 514/8.8;
514/8.9; 514/9.3 |
Current CPC
Class: |
A61K 38/363 20130101;
A61K 38/4833 20130101; A61B 17/11 20130101; A61L 27/54 20130101;
A61L 2300/412 20130101; A61L 2430/38 20130101; A61B 17/12168
20130101; A61K 38/38 20130101; A61K 45/06 20130101; A61B 17/12022
20130101; A61F 2250/0067 20130101; A61K 38/363 20130101; A61K 38/39
20130101; A61K 38/39 20130101; A61B 17/12099 20130101; A61K 2300/00
20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61P 43/00 20180101; A61B 17/68 20130101; A61B
17/1219 20130101; A61L 2300/00 20130101; A61P 9/00 20180101; A61B
17/12186 20130101; A61K 38/4833 20130101; A61P 1/00 20180101; A61L
31/16 20130101; A61P 19/00 20180101; A61B 17/12109 20130101; A61B
17/1214 20130101; A61K 38/38 20130101 |
Class at
Publication: |
514/012 ;
514/055; 514/008; 514/053; 514/023; 514/154; 514/724; 424/680;
424/085.1; 424/085.2 |
International
Class: |
A61K 038/17; A61K
031/7012; A61K 031/70; A61K 031/65; A61K 031/045; A61K 033/14; A61K
038/19; A61K 038/20; A61K 038/18; A61K 038/24 |
Claims
1. A method comprising introducing into an intervertebral disc
space of a patient in need thereof, a therapeutically effective
amount of a fibrosing agent or a composition comprising a fibrosing
agent, where the fibrosing agent induces a fibrotic response at the
intervertebral disc space of the patient, thereby providing the
patient with a beneficial result.
2-5. (canceled)
6. The method of claim 1 wherein the fibrosing agent promotes
angiogenesis.
7. The method of claim 1 wherein the fibrosing agent promotes
fibroblast migration.
8. The method of claim 1 wherein the fibrosing agent promotes
fibroblast proliferation.
9. The method of claim 1 wherein the fibrosing agent promotes
deposition of extracellular matrix (ECM).
10. The method of claim 1 wherein the fibrosing agent promotes
tissue remodeling.
11. The method of claim 1 wherein the fibrosing agent is an
arterial vessel wall irritant.
12. The method of claim 1 wherein the fibrosing agent is or
comprises silk.
13. The method of claim 1 wherein the fibrosing agent is or
comprises silkworm silk.
14. The method of claim 1 wherein the fibrosing agent is or
comprises spider silk.
15. The method of claim 1 wherein the fibrosing agent is or
comprises recombinant silk.
16. The method of claim 1 wherein the fibrosing agent is or
comprises raw silk.
17. The method of claim 1 wherein the fibrosing agent is or
comprises hydrolyzed silk.
18. The method of claim 1 wherein the fibrosing agent is or
comprises acid-treated silk.
19. The method of claim 1 wherein the fibrosing agent is or
comprises acylated silk.
20-23. (canceled)
24. The method of claim 1 wherein the fibrosing agent is or
comprises talc.
25. The method of claim 1 wherein the fibrosing agent is or
comprises chitosan.
26. The method of claim 1 wherein the fibrosing agent is or
comprises polylysine.
27. The method of claim 1 wherein the fibrosing agent is or
comprises fibronectin.
28. The method of claim 1 wherein the fibrosing agent is or
comprises bleomycin.
29. The method of claim 1 wherein the fibrosing agent is or
comprises CTGF.
30-47. (canceled)
48. The method of claim 1 wherein the composition further comprises
an agent that promotes bone growth.
49. The method of claim 48 wherein the fibrosing agent that
promotes bone growth is a bone morphogenic protein.
50. The method of claim 48 wherein the fibrosing agent that
promotes bone growth is an osteogenic growth factor.
51. The method of claim 50 wherein the osteogenic growth factor is
selected from transforming growth factor, platelet-derived growth
factor, and fibroblast growth factor.
52. The method of claim I wherein the composition further comprises
a pharmaceutical agent that induces sclerosis (a sclerosant).
53. The method of claim 52 wherein the sclerosant is selected from
the group consisting of ethanol, dimethyl sulfoxide, sucrose,
sodium chloride, dextrose, glycerin, minocycline, tetracycline,
doxycycline, polidocanol, sodium tetradecyl sulfate, sodium
morrhuate, and sotradecol.
54. (canceled)
55. The method of claim I wherein the composition further comprises
an inflammatory cytokine.
56. The method of claim 55 wherein the inflammatory cytokine is
selected from the group consisting of TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone.
57. The method of claim 1 wherein the composition further comprises
an agent that stimulates cell proliferation.
58-7018. (canceled)
7019. A medical device comprising a spinal fusion device and a
fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
7020. (canceled)
7021. The device of claim 7019 wherein the fibrosing agent promotes
angiogenesis.
7022. The device of claim 7019 wherein the fibrosing agent promotes
fibroblast migration.
7023. The device of claim 7019 wherein the fibrosing agent promotes
fibroblast proliferation.
7024. The device of claim 7019 wherein the fibrosing agent promotes
deposition of extracellular matrix (ECM).
7025. The device of claim 7019 wherein the fibrosing agent promotes
tissue remodeling.
7026. The device of claim 7019 wherein the fibrosing agent is an
arterial vessel wall irritant.
7027. (canceled)
7028. (canceled)
7029. The device of claim 7019 wherein the fibrosing agent is or
comprises silk.
7030. (canceled)
7031. The device of claim 7019 wherein the fibrosing agent is or
comprises chitosan.
7032. The device of claim 7019 wherein the fibrosing agent is or
comprises polylysine.
7033. The device of claim 7019 wherein the fibrosing agent is or
comprises fibronectin.
7034. The device of claim 7019 wherein the fibrosing agent is or
comprises bleomycin.
7035. The device of claim 7019 wherein the fibrosing agent is or
comprises CTGF.
7036-7090. (canceled)
7091. The device of claim 7019, further comprising a second
pharmaceutically active agent.
7092. (canceled)
7093. The device of claim 7019, further comprising an agent that
inhibits infection.
7094-9860. (canceled)
9861. A method of making a medical device comprising combining i) a
spinal fusion implant, with ii) a fibrosing agent or a composition
comprising a fibrosing agent, where the fibrosing agent induces a
fibrotic response between the device and a patient in which the
device is implanted.
9862. (canceled)
9863. The method of claim 9861 wherein the fibrosing agent promotes
angiogenesis.
9864. The method of claim 9861 wherein the fibrosing agent promotes
fibroblast migration.
9865. The method of claim 9861 wherein the fibrosing agent promotes
fibroblast proliferation.
9866. The method of claim 9861 wherein the fibrosing agent promotes
deposition of extracellular matrix (ECM).
9867. The method of claim 9861 wherein the fibrosing agent promotes
tissue remodeling.
9868. The method of claim 9861 wherein the fibrosing agent is an
arterial vessel wall irritant.
9869. (canceled)
9870. (canceled)
9871. The method of claim 9861 wherein the fibrosing agent is or
comprises silk.
9872. (canceled)
9873. The method of claim 9861 wherein the fibrosing agent is or
comprises chitosan.
9874. The method of claim 9861 wherein the fibrosing agent is or
comprises polylysine.
9875. The method of claim 9861 wherein the fibrosing agent is or
comprises fibronectin.
9876. The method of claim 9861 wherein the fibrosing agent is or
comprises bleomycin.
9877. The method of claim 9861 wherein the fibrosing agent is or
comprises CTGF.
9878. The method of claim 9861 wherein the fibrosing agent is in
the form of a thread, or is in contact with a thread.
9879-9930. (canceled)
9931. The method of claim 9861, wherein the implant is further
combined with a second pharmaceutically active agent.
9932. (canceled)
9933. The method of claim 9861 wherein the implant is further
combined with an agent that inhibits infection.
9934-10247. (canceled)
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit under 35 USC 119(e) of
U.S. Provisional Application Ser. No. 60/518,785, filed Nov. 10,
2003; U.S. Provisional Application Ser. No. 60/523,908, filed Nov.
20, 2003; U.S. Provisional Application Ser. No. 60/524,023, filed
Nov. 20, 2003; U.S. Provisional Application Ser. No. 60/586,861,
filed Jul. 9, 2004; and U.S. Provisional Application Ser. No.
60/578,471, filed Jul. 9, 2004, which applications are incorporated
herein by reference in their entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates generally to pharmaceutical
compositions, methods and devices, and more specifically, to
compositions and methods for preparing medical implants to make
them more adherent to, or, more readily incorporated within a
living tissue. The pharmaceutical agents and compositions are
utilized to create novel drug-coated implants and medical devices
which induce a fibrotic response in the surrounding tissue such
that the device is effectively anchored in situ and its performance
is enhanced.
[0004] 2. Description of the Related Art
[0005] The clinical performance of numerous medical devices depends
upon the device being effectively anchored into the surrounding
tissue to provide either structural support or to facilitate
scarring and healing. Effective attachment of the device into the
surrounding tissue, however, is not always readily achieved. One
reason for ineffective attachment is that implantable medical
devices generally are composed of materials that are highly
biocompatible and designed to reduce the host tissue response.
These materials (e.g., stainless steel, titanium based alloys,
fluoropolymers, and ceramics) typically do not provide a good
substrate for host tissue attachment and ingrowth during the
scarring process. As a result of poor attachment between the device
and the host tissue, devices can have a tendency to migrate within
the vessel or tissue in which they are implanted. The extent to
which a particular type of medical device can move or migrate after
implantation depends on a variety of factors including the type and
design of the device, the material(s) from which the device is
formed, the mechanical attributes (e.g., flexibility and ability to
conform to the surrounding geometry at the implantation site), the
surface properties, and the porosity of the device or device
surface. The tendency of a device to loosen after implantation also
depends on the type of tissue and the geometry at the treatment
site, where the ability of the tissue to conform around the device
generally can help to secure the device in the implantation site.
Device migration can result in device failure and, depending on the
type and location of the device, can lead to leakage, vessel
occlusion, and/or damage to the surrounding tissue.
[0006] Numerous methods and device modifications have been proposed
to secure implantable medical devices in place in the body. In one
approach, the medical device is anchored mechanically to biological
tissue. For example, artificial implants can be anchored to the
surrounding tissues by physical and mechanical means (e.g., screws,
cements and porous surfaces) or by friction. For example,
mechanical attachment of a device to the site can be effected by
using a fastener, such as a suture or staple. In another approach,
the device includes in its design mechanical means for fastening it
into the surrounding tissue. For example, the device may include
metallic spikes, anchors, hooks, barbs, pins, clamps, or a flange
or lip to affix the device in place (see, e.g., U.S. Pat. Nos.
4,523,592; 6,309,416; 6,302,905; and 6,152,937). A disadvantage of
mechanical fasteners, however, is that they can damage the tissue
or vessel wall when the device is deployed.
[0007] Other methods for preventing device migration have focused
on mechanically altering the surface characteristics of the device.
One such approach involves scoring or abrading the surface of the
implant. The roughened surfaces promote cell, bone or tissue
adhesion for better affixing of the implants in the body (see,
e.g., WO 96/29030A1). Medical devices, such as implantable
orthopedic devices, may be fixed to host tissue (e.g., bone) with
an adhesive, such as a polymethyl methacrylate (PMMA) bone cement
or a bone cement made from calcium phosphates and calcium aluminate
(see, e.g., U.S. Pat. No. 6,723,334). A drawback of bone cements,
however, is that over time the cemented bone-prosthesis interface
can degenerate, and/or the cement itself may weaken and fail,
resulting in loosening of the implant.
[0008] Chemical or biological modifications of the device surface
have been used to enhance adhesion between an implantable medical
device and the surrounding host tissue. For example, devices have
been coated with a substance to enhance the healing process and/or
adhesion of the device to the host tissue. In one approach,
implantable medical devices have been developed which permit
infiltration by specific desirable tissue cells. One type of tissue
infiltration involves the process known as "endothelialization",
i.e., migration of endothelial cells from adjacent tissue onto or
into the device surface. Methods for promoting endothelialization
have included applying a porous coating to the device which allows
tissue growth into the interstices of the implant surface (see,
e.g., WO 96/37165A1). Other efforts at improving host tissue
ingrowth capability and adhesion of the implant to host tissue
include an electrically charged or ionic material (e.g.,
fluoropolymer) in the tissue-contacting surface of the device (see,
e.g., WO 95/19796A1; J. E. Davies, in Surface Characterization of
Biomaterials, B. D. Ratner, ed., pp. 219-234 (1988); and U.S. Pat.
No. 5,876,743); biocompatible organic polymers (e.g., polymers
substituted with carbon, sulfur or phosphorous oxyacid groups) to
promote osteogenesis at the host-implant interface (see, e.g., U.S.
Pat. No. 4,795,475); and coatings made from biological materials
(e.g., collagen) to enhance tissue repair, growth and adaptation at
the implant-tissue interface (e.g., U.S. Pat. No. 5,002,583).
[0009] The above-described approaches, however, have failed to
provide a satisfactory long-term solution to the problem of device
migration. Thus, there is still a need for an effective,
long-lasting and biocompatible approach for anchoring implantable
medical devices into or onto biological tissue.
BRIEF SUMMARY OF THE INVENTION
[0010] Briefly stated, the present invention provides compositions
for delivery of selected therapeutic agents via medical implants or
implantable medical devices, as well as methods for making and
using these implants and devices. Within one aspect of the
invention, drug-coated or drug-impregnated implants and medical
devices are provided which induce adhesion or fibrosis in the
surrounding tissue, or facilitate "anchoring" of the device/implant
in situ, thus enhancing the efficacy. Within various embodiments,
fibrosis is induced by local or systemic release of specific
pharmacological agents that become localized to the adjacent
tissue.
[0011] The repair of tissues following a mechanical or surgical
intervention involves two distinct processes: (1) regeneration (the
replacement of injured cells by cells of the same type) and (2)
fibrosis (the replacement of injured cells by connective tissue).
There are four general components to the process of fibrosis (or
scarring) including: formation of new blood vessels (angiogenesis),
migration and proliferation of fibroblasts, deposition of
extracellular matrix (ECM), and remodeling (maturation and
organization of the fibrous tissue). As utilized herein, "induces
(promotes) fibrosis" should be understood to refer to agents or
compositions which increase or accelerate the formation of fibrous
tissue (i.e., by inducing or promoting one or more of the processes
of angiogenesis, fibroblast migration or proliferation, ECM
production, and/or remodeling). In addition, numerous therapeutic
agents described in this invention can have the additional benefit
of also promoting tissue regeneration.
[0012] Within one embodiment of the invention, an implant or device
is adapted to include or to release an agent that induces fibrosis
or regeneration through one or more of the mechanisms sited above.
Thus, the present invention provides devices that comprise a
medical implant and at least one of (i) a fibrosis-inducing agent
and (ii) a composition that comprises a fibrosis-inducing agent.
The agent is present so as to induce fibrosis formation that may
otherwise not occur or increase fibrosis in a statistically
significant manner when the implant is placed within an animal. In
another aspect the present invention is directed to methods wherein
both an implant and at least one of (i) a fibrosis-inducing agent
and (ii) a composition that comprises a fibrosis-inducing agent,
are placed into an animal, and the agent causes the formation of
fibrosis that may otherwise not occur or increase fibrosis in a
statistically significant manner. These and other aspects of the
invention are summarized below.
[0013] Thus, in various independent aspects, the present invention
provides the following: a device, comprising an orthopedic implant
and a fibrosis-inducing agent or a composition comprising a
fibrosis-inducing agent, wherein the agent induces fibrosis; a
device, comprising a male or female sterilization implant and a
fibrosis-inducing agent or a composition comprising a
fibrosis-inducing agent, wherein the agent induces fibrosis; a
device, comprising an implant for treating or preventing urinary
incontinence device and a fibrosis-inducing agent or a composition
comprising a fibrosis-inducing agent, wherein the agent induces
fibrosis; a device, comprising an implant for treating or
preventing gastroesophageal reflux disease (GERD) and a
fibrosis-inducing agent or a composition comprising a
fibrosis-inducing agent, wherein the agent induces fibrosis; a
device, comprising an implant for treating or preventing obesity
and a fibrosis-inducing agent or a composition comprising a
fibrosis-inducing agent, wherein the agent induces fibrosis; a
device, comprising an implant for treating or preventing fecal
incontinence device and a fibrosis-inducing agent or a composition
comprising a fibrosis-inducing agent, wherein the agent induces
fibrosis; a device, comprising an embolization implant and a
fibrosis-inducing agent or a composition comprising a
fibrosis-inducing agent, wherein the agent induces fibrosis; a
device, comprising a soft palate implant and a fibrosis-inducing
agent or a composition comprising a fibrosis-inducing agent,
wherein the agent induces fibrosis; a device, comprising a hernia
repair mesh implant and a fibrosis-inducing agent or a composition
comprising a fibrosis-inducing agent, wherein the agent induces
fibrosis; and a device, comprising a stent graft and a
fibrosis-inducing agent or a composition comprising a
fibrosis-inducing agent, wherein the agent induces fibrosis. These
and other devices are described in more detail herein.
[0014] In each of the aforementioned devices, in separate aspects
the present invention provides that the agent is: an arterial
vessel wall irritan; selected from the group consisting of talcum
powder, metallic beryllium and oxides thereof, copper, silk,
silica, crystalline silicates, talc, quartz dust, and ethanol; a
component of extracellular matrix selected from fibronectin,
collagen, fibrin, or fibrinogen; a polymer is selected from the
group consisting of polylysine, poly(ethylene-co-vinylacetate),
chitosan, N-carboxybutylchitosan, and RGD proteins; vinyl chloride
or a polymer of vinyl chloride; an adhesive selected from the group
consisting of cyanoacrylates and crosslinked poly(ethylene
glycol)-methylated collagen; an inflammatory cytokine (e.g.,
TGF.beta., PDGF, VEGF, bFGF, TNF.alpha., NGF, GM-CSF, IGF-a, IL-1,
IL-1-.beta., IL-8, IL-6, and growth hormone); connective tissue
growth factor (CTGF); a bone morphogenic protein (BMP) (e.g.,
BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7); leptin, and bleomycin
or an analogues or derivative thereof. Optionally, the device may
additionally comprise a proliferative agent that stimulates
cellular proliferation. Examples of proliferative agents include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof.
[0015] In additional aspects, for each of the aforementioned
devices combined with each of the aforementioned agents, it is, for
each combination, independently disclosed that the agent may be
present in a composition along with a polymer. In one embodiment of
this aspect, the polymer is biodegradable. In another embodiment of
this aspect, the polymer is non-biodegradable. Other features and
characteristics of the polymer, which may serve to describe the
present invention for every combination of device and agents
described above, are set forth in greater detail herein.
[0016] In another aspect, the invention provides a composition,
comprising a fibrosis-inducing agent and a bulking agent, wherein
the fibrosis-inducing agent induces fibrosis. In another aspect,
the invention provides a composition, comprising a
fibrosis-inducing agent and a sealant, wherein the agent induces
fibrosis. Exemplary fibrosis-inducing agents include, without
limitation: an arterial vessel wall irritant selected from the
group consisting of talcum powder, metallic beryllium and oxides
thereof, copper, silk, silica, crystalline silicates, talc, quartz
dust, and ethanol; a component of extracellular matrix selected
from fibronectin, collagen, fibrin, or fibrinogen; a polymer
selected from polylysine, poly(ethylene-co-vinylacetate), chitosan,
N-carboxybutylchitosan, and RGD proteins; vinyl chloride or a
polymer of vinyl chloride; an adhesive selected from the group
consisting of cyanoacrylates and crosslinked poly(ethylene
glycol)-methylated collagen; an inflammatory cytokine (e.g.,
TGF.beta., PDGF, VEGF, bFGF, TNF.alpha., NGF, GM-CSF, IGF-a, IL-1,
IL-8, IL-6, and growth hormone); CTGF; BMP (e.g., BMP-2, BMP-3,
BMP-4, BMP-5, BMP-6, or BMP-7); and bleomycin or an analogue or
derivative thereof. Optionally, the device may additionally
comprise an agent that stimulates cellular proliferation. Examples
of proliferative agents include: dexamethasone, isotretinoin,
17-.beta.-estradiol, estradiol, diethylstibesterol, cyclosporine A,
all-trans retinoic acid (ATRA), and analogues and derivatives
thereof. Bulking agents and sealants are described herein.
[0017] In addition to devices, the present invention also provides
methods. For example, in additional aspects of the present
invention, for each of the aforementioned devices, and for each of
the aforementioned combinations of the devices with the
fibrosis-inducing agents, the present invention provides methods
whereby a specified device is implanted into an animal, and a
specified agent associated with the device induces fibrosis that
may otherwise not occur or increases fibrosis in a statistically
significant manner. Each of the devices identified herein may be a
"specified device", and each of the fibrosis-inducing agents
identified herein may be a "fibrosis-inducing agent", where the
present invention provides, in independent embodiments, for each
possible combination of the device and the agent.
[0018] The agent may be associated with the device prior to the
device being placed within the animal. For example, the agent (or
composition comprising the agent) may be coated onto an implant,
and the resulting device then placed within the animal. In
addition, or alternatively, the agent may be independently placed
within the animal in the vicinity of where the device is to be, or
is being, placed within the animal. For example, the agent may be
sprayed or otherwise placed onto the tissue that can be contacting
the medical implant or may otherwise undergo scarring. To this end,
the present invention provides, in independent aspects: a method
for treating or preventing spider veins or varicose veins,
comprising injecting into the vein a composition comprising a
fibrosis-inducing agent; a method for sterilizing a female patient,
comprising injecting into a Fallopian tube a composition comprising
a fibrosis-inducing agent; a method for treating or preventing
urinary incontinence, comprising injecting into an urethra a
composition comprising a fibrosis-inducing agent; a method for
treating or preventing GERD, comprising injecting into a lower
esophageal sphincter a composition comprising a fibrosis-inducing
agent; a method for treating or preventing fecal incontinence,
comprising injecting into an anal sphincter a composition
comprising a fibrosis-inducing agent; a method for treating or
preventing snoring or sleep apnea, comprising injecting into a soft
palate a composition comprising a fibrosis-inducing agent; a method
for blocking an artery, comprising injecting into the artery a
composition comprising a fibrosis-inducing agent; a method for
sealing an air leak in a lung, comprising spraying onto the surface
of the lung a composition comprising a fibrosis-inducing agent; a
method for treating or preventing diverticulitis, comprising
delivering into a diverticulum a composition comprising a
fibrosis-inducing agent; a method for treating or preventing
arthritis, comprising injecting into a damaged joint a composition
comprising a fibrosis-inducing agent; a method for repairing a
damaged shoulder capsule, comprising spraying onto an anterior
capsule a composition comprising a fibrosis-inducing agent; a
method for repairing a damaged tendon or ligament, comprising
spraying onto the tendon or ligament a composition comprising a
fibrosis-inducing agent; a method for treating a damaged spinal
disc, comprising injecting into an intervertebral disc space a
composition comprising a fibrosis-inducing agent.
[0019] In additional aspects, for each of the aforementioned
methods used in combination with each of the aforementioned agents,
it is, for each combination, independently disclosed that the agent
may be present in a composition along with a polymer. In one
embodiment of this aspect, the polymer is biodegradable. In another
embodiment of this aspect, the polymer is non-biodegradable. Other
features and characteristics of the polymer, which may serve to
describe the present invention for every combination of device and
agents described above, are set forth in greater detail herein. In
addition to, or in lieu of the polymer, the composition may contain
collagen.
[0020] These and other aspects of the present invention can become
evident upon reference to the following detailed description. In
addition, various references are set forth herein which describe in
more detail certain procedures and/or compositions (e.g.,
polymers), and are therefore incorporated by reference in their
entirety.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] FIG. 1 is a graph showing the effect of cyclosporine A on
proliferation of human smooth muscle cells.
[0022] FIG. 2 is a graph showing the effect of dexamethasone on
proliferation of human fibroblasts.
[0023] FIG. 3 is a graph showing the effect of all-trans retinoic
acid (ATRA) on proliferation of human smooth muscle cells.
[0024] FIG. 4 is a graph showing the effect of isotretinoin on
proliferation of human smooth muscle cells.
[0025] FIG. 5 is a graph showing the effect of 17-.beta.-estradiol
on proliferation of human fibroblasts.
[0026] FIG. 6 is a graph showing the effect of
1a,25-dihydroxy-vitamin D.sub.3 on proliferation of human smooth
muscle cells.
[0027] FIG. 7 is a graph showing the effect of PDGF-BB on smooth
muscle cell migration.
[0028] FIG. 8 is a bar graph showing the area of granulation tissue
in carotid arteries exposed to silk coated perivascular
polyurethane (PU) films relative to arteries exposed to uncoated PU
films.
[0029] FIG. 9 is a bar graph showing the area of granulation tissue
in carotid arteries exposed to silk suture coated perivascular PU
films relative to arteries exposed to uncoated PU films.
[0030] FIG. 10 is a bar graph showing the area of granulation
tissue in carotid arteries exposed to natural and purified silk
powder and wrapped with perivascular PU film relative to a control
group in which arteries are wrapped with perivascular PU film
only.
[0031] FIG. 11 is a bar graph showing the area of granulation
tissue (at 1 month and 3 months) in carotid arteries sprinkled with
talcum powder and wrapped with perivascular PU film relative to a
control group in which arteries are wrapped with perivascular PU
film only.
[0032] FIG. 12 is a bar graph showing indicating the area of
perivascular granulation tissue quantified by computer-assisted
morphometric analysis in rat carotid arteries treated with control
uncoated PU films and with PU films treated with degummed and
virgin silk strands. As shown in the figure, both types of silk
markedly increased granulation tissue growth around the blood
vessel to the same extent.
[0033] FIG. 13 shows representative histology sections of rat
carotid arteries treated with PU films coated with degummed and
virgin silk strands. As shown in the figure, both types of silk
induced a marked tissue reaction around the treated blood vessel.
Movat stain, 100.times..
[0034] FIG. 14 shows representative histology sections of rat
carotid arteries treated with PU films coated with degummed and
virgin silk strands showing the granulation tissue that has grown
around the treated vessels. The silk strands have broken down into
small particles surrounded by giant cells and macrophages. The
granulation tissue is highly vascularized and contains numerous
inflammatory cells and fibroblasts. Extracellular matrix deposition
is also extensive. H&E stain 200.times..
[0035] FIG. 15 shows the release profile for cyclosporine A from a
polyurethane film as analyzed by HPLC.
DETAILED DESCRIPTION OF THE INVENTION
[0036] The present invention discloses pharmaceutical agents which
promote one or more aspects of the production of fibrous (scar)
tissue or tissue regeneration. Furthermore, compositions and
methods are described for coating medical devices and implants with
drug-delivery compositions such that the pharmaceutical agent is
delivered in therapeutic levels over a period sufficient for
fibrosis and healing to occur. The present invention also describes
various compositions and methods for enhancing the production of
scar tissue adjacent to or on the surface of the implant are
described. Numerous specific implants and devices are described
that are capable of producing superior clinical results as a result
of being coated with agents that promote scarring and healing, as
well as other related advantages.
[0037] Definitions
[0038] Prior to setting forth the invention, it may be helpful to
an understanding thereof to first set forth definitions of certain
terms that is used hereinafter.
[0039] "Medical Device" (or "implant," or "medical implant," or
implantable medical device") refers to any object placed in the
body for the purpose of restoring physiological function,
reducing/alleviating symptoms associated with disease, and/or
repairing/replacing damaged or diseased organs and tissues. While
normally composed of biologically compatible synthetic materials
(e.g., medical-grade stainless steel, titanium and other metals,
polymers such as polyurethane, silicon, polylactic acid (PLA),
polyglycolic acid (PLGA) and other materials), other materials that
are exogenous, some medical devices and implants include materials
derived from animals (e.g., "xenografts" such as whole animal
organs; animal tissues such as heart valves; naturally occurring or
chemically-modified molecules such as collagen, hyaluronic acid,
proteins, carbohydrates and others), human donors (e.g.,
"allografts" such as whole organs; tissues such as bone grafts,
skin grafts and others), or from the patients themselves (e.g.,
"autografts" such as saphenous vein grafts, skin grafts,
tendon/ligament/muscle transplants). Medical devices of particular
utility in the present invention include, but are not restricted
to, orthopaedic implants (artificial joints, ligaments and tendons,
screws, plates, and other implantable hardware), dental implants,
intravascular implants (particularly arterial and venous occlusion
devices and implants; vascular destructive implants), male and
female contraceptive or sterilization devices and implants,
implantable tissue bulking agents for incontinence (esophageal,
urethral, anal), soft palate implants, embolization agents,
pulmonary sealants, surgical meshes (e.g., hernia repair meshes,
tissue scaffolds), fistula treatments, and spinal implants (e.g.,
artificial intervertebral discs, spinal fusion devices, etc.).
[0040] "Fibrosis," "Scarring," or "Fibrotic Response" refers to the
formation of fibrous tissue in response to injury or medical
intervention. Therapeutic agents which promote (also referred to
interchangeably herein as "induce," "stimulate," "cause," and the
like) fibrosis or scarring are referred to interchangeably herein
as "fibrosis-inducing agents," "scarring agents," "fibrosing
agents," "adhesion-inducing agents," and the like, where these
agents do so through one or more mechanisms including: inducing or
promoting angiogenesis, stimulating migration or proliferation of
connective tissue cells (such as fibroblasts, smooth muscle cells,
vascular smooth muscle cells), inducing ECM production, and/or
promoting tissue remodeling. In addition, numerous therapeutic
agents described in this invention can have the additional benefit
of also promoting tissue regeneration (the replacement of injured
cells by cells of the same type).
[0041] "Sclerosing" refers to a tissue reaction in which an
irritant is applied locally to a tissue which results in an
inflammatory reaction and is followed by scar tissue formation at
the site of irritation. A pharmaceutical agent that induces or
promotes sclerosis is referred to as a "sclerosant," or a
"sclerosing agent." Representative examples of sclerosants include
ethanol, dimethyl sulfoxide, surfactants (e.g., Triton X, sorbitan
monolaurate, sorbitan sesquioleate, glycerol monostearate and
polyoxyethylene, polyoxyethylene cetyl ether, etc.), sucrose,
sodium chloride, dextrose, glycerin, minocycline, tetracycline,
doxycycline, polidocanol, sodium tetradecyl sulfate, sodium
morrhuate, ethanolamine, phenol, sarapin and sotradecol.
[0042] "Release of an agent" refers to any statistically
significant presence of the agent, or a subcomponent thereof, which
has disassociated from the implant/device.
[0043] Any concentration ranges, percentage range, or ratio range
recited herein are to be understood to include concentrations,
percentages or ratios of any integer within that range and
fractions thereof, such as one tenth and one hundredth of an
integer, unless otherwise indicated. Also, any number range recited
herein relating to any physical feature, such as polymer subunits,
size or thickness, are to be understood to include any integer
within the recited range, unless otherwise indicated. It should be
understood that the terms "a" and "an" as used above and elsewhere
herein refer to "one or more" of the enumerated components. As used
herein, the term "about" means.+-.15%.
[0044] As discussed above, the present invention provides
compositions, methods and devices relating to medical implants,
which greatly increase their ability to scar in place and
incorporate into the surrounding tissue. Described in more detail
below are methods for constructing medical implants, compositions
and methods for generating medical implants which promote fibrosis,
and methods for utilizing such medical implants.
[0045] A. Medical Implants
[0046] Medical implants of the present invention contain and/or are
adapted to release an agent which induces or promotes adhesion
between the implant and tissue or a fibrotic reaction. In certain
embodiments, the medical implant, when placed in to a tissue,
releases an agent that induces or promotes adhesion between the
implant and the tissue or a fibrotic reaction. In other
embodiments, the medical implant contains or is made of a fibrosing
agent, but does not release the fibrosing agent. In such
embodiments, the fibrosing agent contained in the medical implant
induces or promotes fibrosis by direct contact of the agent to the
tissue where the implant is placed.
[0047] Representative examples of medical implants include:
orthopaedic implants (artificial joints, ligaments and tendons,
screws, plates, and other implantable hardware), dental implants,
intravascular implants (particularly arterial and venous occlusion
devices and implants; vascular destructive implants), male and
female contraceptive or sterilization devices and implants,
implantable tissue bulking agents for incontinence (esophageal,
urethral, anal), soft palate implants, embolization agents,
pulmonary sealants, surgical meshes (e.g., hernia repair meshes,
tissue scaffolds), fistula treatments, and spinal implants (e.g.,
artificial intervertebral discs, spinal fusion devices, etc.).
[0048] B. Therapeutic Agents
[0049] Briefly, numerous therapeutic agents (also referred to
herein as `therapeutic agents` or `drugs`) have been identified
that can be utilized within the context of the present invention.
The agent may be formulated with one or more other materials, e.g.,
a polymeric carrier, where formulations are discussed below. Many
suitable therapeutic agents are specifically identified herein, and
others may be readily determined based upon in vitro and in vivo
(animal) models such as those provided in Examples 13-20; 33-34;
and 40. Therapeutic agents which promote fibrosis can be identified
through in vivo models such as the rat carotid artery model
(Examples 17-20).
[0050] In one aspect, the fibrosis or adhesion-inducing agent is
silk. Silk refers to a fibrous protein, and may be obtained from a
number of sources, typically spiders and silkworms. Typical silks
contain about 75% of actual fiber, referred to as fibroin, and
about 35% sericin, which is a gummy protein that holds the
filaments together. Silk filaments are generally very fine and
long--as much as 300-900 meters long. There are several species of
domesticated silkworm that are used in commercial silk production,
however, Bombyx mori is the most common, and most silk comes from
this source. Other suitable silkworms include Philosamia cynthia
ricini, Antheraea yamamai, Antheraea pernyi, and Antheraea mylitta.
Spider silk is relatively more difficult to obtain, however,
recombinant techniques hold promise as a means to obtain spider
silk at economical prices (see, e.g., U.S. Pat. Nos. 6,268,169;
5,994,099; 5,989,894; and 5,728,810, which are exemplary only).
Biotechnology has allowed researchers to develop other sources for
silk production, including animals (e.g., goats) and vegetables
(e.g., potatoes). Silk from any of these sources may be used in the
present invention.
[0051] A commercially available silk protein is available from
Croda, Inc., of Parsippany, N.J., and is sold under the trade names
CROSILK LIQUID (silk amino acids), CROSILK 10,000 (hydrolyzed
silk), CROSILK POWDER (powdered silk), and CROSILKQUAT
(cocodiammonium hydroxypropyl silk amino acid). Another example of
a commercially available silk protein is SERICIN, available from
Pentapharm, LTD, a division of Kordia, BV, of the Netherlands.
Further details of such silk protein mixtures can be found in U.S.
Pat. No. 4,906,460, to Kim, et al., assigned to Sorenco. Silk
useful in the present invention includes natural (raw) silk,
hydrolyzed silk, and modified silk, i.e., silk that has undergone a
chemical, mechanical, or vapor treatment, e.g., acid treatment or
acylation (see, e.g., U.S. Pat. No. 5,747,015).
[0052] Raw silk is typically twisted into a strand sufficiently
strong for weaving or knitting. Four different types of silk thread
may be produced by this procedure: organzine, crepe, tram and
thrown singles. Organzine is a thread made by giving the raw silk a
preliminary twist in one direction and then twisting two of these
threads together in the opposite direction. Crepe is similar to
organzine but is twisted to a much greater extent. Twisting in only
one direction two or more raw silk threads makes tram. Thrown
singles are individual raw silk threads that are twisted in only
one direction. Any of these types of silk threads may be used in
the present invention.
[0053] The silk used in the present invention may be in any
suitable form that allows the silk to be joined with the medical
implant, e.g., the silk may be in thread or powder-based forms. The
silk can be prepared in the powdered form by several different
methods. For example the silk can be milled (e.g., cryomill) into a
powdered form. Alternatively the silk can be dissolved in a
suitable solvent (e.g., HFIP or 9M LiBr) and then sprayed
(electrospray, spray dry) or added to a non-solvent to produce a
powder. Furthermore, the silk may have any molecular weight, where
various molecular weights are typically obtained by the hydrolysis
of natural silk, where the extent and harshness of the hydrolysis
conditions determines the product molecular weight. For example,
the silk may have an average (number or weight) molecular weight of
about 200 to 5,000. See, e.g., JP-B-59-29199 (examined Japanese
patent publication) for a description of conditions that may be
used to hydrolyze silk.
[0054] A discussion of silk may be found in the following
documents, which are exemplary only: Hinman, M. B., et al.
"Synthetic spider silk: a modular fibre" Trends in Biotechnology,
2000, 18(9) 374-379; Vollrath, F. and Knight, D. P. "Liquid
crystalline spinning of spider silk" Nature, 2001, 410(6828)
541-548; and Hayashi, C. Y., et al. "Hypotheses that correlate the
sequence, structure, and mechanical properties of spider silk
proteins" Int. J. Biol. Macromolecules, 1999, 24(2-3), 265-270; and
U.S. Pat. No. 6,427,933.
[0055] Other representative examples of fibrosis and
adhesion-inducing agents include irritants (e.g., talc, talcum
powder, copper, metallic beryllium (or its oxides), wool (e.g.,
animal wool, wood wolol, and synthetic wool), quartz dust, silica,
crystalline silicates), polymers (e.g., polylysine, polyurethanes,
poly(ethylene terephthalate), polytetrafluoroethylene (PTFE),
poly(alkylcyanoacrylates), and poly(ethylene-co-vinylacetate));
vinyl chloride and polymers of vinyl chloride; peptides with high
lysine content; growth factors and inflammatory cytokines involved
in angiogenesis, fibroblast migration, fibroblast proliferation,
ECM synthesis and tissue remodeling, such as epidermal growth
factor (EGF) family, transforming growth factor-.alpha.
(TGF-.alpha.), transforming growth factor-.beta. (TGF-9-1, TGF-9-2,
TGF-9-3, platelet-derived growth factor (PDGF), fibroblast growth
factor (acidic--aFGF; and basic--bFGF), fibroblast stimulating
factor-1, activins, vascular endothelial growth factor (including
VEGF-2, VEGF-3, VEGF-A, VEGF-B, VEGF-C, placental growth
factor--PIGF), angiopoietins, insulin-like growth factors (IGF),
hepatocyte growth factor (HGF), connective tissue growth factor
(CTGF), myeloid colony-stimulating factors (CSFs), monocyte
chemotactic protein, granulocyte-macrophage colony-stimulating
factors (GM-CSF), granulocyte colony-stimulating factor (G-CSF),
macrophage colony-stimulating factor (M-CSF), erythropoietin,
interleukins (particularly IL-1, IL-8, and IL-6), tumor necrosis
factor-.alpha. (TNF9), nerve growth factor (NGF),
interferon-.alpha., interferon-.beta., histamine, endothelin-1,
angiotensin II, growth hormone (GH), and synthetic peptides,
analogues or derivatives of these factors are also suitable for
release from specific implants and devices to be described later.
Other examples include CTGF (connective tissue growth factor);
inflammatory microcrystals (e.g., crystalline minerals such as
crystalline silicates); bromocriptine, methylsergide, methotrexate,
chitosan, N-carboxybutyl chitosan, carbon tetrachloride,
thioacetamide, fibrosin, ethanol, bleomycin, naturally occurring or
synthetic peptides containing the Arg-Gly-Asp (RGD) sequence,
generally at one or both termini (see e.g., U.S. Pat. No.
5,997,895), and tissue adhesives, such as cyanoacrylate and
crosslinked poly(ethylene glycol)-methylated collagen compositions,
such as described below. Other examples of fibrosis-inducing agents
include bone morphogenic proteins (e.g., BMP-2, BMP-3, BMP-4,
BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10, BMP-11,
BMP-12, BMP-13, BMP-14, BMP-15, and BMP-16. Of these, BMP-2, BMP-3,
BMP-4, BMP-5, BMP-6, and BMP-7 are of particular utility. Bone
morphogenic proteins are described, for example, in U.S. Pat. Nos.
4,877,864; 5,013,649; 5,661,007; 5,688,678; 6,177,406; 6,432,919;
and 6,534,268 and Wozney, J. M., et al. (1988) Science: 242(4885);
1528-1534.
[0056] Other representative examples of fibrosis-inducing agents
include crosslinked compositions that comprise amino-functional
groups. For example, amino-functionalized polyethylene glycol
(e.g., 4-armed tetra-amino PEG [10k]) can be reacted with a 4-armed
NHS functionalized PEG (e.g., pentaerythritol poly(ethylene
glycol)ether tetra-succinimidyl glutarate) under basic buffer
conditions. In another example a 4-armed thiol functionalized PEG
(e.g., pentaerythritol poly(ethylene glycol)ether tetra-thiol) can
be substituted for the 4-arm amino-functionalized PEG such that the
amount of amino functional groups in the final composition can be
varied. These reagents can be mixed at the time of application to
provide an in situ forming crosslinked hydrogel. These reagents
could be premixed to produce the crosslinked material. The material
can be made in various forms such as rods, tubes, films, slabs or
spheres. The crosslinked material could also be milled to produce a
particulate material. These materials can be dried (e.g., air,
vacuum, freeze-dried) and used as a dry powdered material.
Alternatively the materials can be hydrated just prior to
application. These materials can further comprise one of the
fibrosis-inducing agents described herein.
[0057] Other representative examples of fibrosis-inducing agents
include components of extracellular matrix (e.g., fibronectin,
fibrin, fibrinogen, collagen (e.g., bovine collagen), fibrillar and
non-fibrillar collagen, adhesive glycoproteins, proteoglycans
(e.g., heparin sulfate, chondroitin sulfate, dermatan sulfate),
hyaluronan, secreted protein acidic and rich in cysteine (SPARC),
thrombospondins, tenacin, and cell adhesion molecules (including
integrins, vitronectin, fibronectin, laminin, hyaluronic acid,
elastin, bitronectin), proteins found in basement membranes, and
fibrosin) and inhibitors of matrix metalloproteinases, such as
TIMPs (tissue inhibitors of matrix metalloproteinases) and
synthetic TIMPs, e.g., marimistat, batimistat, doxycycline,
tetracycline, minocycline, TROCADE, Ro-1130830, CGS 27023A, and
BMS-275291.
[0058] Within various embodiments of the invention, a device is
coated with a first composition that promotes fibrosis (and/or
restenosis) and a second composition or compound which acts to have
an inhibitory effect on pathological processes in or around the
treatment site. Representative examples of agents which can inhibit
pathological processes in the treatment site include, but not
limited to, the following classes of compounds: anti-inflammatory
agents (e.g., dexamethasone, cortisone, fludrocortisone,
prednisone, prednisolone, 6.alpha.-methylprednisolone,
triamcinolone, and betamethasone); Matrix Metalloproteinase (MMP)
inhibitors (e.g., marimistat, batimistat, TIMP's representative
examples of which are included in U.S. Pat. Nos. 5,665,777;
5,985,911; 6,288,261; 5,952,320; 6,441,189; 6,235,786; 6,294,573;
6,294,539; 6,563,002; 6,071,903; 6,358,980; 5,852,213; 6,124,502;
6,160,132; 6,197,791; 6,172,057; 6,288,086; 6,342,508; 6,228,869;
5,977,408; 5,929,097; 6,498,167; 6,534,491; 6,548,524; 5,962,481;
6,197,795; 6,162,814; 6,441,023; 6,444,704; 6,462,073; 6,162,821;
6,444,639; 6,262,080; 6,486,193; 6,329,550; 6,544,980; 6,352,976;
5,968,795; 5,789,434; 5,932,763; 6,500,847; 5,925,637; 6,225,314;
5,804,581; 5,863,915; 5,859,047; 5,861,428; 5,886,043; 6,288,063;
5,939,583; 6,166,082; 5,874,473; 5,886,022; 5,932,577; 5,854,277;
5,886,024; 6,495,565; 6,642,255; 6,495,548; 6,479,502; 5,696,082;
5,700,838; 6,444,639; 6,262,080; 6,486,193; 6,329,550; 6,544,980;
6,352,976; 5,968,795; 5,789,434; 5,932,763; 6,500,847; 5,925,637;
6,225,314; 5,804,581; 5,863,915; 5,859,047; 5,861,428; 5,886,043;
6,288,063; 5,939,583; 6,166,082; 5,874,473; 5,886,022; 5,932,577;
5,854,277; 5,886,024; 6,495,565; 6,642,255; 6,495,548; 6,479,502;
5,696,082; 5,700,838; 5,861,436; 5,691,382; 5,763,621; 5,866,717;
5,902,791; 5,962,529; 6,017,889; 6,022,873; 6,022,898; 6,103,739;
6,127,427; 6,258,851; 6,310,084; 6,358,987; 5,872,152; 5,917,090;
6,124,329; 6,329,373; 6,344,457; 5,698,706; 5,872,146; 5,853,623;
6,624,144; 6,462,042; 5,981,491; 5,955,435; 6,090,840; 6,114,372;
6,566,384; 5,994,293; 6,063,786; 6,469,020; 6,118,001; 6,187,924;
6,310,088; 5,994,312; 6,180,611; 6,110,896; 6,380,253; 5,455,262;
5,470,834; 6,147,114; 6,333,324; 6,489,324; 6,362,183; 6,372,758;
6,448,250; 6,492,367; 6,380,258; 6,583,299; 5,239,078; 5,892,112;
5,773,438; 5,696,147; 6,066,662; 6,600,057; 5,990,158; 5,731,293;
6,277,876; 6,521,606; 6,168,807; 6,506,414; 6,620,813; 5,684,152;
6,451,791; 6,476,027; 6,013,649; 6,503,892; 6,420,427; 6,300,514;
6,403,644; 6,177,466; 6,569,899; 5,594,006; 6,417,229; 5,861,510;
6,156,798; 6,387,931; 6,350,907; 6,090,852; 6,458,822; 6,509,337;
6,147,061; 6,114,568; 6,118,016; 5,804,593; 5,847,153; 5,859,061;
6,194,451; 6,482,827; 6,638,952; 5,677,282; 6,365,630; 6,130,254;
6,455,569; 6,057,369; 6,576,628; 6,110,924; 6,472,396; 6,548,667;
5,618,844; 6,495,578; 6,627,411; 5,514,716; 5,256,657; 5,773,428;
6,037,472; 6,579,890; 5,932,595; 6,013,792; 6,420,415; 5,532,265;
5,639,746; 5,672,598; 5,830,915; 6,630,516; 5,324,634; 6,277,061;
6,140,099; 6,455,570; 5,595,885; 6,093,398; 6,379,667; 5,641,636;
5,698,404; 6,448,058; 6,008,220; 6,265,432; 6,169,103; 6,133,304;
6,541,521; 6,624,196; 6,307,089; 6,239,288; 5,756,545; 6,020,366;
6,117,869; 6,294,674; 6,037,361; 6,399,612; 6,495,568; 6,624,177;
5,948,780; 6,620,835; 6,284,513; 5,977,141; 6,153,612; 6,297,247;
6,559,142; 6,555,535; 6,350,885; 5,627,206; 5,665,764; 5,958,972;
6,420,408; 6,492,422; 6,340,709; 6,022,948; 6,274,703; 6,294,694;
6,531,499; 6,465,508; 6,437,177; 6,376,665; 5,268,384; 5,183,900;
5,189,178; 6,511,993; 6,617,354; 6,331,563; 5,962,466; 5,861,427;
5,830,869; and 6,087,359), cytokine inhibitors (chlorpromazine,
mycophenolic acid, rapamycin, 1.alpha.-hydroxy vitamin D.sub.3),
IMPDH (inosine monophosplate dehydrogenase) inhibitors (e.g.,
mycophenolic acid, ribaviran, aminothiadiazole, thiophenfurin,
tiazofurin, viramidine) (Representative examples are included in
U.S. Pat. Nos. 5,536,747; 5,807,876; 5,932,600; 6,054,472;
6,128,582; 6,344,465; 6,395,763; 6,399,773; 6,420,403; 6,479,628;
6,498,178; 6,514,979; 6,518,291; 6,541,496; 6,596,747; 6,617,323;
and 6,624,184, U.S. Patent Application Nos. 2002/0040022A1,
2002/0052513A1, 2002/0055483A1, 2002/0068346A1, 2002/0111378A1,
2002/0111495A1, 2002/0123520A1, 2002/0143176A1, 2002/0147160A1,
2002/0161038A1, 2002/0173491A1, 2002/0183315A1, 2002/0193612A1,
2003/0027845A1, 2003/0068302A1, 2003/0105073A1, 2003/0130254A1,
2003/0143197A1, 2003/0144300A1, 2003/0166201A1, 2003/0181497A1,
2003/0186974A1, 2003/0186989A1, and 2003/0195202A1, and PCT
Publication Nos. WO 00/24725A1, WO 00/25780A1, WO 00/26197A1, WO
00/51615A1, WO 00/56331A1, WO 00/73288A1, WO 01/00622A1, WO
01/66706A1, WO 01/79246A2, WO 01/81340A2, WO 01/85952A2, WO
02/16382A1, WO 02/18369A2, WO 02/051814A1, WO 02/057287A2, WO
02/057425A2, WO 02/060875A1, WO 02/060896A1, WO 02/060898A1, WO
02/068058A2, WO 03/020298A1, WO 03/037349A1, WO 03/039548A1, WO
03/045901A2, WO 03/047512A2, WO 03/053958A1, WO 03/055447A2, WO
03/059269A2, WO 03/063573A2, WO 03/087071A1, WO 99/001545A1, WO
97/40028A1, WO 97/41211A1, WO 98/40381A1, and WO 99/55663A1), p38
MAP kinase inhibitors (MAPK) (e.g., GW-2286, CGP-52411, BIRB-798,
SB220025, RO-320-1195, RWJ-67657, RWJ-68354, SCIO-469)
(Representative examples are included in U.S. Pat. Nos. 6,300,347;
6,316,464; 6,316,466; 6,376,527; 6,444,696; 6,479,507; 6,509,361;
6,579,874, and 6,630,485, and U.S. Patent Application Publication
Nos. 2001/0044538A1, 2002/0013354A1, 2002/0049220A1,
2002/0103245A1, 2002/0151491A1, 2002/0156114A1, 2003/0018051A1,
2003/0073832A1, 2003/0130257A1, 2003/0130273A1, 2003/0130319A1,
2003/0139388A1, 2003/0139462A1, 2003/0149031A1, 2003/0166647A1, and
2003/0181411A1, and PCT Publication Nos. WO 00/63204A2, WO
01/21591A1, WO 01/35959A1, WO 01/74811A2, WO 02/18379A2, WO
02/064594A2, WO 02/083622A2, WO 02/094842A2, WO 02/096426A1, WO
02/101015A2, WO 02/103000A2, WO 03/008413A1, WO 03/016248A2, WO
03/020715A1, WO 03/024899A2, WO 03/031431A1, WO 03/040103A1, WO
03/053940A1, WO 03/053941A2, WO 03/063799A2, WO 03/079986A2, WO
03/080024A2, WO 03/082287A1, WO 97/44467A1, WO 99/01449A1, and WO
99/58523A1), and immunomodulatory agents (rapamycin, everolimus,
ABT-578, azathioprine azithromycin, analogues of rapamycin,
tacrolimus and derivatives thereof (e.g., EP 0184162B1 and those
described in U.S. Pat. No. 6,258,823) and everolimus and
derivatives thereof (e.g., U.S. Pat. No. 5,665,772). Further
representative examples of sirolimus analogues and derivatives
include ABT-578 and those found in PCT Publication Nos. WO
97/10502, WO 96/41807, WO 96/35423, WO 96/03430, WO 96/00282, WO
95/16691, WO 95/15328, WO 95/07468, WO 95/04738, WO 95/04060, WO
94/25022, WO 94/21644, WO 94/18207, WO 94/10843, WO 94/09010, WO
94/04540, WO 94/02485, WO 94/02137, WO 94/02136, WO 93/25533, WO
93/18043, WO 93/13663, WO 93/11130, WO 93/10122, WO 93/04680, WO
92/14737, and WO 92/05179 and in U.S. Pat. Nos. 6,342,507;
5,985,890; 5,604,234; 5,597,715; 5,583,139; 5,563,172; 5,561,228;
5,561,137; 5,541,193; 5,541,189; 5,534,632; 5,527,907; 5,484,799;
5,457,194; 5,457,182; 5,362,735; 5,324,644; 5,318,895; 5,310,903;
5,310,901; 5,258,389; 5,252,732; 5,247,076; 5,225,403; 5,221,625;
5,210,030; 5,208,241; 5,200,411; 5,198,421; 5,147,877; 5,140,018;
5,116,756; 5,109,112; 5,093,338; and 5,091,389.
[0059] Other examples of drugs that may be included in the
compositions and devices of the invention include tyrosine kinase
inhibitors, such as imantinib, ZK-222584, CGP-52411, CGP-53716,
NVP-MK980-NX, CP-127374, CP-564959, PD-171026, PD-173956,
PD-180970, SU-0879, and SKI-606. Other examples of drugs that may
be included in the compositions and devices of the invention
include MMP inhibitors such as nimesulide, PKF-241-466,
PKF-242-484, CGS-27023A, SAR-943, primomastat, SC-77964,
PNU-171829, AG-3433, PNU-142769, SU-5402, and dexlipotam. Other
examples of drugs that may be included in the compositions and
devices of the invention include p38 MAP kinase inhibitors such as
CGH-2466 and PD-98-59. Other examples of of drugs that may be
included in the compositions and devices of the invention include
immunosuppressants such as argyrin B, macrocyclic lactone,
ADZ-62-826, CCl-779, tilomisole, amcinonide, FK-778, AVE-1726, and
MDL-28842. Other examples of cytokine inhibitors include TNF-484A,
PD-172084, CP-293121, CP-353164, and PD-168787. Other examples of
drugs that may be included in the compositions and devices of the
invention include include NFKB inhibitors, such as, AVE-0547,
AVE-0545, and IPL-576092. Other examples of drugs that may be
included in the compositions and devices of the invention include
include HMGCoA reductase inhibitors, such as, pravestatin,
atorvastatin, fluvastatin, dalvastatin, glenvastatin, pitavastatin,
CP-83101, U-20685, apoptosis antagonist (e.g., troloxamine, TCH-346
(N-methyl-N-propargyl-10-aminometh- yl-dibenzo(b,f)oxepin), caspase
inhibitors (e.g., PF-5901 (benzenemethanol,
alpha-pentyl-3-(2-quinolinylmethoxy)-), and JNK inhibitor (e.g.,
AS-602801).
[0060] Within various embodiments of the invention, a device
incorporates or is coated with a composition which promotes
fibrosis (and/or restenosis), as well as a composition or compound
which acts to stimulate cellular proliferation. Representative
examples of agents that stimulate cellular proliferation include,
pyruvic acid, naltrexone, leptin, D-glucose, insulin, amlodipine,
alginate oligosaccharides, minoxidil, dexamethasone, isotretinoin
(13-cis retinoic acid), 17-.beta.-estradiol, estradiol, 1-a-25
dihydroxyvitamin D.sub.3, diethylstibesterol, cyclosporine A,
L-NAME (L-NG-nitroarginine methyl ester (hydrochloride)), all-trans
retinoic acid (ATRA), and analogues and derivatives thereof. Other
examples of agents that stimulate cellular proliferation include:
sphingosine 1-phosphate receptor agonist (e.g., FTY-720
(1,3-propanediol, 2-amino-2-(2-(4-octylphenyl)ethyl)-,
hydrochloride; immunostimulants, such as Imupedone (methanone,
[5-amino-2-(4-methyl-1-piperidinyl)phenyl](- 4-chlorophenyl)-,
DIAPEP227 synthetic peptide (Peptor Ltd., Israel)); and nerve
growth factor agonist, e.g., NG-012
(5H,9H,13H,21H,25H,-dibenzo[k,u-
][1,5,9,15,19]pentaoxacyclotetracosin-5,9,13,21,25-pentone,
7,8,11,12,15,16,23,24,27,28-decahydro-2,4,18,20-tetrahydroxy-11-(hydroxym-
ethyl)-7,15,23,27-tetramethyl-, NG-121, SS-701
(2,2':6',2"-terpyridine, 4'-(4-methylphenyl)-, trihydrochloride,
AMPAlex (piperidine, 1-(6-quinoxalinylcarbonyl)-, RG H-2716
(8-[4,4-bis(4-fluorophenyl)butyl]--
3-(1,1-dimethylethyl)-4-methylene-1-oxa-3,8-diaza-spiro[4.5]decan-2-one,
and TDN-345 (1-oxa-3,8-diazaspiro[4.5]decan-2-one,
8-[4,4-bis(4-fluorophenyl)butyl]-3-(1,1-dimethylethyl)-4-methylene-).
[0061] Within various embodiments of the invention, a device
incorporates or is coated on one aspect with a composition which
promotes fibrosis (and/or restenosis), as well as with a
composition or compound which prevents restenosis on another aspect
of the device. Representative examples of agents that inhibit
restenosis include paclitaxel, sirolimus, everolimus, vincristine,
biolimus, mycophenolic acid, ABT-578, cervistatin, simvastatin,
methylprednisolone, dexamethasone, actinomycin-D, angiopeptin,
L-arginine, estradiol, 17-.beta.-estradiol, tranilast,
methotrexate, batimistat, halofuginone, BCP-671, QP-2, lantrunculin
D, cytochalasin A, nitric oxide, and analogues and derivatives
thereof.
[0062] The medical implant may include a fibrosing agent and an
anti-thrombotic agent and/or antiplatelet agent, which reduces the
likelihood of thrombotic events upon implantation of a medical
implant. Within various embodiments of the invention, a device is
coated on one aspect with a composition which promotes fibrosis
(and/or restenosis), as well as being coated with a composition or
compound which prevents thrombosis on another aspect of the device.
Representative examples of anti-thrombotic and/or antiplatelet
agents include heparin, heparin fragments, organic salts of
heparin, heparin complexes (e.g., benzalkonium heparinate,
tridodecylammonium heparinate), dextran, sulfonated carbohydrates
such as dextran sulphate, coumadin, coumarin, heparinoid,
danaparoid, argatroban chitosan sulfate, chondroitin sulfate,
danaparoid, lepirudin, hirudin, AMP, adenosine, 2-chloroadenosine,
aspirin, phenylbutazone, indomethacin, meclofenamate,
hydrochloroquine, dipyridamole, iloprost, streptokinase, and factor
Xa inhibitors, such as DX9065a, magnesium, and tissue plasminogen
activator. In one aspect, the anti-thrombotic agent is a modified
heparin compound, such as a hydrophobically modified heparin or
modified hirudin compound (e.g., stearylkonium heparin,
benzalkonium heparin, cetylkonium heparin, or trdodecylmethyl
ammonium heparin). Further examples of anti-thrombotic agents
include plasminogen, lys-plasminogen, alpha-2-antiplasmin,
urokinase, ticlopidine, clopidogrel, glycoprotein IIb/IIIa
inhibitors such as abcixamab, eptifibatide, and tirogiban. Other
agents capable of affecting the rate of clotting include
glycosaminoglycans, danaparoid, 4-hydroxycourmarin, warfarin
sodium, dicumarol, phenprocoumon, indan-1,3-dione, acenocoumarol,
anisindione, and rodenticides including bromadiolone, brodifacoum,
diphenadione, chlorophacinone, and pidnone. The thrombogenicity of
a medical implant may be reduced by coating the implant with a
polymeric formulation that has anti-thrombogenic properties. For
example, a medical device may be coated with a hydrophilic polymer
gel. The polymer gel can comprise a hydrophilic, biodegradable
polymer that is physically removed from the surface of the device
over time, thus reducing adhesion of platelets to the device
surface. The gel composition can include a polymer or a blend of
polymers. Representative examples include alginates, chitosan and
chitosan sulfate, hyaluronic acid, dextran sulfate, PLURONIC
polymers (e.g., F-127 or F87) and chain extended PLURONIC polymers
(BASF Corporation, Mt. Olive, N.J.), various polyester-polyether
block copolymers of various configurations (e.g., AB, ABA, or BAB,
where A is a polyester such as PLA, PGA, PLGA, PCL or the like),
examples of which include MePEG-PLA, PLA-PEG-PLA, and the like). In
one embodiment, the anti-thrombotic composition can include a
crosslinked gel formed from a combination of molecules (e.g., PEG)
having two or more terminal electrophilic groups and two or more
nucleophilic groups.
[0063] In one aspect, the present invention also provides for the
combination of a medical implant (as well as compositions and
methods for making medical implants) that includes a fibrosing
agent and an anti-infective agent, which reduces the likelihood of
infections in medical implants. Infection is a common complication
of the implantation of foreign bodies such as medical devices.
Foreign materials provide an ideal site for micro-organisms to
attach and colonize. It is also hypothesized that there is an
impairment of host defenses to infection in the microenvironment
surrounding a foreign material. These factors make medical implants
particularly susceptible to infection and make eradication of such
an infection difficult, if not impossible, in most cases.
[0064] The present invention provides agents (e.g.,
chemotherapeutic agents) that can be incorporated onto or into, or
released from, an implantable device, and which have potent
antimicrobial activity at extremely low doses. A wide variety of
anti-infective agents can be utilized in combination with a
fibrosing agent according to the invention. Discussed in more
detail below are several representative examples of
Chemotehrapeutic/anti-infective agents that can be used: (A)
anthracyclines (e.g., doxorubicin and mitoxantrone), (B)
fluoropyrimidines (e.g., 5-FU), (C) folic acid antagonists (e.g.,
methotrexate), (D) podophylotoxins (e.g., etoposide), (E)
camptothecins, (F) hydroxyureas, and (G) platinum complexes (e.g.,
cisplatin).
[0065] (A) Anthracyclines
[0066] Anthracyclines have the following general structure, where
the R groups may be a variety of organic groups: 1
[0067] According to U.S. Pat. No. 5,594,158, suitable R groups are
as follows: R.sub.1 is CH.sub.3 or CH.sub.2OH; R.sub.2 is
daunosamine or H; R.sub.3 and R.sub.4 are independently one of OH,
NO.sub.2, NH.sub.2, F, Cl, Br, I, CN, H or groups derived from
these; R.sub.5 is hydrogen, hydroxyl, or methoxy; and R.sub.6-8 are
all hydrogen. Alternatively, R.sub.5 and R.sub.6 are hydrogen and
R.sub.7 and R.sub.8 are alkyl or halogen, or vice versa.
[0068] According to U.S. Pat. No. 5,843,903, R.sub.1 may be a
conjugated peptide. According to U.S. Pat. No. 4,296,105, R.sub.5
may be an ether linked alkyl group. According to U.S. Pat. No.
4,215,062, R.sub.5 may be OH or an ether linked alkyl group.
R.sub.1 may also be linked to the anthracycline ring by a group
other than C(O), such as an alkyl or branched alkyl group having
the C(O) linking moiety at its end, such as
--CH.sub.2CH(CH.sub.2--X)C(O)--R.sub.1, wherein X is H or an alkyl
group (see, e.g., U.S. Pat. No. 4,215,062). R.sub.2 may alternately
be a group linked by the functional group .dbd.N--NHC(O)--Y, where
Y is a group such as a phenyl or substituted phenyl ring.
Alternately R.sub.3 may have the following structure: 2
[0069] in which R.sub.9 is OH either in or out of the plane of the
ring, or is a second sugar moiety such as R.sub.3. R.sub.10 may be
H or form a secondary amine with a group such as an aromatic group,
saturated or partially saturated 5 or 6 membered heterocyclic
having at least one ring nitrogen (see U.S. Pat. No. 5,843,903).
Alternately, R.sub.10 may be derived from an amino acid, having the
structure --C(O)CH(NHR.sub.11)(R.s- ub.12), in which R.sub.11 is H,
or forms a C.sub.3-4 membered alkylene with R.sub.12. R.sub.12 may
be H, alkyl, aminoalkyl, amino, hydroxyl, mercapto, phenyl, benzyl
or methylthio (see U.S. Pat. No. 4,296,105).
[0070] Exemplary anthracyclines are doxorubicin, daunorubicin,
idarubicin, epirubicin, pirarubicin, zorubicin, and carubicin.
Suitable compounds have the structures:
1 3 R.sub.1 R.sub.2 R.sub.3 Doxorubicin: OCH.sub.3 C(O)CH.sub.2OH
OH out of ring plane Epirubicin: OCH.sub.3 C(O)CH.sub.2OH OH in
ring plane (4' epimer of doxorubicin) Daunorubicin: OCH.sub.3
C(O)CH.sub.3 OH out of ring plane Idarubicin: H C(O)CH.sub.3 OH out
of ring plane Pirarubicin: OCH.sub.3 C(O)CH.sub.2OH 4 Zorubicin:
OCH.sub.3 C(CH.sub.3)(.dbd.N)NHC(O)C.sub.6H.sub.5 OH Carubicin: OH
C(O)CH.sub.3 OH out of ring plane
[0071] Other suitable anthracyclines are anthramycin, mitoxantrone,
menogaril, nogalamycin, aclacinomycin A, olivomycin A, chromomycin
A.sub.3, and plicamycin having the structures:
2 5 R.sub.1 R.sub.2 R.sub.3 Menogaril H OCH.sub.3 H Nogalamycin
O-sugar H COOCH.sub.3 6 R.sub.1 R.sub.2 R.sub.3 R.sub.4 Olivomycin
A COCH(CH.sub.3).sub.2 CH.sub.3 COCH.sub.3 H Chromomycin A.sub.3
COCH.sub.3 CH.sub.3 COCH.sub.3 CH.sub.3 Plicamycin H H H CH.sub.3
7
[0072] Other representative anthracyclines include, FCE 23762, a
doxorubicin derivative (Quaglia et al., J. Liq. Chromatogr. 17(18):
3911-3923, 1994), annamycin (Zou et al., J. Pharm. Sci. 82(11):
1151-1154, 1993), ruboxyl (Rapoport et al., J. Controlled Release
58(2): 153-162, 1999), anthracycline disaccharide doxorubicin
analogue (Pratesi et al., Clin. Cancer Res. 4(11): 2833-2839,
1998), N-(trifluoroacetyl)doxorubicin and
4'-O-acetyl-N-(trifluoroacetyl)doxorub- icin (Berube & Lepage,
Synth. Commun. 28(6): 1109-1116, 1998), 2-pyrrolinodoxorubicin
(Nagy et al., Proc. Natl. Acad. Sci. U.S.A. 95(4): 1794-1799,
1998), disaccharide doxorubicin analogues (Arcamone et al., J.
Nat'l Cancer lnst 89(16): 1217-1223, 1997),
4-demethoxy-7-O-[2,6-dideoxy--
4-O-(2,3,6-trideoxy-3-amino-.alpha.-L-lyxo-hexopyranosyl)-.alpha.-L-lyxo-h-
exopyranosyl]adriamicinone doxorubicin disaccharide analogue
(Monteagudo et al., Carbohydr. Res. 300(1): 11-16, 1997),
2-pyrrolinodoxorubicin (Nagy et al., Proc. Nat'lAcad. Sci. U.S.A.
94(2): 652-656, 1997), morpholinyl doxorubicin analogues (Duran et
al., Cancer Chemother. Pharmacol. 38(3): 210-216, 1996),
enaminomalonyl-.beta.-alanine doxorubicin derivatives (Seitz et
al., Tetrahedron Lett. 36(9): 1413-16, 1995), cephalosporin
doxorubicin derivatives (Vrudhula et al., J. Med. Chem. 38(8):
1380-5, 1995), hydroxyrubicin (Solary et al., Int. J. Cancer 58(1):
85-94, 1994), methoxymorpholino doxorubicin derivative (Kuhl et
al., Cancer Chemother. Pharmacol. 33(1): 10-16, 1993),
(6-maleimidocaproyl)hydrazone doxorubicin derivative (Willner et
al., Bioconjugate Chem. 4(6): 521-7, 1993),
N-(5,5-diacetoxypent-1-yl) doxorubicin (Cherif & Farquhar, J.
Med. Chem. 35(17): 3208-14, 1992), FCE 23762 methoxymorpholinyl
doxorubicin derivative (Ripamonti et al., Br. J. Cancer 65(5):
703-7, 1992), N-hydroxysuccinimide ester doxorubicin derivatives
(Demant et al., Biochim. Biophys. Acta 1118(1): 83-90, 1991),
polydeoxynucleotide doxorubicin derivatives (Ruggiero et al.,
Biochim. Biophys. Acta 1129(3): 294-302, 1991), morpholinyl
doxorubicin derivatives (EPA 434960), mitoxantrone doxorubicin
analogue (Krapcho et al., J. Med. Chem. 34(8): 2373-80. 1991),
AD198 doxorubicin analogue (Traganos et al., Cancer Res. 51(14):
3682-9, 1991), 4-demethoxy-3'-N-trifluoroacetyidoxorubicin (Horton
et al., Drug Des. Delivery 6(2): 123-9, 1990), 4'-epidoxorubicin
(Drzewoski et al., Pol. J. Pharmacol. Pharm. 40(2): 159-65, 1988;
Weenen et al., Eur. J. Cancer Clin. Oncol. 20(7): 919-26, 1984),
alkylating cyanomorpholino doxorubicin derivative (Scudder et al.,
J. Nat'l Cancer Inst 80(16): 1294-8, 1988),
deoxydihydroiodooxorubicin (EPA 275966), adriblastin (Kalishevskaya
et al., Vestn. Mosk. Univ., 16(Biol. 1): 21-7, 1988),
4'-deoxydoxorubicin (Schoeizel et al., Leuk. Res. 10(12): 1455-9,
1986), 4-demethyoxy-4'--O-- methyldoxorubicin (Giuliani et al.,
Proc. Int. Congr. Chemother. 16: 285-70-285-77, 1983),
3'-deamino-3'-hydroxydoxorubicin (Horton et al., J. Antibiot 37(8):
853-8, 1984), 4-demethyoxy doxorubicin analogues (Barbieri et al.,
Drugs Exp. Clin. Res. 10(2): 85-90, 1984), N-L-leucyl doxorubicin
derivatives (Trouet et al., Anthracyclines (Proc. Int. Symp. Tumor
Pharmacother.), 179-81, 1983),
3'-deamino-3'-(4-methoxy-1-piperidin- yl) doxorubicin derivatives
(U.S. Pat. No. 4,314,054), 3'-deamino-3'-(4-mortholinyl)
doxorubicin derivatives (U.S. Pat. No. 4,301,277),
4'-deoxydoxorubicin and 4'-o-methyldoxorubicin (Giuliani et al.,
Int. J. Cancer 27(1): 5-13, 1981), aglycone doxorubicin derivatives
(Chan & Watson, J. Pharm. Sci. 67(12): 1748-52, 1978), SM 5887
(Pharma Japan 1468: 20, 1995), MX-2 (Pharma Japan 1420: 19, 1994),
4'-deoxy-13(S)-dihydro-4'-iododoxorubicin (EP 275966), morpholinyl
doxorubicin derivatives (EPA 434960),
3'-deamino-3'-(4-methoxy-1-piperidi- nyl) doxorubicin derivatives
(U.S. Pat. No. 4,314,054), doxorubicin-14-valerate,
morpholinodoxorubicin (U.S. Pat. No. 5,004,606),
3'-deamino-3'-(3"-cyano-4"-morpholinyl doxorubicin;
3'-deamino-3'-(3"-cyano-4"-morpholinyl)-13-dihydoxorubicin);
(3'-deamino-3'-(3"-cyano-4"-morpholinyl) daunorubicin;
3'-deamino-3'-(3"-cyano-4"-morpholinyl)-3-dihydrodaunorubicin; and
3'-deamino-3'-(4"-morpholinyl-5-iminodoxorubicin and derivatives
(U.S. Pat. No. 4,585,859), 3'-deamino-3'-(4-methoxy-1-piperidinyl)
doxorubicin derivatives (U.S. Pat. No. 4,314,054) and
3-deamino-3-(4-morpholinyl) doxorubicin derivatives (U.S. Pat. No.
4,301,277).
[0073] (B) Fluoropyrimidine Analogues
[0074] In another aspect, the therapeutic agent is a
fluoropyrimidine analog, such as 5-fluorouracil, or an analogue or
derivative thereof, including carmofur, doxifluridine, emitefur,
tegafur, and floxuridine. Exemplary compounds have the
structures:
3 A 8 R.sub.1 R.sub.2 5-Fluorouracil H H Carmofur
C(O)NH(CH.sub.2).sub.5CH.sub.3 H Doxifluridine A.sub.1 H
Floxuridine A.sub.2 H Emitefur CH.sub.2OCH.sub.2CH.sub.3 B Tegafur
C H B 9 C 10
[0075] Other suitable fluoropyrimidine analogues include 5-FudR
(5-fluoro-deoxyuridine), or an analogue or derivative thereof,
including 5-iododeoxyuridine (5-ludR), 5-bromodeoxyuridine
(5-BudR), fluorouridine triphosphate (5-FUTP), and
fluorodeoxyuridine monophosphate (5-dFUMP). Exemplary compounds
have the structures:
4 11 5-Fluoro-2'-deoxyuridine: R = F 5-Bromo-2'-deoxyuridine: R =
Br 5-Iodo-2'-deoxyuridine: R = I
[0076] Other representative examples of fluoropyrimidine analogues
include N3-alkylated analogues of 5-fluorouracil (Kozai et al., J.
Chem. Soc., Perkin Trans. 1(19): 3145-3146, 1998), 5-fluorouracil
derivatives with 1,4-oxaheteroepane moieties (Gomez et al.,
Tetrahedron 54(43): 13295-13312, 1998), 5-fluorouracil and
nucleoside analogues (Li, Anticancer Res. 17-(1A): 21-27, 1997),
cis- and trans-5-fluoro-5,6-dihydr- o-6-alkoxyuracil (Van der Wilt
et al., Br. J. Cancer 68(4): 702-7, 1993), cyclopentane
5-fluorouracil analogues (Hronowski & Szarek, Can. J. Chem.
70(4): 1162-9, 1992), A-OT-fluorouracil (Zhang et al., Zongguo
Yiyao Gongye Zazhi 20(11): 513-15, 1989),
N4-trimethoxybenzoyl-5'-deoxy-5-fluor- ocytidine and
5'-deoxy-5-fluorouridine (Miwa et al., Chem. Pharm. Bull. 38(4):
998-1003, 1990), 1-hexylcarbamoyl-5-fluorouracil (Hoshi et al., J.
Pharmacobio-Dun. 3(9): 478-81, 1980; Maehara et al., Chemotherapy
(Basel) 34(6): 484-9, 1988), B-3839 (Prajda et al., In Vivo 2(2):
151-4, 1988), uracil-1-(2-tetrahydrofuryl)-5-fluorouracil (Anai et
al., Oncology 45(3): 144-7, 1988),
1-(2'-deoxy-2'-fluoro-.beta.-D-arabinofuranosyl)-5-fluorour- acil
(Suzuko et al., Mol. Pharmacol. 31(3): 301-6, 1987), doxifluridine
(Matuura et al., Oyo Yakuri 29(5): 803-31, 1985),
5'-deoxy-5-fluorouridin- e (Bollag & Hartmann, Eur. J. Cancer
16(4): 427-32, 1980), 1-acetyl-3-O-toluyl-5-fluorouracil (Okada,
Hiroshima J. Med. Sci. 28(1): 49-66, 1979),
5-fluorouracil-m-formylbenzene-sulfonate (JP 55059173),
N'-(2-furanidyl)-5-fluorouracil (JP 53149985) and
1-(2-tetrahydrofuryl)-5- -fluorouracil (JP 52089680).
[0077] These compounds are believed to function as therapeutic
agents by serving as antimetabolites of pyrimidine.
[0078] (C) Folic Acid Antagonists
[0079] In another aspect, the therapeutic agent is a folic acid
antagonist, such as methotrexate or derivatives or analogues
thereof, including edatrexate, trimetrexate, raltitrexed,
piritrexim, denopterin, tomudex, and pteropterin. Methotrexate
analogues have the following general structure: 12
[0080] The identity of the R group may be selected from organic
groups, particularly those groups set forth in U.S. Pat. Nos.
5,166,149 and 5,382,582. For example, R.sub.1 may be N, R.sub.2 may
be N or C(CH.sub.3), R.sub.3 and R.sub.3' may H or alkyl, e.g.,
CH.sub.3, R.sub.4 may be a single bond or NR, where R is H or alkyl
group. R.sub.5, R.sub.6, and/or R.sub.8 may be H, OCH.sub.3, or
alternately they can be halogens or hydro groups. R.sub.7 is a side
chain of the general structure: 13
[0081] wherein n=1 for methotrexate, n=3 for pteropterin. The
carboxyl groups in the side chain may be esterified or form a salt
such as a Zn.sup.2+ salt. R.sub.9 and R.sub.10 can be NH.sub.2 or
may be alkyl substituted.
[0082] Exemplary folic acid antagonist compounds have the
structures:
5 14 R.sub.0 R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 R.sub.6
R.sub.7 R.sub.8 Methotrexate NH.sub.2 N N H N(CH.sub.3) H H A (n =
1) H Edatrexate NH.sub.2 N N H CH(CH.sub.2CH.sub.3) H H A (n = 1) H
Trimetrexate NH.sub.2 CH C(CH.sub.3) H NH H OCH.sub.3 OCH.sub.3
OCH.sub.3 Pteropterin OH N N H NH H H A (n = 3) H Denopterin OH N N
CH.sub.3 N(CH.sub.3) H H A (n = 1) H Peritrexim NH.sub.2 N
C(CH.sub.3) H single bond OCH.sub.3 H H OCH.sub.3 15 16
[0083] Other representative examples include 6-S-aminoacyloxymethyl
mercaptopurine derivatives (Harada et al., Chem. Pharm. Bull.
43(10): 793-6, 1995), 6-mercaptopurine (6-MP) (Kashida et al.,
Biol. Pharm. Bull. 18(11): 1492-7, 1995),
7,8-polymethyleneimidazo-1,3,2-diazaphosphorines (Nilov et al.,
Mendeleev Commun. 2: 67, 1995), azathioprine (Chifotides et al., J.
Inorg. Biochem. 56(4): 249-64, 1994), methyl-D-glucopyranoside
mercaptopurine derivatives (Da Silva et al., Eur. J. Med. Chem.
29(2): 149-52, 1994) and s-alkynyl mercaptopurine derivatives
(Ratsino et al., Khim.-Farm. Zh. 15(8): 65-7, 1981); indoline ring
and a modified ornithine orglutamic acid-bearing methotrexate
derivatives (Matsuoka et al., Chem. Pharm. Bull. 45(7): 1146-1150,
1997), alkyl-substituted benzene ring C bearing methotrexate
derivatives (Matsuoka et al., Chem. Pharm. Bull. 44(12): 2287-2293,
1996), benzoxazine or benzothiazine moiety-bearing methotrexate
derivatives (Matsuoka et al., J. Med. Chem. 40(1): 105-111, 1997),
10-deazaminopterin analogues (DeGraw et al., J. Med. Chem. 40(3):
370-376, 1997), 5-deazaminopterin and 5,10-dideazaminopterin
methotrexate analogues (Piper et al., J. Med. Chem. 40(3): 377-384,
1997), indoline moiety-bearing methotrexate derivatives (Matsuoka
et al., Chem. Pharm. Bull. 44(7): 1332-1337, 1996), lipophilic
amide methotrexate derivatives (Pignatello et al., World Meet.
Pharm. Biopharm. Pharm. Technol., 563-4, 1995),
L-threo-(2S,4S)-4-fluorog- lutamic acid and DL-3,3-difluoroglutamic
acid-containing methotrexate analogues (Hart et al., J. Med. Chem.
39(1): 56-65, 1996), methotrexate tetrahydroquinazoline analogue
(Gangjee, et al, J. Heterocycl. Chem. 32(1): 243-8, 1995),
N-(.alpha.-aminoacyl)methotrexate derivatives (Cheung et al.,
Pteridines 3(1-2): 101-2, 1992), biotin methotrexate derivatives
(Fan et al., Pteridines 3(1-2): 131-2, 1992), D-glutamic acid or
D-erythrou, threo-4-fluoroglutamic acid methotrexate analogues
(McGuire et al., Biochem. Pharmacol. 42(12): 2400-3, 1991),
.beta.,.gamma.-methano methotrexate analogues (Rosowsky et al.,
Pteridines 2(3): 133-9, 1991), 10-deazaminopterin (10-EDAM)
analogue (Braakhuis et al., Chem. Biol. Pteridines, Proc. Int Symp.
Pteridines Folic Acid Deriv., 1027-30, 1989), .gamma.-tetrazole
methotrexate analogue (Kalman et al., Chem. Biol. Pteridines, Proc.
Int Symp. Pteridines Folic Acid Deriv., 1154-7, 1989),
N-(L-.alpha.-aminoacyl)metho- trexate derivatives (Cheung et al.,
Heterocycles 28(2): 751-8, 1989), meta and ortho isomers of
aminopterin (Rosowsky et al., J. Med. Chem. 32(12): 2582, 1989),
hydroxymethylmethotrexate (DE 267495), .gamma.-fluoromethotrexate
(McGuire et al., Cancer Res. 49(16): 4517-25, 1989), polyglutamyl
methotrexate derivatives (Kumar et al., Cancer Res. 46(10): 5020-3,
1986), gem-diphosphonate methotrexate analogues (WO 88/06158),
.alpha.- and .gamma.-substituted methotrexate analogues (Tsushima
et al., Tetrahedron 44(17): 5375-87, 1988), 5-methyl-5-deaza
methotrexate analogues (U.S. Pat. No. 4,725,687),
N.delta.-acyl-Na-(4-ami- no-4-deoxypteroyl)-L-ornithine derivatives
(Rosowsky et al., J. Med. Chem. 31(7): 1332-7, 1988), 8-deaza
methotrexate analogues (Kuehl et al., Cancer Res. 48(6): 1481-8,
1988), acivicin methotrexate analogue (Rosowsky et al., J. Med.
Chem. 30(8): 1463-9, 1987), polymeric platinol methotrexate
derivative (Carraher et al., Polym. Sci. Technol. (Plenum), 35(Adv.
Biomed. Polym.): 311-24, 1987), methotrexate-.gamma.-dimyristoylp-
hophatidylethanolamine (Kinsky et al., Biochim. Biophys. Acta
917(2): 211-18, 1987), methotrexate polyglutamate analogues
(Rosowsky et al., Chem. Biol. Pteridines, Pteridines Folic Acid
Deriv., Proc. Int. Symp. Pteridines Folic Acid Deriv.: Chem., Biol.
Clin. Aspects: 985-8, 1986), poly-.gamma.-glutamyl methotrexate
derivatives (Kisliuk et al., Chem. Biol. Pteridines, Pteridines
Folic Acid Deriv., Proc. Int. Symp. Pteridines Folic Acid Deriv.:
Chem., Biol. Clin. Aspects: 989-92, 1986), deoxyuridylate
methotrexate derivatives (Webber et al., Chem. Biol. Pteridines,
Pteridines Folic Acid Deriv., Proc. Int. Symp. Pteridines Folic
Acid Deriv.: Chem., Biol. Clin. Aspects: 659-62, 1986), iodoacetyl
lysine methotrexate analogue (Delcamp et al., Chem. Biol.
Pteridines, Pteridines Folic Acid Deriv., Proc. Int. Symp.
Pteridines Folic Acid Deriv.: Chem., Biol. Clin. Aspects: 807-9,
1986), 2,.omega.-diaminoalkano- id acid-containing methotrexate
analogues (McGuire et al., Biochem. Pharmacol. 35(15): 2607-13,
1986), polyglutamate methotrexate derivatives (Kamen & Winick,
Methods Enzymol. 122 (Vitam. Coenzymes, Pt. G): 339-46, 1986),
5-methyl-5-deaza analogues (Piper et al., J. Med. Chem. 29(6):
1080-7, 1986), quinazoline methotrexate analogue (Mastropaolo et
al., J. Med. Chem. 29(1): 155-8, 1986), pyrazine methotrexate
analogue (Lever & Vestal, J. Heterocycl. Chem. 22(1): 5-6,
1985), cysteic acid and homocysteic acid methotrexate analogues
(U.S. Pat. No. 4,490,529), .gamma.-tert-butyl methotrexate esters
(Rosowsky et al., J. Med. Chem. 28(5): 660-7, 1985), fluorinated
methotrexate analogues (Tsushima et al., Heterocycles 23(1): 45-9,
1985), folate methotrexate analogue (Trombe, J. Bacteriol 160(3):
849-53, 1984), phosphonoglutamic acid analogues (Sturtz &
Guillamot, Eur. J. Med. Chem.--Chim. Ther. 19(3): 267-73, 1984),
poly(L-lysine)methotrexate conjugates (Rosowsky et al., J. Med.
Chem. 27(7): 888-93, 1984), dilysine and trilysine methotrexate
derivates (Forsch & Rosowsky, J. Org. Chem. 49(7): 1305-9,
1984), 7-hydroxymethotrexate (Fabre et al., Cancer Res. 43(10):
4648-52, 1983), poly-.gamma.-glutamyl methotrexate analogues (Piper
& Montgomery, Adv. Exp. Med. Biol., 163 (Folyl Antifolyl
Polyglutamates): 95-100, 1983), 3',5'-dichloromethotrexate
(Rosowsky & Yu, J. Med. Chem. 26(10): 1448-52, 1983),
diazoketone and chloromethylketone methotrexate analogues (Gangjee
et al., J. Pharm. Sci. 71(6): 717-19, 1982),
10-propargylaminopterin and alkyl methotrexate homologs (Piper et
al., J. Med. Chem. 25(7): 877-80, 1982), lectin derivatives of
methotrexate (Lin et al., JNCI 66(3): 523-8, 1981), polyglutamate
methotrexate derivatives (Galivan, Mol. Pharmacol. 17(1): 105-10,
1980), halogentated methotrexate derivatives (Fox, JNCI 58(4):
J955-8, 1977), 8-alkyl-7,8-dihydro analogues (Chaykovsky et al., J.
Med. Chem. 20(10): J1323-7, 1977), 7-methyl methotrexate
derivatives and dichloromethotrexate (Rosowsky & Chen, J. Med.
Chem. 17(12): J1308-11, 1974), lipophilic methotrexate derivatives
and 3',5'-dichloromethotrexate (Rosowsky, J. Med. Chem. 16(10):
J1190-3, 1973), deaza amethopterin analogues (Montgomery et al.,
Ann. N.Y. Acad. Sci. 186: J227-34, 1971), MX068 (Pharma Japan,
1658: 18, 1999) and cysteic acid and homocysteic acid methotrexate
analogues (EPA 0142220);
[0084] These compounds are believed to act as antimetabolites of
folic acid.
[0085] (D) Podophyllotoxins
[0086] In another aspect, the therapeutic agent is a
Podophyllotoxin, or a derivative or an analogue thereof. Exemplary
compounds of this type are etoposide or teniposide, which have the
following structures: 17
[0087] Other representative examples of podophyllotoxins include
Cu(II)-VP-16 (etoposide) complex (Tawa et al., Bioorg. Med. Chem.
6(7): 1003-1008, 1998), pyrrolecarboxamidino-bearing etoposide
analogues (Ji et al., Bioorg. Med. Chem. Lett. 7(5): 607-612,
1997), 4.beta.-amino etoposide analogues (Hu, University of North
Carolina Dissertation, 1992), .gamma.-lactone ring-modified
arylamino etoposide analogues (Zhou et al., J. Med. Chem. 37(2):
287-92, 1994), N-glucosyl etoposide analogue (Allevi et al.,
Tetrahedron Lett. 34(45): 7313-16, 1993), etoposide A-ring
analogues (Kadow et al., Bioorg. Med. Chem. Leff. 2(1): 17-22,
1992), 4'-deshydroxy-4'-methyl etoposide (Saulnier et al., Bioorg.
Med. Chem. Lett. 2(10): 1213-18, 1992), pendulum ring etoposide
analogues (Sinha et al., Eur. J. Cancer 26(5): 590-3, 1990) and
E-ring desoxy etoposide analogues (Saulnier et al., J. Med. Chem.
32(7): 1418-20, 1989).
[0088] These compounds are believed to act as topoisomerase 11
inhibitors and/or DNA cleaving agents.
[0089] (E) Camptothecins
[0090] In another aspect, the therapeutic agent is camptothecin, or
an analogue or derivative thereof. Camptothecins have the following
general structure. 18
[0091] In this structure, X is typically 0, but can be other
groups, e.g., NH in the case of 21-lactam derivatives. R.sub.1 is
typically H or OH, but may be other groups, e.g., a terminally
hydroxylated C.sub.1-3 alkane. R.sub.2 is typically H or an amino
containing group such as (CH.sub.3).sub.2NHCH.sub.2, but may be
other groups e.g., NO.sub.2, NH.sub.2, halogen (as disclosed in,
e.g., U.S. Pat. No. 5,552,156) or a short alkane containing these
groups. R.sub.3 is typically H or a short alkyl such as
C.sub.2H.sub.5. R.sub.4 is typically H but may be other groups,
e.g., a methylenedioxy group with R.sub.1.
[0092] Exemplary camptothecin compounds include topotecan,
irinotecan (CPT-11), 9-aminocamptothecin,
21-lactam-20(S)-camptothecin, 10,11-methylenedioxycamptothecin,
SN-38, 9-nitrocamptothecin, 10-hydroxycamptothecin. Exemplary
compounds have the structures:
6 19 R.sub.1 R.sub.2 R.sub.3 Camptothecin: H H H Topotecan: OH
(CH.sub.3).sub.2NHCH.sub.2 H SN-38: OH H C.sub.2H.sub.5 X: O for
most analogs, NH for 21-lactam analogs
[0093] Camptothecins have the five rings shown here. The ring
labeled E must be intact (the lactone rather than carboxylate form)
for maximum activity and minimum toxicity.
[0094] Camptothecins are believed to function as topoisomerase I
inhibitors and/or DNA cleavage agents.
[0095] (F) Hydroxyureas
[0096] The therapeutic agent of the present invention may be a
hydroxyurea. Hydroxyureas have the following general structure:
20
[0097] Suitable hydroxyureas are disclosed in, for example, U.S.
Pat. No. 6,080,874, wherein R.sub.1 is: 21
[0098] and R.sub.2 is an alkyl group having 1-4 carbons and R.sub.3
is one of H, acyl, methyl, ethyl, and mixtures thereof, such as a
methylether.
[0099] Other suitable hydroxyureas are disclosed in, e.g., U.S.
Pat. No. 5,665,768, wherein R.sub.1 is a cycloalkenyl group, for
example
N-[3-[5-(4-fluorophenylthio)-furyl]-2-cyclopenten-1-yl]N-hydroxyurea;
R.sub.2 is H or an alkyl group having 1 to 4 carbons and R.sub.3 is
H; X is H or a cation.
[0100] Other suitable hydroxyureas are disclosed in, e.g., U.S.
Pat. No. 4,299,778, wherein R.sub.1 is a phenyl group substituted
with one or more fluorine atoms; R.sub.2 is a cyclopropyl group;
and R.sub.3 and X is H.
[0101] Other suitable hydroxyureas are disclosed in, e.g., U.S.
Pat. No. 5,066,658, wherein R.sub.2 and R.sub.3 together with the
adjacent nitrogen form: 22
[0102] wherein m is 1 or 2, n is 0-2 and Y is an alkyl group.
[0103] In one aspect, the hydroxyurea has the structure: 23
[0104] These compounds are thought to function by inhibiting DNA
synthesis.
[0105] (G) Platinum Complexes
[0106] In another aspect, the therapeutic agent is a platinum
compound. In general, suitable platinum complexes may be of Pt(II)
or Pt(IV) and have this basic structure: 24
[0107] wherein X and Y are anionic leaving groups such as sulfate,
phosphate, carboxylate, and halogen; R.sub.1 and R.sub.2 are alkyl,
amine, amino alkyl may be further substituted, and are basically
inert or bridging groups. For Pt(II) complexes Z.sub.1 and Z.sub.2
are non-existent. For Pt(IV) Z.sub.1 and Z.sub.2 may be anionic
groups such as halogen, hydroxy, carboxylate, ester, sulfate or
phosphate. See, e.g., U.S. Pat. Nos. 4,588,831 and 4,250,189.
[0108] Suitable platinum complexes may contain multiple Pt atoms.
See, e.g., U.S. Pat. Nos. 5,409,915 and 5,380,897. For example
bisplatinum and triplatinum complexes of the type: 25
[0109] Exemplary platinum compounds are cisplatin, carboplatin,
oxaliplatin, and miboplatin having the structures: 26
[0110] Other representative platinum compounds include
(CPA).sub.2Pt[DOLYM] and (DACH)Pt[DOLYM] cisplatin (Choi et al.,
Arch. Pharmacal Res. 22(2): 151-156, 1999),
Cis-[PtCl.sub.2(4,7-H-5-methyl-7-ox-
o]1,2,4[triazolo[1,5-a]pyrimidine).sub.2] (Navarro et al., J. Med.
Chem. 41(3): 332-338, 1998),
[Pt(cis-1,4-DACH)(trans-C[.sub.2)(CBDCA)].{fractio- n (1/2)}MeOH
cisplatin (Shamsuddin et al., Inorg. Chem. 36(25): 5969-5971,
1997), 4-pyridoxate diammine hydroxy platinum (Tokunaga et al.,
Pharm. Sci. 3(7): 353-356, 1997), Pt(II) . . . Pt(II)
(Pt.sub.2[NHCHN(C(CH.sub.2- )(CH.sub.3))].sub.4) (Navarro et al.,
Inorg. Chem. 35(26): 7829-7835, 1996), 254-S cisplatin analogue
(Koga et al., Neurol. Res. 18(3): 244-247, 1996),
o-phenylenediamine ligand bearing cisplatin analogues (Koeckerbauer
& Bednarski, J. Inorg. Biochem. 62(4): 281-298, 1996), trans,
cis-[Pt(OAc).sub.2I.sub.2(en)] (Kratochwil et al., J. Med. Chem.
39(13): 2499-2507, 1996), estrogenic 1,2-diarylethylenediamine
ligand (with sulfur-containing amino acids and glutathione) bearing
cisplatin analogues (Bednarski, J. Inorg. Biochem. 62(1): 75,
1996), cis-1,4-diaminocyclohexane cisplatin analogues (Shamsuddin
et al., J. Inorg. Biochem. 61(4): 291-301, 1996), 5' orientational
isomer of cis-[Pt(NH.sub.3)(4-aminoTEMP-O){d(GpG)}] (Dunham &
Lippard, J. Am. Chem. Soc. 117(43): 10702-12, 1995), chelating
diamine-bearing cisplatin analogues (Koeckerbauer & Bednarski,
J. Pharm. Sci. 84(7): 819-23, 1995), 1,2-diarylethyleneamine
ligand-bearing cisplatin analogues (Otto et al., J. Cancer Res.
Clin. Oncol. 121(1): 31-8, 1995), (ethylenediamine)platinu- m(II)
complexes (Pasini et al., J. Chem. Soc., Dalton Trans. 4: 579-85,
1995), C.sub.1-973 cisplatin analogue (Yang et al., Int. J. Oncol.
5(3): 597-602, 1994), cis-diaminedichloroplatinum(II) and its
analogues
cis-1,1-cyclobutanedicarbosylato(2R)-2-methyl-1,4-butanediamineplatinum(I-
I) and cis-diammine(glycolato)platinum (Claycamp & Zimbrick, J.
Inorg. Biochem. 26(4): 257-67, 1986; Fan et al., Cancer Res.
48(11): 3135-9, 1988; Heiger-Bernays et al., Biochemistry 29(36):
8461-6, 1990; Kikkawa et al., J. Exp. Clin. Cancer Res. 12(4):
233-40, 1993; Murray et al., Biochemistry 31(47): 11812-17, 1992;
Takahashi et al., Cancer Chemother. Pharmacol. 33(1): 31-5, 1993),
cis-amine-cyclohexylamine-dichloroplatinum- (II) (Yoshida et al.,
Biochem. Pharmacol. 48(4): 793-9, 1994), gem-diphosphonate
cisplatin analogues (FR 2683529),
(meso-1,2-bis(2,6-dichloro-4-hydroxyplenyl)ethylenediamine)
dichloroplatinum(II) (Bednarski et al., J. Med. Chem. 35(23):
4479-85, 1992), cisplatin analogues containing a tethered dansyl
group (Hartwig et al., J. Am. Chem. Soc. 114(21): 8292-3, 1992),
platinum(II) polyamines (Siegmann et al., Inorg. Met.-Containing
Polym. Mater., (Proc. Am. Chem. Soc. Int. Symp.), 335-61, 1990),
cis-(3H)dichloro(ethylenediamine)platinu- m(II) (Eastman, Anal.
Biochem. 197(2): 311-15, 1991), trans-diamminedichloroplatinum(II)
and cis-(Pt(NH.sub.3).sub.2(N.sub.3-cy- tosine)Cl) (Bellon &
Lippard, Biophys. Chem. 35(2-3): 179-88, 1990),
3H-cis-1,2-diaminocyclohexanedichloroplatinum(II) and
3H-cis-1,2-diaminocyclohexane-malonatoplatinum (II) (Oswald et al.,
Res. Commun. Chem. Pathol. Pharmacol. 64(1): 41-58, 1989),
diaminocarboxylatoplatinum (EPA 296321),
trans-(D,1)-1,2-diaminocyclohexa- ne carrier ligand-bearing
platinum analogues (Wyrick & Chaney, J. Labelled Compd.
Radiopharm. 25(4): 349-57, 1988), aminoalkylaminoanthraquinone-der-
ived cisplatin analogues (Kitov et al., Eur. J. Med. Chem. 23(4):
381-3, 1988), spiroplatin, carboplatin, iproplatin and JM40
platinum analogues (Schroyen et al., Eur. J. Cancer Clin. Oncol.
24(8): 1309-12, 1988), bidentate tertiary diamine-containing
cisplatinum derivatives (Orbell et al., Inorg. Chim. Acta 152(2):
125-34, 1988), platinum(II), platinum(IV) (Liu & Wang, Shandong
Yike Daxue Xuebao 24(1): 35-41, 1986),
cis-diammine(1,1-cyclobutanedicarboxylato-)platinum(II)
(carboplatin, JM8) and ethylenediammine-malonatoplatinum(II) (JM40)
(Begg et al., Radiother. Oncol. 9(2): 157-65, 1987), JM8 and JM9
cisplatin analogues (Harstrick et al., Int J. Androl. 10(1);
139-45, 1987), (NPr4).sub.2((PtCL4).cis-(PtCl2--(NH2Me).sub.2))
(Brammer et al., J. Chem. Soc., Chem. Commun. 6: 443-5, 1987),
aliphatic tricarboxylic acid platinum complexes (EPA 185225), and
cis-dichloro(amino acid)(tert-butylamine)platinum(II) complexes
(Pasini & Bersanetti, Inorg. Chim. Acta 107(4): 259-67, 1985).
These compounds are thought to function by binding to DNA, i.e.,
acting as alkylating agents of DNA.
[0111] As medical implants are made in a variety of configurations
and sizes, the exact dose administered will vary with device size,
surface area, design and portions of the implant coated. However,
certain principles can be applied in the application of this art.
Drug dose can be calculated as a function of dose per unit area (of
the portion of the device being coated), total drug dose
administered can be measured and appropriate surface concentrations
of active drug can be determined. Regardless of the method of
application of the drug to the medical implant, the preferred
anticancer/anti-infective agents, used alone or in combination,
should be administered under the following dosing guidelines:
[0112] (a) Anthracyclines. Utilizing the anthracycline doxorubicin
as an example, whether applied as a polymer coating, incorporated
into the polymers which make up the implant components, or applied
without a carrier polymer, the total dose of doxorubicin applied to
the implant should not exceed 25 mg (range of 0.1 .mu.g to 25 mg).
In a particularly preferred embodiment, the total amount of drug
applied should be in the range of 1 .mu.g to 5 mg. The dose per
unit area (i.e., the amount of drug as a function of the surface
area of the portion of the implant to which drug is applied and/or
incorporated) should fall within the range of 0.01 .mu.g-100 .mu.g
per mm.sup.2 of surface area. In a particularly preferred
embodiment, doxorubicin should be applied to the implant surface at
a dose of 0.1 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2. As different
polymer and non-polymer coatings will release doxorubicin at
differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the implant
surface such that a minimum concentration of 10.sup.-7-10.sup.-4 M
of doxorubicin is maintained on the surface. It is necessary to
insure that surface drug concentrations exceed concentrations of
doxorubicin known to be lethal to multiple species of bacteria and
fungi (i.e., are in excess of 10.sup.-4 M; although for some
embodiments lower concentrations are sufficient). In a preferred
embodiment, doxorubicin is released from the surface of the implant
such that anti-infective activity is maintained for a period
ranging from several hours to several months. In a particularly
preferred embodiment the drug is released in effective
concentrations for a period ranging from 1 week-6 months. It should
be readily evident based upon the discussions provided herein that
analogues and derivatives of doxorubicin (as described previously)
with similar functional activity can be utilized for the purposes
of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as doxorubicin is administered at half the above parameters, a
compound half as potent as doxorubicin is administered at twice the
above parameters, etc.).
[0113] Utilizing mitoxantrone as another example of an
anthracycline, whether applied as a polymer coating, incorporated
into the polymers which make up the implant, or applied without a
carrier polymer, the total dose of mitoxantrone applied should not
exceed 5 mg (range of 0.01 .mu.g to 5 mg). In a particularly
preferred embodiment, the total amount of drug applied should be in
the range of 0.1 .mu.g to 1 mg. The dose per unit area (i.e., the
amount of drug as a function of the surface area of the portion of
the implant to which drug is applied and/or incorporated) should
fall within the range of 0.01 .mu.g-20 .mu.g per mm.sup.2 of
surface area. In a particularly preferred embodiment, mitoxantrone
should be applied to the implant surface at a dose of 0.05
.mu.g/mm.sup.2-3 .mu.g/mm.sup.2. As different polymer and
non-polymer coatings will release mitoxantrone at differing rates,
the above dosing parameters should be utilized in combination with
the release rate of the drug from the implant surface such that a
minimum concentration of 10.sup.-5-10.sup.-6 M of mitoxantrone is
maintained. It is necessary to insure that drug concentrations on
the implant surface exceed concentrations of mitoxantrone known to
be lethal to multiple species of bacteria and fungi (i.e., are in
excess of 10.sup.-5 M; although for some embodiments lower drug
levels will be sufficient). In a preferred embodiment, mitoxantrone
is released from the surface of the implant such that
anti-infective activity is maintained for a period ranging from
several hours to several months. In a particularly preferred
embodiment the drug is released in effective concentrations for a
period ranging from 1 week-6 months. It should be readily evident
based upon the discussions provided herein that analogues and
derivatives of mitoxantrone (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
mitoxantrone is administered at half the above parameters, a
compound half as potent as mitoxantrone is administered at twice
the above parameters, etc.).
[0114] (b) Fluoropyrimidines Utilizing the fluoropyrimidine
5-fluorouracil as an example, whether applied as a polymer coating,
incorporated into the polymers which make up the implant, or
applied without a carrier polymer, the total dose of 5-fluorouracil
applied should not exceed 250 mg (range of 1.0 .mu.g to 250 mg). In
a particularly preferred embodiment, the total amount of drug
applied should be in the range of 10 .mu.g to 25 mg. The dose per
unit area (i.e., the amount of drug as a function of the surface
area of the portion of the implant to which drug is applied and/or
incorporated) should fall within the range of 0.1 .mu.g-1 mg per
mm.sup.2 of surface area. In a particularly preferred embodiment,
5-fluorouracil should be applied to the implant surface at a dose
of 1.0 .mu.g/mm.sup.2-50 .mu.g/mm.sup.2. As different polymer and
non-polymer coatings will release 5-fluorouracil at differing
rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the implant
surface such that a minimum concentration of 10.sup.-4-10.sup.-7 M
of 5-fluorouracil is maintained. It is necessary to insure that
surface drug concentrations exceed concentrations of 5-fluorouracil
known to be lethal to numerous species of bacteria and fungi (i.e.,
are in excess of 10.sup.-4 M; although for some embodiments lower
drug levels will be sufficient). In a preferred embodiment,
5-fluorouracil is released from the implant surface such that
anti-infective activity is maintained for a period ranging from
several hours to several months. In a particularly preferred
embodiment the drug is released in effective concentrations for a
period ranging from 1 week-6 months. It should be readily evident
based upon the discussions provided herein that analogues and
derivatives of 5-fluorouracil (as described previously) with
similar functional activity can be utilized for the purposes of
this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as 5-fluorouracil is administered at half the above parameters, a
compound half as potent as 5-fluorouracil is administered at twice
the above parameters, etc.).
[0115] (c) Podophylotoxins Utilizing the podophylotoxin etoposide
as an example, whether applied as a polymer coating, incorporated
into the polymers which make up the cardiac implant, or applied
without a carrier polymer, the total dose of etoposide applied
should not exceed 25 mg (range of 0.1 .mu.g to 25 mg). In a
particularly preferred embodiment, the total amount of drug applied
should be in the range of 1 .mu.g to 5 mg. The dose per unit area
(i.e., the amount of drug as a function of the surface area of the
portion of the implant to which drug is applied and/or
incorporated) should fall within the range of 0.01 .mu.g-100 .mu.g
per mm.sup.2 of surface area. In a particularly preferred
embodiment, etoposide should be applied to the implant surface at a
dose of 0.1 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2. As different polymer
and non-polymer coatings will release etoposide at differing rates,
the above dosing parameters should be utilized in combination with
the release rate of the drug from the implant surface such that a
concentration of 10.sup.-5-10.sup.-6 M of etoposide is maintained.
It is necessary to insure that surface drug concentrations exceed
concentrations of etoposide known to be lethal to a variety of
bacteria and fungi (i.e., are in excess of 10.sup.-5 M; although
for some embodiments lower drug levels will be sufficient). In a
preferred embodiment, etoposide is released from the surface of the
implant such that anti-infective activity is maintained for a
period ranging from several hours to several months. In a
particularly preferred embodiment the drug is released in effective
concentrations for a period ranging from 1 week-6 months. It should
be readily evident based upon the discussions provided herein that
analogues and derivatives of etoposide (as described previously)
with similar functional activity can be utilized for the purposes
of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as etoposide is administered at half the above parameters, a
compound half as potent as etoposide is administered at twice the
above parameters, etc.).
[0116] (d) Combination therapy. It should be readily evident based
upon the discussions provided herein that combinations of
anthracyclines (e.g., doxorubicin or mitoxantrone),
fluoropyrimidines (e.g., 5-fluorouracil), folic acid antagonists
(e.g., methotrexate and/or podophylotoxins (e.g., etoposide) can be
utilized to enhance the antibacterial activity of the implant
coating. Similarly anthracyclines (e.g., doxorubicin or
mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acid
antagonists (e.g., methotrexate and/or podophylotoxins (e.g.,
etoposide) can be combined with traditional antibiotic and/or
antifungal agents to enhance efficacy. The anti-infective agent may
be further combined with antithrombotic and/or antiplatelet agents
(for example, heparin, dextran sulphate, danaparoid, lepirudin,
hirudin, AMP, adenosine, 2-chloroadenosine, aspirin,
phenylbutazone, indomethacin, meclofenamate, hydrochloroquine,
dipyridamole, iloprost, ticlopidine, clopidogrel, abcixamab,
eptifibatide, tirofiban, streptokinase, and/or tissue plasminogen
activator) to enhance efficacy.
[0117] C. Methods for Generating Medical Devices which Contain or
Release a Fibrosis-Inducing Agent
[0118] In the practice of this invention, drug-coated,
drug-impregnated, or drug containing implants and medical devices
are provided which induce adhesion or fibrosis in the surrounding
tissue, or facilitate "anchoring" of the device/implant in situ,
thus enhancing the efficacy. Within various embodiments, fibrosis
is induced by local or systemic release of specific pharmacological
agents that become localized to the tissue adjacent to the device
or implant. There are numerous methods available for optimizing
delivery of the fibrosis-inducing agent to the site of the
intervention and several of these are described below.
[0119] 1) Devices and Implants that Contain or Release
Fibrosis-Inducing Agents
[0120] Medical devices or implants of the present invention contain
and/or are adapted to release an agent which induces fibrosis or
adhesion to the surrounding tissue. Medical devices or implants may
be adapted to have incorporated into their structure a
fibrosis-inducing agent, adapted to have a surface coating of a
fibrosis-inducing agent and/or adapted to release a
fibrosis-inducing agent by (a) directly affixing to the implant or
device a desired fibrosis-inducing agent or composition containing
the fibrosis-inducing agent (e.g., by either spraying the medical
implant with a drug and/or carrier (polymeric or
non-polymeric)-drug composition to create a film or coating on all,
or parts of the internal or external surface of the device; by
dipping the implant or device into a drug and/or carrier (polymeric
or non-polymeric)-drug solution to coat all or parts of the device
or implant; or by other covalent or non-covalent (e.g.,
mechanically attached via knotting or the use of an adhesive or
thermal treatment, electrostatic, ionic, hydrogen bonded or
hydrophobic interactions) attachment of the therapeutic agent to
the device or implant surface); (b) by coating the medical device
or implant with a substance such as a hydrogel which can in turn
absorb the desired fibrosis-inducing agent or composition; (c) by
interweaving a "thread" composed of, or coated with, the
fibrosis-inducing agent into the medical implant or device (e.g., a
polymeric strand composed of materials that induce fibrosis (e.g.,
silk, collagen, EVA, PLA, polyurethanes, polymerized drug
compositions) or polymers which comprise and/or release a
fibrosis-inducing agent from the thread); (d) by covering all, or
portions of the device or implant with a sleeve, cover or mesh
containing a fibrosis-inducing agent (i.e., a covering comprised of
a fibrosis-inducing agent--polymers such as silk, collagen, EVA,
PLA, polyurethanes or polymerized compositions containing
fibrosis-inducing agents); (e) constructing all, or parts of the
device or implant itself with the desired agent or composition
(e.g., constructing the device from polymers such as silk,
collagen, EVA, PLA, polyurethanes or polymerized compositions of
fibrosis-inducing agents); (f) otherwise impregnating the device or
implant with the desired fibrosis-inducing agent or composition;
(g) scoring (i.e., creating ridges or indentations) on all, or
parts, of the device or implant surface to produce irritation of
the tissue and ultimately fibrosis; (h) composing all, or parts, of
the device or implant from metal alloys that induce fibrosis (e.g.,
copper); (i) constructing all, or parts of the device or implant
itself from a degradable or non-degradable polymer that releases
one or more fibrosis-inducing agents; (j) utilizing specialized
multi-drug releasing medical device systems (described, e.g., in
U.S. Pat. No. 6,562,065; U.S. Patent Application Publication Nos.
2003/0199970 and 2003/0167085; and in PCT Publication Nos. WO
03/015664 and WO 02/32347) to deliver fibrosis-inducing agents
alone or in combination.
[0121] In one aspect, a medical device may be modified by attaching
fibers (threads) to the surface of the device. The fibers may be
polymeric and/or may be formed of or coated with a fibrosing
material, such as silk. For example, the threads may be formed from
a silk suture material. The presence of the threads can result in
an enhanced cellular and/or extracellular matrix response to the
exterior of the device. The threads can be attached to the device
by using any one or a combination of the following methods,
including use of an adhesive, thermal welding, stitching, wrapping,
weaving, knotting, and the like. The threads can be coated with a
material that delays the time it takes for the thread material to
come into contact with the surrounding tissue and blood, thus
allowing placement of the device without concern of thrombotic
events due to the presence of the polymeric threads. Examples of
materials that can be used to prepare coatings capable of degrading
or dissolving upon implantation include gelatin, polyesters (e.g.,
PLGA, PLA, MePEG-PLGA, PLGA-PEG-PLGA, and blends thereof), lipids,
fatty acids, sugar esters, nucleic acid esters, polyanhydrides,
polyorthoesters, and PVA. The coating may further contain a
fibrosing agent and/or a biologically active agent that may, for
example, reduce the probability of an immediate thrombotic event
(e.g., heparin, hydrophobic quaternary amine heparin complexes, and
the like). In addition to the polymeric threads, all or a portion
of the device may be coated with a polymeric carrier that contains
a fibrosis-inducing agent.
[0122] The fibers (threads) may further comprise a coating or
composition that is affected by an applied magnetic field. For
example, a device such as a stent graft may be coated with
polymeric threads that are coated, contain, or are formed from a
fibrosing agent (e.g., silk suture). A magnetic field can be
applied to the coated device to orient and align the polymeric
fibers relative to each other and the surface of the device to
increase the surface area of the fibers exposed to biological
mediators which would stimulate a fibrotic reaction. The
magnetically active component can be associated with the polymeric
fiber using a variety of methods. The magnetically active component
may be incorporated during manufacture of the fiber, for example,
by incorporating a magnetically active material such as magnetite
into a polymer feed prior to extrusion of the polymeric fiber. The
magnetically active component can be coated onto the entire fiber
or a portion of the fiber using, for example, an adhesive or a
polymeric coating. The polymeric fiber (or a portion thereof) can
be heated or plasticized with a solvent and then rolled in the
magnetically active component, such that the magnetic material
protrudes above the surface of the fiber or is embedded into the
surface of the fiber.
[0123] The threads (either with or without a magnetic component)
may be attached to the device in various configurations that can
result in either partial or complete coverage of the exterior of
the device. The polymeric threads may be affixed to the ends of a
device or to the central portion of a device, and the attachment
may be in a vertical, horizontal, or diagonal manner.
[0124] 2) Systemic, Regional and Local Delivery of
Fibrosis-inducing Agents
[0125] A variety of drug-delivery technologies are available for
systemic, regional and local delivery of therapeutic agents.
Several of these techniques may be suitable to achieve
preferentially elevated levels of fibrosis-inducing agents in the
vicinity of the medical device or implant, including: (a) using
drug-delivery catheters for local, regional or systemic delivery of
fibrosing agents to the tissue surrounding the device or implant
(typically, drug delivery catheters are advanced through the
circulation or inserted directly into tissues under radiological
guidance until they reach the desired anatomical location; the
fibrosing agent can then be released from the catheter lumen in
high local concentrations in order to deliver therapeutic doses of
the drug to the tissue surrounding the device or implant); (b) drug
localization techniques such as magnetic, ultrasonic or MRI-guided
drug delivery; (c) chemical modification of the fibrosis-inducing
drug or formulation designed to increase uptake of the agent into
damaged tissues (e.g., modification of the drug or formulation to
include antibodies directed against damaged or healing tissue
components such as macrophages, neutrophils, smooth muscle cells,
fibroblasts, extracellular matrix components, neovascular tissue);
(d) chemical modification of the fibrosis-inducing drug or
formulation designed to localize the drug to areas of bleeding or
disrupted vasculature such as encapsulation of the drug into site
directed liposomes; and/or (e) direct injection of the
fibrosis-inducing agent, for example under endoscopic vision.
[0126] 3) Infiltration of Fibrosis-Inducing Agents into the Tissue
Surrounding a Device or Implant
[0127] Alternatively, the tissue cavity into which the device or
implant is placed can be treated with a fibrosis-inducing agent
prior to, during, or after the implantation procedure. This can be
accomplished in several ways including: (a) topical application of
the fibrosing agent into the anatomical space where the device can
be placed (particularly useful for this embodiment is the use of
polymeric carriers which release the fibrosing agent over a period
ranging from several hours to several weeks--fluids, suspensions,
emulsions, microemulsions, microspheres, pastes, gels,
microparticulates, sprays, aerosols, solid implants and other
formulations which release a fibrosing agent can be delivered into
the region where the device or implant can be inserted via
specialized delivery catheters or other applicators); (b)
microparticulate silk and/or silk strands (e.g., linear, branched,
and/or coiled) are also useful for directed delivery into the
implantation site; (c) sprayable collagen-containing formulations
such as COSTASIS (Angiotech Pharmaceuticals, Inc., Vancouver, BC)
or materials made from 4-armed thiol PEG (10K), a 4-armed NHS
PEG(10K) and methylated collagen (described below), or materials
made from 4-armed thiol PEG (10K), a 4-armed NHS PEG(10K) and
collagen or gelatin, either alone, or loaded with a
fibrosis-inducing agent, applied to the implantation site (or the
implant/device surface); (d) sprayable in situ forming
PEG-containing formulations such as COSEAL (Angiotech
Pharmaceuticals, Inc., Canada), FOCALSEAL (Genzyme Corporation,
Cambridge, Mass.), SPRAYGEL or DURASEAL (both from Confluent
Surgical, Inc., Waltham, Mass.), either alone, or loaded with a
fibrosis-inducing agent, applied to the implantation site (or the
implant/device surface);
[0128] (e) fibrinogen-containing formulations such as FLOSEAL or
TISSEAL (both from Baxter Healthcare Corporation; Fremont, Calif.),
either alone, or loaded with a fibrosis-inducing agent, applied to
the implantation site (or the implant/device surface); (f)
hyaluronic acid-containing formulations (either non-crosslinked,
crosslinked or chemically modified) such as PERLANE or RESTYLANE
(both from Q-Med AB, Sweden), HYLAFORM (Inamed Corporation; Santa
Barbara, Calif.), SYNVISC (Biomatrix, Inc.; Ridgefied, N.J.),
SEPRAFILM or SEPRACOAT (both from Genzyme Corporation; Cambridge,
Mass.) loaded with a fibrosis with a fibrosis-inducing agent
applied to the implantation site (or the implant/device surface);
(g) polymeric gels for surgical implantation such as REPEL (Life
Medical Sciences, Inc.; Princeton, N.J.) or FLOWGEL (Baxter
Healthcare Corporation, Deerfield, Ill.) loaded with a
fibrosis-inducing agent applied to the implantation site (or the
implant/device surface); (h) orthopedic "cements" used to hold
prostheses and tissues in place loaded with a fibrosis-inducing
agent applied to the implantation site (or the implant/device
surface), such as OSTEOBOND (Zimmer, Inc., Warsaw, Ind.), LVC
(Wright Medical Technology, Inc., Arlington, Tenn.), SIMPLEX P
(Stryker Corporation, Kalamazoo, Mich.), PALACOS (Smith &
Nephew PLC Corporation, United Kingdom), and ENDURANCE (Johnson
& Johnson, Inc., New Brunswick, N.J.); (i) surgical adhesives
containing one or more cyanoacrylate monomers (e.g., methyl
cyanoacrylate, ethyl cyanoacrylate, butyl cyanoacrylate, octyl
cyanoacrylate, methoxypropyl cyanoacrylate) such as DERMABOND
(Johnson & Johnson, Inc.), INDERMIL (United States Surgical;
Norwalk, Conn.), GLUSTITCH (Blacklock Medical Products, Inc.,
Canada) or TISSUMEND II (Veterinary Products Laboratories; Phoenix,
Ariz.), VETBOND (3M Company; St. Paul, Minn.), TISSUEMEND (TEI
Biosciences, Inc.; Boston, Mass.), HISTOACRYL or HISTOACRYL BLUE
(Davis & Geck; St. Louis, Mo.) and ORABASE SOOTHE-N-SEAL LIQUID
PROTECTANT (Colgate-Palmolive Company; New York; N.Y.), either
alone, or loaded with a fibrosis-inducing agent, applied to the
implantation site (or the implant/device surface); (j) implants
containing hydroxyapatite (or synthetic bone material such as
calcium sulfate, VITOSS and CORTOSS (both from Orthovita, Inc.,
Malvern, Pa.)) loaded with a fibrosis-inducing agent applied to the
implantation site (or the implant/device surface); (k) other
biocompatible tissue fillers loaded with a fibrosis-inducing agent,
such as those made by BioCure, Inc. (Norcross, Ga.), 3M Company and
Neomend, Inc. (Sunnyvale, Calif.), loaded with a fibrosis-inducing
agent applied to the implantation site (or the implant/device
surface); (l) polysaccharide gels such as the ADCON series of gels
(Gliatech, Inc.; Cleveland, Ohio); (m) films, sponges or meshes
such as INTERCEED or VICRYL mesh (Ethicon, Inc., a Johnson &
Johnson Company, Somerville, N.J.), and GELFOAM (Pharmacia &
Upjohn Company; Kalamazoo, Mich.) loaded with a fibrosis-inducing
agent applied to the implantation site (or the implant/device
surface); (n) a hydrogel that is formed from an
amino-functionalized polyethylene glycol (e.g., 4-armed tetra-amino
PEG [10k]) and a 4-armed NHS functionalized PEG (e.g.,
pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl
glutarate [10K]). This hydrogel may further contain collagen,
methylated collagen and/or gelatin. This hydrogel can further
comprise the fibrosis-inducing agents described above (e.g., silk
powder or silk threads), and (O) compositions that enhance
osteointegration and/or osteogenesis, including materials composed
of beta-tricalcium phosphate (e.g., VITOSS, PROOSTEON 500R made by
E-Interpore-Cross International), hydroxyapatite or
Ca.sub.10(PO.sub.4).sub.6OH (e.g., OSTEOGRAF made by Ceramed Denta,
Inc., Lakewood, Colo.), calcium carbonate or CaCO.sub.3, calcium
sulfate (e.g., OSTEOSET and ALLOMATRIX made by Wright Medical
Technology, Inc.), calcium phosphate (e.g., CALCIBON made by Merck
& Co., Inc., Whitehouse Station, N.J., NORIAN SRS made by
Synthes-Strates, Switzerland), as well as synthetic bone fillers
(e.g., CORTOSS and processed bone fillers, e.g., BIOOSS made by
Geistlich Biomaterials, Inc., Switzerland). Representative examples
of these materials are described in U.S. Pat. Nos. 3,929,971,
4,861,733; 6,527,810; 4,772,468; 4,882,149; 5,167,961; 6,576,015;
4,839,215; 5,614,206; 5,807,567; 6,030,636; 6,652,887; 6,206,957;
6,485,754; 4,347,234; 4,291,013; 5,129,905; 5,336,264; 5,569,442;
5,571,493; 5,683,667; 5,709,742; 5,820,632; 5,658,332; 5,681,872;
5,914,356; 5,939,039; 6,325,987; 6,383,519; 6,458,162; 6,736,799;
6,521,246; and 6,709,744.
[0129] In one aspect, the fibrosis-inducing agent may be delivered
as a solution. The fibrosis-inducing agent can be incorporated
directly into the solution to provide a homogeneous solution or
dispersion. In certain embodiments, the solution is an aqueous
solution. The aqueous solution may further include buffer salts, as
well as viscosity modifying agents (e.g., hyaluronic acid,
alginates, CMC, and the like). In another aspect of the invention,
the solution can include a biocompatible solvent, such as ethanol,
DMSO, glycerol, PEG-200, PEG-300 or NMP.
[0130] 4) Coating and Sustained-Release Preparations of
Fibrosis-Inducing Agents
[0131] For many of the aforementioned embodiments, the
fibrosis-inducing agent can be incorporated or coated onto the
device. For example, a desired fibrosis-inducing agent may be
admixed with, blended with, conjugated to, or, otherwise modified
to contain a polymeric composition (which may be either
biodegradable or non-biodegradable) or non-polymeric composition.
The polymeric or non-polymeric composition (i.e., carrier) can be
used to coat the device or as a component of the materials used to
manufacture the device. In other embodiments, the localized
sustained delivery of the fibrosis inhibiting agent may be
required. For example, a desired fibrosis-inducing agent may be
admixed with, blended with, conjugated to, or, otherwise modified
to contain a polymeric composition (which may be either
biodegradable or non-biodegradable) or non-polymeric composition in
order to release the fibrosis-inducing agent over a period of time.
For the above embodiments, biodegradable and non-biodegradable
polymers, polymer conjugates as well as non-polymeric materials can
be used to accomplish the incorporation of the fibrosis-inducing
agent onto or into the device.
[0132] Representative examples of biodegradable polymers suitable
for the delivery of fibrosis-inducing agents include albumin,
collagen, gelatin, hyaluronic acid, starch, cellulose and cellulose
derivatives (e.g., methylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose, carboxymethylcellulose, cellulose
acetate phthalate, cellulose acetate succinate,
hydroxypropylmethylcellulose phthalate), casein, dextrans,
polysaccharides, fibrinogen, poly(ether ester) multiblock
copolymers, based on poly(ethylene glycol) and poly(butylene
terephthalate), tyrosine-derived polycarbonates (e.g., U.S. Pat.
No. 6,120,491), poly(hydroxyl acids), poly(D,L-lactide),
poly(D,L-lactide-co-glycolide), poly(glycolide),
poly(hydroxybutyrate), polydioxanone, poly(alkylcarbonate) and
poly(orthoesters), polyesters, poly(hydroxyvaleric acid),
polydioxanone, poly(ethylene terephthalate), poly(malic acid),
poly(tartronic acid), poly(acrylamides), polyanhydrides,
poly(ester-amides), poly(ester-imides), poly(ester-ureas),
poly(ester-urethane-ureas), poly(anhydride-esters),
poly(anhydride-imides), polyphosphazenes, poly(amino acids),
poly(alkylene oxide)-poly(ester) block copolymers (e.g., X--Y,
X--Y--X or Y--X--Y, where X is a polyalkylene oxide and Y is a
polyester (e.g., PLGA, PLA, PCL, polydioxanone and copolymers
thereof), and copolymers as well as blends thereof. (see generally,
Ilium, L., Davids, S. S. (eds.) "Polymers in Controlled Drug
Delivery" Wright, Bristol, 1987; Arshady, J. Controlled Release 17:
1-22, 1991; Pitt, Int. J. Phar. 59: 173-196, 1990; Holland et al.,
J. Controlled Release 4: 155-0180, 1986).
[0133] Representative examples of non-degradable polymers suitable
for the delivery of fibrosis-inducing agents include
poly(ethylene-co-vinyl acetate) ("EVA") copolymers, silicone
rubber, acrylic polymers (e.g., polyacrylic acid, polymethylacrylic
acid, polymethylmethacrylate, poly(butyl methacrylate)),
poly(alkylcyanoacrylate) (e.g., poly(ethylcyanoacrylate),
poly(butylcyanoacrylate), poly(hexylcyanoacrylate), and
poly(octylcyanoacrylate)), polyethylene, polypropylene, polyamides
(nylon 6,6), polyurethanes (including hydrophilic polyurethanes),
poly(ester-urethanes), poly(ether-urethanes), poly(ester-urea),
poly(carbonate urethane)s, polyethers (poly(ethylene oxide),
poly(propylene oxide), polyoxyalkylene ether block copolymers based
on ethylene oxide and propylene oxide such as PLURONICs and
PLURONICs R and poly(tetramethylene glycol)), styrene-based
polymers (polystyrene, poly(styrene sulfonic acid),
poly(styrene)-block-poly(isobu- tylene)-block-poly(styrene),
poly(styrene)-poly(isoprene) block copolymers], and vinyl polymers
(polyvinylpyrrolidone, poly(vinyl alcohol), poly(vinyl acetate
phthalate) as well as copolymers and blends thereof. Polymers may
also be developed which are either anionic (e.g., alginate,
carrageenan, carboxymethyl cellulose, poly(acrylamido-2-methyl
propane sulfonic acid) and copolymers thereof, poly(methacrylic
acid) and copolymers thereof, and poly(acrylic acid) and copolymers
thereof, as well as blends thereof) or cationic (e.g., chitosan,
poly-L-lysine, polyethylenimine, and poly(allyl amine) and blends
thereof (see generally, Dunn et al., J. Applied Polymer Sci. 50:
353-365, 1993; Cascone et al., J. Materials Sci.: Materials in
Medicine 5: 770-774, 1994; Shiraishi et al., Biol. Pharm. Bull.
16(11): 1164-1168, 1993; Thacharodi and Rao, Int'l J. Pharm. 120:
115-118, 1995; Miyazaki et al., Intl J. Pharm. 118: 257-263,
1995).
[0134] Particularly preferred polymeric carriers include
poly(ethylene-co-vinyl acetate), cellulose esters (nitrocellulose),
poly(hydroxymethacrylate), poly(methylmethacrylate),
poly(ethylene-co-acrylic acid), poly(vinylpyrrolidone)
polyurethanes (e.g., CHRONOFLEX AL and CHRONOFLEX AR (both from
CardioTech International, Inc., Woburn, Mass.) and BIONATE (Polymer
Technology Group, Inc., Emeryville, Calif.), poly(D,L-lactic acid)
oligomers and polymers, poly(L-lactic acid) oligomers and polymers,
poly(glycolic acid), copolymers of lactic acid and glycolic acid,
poly(caprolactone), poly(valerolactone), polyanhydrides,
poly(anhydride esters), poly(ester-amides), poly(ester-ureas),
copolymers of poly(caprolactone) or poly(lactic acid) with a
polyethylene glycol (e.g., MePEG), silicone rubbers,
poly(styrene)block-poly(isobutylene)-block-poly(styrene),
poly(acrylate) polymers, and blends, admixtures, or co-polymers of
any of the above. Other preferred polymers include collagen,
poly(alkylene oxide)-based polymers, polysaccharides such as
hyaluronic acid, chitosan and fucans, and copolymers of
polysaccharides with degradable polymers, as well as crosslinked
compositions of the above.
[0135] Other representative polymers capable of sustained localized
delivery of fibrosis-inducing agents include carboxylic polymers,
polyacetates, polyacrylamides, polycarbonates, polyethers,
substituted polyethylenes, polyvinylbutyrals, polysilanes,
polyureas, polyoxides, polystyrenes, polysulfides, polysulfones,
polysulfonides, polyvinylhalides, pyrrolidones, isoprene rubbers,
thermal-setting polymers, cross-linkable acrylic and methacrylic
polymers, ethylene acrylic acid copolymers, styrene acrylic
copolymers, vinyl acetate polymers and copolymers, vinyl acetal
polymers and copolymers, epoxies, melamines, other amino resins,
phenolic polymers, and copolymers thereof, water-insoluble
cellulose ester polymers (including cellulose acetate propionate,
cellulose acetate, nitrocellulose, cellulose acetate butyrate,
cellulose nitrate, cellulose acetate phthalate, and mixtures
thereof), polyvinylpyrrolidone (pvp), polyethylene glycols,
polyethylene oxides, polyvinyl alcohol, polyethers,
polyhydroxyacrylate, dextran, xanthan, hydroxypropyl cellulose,
methyl cellulose, and homopolymers and copolymers of
N-vinylpyrrolidone, N-vinyllactam, N-vinyl butyrolactam, N-vinyl
caprolactam, other vinyl compounds having polar pendant groups,
acrylate and methacrylate having hydrophilic esterifying groups,
hydroxyacrylate, and acrylic acid, and combinations thereof;
cellulose esters and ethers, ethyl cellulose, nitro-cellulose,
hydroxyethyl cellulose, cellulose nitrate, cellulose acetate,
cellulose acetate butyrate, cellulose acetate propionate,
polyacrylate, natural and synthetic elastomers, acetal, styrene
polybutadiene, acrylic resin, polyvinylidene chloride,
polycarbonate, homopolymers and copolymers of vinyl compounds,
polyvinylchloride, and polyvinylchloride acetate.
[0136] Representative examples of patents relating to drug-delivery
polymers and their preparation include PCT Publication Nos. WO
98/19713, WO 01/17575, WO 01/41821, WO 01/41822, and WO 01/15526
(as well as their corresponding U.S. applications), and U.S. Pat.
Nos. 4,500,676, 4,582,865, 4,629,623, 4,636,524, 4,713,448,
4,795,741, 4,913,743, 5,069,899, 5,099,013, 5,128,326, 5,143,724,
5,153,174, 5,246,698, 5,266,563, 5,399,351, 5,525,348, 5,800,412,
5,837,226, 5,942,555, 5,997,517, 6,007,833, 6,071,447, 6,090,995,
6,106,473, 6,110,483, 6,121,027, 6,156,345, 6,214,901, 6,368,611
6,630,155, 6,528,080, RE37,950, 6,46,1631, 6,143,314, 5,990,194,
5,792,469, 5,780,044, 5,759,563, 5,744,153, 5,739,176, 5,733,950,
5,681,873, 5,599,552, 5,340,849, 5,278,202, 5,278,201, 6,589,549,
6,287,588, 6,201,072, 6,117,949, 6,004,573, 5,702,717, 6,413,539,
and 5,714,159, 5,612,052 and U.S. Patent Application Publication
Nos. 2003/0068377, 2002/0192286, 2002/0076441, and
2002/0090398.
[0137] It should be obvious to one of skill in the art that the
polymers as described herein can also be blended or copolymerized
in various compositions as required to deliver therapeutic doses of
fibrosis-inducing agents to blood vessels in the treatment
site.
[0138] Polymeric carriers for fibrosis-inducing agents can be
fashioned in a variety of forms, with desired release
characteristics and/or with specific properties depending upon the
device, composition or implant being utilized. For example,
polymeric carriers may be fashioned to release a fibrosis-inducing
agent upon exposure to a specific triggering event such as pH (see,
e.g., Heller et al., "Chemically Self-Regulated Drug Delivery
Systems," in Polymers in Medicine III, Elsevier Science Publishers
B.V., Amsterdam, 1988, pp. 175-188; Kang et al., J. Applied Polymer
Sci. 48: 343-354, 1993; Dong et al., J. Controlled Release 19:
171-178, 1992; Dong and Hoffman, J. Controlled Release 15: 141-152,
1991; Kim et al., J. Controlled Release 28: 143-152, 1994;
Cornejo-Bravo et al., J. Controlled Release 33: 223-229, 1995; Wu
and Lee, Pharm. Res. 10(10): 1544-1547, 1993; Serres et al., Pharm.
Res. 13(2): 196-201, 1996; Peppas, "Fundamentals of pH- and
Temperature-Sensitive Delivery Systems," in Gurny et al. (eds.),
Pulsatile Drug Delivery, Wissenschaftliche Verlagsgesellschaft mbH,
Stuttgart, 1993, pp. 41-55; Doelker, "Cellulose Derivatives," 1993,
in Peppas and Langer (eds.), Biopolymers I, Springer-Verlag,
Berlin). Representative examples of pH-sensitive polymers include
poly(acrylic acid) and its derivatives (including for example,
homopolymers such as poly(aminocarboxylic acid); poly(acrylic
acid); poly(methyl acrylic acid), copolymers of such homopolymers,
and copolymers of poly(acrylic acid) and acrylmonomers such as
those discussed above. Other pH sensitive polymers include
polysaccharides such as cellulose acetate phthalate;
hydroxypropylmethylcellulose phthalate;
hydroxypropylmethylcellulose acetate succinate; cellulose acetate
trimellilate; and chitosan. Yet other pH sensitive polymers include
any mixture of a pH sensitive polymer and a water-soluble
polymer.
[0139] Likewise, fibrosis-inducing agents can be delivered via
polymeric carriers which are temperature sensitive (see, e.g., Chen
et al., "Novel Hydrogels of a Temperature-Sensitive Pluronic
Grafted to a Bioadhesive Polyacrylic Acid Backbone for Vaginal Drug
Delivery," in Proceed. Intern. Symp. Control. Rel. Bioact Mater.
22: 167-168, Controlled Release Society, Inc., 1995; Okano,
"Molecular Design of Stimuli-Responsive Hydrogels for Temporal
Controlled Drug Delivery," in Proceed. Intern. Symp. Control. Rel.
Bioact Mater. 22: 111-112, Controlled Release Society, Inc., 1995;
Johnston et al., Pharm. Res. 9(3): 425-433, 1992; Tung, Int'l J.
Pharm. 107: 85-90, 1994; Harsh and Gehrke, J. Controlled Release
17: 175-186, 1991; Bae et al., Pharm. Res. 8(4): 531-537, 1991;
Dinarvand and D'Emanuele, J. Controlled Release 36: 221-227, 1995;
Yu and Grainger, "Novel Thermo-sensitive Amphiphilic Gels: Poly
N-isopropylacrylamide-co-sodium acrylate-co-n-N-alkylacrylamide
Network Synthesis and Physicochemical Characterization," Dept. of
Chemical & Biological Sci., Oregon Graduate Institute of
Science & Technology, Beaverton, Oreg., pp. 820-821; Zhou and
Smid, "Physical Hydrogels of Associative Star Polymers," Polymer
Research Institute, Dept. of Chemistry, College of Environmental
Science and Forestry, State Univ. of New York, Syracuse, N.Y., pp.
822-823; Hoffman et al., "Characterizing Pore Sizes and Water
`Structure` in Stimuli-Responsive Hydrogels," Center for
Bioengineering, Univ. of Washington, Seattle, Wash., p. 828; Yu and
Grainger, "Thermo-sensitive Swelling Behavior in Crosslinked
N-isopropylacrylamide Networks: Cationic, Anionic and Ampholytic
Hydrogels," Dept. of Chemical & Biological Sci., Oregon
Graduate Institute of Science & Technology, Beaverton, Oreg.,
pp. 829-830; Kim et al., Pharm. Res. 9(3): 283-290, 1992; Bae et
al., Pharm. Res. 8(5): 624-628, 1991; Kono et al., J. Controlled
Release 30: 69-75, 1994; Yoshida et al., J. Controlled Release 32:
97-102, 1994; Okano et al., J. Controlled Release 36: 125-133,
1995; Chun and Kim, J. Controlled Release 38: 39-47, 1996;
D'Emanuele and Dinarvand, Int'l J. Pharm. 118: 237-242, 1995;
Katono et al., J. Controlled Release 16: 215-228, 1991; Hoffman,
"Thermally Reversible Hydrogels Containing Biologically Active
Species," in Migliaresi et al. (eds.), Polymers in Medicine III,
Elsevier Science Publishers B.V., Amsterdam, 1988, pp. 161-167;
Hoffman, "Applications of Thermally Reversible Polymers and
Hydrogels in Therapeutics and Diagnostics," in Third International
Symposium on Recent Advances in Drug Delivery Systems, Salt Lake
City, Utah, Feb. 24-27, 1987, pp. 297-305; Gutowska et al., J.
Controlled Release 22: 95-104, 1992; Palasis and Gehrke, J.
Controlled Release 18: 1-12, 1992; Paavola et al., Pharm. Res.
12(12): 1997-2002, 1995).
[0140] Representative examples of thermogelling polymers, and their
gelatin temperature [LCST (.degree. C.)] include homopolymers such
as poly(N-methyl-N-n-propylacrylamide), 19.8;
poly(N-n-propylacrylamide), 21.5;
poly(N-methyl-N-isopropylacrylamide), 22.3;
poly(N-n-propylmethacry- lamide), 28.0;
poly(N-isopropylacrylamide), 30.9; poly(N, n-diethylacrylamide),
32.0; poly(N-isopropylmethacrylamide), 44.0;
poly(N-cyclopropylacrylamide), 45.5; poly(N-ethylmethyacrylamide),
50.0; poly(N-methyl-N-ethylacrylamide), 56.0;
poly(N-cyclopropylmethacrylamide)- , 59.0; and
poly(N-ethylacrylamide), 72.0. Moreover, thermogelling polymers may
be made by preparing copolymers between (among) monomers of the
above, or by combining such homopolymers with other water-soluble
polymers such as acrylmonomers (e.g., acrylic acid and derivatives
thereof, such as methylacrylic acid, acrylate and derivatives
thereof, such as butyl methacrylate, acrylamide, and N-n-butyl
acrylamide).
[0141] Other representative examples of thermogelling polymers
include cellulose ether derivatives such as hydroxypropyl
cellulose, 41.degree. C.; methyl cellulose, 55.degree. C.;
hydroxypropylmethyl cellulose, 66.degree. C.; and ethylhydroxyethyl
cellulose, polyalkylene oxide-polyester block copolymers of the
structure X--Y, Y--X--Y and X--Y--X where X is a polyalkylene oxide
and Y is a biodegradable polyester (e.g., PLG-PEG-PLG) and
PLURONICS such as F-127, 10-15.degree. C.; L-122, 19.degree. C.;
L-92, 26.degree. C.; L-81, 20.degree. C.; and L-61, 24.degree.
C.
[0142] Representative examples of patents relating to thermally
gelling polymers and their preparation include U.S. Pat. Nos.
6,451,346; 6,201,072; 6,117,949; 6,004,573; 5,702,717; and
5,484,610 and PCT Publication Nos. WO 99/07343; WO 99/18142; WO
03/17972; WO 01/82970; WO 00/18821; WO 97/15287; WO 01/41735; WO
00/00222 and WO 00/38651.
[0143] Fibrosis-inducing agents may be linked by occlusion in the
matrices of the polymer, bound by covalent linkages, or
encapsulated in microcapsules. Within certain preferred embodiments
of the invention, therapeutic compositions are provided in
non-capsular formulations such as microspheres (ranging from
nanometers to micrometers in size), pastes, and threads of various
size, films and sprays.
[0144] Within certain aspects of the present invention, therapeutic
compositions may be fashioned in any size ranging from 50 nm to 500
.mu.m, depending upon the particular use. These compositions can be
in the form of microspheres (porous or non-porous), microparticles,
and/or nanoparticles. These compositions can be formed, for
example, by spray-drying methods, milling methods, coacervation
methods, W/O (water-oil) emulsion methods, W/O/W emulsion methods,
and solvent evaporation methods. In some embodiments, these
compositions can include microemulsions, emulsions, liposomes and
micelles. Alternatively, such compositions may also be readily
applied as a "spray", which solidifies into a film or coating for
use as a device/implant surface coating or to line the tissues of
the implantation site. Such sprays may be prepared from
microspheres of a wide array of sizes, including for example, from
0.1 .mu.m to 3 .mu.m, from 10 .mu.m to 30 .mu.m, and from 30 .mu.m
to 100 .mu.m.
[0145] Therapeutic compositions of the present invention may also
be prepared in a variety of paste or gel forms. For example, within
one embodiment of the invention, therapeutic compositions are
provided which are liquid at one temperature (e.g., temperature
greater than 37.degree. C., such as 40.degree. C., 45.degree. C.,
50.degree. C., 55.degree. C. or 60.degree. C.), and solid or
semi-solid at another temperature (e.g., ambient body temperature,
or any temperature lower than 37.degree. C.). Such "thermopastes"
may be readily made utilizing a variety of techniques (see, e.g.,
PCT Publication WO 98/24427). Other pastes may be applied as a
liquid, which solidify in vivo due to dissolution of a
water-soluble component of the paste and precipitation of
encapsulated drug into the aqueous body environment. These pastes
and gels containing fibrosis-inducing agents are particularly
useful for application to the surface of tissues which can be in
contact with the implant or device.
[0146] In one aspect, the fibrosing agent or a composition
comprising the fibrosing agent may be combined with a film or mesh
or may be in the form or a film or mesh.
[0147] Films or meshes may take a variety of forms including, but
not limited to, surgical meshes, membranes (e.g., barrier
membranes), surgical sheets, surgical patches, surgical wraps,
bandages, liquid bandages, surgical dressings, gauze, fabrics,
tapes, surgical membranes, polymer matrices, shells, envelopes,
tissue coverings, and other types of surgical matrices, and
scaffolds.
[0148] In one aspect, the device comprises or may be in the form of
a film. The film may be formed into one of many geometric shapes.
Depending on the application, the film may be formed into the shape
of a tube or may be a thin, elastic sheet of polymer. Generally,
films are less than 5, 4, 3, 2, or 1 mm thick, more preferably less
than 0.75 mm, 0.5 mm, 0.25 mm, or, 0.10 mm thick. Films can also be
generated of thicknesses less than 50 .mu.m, 25 .mu.m or 10 .mu.m.
Films generally are flexible with a good tensile strength (e.g.,
greater than 50, preferably greater than 100, and more preferably
greater than 150 or 200 N/cm.sup.2), good adhesive properties
(i.e., adheres to moist or wet surfaces), and have controlled
permeability. Polymeric films (which may be porous or non-porous)
are particularly useful for application to the surface of a device
or implant as well as to the surface of tissue, cavity or an
organ.
[0149] Films may be made by several processes, including for
example, by casting, and by spraying, or may be formed at the
treatment site in situ. For example, a sprayable formulation may be
applied onto the treatment site which then forms into a solid
film.
[0150] In another aspect, the device may comprise or be in the form
of a mesh. A mesh, as used herein, is a material composed of a
plurality of fibers or filaments (i.e., a fibrous material), where
the fibers or filaments are arranged in such a manner (e.g.,
interwoven, knotted, braided, overlapping, looped, knitted,
interlaced, intertwined, webbed, felted, and the like) so as to
form a porous structure. Typically, a mesh is a pliable material,
such that it has sufficient flexibility to be wrapped around a
device. In certain aspects, the mesh may be sufficiently pliable so
as to be capable of being wrapped around the external surface of a
body passageway or cavity, or a portion thereof. The mesh may be
capable of providing support to the structure (e.g., the vessel or
cavity wall). In certain aspects, the mesh may be adapted to
release an amount of the therapeutic agent.
[0151] Mesh materials may take a variety of forms. For example, the
mesh may be in a woven, knit, or non-woven form and may include
fibers or filaments that are randomly oriented relative to each
other or that are arranged in an ordered array or pattern. In one
embodiment, for example, a mesh may be in the form of a fabric,
such as, for example, a knitted, braided, crocheted, woven,
non-woven (e.g., a melt-blown or wet-laid) or webbed fabric. In one
embodiment, a mesh may include a natural or synthetic biodegradable
polymer that may be formed into a knit mesh, a weave mesh, a
sprayed mesh, a web mesh, a braided mesh, a looped mesh, and the
like. Preferably, a mesh or wrap has intertwined threads that form
a porous structure, which may be, for example, knitted, woven, or
webbed.
[0152] The structure and properties of the mesh used in a device
depend on the application and the desired mechanical (i.e.,
flexibility, tensile strength, and elasticity), degradation
properties, and the desired loading and release characteristics for
the selected therapeutic agent(s). The mesh should have mechanical
properties, such that the device can remain sufficiently strong
until the surrounding tissue has healed. Factors that affect the
flexibility and mechanical strength of the mesh include, for
example, the porosity, fabric thickness, fiber diameter, polymer
composition (e.g., type of monomers and initiators), process
conditions, and the additives that are used to prepare the
material.
[0153] Typically, the mesh possesses sufficient porosity to permit
the flow of fluids through the pores of the fiber network and to
facilitate tissue ingrowth. Generally, the interstices of the mesh
should be wide enough apart to allow light visible by eye, or
fluids, to pass through the pores. However, materials having a more
compact structure also may be used. The flow of fluid through the
interstices of the mesh may depend on a variety of factors,
including, for example, the stitch count or thread density. The
porosity of the mesh may be further tailored by, for example,
filling the interstices of the mesh with another material (e.g.,
particles or polymer) or by processing the mesh (e.g., by heating)
in order to reduce the pore size and to create non-fibrous areas.
Fluid flow through the mesh of the invention can vary depending on
the properties of the fluid, such as viscosity,
hydrophilicity/hydrophobicity, ionic concentration, temperature,
elasticity, pseudoplasticity, particulate content, and the like.
The interstices of the mesh can be large enough so as to not
prevent the release of impregnated or coated therapeutic agent(s)
from the mesh, and the interstices preferably do not prevent the
exchange of tissue fluid at the application site.
[0154] Mesh materials should be sufficiently flexible so as to be
capable of conforming to the shape of a device surface or an
anatomotical surface. In certain cases, the mesh material may be
sufficiently flexible so as to be capable of being wrapped around
all or a portion of the external surface of a body passageway or
cavity. Flexible mesh materials are typically in the form of
flexible woven or knitted sheets having a thickness ranging from
about 25 microns to about 3000 microns; preferably from about 50 to
about 1000 microns. Mesh materials for use in the practice of the
invention typically range from about 100 to 400 microns in
thickness.
[0155] The diameter and length of the fibers or filaments may range
in size depending on the form of the material (e.g., knit, woven,
or non-woven), and the desired elasticity, porosity, surface area,
flexibility, and tensile strength. The fibers may be of any length,
ranging from short filaments to long threads (i.e., several microns
to hundreds of meters in length). Depending on the application, the
fibers may have a monofilament or a multifilament construction.
[0156] The mesh may include fibers that are of same dimension or of
different dimensions, and the fibers may be formed from the same or
different types of biodegradable polymers. Woven materials, for
example, may include a regular or irregular array of warp and weft
strands and may include one type of polymer in the weft direction
and another type (having the same or a different degradation
profile from the first polymer) in the warp direction. The
degradation profile of the weft polymer may be different than or
the same as the degradation profile of the warp polymer. Similarly,
knit materials may include one or more types (e.g., monofilament,
multi-filament) and sizes of fibers and may include fibers made
from the same or from different types of biodegradable
polymers.
[0157] The structure of the mesh (e.g., fiber density and porosity)
may impact the amount of therapeutic agent that may be loaded into
or onto the device. For example, a fabric having a loose weave
characterized by a low fiber density and high porosity can have a
lower thread count, resulting in a reduced total fiber volume and
surface area. As a result, the amount of agent that may be loaded
into or onto, with a fixed carrier: therapeutic agent ratio, the
fibers can be lower than for a fabric having a high fiber density
and lower porosity. It is generally preferable that the mesh also
should not invoke biologically detrimental inflammatory or toxic
response, should be capable of being fully metabolized in the body,
have an acceptable shelf life (of about at least one year or more),
and be easily sterilized.
[0158] The device may include multiple mesh materials in any
combination or arrangement. For example, a portion of the device
may be a knitted material and another portion may be a woven
material. In another embodiment, the device may more than one layer
(e.g., a layer of woven material fused to a layer of knitted
material or to another layer of the same type or a different type
of woven material). In some embodiments, multi-layer constructions
(e.g., device having two or more layers of material) may be used,
for example, to enhance the performance properties of the device
(e.g. for enhancing the rigidity or for altering the porosity,
elasticity, or tensile strength of the device) or for increasing
the amount of drug loading.
[0159] The mesh or film may be formed of or include a polymer. The
polymer may be a biodegradable or a non-biodegradable polymer, or a
combination thereof.
[0160] Biodegradable compositions that may be used to prepare the
mesh of film include polymers that comprise albumin, collagen,
hyaluronic acid and derivatives, sodium alginate and derivatives,
chitosan and derivatives gelatin, starch, cellulose polymers (for
example methylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose, carboxymethylcellulose, cellulose
acetate phthalate, cellulose acetate succinate,
hydroxypropylmethylcellulose phthalate), casein, dextran and
derivatives, polysaccharides, poly(caprolactone), fibrinogen,
poly(hydroxyl acids), poly(L-lactide) poly(D, L lactide), poly(D,
L-lactide-co-glycolide), poly(L-lactide-co-glycolide), copolymers
of lactic acid and glycolic acid, copolymers of
.epsilon.-caprolactone and lactide, copolymers of glycolide and
.epsilon.-caprolactone, copolymers of lactide and
1,4-dioxane-2-one, polymers and copolymers that include one or more
of the residue units of the monomers D-lactide, L-lactide,
D,L-lactide, glycolide, .epsilon.-caprolactone, trimethylene
carbonate, 1,4-dioxane-2-one or 1,5-dioxepan-2-one,
poly(glycolide), poly(hydroxybutyrate), poly(alkylcarbonate) and
poly(orthoesters), polyesters, poly(hydroxyvaleric acid),
polydioxanone, poly(ethylene terephthalate), poly(malic acid),
poly(tartronic acid), polyanhydrides, polyphosphazenes, poly(amino
acids). These compositions include copolymers of the above polymers
as well as blends and combinations of the above polymers. (see,
generally, Illum, L., Davids, S. S. (eds.) "Polymers in Controlled
Drug Delivery" Wright, Bristol, 1987; Arshady, J. Controlled
Release 17: 1-22, 1991; Pitt, Int. J. Phar. 59: 173-196, 1990;
Holland et al., J. Controlled Release 4: 155-0180, 1986).
[0161] In one aspect, the mesh or film includes a biodegradable or
resorbable polymer that is formed from one or more monomers
selected from the group consisting of lactide, glycolide,
e-caprolactone, trimethylene carbonate, 1,4-dioxan-2-one,
1,5-dioxepan-2-one, 1,4-dioxepan-2-one, hydroxyvalerate, and
hydroxybutyrate. In one aspect, the polymer may include, for
example, a copolymer of a lactide and a glycolide. In another
aspect, the polymer includes a poly(caprolactone). In yet another
aspect, the polymer includes a poly(lactic acid),
poly(L-lactide)/poly(D,- L-Lactide) blends or copolymers of
L-lactide and D,L-lactide. In yet another aspect, the polymer
includes a copolymer of lactide and e-caprolactone. In yet another
aspect, the polymer includes a polyester (e.g., a
poly(lactide-co-glycolide). The poly(lactide-co-glycolide) may have
a lactide:glycolide ratio ranges from about 20:80 to about 2:98, a
lactide:glycolide ratio of about 10:90, or a lactide:glycolide
ratio of about 5:95. In one aspect, the poly(lactide-co-glycolide)
is poly(L-lactide-co-glycolide). Other examples of biodegradable
materials include polyglactin, polyglycolic acid, autogenous,
heterogenous, and xenogeneic tissue (e.g., pericardium or small
intestine submucosa), and oxidized, regenerated cellulose. These
meshes can be knitted, woven or non-woven meshes. Other examples of
non-woven meshes include electrospun materials.
[0162] Representative examples of non-biodegradable compositions
for use in forming films and meshes include ethylene-co-vinyl
acetate copolymers, acrylic-based and methacrylic-based polymers
(e.g., poly(acrylic acid), poly(methylacrylic acid),
poly(methylmethacrylate), poly(hydroxyethylmethacrylate),
poly(alkylcynoacrylate), poly(alkyl acrylates), poly(alkyl
methacrylates)), polyolefins such as poly(ethylene) or
poly(propylene), polyamides (e.g., nylon 6,6), poly(urethanes)
(e.g. poly(ester urethanes), poly(ether urethanes), poly(carbonate
urethanes), poly(ester-urea)), polyesters (e.g., PET,
polybutyleneterephthalate, and polyhexyleneterephthalate),
polyethers (poly(ethylene oxide), poly(propylene oxide),
poly(ethylene oxide)-poly(propylene oxide) copolymers, diblock and
triblock copolymers, poly(tetramethylene glycol)), silicone
containing polymers and vinyl-based polymers (polyvinylpyrrolidone,
poly(vinyl alcohol), poly(vinyl acetate phthalate),
poly(styrene-co-isobutylene-co-styrene), fluorine containing
polymers (fluoropolymers) such as fluorinated ethylene propylene
(FEP) or polytetrafluoroethylene (e.g., expanded PTFE).
[0163] A variety of film mesh materials have been described which
may be combined with a scarring agent. For example, the film or
mesh may be a biodegradable polymeric matrix that conforms to the
tissue and releases the agent in a controlled release manner. See
e.g., U.S. Pat. No. 6,461,640. The film or mesh may be a
self-adhering silicone sheet which is impregnated with an
antioxidant and/or antimicrobial. See e.g., U.S. Pat. No.
6,572,878. The film or mesh may be a pliable shield with attachment
ports and fenestrations that is adapted to cover a bony dissection
in the spine. See e.g., U.S. Pat. No. 5,868,745 and U.S. Patent
Application No. 2003/0078588. The film or mesh may be a resorbable
micro-membrane having a single layer of non-porous polymer base
material of poly-lactide. See e.g., U.S. Pat. No. 6,531,146 and
U.S. Application No. 2004/0137033. The film or mesh may be a wound
dressing garment composed of an outer pliable layer and a
self-adhesive inner gel lining which serves as a dressing for
contacting wounds. See e.g., U.S. Pat. No. 6,548,728. The film or
mesh may be a bandage with a scar treatment pad with a layer of
silicone elastomer or silicone gel. See e.g., U.S. Pat. Nos.
6,284,941 and 5,891,076. The film or mesh may be a crosslinkable
system with at least three reactive compounds each having a
polymeric molecular core with at least one functional group. See
e.g., U.S. Pat. No. 6,458,889. The film or mesh may be composed of
a prosthetic fabric having a 3-dimensional structure separating two
surfaces in which one is open to post-surgical cell colonization
and one is linked to a film of collagenous material. See e.g., U.S.
Pat. No. 6,451,032. The film or mesh may be composed by
crosslinking two synthetic polymers, one having nucleophilic groups
and the other having electrophilic groups, such that they form a
matrix that may be used to incorporate a biologically active
compound. See e.g., U.S. Pat. Nos. 6,323,278; 6,166,130; 6,051,648
and 5,874,500. The film or mesh may be a conformable warp-knit
fabric of oxidized regenerated cellulose or other bioresorbable
material which acts like a physical barrier to prevent
postoperative adhesions. See e.g., U.S. Pat. No. 5,007,916. Meshes
for use in the practice of the invention also are described in U.S.
Pat. No. 6,575,887, and co-pending application, entitled
"Perivascular Wraps," filed Sep. 26, 2003 (U.S. Ser. No. (U.S. Ser.
No. 10/673,046), which is hereby incorporated by reference in its
entirety.
[0164] In one aspect, the fibrosing agent can be incorporated into
a biodegradable or dissolvable film or mesh that is then applied to
the treatment site prior or post implantation of the
prosthesis/implant. Exemplary materials for the manufacture of
these films or meshes are hyaluronic acid (crosslinked or
non-crosslinked), cellulose derivatives (e.g., hydroxypropyl
cellulose), PLGA, collagen and crosslinked poly(ethylene
glycol).
[0165] Films and meshes, which may be combined with one or more
scarring agents according to the present invention, include
commercially available products. Examples of films and meshes into
which a fibrosis-inducing agent can be incorporated include
INTERCEED (Johnson & Johnson, Inc.), PRECLUDE (W.L. Gore), and
POLYACTIVE (poly(ether ester) multiblock copolymers (Osteotech,
Inc., Shrewsbury, N.J.), based on poly(ethylene glycol) and
poly(butylene terephthalate), and SURGICAL absorbable hemostat
gauze-like sheet from Johnson & Johnson. Another mesh is a
prosthetic polypropylene mesh with a bioresorbable coating called
SEPRAMESH Biosurgical Composite (Genzyme Corporation, Cambridge,
Mass.). One side of the mesh is coated with a bioresorbable layer
of sodium hyaluronate and carboxymethylcellulose, providing a
temporary physical barrier that separates the underlying tissue and
organ surfaces from the mesh. The other side of the mesh is
uncoated, allowing for complete tissue ingrowth similar to bare
polypropylene mesh. In one embodiment, the fibrosis-inducing agent
may be applied only to the uncoated side of SEPRAMESH and not to
the sodium hyaluronate/carboxymethylcellulose coated side. Other
films and meshes include: (a) BARD MARLEX mesh (C.R. Bard, Inc.),
which is a very dense knitted fabric structure with low porosity;
(b) monofilament polypropylene mesh such as PROLENE available from
Ethicon, Inc. Somerville, N.J. (see, e.g., U.S. Pat. Nos. 5,634,931
and 5,824,082)); (c) SURGISIS GOLD and SURGISIS IHM soft tissue
graft (both from Cook Surgical, Inc.) which are devices
specifically configured for use to reinforce soft tissue in repair
of inguinal hernias in open and laparoscopic procedures; (d) thin
walled polypropylene surgical meshes such as are available from
Atrium Medical Corporation (Hudson, N.H.) under the trade names
PROLITE, PROLITE ULTRA, and LITEMESH; (e) COMPOSIX hernia mesh
(C.R. Bard, Murray Hill, N.J.), which incorporates a mesh patch
(the patch includes two layers of an inert synthetic mesh,
generally made of polypropylene, and is described in U.S. Pat. No.
6,280,453) that includes a filament to stiffen and maintain the
device in a flat configuration; (f) VISILEX mesh (from C.R. Bard,
Inc.), which is a polypropylene mesh that is constructed with
monofilament polypropylene; (g) other meshes available from C.R.
Bard, Inc. which include PERFIX Plug, KUGEL Hernia Patch, 3D MAX
mesh, LHI mesh, DULEX mesh, and the VENTRALEX Hernia Patch; and (h)
other types of polypropylene monofilament hernia mesh and plug
products include HERTRA mesh 1, 2, and 2A, HERMESH 3, 4 & 5 and
HERNIAMESH plugs T1, T2, and T3 from Herniamesh USA, Inc. (Great
Neck, N.Y.).
[0166] Other examples of commercially available meshes which may be
combined with fibrosing agents include the following. Boston
Scientific Corporation sells the TRELEX NATURAL Mesh which is
composed of a knitted polypropylene material. Ethicon, Inc. makes
the absorbable VICRYL (polyglactin 910) meshes (knitted and woven)
and MERSILENE Polyester Fiber Mesh. Dow Corning Corporation
(Midland, Mich.) sells a mesh material formed from silicone
elastomer known as SILASTIC Rx Medical Grade Sheeting (Platinum
Cured). United States Surgical/Syneture (Norwalk, Conn.) sells a
mesh made from absorbable polyglycolic acid under the trade name
DEXON Mesh Products. Membrana Accurel Systems (Germany) sells the
CELGARD microporous polypropylene fiber and membrane. Gynecare
Worldwide, a division of Ethicon, Inc. sells a mesh material made
from oxidized, regenerated cellulose known as INTERCEED TC7.
[0167] Numerous types of meshes and films and polymers for use with
meshes and films have been described above. Methods for
incorporating the fibrosing compositions onto or into the film or
mesh include: (a) affixing (directly or indirectly) to the film or
mesh a fibrosing composition (e.g., by either a spraying process or
dipping process as described above, with or without a carrier), (b)
incorporating or impregnating into the film or mesh a fibrosing
composition (e.g., by either a spraying process or dipping process
as described above, with or without a carrier (c) by coating the
film or mesh with a substance such as a hydrogel which can in turn
absorb the fibrosing composition, (d) constructing the film or mesh
itself or a portion of the film or mesh with a fibrosing
composition, or (e) by covalently binding the fibrosing agent
directly to the film or mesh surface or to a linker (small molecule
or polymer) that is coated or attached to the film or mesh surface.
For devices that are coated, the coating process can be performed
in such a manner as to (a) coat only one surface of the film or
mesh or (b) coat all or parts of both sides of the film or
mesh.
[0168] The therapeutic agent(s) may be an integral part of the film
or mesh (i.e., may reside within the fibers of the mesh). The
fibrosis inhibiting agent can be incorporated directly into the
film or mesh or it can be incorporated into a secondary carrier
(polymeric or non-polymeric), as described above, that is then
incorporated into the film or mesh.
[0169] Alternatively, or in addition, the film or mesh may be
coated with a fibrosing agent or a composition that includes the
fibrosing agent. The coating may take the form of a
surface-adherent coating, mask, film, gel, foam, or mold.
[0170] A variety of polymeric compositions have been described that
may be used in conjunction with the films and meshes of the
invention. Such compositions may be in the form of, for example,
gels, sprays, liquids, and pastes, or may be polymerized from
monomeric or prepolymeric constituents in situ. For example, the
composition may be a polymeric tissue coating which is formed by
applying a polymerization initiator to the tissue and then covering
it with a water-soluble macromer that is polymerizable using free
radical initiators under the influence of UV light. See e.g., U.S.
Pat. Nos. 6,177,095 and 6,083,524. The composition may be an
aqueous composition including a surfactant, pentoxifylline and a
polyoxyalkylene polyether. See e.g., U.S. Pat. No. 6,399,624. The
composition may be a hydrogel-forming, self-solvating, absorbable
polyester copolymers capable of selective, segmental association
into compliant hydrogels mass upon contact with an aqueous
environment. See e.g., U.S. Pat. No. 5,612,052. The composition may
be composed of fluent pre-polymeric material that is emitted to the
tissue surface and then exposed to activating energy in situ to
initiate conversion of the applied material to non-fluent polymeric
form. See e.g., U.S. Pat. Nos. 6,004,547 and 5,612,050. The
composition may be composed of a gas mixture of oxygen present in a
volume ratio of 1 to 20%. See e.g., U.S. Pat. No. 6,428,500. The
composition may be composed of an anionic polymer having an acid
sulfate and sulfur content greater than 5% which acts to inhibit
monocyte or macrophage invasion. See e.g., U.S. Pat. No. 6,417,173.
The composition may be composed of a non-gelling polyoxyalkylene
composition with or without a therapeutic agent. See e.g., U.S.
Pat. No. 6,436,425. The composition may be coated onto tissue
surfaces and may be composed of an aqueous solution of a
hydrophilic, polymeric material (e.g., polypeptides or
polysaccharide) having greater than 50,000 molecular weight and a
concentration range of 0.01% to 15% by weight. See e.g., U.S. Pat.
No. 6,464,970.
[0171] Other representative examples of polymeric compositions
which may be coated onto the film or mesh include poly(ethylene
glycol)-based systems, hyaluronic acid and crosslinked hyaluronic
acid compositions. These compositions can be applied as the final
composition or they can be applied as materials that form
crosslinked gel in situ.
[0172] Other compositions that can be combined with scarring agents
in conjunction with films and meshes, include, but are not limited
to: (a) sprayable PEG-containing formulations such as COSEAL,
SPRAYGEL, FOCALSEAL or DURASEAL; (b) hyaluronic acid-containing
formulations such as RESTYLANE, HYLAFORM, PERLANE, SYNVISC,
SEPRAFILM, SEPRACOAT, INTERGEL, (c) polymeric gels such as REPEL or
FLOWGEL, (d) dextran sulfate gels such as the ADCON range of
products, and (e) lipid based compositions such as ADSURF
(Brittania Pharmaceuticals).
[0173] Prior to implantation, the film or mesh may be trimmed or
cut from a sheet of bulk material to match the configuration of the
widened foramen, canal, or dissection region, or at a minimum, to
overlay the exposed tissue area. The film or mesh may be bent or
shaped to match the particular configuration of the placement
region. The film or mesh may also be rolled in a cuff shape or
cylindrical shape and placed around the exterior periphery of the
desired tissue. The film or mesh may be provided in a relatively
large bulk sheet and then cut into shapes to mold the particular
structure and surface topography of the tissue or device to be
wrapped. Alternatively, the film or mesh may be pre-shaped into one
or more patterns for subsequent use. The films and meshes may be
typically rectangular in shape and be placed at the desired
location within the surgical site by direct surgical placement or
by endoscopic techniques. The film or mesh may be secured into
place by wrapping it onto itself (i.e., self-adhesive), or by
securing it with sutures, staples, sealant, and the like.
Alternatively, the film or mesh may adhere readily to tissue and
therefore, additional securing mechanisms may not be required.
[0174] Within further aspects of the present invention, polymeric
carriers are provided which are adapted to contain and release a
hydrophobic fibrosis-inducing compound, and/or the carrier
containing the hydrophobic compound, in combination with a
carbohydrate, protein or polypeptide. Within certain embodiments,
the polymeric carrier contains or comprises regions, pockets, or
granules of one or more hydrophobic compounds. For example, within
one embodiment of the invention, hydrophobic compounds may be
incorporated within a matrix which contains the hydrophobic
fibrosis-inducing compound, followed by incorporation of the matrix
within the polymeric carrier. A variety of matrices can be utilized
in this regard, including for example, carbohydrates and
polysaccharides such as starch, cellulose, dextran,
methylcellulose, sodium alginate, heparin, chitosan and hyaluronic
acid and proteins or polypeptides such as albumin, collagen and
gelatin. Within alternative embodiments, hydrophobic compounds may
be contained within a hydrophobic core, and this core contained
within a hydrophilic shell.
[0175] Within another aspect of the present invention, polymeric
carriers can be materials that are formed in situ. In one
embodiment, the precursors can be monomers or macromers that
contain unsaturated groups which can be polymerized or crosslinked.
The monomers or macromers can then, for example, be injected into
the treatment area or onto the surface of the treatment area and
polymerized or crosslinked in situ using a radiation source (e.g.,
visible or UV light) or a free radical system (e.g., potassium
persulfate and ascorbic acid or iron and hydrogen peroxide). The
polymerization or crosslinking step can be performed immediately
prior to, simultaneously to, or post injection of the reagents into
the treatment site. Representative examples of compositions that
undergo free radical polymerization or crosslinking reactions are
described in WO 01/44307, WO 01/68720, WO 02/072166, WO 03/043552,
WO 93/17669, and WO 00/64977, U.S. Pat. Nos. 5,900,245; 6,051,248;
6,083,524; 6,177,095; 6,201,065; 6,217,894; 6,639,014; 6,352,710;
6,410,645; 6,531,147; 5,567,435; 5,986,043; and 6,602,975, and U.S.
Patent Application Publication Nos. 2002/012796, 2002/0127266,
2002/0151650, 2003/0104032, 2002/0091229, and 2003/0059906.
[0176] In another embodiment, the reagents can undergo an
electrophilic-nucleophilic reaction to produce a crosslinked
matrix. Polymers terminated with nucleophilic groups such as amine,
sulfhydryl, hydroxyl, --PH.sub.2 or CO--NH--NH.sub.2 can be used as
the nucleophilic reagents and polymers terminated with
electrophilic groups such as succinimidyl, carboxylic acid,
aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, maleimide,
--S--S--(C.sub.5H.sub.4N) or activated esters, such as are used in
peptide synthesis can be used as the electrophilic reagents. For
example, a 4-armed thiol derivatized poly(ethylene glycol) (e.g.,
pentaerythritol poly(ethylene glycol)ether tetra-sulfhydryl) can be
reacted with a 4 armed NHS-derivatized polyethylene glycol (e.g.,
pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl
glutarate) under basic conditions (pH>about 8). Representative
examples of compositions that undergo such
electrophilic-nucleophilic crosslinking reactions are described,
for example, in U.S. Pat. Nos. 5,752,974; 5,807,581; 5,874,500;
5,936,035; 6,051,648; 6,165,489; 6,312,725; 6,458,889; 6,495,127;
6,534,591; 6,624,245; 6,566,406; 6,610,033; 6,632,457; U.S. Patent
Application Publication No. 2003/0077272A1; and co-pending patent
applications entitled "Tissue Reactive Compounds and Compositions
and Uses Thereof" (U.S. Ser. No. 60/437,384, filed Dec. 30, 2002,
and U.S. Ser. No. 60/44,924, filed Jan. 17, 2003) and "Drug
Delivery from Rapid Gelling Polymer Composition" (U.S. Ser. No.
60/437,471, filed Dec. 30, 2002, and U.S. Ser. No. 60/440,875,
filed Jan. 17, 2003).
[0177] In another embodiment, the electrophilic- or
nucleophilic-terminated polymers can further comprise a polymer
that can enhance the mechanical and/or adhesive properties of the
in situ forming compositions. This polymer can be a degradable or
non-degradable polymer. For example, the polymer may be collagen or
a collagen derivative, for example methylated collagen. An example
of an in situ forming composition uses pentaerythritol
poly(ethylene glycol)ether tetra-sulfhydryl] (4-armed thiol PEG),
pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl
glutarate] (4-armed NHS PEG) and methylated collagen as the
reactive reagents. This composition, when mixed with the
appropriate buffers can produce a crosslinked hydrogel. (See, e.g.,
U.S. Pat. Nos. 5,874,500; 6,051,648; 6,166,130; 5,565,519 and
6,312,725).
[0178] In another embodiment, the in situ forming material polymer
can be a polyester. Polyesters that can be used in in situ forming
compositions include poly(hydroxyesters). In another embodiment,
the polyester can comprise the residues of one or more of the
monomers selected from lactide, lactic acid, glycolide, glycolic
acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid,
hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone,
gamma-valerolactone, ?-decanolactone, d-decanolactone, trimethylene
carbonate, 1,4-dioxane-2-one or 1,5-dioxepan-2-one. Representative
examples of these types of compositions are described in U.S. Pat.
Nos. 5,874,500; 5,936,035; 6,312,725; 6,495,127 and PCT Publication
Nos. WO 2004/028547.
[0179] In another embodiment, the electrophilic-terminated polymer
can be partially or completely replaced by a small molecule or
oligomer that comprises an electrophilic group (e.g.,
disuccinimidyl glutarate).
[0180] In another embodiment, the nucleophilic-terminated polymer
can be partially or completely replaced by a small molecule or
oligomer that comprises a nucleophilic group (e.g., dicysteine,
dilysine, trilysine, etc.).
[0181] Other examples of in situ forming materials that can be used
include those based on the crosslinking of proteins (described in,
for example, U.S. Pat. Nos. RE38158; 4,839,345; 5,514,379,
5,583,114; 6,310,036; 6,458,147; 6,371,975; U.S. Patent Application
Publication Nos. 2004/0063613A1, 2002/0161399A1, and
2001/0018598A1, and PCT Publication Nos. WO 03/090683, WO 01/45761,
WO 99/66964, and WO 96/03159) and those based on isocyanate or
isothiocyanate capped polymers (see, e.g., PCT Publication No. WO
04/021983).
[0182] Other examples of in situ forming materials can include
reagents that comprise one or more cyanoacrylate groups. These
reagents can be used to prepare a poly(alkylcyanoacrylate) or
poly(carboxyalkylcyanoacryl- ate) (e.g., poly(ethylcyanoacrylate),
poly(butylcyanoacrylate), poly(isobutylcyanoacrylate),
poly(hexylcyanoacrylate), poly(methoxypropylcyanoacrylate), and
poly(octylcyanoacrylate)).
[0183] Examples of commercially available cyanoacrylates that can
be used include DERMABOND, INDERMIL, GLUSTITCH, VETBOND,
HISTOACRYL, TISSUEMEND, TISSUMEND II, HISTOACRYL BLUE and ORABASE
SOOTHE-N-SEAL LIQUID PROTECTANT.
[0184] In another embodiment, the cyanoacrylate compositions can
further comprise additives to stabilize the reagents or alter the
rate of reaction of the cyanoacrylate. For example, a trimethylene
carbonate based polymer or an oxalate polymer of poly(ethylene
glycol) or a .epsilon.-caprolactone based copolymer can be mixed
with a 2-alkoxyalkylcyanoacrylate (e.g.,
2-methoxypropylcyanoacrylate). Representative examples of these
compositions are described in U.S. Pat. Nos. 5,350,798 and
6,299,631.
[0185] In another embodiment, the cyanoacrylate composition can be
prepared by capping heterochain polymers with a cyanoacrylate
group. The cyanoacrylate-capped heterochain polymer preferably has
at least two cyanoacrylate ester groups per chain. The heterochain
polymer can comprise an absorbable poly(ester),
poly(ester-carbonate), poly(ether-carbonate) and poly(ether-ester).
The poly(ether-ester)s described in U.S. Pat. Nos. 5,653,992 and
5,714,159 can also be used as the heterochain polymers. A triaxial
poly(.epsilon.-caprolactone-co-trime- thylene carbonate) is an
example of a poly(ester-carbonate) that can be used. The
heterochain polymer may be a polyether. Examples of polyethers that
can be used include poly(ethylene glycol), poly(propylene glycol)
and block copolymers of poly(ethylene glycol) and poly(propylene
glycol) (e.g., PLURONICS group of polymers including but not
limited to PLURONIC F127 or F68). Representative examples of these
compositions are described in U.S. Pat. No. 6,699,940.
[0186] As described above, the fibrosing agent can be coated onto
the entire device or a portion of the device using the polymeric
coatings described above. This can be accomplished, for example, by
dipping, spraying, electrospinning, painting or by vacuum
deposition. In addition to the coating compositions and methods
described above, there are various other coating compositions and
methods that are known in the art. Representative examples of these
coating compositions and methods are described in U.S. Pat. Nos.
6,610,016; 6,358,557; 6,306,176; 6,110,483; 6,106,473; 5,997,517;
5,800,412; 5,525,348; 5,331,027; 5,001,009; 6,562,136; 6,406,754;
6,344,035; 6,254,921; 6,214,901; 6,077,698; 6,603,040; 6,278,018;
6,238,799; 6,096,726; 5,766,158; 5,599,576; 4,119,094; 4,100,309;
6,599,558; 6,369,168; 6,521,283; 6,497,916; 6251964; 6,225,431;
6,087,462; 6,083,257; 5,739,237; 5,739,236; 5,705,583; 5648442;
5645883; 5,556,710; 5,496,581; 4,689,386; 6,214,115; 6,090,901;
6,599,448; 6,054,504; 4,987,182; 4,847,324; and 4,642,267, U.S.
Patent Application Publication Nos. 2003/0129130; 2001/0026834;
2003/0190420; 2001/0000785; 2003/0059631; 2003/0190405;
2002/0146581; 2003/020399; 2003/0129130, 2001/0026834;
2003/0190420; 2001/0000785; 2003/0059631; 2003/0190405;
2002/0146581; and 2003/020399, and PCT Publication Nos. WO
02/055121; WO 01/57048; WO 01/52915; and WO 01/01957.
[0187] Within another aspect of the invention, the biologically
active agent can be delivered with a non-polymeric agent. Examples
of non-polymeric agents include sucrose derivatives (e.g., sucrose
acetate isobutyrate, sucrose oleate), sterols such as cholesterol,
stigmasterol, beta-sitosterol, and estradiol; cholesteryl esters
such as cholesteryl stearate; C.sub.12-C.sub.24 fatty acids such as
lauric acid, myristic acid, palmitic acid, stearic acid, arachidic
acid, behenic acid, and lignoceric acid; C.sub.18-C.sub.36 mono-,
di- and triacylglycerides such as glyceryl monooleate, glyceryl
monolinoleate, glyceryl monolaurate, glyceryl monodocosanoate,
glyceryl monomyristate, glyceryl monodicenoate, glyceryl
dipalmitate, glyceryl didocosanoate, glyceryl dimyristate, glyceryl
didecenoate, glyceryl tridocosanoate, glyceryl trimyristate,
glyceryl tridecenoate, glycerol tristearate and mixtures thereof;
sucrose fatty acid esters such as sucrose distearate and sucrose
palmitate; sorbitan fatty acid esters such as sorbitan
monostearate, sorbitan monopalmitate and sorbitan tristearate;
C.sub.16-C.sub.18 fatty alcohols such as cetyl alcohol, myristyl
alcohol, stearyl alcohol, and cetostearyl alcohol; esters of fatty
alcohols and fatty acids such as cetyl palmitate and cetearyl
palmitate; anhydrides of fatty acids such as stearic anhydride;
phospholipids including phosphatidylcholine (lecithin),
phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol,
and lysoderivatives thereof; sphingosine and derivatives thereof;
spingomyelins such as stearyl, palmitoyl, and tricosanyl
spingomyelins; ceramides such as stearyl and palmitoyl ceramides;
glycosphingolipids; lanolin and lanolin alcohols, calcium
phosphate, sintered and unscintered hydoxyapatite, zeolites; and
combinations and mixtures thereof.
[0188] Representative examples of patents relating to non-polymeric
delivery systems and their preparation include U.S. Pat. Nos.
5,736,152; 5,888,533; 6,120,789; 5,968,542; and 5,747,058.
[0189] Other carriers that may likewise be utilized to contain and
deliver fibrosis-inducing agents described herein include:
hydroxypropyl cyclodextrin (Cserhati and Hollo, Int. J. Pharm. 108:
69-75, 1994), liposomes (see, e.g., Sharma et al., Cancer Res. 53:
5877-5881, 1993; Sharma and Straubinger, Pharm. Res. 11(60):
889-896, 1994; WO 93/18751; U.S. Pat. No. 5,242,073), liposome/gel
(WO 94/26254), nanocapsules (Bartoli et al., J. Microencapsulation
7(2): 191-197, 1990), micelles (Alkan-Onyuksel et al., Pharm. Res.
11(2): 206-212, 1994), nanoparticles (Violante and Lanzafame PMCR),
nanoparticles--modified (U.S. Pat. No. 5,145,684), nanoparticles
(surface modified) (U.S. Pat. No. 5,399,363), micelle (surfactant)
(U.S. Pat. No. 5,403,858), synthetic phospholipid compounds (U.S.
Pat. No. 4,534,899), gas borne dispersion (U.S. Pat. No.
5,301,664), liquid emulsions, foam, spray, gel, lotion, cream,
ointment, dispersed vesicles, particles or droplets solid- or
liquid-aerosols, microemulsions (U.S. Pat. No. 5,330,756),
polymeric shell (nano- and micro-capsule) (U.S. Pat. No.
5,439,686), emulsions (Tarr et al., Pharm Res. 4: 62-165, 1987),
nanospheres (Hagan et al., Proc. Intern. Symp. Control Rel. Bioact.
Mater. 22, 1995; Kwon et al., Pharm Res. 12(2): 192-195; Kwon et
al., Pharm Res. 10(7): 970-974; Yokoyama et al., J. Contr. Rel. 32:
269-277, 1994; Gref et al., Science 263: 1600-1603, 1994; Bazile et
al., J. Pharm. Sci. 84: 493-498, 1994) and implants (U.S. Pat. No.
4,882,168, Jampel et al., Invest Ophthalm. Vis. Science 34(11):
3076-3083, 1993; Walter et al., Cancer Res. 54: 22017-2212,
1994).
[0190] In another embodiment, the fibrosis inducing agent can be
incorporated into a composition that enhances osteointegration
and/or osteogenesis. Examples of these compositions include
materials composed of beta-tricalcium phosphate (e.g., VITOSS,
PROOSTEON 500R), hydroxyapatite or Ca.sub.10(PO.sub.4).sub.6OH
(e.g., OSTEOGRAF, calcium carbonate or CaCO.sub.3, calcium sulfate
(e.g., OSTEOSET and ALLOMATRIX), calcium phosphate (e.g., CALCIBON
or NORIAN SRS) as well as synthetic bone fillers (e.g., CORTOSS)
and processed bone fillers (e.g., BIOOSS). Representative examples
of these materials are described in U.S. Pat. Nos. 3,929,971,
4,861,733; 6,527,810; 4,772,468; 4,882,149; 5,167,961; 6,576,015;
4,839,215; 5,614,206; 5,807,567; 6,030,636; 6,652,887; 6,206,957;
6,485,754; 4,347,234; 4,291,013; 5,129,905; 5,336,264; 5,569,442;
5,571,493; 5,683,667; 5,709,742; 5,820,632; 5,658,332; 5,681,872;
5,914,356; 5,939,039; 6,325,987; 6,383,519; 6,458,162; 6,736,799;
6,521,246; and 6,709,744.
[0191] Within another aspect of the invention, the
fibrosis-inducing agent can further comprise a secondary carrier.
The secondary carrier can be in the form of microspheres (e.g.,
PLGA, PLLA, PDLLA, PCL, gelatin, polydioxanone,
poly(alkylcyanoacrylate)), nanospheres (e.g., PLGA, PLLA, PDLLA,
PCL, gelatin, polydioxanone, poly(alkylcyanoacrylate)), liposomes,
emulsions, microemulsions, micelles (e.g., SDS, block copolymers of
the form X--Y, X--Y--X or Y--X--Y, where X is a poly(alkylene
oxide) or an alkyl ether thereof and Y is a polyester (e.g., PLGA,
PLLA, PDLLA, PCL, polydioxanone)), zeolites or cyclodextrins.
[0192] Within another aspect of the invention, these
fibrosis-inducing agent/secondary carrier compositions can be a)
incorporated directly into or onto the device, b) incorporated into
a solution, c) incorporated into a gel or viscous solution, d)
incorporated into the composition used for coating the device, or
e) incorporated into or onto the device following coating of the
device with a coating composition.
[0193] For example, fibrosis-inducing agent loaded PLGA
microspheres may be incorporated into a polyurethane coating
solution which is then coated onto the device.
[0194] In yet another example, the device can be coated with a
polyurethane and then allowed to partially dry such that the
surface is still tacky. A particulate form of the fibrosis-inducing
agent or fibrosis-inducing agent/secondary carrier can then be
applied to all or a portion of the tacky coating after which the
device is dried.
[0195] In yet another example, the device can be coated with one of
the coatings described above. A thermal treatment process can then
be used to soften the coating, after which the fibrosis-inducing
agent or the fibrosis-inducing agent/secondary carrier is applied
to the entire device or to a portion of the device (e.g., outer
surface).
[0196] Within another aspect of the invention, a coated device
which inhibits or reduces an in vivo fibrotic reaction is further
coated with a compound or composition which delays the release of
and/or activity of the fibrosis-inducing agent. Representative
examples of such agents include biologically inert materials such
as gelatin, PLGA/MePEG film, PLA, polyurethanes, silicone rubbers,
surfactants, lipids, or polyethylene glycol, as well as
biologically active materials such as heparin (e.g., to induce
coagulation).
[0197] For example, in one embodiment of the invention, the active
agent on the device is top-coated with a physical barrier. Such
barriers can include non-degradable materials or biodegradable
materials such as gelatin, PLGA/MePEG film, PLA, polyethylene
glycol, or the like. In one embodiment, the rate of diffusion of
the therapeutic agent in the barrier coat is slower that the rate
of diffusion of the therapeutic agent in the coating layer. In the
case of PLGA/MePEG, once the PLGA/MePEG becomes exposed to the
bloodstream, the MePEG can dissolve out of the PLGA, leaving
channels through the PLGA to an underlying layer containing the
fibrosis-inducing agent (e.g., silk or cyclosporine A), which can
then diffuse into the vessel wall and initiate its biological
activity.
[0198] In another embodiment of the invention, for example, a
particulate form of the active agent (e.g., silk or cyclosporine A)
may be coated onto the device using a polymer (e.g., PLG, PLA, or
polyurethane). A second polymer, that dissolves slowly or degrades
(e.g., MePEG-PLGA or PLG) and that does not contain the active
agent, may be coated over the first layer. Once the top layer
dissolves or degrades, it exposes the under coating, which allows
the active agent to be exposed to the treatment site or to be
released from the coating.
[0199] Within another aspect of the invention, the outer layer of
the coated device, which induces an in vivo fibrotic response, is
further treated to crosslink the outer layer of the coating. This
can be accomplished by subjecting the coated device to a plasma
treatment process. The degree of crosslinking and nature of the
surface modification can be altered by changing the RF power
setting, the location with respect to the plasma, the duration of
treatment as well as the gas composition introduced into the plasma
chamber.
[0200] Protection of a biologically active surface can also be
utilized by coating the device or implant surface with an inert
molecule that prevents access to the active site through steric
hindrance, or by coating the surface with an inactive form of the
fibrosis-inducing agent, which is later activated. For example, the
device can be coated with an enzyme, which causes either release of
the fibrosis-inducing agent or activates the fibrosis-inducing
agent.
[0201] Another example of a suitable device surface coating
includes an anti-coagulant such as heparin, which can be coated on
top of the fibrosis-inducing agent such that the presence of the
heparin or other anti-coagulant delays coagulation at the treatment
site. As the heparin or other anticoagulant dissolves away, the
anticoagulant activity may slow or stop, and the newly exposed
fibrosis-inducing agent (e.g., silk or cyclosporine A) is capable
of inhibiting or reducing fibrosis from occurring in the adjacent
tissue.
[0202] In another strategy, the device can be coated with an
inactive form of the fibrosis-inducing agent, which is then
activated once the device is deployed. Such activation may be
achieved by injecting another material into the treatment area
after the device (as described below) is deployed or after the
fibrosis-inducing agent has been administered to the treatment area
(via, e.g., injections, spray, wash, drug delivery catheters or
balloons). For example, the device may be coated with an inactive
form of the fibrosis-inducing agent. Once the device is deployed,
the activating substance is injected or applied into or onto the
treatment site where the inactive form of the fibrosis-inducing
agent has been applied.
[0203] For example, a device may be coated with a biologically
active fibrosis-inducing agent, in the usual manner. The coating
containing the active fibrosis-inducing agent may then be covered
(e.g., coated) with polyethylene glycol. The PEG and the fibrosing
agent containing coating may be bonded through the formulation of a
bond between reactive groups on the two layers. For example, an
ester bond may be formed using a condensation reaction. Prior to
the deployment of the device, an esterase is injected into the
treatment site around the outside of the implanted device. The
esterase can cleave the bond between the ester and the
fibrosis-inducing agent, thereby allowing the agent to initiate
fibrosis.
[0204] In another aspect, a medical device may include a plurality
of reservoirs within its structure, each reservoir configured to
house and protect a therapeutic drug. The reservoirs may be formed
from divets in the device surface or micropores or channels in the
device body. In one aspect, the reservoirs are formed from voids in
the structure of the device. The reservoirs may house a single type
of drug or more than one type of drug. The druG(s) may be
formulated with a carrier (e.g., a polymeric or non-polymeric
material) that is loaded into the reservoirs. The filled reservoir
can function as a drug delivery depot which can release drug over a
period of time dependent on the release kinetics of the drug from
the carrier. In certain embodiments, the reservoir may be loaded
with a plurality of layers. Each layer may include a different drug
having a particular amount (dose) of drug, and each layer may have
a different composition to further tailor the amount of drug that
is released from the substrate. The multi-layered carrier may
further include a barrier layer that prevents release of the
druG(s). The barrier layer can be used, for example, to control the
direction that the drug elutes from the void.
[0205] Within certain embodiments of the invention, the therapeutic
compositions may also comprise additional ingredients such as
surfactants (e.g., PLURONICS, such as F-127, L-122, L-101, L-92,
L-81, and L-61), anti-inflammatory agents, anti-thrombotic agents,
anti-infective agents, preservatives, anti-oxidants and/or
anti-platelet agents.
[0206] Within certain embodiments of the invention, the therapeutic
agent or carrier can also comprise radio-opaque, echogenic
materials and magnetic resonance imaging (MRI) responsive materials
(i.e., MRI contrast agents) to aid in visualization of the device
under ultrasound, fluoroscopy and/or MRI. For example, a device may
be made with or coated with a composition which is echogenic or
radiopaque (e.g., made with echogenic or radiopaque with materials
such as powdered tantalum, tungsten, barium carbonate, bismuth
oxide, barium sulfate, metrazimide, iopamidol, iohexol, iopromide,
iobitridol, iomeprol, iopentol, ioversol, ioxilan, iodixanol,
iotrolan, acetrizoic acid derivatives, diatrizoic acid derivatives,
iothalamic acid derivatives, ioxithalamic acid derivatives,
metrizoic acid derivatives, iodamide, lypophylic agents, iodipamide
and ioglycamic Acid or, by the addition of microspheres or bubbles
which present an acoustic interface). Visualization of a device by
ultrasonic imaging may be achieved using an echogenic coating.
Echogenic coatings are described in, e.g., U.S. Pat. Nos. 6,106,473
and 6,610,016. For visualization under MRI, contrast agents (e.g.,
gadolinium (III) chelates or iron oxide compounds) may be
incorporated into or onto the device, such as, as a component in a
coating or within the void volume of the device (e.g., within a
lumen, reservoir, or within the structural material used to form
the device). In some embodiments, a medical device may include
radio-opaque or MRI visible markers (e.g., bands) that may be used
to orient and guide the device during the implantation
procedure.
[0207] Medical implants may, alternatively, or in addition, be
visualized under visible light, using fluorescence, or by other
spectroscopic means. Visualization agents that can be included for
this purpose include dyes, pigments, and other colored agents. In
one aspect, the medical implant may further include a colorant to
improve visualization of the implant in vivo and/or ex vivo.
Frequently, implants can be difficult to visualize upon insertion,
especially at the margins of implant. A coloring agent can be
incorporated into a medical implant to reduce or eliminate the
incidence or severity of this problem. The coloring agent provides
a unique color, increased contrast, or unique fluorescence
characteristics to the device. In one aspect, a solid implant is
provided that includes a colorant such that it is readily visible
(under visible light or using a fluorescence technique) and easily
differentiated from its implant site. In another aspect, a colorant
can be included in a liquid or semi-solid composition. For example,
a single component of a two component mixture may be colored, such
that when combined ex-vivo or in-vivo, the mixture is sufficiently
colored.
[0208] The coloring agent may be, for example, an endogenous
compound (e.g., an amino acid or vitamin) or a nutrient or food
material and may be a hydrophobic or a hydrophilic compound.
Preferably, the colorant has a very low or no toxicity at the
concentration used. Also preferred are colorants that are safe and
normally enter the body through absorption such as .beta.-carotene.
Representative examples of colored nutrients (under visible light)
include fat soluble vitamins such as Vitamin A (yellow); water
soluble vitamins such as Vitamin B12 (pink-red) and folic acid
(yellow-orange); carotenoids such as .beta.-carotene
(yellow-purple) and lycopene (red). Other examples of coloring
agents include natural product (berry and fruit) extracts such as
anthrocyanin (purple) and saffron extract (dark red). The coloring
agent may be a fluorescent or phosphorescent compound such as
.alpha.-tocopherolquinol (a Vitamin E derivative) or L-tryptophan.
Derivatives, analogues, and isomers of any of the above colored
compounds also may be used. The method for incorporating a colorant
into an implant or therapeutic composition may be varied depending
on the properties of and the desired location for the colorant. For
example, a hydrophobic colorant may be selected for hydrophobic
matrices. The colorant may be incorporated into a carrier matrix,
such as micelles. Further, the pH of the environment may be
controlled to further control the color and intensity.
[0209] In one aspect, the composition of the present invention
include one or more coloring agents, also referred to as dyestuffs,
which will be present in an effective amount to impart observable
coloration to the composition, e.g., the gel. Examples of coloring
agents include dyes suitable for food such as those known as F. D.
& C. dyes and natural coloring agents such as grape skin
extract, beet red powder, beta carotene, annato, carmine, turmeric,
paprika, and so forth. Derivatives, analogues, and isomers of any
of the above colored compound also may be used. The method for
incorporating a colorant into an implant or therapeutic composition
may be varied depending on the properties of and the desired
location for the colorant. For example, a hydrophobic colorant may
be selected for hydrophobic matrices. The colorant may be
incorporated into a carrier matrix, such as micelles. Further, the
pH of the environment may be controlled to further control the
color and intensity.
[0210] In one aspect, the compositions of the present invention
include one or more preservatives or bacteriostatic agents, present
in an effective amount to preserve the composition and/or inhibit
bacterial growth in the composition, for example, bismuth
tribromophenate, methyl hydroxybenzoate, bacitracin, ethyl
hydroxybenzoate, propyl hydroxybenzoate, erythromycin,
chlorocresol, benzalkonium chlorides, and the like. Additional
examples of the preservative include paraoxybenzoic acid esters,
chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic
acid, sorbic acid, and the like. In one aspect, the compositions of
the present invention include one or more bactericidal (also known
as bacteriacidal) agents.
[0211] In one aspect, the compositions of the present invention
include one or more antioxidants, present in an effective amount.
Examples of the antioxidant include sulfites, alpha-tocopherol and
ascorbic acid.
[0212] Within related aspects of the present invention, devices and
compositions are provided that may or may not be associated with a
device, which release an agent which induces fibrosis in vivo upon
deployment of the device or administration of the composition. In
certain aspects, the fibrosis-inducing agent or composition that
comprises the fibrosis-inducing agent is delivered locally or
regionally to the treatment site from the device or
composition.
[0213] Within certain aspects of the present invention, the
therapeutic composition should be biocompatible, and release one or
more fibrosing agents over a period of several hours, days, or
months.
[0214] The devices of the present invention may be configured to
release the scarring agent at one or more phases, the one or more
phases having similar or different performance (e.g., release)
profiles. The therapeutic agent may be made available to the tissue
at amounts which may be sustainable, intermittent, or continuous;
in one or more phases; and/or rates of delivery; effective to
increase or promote any one or more components of fibrosis (or
scarring), including: formation of new blood vessels
(angiogenesis), migration and proliferation of connective tissue
cells (such as fibroblasts or smooth muscle cells), deposition of
extracellular matrix (ECM), and remodeling (maturation and
organization of the fibrous tissue); or the agent can act as a
vascular wall irritant.
[0215] Thus, the release rate may be programmed to impact fibrosis
(or scarring) by releasing the scarring agent at a time such that
at least one of the components of fibrosis is promoted or
increased. Moreover, the predetermined release rate may reduce
agent loading and/or concentration as well as potentially providing
minimal drug washout and thus, increases efficiency of drug effect.
Any one of at least one scarring agent(s) may perform one or more
functions, including promoting the formation of new blood vessels
(angiogenesis), promoting the migration and proliferation of
connective tissue cells (such as fibroblasts or smooth muscle
cells), promoting the deposition of extracellular matrix (ECM),
promoting remodeling (maturation and organization of the fibrous
tissue) and/or acting as a vascular wall irritant. In one
embodiment, the rate of release may provide a sustainable level of
the scarring agent to the treatment site. In another embodiment,
the rate of release is substantially constant. The rate may
decrease and/or increase over time, and it may optionally include a
substantially non-release period. The release rate may comprise a
plurality of rates. In an embodiment, the plurality of release
rates may include rates selected from the group consisting of
substantially constant, decreasing, increasing, and substantially
non-releasing.
[0216] The total amount of scarring agent made available on, in or
near the device may be in an amount ranging from about 0.01 .mu.g
(micrograms) to about 2500 mg (milligrams). Generally, the scarring
agent may be in the amount ranging from 0.01 .mu.g to about 10
.mu.g; or from 10 .mu.g to about 1 mg; or from 1 mg to about 10 mg;
or from 10 mg to about 100 mg; or from 100 mg to about 500 mg; or
from 500 mg to about 2500 mg.
[0217] The surface amount of scarring agent on, in or near the
device may be in an amount ranging from less than 0.01 .mu.g to
about 250 .mu.g per mm.sup.2 of device surface area. Generally, the
scarring agent may be in the amount ranging from less than 0.01
.mu.g/mm.sup.2; or from 0.01 .mu.g to about 10 .mu.g/mm.sup.2; or
from 10 .mu.g to about 25 .mu.g/mm.sup.2; or from 25 .mu.g to about
250 .mu.g/mm.sup.2.
[0218] The scarring agent that is on, in or near the device may be
released from the composition and/or device in a time period that
may be measured from the time of implantation, which ranges from
about less than 1 day to about 180 days. Generally, the release
time may also be from about less than 1 day to about 7 days; from 7
days to about 14 days; from 14 days to about 28 days; from 28 days
to about 56 days; from 56 days to about 90 days; from 90 days to
about 180 days.
[0219] In one aspect, "quick release" or "burst" therapeutic
compositions are provided that release greater than 10%, 20%, or
25% (w/v) of a fibrosis-inducing agent over a period of 7 to 10
days. Such "quick release" compositions should, within certain
embodiments, be capable of releasing therapeutic levels (where
applicable) of a desired fibrosing agent. Within other embodiments,
"slow release" therapeutic compositions are provided that release
less than 1% (w/v) of a fibrosis-inducing agent over a period of 7
to 10 days. Within other embodiments therapeutic compositions are
provided that release either less than 1% (w/v) of a
fibrosing-inducing agent over a period longer than 10 days or do
not release the therapeutic composition at all, but maintain the
composition for a very long period of time such as for the entire
duration of the device placement in the body.
[0220] The amount of scarring agent released from the composition
and/or device as a function of time may be determined based on the
in vitro release characteristics of the agent from the composition.
The in vitro release rate may be determined by placing the scarring
agent within the composition or device in an appropriate buffer
such as 0.1M phosphate buffer (pH 7.4)) at 37.degree. C. Samples of
the buffer solution are then periodically removed for analysis by
either HPLC or by gravimetric means, and the buffer is replaced to
avoid any saturation effects.
[0221] Based on the in vitro release rates, the release of scarring
agent per day may range from an amount ranging from about 0.0 .mu.g
(micrograms) to about 2500 mg (milligrams). Generally, the scarring
agent that may be released in a day may be in the amount ranging
from 0.0 to 0.01 .mu.g; 0.01 .mu.g to about 10 .mu.g; or from 10
.mu.g to about 1 mg; or from 1 mg to about 10 mg; or from 10 mg to
about 100 mg; or from 100 mg to about 500 mg; or from 500 mg to
about 2500 mg. In one embodiment, the scarring agent is made
available to the susceptible tissue site in a constant but
substantially unchanging manner so that the agent remains at the
tissue essentially permanently. In another embodiment, the scarring
agent is made available to the susceptible tissue in a sustained
and/or controlled manner which results in increased efficiency
and/or efficacy. Further, the release rates may vary during either
or both of the initial and subsequent release phases. There may
also be additional phase(s) for release of the same substance(s)
and/or different substance(s).
[0222] Further, therapeutic compositions of the present invention
should preferably be have a stable shelf-life for at least several
months and capable of being produced and maintained under sterile
conditions. The composition may be sterile either by preparing them
under aseptic environment and/or they may be terminally sterilized
using methods available in the art. Many pharmaceuticals are
manufactured to be sterile and this criterion is defined by the USP
XXII <1211>. The term "USP" refers to U.S. Pharmacopeia (see
www.usp.org, Rockville, Md.). Sterilization may be accomplished by
a number of means accepted in the industry and listed in the USP
XXII <1211>, including gas sterilization, ionizing radiation
or, when appropriate, filtration. Sterilization may be maintained
by what is termed asceptic processing, defined also in USP XXII
>1211>. Acceptable gases used for gas sterilization include
ethylene oxide. Acceptable radiation types used for ionizing
radiation methods include gamma, for instance from a cobalt 60
source and electron beam. A typical dose of gamma radiation is 2.5
MRad. Sterilization may also occur by terminally using gamma
radiation or electron beam sterilization methods. Filtration may be
accomplished using a filter with suitable pore size, for example
0.22 .mu.m and of a suitable material, for instance
polytetrafluoroethylene (e.g., TEFLON). A combination of these
methods may also be used to prepare the composition in the sterile
form.
[0223] In another aspect, the compositions and devices of the
present invention are contained in a container that allows them to
be used for their intended purpose. Properties of the container
that are important are a volume of empty space to allow for the
addition of a constitution medium, such as water or other aqueous
medium, e.g., saline, acceptable light transmission characteristics
in order to prevent light energy from damaging the composition in
the container (refer to USP XXII <661>), an acceptable limit
of extractables within the container material (refer to USP XXII),
an acceptable barrier capacity for moisture (refer to USP XXII
<671>) or oxygen. In the case of oxygen penetration, this may
be controlled by including in the container, a positive pressure of
an inert gas, such as high purity nitrogen, or a noble gas, such as
argon.
[0224] Typical materials used to make containers for
pharmaceuticals include USP Type I through III and Type NP glass
(refer to USP XXII <661>), polyethylene, TEFLON, silicone,
and gray-butyl rubber. For parenterals, USP Types I to III glass
and polyethylene are preferred.
[0225] It should be readily evident to one of skill in the art that
any of the previously described fibrosis inducing agents, or
derivatives and analogues thereof, can be utilized to create
variations of the above compositions without deviating from the
spirit and scope of the invention. It should also be apparent that
the agent can be utilized in a composition with or without polymer
carrier and that altering the carrier does not deviate from the
scope of this invention.
[0226] For all the previously described embodiments, examples of
suitable fibrosing agents include tissue irritants such tissue as
silk, wool, asbestos, silica, bleomycin, neomycin, talcum powder,
metallic beryllium, and copper are particularly suitable for the
practice of this invention. Other agents which may be incorporated
into or onto the implant or device or released from the implant or
device include extracellular matrix components such as fibrous
structural proteins (e.g., fibrillar collagens, nonfibrillar
collagen and elastins), adhesive glycoproteins (e.g., laminin and
fibronectin), proteoglycans (e.g., heparin sulphate, chondroitin
sulphate, dermatan sulphate), hyaluronan (e.g., hyaluronic acid),
secreted protein acidic and rich in cysteine (SPARC),
thrombospondins, tenacin, inhibitors of matrix metalloproteinases
(e.g., TIMPs and synthetic TIMPs such as marimistat, batimistat,
doxycycline, tetracycline, minocycline, TROCADE, Ro-1130830, CGS
27023A, BMS-275291) and polylysine. Growth factors and inflammatory
cytokines involved in angiogenesis, fibroblast migration,
fibroblast proliferation, ECM synthesis and tissue remodeling such
as epidermal growth factor (EGF) family, transforming growth
factor-.alpha. (TGF-.alpha.), transforming growth factor-.beta.
(TGF-9-1, TGF-9-2, TGF-9-3), platelet-derived growth factor (PDGF),
fibroblast growth factor (acidic--aFGF; and basic--bFGF), bone
morphogenic proteins, activins, vascular endothelial growth factor
(VEGF, VEGF-B, VEGF-C, placental growth factor--PIGF),
angiopoietins, insulin-like growth factors (IGF), hepatocyte hrowth
factor (HGF), connective tissue growth factor (CTGF), myeloid
colony-stimulating factors (CSFs), granulocyte-macrophage
colony-stimulating factors (GM-CSF), granulocyte colony-stimulating
factor (G-CSF), macrophage colony-stimulating factor (M-CSF),
erythropoietin, interleukins (particularly IL-1, IL-8, IL-6), tumor
necrosis factor-.alpha. (TNF9), nerve growth factor (NGF),
interferon-.alpha., interferon-.beta., and growth hormone (GH) are
also suitable for incorporation and release from specific
intravascular devices. Other agents which may be coated onto or
released by the implant or device include adhesives such as
cyanoacrylate or materials made from 4-armed thiol PEG (10K), a
4-armed NHS PEG(10K) and methylated collagen.
[0227] 5) Coating of Devices with Fibrosis-Inducing Agents
[0228] As described above, a range of polymeric and non-polymeric
materials can be used to incorporate the fibrosis-inducing agent
onto or into a device. Coating of the device with these
fibrosis-inducing agent containing compositions or with the
fibrosis-inducing agent only is one process that can be used to
incorporate the fibrosis-inducing agent into or onto the
device.
[0229] a) Dip Coating
[0230] Dip coating is an example of a coating process that can be
used to associate the fibrosis-inducing agent with the device. In
one embodiment, the fibrosis-inducing agent is dissolved in a
solvent for the fibrosis agent and is then coated onto the
device.
[0231] Fibrosis-Inducing Agent with an Inert Solvent
[0232] In one embodiment, the solvent is an inert solvent for the
device such that the solvent does not dissolve the medical device
to any great extent and is not absorbed by the device to any great
extent. The device can be immersed, either partially or completely,
in the fibrosis-inducing agent/solvent solution for a specific
period of time. The rate of immersion into the fibrosis-inducing
agent/solvent solution can be altered (e.g., 0.001 cm per sec to 50
cm per sec). The device can then be removed from the solution. The
rate at which the device can be withdrawn from the solution can be
altered (e.g., 0.001 cm per sec to 50 cm per sec). The coated
device can be air-dried. The dipping process can be repeated one or
more times depending on the specific application. The device can be
dried under vacuum to reduce residual solvent levels. This process
can result in the fibrosis-inducing agent being coated on the
surface of the device.
[0233] Fibrosis-Inducing Agent with a Swelling Solvent
[0234] In one embodiment, the solvent is one that can not dissolve
the device but can be absorbed by the device. These solvents can
thus swell the device to some extent. The device can be immersed,
either partially or completely, in the fibrosis-inducing
agent/solvent solution for a specific period of time (seconds to
days). The rate of immersion into the fibrosis-inducing
agent/solvent solution can be altered (e.g., 0.001 cm per sec to 50
cm per sec). The device can then be removed from the solution. The
rate at which the device can be withdrawn from the solution can be
altered (e.g., 0.001 cm per sec to 50 cm per sec). The coated
device can be air-dried. The dipping process can be repeated one or
more times depending on the specific application. The device can be
dried under vacuum to reduce residual solvent levels. This process
can result in the fibrosis-inducing agent being adsorbed into the
medical device. The fibrosis-inducing agent may also be present on
the surface of the device. The amount of surface associated
fibrosis-inducing agent may be reduced by dipping the coated device
into a solvent for the fibrosis-inducing agent or by spraying the
coated device with a solvent for the fibrosis-inducing agent.
[0235] Fibrosis-Inducing Agent with a Solvent
[0236] In one embodiment, the solvent is one that can be absorbed
by the device and that can dissolve the device. The device can be
immersed, either partially or completely, in the fibrosis-inducing
agent/solvent solution for a specific period of time (seconds to
hours). The rate of immersion into the fibrosis-inducing
agent/solvent solution can be altered (e.g., 0.001 cm per sec to 50
cm per sec). The device can then be removed from the solution. The
rate at which the device can be withdrawn from the solution can be
altered (e.g., 0.001 cm per sec to 50 cm per sec). The coated
device can be air-dried. The dipping process can be repeated one or
more times depending on the specific application. The device can be
dried under vacuum to reduce residual solvent levels. This process
can result in the fibrosis-inducing agent being adsorbed into the
medical device as well as being surface associated. Preferably, the
exposure time of the device to the solvent may be such as to not
incur significant permanent dimensional changes to the device. The
fibrosis-inducing agent may also be present on the surface of the
device. The amount of surface associated fibrosis-inducing agent
may be reduced by dipping the coated device into a solvent for the
fibrosis-inducing agent or by spraying the coated device with a
solvent for the fibrosis-inducing agent.
[0237] In one embodiment, the fibrosis-inducing agent and a polymer
are dissolved in a solvent, for both the polymer and the fibrosing
agent, and are then coated onto the device.
[0238] In the above description, the device can be a device that
has not been modified or device that has been further modified by
coating with a polymer, surface treated by plasma treatment, flame
treatment, corona treatment, surface oxidation or reduction,
surface etching, mechanical smoothing or roughening, or grafting
prior to the coating process.
[0239] In any one of the above dip coating methods, the surface of
the device can be treated with a plasma polymerization method prior
to coating of the scarring agent or scarring agent containing
composition, such that a thin polymeric layer is deposited onto the
device surface. Examples of such methods include parylene coating
of devices and the use of various monomers such hydrocyclosiloxane
monomers. Parylene coating may be especially advantageous if the
device, or portions of the device, are composed of materials (e.g.,
stainless steel, nitinol) that do not allow incorporation of the
therapeutic agent(s) into the surface layer using one of the above
methods. A parylene primer layer may be deposited onto the device
using a parylene coater (e.g., PDS 2010 LABCOTER2 from Cookson
Electronics) and a suitable reagent (e.g., di-p-xylylene or
dichloro-di-p-xylylene) as the coating feed material. Parylene
compounds are commercially available, for example, from Specialty
Coating Systems, Indianapolis, Ind.), including PARYLENE N
(di-p-xylylene), PARYLENE C (a monchlorinated derivative of
PARYLENE N, and PARYLENE D, a dichlorinated derivative of Parylene
N.J.).
[0240] Fibrosis-Inducing Agent/Polymer with an Inert Solvent
[0241] In one embodiment, the solvent is an inert solvent for the
device such that the solvent does not dissolve the medical device
to any great extent and is not absorbed by the device to any great
extent. The device can be immersed, either partially or completely,
in the fibrosis-inducing agent/polymer/solvent solution for a
specific period of time. The rate of immersion into the
fibrosis-inducing agent/polymer/solvent solution can be altered
(e.g., 0.001 cm per sec to 50 cm per sec). The device can then be
removed from the solution. The rate at which the device can be
withdrawn from the solution can be altered (e.g., 0.001 cm per sec
to 50 cm per sec). The coated device can be air-dried. The dipping
process can be repeated one or more times depending on the specific
application. The device can be dried under vacuum to reduce
residual solvent levels. This process can result in the
fibrosis-inducing agent/polymer being coated on the surface of the
device.
[0242] Fibrosis-Inducing Agent/Polymer with a Swelling Solvent
[0243] In one embodiment, the solvent is one that can not dissolve
the device but can be absorbed by the device. These solvents can
thus swell the device to some extent. The device can be immersed,
either partially or completely, in the fibrosis-inducing
agent/polymer/solvent solution for a specific period of time
(seconds to days). The rate of immersion into the fibrosis-inducing
agent/polymer/solvent solution can be altered (e.g., 0.001 cm per
sec to 50 cm per sec). The device can then be removed from the
solution. The rate at which the device can be withdrawn from the
solution can be altered (e.g., 0.001 cm per sec to 50 cm per sec).
The coated device can be air-dried. The dipping process can be
repeated one or more times depending on the specific application.
The device can be dried under vacuum to reduce residual solvent
levels. This process can result in the fibrosis-inducing
agent/polymer being coated onto the surface of the device as well
as the potential for the fibrosis-inducing agent being adsorbed
into the medical device. The fibrosis-inducing agent may also be
present on the surface of the device. The amount of surface
associated fibrosis-inducing agent may be reduced by dipping the
coated device into a solvent for the fibrosis-inducing agent or by
spraying the coated device with a solvent for the fibrosis-inducing
agent.
[0244] Fibrosis-Inducing Agent/Polymer with a Solvent
[0245] In one embodiment, the solvent is one that can be absorbed
by the device and that can dissolve the device. The device can be
immersed, either partially or completely, in the fibrosis-inducing
agent/solvent solution for a specific period of time (seconds to
hours). The rate of immersion into the fibrosis-inducing
agent/solvent solution can be altered (e.g., 0.001 cm per sec to 50
cm per sec). The device can then be removed from the solution. The
rate at which the device can be withdrawn from the solution can be
altered (e.g., 0.001 cm per sec to 50 cm per sec). The coated
device can be air-dried. The dipping process can be repeated one or
more times depending on the specific application. The device can be
dried under vacuum to reduce residual solvent levels. In the
preferred embodiment, the exposure time of the device to the
solvent may be such that there is not significant permanent
dimensional changes to the device (other than those associated with
the coating itself). The fibrosis-inducing agent may also be
present on the surface of the device. The amount of surface
associated fibrosis-inducing agent may be reduced by dipping the
coated device into a solvent for the fibrosis-inducing agent or by
spraying the coated device with a solvent for the fibrosis-inducing
agent.
[0246] In the above description the device can be a device that has
not been modified as well as a device that has been further
modified by coating with a polymer (e.g., parylene), surface
treated by plasma treatment, flame treatment, corona treatment,
surface oxidation or reduction, surface etching, mechanical
smoothing or roughening, or grafting prior to the coating
process.
[0247] In another embodiment, a suspension of the fibrosis-inducing
agent in a polymer solution can be prepared. The suspension can be
prepared by choosing a solvent that can dissolve the polymer but
not the fibrosis-inducing agent or a solvent that can dissolve the
polymer and in which the fibrosis-inducing agent is above its
solubility limit. In similar processes described above, a device
can be dipped into the suspension of the fibrosis-inducing agent
and polymer solution such that the device is coated with a polymer
that has a fibrosing agent suspended within it.
[0248] b) Spray Coating
[0249] Spray coating is another type of coating process that can be
used. In the spray coating process, a solution or suspension of the
fibrosis-inducing agent, with or without a polymeric or
non-polymeric carrier, is nebulized and directed to the device to
be coated by a stream of gas. One can use spray devices such as an
air-brush (for example models 2020, 360, 175, 100, 200, 150, 350,
250, 400, 3000, 4000, 5000, 6000 from Badger Air-brush Company,
Franklin Park, Ill.), spray painting equipment, TLC reagent
sprayers (for example Part # 14545 and 14654, Alltech Associates,
Inc. Deerfield, Ill., and ultrasonic spray devices (for example
those available from Sono-Tek, Milton, N.Y.). One can also use
powder sprayers and electrostatic sprayers.
[0250] In one embodiment, the fibrosis-inducing agent is dissolved
in a solvent for the fibrosis agent and is then sprayed onto the
device.
[0251] Fibrosis-Inducing Agent with an Inert Solvent
[0252] In one embodiment, the solvent is an inert solvent for the
device such that the solvent does not dissolve the medical device
to any great extent and is not absorbed by the device to any great
extent. The device can be held in place or the device can be
mounted onto a mandrel or rod that has the ability to move in an X,
Y or Z plane or a combination of these planes. Using one of the
above described spray devices, the device can be spray coated such
that the device is either partially or completely coated with the
fibrosis-inducing agent/solvent solution. The rate of spraying of
the fibrosis-inducing agent/solvent solution can be altered (e.g.,
0.001 ml per sec to 10 ml per sec) to ensure that a good coating of
the fibrosis-inducing agent is obtained. The coated device can be
air-dried. The spray coating process can be repeated one or more
times depending on the specific application. The device can be
dried under vacuum to reduce residual solvent levels. This process
can result in the fibrosis-inducing agent being coated on the
surface of the device.
[0253] Fibrosis-Inducing Agent with a Swelling Solvent
[0254] In one embodiment, the solvent is one that can not dissolve
the device but can be absorbed by the device. These solvents can
thus swell the device to some extent. The device can be spray
coated, either partially or completely, in the fibrosis-inducing
agent/solvent solution. The rate of spraying of the
fibrosis-inducing agent/solvent solution can be altered (e.g.,
0.001 ml per sec to 10 ml per sec) to ensure that a good coating of
the fibrosis-inducing agent is obtained. The coated device can be
air-dried. The spray coating process can be repeated one or more
times depending on the specific application. The device can be
dried under vacuum to reduce residual solvent levels. This process
can result in the fibrosis-inducing agent being adsorbed into the
medical device. The fibrosis-inducing agent may also be present on
the surface of the device. The amount of surface associated
fibrosis-inducing agent may be reduced by dipping the coated device
into a solvent for the fibrosis-inducing agent or by spraying the
coated device with a solvent for the fibrosis-inducing agent.
[0255] Fibrosis-Inducing Agent with a Solvent
[0256] In one embodiment, the solvent is one that can be absorbed
by the device and that can dissolve the device. The device can be
spray coated, either partially or completely, in the
fibrosis-inducing agent/solvent solution. The rate of spraying of
the fibrosis-inducing agent/solvent solution can be altered (e.g.,
0.001 ml per sec to 10 ml per sec) to ensure that a good coating of
the fibrosis-inducing agent is obtained. The coated device can be
air-dried. The spray coating process can be repeated one or more
times depending on the specific application. The device can be
dried under vacuum to reduce residual solvent levels. This process
can result in the fibrosis-inducing agent being adsorbed into the
medical device as well as being surface associated. Preferably, the
exposure time of the device to the solvent may be such as to not
incur significant permanent dimensional changes to the device. The
fibrosis-inducing agent may also be present on the surface of the
device. The amount of surface associated fibrosis-inducing agent
may be reduced by dipping the coated device into a solvent for the
fibrosis-inducing agent or by spraying the coated device with a
solvent for the fibrosis-inducing agent.
[0257] In one embodiment, the fibrosis-inducing agent and a polymer
are dissolved in a solvent, for both the polymer and the fibrosing
agent, and are then spray coated onto the device. In the above
description, the device can be a device that has not been modified
as well as a device that has been further modified by coating with
a polymer (e.g., parylene), surface treated by plasma treatment,
flame treatment, corona treatment, surface oxidation or reduction,
surface etching, mechanical smoothing or roughening, or grafting
prior to the coating process.
[0258] Fibrosis-Inducing Agent/Polymer with an Inert Solvent
[0259] In one embodiment, the solvent is an inert solvent for the
device such that the solvent does not dissolve the medical device
to any great extent and is not absorbed by the device to any great
extent. The device can be spray coated, either partially or
completely, in the fibrosis-inducing agent/polymer/solvent solution
for a specific period of time. The rate of spraying of the
fibrosis-inducing agent/solvent solution can be altered (e.g.,
0.001 ml per sec to 10 ml per sec) to ensure that a good coating of
the fibrosis-inducing agent is obtained. The coated device can be
air-dried. The spray coating process can be repeated one or more
times depending on the specific application. The device can be
dried under vacuum to reduce residual solvent levels. This process
can result in the fibrosis-inducing agent/polymer being coated on
the surface of the device.
[0260] Fibrosis-Inducing Agent/Polymer with a Swelling Solvent
[0261] In one embodiment, the solvent is one that can not dissolve
the device but can be absorbed by the device. These solvents can
thus swell the device to some extent. The device can be spray
coated, either partially or completely, in the fibrosis-inducing
agent/polymer/solvent solution. The rate of spraying of the
fibrosis-inducing agent/solvent solution can be altered (e.g.,
0.001 ml per sec to 10 ml per sec) to ensure that a good coating of
the fibrosis-inducing agent is obtained. The coated device can be
air-dried. The spray coating process can be repeated one or more
times depending on the specific application. The device can be
dried under vacuum to reduce residual solvent levels. This process
can result in the fibrosis-inducing agent/polymer being coated onto
the surface of the device as well as the potential for the
fibrosis-inducing agent being adsorbed into the medical device. The
fibrosis-inducing agent may also be present on the surface of the
device. The amount of surface associated fibrosis-inducing agent
may be reduced by dipping the coated device into a solvent for the
fibrosis-inducing agent or by spraying the coated device with a
solvent for the fibrosis-inducing agent.
[0262] Fibrosis-Inducing Agent/Polymer with a Solvent
[0263] In one embodiment, the solvent is one that can be absorbed
by the device and that can dissolve the device. The device can be
spray coated, either partially or completely, in the
fibrosis-inducing agent/solvent solution. The rate of spraying of
the fibrosis-inducing agent/solvent solution can be altered (e.g.,
0.001 ml per sec to 10 ml per sec) to ensure that a good coating of
the fibrosis-inducing agent is obtained. The coated device can be
air-dried. The spray coating process can be repeated one or more
times depending on the specific application. The device can be
dried under vacuum to reduce residual solvent levels. Preferably,
the exposure time of the device to the solvent may be such as to
not incur significant permanent dimensional changes to the device
(other than those associated with the coating itself). The
fibrosis-inducing agent may also be present on the surface of the
device. The amount of surface associated fibrosis-inducing agent
may be reduced by dipping the coated device into a solvent for the
fibrosis-inducing agent or by spraying the coated device with a
solvent for the fibrosis-inducing agent.
[0264] In the above description, the device can be a device that
has not been modified as well as a device that has been further
modified by coating with a polymer (e.g., parylene), surface
treated by plasma treatment, flame treatment, corona treatment,
surface oxidation or reduction, surface etching, mechanical
smoothing or roughening, or grafting prior to the coating
process.
[0265] c) Direct Attachment
[0266] In certain embodiments, the fibrosis inducing agent can be
attached directly to the device. This can be accomplished by using
an adhesive (e.g., cyanoacrylate, polymer/solvent solution), using
a thermal process and or by sewing the fibrosis agent into or onto
the device. In one embodiment, the fibrosis inducing agent can be
in the form of particles (irregular, regular, porous, spherical),
threads, fibers, knits, weaves or electrospun material. For
example, silk can be prepared as a knitted, woven or electrospun
material. This material can then be placed on the surface of the
device. Sutures and/or an adhesive can then be used to secure the
silk material to the device.
[0267] In another embodiment, the fibrosis inducing agent can be
dissolved in a suitable solvent. This solution can then be applied
to the device using an electrospraying or electrospinning process.
Polymeric or non-polymeric additives can be added to this solution
to assist in the electrospraying or electrospinning process and or
to assist in the adhesion of the fibrosis inducing agent to the
device. For example, silk can be dissolved in HFIP and this can
then be electrosprayed or electrospun onto the device (e.g.,
stent).
[0268] In another embodiment, the fibrosis-inducing agent can be
incorporated into the device during or post manufacture of the
device. For example silk fibers could be woven into a hernia mesh
to provide a product that contains the fibrosis-inducing agent that
is incorporated into the device.
[0269] D. Methods for Utilizing Medical Implants
[0270] Medical devices and implants of the present invention may be
utilized to induce a fibrotic reaction around the device/implant
that results in an enhanced bond between the tissue and the
prosthesis. Such medical devices and implants provide a solution to
the following common problems associated with a variety of clinical
interventions.
[0271] 1. Treatments for Degenerative Disc Disease (DDD)
[0272] Back pain is the number one cause of healthcare expenditures
in the United States and accounts for over $50 billion in costs
annually ($100 billion worldwide). Over 12 million people in the
U.S. have some form of degenerative disc disease (DDD) and 10% of
them (1.2 million) can require surgery to correct their
problem.
[0273] In healthy individuals, the vertebral column is composed of
vertebral bone plates separated by intervertebral discs that form
strong joints and absorb spinal compression during movement. The
intervertebral disc is comprised of an inner gel-like substance
called the nucleus pulposus which is surrounded by a tough
fibrocartilagenous capsule called the annulus fibrosis. The nucleus
pulposus is composed of a loose framework of collagen fibrils and
connective tissue cells (resembling fibroblasts and chondrocytes)
embedded in a gelatinous matrix of glycosaminoglycans and water.
The annulus fibrosus is composed of numerous concentric rings of
fibrocartilage that anchor into the vertebral bodies. The most
common cause of DDD occurs when tears in the annulus fibrosis
create an area of localized weakness that allow bulging, herniation
or sequestration of the nucleus pulposis and annulus fibrosis into
the spinal canal and/or spinal foramena. The bulging or herniated
disc often compresses nerve tissue such as spinal cord fibers or
spinal cord nerve root fibers. Pressure on the spinal cord or nerve
roots from the damaged intervertebral disc results in neuronal
dysfunction (numbness, weakness, tingling), crippling pain, bowel
or bladder disturbances and can frequently cause long-term
disability. Although many cases of DDD can spontaneously resolve, a
significant number of patients can require surgical intervention in
the form of minimally invasive procedures, microdiscectomy, major
surgical resection of the disc, spinal fusion (fusion of adjacent
vertebral bone plates using various techniques and devices), and/or
implantation of an artificial disc. The present invention provides
for the application of an adhesion or fibrosis-inducing agent in
the surgical management of DDD.
[0274] (i) Minimally Invasive Treatments of DDD
[0275] The present invention provides injectable compositions that
iriclude a bulking or filling agent and a fibrosing agent for
direct injection into damaged intervertebral discs. An injectable
material containing a fibrosis-inducing agent that can be injected
into an intervertebral disc space (alone or in combination with
polymeric carrier, which may be in the form, e.g., of a gel, paste,
or spray) is used to enhance scarring and support the annular ring
of the disc (e.g., by inducing the production of fibrous tissue and
fibrocartilage), thus reducing the risk of disc rupture and
restoring disc function without surgery (embodiments for
application during disc surgery are described below). In another
embodiment, the injectable composition containing a
fibrosis-inducing agent can further contain an agent that promotes
bone growth if permanent fixation (immobilization) of adjacent
vertebra is desired.
[0276] In this procedure, a needle is inserted into the
intervertebral disc, a guidewire is advanced into the tissue and a
dual lumen catheter (for many of the hydrogels described below such
as COSEAL, COSTASIS, FLOSEAL, TISSEAL, VITOSS, and materials made
from 4-armed thiol PEG (10K), 4-armed NHS PEG(10K) and methylated
collagen, such as described above or a single lumen catheter (for
materials such as cyanoacrylate, CORTOSS, bone cement,
apatitehydroxyapatite, calcium phosphate, calcium sulfate,
hyaluronic acid, proteins, carbohydrates, sclerosing agents, and
the like) is advanced into the disc. When performing direct
injection of the intervertebral disc, techniques can be used to
enhance visualization of needle (or catheter) placement within the
disc including, but not limited to, the use of a needle coated with
an ultrasound imaging coating formulation, such as ECHO--COAT
(Angiotech Pharmaceuticals, Inc.) or the addition of contrast
agents (e.g., barium, tantalum, technitium, gadolinium, etc.) for
localization by x-ray. After correct positioning has been
confirmed, the guidewire is removed, and a composition containing a
fibrosis-inducing agent, with or without a bone morphogenic
protein(s), and/or an osteogenic growth factor (such as
transforming growth factor, platelet-derived growth factor,
fibroblast growth factor) is injected via the catheter into the
disc. Chemonucleolysis agents such as collagenase, chymopapain or
other tissue-degrading enzymes may also be used to chemically
degrade the remaining disc tissue prior to the injection of the
fibrosing composition. Over time the fibrosis-inducing agent, with
or without a bone morphogenic protein, and/or an osteogenic growth
factor can encourage fibrous ankylosis, followed by bony ankylosis
of the intervertebral space leading to increased stability and
reduced pain.
[0277] The injectable material may contain a polymer system that
can provide sustained release of the fibrosis-inducing agent, bone
morphogenic protein, and/or osteogenic growth factor to enhance
efficacy and reduce the need for repeat administrations of active
agents. The polymeric injection material suitable for delivery of a
fibrosis-inducing agent, bone morphogenic protein, and/or growth
factor that promotes bone growth can be either a non-degradable or
a degradable material. Suitable non-degradable materials include
crosslinked compositions that comprise PVA, PVP, polyacrylamide,
methyl methacrylate (MMA) and methyl methacrylate-styrene
(MMA-styrene) which when mixed together form polymethyl
methacrylate (PMMA) or bone cement (e.g., SIMPLEX P made by Stryker
Howmedica, ZIMMER REGULAR and ZIMMER LOW VISCOSITY CEMENT, PALACOS,
CMW-1 and CMW-2, ENDURANCE), synthetic cancellous bone void fillers
(e.g., CORTOSS), pHEMA, poly(vinyl PEG), poly(styrene sulfonate),
poly(acrylic acid), poly(methacrylic acid), as well as other
polymers that are known to form hydrogels. Other compositions
include blends and copolymers of the agents listed above. Suitable
degradable materials include, but are not limited to, resorbable
ceramics composed of .beta.-tricalcium phosphate (e.g., VITOSS and
PROOSTEON 500R), hydroxyapatite or Ca.sub.10(PO.sub.4).sub.6OH
(e.g., BIOOSS and OSTEOGRAF), calcium carbonate or CaCO.sub.3,
calcium sulfate (e.g., OSTEOSET and ALLOMATRIX made by Wright
Medical Technology, Inc.), calcium phosphate (e.g., CALCIBON or
NORIAN SRS), crosslinked materials of PEG, gelatin, collagen, bone
allografts (e.g., ALLOGRO (Allosource Corporation, Centennial,
Colo.), ORTHOBLAST (GenSci Regeneration Sciences, Inc., Canada),
OPTEFORM (Exactech, Inc., Gainesville, Fla.), GRAFTON (Osteotech,
Inc., Eatontown, N.J.), mesenchymal stem cells, hyaluronic acid,
hyaluronic acid derivatives, polysaccharides, carbohydrates,
proteins (e.g., albumin, casein, whey proteins, plant proteins, and
fish proteins), autologous bone, demineralized bone matrix,
cellulose derivatives (e.g., HPC), chitosan, chitosan derivatives,
polyester-polyalkylene oxide block copolymers (e.g., PLGA-PEG-PLGA
and MePEG-PLGA, and the like) and other low molecular weight
polymers that can be excreted. An injectable material of particular
interest is prepared from a 4-armed thiol PEG (10K), a 4-armed NHS
PEG(10K) and methylated collagen such as described above.
[0278] In a preferred embodiment, the injectable material also
contains a biologically active agent capable of inducing fibrosis
and ankylosis in the disc space. In one embodiment, the injectable
material is loaded with a fibrosis-inducing agent and injected into
the intervertebral disc to help repair the annulus and prevent
herniation of the nucleus pulposis. In another embodiment, the
injectable material contains biologically active agents capable of
inducing bone growth such bone morphogenic proteins and growth
factors (transforming growth factor, platelet-derived growth
factor, fibroblast growth factor) to promote bony ankylosis and
fusion of adjacent vertebra.
[0279] In addition to, or in lieu of, fibrosis-inducing agents,
bone morphogenic proteins and growth factors, the injectable
material can be utilized to deliver a sclerosant to the articular
space. Sclerosants include compounds such as ethanol, DMSO,
surfactants, sucrose, NaCl, dextrose, glycerin, minocycline,
tetracycline, doxycycline, polidocanol, sodium tetradecyl sulfate,
sodium morrhuate, sotradecol and others. The injectable material
can further comprise agents such as glycerol, glycerin, PEG 200,
triethyl citrate, and triacetin as plasticizers.
[0280] The injectable materials described above can be further
modified to be comprised of, or contain, polymeric threads.
Polymeric threads have the ability to induce a fibroproliferative
response from the surrounding tissue. These polymer threads can be
degradable or non-degradable. Degradable threads can be composed of
degradable polyesters, polyanhydrides, poly(anhydride esters),
poly(ester-amides), poly(ester-ureas), polyorthoesters,
polyphosphoesters, polyphosphazines, cyanoacrylate polymers,
collagen, chitosan, hyaluronic acid, chromic cat gut, alginates,
starch, cellulose, cellulose esters, blends and copolymers thereof,
as well as other known degradable polymers. Non-degradable polymers
that can be used include, but are not limited to, polyesters (e.g.,
PET), polyurethanes, silicones, PE, PP, PS, PAA, PMA, silk, blends,
copolymers thereof as well as other known polymers. The threads can
be composed of a single composition or composed of a blend of
differing compositions. The polymeric threads themselves can be
further modified through the addition of a polymeric coating
applied to the threads. The polymer used for coating the thread can
be similar to that described above for the threads themselves. The
polymer coating may further comprise a biologically active agent
that has the ability to induce a fibroproliferative or osteogenic
response. The agents that can be used are further described in the
section (vi) below.
[0281] The injectable materials described above can be utilized to
deliver a particulate material that has the ability to induce
fibrosis in the intervertebral disc. These particles can be either
degradable or non-degradable and are similar to those described
above for threads. Additional particulate materials useful for the
practice of this embodiment include silk, talc, starch, glass,
silicates, silica, calcium phosphate, calcium sulfate, calcium
carbonate, hydroxyapatite, synthetic mineral (e.g., VITOSS and
CORTOSS, PMMA, silver nitrate, ceramic particles and other
inorganic particles known in the art to induce a fibroprqliferative
response followed by mineralization. The particles used in this
embodiment can be all of the same composition or a blend of
differing compositions. These particles can also be used as a
coating applied to the polymeric strands as described above.
[0282] The injectable materials can also be constructed such that
it is comprised of both polymeric threads and particles. The
threads and particles used are similar to those described above and
may be of uniform composition or blended composition. Virtually any
combination of threads of differing compositions and particles of
differing compositions can be utilized in this embodiment. The
hydrogel, the polymeric threads, and the particles can all be
utilized to deliver one or more biologically active agents, as
described below.
[0283] One specific composition comprises rods prepared from a
methylated collagen-crosslinked poly(ethylene glycol) composition
such as described above, which has powdered silk particles and/or
mineral particles added to the composition prior to curing. Once
deployed, the rod can absorb water, fill the disc space and adhere
to any fibrocartilage or exposed bone. This expansion can prevent
the rod from moving, while the powdered silk and/or mineral
particles can initiate an ankylosing response. As the material
starts to degrade, the material can support the bone tissue
ingrowth that is initiated and potentiated by the particles. Bone
morphogenic proteins and/or growth factors (described previously
and below) are also useful for inclusion in this composition. To
further increase the rate of initiation of this fibroproliferative
response, a sclerosant such as a surfactant (SDS), ethanolamine
oleate or DMSO can be added. In addition, one can also add or
replace all (or a portion) of the 4-armed thiol PEG with a 4-armed
amino PEG. The amino PEG can provide a gel that can take a longer
time to degrade and can provide some positive charge to further
attract cellular material.
[0284] Another embodiment consists of an injectable implant
composed of silk fibers or from a polymerized version of the
fibrosing agent itself (i.e., repeating units of the fibrosing
agent polymerized together). Bone morphogenic proteins and/or
growth factors (described previously and below) also may be added
to this composition.
[0285] In addition to the hydrogels, bone cements, and materials
containing calcium phosphate described above, there are several
other injectable compositions suitable for use in minimally
invasive intervertebral disc procedures. All involve the deployment
of a biomaterial into the nucleus pulposis with or without the
addition of a fibrosis-inducing agent, bone morphogenic protein(s),
and/or a suitable growth factor(s). The following compositions can
be delivered into the intervertebral disc via specialized delivery
catheters, an endoscope, a needle or other applicator, a surgically
placed drain or access port, or other transdermal access device,
including administration of: (a) fluids, suspensions, emulsions,
microemulsions, microspheres, pastes, gels, microparticulates,
sprays, aerosols, solid implants and other formulations which
release a biologically active fibrosis-inducing agent(s); (b)
microparticulate silk and/or silk strands (linear, branched, and/or
coiled) either alone, or loaded with an additional
fibrosis-inducing agent, bone morphogenic protein, and/or growth
factor are also useful for directed injection into the
intervertebral disc; (c) injectable collagen-containing
formulations such as COSTASIS or materials made from 4-armed thiol
PEG (10K), 4-armed NHS PEG(10K) and methylated collagen such as
described above, either alone, or loaded with a fibrosis-inducing
agent, bone morphogenic protein, and/or growth factor, injected
into the intervertebral disc; (d) injectable PEG-containing
formulations such as COSEAL, FOCALSEAL, SPRAYGEL or DURASEAL,
either alone, or loaded with a fibrosis-inducing agent, bone
morphogenic protein, and/or growth factor, injected into the
intervertebral disc; (e) fibrinogen-containing formulations such as
FLOSEAL or TISSEAL, either alone, or loaded with a
fibrosis-inducing agent, bone morphogenic protein, and/or growth
factor, injected into the intervertebral disc; (f) hyaluronic
acid-containing formulations such as RESTYLANE, HYLAFORM, PERLANE,
SYNVISC, SEPRAFILM, SEPRACOAT either alone, or loaded with a
fibrosis-inducing agent, bone morphogenic protein, and/or growth
factor injected into the intervertebral disc; (g) polymeric gels
for surgical implantation such as REPEL or FLOWGEL either alone, or
loaded with a fibrosis-inducing agent, bone morphogenic protein,
and/or growth factor injected into the intervertebral disc; (h)
orthopedic "cements" such as OSTEOBOND, low viscosity cement (LVC),
SIMPLEX P, PALACOS, CORTOSS and ENDURANCE, either alone, or loaded
with a fibrosis-inducing agent, bone morphogenic protein, and/or
growth factor injected into the intervertebral disc; (i) surgical
adhesives containing cyanoacrylates such as DERMABOND, INDERMIL,
GLUSTITCH, VETBOND, HISTOACRYL, TISSUEMEND, TISSUMEND II,
HISTOACRYL BLUE and ORABASE SOOTHE-N-SEAL LIQUID PROTECTANT or as
described above, either alone, or loaded with a fibrosis-inducing
agent, bone morphogenic protein, and/or growth factor, injected
into the intervertebral disc; (j) surgical implants containing
hydroxyapatite, calcium phosphate (such as VITOSS), or calcium
sulfate, alone or loaded with a fibrosis-inducing agent, bone
morphogenic protein, and/or growth factor, injected into the
intervertebral disc; (k) other biocompatible tissue fillers, such
as those made by BioCure, 3M Company and Neomend, either alone, or
loaded with a fibrosis-inducing agent, bone morphogenic protein,
and/or growth factor, injected into the intervertebral disc; (l)
polysaccharide gels such as the ADCON series of gels, either alone,
or loaded with a fibrosis-inducing agent, bone morphogenic protein,
and/or growth factor, injected into the intervertebral disc; (m)
films, sponges or meshes such as INTERCEED, VICRYL mesh, and
GELFOAM either alone, or loaded with a fibrosis-inducing agent,
bone morphogenic protein, and/or growth factor, injected into the
intervertebral disc; and/or (n) a hydrogel that is formed from an
amino-functionalized polyethylene glycol (e.g., 4-armed tetra-amino
PEG [10k]) and a 4-armed NHS functionalized PEG (e.g.,
pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl
glutarate [10K]). This hydrogel may further contain collagen,
methylated collagen and/or gelatin. This hydrogel can further
comprise the fibrosis-inducing agents described above (e.g., silk
powder or silk threads). In many of these embodiments, it may also
be useful to add a radio-opaque material (e.g., tantalum, barium,
other metal, or a contrast material) such that the injected
material can be visualized radiographically or by MRI.
[0286] It should be apparent to one of skill in the art that
potentially any fibrosis-inducing agents described above may be
utilized alone, or in combination, in the practice of this
embodiment. Exemplary fibrosing agents for use in spinal prostheses
(e.g., devices and bulking agents) include talc, silk, wool,
chitosan, polylysine, fibronectin, bleomycin, and CTGF, as well as
analogues and derivatives of the aforementioned.
[0287] Optionally, the device may additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, or
growth hormone) and/or a bone morphogenic protein (BMP) (e.g.,
BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or an analogue or
derivative thereof).
[0288] Furthermore, the device may comprise an agent that
stimulates cellular proliferation. Examples include: dexamethasone,
isotretinoin (13-cis retinoic acid), 17-.beta.-estradiol,
estradiol, 1-a-25 dihydroxyvitamin D.sub.3, diethylstibesterol,
cyclosporine A, L-NAME, all-trans retinoic acid (ATRA), and
analogues and derivatives thereof. The administration and dosages
of these agents for use in these embodiments are described in
section (vi) below.
[0289] (ii) Open Surgical Disc Resection and Microdiscectomy
[0290] Spinal disc removal is mandatory and urgent in cauda equine
syndrome when there is a significant neurological deficit;
particularly bowel or bladder dysfunction. It is also performed
electively to relieve pain and eliminate lesser neurological
symptoms.
[0291] For open surgical resection of a ruptured lumbar disc
(laminectomy) the patient is placed in a modified kneeling position
under general anesthesia. An incision is made in the posterior
midline and the tissue is dissected away to expose the appropriate
interspace; the ligamentum flavum is dissected and in some cases
portions of the bony lamina are removed to allow adequate
visualization. The nerve root is carefully retracted away to expose
the herniated fragment and the defect in the annulus. Typically,
the cavity of the disc is entered from the tear in the annulus and
the loose fragments of the nucleus pulposus are removed with
pituitary forceps. Any additional fragments of disc sequestered
inside or outside of the disc space are also carefully removed and
the disc space is forcefully irrigated to remove to remove any
residual fragments. If tears are present in the dura, the dura is
closed with sutures that are often augmented with fibrin glue. The
tissue is then closed with absorbable sutures.
[0292] Microlumbar disc excision (microdiscectomy) can be performed
as an outpatient procedure and has largely replaced laminectomy as
the intervention of choice for herniated discs. A one inch incision
is made from the spinous process above the disc affected to the
spinous process below. Using an operating microscope, the tissue is
dissected down to the ligamentum flavum and bone is removed from
the lamina until the nerve root can be clearly identified. The
nerve root is carefully retracted and the tears in the annulus are
visualized under magnification. Microdisc forceps are used to
remove disc fragments through the annular tear and any sequestered
disc fragments are also removed. As with laminectomy, the disc
space is irrigated to remove any disc fragments, any dural tears
are repaired and the tissue is closed with absorbable sutures. It
should be noted that anterior (abdominal) approaches can also be
used for both open and endoscopic lumbar disc excision. Cervical
and thoracic disc excisions are similar to lumbar procedures and
can also be performed from a posterior approach (with laminectomy)
or as an anterior discectomy with fusion.
[0293] The present invention provides injectable compositions to
promote scarring of the annulus, scarring of dural defects and
stabilization of adjacent vertebra. The fibrosing agent or
fibrosing agent containing composition is delivered under direct
vision during open or endoscopic disc excision. Here the
composition containing the fibrosis-inducing agent is applied to
the annulus or the dural defect directly (in open surgical
procedures) or through the side port of an endoscope. The
fibrosis-inducing agent can assist in the production of strong
fibrotic tissue in the annulus fibrosis at the previous site of
herniation or rupture. This can reinforce the weak portion of the
intervertebral disc and reduce the likelihood of subsequent
re-rupture. In dural defects, the fibrosis-inducing agent can
assist in the healing of the dura and prevent complications such as
CSF leakage.
[0294] The material may also be composed of a polymer system to
provide sustained release of the fibrosis-inducing agent. The
material suitable for delivery of a fibrosis-inducing agent for the
purposes of this invention can be composed of a non-degradable or a
degradable material. Suitable non-degradable materials can include
crosslinked compositions that comprise PVA, PVP, polyacrylamide,
methyl methacrylate (MMA) and methyl methacrylate styrene
(MMA-styrene) which when mixed together form polymethyl
methacrylate (PMMA) or bone cement (e.g., SIMPLEX P ZIMMER REGULAR
or ZIMMER LOW VISCOSITY CEMENT, PALACOS, CMW-1, CMW-2 or
ENDURANCE), synthetic cancellous bone void fillers (e.g., CORTOSS),
PHEMA, poly(vinyl PEG), poly(styrene sulfonate), poly(acrylic
acid), poly(methacrylic acid), as well as other polymers that are
known to form hydrogels. Additional compositions include blends and
copolymers of the agents listed above. Suitable degradable
materials include, but are not limited to, resorbable ceramics
composed of .beta.-tricalcium phosphate (e.g., VITOSS and PROOSTEON
500R), hydroxyapatite or Ca.sub.10(PO.sub.4).sub.6OH (e.g., BIOOSS,
OSTEOGRAF), calcium carbonate or CaCO.sub.3, calcium sulfate (e.g.,
OSTEOSET and ALLOMATRIX), calcium phosphate (e.g., CALCIBON or
NORIAN SRS), crosslinked materials of PEG, gelatin, collagen, bone
allografts (e.g., ALLOGRO, ORTHOBLAST, OPTEFORM, GRAFTON),
mesenchymal stem cells, hyaluronic acid, hyaluronic acid
derivatives, polysaccharides, carbohydrates, proteins (e.g.,
albumin, casein, whey proteins, plant proteins, and fish proteins),
autologous bone, demineralized bone matrix, cellulose derivatives
(HPC etc), chitosan, chitosan derivatives, polyester-polyalkylene
oxide block copolymers (e.g., PLGA-PEG-PLGA and MePEG-PLGA, and the
like) and other low molecular weight polymers that can be
excreted.
[0295] One material that is of particular interest for use in
annulus and dural repairs during intervertebral disc surgery is an
injectable material prepared from a 4-armed thiol PEG (10K), a
4-armed NHS PEG(10K) and methylated collagen such as described
above. In a preferred embodiment, the injectable material also
contains a biologically active agent capable of inducing fibrosis
to reinforce the annulus fibrosis (to reduce the risk of repeat
herniation or rupture) or assist in the repair of dural defects (to
prevent CSF leaks). Preferred biologically active agents for use in
combination with the injectable material include fibrosis-inducing
agents and growth factors (e.g., transforming growth factor,
platelet-derived growth factor, fibroblast growth factor), whose
dosages and release kinetics are all described in detail in section
(vi) below.
[0296] The materials described above can further modified to be
comprised of, or contain, polymeric threads. Polymeric threads have
the ability to induce a fibroproliferative response in the annulus
fibrosis or the dura. These polymer threads can be degradable or
non-degradable. Degradable threads can be composed of degradable
polyesters, polyanhydrides, poly(anhydride esters),
poly(ester-amides), poly(ester-ureas), polyorthoesters,
polyphosphoesters, polyphosphazines, cyanoacrylate polymers,
collagen, chitosan, hyaluronic acid, chromic cat gut, alginates,
starch, cellulose, cellulose esters, blends and copolymers thereof,
as well as other known degradable polymers. Non-degradable polymers
that can be used include, but are not limited to, polyesters (e.g.,
PET), polyurethanes, silicones, PE, PP, PS, PM, PMA, silk, blends,
copolymers thereof. The threads used can be composed of a single
composition or composed of a blend of differing compositions. The
polymeric threads themselves can be further modified through the
addition of a polymeric coating applied to the threads. The polymer
used for coating the thread can be similar to that described above
for the threads themselves. The polymer coating may further
comprise a biologically active agent that has the ability to induce
a fibroproliferative response. The agents that can be used are
further described in the section (vi) below.
[0297] The materials described above can also be utilized to
deliver a particulate material that has the ability to induce
fibrosis. These particles can be either degradable or
non-degradable and are similar to those described above for
threads. In addition to those, particulate materials useful for the
practice of this embodiment include silk, talc, starch, glass,
silicates, silica, calcium phosphate, calcium sulfate, calcium
carbonate, hydroxyapatite, synthetic mineral (e.g., VITOSS and
CORTOSS), PMMA, silver nitrate, ceramic particles and other
inorganic particles known in the art to induce a fibroproliferative
response followed by mineralization. The particles used in this
embodiment can be all of the same composition or a blend of
differing compositions. These particles can also be used as a
coating applied to the polymeric strands as described above.
[0298] As is readily apparent, the materials used in the present
invention can also be constructed such that they are comprised of
both polymeric threads and particles. The threads and particles
used are similar to those described above and may be of uniform
composition or blended composition. Virtually any combination of
threads of differing compositions and particles of differing
compositions can be utilized in this embodiment. The hydrogels
(e.g., injectable materials prepared from a 4-armed thiol PEG
(10K), a 4-armed NHS PEG(10K) and methylated collagen), the
polymeric threads, and the particles can all be utilized to deliver
one or more biologically active agents, as described below.
[0299] Other compositions are suitable for use in open surgical
disc resection and microdiscectomy. All involve the deployment of a
biomaterial and a fibrosis-inducing agent to reinforce the annulus
fibrosis or assist in dural repair. The following compositions can
be delivered during surgical disc resection and microdiscectomy
either directly, using specialized delivery catheters, via an
endoscope, or through a needle or other applicator: (a) fluids,
suspensions, emulsions, microemulsions, microspheres, pastes, gels,
microparticulates, sprays, aerosols, solid implants and other
formulations which release a fibrosis-inducing agent(s); (b)
microparticulate silk and/or silk strands (linear, branched, and/or
coiled) either alone, or loaded with an additional
fibrosis-inducing agent and/or growth factor; (c)
collagen-containing formulations such as COSTASIS or materials made
from 4-armed thiol PEG (10K), 4-armed NHS PEG (10K) and methylated
collagen such as described above, either alone, or loaded with a
fibrosis-inducing agent and/or growth factor; (d) injectable
PEG-containing formulations such as COSEAL, FOCALSEAL, SPRAYGEL or
DURASEAL loaded with a fibrosis-inducing agent and/or growth
factor; (e) fibrinogen-containing formulations such as FLOSEAL or
TISSEAL loaded with a fibrosis-inducing agent and/or growth factor;
(f) hyaluronic acid-containing formulations such as RESTYLANE,
HYLAFORM, PERLANE, SYNVISC, SEPRAFILM, SEPRACOAT loaded with a
fibrosis-inducing agent and/or growth factor; (g) polymeric gels
for surgical implantation such as REPEL or FLOWGEL loaded with a
fibrosis-inducing agent and/or growth factor injected into the
joint space; (h) orthopedic "cements" such as OSTEOBOND, LVC,
SIMPLEX P, PALACOS, CORTOSS, and ENDURANCE loaded with a
fibrosis-inducing agent and/or growth factor; (i) surgical
adhesives containing cyanoacrylates such as DERMABOND, INDERMIL,
GLUSTITCH, VETBOND, HISTOACRYL, TISSUEMEND, TISSUMEND II,
HISTOACRYL BLUE and ORABASE SOOTHE-N-SEAL LIQUID PROTECTANT or as
described above, loaded with a fibrosis-inducing agent and/or
growth factor; (j) surgical implants containing hydroxyapatite,
calcium phosphate (such as VITOSS, Orthovita), or calcium sulfate
loaded with a fibrosis-inducing agent and/or growth factor; (k)
other biocompatible tissue fillers, such as those made by BioCure,
3M Company and Neomend loaded with a fibrosis-inducing agent and/or
growth factor; (l) polysaccharide gels such as the ADCON series of
gels loaded with a fibrosis-inducing agent and/or growth factor;
(m) films, sponges or meshes such as INTERCEED, VICRYL mesh, and
GELFOAM either alone, or loaded with a fibrosis-inducing agent,
bone morphogenic protein, and/or growth factor, injected into the
intervertebral disc; and/or (n) a hydrogel that is formed from an
amino-functionalized polyethylene glycol (e.g., 4-armed tetra-amino
PEG [10k]) and a 4-armed NHS functionalized PEG (e.g.,
pentaerythritol poly(ethylene glycol)ethertetra-succinimidyl
glutarate [10K]). This hydrogel mayfurther contain collagen,
methylated collagen and/or gelatin. This hydrogel can further
comprise the fibrosis-inducing agents described above (e.g., silk
powder or silk threads). and/or (m) films, sponges or meshes such
as INTERCEED, VICRYL mesh, and GELFOAM either alone, or loaded with
a fibrosis-inducing agent and/or growth factor.
[0300] It should be apparent to one of skill in the art that
potentially any fibrosis-inducing agents described above may be
utilized alone, or in combination, in the practice of this
embodiment. Exemplary fibrosing agents for use in spinal prostheses
(e.g., devices and bulking agents) include talc, silk, wool,
chitosan, polylysine, fibronectin, bleomycin, and CTGF, as well as
analogues and derivatives of the aforementioned.
[0301] Optionally, the device may additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone) and/or a bone morphogenic protein (BMP) (e.g.,
BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or an analogue or
derivative thereof).
[0302] Furthermore, the device may alone or additionally comprise
an agent that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof. The administration
and dosages of these agents for use in these embodiments are
described in section (vi) below.
[0303] (iii) Treatments of Vertebral Compression Fractures
[0304] Osteoporosis is a progressive degenerative bone disease
characterized by decreased bone mineral density, degradation of
bone microarchitecture and reduced bone strength. The weakened bone
is often unable to withstand stress, or even normal weight-bearing
activities, and is at an increased risk for sustaining fractures.
Fractures are the most common clinical manifestation of
osteoporosis and the condition is often asymptomatic until the
breakage occurs. Osteoporosis is the cause of 1.3 million fractures
each year in the U.S. and is estimated to cost the healthcare
system over $10 billion annually. Fractures of the hip, wrist and
other long bones are common in osteoporosis, but approximately
550,000 patients in the U.S. (700,000 worldwide) suffer vertebral
compression fractures as a result of their disease. Here, the
weakened cancellous bone of the vertebral column essentially
collapses (compresses) under the weight placed on it during normal
activities and the vertebra loses height (i.e., the center of the
vertebra collapses and the two endplates of the vertebra move
closer together). Compression of the vertebra leads to pain, a loss
of height, curvature of the spine (kyphosis), and in some cases,
breathing problems due to pressure placed on the chest cavity and
lungs.
[0305] Traditionally, vertebral compression fractures have been
treated conservatively with bed rest. In severe cases, spinal
fusion and/or open fracture reduction (repairing the fracture with
surgically placed orthopedic plates and screws) have also been used
in the management of vertebral compression fractures. Recently, two
minimally invasive procedures--vertebroplasty and kyphoplasty--have
been developed to treat vertebral compression fractures due to
osteoporosis or, less commonly, due to bone tumors. Vertebroplasty
utilizes bone cement (polymethylmethacrylate --PMMA) injected under
pressure into the fracture under x-ray guidance to stabilize the
fracture, provide support and reduce pain. This procedure can often
be performed as an outpatient and provides almost immediate
symptomatic relief and early mobilization. Kyphoplasty involves the
insertion of a balloon (KYPHX Inflatable Bone Tamp made by Kyphon
Inc., Sunnyvale, Calif.) into the fracture which is then inflated
inside the bone to create a void, stabilize the fracture and
straighten the bone and spine (i.e., restore the vertebral height
lost as a result of the compression fracture). The surgeon then
injects bone filler (typically PMMA or a calcium phosphate-based
material) via specialized access devices (Inflation Syringe and
Bone Access System also made by Kyphon, Inc. (Sunnyvale, Calif.)
into the space under C-arm image-guided fluoroscopy to support the
fractured vertebra). Injecting the bone cement into the
balloon-created cavity enables the injection to be performed under
low pressure and reduces the incidence of neurological injury
associated with cement leakage. In vertebroplasty, where the cement
is injected under pressure, cement leakage occurs in 30-73% of
patients versus only 8-9% of those treated with kyphoplasty.
[0306] In both vertebroplasty and kyphoplasty the fractured bone is
reinforced and replaced by bone cement. Unfortunately, bone cement
is significantly stronger than the adjacent bone and can exert an
incompressible mass effect on the surrounding vertebra leading to
compressions and fractures in the vertebra above and below the
treated segment. The present invention provides injectable
compositions that include a bulking or filling agent and a
fibrosing agent for direct injection into vertebral compression
fractures as part of vertebroplasty or kyphoplasty. A material
containing a fibrosis-inducing agent (alone or in combination with
polymeric carrier, which may be in the form of, e.g., a gel, paste,
or spray) is injected into a vertebral compression fracture can be
used to promote the growth of endogenous scar tissue to fill the
vertebral body defect, thus more closely mimicking normal tissue
dynamics and reducing the incidence of adjacent vertebral
fractures. In another embodiment, the injectable composition
containing a fibrosis-inducing agent can further contain an agent
that promotes bone growth (e.g., bone morphogenic proteins, growth
factors, etc.). When performing an injection into a vertebral
compression fracture, it may also be necessary to add compositions
to enhance visualization of needle (or catheter). Suitable agents
and methods for use in combination with a fibrosis-inducing agent
(with or without an agent that promotes bone growth) include, but
are not limited to, the use of a needle coated with ECHO--COAT or
the addition of contrast agents (e.g., barium, tantalum,
technitium, gadolinium) for localization by x-ray or MRI.
[0307] The injectable material may also contain a polymer system
that can provide sustained release of the fibrosis-inducing agent
(with or without a concominant bone morphogenic protein, and/or
osteogenic growth factor) to enhance efficacy and reduce the need
for repeat administrations of active agents. Preferred polymeric
carriers for delivery of a injectable fibrosis-inducing agent (with
or without a bone morphogenic protein, and/or growth factor that
promotes bone growth) for the treatment of vertebral compression
fractures are degradable materials which, after providing initial
tissue support, are gradually replaced by the body's own scar
tissue. Suitable degradable materials for use in this embodiment
include, but are not limited to, resorbable ceramics composed of
.beta.-tricalcium phosphate (e.g., VITOSS and PROOSTEON 500R),
hydroxyapatite or Ca.sub.10(PO.sub.4).sub.6OH (e.g., BIOOSS and
OSTEOGRAF), calcium carbonate or CaCO.sub.3, calcium sulfate (e.g.,
OSTEOSET and ALLOMATRIX), calcium phosphate (e.g., CALCIBON or
NORIAN SRS), crosslinked materials of PEG, gelatin, collagen, bone
allografts (e.g., ALLOGRO, ORTHOBLAST, OPTEFORM, GRAFTON),
mesenchymal stem cells, hyaluronic acid (such as RESTYLANE,
HYLAFORM, PERLANE, SYNVISC, SEPRAFILM, SEPRACOAT), hyaluronic acid
derivatives, polysaccharides, carbohydrates, fibrinogen-containing
formulations (such as FLOSEAL or TISSEAL), proteins (e.g., albumin,
casein, whey proteins, plant proteins, and fish proteins, and the
like), autologous bone, demineralized bone matrix, cellulose
derivatives (e.g., HPC etc), chitosan, chitosan derivatives,
polyester-polyalkylene oxide block copolymers (e.g., PLGA-PEG-PLGA
and MePEG-PLGA, and the like) and other low molecular weight
polymers that can be excreted. Injectable PEG-containing
formulations such as COSEAL, FOCALSEAL, SPRAYGEL or DURASEAL loaded
with a fibrosis-inducing agent, bone morphogenic protein, and/or
growth factor can also be used for injection into a vertebral
compression fracture. Loading these materials with a
fibrosis-inducing agent (with or without a bone morphogenic
protein, and/or growth factor that promotes bone growth) can
produce an injectable material that can provide initial support and
symptomatic relief, but degrade with time as the body's own scar
tissue grows in to repair the defect.
[0308] One injectable material that is of particular interest for
injection into vertebral compression fractures is prepared from a
4-armed thiol PEG (10K), a 4-armed NHS PEG(10K) and methylated
collagen such as described above. In a preferred embodiment, the
injectable material also contains a biologically active
fibrosis-inducing agent (with or without a bone morphogenic
protein, and/or growth factor that promotes bone growth). In one
embodiment, the injectable material is loaded with a
fibrosis-inducing agent is injected into a vertebral compression
fracture to provide stability and symptomatic relief, form a
scaffold that supports fibrous and bony ingrowth, deliver active
agents that can promote repair, and degrade once tissue repair is
complete. In another embodiment, the injectable material contains
biologically active agents capable of inducing bone growth such
bone morphogenic proteins and growth factors (transforming growth
factor, platelet-derived growth factor, fibroblast growth factor)
to promote bony ankylosis and fusion of adjacent vertebra. In some
circumstances, the injectable material may contain a
fibrosis-inducing agent as well as a bone morphogenic protein
and/or growth factors that promote bone growth.
[0309] In certain embodiments (for example, in the treatment of
more unstable fractures) it may be desirable to use a bone cement
to deliver the fibrosis-inducing agent to a vertebral compression
fracture. Suitable non-degradable materials include crosslinked
compositions that comprise PVA, PVP, polyacrylamide, methyl
methacrylate (MMA) and methyl methacrylate styrene (MMA-styrene)
which when mixed together form polymethyl methacrylate (PMMA) or
bone cement (e.g., SIMPLEX P, ZIMMER REGULAR and ZIMMER LOW
VISCOSITY CEMENT, PALACOS, CMW-1, CMW-2 or ENDURANCE). Also of
utility in this embodiment are synthetic cancellous bone void
fillers (e.g., CORTOSS), PHEMA, poly(vinyl PEG), poly(styrene
sulfonate), poly(acrylic acid), poly(methacrylic acid), as well as
other polymers that are known to form hydrogels. Surgical adhesives
containing cyanoacrylates such as DERMABOND, INDERMIL, GLUSTITCH,
TISSUEMEND, VETBOND, HISTOACRYL BLUE and ORABASE SOOTHE-N-SEAL
LIQUID PROTECTANT loaded with a fibrosis-inducing agent, bone
morphogenic protein, and/or growth factor are also suitable for
injection into vertebral compression fracture. Additional
compositions include blends and copolymers of the agents listed
above. In each case the material is loaded with a fibrosis-inducing
agent (with or without a bone morphogenic protein, and/or growth
factor that promotes bone growth) and injected into a vertebral
compression fracture (as part of vertebroplasty or kyphoplasty) to
stabilize the fracture and encourage the ingrowth of tissue. The
addition of fibrous tissue in and around the non-degradable implant
can make the material behave more like native tissue and reduce the
incidence of adjacent fractures.
[0310] All of the injectable materials described above can be
further modified to be comprised of, or contain, polymeric threads.
Polymeric threads have the ability to induce a fibroproliferative
response from the surrounding tissue. These polymer threads can be
degradable or non-degradable. Degradable threads can be composed of
degradable polyesters, polyanhydrides, polyorthoesters,
polyphosphoesters, polyphosphazines, cyanoacrylate polymers,
collagen, chitosan, hyaluronic acid, chromic cat gut, alginates,
starch, cellulose, cellulose esters, blends and copolymers thereof,
as well as other known degradable polymers. Non-degradable polymers
that can be used include, but are not limited to, polyesters (e.g.,
PET), polyurethanes, silicones, PE, PP, PS, PM, PMA, silk, blends,
copolymers thereof as well as other known polymers. The threads
used can be composed of a single composition or composed of a blend
of differing compositions. The polymeric threads themselves can be
further modified through the addition of a polymeric coating
applied to the threads. The polymer used for coating the thread can
be similar to that described above for the threads themselves. The
polymer coating may further comprise a biologically active agent
that has the ability to induce a fibroproliferative or osteogenic
response. The fibrosis-inducing agents that can be used are further
described in the section (vi) below.
[0311] The injectable materials described above can be utilized to
deliver a particulate material that has the ability to induce
fibrosis in an intervertebral fracture. These particles can be
either degradable or non-degradable and are similar to those
described above for threads. Microparticulate silk and/or silk
strands (linear, branched, and/or coiled) either alone, or loaded
with an additional fibrosis-inducing agent, bone morphogenic
protein, and/or growth factor are also useful for directed
injection into a vertebral compression fracture. Additional
particulate materials useful for the practice of this embodiment
include talc, starch, glass, silicates, silica, calcium phosphate,
calcium sulfate, calcium carbonate, hydroxyapatite, synthetic
mineral (e.g., VITOSS and CORTOSS), PMMA, silver nitrate, ceramic
particles and other inorganic particles known in the art to induce
a fibroproliferative response followed by mineralization. The
particles used in this embodiment can be all of the same
composition or a blend of differing compositions. These particles
can also be used as a coating applied to the polymeric strands as
described above.
[0312] The injectable materials can also be constructed such that
it is comprised of both polymeric threads and particles. The
threads and particles used are similar to those described above and
may be of uniform composition or blended composition. Virtually any
combination of threads of differing compositions and particles of
differing compositions can be utilized in this embodiment. The
hydrogels, the polymeric threads, and the particles can all be
utilized to deliver one or more biologically active agents, as
described below.
[0313] One specific composition comprising threads and/or particles
is prepared from 4-armed thiol PEG (10K), 4-armed NHS PEG(10K) and
methylated collagen such as described above and contains powdered
silk particles (or silk threads) and/or mineral particles added to
the composition prior to curing. Once deployed, the composition can
absorb water, fill the fracture space and adhere to adjacent bone.
This expansion can stabilize the fracture and restore vertebral
height, while the powdered silk and/or mineral particles can
initiate an ankylosing response. As the 4-armed thiol PEG (10K),
4-armed NHS PEG(10K) and methylated collagen composition starts to
degrade, the material can support the bone tissue ingrowth that is
initiated and potentiated by the particles. Bone morphogenic
proteins and/or growth factors (described previously and below) are
also useful for inclusion in this composition. In addition, one may
also add or replace all (or a portion) of the 4-armed thiol PEG
with a 4-armed amino PEG. The amino PEG can provide a gel that can
take a longer time to degrade and can provide some positive charge
to further attract cellular material.
[0314] A second specific embodiment consists of an injectable
implant composed of silk fibers or a polymerized version of the
fibrosing agent itself (i.e., repeating units of the fibrosing
agent polymerized together). Bone morphogenic proteins and/or
growth factors (described previously and below) may also be added
to this composition.
[0315] It should be apparent to one of skill in the art that
potentially any fibrosis-inducing agents described above may be
utilized alone, or in combination, in the practice of this
embodiment. Exemplary fibrosing agents for use in spinal prostheses
(e.g., devices and bulking agents) include talc, silk, wool,
chitosan, polylysine, fibronectin, bleomycin, and CTGF, as well as
analogues and derivatives of the aforementioned.
[0316] Optionally, the device may additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone) and/or a bone morphogenic protein (BMP) (e.g.,
BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or an analogue or
derivative thereof).
[0317] Furthermore, the device may alone or additionally comprise
an agent that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof.
[0318] The administration and dosages of these agents for use in
the above embodiments are described in section (vi) below.
[0319] (iv) Spinal Fusion Devices
[0320] In some cases, it may be necessary to promote bony fusion of
adjacent vertebral segments (in effect biologically "welding" the
segments together). Fusion of one or more vertebral segments
alleviates pain by restricting vertebral motion across the damaged
intervertebral disc(s). Surgical spinal fusion can be accomplished
using a variety of procedures, implants and devices.
[0321] Typically, the vertebral canal is exposed through open
surgery (either anteriorly and/or posteriorly) and all or parts of
the damaged disc are removed sufficient to allow decompression of
the affected cord or nerve roots. Bone grafts (autografts or
allografts) or bone substitutes are used to promote vertebral
fusion, while the fixation devices serve to immobilize the region
until bony fixation takes place. As part of the spinal fusion
surgery, it is often necessary to augment the procedure through the
insertion of an implant or device that stabilizes the fusing spinal
segments while the bone graft or bone substitute fuses the mobile
segments. Examples of implants and devices designed to splint the
segments during the healing process include: fusion devices
(including fusion baskets, fusion cage apparatus, interbody cages,
interbody implants, fusion cage anchoring devices, fusion
stabilization chamber, fusion cage anchoring plates), bone fixation
devices (including anchoring bone plates, bone screws, and other
fixation hardware) and tissue fillers/implants (including bone
cement, allograft material, autograft material, collagen, and other
biocompatible tissue fillers). All of these implants are suitable
for coating with, or delivery of, a fibrosis-inducing agent(s) to
promote healing and accelerate fusion of the vertebral bodies.
[0322] Spinal fusion cages are interbody devices that fit within
the intervertebral space and/or the anterior region of the
vertebral column. Fusion cages have various shapes including
rectangular or cylindrical and a plurality of openings and helical
threading. Fusion cages are often composed of an outer body and a
hollow cavity that may or may not be used to insert bone
growth-promoting material for stimulating bone fusion. For example,
the prosthesis may be an interbody fusion cage that has an
externally threaded stem projecting from a domed outer end which is
fixed using an assembly of a plate, a fastener and bone screws. See
e.g., U.S. Pat. No. 6,156,037. The prosthesis may be a fusion cage
with a threaded outer surface adapted for promoting fusion with
bone structures when a bone-growth-inducing substance is packed
into the cage body. See e.g., U.S. Pat. Nos. 4,961,740; 5,015,247;
4,878,915; and 4,501,269. The prosthesis may be a generally tubular
shell with a helical thread projecting with a plurality of pillars
with holes to facilitate bone ingrowth and mechanical anchoring
(see e.g., U.S. Pat. Nos. 6,071,310 and 5,489,308) or it may be
biologically active and serve to promote fusion with the adjacent
vertebral bone plates (see e.g., U.S. Pat. Nos. 5,489,308 and
6,520,993). Other U.S. patents that describe threaded spinal
implants include U.S. Pat. Nos. 5,263,953; 5,458,638; and
5,026,373.
[0323] In another aspect, the prosthesis may be a bone fixation
device designed to promote vertebral fusion in order to limit
movement between adjacent vertebrae. For example, bone dowels,
rods, hooks, wires, wedges, plates, screws and other components may
be used to fix the vertebral segments into place. The fixation
device may fit within the intervertebral space or it may encompass
both the intervertebral space and the anterior region of the
vertebral column or it may only encompass the anterior region of
the vertebral column. A bone fixation device may be used with a
fusion cage to assist in stabilizing the device within the
intervertebral area. For example, the prosthesis may be in the form
of a solid annular body having a plurality of discrete
bone-engaging teeth protruding on the superior and inferior
surfaces and having a central opening that may be filled with a
bone growth-promoting material. See e.g., U.S. Pat. No. 6,520,993.
The prosthesis may have a disk-like body with weld-like raised
parts disposed on opposite surfaces to enhance lateral stability in
situ. See e.g., U.S. Pat. No. 4,917,704. The prosthesis may be
composed of opposite end pieces that maintain the height of the
intervertebral space with an integral central element that is
smaller in diameter wherein osteogenic material is disposed within
the annular pocket between the end pieces. See e.g., U.S. Pat. No.
6,146,420. The prosthesis may be composed of first and second side
surfaces extending parallel to each other with upper and lower
surfaces that engage the adjacent vertebrae. See e.g., U.S. Pat.
No. 5,716,415. The prosthesis may be a fusion stabilization chamber
composed of a hollow intervertebral spacer and an end portion with
at least one hole for affixing into the surrounding bone. See e.g.,
U.S. Pat. No. 6,066,175. The prosthesis may be composed of a
metallic body tapering conically from the ventral to the dorsal end
and having a plurality of fishplates extending from opposite sides
with openings for bone screws. See e.g., U.S. Pat. No. 4,955,908.
The prosthesis may be composed of a pair of plates which may have
protrusions for engaging the adjacent vertebrae and an alignment
device disposed between the engaging plates for separating the
plates to maintain them in lordotic alignment. See e.g., U.S. Pat.
No. 6,576,016. The prosthesis may be a plurality of implants that
are inserted side by side into the disc space to promote bone
fusion across an intervertebral space. See e.g., U.S. Pat. No.
5,522,899. The prosthesis may be an anchoring device composed of an
anchoring plate with a central portion configured for attachment to
a vertebral implant (e.g., fusion cage) and the end portions
adapted to fasten in a fixed manner to a bony segment of the
vertebra. See e.g., U.S. Pat. No. 6,306,170. The prosthesis may be
a bone fixation apparatus composed of a bone plate and a fastener
apparatus (e.g., bone screws). See e.g., U.S. Pat. Nos. 6,342,055;
6,454,769; 6,602,257; and 6,620,163.
[0324] Spinal prostheses, which may be combined with one or more
fibrosis-inducing agents according to the present invention,
include commercially available products. Examples include: the
INTERFIX Threaded Fusion Device (by Medtronic Sofamor Danek,
Memphis, Term.), the BAK/C Cervical Interbody Fusion System and the
CERVI-LOK Cervical Fixation System (by Centerpulse SPINE-TECH,
Minneapolis, Minn.), the SC-ACUFIX Anterior Cervical Plate System
(by Spinal Concepts, Austin, Tex.), the ACROFLE TDR prostheses and
the CHARITE Artificial Disc (by DePuy Spine, Inc., Raynham, Mass.),
the PRODISC system and PRODISC Cervical-C IDE disc replacement (by
Synthes-Stratec, Switzerland) and the PROSTHETIC DISC NUCLEUS (by
Raymedica, Inc., Minneapolis, Minn.).
[0325] In all of the aforementioned spinal fusion devices, the
addition of a fibrosis-inducing agent may assist in the spinal
fusion process by promoting the production of fibrous tissue. In
one aspect, the present invention provides spinal fusion devices
(including fusion baskets, fusion cage apparatus, interbody cages,
interbody implants, fusion cage anchoring devices, fusion
stabilization chamber, fusion cage anchoring plates; bone fixation
devices including anchoring bone plates, bone screws, and other
fixation hardware; and tissue fillers/implants including bone
cement, allograft material, autograft material, collagen, and other
biocompatible tissue fillers) that include a fibrosis-inducing
agent or a composition that includes a fibrosis-inducing agent to
promote scarring and fixation of the device into the surrounding
bone. In one aspect, a spinal fusion device is coated with a
fibrosing agent or a composition that includes the fibrosing agent
to enhance healing. In another aspect, the fibrosing agent may be
incorporated into the glue/cement that holds the spinal fusion
device in place. In another aspect, the spinal fusion device is
covered (all or in part) with a silk mesh or lattice to encourage
scarring and anchoring into the surrounding bone. For example, a
silk mesh or lattice can be coated onto all or a portion of the
surface of fusion cage or other bone fixation hardware to encourage
scarring and anchoring into the surrounding bone.
[0326] Numerous polymeric and non-polymeric carrier systems
described previously can be used to provide sustained release of
the fibrosis-inducing agent from the spinal fusion device. Methods
for incorporating fibrosing compositions onto or into the spinal
fusion devices include: (a) directly affixing to the device a
fibrosing composition (e.g., by either a spraying process or
dipping process as described above, with or without a carrier); (b)
directly incorporating into the device a fibrosing composition
(e.g., by either a spraying process or dipping process as described
above, with or without a carrier); (c) by coating the device with a
substance such as a hydrogel which can in turn absorb the fibrosing
composition; (d) by interweaving a fibrosing composition (for
example a silk strand or another polymeric thread which releases a
fibrosis-inducing agent) into the device structure; (e) by
inserting the device into a sleeve or mesh which is comprised of,
or coated with, a fibrosing composition; (f) constructing the
device itself, or a portion of the device, with a fibrosing
composition; or (g) by covalently binding the fibrosing agent
directly to the device surface, or to a linker (small molecule or
polymer) that is coated or attached to the device surface. For
these devices, the coating process can be performed in such a
manner as to (a) coat the surfaces of the device that is in contact
with the bone, (b) coat the surfaces of the device that are not in
contact with the bone or (c) coat all or parts of both the
bone-contacting and non-bone contacting surfaces of the device.
[0327] In addition to coating the spinal fusion device with the
fibrosing composition, the fibrosis-inducing agent can be mixed
with the materials that are used in the construction of the device
such that the fibrosing agent is incorporated into the final
device.
[0328] It should be apparent to one of skill in the art that
potentially any adhesion or fibrosis-inducing agents described
above may be utilized alone, or in combination, in the practice of
this embodiment. Exemplary fibrosing agents for use in spinal
fusion devices (including fusion baskets, fusion cage apparatus,
interbody cages, interbody implants, fusion cage anchoring devices,
fusion stabilization chamber, fusion cage anchoring plates; bone
fixation devices including anchoring bone plates, bone screws, and
other fixation hardware; and tissue fillers/implants including bone
cement, allograft material, autograft material, collagen, and other
biocompatible tissue fillers) include talc, silk, wool, chitosan,
polylysine, fibronectin, bleomycin, and CTGF, as well as analogues
and derivatives of the aforementioned.
[0329] Optionally, the device may additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone) and/or a bone morphogenic protein (BMP) (e.g.,
BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or an analogue or
derivative thereof).
[0330] Furthermore, the device may alone or additionally comprise
an agent that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof.
[0331] The administration and dosages of these agents for use in
these embodiments are described in section (vi) below.
[0332] (v) Intervertebral Disc Prostheses
[0333] In certain cases of DDD, the damaged vertebral segment may
be treated using a intervertebral disc prosthesis that maintains
vertebral anatomy and movement within the vertebral joint. This is
often conducted when damage to more than one vertebral segment
occurs. As used herein, the term "intervertebral disc prostheses"
(or "artificial disc") refers to implants and/or devices that are
located in, on, or near the spine and which enhance the ability of
the spine to perform its function in the patient. Examples of
intervertebral disc prostheses include, without limitation,
artificial spinal discs and related devices including vertebral
implants, vertebral disc prostheses, lumbar disc implants, cervical
disc implants, implantable intervertebral prostheses, spinal
prostheses, artificial discs, prosthetic implants, prosthetic
spinal discs, spinal disc endoprostheses, spinal implants,
artificial spinal discs, intervertebral implants, implantable
spinal grafts, artificial lumbar discs, spinal nucleus implants,
and intervertebral disc spacers.
[0334] An artificial disc suitable for combining with a
fibrosis-inducing agent according to the present invention may be
composed of a single material or several materials including,
without limitation, allograft bone material (see e.g., U.S. Pat.
No. 6,143,033), metals (see e.g., U.S. Pat. No. 4,955,908), and/or
synthetic materials (see e.g., U.S. Pat. Nos. 6,264,695; 6,419,706;
5,824,093; and 4,911,718). The prosthesis must be biocompatible and
may consist of biodegradable or non-biodegradable components
depending on the intended function of the device. See e.g., U.S.
Pat. No. 4,772,287. The intervertebral disc prosthesis may be
biologically inert and serve as a mechanical means of stabilizing
the vertebral column (see e.g., U.S. Pat. Nos. 4,955,908 and
5,716,415) or as a means of preserving spinal function. In another
aspect, the prosthesis may be an alternative to spinal fusion. The
prosthesis may be a disc designed to provide normal movement
between vertebral bone plates. The artificial disc may be intended
to mimic the natural shock absorbent function of the natural disc.
The artificial disc may be composed of a center core and end
elements that support the disc against the adjacent vertebra or it
may be intended to replace only a portion of the natural
intervertebral disc (e.g., nucleus pulposus). For example, the
artificial disc may be in the form of an elastomeric section
sandwiched between two rigid plates. See e.g., U.S. Pat. Nos.
6,162,252; 5,534,030; 5,017,437; and 5,031,437. The intervertebral
disc prosthesis may be an elongated prosthetic disc nucleus
composed of a hydrogel core and a constraining flexible jacket that
allows the core to deform and reform. See e.g., U.S. Pat. No.
5,824,093. The artificial disc may be composed of a rigid superior
and inferior concaval-convex elements and a nuclear body which is
located between the concave surfaces to permit movement. See e.g.,
U.S. Pat. No. 6,156,067. The artificial disc may be a partial
spinal prosthesis composed of a core made of an elastic material
such as silicone polymer or an elastomer which is covered by a
casing made of a rigid material which is in contact with the
adjacent vertebrae. See e.g., U.S. Pat. No. 6,419,706. The
intervertebral disc prosthesis may replace only the nucleus
pulposus tissue by using a spinal nucleus implant comprised of a
swellable, biomimetic plastic with a hydrophobic and hydrophilic
phase which can be expanded in situ to conform to the natural size
and shape. See e.g., U.S. Pat. No. 6,264,695. The artificial disc
may be composed of a central core formed from a biocompatible
elastomer wrapped by multi-layered laminae made from elastomer and
fibers. See e.g., U.S. Pat. No. 4,911,718. The intervertebral disc
prosthesis may be composed of a fluid-filled inner bladder with an
outer layer of strong, inert fibers intermingled with a
bioresorbable material which promotes tissue ingrowth. See e.g.,
U.S. Pat. No. 4,772,287.
[0335] In one aspect, the present invention provides intervertebral
disc prostheses that include a fibrosis-inducing agent or a
composition that includes a fibrosis-inducing agent to promote
scarring and fixation of the device into the surrounding bone and
yet retain the flexibility of the natural disc. In one aspect, an
artificial disc is coated with a fibrosis-inducing agent (or a
composition that includes a fibrosis-inducing agent) to enhance
healing and the formation of fibrous tissue similar to the annulus
fibrosis. In another aspect, the fibrosing agent may be
incorporated into the glue/cement that holds the artificial disc in
place. In another aspect, the intervertebral disc prosthesis is
covered (all or in part) with a silk mesh or lattice to encourage
scarring and anchoring of the implant into the surrounding
bone.
[0336] Numerous polymeric and non-polymeric carrier systems
described previously can be used to provide sustained release of
the fibrosis-inducing agent from the artificial disc. Methods for
incorporating fibrosing compositions onto or into intervertebral
disc prostheses include: (a) directly affixing to the device a
fibrosing composition (e.g., by either a spraying process or
dipping process as described above, with or without a carrier); (b)
directly incorporating into the device a fibrosing composition
(e.g., by either a spraying process or dipping process as described
above, with or without a carrier); (c) by coating the device with a
substance such as a hydrogel which can in turn absorb the fibrosing
composition; (d) by interweaving a fibrosing composition (for
example a silk strand or another polymeric thread which releases a
fibrosis-inducing agent) into the device structure; (e) by
inserting the device into a sleeve or mesh which is comprised of,
or coated with, a fibrosing composition; (f) constructing the
device itself, or a portion of the device, with a fibrosing
composition; or (g) by covalently binding the fibrosing agent
directly to the device surface, or to a linker (small molecule or
polymer) that is coated or attached to the device surface. For
these devices, the coating process can be performed in such a
manner as to (a) coat the surfaces of the device that is in contact
with the vertebral bone, (b) coat the surfaces of the device that
are not in contact with the bone or (c) coat all or parts of both
the bone-contacting and non-bone contacting surfaces of the
device.
[0337] In addition to coating the artificial disc with the
fibrosing composition, the fibrosing agent can be mixed with the
materials that are used to make the device such that the fibrosing
agent is incorporated into the final prosthetic intervertebral
disc.
[0338] In one embodiment, the therapeutic agent can be incorporated
directly into the formulation (for example, direct incorporation of
the fibrosis-inducing agent into the swellable, biomimetic polymers
used to create an artificial nucleus pulposus tissue that expands
in situ to conform to the natural size and shape of the
intervertebral disc core). In another embodiment, the
fibrosis-inducing agent can be incorporated into a secondary
carrier (e.g., micelles, liposomes, emulsions, microspheres,
nanospheres etc, as described above) that are then used in the
construction of, or as constituents of, an artificial disc.
[0339] It should be apparent to one of skill in the art that
potentially any fibrosis-inducing agents described above may be
utilized alone, or in combination, in the practice of this
embodiment. Exemplary fibrosing agents for use in spinal prostheses
(e.g., devices and bulking agents) include talc, silk, wool,
chitosan, polylysine, fibronectin, bleomycin, and CTGF, as well as
analogues and derivatives of the aforementioned.
[0340] Optionally, the device may additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone) and/or a bone hormone) and/or a bone morphogenic
protein (BMP) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or
an analogue or derivative thereof).
[0341] Furthermore, the device may alone or additionally comprise
an agent that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof.
[0342] The administration and dosages of these agents for use in
these embodiments are described in section (vi) below.
[0343] (vi) Fibrosis-inducing Agents for Use in Spinal
Conditions
[0344] As spinal prostheses and injectables are made in a variety
of configurations and sizes, the exact dose administered can vary
with the amount injected or with the device size, surface area and
design. However, certain principles can be applied in the
application of this art. Drug dose can be calculated as a function
of dose per unit area (of the portion of the device being coated),
total drug dose administered can be measured, and appropriate
surface concentrations of active drug can be determined. Regardless
of the method of application of the drug to the spinal prostheses,
the exemplary fibrosing agents, used alone or in combination,
should be administered under the following dosing guidelines:
[0345] Utilizing talc as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of talc delivered from
a spinal prosthesis, or coated onto the surface of a spinal
prosthesis, should not exceed 100 mg (range of 1 .mu.g to 100 mg).
In one embodiment, the total amount of talc released from the
prosthesis should be in the range of 10 .mu.g to 50 mg. The dose
per unit area of the device (i.e., the dosage of talc as a function
of the surface area of the portion of the device to which drug is
applied and/or incorporated) should fall within the range of 0.05
.mu.g-10 .mu.g per mm.sup.2 of surface area coated. In another
embodiment, talc should be applied to a spinal prosthesis surface
at a dose of 0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area
coated. In one embodiment, talc is released from the surface of a
spinal prosthesis or from composition (e.g., a bulking agent) such
that fibrosis in the tissue is promoted for a period ranging from
several hours to several months. Drug concentrations in a bulking
agent or other such material should be within the range described
above except values are in mm.sup.3. For example, talc may be
released in effective concentrations for a period ranging from 1
hour-30 days. It should be readily evident given the discussions
provided herein that analogues and derivatives of talc (as
described previously) with similar functional activity can be
utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound
(e.g., a compound twice as potent as talc is administered at half
the above parameters, a compound half as potent as talc is
administered at twice the above parameters, etc.).
[0346] Utilizing silk as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of silk delivered from
a spinal prosthesis, or coated onto the surface of a spinal
prosthesis, should not exceed 100 mg (range of 1 .mu.g to 100 mg).
In one embodiment, the total amount of silk released from the
prosthesis should be in the range of 10 .mu.g to 50 mg. The dose
per unit area of the device (i.e., the dosage of silk as a function
of the surface area of the portion of the device to which drug is
applied and/or incorporated) should fall within the range of 0.05
.mu.g-10 .mu.g per mm.sup.2 of surface area coated. In another
embodiment, silk should be applied to a spinal prosthesis surface
at a dose of 0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area
coated. As specific (polymeric and non-polymeric) drug delivery
vehicles and specific medical devices can release silk at differing
rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the spinal
prosthesis such that a minimum concentration of 0.01 nM to 1000
.mu.M of silk is delivered to the tissue. In one embodiment, silk
is released from the surface of a spinal prosthesis or from an
injectable composition (e.g., a bulking agent) such that fibrosis
in the tissue is promoted for a period ranging from several hours
to several months. For example, silk may be released in effective
concentrations for a period ranging from 1 hour-30 days. It should
be readily evident given the discussions provided herein that
analogues and derivatives of silk (as described previously) with
similar functional activity can be utilized for the purposes of
this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as silk is administered at half the above parameters, a compound
half as potent as silk is administered at twice the above
parameters, etc.).
[0347] Utilizing chitosan as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of chitosan delivered
from a spinal prosthesis, or coated onto the surface of a spinal
prosthesis, should not exceed 100 mg (range of 1 .mu.g to 100 mg).
In one embodiment, the total amount of chitosan released from the
prosthesis should be in the range of 10 .mu.g to 50 mg. The dose
per unit area of the device (i.e., the dosage of chitosan as a
function of the surface area of the portion of the device to which
drug is applied and/or incorporated) should fall within the range
of 0.05 .mu.g-10 .mu.g per mm.sup.2 of surface area coated. In
another embodiment, chitosan should be applied to a spinal
prosthesis surface at a dose of 0.05 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific medical devices
can release chitosan at differing rates, the above dosing
parameters should be utilized in combination with the release rate
of the drug from the spinal prosthesis such that a minimum
concentration of 0.01 nM to 1000 .mu.M of chitosan is delivered to
the tissue. In one embodiment, chitosan is released from the
surface of a spinal prosthesis or from an injectable composition
(e.g., a bulking agent) such that fibrosis in the tissue is
promoted for a period ranging from several hours to several months.
For example, chitosan may be released in effective concentrations
for a period ranging from 1 hour-30 days. It should be readily
evident given the discussions provided herein that analogues and
derivatives of chitosan (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
chitosan is administered at half the above parameters, a compound
half as potent as chitosan is administered at twice the above
parameters, etc.).
[0348] Utilizing polylysine as an exemplary fibrosis-inducing
agent, whether it is applied using a polymer coating, incorporated
into the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of polylysine delivered
from a spinal prosthesis, or coated onto the surface of a spinal
prosthesis, should not exceed 100 mg (range of 1 .mu.g to 100 mg).
In one embodiment, the total amount of polylysine released from the
prosthesis should be in the range of 10 .mu.g to 50 mg. The dose
per unit area of the device (i.e., the dosage of polylysine as a
function of the surface area of the portion of the device to which
drug is applied and/or incorporated) should fall within the range
of 0.05 .mu.g-10 .mu.g per mm.sup.2 of surface area coated. In
another embodiment, polylysine should be applied to a spinal
prosthesis surface at a dose of 0.05 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific medical devices
can release polylysine at differing rates, the above dosing
parameters should be utilized in combination with the release rate
of the drug from the spinal prosthesis such that a minimum
concentration of 0.01 nM to 1000 .mu.M of polylysine is delivered
to the tissue. In one embodiment, polylysine is released from the
surface of a spinal prosthesis or from a composition (e.g., a
bulking agent) such that fibrosis in the tissue is promoted for a
period ranging from several hours to several months. For example,
polylysine may be released in effective concentrations for a period
ranging from 1 hour-30 days. It should be readily evident given the
discussions provided herein that analogues and derivatives of
polylysine (as described previously) with similar functional
activity can be utilized for the purposes of this invention; the
above dosing parameters are then adjusted according to the relative
potency of the analogue or derivative as compared to the parent
compound (e.g., a compound twice as potent as polylysine is
administered at half the above parameters, a compound half as
potent as polylysine is administered at twice the above parameters,
etc.).
[0349] Utilizing fibronectin as an exemplary fibrosis-inducing
agent, whether it is applied using a polymer coating, incorporated
into the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of fibronectin
delivered from a spinal prosthesis, or coated onto the surface of a
spinal prosthesis, should not exceed 100 mg (range of 1 .mu.g to
100 mg). In one embodiment, the total amount of fibronectin
released from the prosthesis should be in the range of 10 .mu.g to
50 mg. The dose per unit area of the device (i.e., the dosage of
fibronectin as a function of the surface area of the portion of the
device to which drug is applied and/or incorporated) should fall
within the range of 0.05 .mu.g-10 .mu.g per mm.sup.2 of surface
area coated. In another embodiment, talc should be applied to a
spinal prosthesis surface at a dose of 0.05 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific medical devices
can release fibronectin at differing rates, the above dosing
parameters should be utilized in combination with the release rate
of the drug from the spinal prosthesis such that a minimum
concentration of 0.01 nM to 1000 .mu.M of fibronectin is delivered
to the tissue. In one embodiment, fibronectin is released from the
surface of a spinal prosthesis or from a composition (e.g., a
bulking agent) such that fibrosis in the tissue is promoted for a
period ranging from several hours to several months. For example,
fibronectin may be released in effective concentrations for a
period ranging from 1 hour-30 days. It should be readily evident
given the discussions provided herein that analogues and
derivatives of fibronectin (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
fibronectin is administered at half the above parameters, a
compound half as potent as fibronectin is administered at twice the
above parameters, etc.).
[0350] Utilizing bleomycin as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of bleomycin delivered
from a spinal prosthesis, or coated onto the surface of a spinal
prosthesis, should not exceed 100 mg (range of 0.01 .mu.g to 100
mg). In one embodiment, the total amount of bleomycin released from
the prosthesis should be in the range of 0.10 .mu.g to 50 mg. The
dose per unit area of the device (i.e., the dosage of bleomycin as
a function of the surface area of the portion of the device to
which drug is applied and/or incorporated) should fall within the
range of 0.005 .mu.g-10 .mu.g per mm.sup.2 of surface area coated.
In another embodiment, bleomycin should be applied to a spinal
prosthesis surface at a dose of 0.005 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific medical devices
can release bleomycin at differing rates, the above dosing
parameters should be utilized in combination with the release rate
of the drug from the spinal prosthesis such that a minimum
concentration of 0.001 nM to 1000 .mu.M of bleomycin is delivered
to the tissue. In one embodiment, bleomycin is released from the
surface of a spinal prosthesis or from a composition (e.g., a
bulking agent) such that fibrosis in the tissue is promoted for a
period ranging from several hours to several months. For example,
bleomycin may be released in effective concentrations for a period
ranging from 1 hour-30 days. It should be readily evident given the
discussions provided herein that analogues and derivatives of
bleomycin (as described previously) with similar functional
activity can be utilized for the purposes of this invention; the
above dosing parameters are then adjusted according to the relative
potency of the analogue or derivative as compared to the parent
compound (e.g., a compound twice as potent as bleomycin is
administered at half the above parameters, a compound half as
potent as bleomycin is administered at twice the above parameters,
etc.).
[0351] Utilizing CTGF as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of CTGF delivered from
a spinal prosthesis, or coated onto the surface of a spinal
prosthesis, should not exceed 100 mg (range of 0.01 .mu.g to 100
mg). In one embodiment, the total amount of CTGF released from the
prosthesis should be in the range of 0.10 .mu.g to 50 mg. The dose
per unit area of the device (i.e., the dosage of CTGF as a function
of the surface area of the portion of the device to which drug is
applied and/or incorporated) should fall within the range of 0.005
.mu.g-10 .mu.g per mm.sup.2 of surface area coated. In another
embodiment, CTGF should be applied to a spinal prosthesis surface
at a dose of 0.005 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area
coated. As specific (polymeric and non-polymeric) drug delivery
vehicles and specific medical devices can release CTGF at differing
rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the spinal
prosthesis such that a minimum concentration of 0.001 nM to 1000
.mu.M of CTGF is delivered to the tissue. In one embodiment, CTGF
is released from the surface of a spinal prosthesis or from a
composition (e.g., a bulking agent) such that fibrosis in the
tissue is promoted for a period ranging from several hours to
several months. For example, CTGF may be released in effective
concentrations for a period ranging from 1 hour-30 days. It should
be readily evident given the discussions provided herein that
analogues and derivatives of CTGF (as described previously) with
similar functional activity can be utilized for the purposes of
this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as CTGF is administered at half the above parameters, a compound
half as potent as CTGF is administered at twice the above
parameters, etc.).
[0352] As described above, the device may additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone) and/or a bone morphogenic protein (BMP) (e.g.,
BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or an analogue or
derivative thereof.
[0353] Bone morphogenic protein(s) (e.g., BMP-2, BMP-3, BMP-4,
BMP-5, BMP-6, or BMP-7 or an analogue or derivative thereof) are to
be used in formulations at concentrations that range from 0.001
.mu.g/ml to approximately 20 mg/ml depending on the specific
clinical application, formulation type (e.g., gel, liquid, solid,
semi-solid), formulation chemistry, duration of required
application, type of medical device interface and formulation
volume and or surface area coverage required. Preferably, the bone
morphogenic protein is released in effective concentrations for a
period ranging from 1-180 days. The total dose for a single
application is typically not to exceed 500 mg (range of 0.001 .mu.g
to 500 mg); preferred 1 .mu.g to 250 mg. When used as a device
coating, the dose is per unit area of 0.001 .mu.g-1000 .mu.g per
mm.sup.2; with a preferred dose of 0.01 .mu.g/mm.sup.2-200
.mu.g/mm.sup.2. Minimum concentration of 10.sup.-9-10.sup.-4 M of
bone morphogenic protein is to be maintained on the device
surface.
[0354] Inflammatory cytokines are to be used in formulations at
concentrations that range from 0.0001 .mu.g/ml to approximately 20
mg/ml depending on the specific clinical application, formulation
type (e.g., gel, liquid, solid, semi-solid), formulation chemistry,
duration of required application, type of medical device interface
and formulation volume and or surface area coverage required.
Preferably, the inflammatory cytokine is released in effective
concentrations for a period ranging from 1-180 days. The total dose
for a single application is typically not to exceed 500 mg (range
of 0.0001 .mu.g to 100 mg); preferred 0.001 .mu.g to 50 mg. When
used as a device coating, the dose is per unit area of 0.0001
.mu.g-500 .mu.g per mm.sup.2; with a preferred dose of 0.001
.mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-10-10.sup.-4 g/ml of inflammatory cytokine is to be
maintained on the device surface.
[0355] Furthermore, the device may alone or additionally comprise
an agent that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof. Doses used are those
concentrations which are demonstrated to stimulate cell
proliferation (see Example 16). The proliferative agents are to be
used in formulations at concentrations that range from 0.1 ng/ml to
25 mg/ml depending on the specific clinical application,
formulation type (e.g., gel, liquid, solid, semi-solid),
formulation chemistry, duration of required application, type of
medical device interface and formulation volume and or surface area
coverage required. Preferably, the proliferative agent is released
in effective concentrations for a period ranging from 1-180 days.
The total dose for a single application is typically not to exceed
500 mg (range of 0.0001 .mu.g to 200 mg); preferred 0.001 .mu.g to
100 mg. When used as a device coating, the dose is per unit area of
0.00001 .mu.g-500 .mu.g per mm.sup.2; with a preferred dose of
0.0001 .mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-11-10.sup.-6 M of proliferative agent is to be maintained
on the device surface.
[0356] It should be readily evident to one of skill in the art that
any of the previously described fibrosis inducing agents, or
derivatives and analogues thereof, can be utilized to create
variations of the above compositions without deviating from the
spirit and scope of the invention. It should also be apparent that
the agent can be utilized in a composition with or without polymer
carrier and that altering the carrier does not deviate from the
scope of this invention. Briefly then, some aspects of the present
invention are: a method comprising introducing into an
intervertebral disc space of a patient in need thereof, a
therapeutically effective amount of a fibrosing agent or a
composition comprising a fibrosing agent, where the fibrosing agent
induces a fibrotic response at the intervertebral disc space of the
patient, thereby providing the patient with a beneficial result.
Optionally, any one or more of the following criteria may be used
to describe this aspect of the invention: the beneficial result is
the repair of a spinal disc; the beneficial result is fibrous
ankylosis; the beneficial result is bony ankylosis; the agent
promotes regeneration; the agent promotes angiogenesis; the agent
promotes fibroblast migration; the agent promotes fibroblast
proliferation; the agent promotes deposition of extracellular
matrix (ECM); the agent promotes remodeling, i.e., the maturation
and organization of fibrous tissue; the agent is an arterial vessel
wall irritant; the fibrosing agent is or comprises silk; the
fibrosing agent is or comprises silkworm silk; the fibrosing agent
is or comprises spider silk; the fibrosing agent is or comprises
recombinant silk; the fibrosing agent is or comprises raw silk; the
fibrosing agent is or comprises hydrolyzed silk; the fibrosing
agent is or comprises acid-treated silk; the fibrosing agent is or
comprises acylated silk; the fibrosing agent is in the form of
strands; the fibrosing agent is in the form of tufts; the fibrosing
agent is in the form of microparticulates; the fibrosing agent is
or comprises mineral particles; the fibrosing agent is or comprises
talc; the fibrosing agent is or comprises chitosan; the fibrosing
agent is or comprises polylysine; the fibrosing agent is or
comprises fibronectin; the fibrosing agent is or comprises
bleomycin; the fibrosing agent is or comprises CTGF; the fibrosing
agent is in the form of a thread, or is in contact with a thread
where, optionally, the thread is biodegradable (e.g., it comprises
a material selected from the group consisting of polyester,
polyanhydride, poly(anhydride ester), poly(ester-amide),
poly(ester-urea), polyorthoester, polyphosphoester,
polyphosphazine, polycyanoacrylate, collagen, chitosan, hyaluronic
acid, chromic cat gut, alginate, starch, cellulose and cellulose
ester) or the thread is non-biodegradable (e.g., it comprises a
material selected from the group consisting of polyester,
polyurethane, silicone, polyethylene, polypropylene, polystyrene,
polyacrylate, polymethacrylate, and silk), the thread is coated
with a polymer, the thread is coated with a pharmaceutical agent
that induces a fibrotic response in the patient, the thread is
coated with a pharmaceutical agent that induces an osteogenic
response in the patient; the composition further comprises an agent
that promotes bone growth; the agent that promotes bone growth is a
bone morphogenic protein or the agent that promotes bone growth is
an osteogenic growth factor (e.g., transforming growth factor,
platelet-derived growth factor, and fibroblast growth factor); the
composition further comprises a pharmaceutical agent that induces
sclerosis (a sclerosant, e.g., a sclerosant is selected from the
group consisting of ethanol, dimethyl sulfoxide, sucrose, sodium
chloride, dextrose, glycerin, minocycline, tetracycline,
doxycycline, polidocanol, sodium tetradecyl sulfate, sodium
morrhuate, and sotradecol, or the sclerosant may be a surfactant);
the composition further comprises an inflammatory cytokine (e.g.,
an inflammatory cytokine selected from the group consisting of
TGF.beta., PDGF, VEGF, bFGF, TNF.alpha., NGF, GM-CSF, IGF-a, IL-1,
IL-1-.beta., IL-8, IL-6, and growth hormone); the composition
further comprises an agent that stimulates cell proliferation
(e.g., a cell proliferation agent selected from the group
consisting of dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof); the composition
further comprises a bulking agent; the composition further
comprises a sealant; the composition further comprises a polymeric
carrier; the composition further comprises a resorbable ceramic;
the composition further comprises a contrast agent; the composition
further comprises a thread; the composition is in the form of a
gel; the composition is in the form of a paste; the composition is
in the form of a spray; the composition is in the form of an
aerosol; the composition is in the form of a suspension; the
composition is in the form of an emulsion or microemulsion; the
composition is in the form of a microsphere; the composition is in
the form of a microparticulate; the composition is in the form of a
solid implant.
[0357] 2. Joint Implants
[0358] The present invention provides for the combination of a
fibrosis-inducing agent and a prosthetic joint implant. As used
herein, the term "joint implants" refer to implants that are
designed to replace joints that have been physically impaired or
damaged. Examples of joint implants include, without limitation,
orthopedic implants, orthopedic prostheses, modular implants,
prosthetic joints, modular prostheses, joint prostheses, partial
prostheses, hip implants, knee implants, shoulder implants and
digit implants. Other types of orthopedic implants that may be used
in conjunction with joint implants include, e.g., hardware, such as
internal and external fixation devices, pins, plates and
screws.
[0359] In one aspect, the orthopedic implant is an internal
fixation implant. Internal fixation implants are medical devices
that can be implanted (usually permanently) into a patient in
minimally invasive orthopedic reconstructions and are often
indicated for immobilization and stabilization of extremity
fractures and unstable fractures.
[0360] Representative examples of internal fixation implants
include intramedullary fixation devices such as intermedullary
nails and plate and screw combinations; intramedullary rods,
vertical transarticular pins for stabilization of severe ankle
fractures, plates (e.g., plates made from titanium, stainless
steel, and the like), plates with prongs to support subchondral
bone, dorsal plates for volar applications, elastic plates, screws,
clips, pins, staples, pegs, wires, sublaminar wires, and metal
prostheses for holding vertebrae in place.
[0361] Internal fixation implants may be used in a variety of open
reduction internal fixation (ORIF) procedures. Open reduction
internal fixation is a method of surgically repairing a fractured
bone that typically involves either the use of plates and screws or
an intramedullary (IM) rod to align and stabilize fractures. For
example, IM rods can be inserted into the bone marrow canal in the
center of the long bones of the extremities (e.g., femur or
tibia).
[0362] In another aspect, the orthopedic implant is a component
(e.g., a pin, wire, stopper, or dowel) of an external fixation
device or an implanted portion (i.e., a portion that is situated
within the body of the patient) of an external fixation device
(also referred to herein as an "external fixation implant").
External fixation devices are medical devices that can be used to
immobilize bones to allow a fracture to heal. External fixation
devices are used in a variety of minimally invasive orthopedic
surgeries as an alternative to other types of fixation devices,
such as casts and internal fixation devices.
[0363] Briefly, external fixation may be accomplished by placing
pins or screws into the bone on both sides of the fracture. The
pins are then secured together outside the skin with clamps and
rods which can form an external frame.
[0364] An external fixation device typically includes a scaffold or
frame that has attached to it wires, pins, and the like which is
placed outside of an extremity, such as a limb. The device remains
in place until healing has occurred, at which point it is then
removed, leaving no foreign material in the extremity.
[0365] External fixation devices may take a variety of forms and
may have monolateral, multiplanar or hybrid constructions. A
monolateral fixation device includes a bar or rail with attached
pins that transfix a bone (e.g., a femur). A multiplanar external
fixation device can include rings or sections of rings, with
attached pins and/or wires, which are used to secure fixation of a
bone. A hybrid system can include a frame consisting of both rings
(multiplanar) and bars (monolateral).
[0366] External fixation devices also may be classified by their
function, for example, the device may be stationary or moving.
Stationary devices may be used for alignment of the bony fragments
(e.g., for acute stabilization of fractures) and remain in place
from the time of application to removal. Moving fixation devices,
in contrast, may be used in gradual reduction of acute extremity
fractures. The configuration of a moving fixation device can change
over time for gradual correction.
[0367] External fixation devices may be used to treat a variety of
conditions. For example, an external fixation device may be used
for the fixation of injuries such as joint fractures. External
fixation can provide for acute or gradual fracture reduction. In
particular, external fixation devices may be used in the treatment
of juxta-articular fractures, open fractures, and fractures with
bone loss, including, for example, fractures near joints such as
distal radius, proximal tibial plateau, and distal tibial pilon
fractures. Other applications of external fixation devices include
reconstructive orthopedic procedures such as treatment of
deformities, bone loss, contractures, treatment of non-unions
(hypertrophic or atrophic), and limb length discrepancy.
[0368] A modular prosthesis is a prosthesis that has multiple (two
or more) components, which can be assembled to form a unitary
biomechanical structure. Various features of the components can be
adjusted by the surgeon prior to implantation of the prosthesis so
as to accommodate the needs of each patient. For example, a modular
prosthesis can have component that can be independently adjusted
(rotationally and axially) by the surgeon, or the length of a
component may be changed. Modular prostheses can be used in a
variety of surgical procedures. The modular prosthesis may be an
adjustable long bone prosthesis that can be adjusted within the
patient to account for discrepancies in the measurement of a long
bone to be replaced. Prosthetic joints having modular components
exist for replacement of the hip, knee, and ankle joints. Other
representative examples of modular orthopedic prostheses include a
modular femoral stem, modular shoulder prosthesis, and modular
elbow prostheses.
[0369] The long-term cause of failure for many artificial joints is
loosening occurring over time between the implant and the
surrounding bone that anchors the implant in place. Inadequate bone
and tissue growth may lead to unsuccessful acute incorporation of
the implant or late loosening may occur with time. In the case of
the hip, for example, up to 5% of patients can suffer from joint
loosening by 10 years post implant. Symptoms include pain that can
become debilitating and ultimately lead to repeat surgery and
possible revision of the implant.
[0370] (i) Hip Implants
[0371] In artificial hip joints, the hip implant replaces the head
of femur (i.e., ball) and/or the acetabulum (i.e., socket) of the
joint. Typically the hip joint is replaced due to irreparable
damage caused by non-inflammatory degenerative joint disease (e.g.,
osteoarthritis, post traumatic arthritis), inflammatory
degenerative joint disease (e.g., rheumatoid arthritis, infectious
arthritis), trauma (e.g., fracture of the pelvis or hip),
congenital hip dysplasia, or joint dislocation and other
fracture-induced damage to the femur and/or acetabulum. Hip
implants typically include two or three component systems, which
include the femoral stem or shank, the femoral neck, and the
spherical ball which adapts to the acetabulum or prosthetic
acetabular cup. The femoral stem, neck and ball, as well as the
acetabular cup may be composed of metal (e.g., titanium, titanium
alloy, cobalt-chromium or chromium-molybdenum) or polymer
composite. To fix the hip implant to the existing femur of the
host, the hip implant may be cemented into the bone using bone
cement (e.g., methylmethacrylate) or the hip implant may be fixed
using a cementless surface treatment (e.g., porous coating, such as
hydroxyapatite porous coating, or spongy coating) whereby the hip
implant allows bony growth from the femur to anchor it into
place.
[0372] In one aspect, hip implants may be used to provide a full
hip replacement. For example, the hip implant may be a
three-modular designed total prosthesis with primary fixation,
which may include a partially threaded elongated pin for insertion
into the femoral body, which provides rotational adjustment between
the body and the pin for various alignments and size combinations.
See e.g., U.S. Pat. No. 4,938,773. The hip implant may be composed
of a ball, neck and fixation element with a bearing element that is
adapted to restrain dislocations of the ball and provide a means
for selecting the orientation of the fixation element. See e.g.,
U.S. Pat. No. 6,042,611. The hip implant may be designed of two
mutually articulating components composed of a cobalt chromium
alloy with one having a low carbon content and the other component
having a high carbon content. See e.g., U.S. Pat. No.
5,904,720.
[0373] In another aspect, hip implants may be adapted for cementing
into place to ensure the implant is stabilized in the accurate
position. For example, hip implants may be composed of cement
spacers along the shaft which, upon implantation within the
medullary canal of the femur, allows for optimal thickness of the
cement mantle. See e.g., U.S. Pat. No. 5,314,489.
[0374] In another aspect, hip implants may be modular in which
components may be adjusted to adapt to the host's shape or
dimensions. For example, the hip implant may be a modular hip
prosthesis composed of a plurality of removable, different size
tubular sleeves that may be used to extend the femoral stem
component or neck size which allows the implant to be custom fitted
to a particular host. See e.g., U.S. Pat. No. 5,507,830.
[0375] In another aspect, hip implants may be designed to provide
shock absorbency within the joint. For example, the hip implant may
be composed of an elongate element that extends coaxially from the
ball section that slidably extends into a chamber that contains a
spring for shock absorbency. See e.g., U.S. Pat. No. 5,389,107. The
hip implant may be a modular shock absorbent prosthesis designed to
have adjustable femoral stem, neck and ball, as well as adjustable
tension due to its unique coupling modular spring mechanism. See
e.g., U.S. Pat. No. 6,336,941.
[0376] In another aspect, hip implants may be composed of a
composite material to provide greater stiffness or retention within
the femur. For example, the hip implant may be composed of a
plurality of layers of fibers (e.g., composed of carbon, ceramic,
metal or fiberglass) in a matrix (e.g., a polymeric matrix) where
the fibers may be substantially unidirectional in each respective
layer. See e.g., U.S. Pat. Nos. 5,522,904, 5,163,962, 5,064,439 and
4,892,552. The hip implant may have a stem composed of an inner
metal core and an outer composite shell having fibers bonded with a
thermoplastic resin and which the distal end is adapted to be
inserted into a cavity formed in a bone. See e.g., U.S. Pat. No.
5,314,492. The hip implant may be composed of an expandable
material that absorbs body fluid and expands within an opening of
the bone of the host's body such that a portion of the implant is
retained within the bone and a portion of the implant is outside
the bone. See e.g., U.S. Pat. No. 6,361,565.
[0377] In another aspect, hip implants may be only partial hip
replacements. For example, the hip implant may be a prosthetic
acetabular cup assembly being composed of a bearing component for
receiving a ball attached to a femur and a shell component for
attachment to an acetabulum. See e.g., U.S. Pat. No. 5,049,158.
Still other hip implants may be revision hip prostheses which have
design features to augment the fixation of the implant into an area
with bone-deficiency. For example, the hip implant may be a long
stem hip joint prosthetic device having a long distal section of
the femoral component which extends beyond the isthmus of the femur
when implanted in the medullary canal and is designed with a
specially curved distal section. See e.g., U.S. Pat. No. 4,871,369.
Additional descriptions of hip implants are provided in U.S. Pat.
Nos. 5,755,810; 5,336,265; 5,286,260; 5,019,108; 4,986,834;
4,808,186; and 4,670,015.
[0378] Hip implants, which may be combined with one or more drugs
according to the present invention, include numerous commercially
available products, for example, the S--ROM Total Hip System and
the AML Total Hip System from DePuy Orthopaedics, Inc. (Warsaw,
Ind.).
[0379] In one aspect, the present invention provides hip prostheses
that include a fibrosis-inducing agent or a composition that
includes a fibrosis-inducing agent to promote scarring to provide
fixation of the device into the surrounding bone. In one aspect,
the hip prosthesis is coated with a fibrosing agent or a
composition that includes the fibrosing agent. In another aspect,
the fibrosing agent may be incorporated into a glue or cement that
holds the prosthesis in place. In another aspect, the hip
prosthesis is covered (all or in part) with a silk mesh or lattice
to encourage scarring and anchoring into the surrounding bone. For
example, a silk mesh or lattice can be coated onto all or a portion
of the surface of the implant stem to encourage scarring and
anchoring into the surrounding bone.
[0380] Numerous polymeric and non-polymeric carrier systems
described previously can be used in the practice of this
embodiment. These compositions can further include one or more
fibrosis-inducing agents to promote the formation of granulation
tissue. Methods for incorporating fibrosing compositions onto or
into the orthopedic implants include: (a) directly affixing to the
device a fibrosing composition (e.g., by either a spraying process
or dipping process as described above, with or without a carrier);
(b) directly incorporating into the device a fibrosing composition
(e.g., by either a spraying process or dipping process as described
above, with or without a carrier); (c) by coating the device with a
substance such as a hydrogel which can in turn absorb the fibrosing
composition; (d) by interweaving fibrosing composition coated
thread (or the polymer itself formed into a thread) into the device
structure; (e) by inserting the device into a sleeve or mesh which
is comprised of or coated with a fibrosing composition; (f)
constructing the device itself or a portion of the device with a
fibrosing composition; and/or (g) by covalently binding the
fibrosing agent directly to the device surface or to a linker
(small molecule or polymer) that is coated or attached to the
device surface. For these devices, the coating process can be
performed in such a manner as to a) coat the surfaces of the device
that is in contact with the bone, b) coat the surfaces of the
device that are not in contact with the bone or c) coat all or
parts of both the bone-contacting and non-bone contacting surface
of the device.
[0381] In addition to coating the device with the fibrosing
composition, the fibrosing agent can be mixed with the materials
that are used to make the device such that the fibrosing agent is
incorporated into the final device.
[0382] It should be apparent to one of skill in the art that
potentially any adhesion or fibrosis-inducing agents described
previously may be utilized alone, or in combination, in the
practice of this embodiment. Exemplary fibrosing agents for use in
hip prostheses implants include talc, silk, wool, chitosan,
polylysine, fibronectin, bleomycin, and CTGF, as well as analogues
and derivatives of the aforementioned.
[0383] As hip prostheses are made in a variety of configurations
and sizes, the exact dose administered can vary with device size,
surface area and design. However, certain principles can be applied
in the application of this art. Drug dose can be calculated as a
function of dose per unit area (of the portion of the device being
coated), total drug dose administered can be measured and
appropriate surface concentrations of active drug can be
determined. Regardless of the method of application of the drug to
the hip prostheses, the exemplary fibrosing agents, used alone or
in combination, should be administered under the following dosing
guidelines:
[0384] Utilizing talc as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of talc delivered from
a hip prosthesis, or coated onto the surface of a hip prosthesis,
should not exceed 100 mg (range of 1 .mu.g to 100 mg). In one
embodiment, the total amount of talc released from the prosthesis
should be in the range of 10 .mu.g to 50 mg. The dose per unit area
of the device (i.e., the dosage of talc as a function of the
surface area of the portion of the device to which drug is applied
and/or incorporated) should fall within the range of 0.05 .mu.g-10
.mu.g per mm.sup.2 of surface area coated. In another embodiment,
talc should be applied to a hip prosthesis surface at a dose of
0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. In
one embodiment, talc is released from the surface of a hip
prosthesis such that fibrosis in the tissue is promoted for a
period ranging from several hours to several months. For example,
talc may be released in effective concentrations for a period
ranging from 1 hour-30 days. It should be readily evident given the
discussions provided herein that analogues and derivatives of talc
(as described previously) with similar functional activity can be
utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound
(e.g., a compound twice as potent as talc is administered at half
the above parameters, a compound half as potent as talc is
administered at twice the above parameters, etc.).
[0385] Utilizing silk as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of silk delivered from
a hip prosthesis, or coated onto the surface of a hip prosthesis,
should not exceed 100 mg (range of 1 .mu.g to 100 mg). In one
embodiment, the total amount of silk released from the prosthesis
should be in the range of 10 .mu.g to 50 mg. The dose per unit area
of the device (i.e., the dosage of silk as a function of the
surface area of the portion of the device to which drug is applied
and/or incorporated) should fall within the range of 0.05 .mu.g-10
.mu.g per mm.sup.2 of surface area coated. In another embodiment,
silk should be applied to a hip prosthesis surface at a dose of
0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. As
specific (polymeric and non-polymeric) drug delivery vehicles and
specific medical devices can release silk at differing rates, the
above dosing parameters should be utilized in combination with the
release rate of the drug from the hip prosthesis such that a
minimum concentration of 0.01 nM to 1000 .mu.M of silk is delivered
to the tissue. In one embodiment, silk is released from the surface
of a hip prosthesis such that fibrosis in the tissue is promoted
for a period ranging from several hours to several months. For
example, silk may be released in effective concentrations for a
period ranging from 1 hour-30 days. It should be readily evident
given the discussions provided herein that analogues and
derivatives of silk (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as silk is
administered at half the above parameters, a compound half as
potent as silk is administered at twice the above parameters,
etc.).
[0386] Utilizing chitosan as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of chitosan delivered
from a hip prosthesis, or coated onto the surface of a hip
prosthesis, should not exceed 100 mg (range of 1 .mu.g to 100 mg).
In one embodiment, the total amount of chitosan released from the
prosthesis should be in the range of 10 .mu.g to 50 mg. The dose
per unit area of the device (i.e., the dosage of chitosan as a
function of the surface area of the portion of the device to which
drug is applied and/or incorporated) should fall within the range
of 0.05 .mu.g-10 .mu.g per mm.sup.2 of surface area coated. In
another embodiment, chitosan should be applied to a hip prosthesis
surface at a dose of 0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of
surface area coated. As specific (polymeric and non-polymeric) drug
delivery vehicles and specific medical devices can release chitosan
at differing rates, the above dosing parameters should be utilized
in combination with the release rate of the drug from the hip
prosthesis such that a minimum concentration of 0.01 nM to 1000
.mu.M of chitosan is delivered to the tissue. In one embodiment,
chitosan is released from the surface of a hip prosthesis such that
fibrosis in the tissue is promoted for a period ranging from
several hours to several months. For example, chitosan may be
released in effective concentrations for a period ranging from 1
hour-30 days. It should be readily evident given the discussions
provided herein that analogues and derivatives of chitosan (as
described previously) with similar functional activity can be
utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound
(e.g., a compound twice as potent as chitosan is administered at
half the above parameters, a compound half as potent as chitosan is
administered at twice the above parameters, etc.).
[0387] Utilizing polylysine as an exemplary fibrosis-inducing
agent, whether it is applied using a polymer coating, incorporated
into the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of polylysine delivered
from a hip prosthesis, or coated onto the surface of a hip
prosthesis, should not exceed 100 mg (range of 1 .mu.g to 100 mg).
In one embodiment, the total amount of polylysine released from the
prosthesis should be in the range of 10 .mu.g to 50 mg. The dose
per unit area of the device (i.e., the dosage of polylysine as a
function of the surface area of the portion of the device to which
drug is applied and/or incorporated) should fall within the range
of 0.05 .mu.g-10 .mu.g per mm.sup.2 of surface area coated. In
another embodiment, polylysine should be applied to a hip
prosthesis surface at a dose of 0.05 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific medical devices
can release polylysine at differing rates, the above dosing
parameters should be utilized in combination with the release rate
of the drug from the hip prosthesis such that a minimum
concentration of 0.01 nM to 1000 .mu.M of polylysine is delivered
to the tissue. In one embodiment, polylysine is released from the
surface of a hip prosthesis such that fibrosis in the tissue is
promoted for a period ranging from several hours to several months.
For example, polylysine may be released in effective concentrations
for a period ranging from 1 hour-30 days. It should be readily
evident given the discussions provided herein that analogues and
derivatives of polylysine (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
polylysine is administered at half the above parameters, a compound
half as potent as polylysine is administered at twice the above
parameters, etc.).
[0388] Utilizing fibronectin as an exemplary fibrosis-inducing
agent, whether it is applied using a polymer coating, incorporated
into the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of fibronectin
delivered from a hip prosthesis, or coated onto the surface of a
hip prosthesis, should not exceed 100 mg (range of 1 .mu.g to 100
mg). In one embodiment, the total amount of fibronectin released
from the prosthesis should be in the range of 10 .mu.g to 50 mg.
The dose per unit area of the device (i.e., the dosage of
fibronectin as a function of the surface area of the portion of the
device to which drug is applied and/or incorporated) should fall
within the range of 0.05 .mu.g-10 .mu.g per mm.sup.2 of surface
area coated. In another embodiment, fibronectin should be applied
to a hip prosthesis surface at a dose of 0.05 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific medical devices
can release fibronectin at differing rates, the above dosing
parameters should be utilized in combination with the release rate
of the drug from the hip prosthesis such that a minimum
concentration of 0.01 nM to 1000 .mu.M of fibronectin is delivered
to the tissue. In one embodiment, fibronectin is released from the
surface of a hip prosthesis such that fibrosis in the tissue is
promoted for a period ranging from several hours to several months.
For example, fibronectin may be released in effective
concentrations for a period ranging from 1 hour-30 days. It should
be readily evident given the discussions provided herein that
analogues and derivatives of fibronectin (as described previously)
with similar functional activity can be utilized for the purposes
of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as fibronectin is administered at half the above parameters, a
compound half as potent as fibronectin is administered at twice the
above parameters, etc.).
[0389] Utilizing bleomycin as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of bleomycin delivered
from a hip prosthesis, or coated onto the surface of a hip
prosthesis, should not exceed 100 mg (range of 0.01 .mu.g to 100
mg). In one embodiment, the total amount of bleomycin released from
the prosthesis should be in the range of 0.10 .mu.g to 50 mg. The
dose per unit area of the device (i.e., the dosage of bleomycin as
a function of the surface area of the portion of the device to
which drug is applied and/or incorporated) should fall within the
range of 0.005 .mu.g-10 .mu.g per mm.sup.2 of surface area coated.
In another embodiment, bleomycin should be applied to a hip
prosthesis surface at a dose of 0.005 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific medical devices
can release bleomycin at differing rates, the above dosing
parameters should be utilized in combination with the release rate
of the drug from the hip prosthesis such that a minimum
concentration of 0.001 nM to 1000 .mu.M of bleomycin is delivered
to the tissue. In one embodiment, bleomycin is released from the
surface of a hip prosthesis such that fibrosis in the tissue is
promoted for a period ranging from several hours to several months.
For example, bleomycin may be released in effective concentrations
for a period ranging from 1 hour-30 days. It should be readily
evident given the discussions provided herein that analogues and
derivatives of bleomycin (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
bleomycin is administered at half the above parameters, a compound
half as potent as bleomycin is administered at twice the above
parameters, etc.).
[0390] Utilizing CTGF as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of CTGF delivered from
a hip prosthesis, or coated onto the surface of a hip prosthesis,
should not exceed 100 mg (range of 0.01 .mu.g to 100 mg). In one
embodiment, the total amount of CTGF released from the prosthesis
should be in the range of 0.10 .mu.g to 50 mg. The dose per unit
area of the device (i.e., the dosage of CTGF as a function of the
surface area of the portion of the device to which drug is applied
and/or incorporated) should fall within the range of 0.005 .mu.g-10
.mu.g per mm.sup.2 of surface area coated. In another embodiment,
CTGF should be applied to a hip prosthesis surface at a dose of
0.005 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. As
specific (polymeric and non-polymeric) drug delivery vehicles and
specific medical devices can release CTGF at differing rates, the
above dosing parameters should be utilized in combination with the
release rate of the drug from the hip prosthesis such that a
minimum concentration of 0.001 nM to 1000 .mu.M of CTGF is
delivered to the tissue. In one embodiment, CTGF is released from
the surface of a hip prosthesis such that fibrosis in the tissue is
promoted for a period ranging from several hours to several months.
For example, CTGF may be released in effective concentrations for a
period ranging from 1 hour-30 days. It should be readily evident
given the discussions provided herein that analogues and
derivatives of CTGF (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as CTGF is
administered at half the above parameters, a compound half as
potent as CTGF is administered at twice the above parameters,
etc.).
[0391] Optionally, the device may additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone) and/or a bone morphogenic protein (BMP) (e.g.,
BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or an analogue or
derivative thereof).
[0392] Bone morphogenic protein(s) (e.g., BMP-2, BMP-3, BMP-4,
BMP-5, BMP-6, or BMP-7 or an analogue or derivative thereof) are to
be used in formulations at concentrations that range from 0.001
.mu.g/ml to approximately 20 mg/ml depending on the specific
clinical application, formulation type (e.g., gel, liquid, solid,
semi-solid), formulation chemistry, duration of required
application, type of medical device interface and formulation
volume and or surface area coverage required. Preferably, the bone
morphogenic protein is released in effective concentrations for a
period ranging from 1-180 days. The total dose for a single
application is typically not to exceed 500 mg (range of 0.001 .mu.g
to 500 mg); preferred 1 .mu.g to 250 mg. When used as a device
coating, the dose is per unit area of 0.001 .mu.g-1000 .mu.g per;
with a preferred dose of 0.01 .mu.g/mm.sup.2-200 .mu.g/mm.sup.2.
Minimum concentration of 10.sup.-9-10.sup.-4 M of bone morphogenic
protein is to be maintained on the device surface.
[0393] Inflammatory cytokines are to be used in formulations at
concentrations that range from 0.0001 .mu.g/ml to approximately 20
mg/ml depending on the specific clinical application, formulation
type (e.g., gel, liquid, solid, semi-solid), formulation chemistry,
duration of required application, type of medical device interface
and formulation volume and or surface area coverage required.
Preferably, the inflammatory cytokine is released in effective
concentrations for a period ranging from 1-180 days. The total dose
for a single application is typically not to exceed 500 mg (range
of 0.0001 .mu.g to 100 mg); preferred 0.001 .mu.g to 50 mg. When
used as a device coating, the dose is per unit area of 0.0001
.mu.g-500 .mu.g per mm.sup.2; with a preferred dose of 0.001
.mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-10-10.sup.-4 g/ml of inflammatory cytokine is to be
maintained on the device surface.
[0394] Furthermore, the device may alone or additionally comprise
an agent that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof. Doses used are those
concentrations which are demonstrated to stimulate cell
proliferation (see Example 16). The proliferative agents are to be
used in formulations at concentrations that range from 0.1 ng/ml to
25 mg/ml depending on the specific clinical application,
formulation type (e.g., gel, liquid, solid, semi-solid),
formulation chemistry, duration of required application, type of
medical device interface and formulation volume and or surface area
coverage required. Preferably, the proliferative agent is released
in effective concentrations for a period ranging from 1-180 days.
The total dose for a single application is typically not to exceed
500 mg (range of 0.0001 .mu.g to 200 mg); preferred 0.001 .mu.g to
100 mg. When used as a device coating, the dose is per unit area of
0.00001 .mu.g-500 .mu.g per mm.sup.2; with a preferred dose of
0.0001 .mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-11-10.sup.-6 M of proliferative agent is to be maintained
on the device surface.
[0395] It should be readily evident to one of skill in the art that
any of the previously described fibrosis inducing agents, or
derivatives and analogues thereof, can be utilized to create
variations of the above compositions without deviating from the
spirit and scope of the invention. It should also be apparent that
the agent can be utilized in a composition with or without polymer
carrier and that altering the carrier does not deviate from the
scope of this invention.
[0396] (ii) Knee Implants
[0397] In one aspect, the present invention provides knee implants
that induce fibrosis or adhesion of the implant into the
surrounding tissue. Knee replacement surgery is generally indicated
for patients with severe knee pain and disability caused by damage
to their articular cartilage as a result of rheumatoid arthritis,
osteoarthritis or trauma. It is highly successful procedure in
relieving pain and restoring joint function. Knee arthroplasty
procedures are broadly categorized as primary or revision and are
either unicompartmental (partial) or total. Knee prostheses
(referred to herein as knee implants) can be used to replace all or
a portion of the knee joint. In a total knee arthroplasty (TKA),
the diseased cartilage surfaces of the thighbone (femur), the
shinbone (tibia) and the kneecap (patella) are replaced by
prostheses made of metal alloys (e.g., titanium- or
cobalt/chromium-based alloys) and high-grade plastics and polymeric
materials (e.g., ultrahigh-density polyethylene). Most of the other
structures of the knee, such as the connecting ligaments, remain
intact. Up to three bone surfaces may be replaced during a TKA: the
distal ends (condyles) of the femur, the proximal surface of the
tibia and the posterior surface of the patella. Components are
designed so that metal always articulates against plastic, which
provides smooth movement and results in minimal wear.
[0398] Knee joint implants typically have three components (i.e., a
femoral, a tibial, and a patellar component). The metal femoral
component curves around the end of the thighbone and has an
interior groove so the patella can move up and down smoothly
against the bone as the knee bends and straightens. Usually, one
large piece is used to resurface the end of the bone. If only one
condyle of the femur is damaged, a smaller piece may be used
(unicompartmental knee replacement) to resurface just that part of
the bone. Some designs (e.g., posterior stabilized designs) have an
internal post with a circular-shaped device (cam) that works with a
corresponding tibial component to help prevent the femur from
sliding forward too far on the tibia when the knee is bent. The
tibial component is a flat metal platform with a polyethylene
cushion. The cushion may be part of the platform (fixed) or
separate (mobile) with either a flat surface (PCL-retaining) or a
raised, sloping surface (PCL-substituting). The patellar component
is a dome-shaped piece of polyethylene that duplicates the shape of
the kneecap anchored to a flat metal plate. Once the knee
prosthesis is implanted and aligned, the knee replacement is fixed
in place by cement, using a cementless procedure, or via a hybrid
fixation procedure.
[0399] A variety of knee prostheses have been described. For
example, knee prostheses have been described in U.S. Pat. Nos.
6,443,991; 6,402,786; 6,068,658; 6,558,427; 6,554,866; 6,447,549;
6,419,707; 6,143,034; 6,120,546; and 6,074,424. Knee implants
suitable for combining with one or more fibrosis-inducing agents
according to the present invention, include numerous commercially
available products. These include, for example, the NEXGEN LEGACY
Knee Posterior Stabilized (LPS) and NEXGEN LEGACY LPS Femoral
Component from Zimmer. Other examples of knee implants suitable for
the delivery of fibrosis-inducing agents include Stryker Howmedica
Osteonics DURACON Total Knee System, SCORPIO Knee System, and
SCORPIO Cruciate Retaining Single Axis Knee; implants available
from DePuy Orthopaedics such as the LCS Total Knee System, P.F.C.
Sigma RP Platform Knee System, Keane Uni-Compartmental Knee System,
P.F.C. Sigma Uni-Compartmental Knee System, AMK Total Knee System,
P.F.C. Sigma Knee System (Cruciate-Retaining), the P.F.C. Sigma
Knee System (Cruciate-Substituting), the Coordinate Revision Knee
System, the P.F.C. Sigma Knee System TC3 Revision implant, and the
S-ROM Noiles Rotating Hinge; knee implants from Smith & Nephew
Orthopaedics such as the GENESID I and GENESIS II Total Knee
Systems. Other manufacturers of primary and revision knee joint
implants suitable for use in this invention include Biomet, Inc.
(Warsaw, Ind.), Sulzer Orthopedics, Inc. (Austin, Tex.), Wright
Medical Technologies, Exactech, Inc., Encore Orthopedics
Corporation (Henderson, Nev.), Implex now known as Zimmer, Inc.,
StelKast Company (McMurray, Pa.), Hayes Medical, Inc. (El Dorado
Hills, Calif.), and Link Orthopedics (PineBrook, N.J.).
[0400] In one aspect, the present invention provides knee
prostheses that include a fibrosis-inducing agent or a composition
that includes a fibrosis-inducing agent to promote scarring and
fixation of the device into the surrounding bone. In one aspect,
the knee prosthesis is coated with a fibrosing agent or a
composition that includes the fibrosing agent. In another aspect,
the fibrosing agent may be incorporated into the glue or cement
that holds the prosthesis in place. In another aspect, the knee
prosthesis is covered (all or in part) with a silk mesh or lattice
to encourage scarring and anchoring into the surrounding bone. For
example, a silk mesh or lattice can be coated onto all or a portion
of the surface of the implant stem to encourage scarring and
anchoring into the surrounding bone.
[0401] Numerous polymeric and non-polymeric carrier systems
described above can be used in the practice of this embodiment.
These compositions can further include one or more
fibrosis-inducing agents to promote the formation of granulation
tissue. Methods for incorporating fibrosing compositions onto or
into the orthopedic implants include: (a) directly affixing to the
device a fibrosing composition (e.g., by either a spraying process
or dipping process as described above, with or without a carrier);
(b) directly incorporating into the device a fibrosing composition
(e.g., by either a spraying process or dipping process as described
above, with or without a carrier); (c) by coating the device with a
substance such as a hydrogel which can in turn absorb the fibrosing
composition; (d) by interweaving fibrosing composition coated
thread (or the polymer itself formed into a thread) into the device
structure; (e) by inserting the device into a sleeve or mesh which
is comprised of or coated with a fibrosing composition; (f)
constructing the device itself or a portion of the device with a
fibrosing composition, or (g) by covalently binding the fibrosing
agent directly to the device surface or to a linker (small molecule
or polymer) that is coated or attached to the device surface. For
these devices, the coating process can be performed in such a
manner as to a) coat the surfaces of the device that is in contact
with the bone, b) coat the surfaces of the device that are not in
contact with the bone or c) coat all or parts of both the
bone-contacting and non-bone contacting surface of the device.
[0402] In addition to coating the device with the fibrosing
composition, the fibrosing agent can be mixed with the materials
that are used to make the device such that the fibrosing agent is
incorporated into the final device.
[0403] It should be apparent to one of skill in the art that
potentially any adhesion or fibrosis-inducing agents described
above may be utilized alone, or in combination, in the practice of
this embodiment. Exemplary fibrosing agents for use in knee
prostheses include talc, silk, wool, chitosan, polylysine,
fibronectin, bleomycin, and CTGF, as well as analogues and
derivatives of the aforementioned.
[0404] As knee prostheses are made in a variety of configurations
and sizes, the exact dose administered can vary with device size,
surface area and design. However, certain principles can be applied
in the application of this art. Drug dose can be calculated as a
function of dose per unit area (of the portion of the device being
coated), total drug dose administered can be measured and
appropriate surface concentrations of active drug can be
determined. Regardless of the method of application of the drug to
the knee prostheses, the exemplary fibrosing agents, used alone or
in combination, should be administered under the following dosing
guidelines:
[0405] Utilizing talc as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of talc delivered from
a knee prosthesis, or coated onto the surface of a knee prosthesis,
should not exceed 100 mg (range of 1 .mu.g to 100 mg). In one
embodiment, the total amount of talc released from the prosthesis
should be in the range of 10 .mu.g to 50 mg. The dose per unit area
of the device (i.e., the dosage of talc as a function of the
surface area of the portion of the device to which drug is applied
and/or incorporated) should fall within the range of 0.05 .mu.g-10
.mu.g per mm.sup.2 of surface area coated. In another embodiment,
talc should be applied to a knee prosthesis surface at a dose of
0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. In
one embodiment, talc is released from the surface of a knee
prosthesis such that fibrosis in the tissue is promoted for a
period ranging from several hours to several months. For example,
talc may be released in effective concentrations for a period
ranging from 1 hour-30 days. It should be readily evident given the
discussions provided herein that analogues and derivatives of talc
(as described previously) with similar functional activity can be
utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound
(e.g., a compound twice as potent as talc is administered at half
the above parameters, a compound half as potent as talc is
administered at twice the above parameters, etc.).
[0406] Utilizing silk as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of silk delivered from
a knee prosthesis, or coated onto the surface of a knee prosthesis,
should not exceed 100 mg (range of 1 .mu.g to 100 mg). In one
embodiment, the total amount of silk released from the prosthesis
should be in the range of 10 .mu.g to 50 mg. The dose per unit area
of the device (i.e., the dosage of silk as a function of the
surface area of the portion of the device to which drug is applied
and/or incorporated) should fall within the range of 0.05 .mu.g-10
.mu.g per mm.sup.2 of surface area coated. In another embodiment,
silk should be applied to a knee prosthesis surface at a dose of
0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. As
specific (polymeric and non-polymeric) drug delivery vehicles and
specific medical devices can release silk at differing rates, the
above dosing parameters should be utilized in combination with the
release rate of the drug from the knee prosthesis such that a
minimum concentration of 0.01 nM to 1000 .mu.M of silk is delivered
to the tissue. In one embodiment, silk is released from the surface
of a knee prosthesis such that fibrosis in the tissue is promoted
for a period ranging from several hours to several months. For
example, silk may be released in effective concentrations for a
period ranging from 1 hour-30 days. It should be readily evident
given the discussions provided herein that analogues and
derivatives of silk (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as silk is
administered at half the above parameters, a compound half as
potent as silk is administered at twice the above parameters,
etc.).
[0407] Utilizing chitosan as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of chitosan delivered
from a knee prosthesis, or coated onto the surface of a knee
prosthesis, should not exceed 100 mg (range of 1 .mu.g to 100 mg).
In one embodiment, the total amount of chitosan released from the
prosthesis should be in the range of 10 .mu.g to 50 mg. The dose
per unit area of the device (i.e., the dosage of chitosan as a
function of the surface area of the portion of the device to which
drug is applied and/or incorporated) should fall within the range
of 0.05 .mu.g-10 .mu.g per mm.sup.2 of surface area coated. In
another embodiment, chitosan should be applied to a knee prosthesis
surface at a dose of 0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of
surface area coated. As specific (polymeric and non-polymeric) drug
delivery vehicles and specific medical devices can release chitosan
at differing rates, the above dosing parameters should be utilized
in combination with the release rate of the drug from the knee
prosthesis such that a minimum concentration of 0.01 nM to 1000
.mu.M of chitosan is delivered to the tissue. In one embodiment,
chitosan is released from the surface of a knee prosthesis (e.g., a
bulking agent) such that fibrosis in the tissue is promoted for a
period ranging from several hours to several months. For example,
chitosan may be released in effective concentrations for a period
ranging from 1 hour-30 days. It should be readily evident given the
discussions provided herein that analogues and derivatives of
chitosan (as described previously) with similar functional activity
can be utilized for the purposes of this invention; the above
dosing parameters are then adjusted according to the relative
potency of the analogue or derivative as compared to the parent
compound (e.g., a compound twice as potent as chitosan is
administered at half the above parameters, a compound half as
potent as chitosan is administered at twice the above parameters,
etc.).
[0408] Utilizing polylysine as a exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of polylysine delivered
from a knee prosthesis, or coated onto the surface of a knee
prosthesis, should not exceed 100 mg (range of 1 .mu.g to 100 mg).
In one embodiment, the total amount of polylysine released from the
prosthesis should be in the range of 10 .mu.g to 50 mg. The dose
per unit area of the device (i.e., the dosage of polylysine as a
function of the surface area of the portion of the device to which
drug is applied and/or incorporated) should fall within the range
of 0.05 .mu.g-10 .mu.g per mm.sup.2 of surface area coated. In
another embodiment, polylysine should be applied to a knee
prosthesis surface at a dose of 0.05 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific medical devices
can release polylysine at differing rates, the above dosing
parameters should be utilized in combination with the release rate
of the drug from the knee prosthesis such that a minimum
concentration of 0.01 nM to 1000 .mu.M of polylysine is delivered
to the tissue. In one embodiment, polylysine is released from the
surface of a knee prosthesis such that fibrosis in the tissue is
promoted for a period ranging from several hours to several months.
For example, polylysine may be released in effective concentrations
for a period ranging from 1 hour-30 days. It should be readily
evident given the discussions provided herein that analogues and
derivatives of polylysine (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
polylysine is administered at half the above parameters, a compound
half as potent as polylysine is administered at twice the above
parameters, etc.).
[0409] Utilizing fibronectin as an exemplary fibrosis-inducing
agent, whether it is applied using a polymer coating, incorporated
into the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of fibronectin
delivered from a knee prosthesis, or coated onto the surface of a
knee prosthesis, should not exceed 100 mg (range of 1 .mu.g to 100
mg). In one embodiment, the total amount of fibronectin released
from the prosthesis should be in the range of 10 .mu.g to 50 mg.
The dose per unit area of the device (i.e., the dosage of
fibronectin as a function of the surface area of the portion of the
device to which drug is applied and/or incorporated) should fall
within the range of 0.05 .mu.g-10 .mu.g per mm.sup.2 of surface
area coated. In another embodiment, fibronectin should be applied
to a knee prosthesis surface at a dose of 0.05 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific medical devices
can release fibronectin at differing rates, the above dosing
parameters should be utilized in combination with the release rate
of the drug from the knee prosthesis such that a minimum
concentration of 0.01 nM to 1000 .mu.M of fibronectin is delivered
to the tissue. In one embodiment, fibronectin is released from the
surface of a knee prosthesis such that fibrosis in the tissue is
promoted for a period ranging from several hours to several months.
For example, fibronectin may be released in effective
concentrations for a period ranging from 1 hour-30 days. It should
be readily evident given the discussions provided herein that
analogues and derivatives of fibronectin (as described previously)
with similar functional activity can be utilized for the purposes
of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as fibronectin is administered at half the above parameters, a
compound half as potent as fibronectin is administered at twice the
above parameters, etc.).
[0410] Utilizing bleomycin as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of bleomycin delivered
from a knee prosthesis, or coated onto the surface of a knee
prosthesis, should not exceed 100 mg (range of 0.01 .mu.g to 100
mg). In one embodiment, the total amount of bleomycin released from
the prosthesis should be in the range of 0.10 .mu.g to 50 mg. The
dose per unit area of the device (i.e., the dosage of bleomycin as
a function of the surface area of the portion of the device to
which drug is applied and/or incorporated) should fall within the
range of 0.005 .mu.g-10 .mu.g per mm.sup.2 of surface area coated.
In another embodiment, bleomycin should be applied to a knee
prosthesis surface at a dose of 0.005 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific medical devices
can release bleomycin at differing rates, the above dosing
parameters should be utilized in combination with the release rate
of the drug from the knee prosthesis such that a minimum
concentration of 0.001 nM to 1000 .mu.M of bleomycin is delivered
to the tissue. In one embodiment, bleomycin is released from the
surface of a knee prosthesis such that fibrosis in the tissue is
promoted for a period ranging from several hours to several months.
For example, bleomycin may be released in effective concentrations
for a period ranging from 1 hour-30 days. It should be readily
evident given the discussions provided herein that analogues and
derivatives of bleomycin (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
bleomycin is administered at half the above parameters, a compound
half as potent as bleomycin is administered at twice the above
parameters, etc.).
[0411] Utilizing CTGF as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of CTGF delivered from
a knee prosthesis, or coated onto the surface of a knee prosthesis,
should not exceed 100 mg (range of 0.01 .mu.g to 100 mg). In one
embodiment, the total amount of CTGF released from the prosthesis
should be in the range of 0.10 .mu.g to 50 mg. The dose per unit
area of the device (i.e., the dosage of CTGF as a function of the
surface area of the portion of the device to which drug is applied
and/or incorporated) should fall within the range of 0.005 .mu.g-10
.mu.g per mm.sup.2 of surface area coated. In another embodiment,
CTGF should be applied to a knee prosthesis surface at a dose of
0.005 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. As
specific (polymeric and non-polymeric) drug delivery vehicles and
specific medical devices can release CTGF at differing rates, the
above dosing parameters should be utilized in combination with the
release rate of the drug from the knee prosthesis such that a
minimum concentration of 0.001 nM to 1000 .mu.M of CTGF is
delivered to the tissue. In one embodiment, CTGF is released from
the surface of a knee prosthesis such that fibrosis in the tissue
is promoted for a period ranging from several hours to several
months. For example, CTGF may be released in effective
concentrations for a period ranging from 1 hour-30 days. It should
be readily evident given the discussions provided herein that
analogues and derivatives of CTGF (as described previously) with
similar functional activity can be utilized for the purposes of
this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as CTGF is administered at half the above parameters, a compound
half as potent as CTGF is administered at twice the above
parameters, etc.).
[0412] Optionally, the device may additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone) and/or a bone morphogenic protein (BMP) (e.g.,
BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or an analogue or
derivative thereof).
[0413] Bone morphogenic protein(s) (e.g., BMP-2, BMP-3, BMP-4,
BMP-5, BMP-6, or BMP-7 or an analogue or derivative thereof) are to
be used in formulations at concentrations that range from 0.001
.mu.g/ml to approximately 20 mg/ml depending on the specific
clinical application, formulation type (e.g., gel, liquid, solid,
semi-solid), formulation chemistry, duration of required
application, type of medical device interface and formulation
volume and or surface area coverage required. Preferably, the bone
morphogenic protein is released in effective concentrations for a
period ranging from 1-180 days. The total dose for a single
application is typically not to exceed 500 mg (range of 0.001 .mu.g
to 500 mg); preferred 1 .mu.g to 250 mg. When used as a device
coating, the dose is per unit area of 0.001 .mu.g-1000 .mu.g per
mm.sup.2; with a preferred dose of 0.01 .mu.g/mm.sup.2-200
.mu.g/mm.sup.2. Minimum concentration of 10.sup.-9-10.sup.-4 M of
bone morphogenic protein is to be maintained on the device
surface.
[0414] Inflammatory cytokines are to be used in formulations at
concentrations that range from 0.0001 .mu.g/ml to approximately 20
mg/ml depending on the specific clinical application, formulation
type (e.g., gel, liquid, solid, semi-solid), formulation chemistry,
duration of required application, type of medical device interface
and formulation volume and or surface area coverage required.
Preferably, the inflammatory cytokine is released in effective
concentrations for a period ranging from 1-180 days. The total dose
for a single application is typically not to exceed 500 mg (range
of 0.0001 .mu.g to 100 mg); preferred 0.001 .mu.g to 50 mg. When
used as a device coating, the dose is per unit area of 0.0001
.mu.g-500 .mu.g per mm.sup.2; with a preferred dose of 0.001
.mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-10-10.sup.-4 g/ml of inflammatory cytokine is to be
maintained on the device surface.
[0415] Furthermore, the device may alone or additionally comprise
an agent that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof. Doses used are those
concentrations which are demonstrated to stimulate cell
proliferation (see, e.g., Example 16). The proliferative agents are
to be used in formulations at concentrations that range from 0.1
ng/ml to 25 mg/ml depending on the specific clinical application,
formulation type (e.g., gel, liquid, solid, semi-solid),
formulation chemistry, duration of required application, type of
medical device interface and formulation volume and or surface area
coverage required. Preferably, the proliferative agent is released
in effective concentrations for a period ranging from 1-180 days.
The total dose for a single application is typically not to exceed
500 mg (range of 0.0001 .mu.g to 200 mg); preferred 0.001 .mu.g to
100 mg. When used as a device coating, the dose is per unit area of
0.00001 .mu.g-500 .mu.g per mm.sup.2; with a preferred dose of
0.0001 .mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-11-10.sup.-6 M of proliferative agent is to be maintained
on the device surface.
[0416] It should be readily evident to one of skill in the art that
any of the previously described fibrosis inducing agents, or
derivatives and analogues thereof, can be utilized to create
variations of the above compositions without deviating from the
spirit and scope of the invention. It should also be apparent that
the agent can be utilized in a composition with or without polymer
carrier and that altering the carrier does not deviate from the
scope of this invention.
[0417] (iii) Shoulder Implants
[0418] Shoulder joint reconstruction is typically indicated to
alleviate pain and restore lost function arising from medical
conditions such as fractures, osteoarthritis, rheumatoid arthritis,
avascular necrosis, and tumor growth (benign or malignant).
Hemiarthroplasties (partial shoulder implants), which involve
implanting only the humeral components, typically are performed on
patients suffering from shoulder fractures and avascular necrosis.
Total shoulder replacement (implanting of both the humeral and
glenoid components) is more common in patients suffering from
osteoarthritis and rheumatoid arthritis. Joint replacement in
conjunction with excision of a tumor is fairly rare, occurring in
less than one percent of patients who receive shoulder replacement
surgeries. In a cancer patient, removal of bone may necessitate
partial or total replacement of the joint.
[0419] Numerous shoulder prostheses have been described (see, e.g.,
U.S. Pat. Nos. 6,494,913; 6,193,758; 6,168,628; 6,102,953;
6,045,582; 5,961,555; 5,593,448; 5,549,682; and 5,108,440).
Shoulder implants suitable for combining with one or more
fibrosis-inducing agents according to the present invention,
include numerous commercially available products. These include
shoulder implants manufactured by DePuy Orthopaedics (e.g., GLOBAL
TX Total Shoulder System, GLOBAL Shoulder Eccentric Head, GLOBAL
Total Shoulder System), Biomet (e.g., Bio-Modular,
Bi-Angular/Bi-Polar, Proximal Humeral Replacement, and Integrated
Shoulder System), Stryker Howmedica Osteonics (e.g., SOLAR Shoulder
Bipolar Heads, Humeral Heads, Humeral Components, and Glenoid
Components), Sulzer (e.g., Anatomical Shoulder and Select
Shoulder), Zimmer (Bigliani/Flatow Shoulder), and Smith &
Nephew Orthopaedics (e.g., COFIELD 2 Total Shoulder System, NEER II
Total Shoulder System, and Modular Shoulder System).
[0420] In one aspect, the present invention provides shoulder
prostheses that include a fibrosis-inducing agent or a composition
that includes a fibrosis-inducing agent to promote scarring and
fixation of the device into the surrounding bone. In one aspect,
the shoulder prosthesis is coated with a fibrosing agent or a
composition that includes the fibrosing agent. In another aspect,
the fibrosing agent may be incorporated into the glue or cement
that holds the prosthesis in place. In another aspect, the shoulder
prosthesis is covered (all or in part) with a silk mesh or lattice
to encourage scarring and anchoring into the surrounding bone. For
example, a silk mesh or lattice can be coated onto all or a portion
of the surface of the implant stem to encourage scarring and
anchoring into the surrounding bone.
[0421] Numerous polymeric and non-polymeric carrier systems
described above can be used in the practice of this embodiment.
These compositions can further include one or more
fibrosis-inducing agents to promote the formation of granulation
tissue. Methods for incorporating fibrosing compositions onto or
into the orthopedic implants include: (a) directly affixing to the
device a fibrosing composition (e.g., by either a spraying process
or dipping process as described above, with or without a carrier);
(b) directly incorporating into the device a fibrosing composition
(e.g., by either a spraying process or dipping process as described
above, with or without a carrier); (c) by coating the device with a
substance such as a hydrogel which can in turn absorb the fibrosing
composition; (d) by interweaving fibrosing composition coated
thread (or the polymer itself formed into a thread) into the device
structure; (e) by inserting the device into a sleeve or mesh which
is comprised of or coated with a fibrosing composition; (f)
constructing the device itself or a portion of the device with a
fibrosing composition; or (g) by covalently binding the fibrosing
agent directly to the device surface or to a linker (small molecule
or polymer) that is coated or attached to the device surface. For
these devices, the coating process can be performed in such a
manner as to a) coat the surfaces of the device that is in contact
with the bone, b) coat the surfaces of the device that are not in
contact with the bone or c) coat all or parts of both the
bone-contacting and non-bone contacting surface of the device.
[0422] In addition to coating the device with the fibrosing
composition, the fibrosing agent can be mixed with the materials
that are used to make the device such that the fibrosing agent is
incorporated into the final device.
[0423] It should be apparent to one of skill in the art that
potentially any adhesion or fibrosis-inducing agents described
above may be utilized alone, or in combination, in the practice of
this embodiment. Exemplary fibrosing agents for use in shoulder
prostheses include talc, silk, wool, chitosan, polylysine,
fibronectin, bleomycin, and CTGF, as well as analogues and
derivatives of the aforementioned.
[0424] As shoulder prostheses are made in a variety of
configurations and sizes, the exact dose administered can vary with
device size, surface area and design. However, certain principles
can be applied in the application of this art. Drug dose can be
calculated as a function of dose per unit area (of the portion of
the device being coated), total drug dose administered can be
measured and appropriate surface concentrations of active drug can
be determined. Regardless of the method of application of the drug
to the shoulder prostheses, the exemplary fibrosing agents, used
alone or in combination, should be administered under the following
dosing guidelines:
[0425] Utilizing talc as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of talc delivered from
a shoulder prosthesis, or coated onto the surface of a shoulder
prosthesis, should not exceed 100 mg (range of 1 .mu.g to 100 mg).
In one embodiment, the total amount of talc released from the
prosthesis should be in the range of 10 .mu.g to 50 mg. The dose
per unit area of the device (i.e., the dosage of talc as a function
of the surface area of the portion of the device to which drug is
applied and/or incorporated) should fall within the range of 0.05
.mu.g-10 .mu.g per mm.sup.2 of surface area coated. In another
embodiment, talc should be applied to a shoulder prosthesis surface
at a dose of 0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area
coated. In one embodiment, talc is released from the surface of a
shoulder prosthesis such that fibrosis in the tissue is promoted
for a period ranging from several hours to several months. For
example, talc may be released in effective concentrations for a
period ranging from 1 hour-30 days. It should be readily evident
given the discussions provided herein that analogues and
derivatives of talc (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as talc is
administered at half the above parameters, a compound half as
potent as talc is administered at twice the above parameters,
etc.).
[0426] Utilizing silk as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of silk delivered from
a shoulder prosthesis, or coated onto the surface of a shoulder
prosthesis, should not exceed 100 mg (range of 1 .mu.g to 100 mg).
In one embodiment, the total amount of silk released from the
prosthesis should be in the range of 10 .mu.g to 50 mg. The dose
per unit area of the device (i.e., the dosage of silk as a function
of the surface area of the portion of the device to which drug is
applied and/or incorporated) should fall within the range of 0.05
.mu.g-10 .mu.g per mm.sup.2 of surface area coated. In another
embodiment, silk should be applied to a shoulder prosthesis surface
at a dose of 0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area
coated. As specific (polymeric and non-polymeric) drug delivery
vehicles and specific medical devices can release silk at differing
rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the shoulder
prosthesis such that a minimum concentration of 0.01 nM to 1000
.mu.M of silk is delivered to the tissue. In one embodiment, silk
is released from the surface of a shoulder prosthesis such that
fibrosis in the tissue is promoted for a period ranging from
several hours to several months. For example, silk may be released
in effective concentrations for a period ranging from 1 hour-30
days. It should be readily evident given the discussions provided
herein that analogues and derivatives of silk (as described
previously) with similar functional activity can be utilized for
the purposes of this invention; the above dosing parameters are
then adjusted according to the relative potency of the analogue or
derivative as compared to the parent compound (e.g., a compound
twice as potent as silk is administered at half the above
parameters, a compound half as potent as silk is administered at
twice the above parameters, etc.).
[0427] Utilizing chitosan as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of chitosan delivered
from a shoulder prosthesis, or coated onto the surface of a
shoulder prosthesis, should not exceed 100 mg (range of 1 .mu.g to
100 mg). In one embodiment, the total amount of chitosan released
from the prosthesis should be in the range of 10 .mu.g to 50 mg.
The dose per unit area of the device (i.e., the dosage of chitosan
as a function of the surface area of the portion of the device to
which drug is applied and/or incorporated) should fall within the
range of 0.05 .mu.g-10 .mu.g per mm.sup.2 of surface area coated.
In another embodiment, chitosan should be applied to a shoulder
prosthesis surface at a dose of 0.05 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific medical devices
can release chitosan at differing rates, the above dosing
parameters should be utilized in combination with the release rate
of the drug from the shoulder prosthesis such that a minimum
concentration of 0.01 nM to 1000 .mu.M of chitosan is delivered to
the tissue. In one embodiment, chitosan is released from the
surface of a shoulder prosthesis such that fibrosis in the tissue
is promoted for a period ranging from several hours to several
months. For example, chitosan may be released in effective
concentrations for a period ranging from 1 hour-30 days. It should
be readily evident given the discussions provided herein that
analogues and derivatives of chitosan (as described previously)
with similar functional activity can be utilized for the purposes
of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as chitosan is administered at half the above parameters, a
compound half as potent as chitosan is administered at twice the
above parameters, etc.).
[0428] Utilizing polylysine as an exemplary fibrosis-inducing
agent, whether it is applied using a polymer coating, incorporated
into the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of polylysine delivered
from a shoulder prosthesis, or coated onto the surface of a
shoulder prosthesis, should not exceed 100 mg (range of 1 .mu.g to
100 mg). In one embodiment, the total amount of polylysine released
from the prosthesis should be in the range of 10 .mu.g to 50 mg.
The dose per unit area of the device (i.e., the dosage of
polylysine as a function of the surface area of the portion of the
device to which drug is applied and/or incorporated) should fall
within the range of 0.05 .mu.g-10 .mu.g per mm.sup.2 of surface
area coated. In another embodiment, polylysine should be applied to
a shoulder prosthesis surface at a dose of 0.05 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific medical devices
can release polylysine at differing rates, the above dosing
parameters should be utilized in combination with the release rate
of the drug from the shoulder prosthesis such that a minimum
concentration of 0.01 nM to 1000 .mu.M of polylysine is delivered
to the tissue. In one embodiment, polylysine is released from the
surface of a shoulder prosthesis such that fibrosis in the tissue
is promoted for a period ranging from several hours to several
months. For example, polylysine may be released in effective
concentrations for a period ranging from 1 hour-30 days. It should
be readily evident given the discussions provided herein that
analogues and derivatives of polylysine (as described previously)
with similar functional activity can be utilized for the purposes
of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as polylysine is administered at half the above parameters, a
compound half as potent as polylysine is administered at twice the
above parameters, etc.).
[0429] Utilizing fibronectin as an exemplary fibrosis-inducing
agent, whether it is applied using a polymer coating, incorporated
into the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of fibronectin
delivered from a shoulder prosthesis, or coated onto the surface of
a shoulder prosthesis, should not exceed 100 mg (range of 1 .mu.g
to 100 mg). In one embodiment, the total amount of fibronectin
released from the prosthesis should be in the range of 10 .mu.g to
50 mg. The dose per unit area of the device (i.e., the dosage of
fibronectin as a function of the surface area of the portion of the
device to which drug is applied and/or incorporated) should fall
within the range of 0.05 .mu.g-10 .mu.g per mm.sup.2 of surface
area coated. In another embodiment, fibronectin should be applied
to a shoulder prosthesis surface at a dose of 0.05
.mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. As
specific (polymeric and non-polymeric) drug delivery vehicles and
specific medical devices can release fibronectin at differing
rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the shoulder
prosthesis such that a minimum concentration of 0.01 nM to 1000
.mu.M of fibronectin is delivered to the tissue. In one embodiment,
fibronectin is released from the surface of a shoulder prosthesis
such that fibrosis in the tissue is promoted for a period ranging
from several hours to several months. For example, fibronectin may
be released in effective concentrations for a period ranging from 1
hour-30 days. It should be readily evident given the discussions
provided herein that analogues and derivatives of fibronectin (as
described previously) with similar functional activity can be
utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound
(e.g., a compound twice as potent as fibronectin is administered at
half the above parameters, a compound half as potent as fibronectin
is administered at twice the above parameters, etc.).
[0430] Utilizing bleomycin as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of bleomycin delivered
from a shoulder prosthesis, or coated onto the surface of a
shoulder prosthesis, should not exceed 100 mg (range of 0.01 .mu.g
to 100 mg). In one embodiment, the total amount of bleomycin
released from the prosthesis should be in the range of 0.10 .mu.g
to 50 mg. The dose per unit area of the device (i.e., the dosage of
bleomycin as a function of the surface area of the portion of the
device to which drug is applied and/or incorporated) should fall
within the range of 0.005 .mu.g-10 .mu.g per mm.sup.2 of surface
area coated. In another embodiment, bleomycin should be applied to
a shoulder prosthesis surface at a dose of 0.005 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific medical devices
can release bleomycin at differing rates, the above dosing
parameters should be utilized in combination with the release rate
of the drug from the shoulder prosthesis such that a minimum
concentration of 0.001 nM to 1000 .mu.M of bleomycin is delivered
to the tissue. In one embodiment, bleomycin is released from the
surface of a shoulder prosthesis such that fibrosis in the tissue
is promoted for a period ranging from several hours to several
months. For example, bleomycin may be released in effective
concentrations for a period ranging from 1 hour-30 days. It should
be readily evident given the discussions provided herein that
analogues and derivatives of bleomycin (as described previously)
with similar functional activity can be utilized for the purposes
of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as bleomycin is administered at half the above parameters, a
compound half as potent as bleomycin is administered at twice the
above parameters, etc.).
[0431] Utilizing CTGF as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of CTGF delivered from
a shoulder prosthesis, or coated onto the surface of a shoulder
prosthesis, should not exceed 100 mg (range of 0.01 .mu.g to 100
mg). In one embodiment, the total amount of CTGF released from the
prosthesis should be in the range of 0.10 .mu.g to 50 mg. The dose
per unit area of the device (i.e., the dosage of CTGF as a function
of the surface area of the portion of the device to which drug is
applied and/or incorporated) should fall within the range of 0.005
.mu.g-10 .mu.g per mm.sup.2 of surface area coated. In another
embodiment, CTGF should be applied to a shoulder prosthesis surface
at a dose of 0.005 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area
coated. As specific (polymeric and non-polymeric) drug delivery
vehicles and specific medical devices can release CTGF at differing
rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the shoulder
prosthesis such that a minimum concentration of 0.001 nM to 1000
.mu.M of CTGF is delivered to the tissue. In one embodiment, CTGF
is released from the surface of a shoulder prosthesis such that
fibrosis in the tissue is promoted for a period ranging from
several hours to several months. For example, CTGF may be released
in effective concentrations for a period ranging from 1 hour-30
days. It should be readily evident given the discussions provided
herein that analogues and derivatives of CTGF (as described
previously) with similar functional activity can be utilized for
the purposes of this invention; the above dosing parameters are
then adjusted according to the relative potency of the analogue or
derivative as compared to the parent compound (e.g., a compound
twice as potent as CTGF is administered at half the above
parameters, a compound half as potent as CTGF is administered at
twice the above parameters, etc.).
[0432] Optionally, the device may additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone) and/or a bone morphogenic protein (BMP) (e.g.,
BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or an analogue or
derivative thereof).
[0433] Bone morphogenic protein(s) (e.g., BMP-2, BMP-3, BMP-4,
BMP-5, BMP-6, or BMP-7 or an analogue or derivative thereof) are to
be used in formulations at concentrations that range from 0.001
.mu.g/ml to approximately 20 mg/ml depending on the specific
clinical application, formulation type (e.g., gel, liquid, solid,
semi-solid), formulation chemistry, duration of required
application, type of medical device interface and formulation
volume and or surface area coverage required. Preferably, the bone
morphogenic protein is released in effective concentrations for a
period ranging from 1-180 days. The total dose for a single
application is typically not to exceed 500 mg (range of 0.001 .mu.g
to 500 mg); preferred 1 .mu.g to 250 mg. When used as a device
coating, the dose is per unit area of 0.001 .mu.g-1000 .mu.g per
mm.sup.2; with a preferred dose of 0.01 .mu.g/mm.sup.2-200
.mu.g/mm.sup.2. Minimum concentration of 10.sup.-9-10.sup.-4 M of
bone morphogenic protein is to be maintained on the device
surface.
[0434] Inflammatory cytokines are to be used in formulations at
concentrations that range from 0.0001 .mu.g/ml to approximately 20
mg/ml depending on the specific clinical application, formulation
type (e.g., gel, liquid, solid, semi-solid), formulation chemistry,
duration of required application, type of medical device interface
and formulation volume and or surface area coverage required.
Preferably, the inflammatory cytokine is released in effective
concentrations for a period ranging from 1-180 days. The total dose
for a single application is typically not to exceed 500 mg (range
of 0.0001 .mu.g to 100 mg); preferred 0.001 .mu.g to 50 mg. When
used as a device coating, the dose is per unit area of 0.0001
.mu.g-500 .mu.g per mm.sup.2; with a preferred dose of 0.001
.mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-10-10.sup.-4 g/ml of inflammatory cytokine is to be
maintained on the device surface.
[0435] Furthermore, the device may alone or additionally comprise
an agent that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof. Doses used are those
concentrations which are demonstrated to stimulate cell
proliferation (see, e.g., Example 16). The proliferative agents are
to be used in formulations at concentrations that range from 0.1
ng/ml to 25 mg/ml depending on the specific clinical application,
formulation type (e.g., gel, liquid, solid, semi-solid),
formulation chemistry, duration of required application, type of
medical device interface and formulation volume and or surface area
coverage required. Preferably, the proliferative agent is released
in effective concentrations for a period ranging from 1-180 days.
The total dose for a single application is typically not to exceed
500 mg (range of 0.0001 .mu.g to 200 mg); preferred 0.001 .mu.g to
100 mg. When used as a device coating, the dose is per unit area of
0.00001 .mu.g-500 .mu.g per mm.sup.2; with a preferred dose of
0.0001 .mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-11-10.sup.-6 M of proliferative agent is to be maintained
on the device surface.
[0436] It should be readily evident to one of skill in the art that
any of the previously described fibrosis inducing agents, or
derivatives and analogues thereof, can be utilized to create
variations of the above compositions without deviating from the
spirit and scope of the invention. It should also be apparent that
the agent can be utilized in a composition with or without polymer
carrier and that altering the carrier does not deviate from the
scope of this invention.
[0437] (iv) Infiltration of Fibrosing-Inducing Agents into the
Tissue Surrounding an Artificial Joint
[0438] Alternatively, the tissue cavity into which the artificial
joint is placed (usually the bony cavity where the stem of the
artificial joint is inserted) can be treated with a
fibrosis-inducing agent prior to, during, or after the implantation
of the prosthetic joint. This can be accomplished in several ways
including: (a) topical application of the fibrosing agent into the
anatomical space where the artificial joint can be placed
(particularly useful for this embodiment is the use of polymeric
carriers which release the fibrosing agent over a period ranging
from several hours to several weeks--fluids, suspensions,
emulsions, microemulsions, microspheres, pastes, gels,
microparticulates, sprays, aerosols, solid implants and other
formulations which release a fibrosing agent can be delivered into
the region where the prosthetic joint can be inserted); (b)
microparticulate silk and/or silk strands (linear, branched, and/or
coiled) for directed delivery into the implantation site; (c)
sprayable collagen-containing formulations such as COSTASIS or
materials made from 4-armed thiol PEG (10K), a 4-armed NHS PEG
(10K) and methylated collagen such as described above, either
alone, or loaded with a fibrosis-inducing agent, applied to the
implantation site (or the implant/device surface); (d) sprayable
PEG-containing formulations such as COSEAL, FOCALSEAL, SPRAYGEL or
DURASEAL, either alone, or loaded with a fibrosis-inducing agent,
applied to the implantation site (or the implant/device surface);
(e) fibrinogen-containing formulations such as FLOSEAL or TISSEAL,
either alone, or loaded with a fibrosis-inducing agent, applied to
the implantation site (or the implant/device surface); (f)
hyaluronic acid-containing formulations such as RESTYLANE,
HYLAFORM, PERLANE, SYNVISC, SEPRAFILM, SEPRACOAT loaded with a
fibrosis-inducing agent applied to the implantation site (or the
implant/device surface); (g) polymeric gels for surgical
implantation such as REPEL or FLOWGEL loaded with a
fibrosis-inducing agent applied to the implantation site (or the
implant/device surface); (h) orthopedic cements used to hold
prostheses and tissues in place loaded with a fibrosis-inducing
agent applied to the implantation site (or the implant/device
surface), such as OSTEOBOND, LVC, SIMPLEX P, PALACOS, and
ENDURANCE; (i) surgical adhesives containing cyanoacrylates such as
DERMABOND, INDERMIL, GLUSTITCH, VETBOND, HISTOACRYL, TISSUEMEND,
TISSUMEND II, HISTOACRYL BLUE and ORABASE SOOTHE-N-SEAL LIQUID
PROTECTANT or as described above, either alone, or loaded with a
fibrosis-inducing agent, applied to the implantation site (or the
implant/device surface); (j) implants containing hydroxyapatite (or
synthetic bone material such as calcium sulfate, VITOSS and
CORTOSS) loaded with a fibrosis-inducing agent applied to the
implantation site (or the implant/device surface); (k) other
biocompatible tissue fillers loaded with a fibrosis-inducing agent,
such as those made by BioCure, 3M Company and Neomend, loaded with
a fibrosis-inducing agent applied to the implantation site (or the
implant/device surface); (l) polysaccharide gels such as the ADCON
series of gels; (m) films, sponges or meshes such as INTERCEED,
VICRYL mesh, and GELFOAM either alone, or loaded with a
fibrosis-inducing agent, bone morphogenic protein, and/or growth
factor, injected into or around the joint; and/or (n) a hydrogel
that is formed from an amino-functionalized polyethylene glycol
(e.g., 4-armed tetra-amino PEG [10k]) and a 4-armed NHS
functionalized PEG (e.g., pentaerythritol poly(ethylene
glycol)ether tetra-succinimidyl glutarate [10K]). This hydrogel may
further contain collagen, methylated collagen and/or gelatin. This
hydrogel can further comprise the fibrosis-inducing agents
described above (e.g., silk powder or silk threads).(m) films,
sponges or meshes such as INTERCEED, VICRYL mesh, and GELFOAM
loaded with a fibrosis-inducing agent applied to the implantation
site (or the implant/device surface).
[0439] It should be apparent to one of skill in the art that
potentially any fibrosis-inducing agents described above may be
utilized alone, or in combination, in the practice of this
embodiment. Exemplary fibrosing agents for infiltration into the
tissues surrounding a joint prosthesis include talc, silk, wool,
chitosan, polylysine, fibronectin, bleomycin, and CTGF, as well as
analogues and derivatives of the aforementioned.
[0440] As joint prostheses are made in a variety of configurations
and sizes, the exact dose administered into the tissue surrounding
the implant can vary with device size, surface area and design.
However, certain principles can be applied in the application of
this art. Drug dose can be calculated as a function of dose per
unit area (of the implanted portion of the device), total drug dose
administered can be measured and appropriate surface concentrations
of active drug can be determined. Regardless of the method of
application of the drug, the exemplary fibrosing agents, used alone
or in combination, should be administered under the following
dosing guidelines:
[0441] Utilizing talc as an exemplary fibrosis-inducing agent,
whether it is applied using a polymeric carrier or applied without
a polymeric carrier, the total dose of talc delivered should not
exceed 100 mg (range of 1 .mu.g to 100 mg). In one embodiment, the
total amount of talc released from around the prosthesis should be
in the range of 10 .mu.g to 50 mg. The dose per unit area of the
device (i.e., the dosage of talc as a function of the surface area
of the implanted portion of the device) should fall within the
range of 0.05 .mu.g-10 .mu.g per mm.sup.2. In one embodiment, talc
is released such that fibrosis in the tissue is promoted for a
period ranging from several hours to several months. For example,
talc may be released in effective concentrations for a period
ranging from 1 hour-30 days. It should be readily evident given the
discussions provided herein that analogues and derivatives of talc
(as described previously) with similar functional activity can be
utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound
(e.g., a compound twice as potent as talc is administered at half
the above parameters, a compound half as potent as talc is
administered at twice the above parameters, etc.).
[0442] Utilizing silk as an exemplary fibrosis-inducing agent,
whether it is applied using a polymeric carrier or applied without
a polymeric carrier, the total dose of silk delivered into the
tissue surrounding a prosthesis should not exceed 100 mg (range of
1 .mu.g to 100 mg). In one embodiment, the total amount of silk
released around the prosthesis should be in the range of 10 .mu.g
to 50 mg. The dose per unit area of the device (i.e., the dosage of
silk as a function of the surface area of the portion of the device
which is implanted) should fall within the range of 0.05 .mu.g-10
.mu.g per mm.sup.2. As specific (polymeric and non-polymeric) drug
delivery vehicles can release silk at differing rates, the above
dosing parameters should be utilized in combination with the
release rate of the drug such that a minimum concentration of 0.01
nM to 1000 .mu.M of silk is delivered to the tissue. In one
embodiment, silk is released into the tissue surrounding a
prosthesis such that fibrosis in the tissue is promoted for a
period ranging from several hours to several months. For example,
silk may be released in effective concentrations for a period
ranging from 1 hour-30 days. It should be readily evident given the
discussions provided herein that analogues and derivatives of silk
(as described previously) with similar functional activity can be
utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound
(e.g., a compound twice as potent as silk is administered at half
the above parameters, a compound half as potent as silk is
administered at twice the above parameters, etc.).
[0443] Utilizing chitosan as an exemplary fibrosis-inducing agent,
whether it is applied using a polymeric carrier or applied without
a polymeric carrier, the total dose of chitosan delivered into the
tissue surrounding a prosthesis should not exceed 100 mg (range of
1 .mu.g to 100 mg). In one embodiment, the total amount of chitosan
released around the prosthesis should be in the range of 10 .mu.g
to 50 mg. The dose per unit area of the device (i.e., the dosage of
chitosan as a function of the surface area of the portion of the
device which is implanted) should fall within the range of 0.05
.mu.g-10 .mu.g per mm.sup.2. As specific (polymeric and
non-polymeric) drug delivery vehicles can release chitosan at
differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug such that a minimum
concentration of 0.01 nM to 1000 .mu.M of chitosan is delivered to
the tissue. In one embodiment, chitosan is released into the tissue
surrounding a prosthesis such that fibrosis in the tissue is
promoted for a period ranging from several hours to several months.
For example, chitosan may be released in effective concentrations
for a period ranging from 1 hour-30 days. It should be readily
evident given the discussions provided herein that analogues and
derivatives of chitosan (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
chitosan is administered at half the above parameters, a compound
half as potent as chitosan is administered at twice the above
parameters, etc.).
[0444] Utilizing polylysine as an exemplary fibrosis-inducing
agent, whether it is applied using a polymeric carrier or applied
without a polymeric carrier, the total dose of polylysine delivered
into the tissue surrounding a prosthesis should not exceed 100 mg
(range of 1 .mu.g to 100 mg). In one embodiment, the total amount
of polylysine released should be in the range of 10 .mu.g to 50 mg.
The dose per unit area of the device (i.e., the dosage of
polylysine as a function of the surface area of the implanted
portion of the device) should fall within the range of 0.05
.mu.g-10 .mu.g per mm.sup.2. As specific (polymeric and
non-polymeric) drug delivery vehicles can release polylysine at
differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug such that a minimum
concentration of 0.01 nM to 1000 .mu.M of polylysine is delivered
to the tissue. In one embodiment, polylysine is released into the
region surrounding a prosthesis such that fibrosis in the tissue is
promoted for a period ranging from several hours to several months.
For example, polylysine may be released in effective concentrations
for a period ranging from 1 hour-30 days. It should be readily
evident given the discussions provided herein that analogues and
derivatives of polylysine (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
polylysine is administered at half the above parameters, a compound
half as potent as polylysine is administered at twice the above
parameters, etc.).
[0445] Utilizing fibronectin as an exemplary fibrosis-inducing
agent, whether it is applied using a polymeric carrier or applied
without a polymeric carrier, the total dose of fibronectin
delivered into the tissue surrounding a prosthesis should not
exceed 100 mg (range of 1 .mu.g to 100 mg). In one embodiment, the
total amount of fibronectin released should be in the range of 10
.mu.g to 50 mg. The dose per unit area of the device (i.e., the
dosage of fibronectin as a function of the surface area of the
portion of the device which is implanted) should fall within the
range of 0.05 .mu.g-10 .mu.g per mm.sup.2. As specific (polymeric
and non-polymeric) drug delivery vehicles can release fibronectin
at differing rates, the above dosing parameters should be utilized
in combination with the release rate of the drug such that a
minimum concentration of 0.01 nM to 1000 .mu.M of fibronectin is
delivered to the tissue surrounding the prosthesis. In one
embodiment, fibronectin is released adjacent to the artificial
joint such that fibrosis in the tissue is promoted for a period
ranging from several hours to several months. For example,
fibronectin may be released in effective concentrations for a
period ranging from 1 hour-30 days. It should be readily evident
given the discussions provided herein that analogues and
derivatives of fibronectin (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
fibronectin is administered at half the above parameters, a
compound half as potent as fibronectin is administered at twice the
above parameters, etc.).
[0446] Utilizing bleomycin as an exemplary fibrosis-inducing agent,
whether it is applied using a polymeric carrier or applied without
a polymeric carrier, the total dose of bleomycin delivered into the
tissue surrounding a prosthesis should not exceed 100 mg (range of
0.01 .mu.g to 100 mg). In one embodiment, the total amount of
bleomycin released should be in the range of 0.10 .mu.g to 50 mg.
The dose per unit area of the device (i.e., the dosage of bleomycin
as a function of the surface area of the portion of the device
which is implanted) should fall within the range of 0.005 .mu.g-10
.mu.g per mm.sup.2. As specific (polymeric and non-polymeric) drug
delivery vehicles can release bleomycin at differing rates, the
above dosing parameters should be utilized in combination with the
release rate of the drug such that a minimum concentration of 0.001
nM to 1000 .mu.M of bleomycin is delivered to the tissue
surrounding the joint prosthesis. In one embodiment, bleomycin is
released around the prosthesis such that fibrosis in the tissue is
promoted for a period ranging from several hours to several months.
For example, bleomycin may be released in effective concentrations
for a period ranging from 1 hour-30 days. It should be readily
evident given the discussions provided herein that analogues and
derivatives of bleomycin (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
bleomycin is administered at half the above parameters, a compound
half as potent as bleomycin is administered at twice the above
parameters, etc.).
[0447] Utilizing CTGF as an exemplary fibrosis-inducing agent,
whether it is applied using a polymeric carrier or applied without
a polymeric carrier, the total dose of CTGF delivered into the
tissue surrounding a prosthesis should not exceed 100 mg (range of
0.01 .mu.g to 100 mg). In one embodiment, the total amount of CTGF
released should be in the range of 0.10 .mu.g to 50 mg. The dose
per unit area of the device (i.e., the dosage of CTGF as a function
of the surface area of the portion of the device which is
implanted) should fall within the range of 0.005 .mu.g-10 .mu.g per
mm.sup.2. As specific (polymeric and non-polymeric) drug delivery
vehicles can release CTGF at differing rates, the above dosing
parameters should be utilized in combination with the release rate
of the drug such that a minimum concentration of 0.001 nM to 1000
.mu.M of CTGF is delivered to the tissue surrounding the artificial
joint. In one embodiment, CTGF is released such that fibrosis in
the tissue is promoted for a period ranging from several hours to
several months. For example, CTGF may be released in effective
concentrations for a period ranging from 1 hour-30 days. It should
be readily evident given the discussions provided herein that
analogues and derivatives of CTGF (as described previously) with
similar functional activity can be utilized for the purposes of
this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as CTGF is administered at half the above parameters, a compound
half as potent as CTGF is administered at twice the above
parameters, etc.).
[0448] Optionally, the device may additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone) and/or a bone morphogenic protein (BMP) (e.g.,
BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or an analogue or
derivative thereof).
[0449] Bone morphogenic protein(s) (e.g., BMP-2, BMP-3, BMP-4,
BMP-5, BMP-6, or BMP-7 or an analogue or derivative thereof) are to
be used in formulations at concentrations that range from 0.001
.mu.g/ml to approximately 20 mg/ml depending on the specific
clinical application, formulation type (e.g., gel, liquid, solid,
semi-solid), formulation chemistry, duration of required
application, type of medical device interface and formulation
volume and or surface area coverage required. Preferably, the bone
morphogenic protein is released in effective concentrations for a
period ranging from 1-180 days. The total dose for a single
application is typically not to exceed 500 mg (range of 0.001 .mu.g
to 500 mg); preferred 1 .mu.g to 250 mg. When used as a device
coating, the dose is per unit area of 0.001 .mu.g-1000 .mu.g per
mm.sup.2; with a preferred dose of 0.01 .mu.g/mm.sup.2-200
.mu.g/mm.sup.2. Minimum concentration of 10.sup.-9-10.sup.4 M of
bone morphogenic protein is to be maintained on the device
surface.
[0450] Inflammatory cytokines are to be used in formulations at
concentrations that range from 0.0001 .mu.g/ml to approximately 20
mg/ml depending on the specific clinical application, formulation
type (e.g., gel, liquid, solid, semi-solid), formulation chemistry,
duration of required application, type of medical device interface
and formulation volume and or surface area coverage required.
Preferably, the inflammatory cytokine is released in effective
concentrations for a period ranging from 1-180 days. The total dose
for a single application is typically not to exceed 500 mg (range
of 0.0001 .mu.g to 100 mg); preferred 0.001 .mu.g to 50 mg. When
used as a device coating, the dose is per unit area of 0.0001
.mu.g-500 .mu.g per mm.sup.2; with a preferred dose of 0.001
.mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-10-10.sup.-4 g/ml of inflammatory cytokine is to be
maintained on the device surface.
[0451] Furthermore, the device may alone or additionally comprise
an agent that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof. Doses used are those
concentrations which are demonstrated to stimulate cell
proliferation (see, e.g., Example 16). The proliferative agents are
to be used in formulations at concentrations that range from 0.1
ng/ml to 25 mg/ml depending on the specific clinical application,
formulation type (e.g., gel, liquid, solid, semi-solid),
formulation chemistry, duration of required application, type of
medical device interface and formulation volume and or surface area
coverage required. Preferably, the proliferative agent is released
in effective concentrations for a period ranging from 1-180 days.
The total dose for a single application is typically not to exceed
500 mg (range of 0.0001 .mu.g to 200 mg); preferred 0.001 .mu.g to
100 mg. When used as a device coating, the dose is per unit area of
0.00001 .mu.g-500 .mu.g per mm.sup.2; with a preferred dose of
0.0001 .mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-11-10.sup.-6 M of proliferative agent is to be maintained
on the device surface.
[0452] It should be readily evident to one of skill in the art that
any of the previously described fibrosis inducing agents, or
derivatives and analogues thereof, can be utilized to create
variations of the above compositions without deviating from the
spirit and scope of the invention. It should also be apparent that
the agent can be utilized in a composition with or without polymer
carrier and that altering the carrier does not deviate from the
scope of this invention.
[0453] 3. Dental Devices
[0454] In one aspect, the present invention provides dental devices
and implants that include a fibrosis or adhesion-inducing agent to
assist in the incorporation of the implant into the surrounding
tissue. A variety of devices is used in dental applications.
Representative examples include dental implants and guided bone
regeneration devices.
[0455] In one aspect, a dental implant of specific importance is a
small titanium fixture that serves as a replacement for the root
portion of a missing natural tooth. The dental implant is placed in
the bone of the upper or lower jaw and functions as an anchor for
the replacement tooth. They may be used to support the replacement
of a single missing tooth or a complete functional set for
individuals who have lost many or all of their teeth. Dental
implants can be implanted in the bone (endosteal) or on the bone
(subperiosteal). Endosteal implants are the most commonly used type
of implant. There are various types of endosteal implants, which
may include screws, cylinders or blades surgically placed into the
jawbone. Each implant holds one or more prosthetic teeth. This type
of implant is generally used as an alternative for patients with
bridges or removable dentures. Subperiosteal implants are placed on
top of the jaw with the metal framework's posts protruding through
the gum to hold the prosthesis. These types of implants are used
for patients who are unable to wear conventional dentures and who
have minimal bone height.
[0456] A variety of dental implants suitable for combination with a
fibrosis-inducing agent have been described (see, e.g., U.S. Pat.
Nos. 6,627,321; 6,582,228; 6,572,373; 6,527,553; and
6,506,051).
[0457] In one aspect, the fibrosing agent may be incorporated into
the glue or cement that holds the device in place. In another
aspect, the dental device is covered (all or in part) with a silk
mesh or lattice to encourage scarring and anchoring into the
surrounding bone. For example, a silk mesh or lattice can be coated
onto all or a portion of the surface of the implant stem to
encourage scarring and anchoring into the surrounding bone.
[0458] In another aspect, the device used to deliver a
fibrosis-inducing agent may be a guided tissue regeneration (GTR)
device, such as a GTR membrane. A GTR membrane is a resorbable or
non-resorbable membrane made of biologically or non-biologically
derived material. GTR membranes may be used in conjunction with a
dental implant or to treat bone loss. GTR membranes may be made
from a variety of materials, including, e.g., collagen (e.g.,
porcine collagen, types I and II), PTFE, polylactic acid, lactide
and glycolide polymers, and ePTFE). GTR membranes are commercially
available from W.L. Gore & Associates (Newark, Del.) (e.g.,
GORE-TEX and GORE-RESOLUT regenerative material), Guidor, Atrix
Laboratories, Inc. (Fort Collins, Colo.), Geistlich Biomaterials,
Inc. (e.g., BIO-GIDE), LifeCore Biomedical, Inc. (Chaska, Minn.),
Ethicon Inc. (e.g., VICRYL), THM Biomedical now known as Kensey
Nash Corporation (Exton, Pa.), and Suzler Calcitek, Inc. (Carlsbad,
Calif.).
[0459] In another aspect, the dental device suitable for combining
with a fibrosis-inducing agent is used for guided bone regeneration
(GBR) to augment insufficient bone tissue and guide regrowth. GBR
devices include, e.g., resorbable bone substitutes for filling bony
defects. Such devices may consist of biomaterials (e.g.,
demineralized bone and bovine-derived materials) and synthetic
materials, such as crystalline hydroxyapatite and calcium sulfate.
A variety of dental bone substitutes are commercially available,
including the following products: OSTEOGRAF/N, OSTEOGRAF/LD,
OSTEOGRAF/D, AND PERMARIDGE (all from Ceramad), bioactive glass,
such as PERIOGLAS (U.S. Biomaterials), OSTEOGEN (Impladent, Inc.),
VITOSS and CORTOSS.
[0460] In another aspect, the present invention provides dental
implants containing a fibrosis-inducing agent for use in the
treatment of common periodontal conditions. Briefly, periodontal
disease is an inflammatory disease of the supporting structures of
the teeth, including the ligaments, cementum, periosteum, alveolar
bone and adjacent gingiva which anchor the teeth in place. The
condition begins with bleeding of the gums, but can progress to
loosening of the teeth, receding gums, abscesses in pockets between
the gums and the teeth, and necrotizing ulcerative gingivitis. In
advanced stages, procedures such as gingivectomy, gingivoplasty,
and correction of the bony architecture of the teeth may be
required for treatment of the condition. Traditional treatment
involves open-flap debridement of the periodontal pocket with
removal of diseased cementum, periodontal ligament and alveolar
bone that have been destroyed by periodontal infection.
Unfortunately, epithelial tissue can occasionally migrate into the
surgically created defect impairing proper healing of the cementum,
ligament and bone.
[0461] Dental implants have been developed in an attempt to control
the healing process and optimize tissue regeneration. Commonly used
implants include permanent implants, such as e-PTFE membranes
(e.g., GORE-TEX from W.L. Gore). Commonly used implants include,
e.g., BIOMEND, available from Sulzer Medica, Inc. (Houston, Tex.),
which is a collagen membrane composed of compressed Type I collagen
matrix derived from bovine Achilles tendon. The collagen membrane
(supplied as sheets, e.g., 15 mm.times.20 mm; 20 mm.times.30 mm;
and 30 mm.times.40 mm) is cut to the appropriate size and shape,
hydrated and placed as a barrier between the overlying gingival
tissue and the debrided periodontal defect; the barrier can be
sutured in place, but this is not always required. The membrane is
placed snugly against the tooth root and draped over the
surrounding alveolar bone (extending at least 3 mm beyond the
defect margins) to effectively maintain the regenerative space.
Primary closure with mucoperiosteal flaps over the collagen
membrane is important as exposure of the membrane to the oral
cavity can result in premature degradation. The barrier prevents
faster growing epithelial tissue from entering the region and
allows the slower growing periodontal ligament and bone cells to
repopulate the area and effect appropriate healing. The collagen
membrane is bioresorbable, is retained for 6 to 7 weeks, and is
fully absorbed by host enzymes (e.g., collagenase) within 8
weeks.
[0462] However, limited durability of the collagen implant can
become a clinical problem if it completely absorbs prior to the
completion of healing--this is particularly relevant with large
tissue defects. In an attempt to address this problem,
manufacturers have attempted to produce a collagen implant with
improved durability through increased collagen crosslinking (often
through exposure of the collagen to aldehydes). Utilizing this
process, products such as BIOMEND EXTEND (Sulzer Medica, Inc.) can
function as a barrier for longer periods of time, such that the
collagen is not absorbed into the surrounding tissue for
approximately 18 weeks. Another collagen dental implant product,
OSSIX (Colbar R&D Ltd., Israel), uses a metabolite to crosslink
collagen and prolong the structural integrity of the matrix for
periods of up to 6 months.
[0463] In addition to the commercially available collagen-based
products for the management of periodontal disease described above,
other types of collagen-based implants may be used in the practice
of the invention. Representative examples of such implants include
those that are used in variety of dental procedures including:
COLLATAPE (Sulzer Medica, Inc.), which is a collagen-based implant
used in the repair of minor oral wounds, closure of grafted sites
and repair of Schneiderian Membranes; COLLACOTE (Sulzer Medica,
Inc.), a collagen-based wound dressing used for palatal donor sites
and in mucosal flaps; and COLLAPLUG (Sulzer Medica, Inc.), a solid
collagen-based implant used in the repair of larger tissue defects
such extraction sites or biopsy sites.
[0464] In one aspect, the present invention provides dental devices
that include a fibrosis-inducing agent or a composition that
includes a fibrosis-inducing agent to promote fibrosis in the
periodontal pocket. In one aspect, the dental device or material
used to fill or maintain the periodontal pocket is coated with,
composed of, or contains a fibrosing agent or a composition that
includes a fibrosing agent.
[0465] Numerous polymeric and non-polymeric carrier systems
described above can be used in the practice of this embodiment.
These compositions can further include one or more
fibrosis-inducing agents to promote the formation of fibrous tissue
around the dental implant. Methods for incorporating fibrosing
compositions onto or into the dental implant (such as endosteal or
perioosteal titanium implants) include: (a) directly affixing to
the dental hardware a fibrosing composition (e.g., by either a
spraying process or dipping process as described above, with or
without a carrier); (b) directly incorporating into the dental
hardware a fibrosing composition (e.g., by either a spraying
process or dipping process as described above, with or without a
carrier); (c) by coating the dental hardware with a substance such
as a hydrogel which can in turn absorb the fibrosing composition;
(d) by interweaving a thread coated with a fibrosis-inducing
composition (or the a fibrosis-inducing polymer itself formed into
a thread) into the device structure; (e) by inserting the device
into a sleeve or mesh which is comprised of, or coated with, a
fibrosing composition; (f) constructing the device itself, or a
portion of the device, with a composition containing a fibrosing
agent; or (g) by covalently binding the fibrosing agent directly to
the device surface or to a linker (small molecule or polymer) that
is coated or attached to the device surface. For dental hardware
devices, the coating process can be performed in such a manner as
to (a) coat the surfaces of the device that is in contact with the
bone, (b) coat the surfaces of the device that are not in contact
with the bone or (c) coat all or parts of both the bone-contacting
and non-bone contacting surface of the device. In addition to
coating the device with the fibrosing composition, the fibrosing
agent can be mixed with the materials that are used to make the
device such that the fibrosing agent is incorporated into the final
device.
[0466] For the management of periodontal disease, polymeric gels,
pastes, injectables, solutions, microparticles and solid implants
placed into the periodontal pocket are a preferred form of locally
delivering a fibrosis-inducing agent. All involve the deployment of
a biomaterial containing a fibrosis-inducing agent into the
surgically-created periodontal pocket (as described above). The
practice of this embodiment can be performed in several ways
including: (a) topical application of the fibrosing agent onto the
periodontal pocket (particularly useful for this embodiment is the
use of polymeric carriers which release the fibrosing agent over a
period ranging from several hours to several weeks--fluids,
suspensions, emulsions, microemulsions, microspheres, pastes, gels,
microparticulates, sprays, aerosols, solid implants and other
formulations which release a fibrosing agent and can be delivered
into the region via specialized delivery catheters or other
applicators); (b) placement of microparticulate silk and/or silk
strands (linear, branched, and/or coiled) into the periodontal
pocket; (c) sprayable collagen-containing formulations such as
COSTASIS or materials made from 4-armed thiol PEG (10K), a 4-armed
NHS PEG(10K) and methylated collagen such as described above,
either alone, or loaded with a fibrosis-inducing agent, applied
into periodontal pocket; (d) sprayable PEG-containing formulations
such as COSEAL, FOCALSEAL, SPRAYGEL or DURASEAL, either alone, or
loaded with a fibrosis-inducing agent, applied to the periodontal
pocket; (e) fibrinogen-containing formulations such as FLOSEAL or
TISSEAL, either alone, or loaded with a fibrosis-inducing agent,
applied to the periodontal pocket; (f) hyaluronic acid-containing
formulations such as RESTYLANE, HYLAFORM, PERLANE, SYNVISC,
SEPRAFILM, SEPRACOAT loaded with a fibrosis-inducing agent applied
to the periodontal pocket; (g) polymeric gels for surgical
implantation such as REPEL or FLOWGEL loaded with a
fibrosis-inducing agent applied to the periodontal pocket; (h)
orthopedic "cements" such as OSTEOBOND, LVC, SIMPLEX P, PALACOS,
ENDURANCE, and CORTOSS loaded with a fibrosis-inducing agent
applied to the periodontal pocket; (i) surgical adhesives
containing cyanoacrylates such as DERMABOND, INDERMIL, GLUSTITCH,
VETBOND, HISTOACRYL, TISSUEMEND, TISSUMEND II, HISTOACRYL BLUE and
ORABASE SOOTHE-N-SEAL LIQUID PROTECTANT or as described above
loaded with a fibrosis-inducing agent, applied to the periodontal
pocket; (j) surgical implants containing hydroxyapatite, calcium
sulfate, or VITOSS loaded with a fibrosis-inducing agent applied to
the periodontal pocket; (k) other biocompatible tissue fillers,
such as those made by BioCure, 3M Company and Neomend, loaded with
a fibrosis-inducing agent, applied to the periodontal pocket; (l)
polysaccharide gels such as the ADCON series of gels loaded with a
fibrosis-inducing agent applied to the periodontal pocket; (m)
films, sponges or meshes such as INTERCEED, VICRYL mesh, and
GELFOAM loaded with a fibrosis-inducing agent applied to the
periodontal pocket; and/or (n) a hydrogel that is formed from an
amino-functionalized polyethylene glycol (e.g., 4-armed tetra-amino
PEG [10k]) and a 4-armed NHS functionalized PEG (e.g.,
pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl
glutarate [10K]). This hydrogel may further contain collagen,
methylated collagen and/or gelatin. This hydrogel can further
comprise the fibrosis-inducing agents described above (e.g., silk
powder or silk threads).
[0467] In many of the embodiments described above it may also be
useful to add a radio-opaque material (such as tantalum, barium,
other metal, or contrast material) such that the injected material
can be visualized radiographically or by MRI. The contrast agent
may be a water soluble or water insoluble radio-opaque
material.
[0468] It should be apparent to one of skill in the art that
potentially any adhesion or fibrosis-inducing agents described
above may be utilized alone, or in combination, in the practice of
this embodiment. Exemplary fibrosing agents for use in dental
prostheses include talc, silk, wool, chitosan, polylysine,
fibronectin, bleomycin, and CTGF, as well as analogues and
derivatives of the aforementioned.
[0469] Optionally, the device may additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone) or a bone morphogenic protein (BMP) (e.g., BMP-2,
BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or an analogue or derivative
thereof).
[0470] As dental prostheses are made in a variety of configurations
and sizes, the exact dose administered can vary with device size,
surface area and design. However, certain principles can be applied
in the application of this art. Drug dose can be calculated as a
function of dose per unit area (of the portion of the device being
coated), total drug dose administered can be measured and
appropriate surface concentrations of active drug can be
determined. Regardless of the method of application of the drug to
the dental prostheses or periodontal implant, the exemplary
fibrosing agents, used alone or in combination, should be
administered under the following dosing guidelines:
[0471] Utilizing talc as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of talc delivered from
a dental prosthesis, or coated onto the surface of a dental
prosthesis, should not exceed 100 mg (range of 1 .mu.g to 100 mg).
In one embodiment, the total amount of talc released from the
prosthesis should be in the range of 10 .mu.g to 50 mg. The dose
per unit area of the device (i.e., the dosage of talc as a function
of the surface area of the portion of the device to which drug is
applied and/or incorporated) should fall within the range of 0.05
.mu.g-10 .mu.g per mm.sup.2 of surface area coated. In another
embodiment, talc should be applied to a dental prosthesis surface
at a dose of 0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area
coated. In one embodiment, talc is released from the surface of a
dental prosthesis such that fibrosis in the tissue is promoted for
a period ranging from several hours to several months. For example,
talc may be released in effective concentrations for a period
ranging from 1 hour-30 days. It should be readily evident given the
discussions provided herein that analogues and derivatives of talc
(as described previously) with similar functional activity can be
utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound
(e.g., a compound twice as potent as talc is administered at half
the above parameters, a compound half as potent as talc is
administered at twice the above parameters, etc.).
[0472] Utilizing silk as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of silk delivered from
a dental prosthesis, or coated onto the surface of a dental
prosthesis, should not exceed 100 mg (range of 1 .mu.g to 100 mg).
In one embodiment, the total amount of silk released from the
prosthesis should be in the range of 10 .mu.g to 50 mg. The dose
per unit area of the device (i.e., the dosage of silk as a function
of the surface area of the portion of the device to which drug is
applied and/or incorporated) should fall within the range of 0.05
.mu.-10 .mu.g per mm.sup.2 of surface area coated. In another
embodiment, silk should be applied to a dental prosthesis surface
at a dose of 0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area
coated. As specific (polymeric and non-polymeric) drug delivery
vehicles and specific medical devices can release silk at differing
rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the dental
prosthesis such that a minimum concentration of 0.01 nM to 1000
.mu.M of silk is delivered to the tissue. In one embodiment, silk
is released from the surface of a dental prosthesis such that
fibrosis in the tissue is promoted for a period ranging from
several hours to several months. For example, silk may be released
in effective concentrations for a period ranging from 1 hour-30
days. It should be readily evident given the discussions provided
herein that analogues and derivatives of silk (as described
previously) with similar functional activity can be utilized for
the purposes of this invention; the above dosing parameters are
then adjusted according to the relative potency of the analogue or
derivative as compared to the parent compound (e.g., a compound
twice as potent as silk is administered at half the above
parameters, a compound half as potent as silk is administered at
twice the above parameters, etc.).
[0473] Utilizing chitosan as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of chitosan delivered
from a dental prosthesis, or coated onto the surface of a dental
prosthesis, should not exceed 100 mg (range of 1 .mu.g to 100 mg).
In one embodiment, the total amount of chitosan released from the
prosthesis should be in the range of 10 .mu.g to 50 mg. The dose
per unit area of the device (i.e., the dosage of chitosan as a
function of the surface area of the portion of the device to which
drug is applied and/or incorporated) should fall within the range
of 0.05 .mu.g-10 .mu.g per mm.sup.2 of surface area coated. In
another embodiment, chitosan should be applied to a dental
prosthesis surface at a dose of 0.05 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific medical devices
can release chitosan at differing rates, the above dosing
parameters should be utilized in combination with the release rate
of the drug from the dental prosthesis such that a minimum
concentration of 0.01 nM to 1000 .mu.M of chitosan is delivered to
the tissue. In one embodiment, chitosan is released from the
surface of a dental prosthesis such that fibrosis in the tissue is
promoted for a period ranging from several hours to several months.
For example, chitosan may be released in effective concentrations
for a period ranging from 1 hour-30 days. It should be readily
evident given the discussions provided herein that analogues and
derivatives of chitosan (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
chitosan is administered at half the above parameters, a compound
half as potent as chitosan is administered at twice the above
parameters, etc.).
[0474] Utilizing polylysine as a exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of polylysine delivered
from a dental prosthesis, or coated onto the surface of a dental
prosthesis, should not exceed 100 mg (range of 1 .mu.g to 100 mg).
In one embodiment, the total amount of polylysine released from the
prosthesis should be in the range of 10 .mu.g to 50 mg. The dose
per unit area of the device (i.e., the dosage of polylysine as a
function of the surface area of the portion of the device to which
drug is applied and/or incorporated) should fall within the range
of 0.05 .mu.g-10 .mu.g per mm.sup.2 of surface area coated. In
another embodiment, polylysine should be applied to a dental
prosthesis surface at a dose of 0.05 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific medical devices
can release polylysine at differing rates, the above dosing
parameters should be utilized in combination with the release rate
of the drug from the dental prosthesis such that a minimum
concentration of 0.01 nM to 1000 .mu.M of polylysine is delivered
to the tissue. In one embodiment, polylysine is released from the
surface of a dental prosthesis such that fibrosis in the tissue is
promoted for a period ranging from several hours to several months.
For example, polylysine may be released in effective concentrations
for a period ranging from 1 hour-30 days. It should be readily
evident given the discussions provided herein that analogues and
derivatives of polylysine (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
polylysine is administered at half the above parameters, a compound
half as potent as polylysine is administered at twice the above
parameters, etc.).
[0475] Utilizing fibronectin as an exemplary fibrosis-inducing
agent, whether it is applied using a polymer coating, incorporated
into the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of fibronectin
delivered from a dental prosthesis, or coated onto the surface of a
dental prosthesis, should not exceed 100 mg (range of 1 .mu.g to
100 mg). In one embodiment, the total amount of fibronectin
released from the prosthesis should be in the range of 10 .mu.g to
50 mg. The dose per unit area of the device (i.e., the dosage of
fibronectin as a function of the surface area of the portion of the
device to which drug is applied and/or incorporated) should fall
within the range of 0.05 .mu.g-10 .mu.g per mm.sup.2 of surface
area coated. In another embodiment, talc should be applied to a
dental prosthesis surface at a dose of 0.05 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific medical devices
can release fibronectin at differing rates, the above dosing
parameters should be utilized in combination with the release rate
of the drug from the dental prosthesis such that a minimum
concentration of 0.01 nM to 1000 .mu.M of fibronectin is delivered
to the tissue. In one embodiment, fibronectin is released from the
surface of a dental prosthesis such that fibrosis in the tissue is
promoted for a period ranging from several hours to several months.
For example, fibronectin may be released in effective
concentrations for a period ranging from 1 hour-30 days. It should
be readily evident given the discussions provided herein that
analogues and derivatives of fibronectin (as described previously)
with similar functional activity can be utilized for the purposes
of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as fibronectin is administered at half the above parameters, a
compound half as potent as fibronectin is administered at twice the
above parameters, etc.).
[0476] Utilizing bleomycin as a exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of bleomycin delivered
from a dental prosthesis, or coated onto the surface of a dental
prosthesis, should not exceed 100 mg (range of 0.01 .mu.g to 100
mg). In one embodiment, the total amount of bleomycin released from
the prosthesis should be in the range of 0.10 .mu.g to 50 mg. The
dose per unit area of the device (i.e., the dosage of bleomycin as
a function of the surface area of the portion of the device to
which drug is applied and/or incorporated) should fall within the
range of 0.005 .mu.g-10 .mu.g per mm.sup.2 of surface area coated.
In another embodiment, bleomycin should be applied to a dental
prosthesis surface at a dose of 0.005 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific medical devices
can release bleomycin at differing rates, the above dosing
parameters should be utilized in combination with the release rate
of the drug from the dental prosthesis such that a minimum
concentration of 0.001 nM to 1000 .mu.M of bleomycin is delivered
to the tissue. In one embodiment, bleomycin is released from the
surface of a dental prosthesis such that fibrosis in the tissue is
promoted for a period ranging from several hours to several months.
For example, bleomycin may be released in effective concentrations
for a period ranging from 1 hour-30 days. It should be readily
evident given the discussions provided herein that analogues and
derivatives of bleomycin (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
bleomycin is administered at half the above parameters, a compound
half as potent as bleomycin is administered at twice the above
parameters, etc.).
[0477] Utilizing CTGF as a exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of CTGF delivered from
a dental prosthesis, or coated onto the surface of a dental
prosthesis, should not exceed 100 mg (range of 0.01 .mu.g to 100
mg). In one embodiment, the total amount of CTGF released from the
prosthesis should be in the range of 0.10 .mu.g to 50 mg. The dose
per unit area of the device (i.e., the dosage of CTGF as a function
of the surface area of the portion of the device to which drug is
applied and/or incorporated) should fall within the range of 0.005
.mu.g-10 .mu.g per mm.sup.2 of surface area coated. In another
embodiment, CTGF should be applied to a dental prosthesis surface
at a dose of 0.005 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area
coated. As specific (polymeric and non-polymeric) drug delivery
vehicles and specific medical devices can release CTGF at differing
rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the dental
prosthesis such that a minimum concentration of 0.001 nM to 1000
.mu.M of CTGF is delivered to the tissue. In one embodiment, CTGF
is released from the surface of a dental prosthesis such that
fibrosis in the tissue is promoted for a period ranging from
several hours to several months. For example, CTGF may be released
in effective concentrations for a period ranging from 1 hour-30
days. It should be readily evident given the discussions provided
herein that analogues and derivatives of CTGF (as described
previously) with similar functional activity can be utilized for
the purposes of this invention; the above dosing parameters are
then adjusted according to the relative potency of the analogue or
derivative as compared to the parent compound (e.g., a compound
twice as potent as CTGF is administered at half the above
parameters, a compound half as potent as CTGF is administered at
twice the above parameters, etc.).
[0478] Bone morphogenic protein(s) (e.g., BMP-2, BMP-3, BMP-4,
BMP-5, BMP-6, or BMP-7 or an analogue or derivative thereof), if
present, are to be used in formulations at concentrations that
range from 0.001 .mu.g/ml to approximately 20 mg/ml depending on
the specific clinical application, formulation type (e.g., gel,
liquid, solid, semi-solid), formulation chemistry, duration of
required application, type of medical device interface and
formulation volume and or surface area coverage required.
Preferably, the bone morphogenic protein is released in effective
concentrations for a period ranging from 1-180 days. The total dose
for a single application is typically not to exceed 500 mg (range
of 0.001 .mu.g to 500 mg); preferred 1 .mu.g to 250 mg. When used
as a device coating, the dose is per unit area of 0.001 .mu.g-1000
.mu.g per mm.sup.2; with a preferred dose of 0.01
.mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-9-10.sup.-4 M of bone morphogenic protein is to be
maintained on the device surface.
[0479] Inflammatory cytokines, if present, are to be used in
formulations at concentrations that range from 0.0001 .mu.g/ml to
approximately 20 mg/ml depending on the specific clinical
application, formulation type (e.g., gel, liquid, solid,
semi-solid), formulation chemistry, duration of required
application, type of medical device interface and formulation
volume and or surface area coverage required. Preferably, the
inflammatory cytokine is released in effective concentrations for a
period ranging from 1-180 days. The total dose for a single
application is typically not to exceed 500 mg (range of 0.0001
.mu.g to 100 mg); preferred 0.001 .mu.g to 50 mg. When used as a
device coating, the dose is per unit area of 0.0001 .mu.g-500 .mu.g
per mm.sup.2; with a preferred dose of 0.001 .mu.g/mm.sup.2-200
.mu.g/mm.sup.2. Minimum concentration of 10.sup.-10-10.sup.-4 g/ml
of inflammatory cytokine is to be maintained on the device
surface.
[0480] Furthermore, the device may alone or additionally comprise
an agent that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof. Doses used are those
concentrations which are demonstrated to stimulate cell
proliferation (see, e.g., Example 16). The proliferative agents are
to be used in formulations at concentrations that range from 0.0.1
ng/ml to 25 mg/ml depending on the specific clinical application,
formulation type (e.g., gel, liquid, solid, semi-solid),
formulation chemistry, duration of required application, type of
medical device interface and formulation volume and or surface area
coverage required. Preferably, the proliferative agent is released
in effective concentrations for a period ranging from 1-180 days.
The total dose for a single application is typically not to exceed
500 mg (range of 0.0001 .mu.g to 200 mg); preferred 0.001 .mu.g to
100 mg. When used as a device coating, the dose is per unit area of
0.00001 .mu.g-500 .mu.g per mm.sup.2; with a preferred dose of
0.0001 .mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-11-10.sup.-6 M of proliferative agent is to be maintained
on the device surface.
[0481] It should be readily evident to one of skill in the art that
any of the previously described fibrosis inducing agents, or
derivatives and analogues thereof, can be utilized to create
variations of the above compositions without deviating from the
spirit and scope of the invention. It should also be apparent that
the agent can be utilized in a composition with or without polymer
carrier and that altering the carrier does not deviate from the
scope of this invention.
[0482] 4. Orthopedic Implants
[0483] In one aspect, the present invention provides orthopedic
implants that include a fibrosis-inducing agent or a composition
that includes a fibrosis-inducing agent to promote scarring and
fixation of the device into the surrounding bone or tissue.
[0484] (i) Orthopedic Hardware Coated with a Fibrosis-Inducing
Agent
[0485] In one aspect, the orthopedic implant is an orthopedic
"hardware" device that has been coated with a fibrosing agent or a
fibrosing agent containing composition. Representative examples of
orthopedic hardware devices include internal and external fixation
devices, fixation screws (degradable or non-degradable),
interferential screws (degradable and non-degradable), trochanteric
screws, plates, wires (e.g., K-wires), pins, and nails used in
fracture repairs, reconstructive procedures, and joint fusion
procedures (e.g., ankle fusions, cervical and lumbar spinal
fusions). Compositions also are provided for coating devices used
in fusion procedures and superior repair of fractures. Orthopedic
implants such as, for example, fixation screws, pins, plates,
nails, wires and plates coated with a fibrosing agent, coated with
a composition containing a fibrosing agent, or composed of a
polymer that releases a fibrosing agent (particularly for
polymeric, biodegradable orthopedic hardware) are used to encourage
better anchorage of the implant into the surrounding bone.
Alternatively, or in addition, the fibrosing agent may be
incorporated into the glue or cement that holds the implant in
place. In another aspect, the orthopedic hardware is covered (all
or in part) with a silk mesh or lattice to encourage scarring and
anchoring into the surrounding bone. For example, a silk mesh or
lattice can be coated onto all or a portion of the surface of the
implant stem to encourage scarring and anchoring into the
surrounding bone.
[0486] In another aspect, the orthopedic implant is a collagen
implant for use as a substitute for autogenous or allogenous bone
grafts. A variety of collagen implants have been developed for use
in orthopedic surgery as a substitute for autogenous or allogenous
bone grafts. Collagen is the principle organic component of bone
and can be combined with mineral formulations, autogenous bone
marrow, bone graft, and/or growth factors (such as BMPs) for use as
a bone substitute or a skeletal repair product. Typical
applications include, but are not restricted to, total joint
replacement surgery (e.g., artificial hips, knees, etc.), spinal
fusion surgery, long bone fractures, repair of traumatic bone
defects, voids, or gaps, to augment an autograft, and as a bone
filler at bone graft harvesting sites. Examples of commercially
available collagen-based bone grafts include COLLAGRAFT Paste and
COLLAGRAFT Strips made by Angiotech Pharmaceuticals, Inc.
COLLAGRAFT is a combination of highly purified Type I bovine dermal
fibrillar collagen and a mixture of 65% hydroxyapatite and 35%
tricalcium phosphate. This material closely resembles human bone
and is resorbed and replaced with bone during the healing process.
Representative examples of bone grafts are described in U.S. Pat.
Nos. 6,083,522 and 6,280,474 and in PCT Publication No. WO
98/52498.
[0487] Numerous polymeric and non-polymeric carrier systems
described above can be used in the practice of this embodiment.
These compositions can further include one or more
fibrosis-inducing agents to promote the formation of granulation
tissue (described further in section (iii) below). Methods for
incorporating fibrosing compositions onto or into the orthopedic
implants include: (a) directly affixing to the device a fibrosing
composition (e.g., by either a spraying process or dipping process
as described above, with or without a carrier); (b) directly
incorporating into the device a fibrosing composition (e.g., by
either a spraying process or dipping process as described above,
with or without a carrier); (c) by coating the device with a
substance such as a hydrogel which can in turn absorb the fibrosing
composition; (d) by interweaving into the device a thread coated
with a fibrosing composition (or a polymeric version of the
fibrosing agent is itself formed into a thread); (e) by inserting
the device into a sleeve or mesh which is comprised of, or coated
with, a fibrosing composition; (f) constructing the device itself
or a portion of the device with a fibrosing composition
(particularly effective for biodegradable orthopedic hardware and
collagen implants); or (g) by covalently binding the fibrosing
agent directly to the device surface or to a linker (small molecule
or polymer) that is coated or attached to the device surface. For
these devices, the coating process can be performed in such a
manner as to (a) coat the surfaces of the device that is in contact
with the bone; (b) coat the surfaces of the device that are not in
contact with bone, or (c) coat all or parts of both the
bone-contacting and non-bone contacting surface of the device.
[0488] It should be apparent to one of skill in the art that
potentially any adhesion or fibrosis-inducing agent may be utilized
alone, or in combination, in the practice of this embodiment as
described above. Exemplary fibrosing agents for use in the coating
of orthopedic hardware include talc, silk, wool, chitosan,
polylysine, fibronectin, bleomycin, and/or CTGF as well as
analogues and derivatives of the aforementioned. The correct
administration and dosage is the same as that described previously
in section 2(i), 2(ii) and 2(iii) for artificial hips, knees and
shoulder prostheses.
[0489] (ii) Minimally-Invasive Joint Fusion
[0490] In another aspect, the present invention provides injectable
compositions to promote scarring and fixation (immobilization) of a
joint without the need for open surgery. In some clinical
situations it is desirable to immobilize a joint that has been
severely damaged or is the cause of chronic pain. For example, a
composition including an adhesion or fibrosis-inducing agent may be
injected into an arthritic or damaged joint to promote scarring and
fixation (i.e., immobilization) of the joint (particularly
interphalageal joints, tarsal-metatarsal joints, metacarpal joints,
ankle joints, knee joints, proximal tibia-fibular joint, hip joint,
sacro-iliac joint, acromio-clavicular joint, sterno-clavicular
joint and facet joints in the cervical, thoracic, and lumbar
spine). In this procedure, a needle is inserted into the joint
cavity, a guidewire is advanced into the joint space, a dual lumen
catheter (for many of the hydrogels described below such as a
material made from 4-armed thiol PEG (10K), a 4-armed NHS PEG(10K)
and methylated collagen such as described above, COSEAL, COSTASIS,
FLOSEAL, TISSEAL, VITOSS) or a single lumen catheter (for materials
such as cyanoacrylate, CORTOSS, bone cement, hydroxyapatite,
calcium phosphate, calcium sulfate, hyaluronic acid, proteins,
carbohydrates, sclerosing agents, and the like) is advanced over
the guidewire into the articular space, the guidewire is removed,
and a composition containing a fibrosis-inducing agent, bone
morphogenic protein(s), and/or osteogenic growth factor (such as
transforming growth factor, platelet-derived growth factor,
fibroblast growth factor) is injected via the catheter into joint
until the joint space is filled. Agents such as collagenase,
chymopapain, or other tissue-degrading enzymes may also be used to
chemically degrade the remaining cartilage prior to, or during, the
injection of the joint-fusing composition. Over time, the
fibrosis-inducing agent, bone morphogenic protein, and/or
osteogenic growth factor can encourage fibrous ankylosis, followed
by bony ankylosis of the treated joint, leading to decreased (or
complete loss of) range of motion, stability, and/or reduced
pain.
[0491] When performing direct injection of the joint, techniques
can be used to enhance visualization of needle (or catheter)
placement within the joint space including, but not limited to, the
use of a needle coated with ECHO--COAT, the injection of air to
enable localization by ultrasound, or the addition of contrast
agents (barium, tantalum, technitium, gadolinium, and the like) for
localization by x-ray or MRI.
[0492] One method of administration, the fibrosing agent and/or
osteogenic agent is delivered under direct vision during
arthroscopic evaluation of the joint. Here the composition
containing the fibrosis-inducing agent, bone morphogenic protein,
and/or osteogenic growth factor is injected into the articular
space through the side port of an arthroscope, preferably after the
remaining articular cartilage has been mechanically or chemically
debrided. In some cases, the fibrosis-inducing agent may also be
delivered directly to the tissue during open joint fusion surgery
to enhance the efficacy of this procedure.
[0493] The injectable material may be also composed of an
injectable polymer system for use in minimally invasive joint
fusion. Additionally, the polymer system can provide sustained
release of the fibrosis-inducing agent, bone morphogenic protein,
and/or osteogenic growth factor to enhance efficacy and reduce the
need for repeated intra-articular administrations of active agents.
The injection material suitable for delivery of a fibrosis-inducing
agent, bone morphogenic protein, and/or growth factor that promotes
bone growth for the purposes of this invention can be composed of a
non-degradable or a degradable material. Suitable non-degradable
materials can include crosslinked compositions that comprise PVA,
PVP, polyacrylamide, methyl methacrylate (MMA) and methyl
methacrylate styrene (MMA-styrene) which when mixed together form
polymethyl methacrylate (PMMA) or bone cement (e.g., SIMPLEX P,
ZIMMER REGULAR and ZIMMER LOW VISCOSITY CEMENT, PALACOS, CMW-1 and
CMW-2, ENDURANCE, synthetic cancellous bone void fillers (e.g.,
CORTOSS), pHEMA, poly(vinyl PEG), poly(styrene sulfonate),
poly(acrylic acid), poly(methacrylic acid), as well as other
polymers that are known to form hydrogels. Additional compositions
include blends and copolymers of the agents listed above. Suitable
degradable materials include, but are not limited to, resorbable
ceramics composed of .beta.-tricalcium phosphate (e.g., VITOSS,
PROOSTEON 500R), hydroxyapatite or Ca.sub.10(PO.sub.4).sub- .6OH
(e.g., BIOOSS, OSTEOGRAF), calcium carbonate or CaCO.sub.3, calcium
sulfate (e.g., OSTEOSET and ALLOMATRIX), calcium phosphate (e.g.,
CALCIBON or NORIAN SRS), crosslinked materials of PEG, gelatin,
collagen, bone allografts (e.g., ALLOGRO, ORTHOBLAST, OPTEFORM,
GRAFTON), mesenchymal stem cells, hyaluronic acid, hyaluronic acid
derivatives, polysaccharides, carbohydrates, proteins (e.g.,
albumin, casein, whey proteins, plant proteins, or fish proteins,
and the like), autologous bone, demineralized bone matrix,
cellulose derivatives (e.g., HPC), chitosan, chitosan derivatives,
polyester-polyalkylene oxide block copolymers (e.g., PLGA-PEG-PLGA
or MePEG-PLGA) and other low molecular weight polymers that can be
excreted. One material that is of particular interest is prepared
from a 4-armed thiol PEG (10K), a 4-armed NHS PEG(10K) and
methylated collagen such as described above. In one embodiment, the
injectable material also contains a biologically active agent
capable of inducing fibrosis and ankylosis in the treated joint.
Preferred biologically active agents include fibrosis-inducing
agents, bone morphogenic proteins, and growth factors (transforming
growth factor, platelet-derived growth factor, fibroblast growth
factor), whose dosages and release kinetics are all described in
detail in section (iii) below.
[0494] In addition to, or in lieu of, fibrosis-inducing agents,
bone morphogenic proteins and growth factors, the injectable
material can be utilized to deliver a sclerosant to the articular
space. Sclerosants include compounds such as ethanol, DMSO,
surfactants, sucrose, NaCl, dextrose, glycerin, minocycline,
tetracycline, doxycycline, polidocanol, sodium tetradecyl sulfate,
sodium morrhuate, sotradecol and others. The hydrogel can further
comprise agents such as glycerol, glycerin, PEG 200, triethyl
citrate, and triacetin as plasticizers.
[0495] The injectable materials described above can further
modified to be comprised of, or contain, polymeric threads.
Polymeric threads have the ability to induce a fibroproliferative
response from the surrounding tissue. These polymer threads can be
degradable or non-degradable. Degradable threads can be composed of
degradable polyesters, polyanhydrides, poly(anhydride esters),
poly(ester-amides), poly(ester-ureas), polyorthoesters,
polyphosphoesters, polyphosphazines, cyanoacrylate polymers,
collagen, chitosan, hyaluronic acid, chromic cat gut, alginates,
starch, cellulose, cellulose esters, blends and copolymers thereof,
as well as other known degradable polymers. Non-degradable polymers
that can be used include, but are not limited to, polyesters (e.g.,
PET), polyurethanes, silicones, PE, PP, PS, PAA, PMA, silk, blends,
copolymers thereof as well as others known polymers. The threads
used can be composed of a single composition or composed of a blend
of differing compositions. The polymeric threads themselves can be
further modified through the addition of a polymeric coating
applied to the threads. The polymer used for coating the thread can
be similar to that described above for the threads themselves. The
polymer coating may further comprise a biologically active agent
that has the ability to induce a fibroproliferative or osteogenic
response. The agents that can be used are further described in the
section (iii) below.
[0496] The injectable materials described above can be utilized to
deliver a particulate material that has the ability to induce
ankylosis in the joint. These particles can be either degradable or
non-degradable and are similar to those described above for
threads. In addition, particulate materials useful for the practice
of this embodiment include talc, starch, glass, silicates, silica,
calcium phosphate, calcium sulfate, calcium carbonate,
hydroxyapatite, synthetic mineral (VITOSS and CORTOSS), PMMA,
silver nitrate, ceramic particles and other inorganic particles
known in the art to induce a fibroproliferative response followed
by mineralization. The particles used in this embodiment can be all
of the same composition or a blend of differing compositions. These
particles can also be used as a coating applied to the polymeric
strands as described above.
[0497] The injectable material can also be constructed such that it
is comprised of both polymeric threads and particles. The threads
and particles used are similar to those described above and may be
of uniform composition or blended composition. Virtually any
combination of threads of differing compositions and particles of
differing compositions can be utilized in this embodiment. The
hydrogel, the polymeric threads, and the particles can all be
utilized to deliver one or more biologically active agents, as
described below.
[0498] One specific composition comprises rods prepared from a
methylated collagen-crosslinked poly(ethylene glycol) composition
such as described above which has powdered silk particles and/or
mineral particles added to the composition prior to curing. Once
deployed, the rod can absorb water, fill the joint space and adhere
to any articular cartilage or exposed bone. This expansion can
prevent the rod from moving, while the powdered and/or mineral silk
can initiate an ankylosing response. As the material starts to
degrade, the material can support the bone tissue ingrowth that is
initiated and potentiated by the particles. Bone morphogenic
proteins and/or growth factors (described previously and below) are
also useful for the addition to this composition. To further
increase the rate of initiation of this fibroproliferative
response, a sclerosant such as a surfactant (SDS), ethanolamine
oleate or DMSO can be added. In addition, one may also add or
replace all (or a portion) of the 4-armed thiol PEG with a 4-armed
amino PEG. The amino PEG can provide a gel that can take a longer
time to degrade and can provide some positive charge to further
attract cellular material.
[0499] A second specific embodiment consists of an injectable
implant composed of silk fibers or a polymerized version of the
fibrosing agent itself (i.e., repeating units of the fibrosing
agent polymerized together). The addition of bone morphogenic
proteins and/or growth factors (described previously and below) is
also useful for the addition to this composition.
[0500] In addition to the hydrogels, bone cements, and materials
containing calcium phosphate described above, there are several
other injectable compositions suitable for use in minimally
invasive joint fusion procedures. All involve the deployment of a
biomaterial into the joint space, with or without, the addition of
a fibrosis-inducing agent, bone morphogenic protein(s), and/or a
suitable growth factor(s). The following compositions can be
delivered into the joint via specialized delivery catheters, an
endoscope (arthroscope; typically via a sideport), a needle or
other applicator, a surgically placed drain or access port, or
other transdermal access device, including administration of: (a)
fluids, suspensions, emulsions, microemulsions, microspheres,
pastes, gels, microparticulates, sprays, aerosols, solid implants
and other formulations which release a biologically active
agent(s); (b) microparticulate silk and/or silk strands (linear,
branched, and/or coiled) either alone, or loaded with an additional
fibrosis-inducing agent, bone morphogenic protein, and/or growth
factor are also useful for directed injection into the joint; (c)
injectable collagen-containing formulations such as COSTASIS or
materials prepared from a 4-armed thiol PEG (10K), a 4-armed NHS
PEG (10K) and methylated collagen such as described above, either
alone, or loaded with a fibrosis-inducing agent, bone morphogenic
protein, and/or growth factor, injected into the joint space; (d)
injectable PEG-containing formulations such as COSEAL, FOCALSEAL,
SPRAYGEL or DURASEAL, either alone, or loaded with a
fibrosis-inducing agent, bone morphogenic protein, and/or growth
factor, injected into the joint space; (e) fibrinogen-containing
formulations such as FLOSEAL or TISSEAL, either alone, or loaded
with a fibrosis-inducing agent, bone morphogenic protein, and/or
growth factor, injected into the joint space; (f) hyaluronic
acid-containing formulations such as RESTYLANE, HYLAFORM, PERLANE,
SYNVISC, SEPRAFILM, SEPRACOAT, either alone, or loaded with a
fibrosis-inducing agent, bone morphogenic protein, and/or growth
factor injected into the joint space; (g) polymeric gels for
surgical implantation such as REPEL or FLOWGEL either alone, or
loaded with a fibrosis-inducing agent, bone morphogenic protein,
and/or growth factor injected into the joint space; (h) orthopedic
"cements" such as OSTEOBOND, LVC, SIMPLEX P, PALACOS, CORTOSS, and
ENDURANCE, either alone, or loaded with a fibrosis-inducing agent,
bone morphogenic protein, and/or growth factor injected into the
joint space; (i) surgical adhesives containing cyanoacrylates such
as DERMABOND, INDERMIL, GLUSTITCH, VETBOND, HISTOACRYL, TISSUEMEND,
TISSUMEND II, HISTOACRYL BLUE and ORABASE SOOTHE-N-SEAL LIQUID
PROTECTANT or as described above, either alone, or loaded with a
fibrosis-inducing agent, bone morphogenic protein, and/or growth
factor, injected into the joint space; (j) surgical implants
containing hydroxyapatite, calcium phosphate (such as VITOSS), or
calcium sulfate, alone or loaded with a fibrosis-inducing agent,
bone morphogenic protein, and/or growth factor, injected into the
joint space; (k) other biocompatible tissue fillers, such as those
made by BioCure, 3M Company and Neomend, either alone, or loaded
with a fibrosis-inducing agent, bone morphogenic protein, and/or
growth factor, injected into the joint space; (l) polysaccharide
gels such as the ADCON series of gels, either alone, or loaded with
a fibrosis-inducing agent, bone morphogenic protein, and/or growth
factor, injected into the joint space; (m) films, sponges or meshes
such as INTERCEED, VICRYL mesh, and GELFOAM either alone, or loaded
with a fibrosis-inducing agent, bone morphogenic protein, and/or
growth factor, injected into the joint space; and/or (n) a hydrogel
that is formed from an amino-functionalized polyethylene glycol
(e.g., 4-armed tetra-amino PEG [10k]) and a 4-armed NHS
functionalized PEG (e.g., pentaerythritol poly(ethylene
glycol)ether tetra-succinimidyl glutarate [10K]). This hydrogel may
further contain collagen, methylated collagen and/or gelatin. This
hydrogel can further comprise the fibrosis-inducing agents
described above (e.g., silk powder or silk threads). In many of
these embodiments, it may also be useful to add a radio-opaque
material (such as tantalum, barium, other metal, or contrast
material) such that the injected material can be visualized
radiographically or MRI.
[0501] It should be apparent to one of skill in the art that
potentially any adhesion or fibrosis-inducing agent may be utilized
alone, or in combination, in the practice of this embodiment as
described above. Exemplary fibrosing agents for use in minimally
invasive joint fusion procedures include talc, silk, wool,
chitosan, polylysine, fibronectin, bleomycin, CTGF, bone
morphogenic proteins, and/or osteogenic growth factors (such as
transforming growth factor, platelet-derived growth factor,
fibroblast growth factor) as well as analogues and derivatives of
the aforementioned.
[0502] Optionally, the device may alone or additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone) or a bone morphogenic protein (BMP) (e.g., BMP-2,
BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or an analogue or derivative
thereof).
[0503] Furthermore, the device may alone or additionally comprise
an agent that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof.
[0504] The correct administration and dosage can be described
further in section (c) below.
[0505] (iii) Fibrosing Agents for Minimally Invasive Joint
Fusion
[0506] Exemplary fibrosing and osteogenic agents for use in
minimally invasive joint fusion include talc, silk, wool, chitosan,
polylysine, fibronectin, bleomycin, CTGF, bone morphogenic
proteins, and/or osteogenic growth factors (such as transforming
growth factor, platelet-derived growth factor, fibroblast growth
factor) as well as analogues and derivatives of the aforementioned.
In some clinical situations, repeated injections of the active
agents described below may be required.
[0507] The exact dose administered can vary depending upon the
particular joint being treated. However, certain principles can be
applied in the application of this art. Drug dose can be calculated
as a function of dose per unit volume (of the amount being
injected), total drug dose administered can be measured and
appropriate surface concentrations of active drug can be
determined. Regardless of the method of application of the drug to
the affected joint, the exemplary fibrosing agents, bone
morphogenic proteins, and/or osteogenic growth factors (such as
transforming growth factor, platelet-derived growth factor,
fibroblast growth factor), used alone or in combination, should be
administered under the following dosing guidelines:
[0508] Utilizing talc as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the injectable, or administered without
a polymeric carrier, the total dose of talc administered into a
joint in any single injection should not exceed 100 mg (range of 1
.mu.g to 100 mg). In one embodiment, the total amount of talc
administered should be in the range of 10 .mu.g to 50 mg. The dose
per unit volume injected should fall within the range of 0.05
.mu.g-10 .mu.g per mm.sup.3. In one embodiment, talc is released
from the injectable such that ankylosis in the joint is promoted
for a period ranging from several hours to several months. For
example, talc may be released in effective concentrations for a
period ranging from 2-12 weeks. It should be readily evident given
the discussions provided herein that analogues and derivatives of
talc (as described previously) with similar functional activity can
be utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound
(e.g., a compound twice as potent as talc is administered at half
the above parameters, a compound half as potent as talc is
administered at twice the above parameters, etc.).
[0509] Utilizing silk as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the injectable, or administered without
a polymeric carrier, the total dose of silk delivered to the joint
in any single injection should not exceed 100 mg (range of 1 .mu.g
to 100 mg). In one embodiment, the total amount of silk
administered to the joint should be in the range of 10 .mu.g to 50
mg. The dose per unit volume injected should fall within the range
of 0.05 .mu.g-10 .mu.g per mm.sup.3. As specific (polymeric and
non-polymeric) drug delivery vehicles can release silk at differing
rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the carrier such
that a minimum concentration of 0.01 nM to 1000 .mu.M of silk is
continuously delivered to the tissue over the desired therapeutic
time period. In one embodiment, silk is released into the joint
such that ankylosis is promoted for a period ranging from several
hours to several months. For example, silk may be released in
effective concentrations for a period ranging from 2-12 weeks. It
should be readily evident given the discussions provided herein
that analogues and derivatives of silk (as described previously)
with similar functional activity can be utilized for the purposes
of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as silk is administered at half the above parameters, a compound
half as potent as silk is administered at twice the above
parameters, etc.).
[0510] Utilizing chitosan as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the injectable, or administered without
a polymeric carrier, the total dose of chitosan delivered into the
joint should not exceed 100 mg (range of 1 .mu.g to 100 mg). In one
embodiment, the total amount of chitosan administered into the
joint in any single injection should be in the range of 10 .mu.g to
50 mg. The dose per unit volume injected should fall within the
range of 0.05 .mu.g-10 .mu.g per mm.sup.3. As specific (polymeric
and non-polymeric) drug delivery vehicles can release chitosan at
differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the carrier such
that a minimum concentration of 0.01 nM to 1000 .mu.M of chitosan
is continuously delivered to the joint tissue. In one embodiment,
chitosan is released into the joint such that ankylosis is promoted
for a period ranging from several hours to several months. For
example, chitosan may be released in effective concentrations for a
period ranging from 2-12 weeks. It should be readily evident given
the discussions provided herein that analogues and derivatives of
chitosan (as described previously) with similar functional activity
can be utilized for the purposes of this invention; the above
dosing parameters are then adjusted according to the relative
potency of the analogue or derivative as compared to the parent
compound (e.g., a compound twice as potent as chitosan is
administered at half the above parameters, a compound half as
potent as chitosan is administered at twice the above parameters,
etc.).
[0511] Utilizing polylysine as a exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the injectable, or administered without
a polymeric carrier, the total dose of polylysine delivered into
the joint in a single injection should not exceed 100 mg (range of
1 .mu.g to 100 mg). In one embodiment, the total amount of
polylysine delivered to the joint should be in the range of 10
.mu.g to 50 mg. The dose per unit volume injected should fall
within the range of 0.05 .mu.g-10 .mu.g per mm.sup.3. In another
embodiment, polylysine should be injected into the joint at a dose
of 0.05-10 .mu.g/mm.sup.3. As specific (polymeric and
non-polymeric) drug delivery vehicles can release polylysine at
differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the carrier such
that a minimum concentration of 0.01 nM to 1000 .mu.M of polylysine
is continuously delivered to the joint tissue. In one embodiment,
polylysine is administered to the joint such that ankylosis is
promoted for a period ranging from several hours to several months.
For example, polylysine may be released in effective concentrations
for a period ranging from 2-12 weeks. It should be readily evident
given the discussions provided herein that analogues and
derivatives of polylysine (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
polylysine is administered at half the above parameters, a compound
half as potent as polylysine is administered at twice the above
parameters, etc.).
[0512] Utilizing fibronectin as an exemplary fibrosis-inducing
agent, whether it is applied using a polymer coating, incorporated
into the polymers which make up the injectable, or administered
without a polymeric carrier, the total dose of fibronectin
delivered into the joint in a single injection should not exceed
100 mg (range of 1 .mu.g to 100 mg). In one embodiment, the total
amount of fibronectin injected into the joint should be in the
range of 10 .mu.g to 50 mg. The dose per unit volume of the
injection should fall within the range of 0.05 .mu.g-10 .mu.g per
mm.sup.3. In another embodiment, talc should be administered at a
dose of 0.05-10 .mu.g/mm.sup.3 of injected material. As specific
(polymeric and non-polymeric) drug delivery vehicles can release
fibronectin at differing rates, the above dosing parameters should
be utilized in combination with the release rate of the drug from
the carrier such that a minimum concentration of 0.01 nM to 1000
.mu.M of fibronectin is continuously delivered to the tissue. In
one embodiment, fibronectin is released into the joint such that
ankylosis is promoted for a period ranging from several hours to
several months. For example, fibronectin may be released in
effective concentrations for a period ranging from 2-12 weeks. It
should be readily evident given the discussions provided herein
that analogues and derivatives of fibronectin (as described
previously) with similar functional activity can be utilized for
the purposes of this invention; the above dosing parameters are
then adjusted according to the relative potency of the analogue or
derivative as compared to the parent compound (e.g., a compound
twice as potent as fibronectin is administered at half the above
parameters, a compound half as potent as fibronectin is
administered at twice the above parameters, etc.).
[0513] Utilizing bleomycin as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the injectable, or administered without
a polymeric carrier, the total dose of bleomycin administered to a
joint in a single injection should not exceed 100 mg (range of 0.01
.mu.g to 100 mg). In one embodiment, the total amount of bleomycin
injected into the joint should be in the range of 0.10 .mu.g to 50
mg. The dose per unit volume injected should fall within the range
of 0.005 .mu.g-10 .mu.g per mm.sup.3. As specific (polymeric and
non-polymeric) drug delivery vehicles can release bleomycin at
differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the carrier such
that a minimum concentration of 0.001 nM to 1000 .mu.M of bleomycin
is continuously delivered to the joint. In one embodiment,
bleomycin is released from the injection such that ankylosis in the
joint is promoted for a period ranging from several hours to
several months. For example, bleomycin may be released in effective
concentrations for a period ranging from 2-12 weeks. It should be
readily evident given the discussions provided herein that
analogues and derivatives of bleomycin (as described previously)
with similar functional activity can be utilized for the purposes
of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as bleomycin is administered at half the above parameters, a
compound half as potent as bleomycin is administered at twice the
above parameters, etc.).
[0514] Utilizing CTGF as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the injectable, or administered without
a polymeric carrier, the total dose of CTGF administered to the
joint in a single injection should not exceed 100 mg (range of 0.01
.mu.g to 100 mg). In one embodiment, the total amount of CTGF
injected into the joint should be in the range of 0.10 .mu.g to 50
mg. The dose per unit volume of the injection should fall within
the range of 0.005 .mu.g-10 .mu.g per mm.sup.3. In another
embodiment, CTGF should be injected at a dose of 0.005-10
.mu.g/mm.sup.3. As specific (polymeric and non-polymeric) drug
delivery vehicles can release CTGF at differing rates, the above
dosing parameters should be utilized in combination with the
release rate of the drug from the carrier such that a minimum
concentration of 0.001 nM to 1000 .mu.M of CTGF is continuously
delivered to the joint. In one embodiment, CTGF is released from
the injectable such that ankylosis in the joint is promoted for a
period ranging from several hours to several months. For example,
CTGF may be released in effective concentrations for a period
ranging from 2-12 weeks. It should be readily evident given the
discussions provided herein that analogues and derivatives of CTGF
(as described previously) with similar functional activity can be
utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound
(e.g., a compound twice as potent as CTGF is administered at half
the above parameters, a compound half as potent as CTGF is
administered at twice the above parameters, etc.).
[0515] Optionally, the device may alone or additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone) or a bone morphogenic protein (BMP) (e.g., BMP-2,
BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or an analogue or derivative
thereof).
[0516] Inflammatory cytokines are to be used in formulations at
concentrations that range from 0.0001 .mu.g/ml to approximately 20
mg/ml depending on the specific clinical application, formulation
type (e.g., gel, liquid, solid, semi-solid), formulation chemistry,
duration of required application, type of medical device interface
and formulation volume and or surface area coverage required.
Preferably, the inflammatory cytokine is released in effective
concentrations for a period ranging from 1-180 days. The total dose
for a single application is typically not to exceed 500 mg (range
of 0.0001 .mu.g to 100 mg); preferred 0.001 .mu.g to 50 mg. When
used as a device coating, the dose is per unit area of 0.0001
.mu.g-500 .mu.g per mm.sup.2; with a preferred dose of 0.001
.mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-10-10.sup.-4 g/ml of inflammatory cytokine is to be
maintained on the device surface.
[0517] Bone morphogenic protein(s) (e.g., BMP-2, BMP-3, BMP-4,
BMP-5, BMP-6, or BMP-7 or an analogue or derivative thereof) are to
be used in formulations at concentrations that range from 0.001
.mu.g/ml to approximately 20 mg/ml depending on the specific
clinical application, formulation type (e.g., gel, liquid, solid,
semi-solid), formulation chemistry, duration of required
application, type of medical device interface and formulation
volume and or surface area coverage required. Preferably, the bone
morphogenic protein is released in effective concentrations for a
period ranging from 1-180 days. The total dose for a single
application is typically not to exceed 500 mg (range of 0.001 .mu.g
to 500 mg); preferred 1 .mu.g to 250 mg. When used as a device
coating, the dose is per unit area of 0.001 .mu.g-1000 .mu.g per
mm.sup.2; with a preferred dose of 0.01 .mu.g/mm.sup.2-200
.mu.g/mm.sup.2. Minimum concentration of 10.sup.-9-10.sup.-4 M of
bone morphogenic protein is to be maintained on the device
surface.
[0518] Furthermore, the device may alone or additionally comprise
an agent that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof. Doses used are those
concentrations which are demonstrated to stimulate cell
proliferation (Example 16). The proliferative agents are to be used
in formulations at concentrations that range from 0.01 ng/mL to 25
mg/ml depending on the specific clinical application, formulation
type (e.g., gel, liquid, solid, semi-solid), formulation chemistry,
duration of required application, type of medical device interface
and formulation volume and or surface area coverage required.
Preferably, the proliferative agent is released in effective
concentrations for a period ranging from 1-180 days. The total dose
for a single application is typically not to exceed 500 mg (range
of 0.0001 .mu.g to 200 mg); preferred 0.001 .mu.g to 100 mg. When
used as a device coating, the dose is per unit area of 0.00001
.mu.g-500 .mu.g per mm.sup.2; with a preferred dose of 0.0001
.mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-11-10.sup.-6 M of proliferative agent is to be maintained
on the device surface.
[0519] It should be readily evident to one of skill in the art that
any of the previously described fibrosis-inducing agents, bone
morphogenic proteins, or osteogenic growth factors, or derivatives
and analogues thereof, can be utilized to create variations of the
above compositions without deviating from the spirit and scope of
the invention. It should also be apparent that the agent can be
utilized in a composition with or without polymer carrier and that
altering the carrier does not deviate from the scope of this
invention.
[0520] 5. Female and Male Sterilization Devices
[0521] Permanent, highly reliable, minimally invasive methods of
preventing conception are required in both men's and women's
health. Although tubal ligation and vasectomy have a low failure
rate (approximately 1%), recently there have been advancements in
making the procedures less invasive. This is particularly true for
tubal ligation where a surgical procedure, either open or
endoscopic, is required to "clip" the fallopian tubes. Newer
implants have been designed to obstruct the fallopian tubes (or vas
deferens in the male) through the non-surgical placement of
implants that block the interior lumen of the reproductive tract.
Unfortunately, since the reproductive tract is not physically
severed (and the two ends clipped shut as in the surgical
procedure), there remains the possibility that the fallopian tube
(or vas deferens) can re-cannulate over time and restore fertility.
The present invention provides compositions, implants and devices
that include a fibrosis-inducing agent to promote scarring of the
walls of the reproductive tract in the vicinity of the implant or
device. The result is the formation of permanent scar tissue
between the walls of the fallopian tube (or vas deferens) that
completely obstructs the lumen, prevents the movement of the
gametes through the tract, and lowers the failure rate of the
procedure (measured as the prevention of unwanted pregnancies).
[0522] (i) Permanent Female Contraceptive Devices
[0523] (a) Fallopian Tube Implants
[0524] Numerous techniques and devices are known and available to
ligate or obstruct the fallopian tube such that the ovum cannot
reach the uterus and conception and implantation cannot occur. As
described above, surgical ligation and/or clipping of the fallopian
tubes has been considered the "gold standard" for permanent
contraception in women for many years. Various clamps and clips for
this purpose have been described, including for example: a duct
clamp described in U.S. Pat. No. 4,489,725; valved sterilization
devices described in U.S. Pat. Nos. 3,704,704 and 3,777,737; and
temporary sterilization devices described in U.S. Pat. No.
3,918,431. These devices are suitable for coating with a
fibrosis-inducing agent to further enhance their effectiveness and
reduce their failure rate. Unfortunately, these procedures have the
obvious disadvantage of requiring placement during open or
endoscopic surgery.
[0525] However, a preferred embodiment of the present invention
involves delivering a fibrosis-inducing agent in combination with a
variety of devices and implants designed for placement in the
fallopian tubes without the need for surgery. Although variable in
design, all are intended to be placed transvaginally (i.e., the
device or implant is inserted into the vagina, through the uterus,
and placed into the interior lumen of the fallopian tube), thus
eliminating the need for surgical access to the external
(intra-abdominal/pelvic) surface of the fallopian tube via the
abdomen. As a result, these implants obstruct the fallopian tube
from the inside (luminal surface) and can be performed in a
conscious patient in much the same manner as a gynecological exam.
Examples of fallopian tube implants suitable for delivering a
fibrosis-inducing agent that enhances tubal occlusion include:
implantable, intrafallopian, female sterilization devices (such as
those described in U.S. Pat. Nos. 6,245,090; 6,068,626; and
3,675,639); occlusive wire or coil fallopian tube implants (such as
those described in U.S. Pat. No. 5,601,600); transcatheter
occluding implants (such as those described in U.S. Pat. No.
6,245,090); and fallopian tube stents (for example those described
in U.S. Pat. No. 5,474,089). In addition, contraceptive uterine
implants, such as intrauterine devices (IUDs), can also be suitable
for use in this embodiment.
[0526] Specific female sterilization devices (fallopian tube
implants) suitable for the delivery of one or more
fibrosis-inducing agents according to the present invention include
several commercially available products. For example, the ESSURE
device is a catheter-delivered stent filled with fiber (a soft
micro-insert) designed to occlude the fallopian tubes (Conceptus,
Inc., San Carlos, Calif.) and is described in U.S. Pat. Nos.
6,176,240; 6,526,979; 5,601,600; and 5,746,769. The ECLIPSE from
Ovion (Redwood City, Calif.) is a self-expanding nitinol stent
filled with polyester fibers that is delivered transvaginally via a
catheter into the fallopian tubes. Other contraceptive fallopian
tube implants include porous plastic fibers (Adiana, Redwood,
Calif.) and single rod implants such as IMPLANON from Organon
Corporation (West Orange, N.J.).
[0527] Regardless of the specific design, the aforementioned
contraceptive implants can be adapted to release an agent which
induces fibrosis or adhesion within the fallopian tube. The result
can be enhanced scarring around the implant, more complete (and
permanent) filling and/or occlusion of the lumen of the fallopian
tube, and a reduction in the likelihood that female or male
reproductive cells can traverse the blockade and come in contact
with each other--thereby reducing the incidence of unwanted
intrauterine pregnancy or tubal pregnancy. Fallopian tube implants
may be adapted to have a fibrosis-inducing agent incorporated into
their structure, adapted to have a surface coating of a
fibrosis-inducing agent and/or adapted to release a
fibrosis-inducing agent. This can be accomplished in several
manners including: (a) directly affixing to the fallopian tube
implant/device a desired fibrosis-inducing agent, or affixing a
composition containing the fibrosis-inducing agent (for example, by
spraying the implant with a drug and/or drug-carrier (polymeric or
non-polymeric) composition to create a film/coating on all (or
parts) of the internal and/or external surface of the device; by
dipping the implant or device into a drug and/or drug-carrier
(polymeric or non-polymeric) solution to coat all (or parts) of the
device/implant; or by covalent or non-covalent attachment (such as
mechanical attachment via knotting, using an adhesive, thermal
treatment, electrostatic attachment, ionic attachment, hydrophobic
interactions, or hydrogen bonding) of the therapeutic agent to the
device/implant surface); (b) by coating the fallopian tube
device/implant with a substance such as a hydrogel which can in
turn absorb the desired fibrosis-inducing agent or composition; (c)
by interweaving a "thread" composed of, or coated with, the
fibrosis-inducing agent into the fallopian tube implant/device
(e.g., a polymeric strand composed of a fibrosis-inducing agent
(e.g., silk, collagen, EVA, PLA, polyurethanes, polymerized drug
compositions) or a thread coated with a polymer which is comprised
of, or releases a fibrosis-inducing agent); (d) by covering all, or
portions of the fallopian tube device/implant with a sleeve, cover
or mesh containing a fibrosis-inducing agent (i.e., a covering
comprised of a fibrosis-inducing agent--polymers such as silk,
collagen, EVA, PLA, polyurethanes--or polymerized compositions that
release fibrosis-inducing agents); (e) constructing all, or parts
of the fallopian tube implant/device from a fibrosis-inducing agent
(e.g., constructing it from polymers such as silk, collagen, EVA,
PLA, polyurethanes or polymerized compositions of fibrosis-inducing
agents)--which may be particularly effective for the IMPLANON rod
or the Adiana porous fibers; (f) for fallopian tube stent devices
(such as the ESSURE or ECLIPSE), the central "filling" material can
be composed of, or coated with, the fibrosis-inducing agent (e.g.,
polymeric fibers composed of a fibrosis-inducing agent (e.g., silk,
collagen, EVA, PLA, polyurethanes, polymerized drug compositions)
or coating the fibers with a polymer which is comprised of, or
releases a fibrosis-inducing agent); (g) otherwise impregnating the
fallopian tube implant/device with the desired fibrosis-inducing
agent or composition; (h) scoring (i.e., creating ridges or
indentations) on all, or parts, of the device or implant surface to
produce irritation and ultimately fibrosis; (i) composing all, or
parts, of the device or implant from metal alloys that induce
fibrosis (e.g., copper); (j) constructing all, or parts of the
device or implant itself from a degradable or non-degradable
polymer that releases one or more fibrosis-inducing agents--which
may be particularly effective for the IMPLANON rod, the Adiana
porous fibers or the central filling material in the ESSURE or
ECLIPSE devices; and/or (k) utilizing specialized multi-drug
releasing medical device systems (described, e.g., in U.S. Pat. No.
6,562,065; U.S. Patent Application Publication Nos. 2003/0199970
and 2003/0167085 and in WO 03/015664 and WO 02/32347) to deliver
fibrosis-inducing agents alone, or in combination.
[0528] It should be apparent to one of skill in the art that
potentially any adhesion or fibrosis-inducing agent may be utilized
alone, or in combination, in the practice of this embodiment as
described above. Exemplary fibrosing agents for use in fallopian
tube implants and devices include talc, silk, wool, chitosan,
polylysine, fibronectin, bleomycin, and CTGF, as well as analogues
and derivatives of the aforementioned.
[0529] Optionally, the device may alone or additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone) or a bone morphogenic protein (BMP) (e.g., BMP-2,
BMP-3, BMP-4, BMP-5, BMP-6, OR BMP-7 or an analogue or derivative
thereof).
[0530] Furthermore, the device may alone or additionally comprise
an agent that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof.
[0531] The correct administration and dosage can be described
further in section (c) below.
[0532] (b) Injectable Fallopian Tube Implants
[0533] Another preferred embodiment of the present invention
involves delivering a fibrosis-inducing agent in combination with a
biomaterial designed for injection into the fallopian tubes to
"plug" or obstruct the tube. Many different biomaterials are
suitable for injection into the fallopian tube via a transvaginal
route of administration (i.e., the delivery device is inserted into
the vagina, through the uterus, placed into the interior lumen of
the fallopian tube, and the biomaterial containing a
fibrosis-inducing agent is injected into the lumen of the fallopian
tube), thus eliminating the need for surgical access to the
external (intra-abdominal/pelvic) surface of the fallopian tube via
the abdomen. As a result, these implants obstruct the fallopian
tube from the inside (luminal surface) and can be performed in a
conscious patient in much the same manner as a gynecological exam.
The biomaterial can obstruct the lumen of the tube, while the
fibrosis-inducing agent encourages the formation of scar tissue
between the walls of the fallopian tube to permanently obstruct the
lumen, prevent the movement of the gametes through the tract, and
lower the failure rate of the procedure (measured as the prevention
of unwanted pregnancies).
[0534] The injectable material may be composed of a hydrogel for
use in the sterilization of a mammalian female. The hydrogel can be
composed of a non-degradable or a degradable material.
Non-degradable materials can include crosslinked compositions that
comprise PVA, PVP, polyacrylamide, pHEMA, poly(vinyl PEG),
poly(styrene sulfonate), poly(acrylic acid), poly(methacrylic
acid), as well as other polymers that are known to form hydrogels.
Additional compositions include blends and copolymers of the agents
listed above. Degradable materials include, but are not limited to,
crosslinked materials of PEG, gelatin, collagen, hyaluronic acid,
hyaluronic acid derivatives, polysaccharides, carbohydrates,
proteins (e.g., albumin, casein, whey proteins, plant proteins, and
fish proteins), cellulose derivatives (e.g., HPC), chitosan,
chitosan derivatives, polyester-polyalkylene oxide block copolymers
(e.g., PLGA-PEG-PLGA and MePEG-PLGA) and other low molecular weight
polymers that can be excreted. One material that is of particular
interest is prepared from a 4-armed thiol PEG (10K), a 4-armed NHS
PEG(10K) and methylated collagen such as described above. In a
preferred embodiment, the hydrogel also contains a biologically
active agent capable of inducing fibrosis in the fallopian tube.
Preferred, biologically active, fibrosis-inducing, agents, their
dosages and their release kinetics, are all described in detail in
section (c) below.
[0535] In addition to, or in lieu of, fibrosis-inducing agents, the
hydrogel can be utilized to deliver a sclerosant to the fallopian
tube. Sclerosants include compounds such as ethanol, DMSO,
surfactants, sucrose, NaCl, dextrose, glycerin, minocycline,
tetracycline, doxycycline, polidocanol, sodium tetradecyl sulfate,
sodium morrhuate, sotradecol and others. The hydrogel can further
comprise agents such as glycerol, glycerin, PEG 200, triethyl
citrate, and triacetin as plasticizers.
[0536] The hydrogels described above can further modified to be
comprised of, or contain, polymeric threads. Polymeric threads have
the ability to induce a fibroproliferative response from the
surrounding tissue in the fallopian tube. These polymer threads can
be degradable or non-degradable. Degradable threads can be composed
of degradable polyesters, polyanhydrides, poly(anhydride esters),
poly(ester-amides), poly(ester-ureas), polyorthoesters,
polyphosphoesters, polyphosphazines, cyanoacrylate polymers,
collagen, chitosan, hyaluronic acid, chromic cat gut, alginates,
starch, cellulose, cellulose esters, blends and copolymers thereof,
as well as other known degradable polymers. Non-degradable polymers
that can be used include, but are not limited to, polyesters (e.g.,
PET), polyurethanes, silicones, PE, PP, PS, PAA, PMA, silk, blends,
copolymers thereof as well as other known polymers. The threads
used can be composed of a single composition or composed of a blend
of differing compositions. The polymeric threads themselves can be
further modified through the addition of a polymeric coating
applied to the threads. The polymer used for coating the thread can
be similar to that described above for the threads themselves. The
polymer coating may further comprise a biologically active agent
that has the ability to induce a fibroproliferative response. The
agents that can be used are further described in the section (c)
below.
[0537] The hydrogels described above can be utilized to deliver a
particulate material that has the ability to induce a
fibroproliferative response in the fallopian tube. These particles
can be either degradable or non-degradable and are similar to those
described above for threads. In addition to those, particulate
materials useful for the practice of this embodiment include talc,
starch, glass, silicates, silica, silver nitrate, ceramic particles
and other inorganic particles known in the art to induce a
fibroproliferative response. The particles used in this embodiment
can be all of the same composition or a blend of differing
compositions. These particles can also be used as a coating applied
to the polymeric strands as described above.
[0538] As is readily apparent, the hydrogel can also be constructed
such that it is comprised of both polymeric threads and particles.
The threads and particles used are similar to those described above
and may be of uniform composition or blended composition. Virtually
any combination of threads of differing compositions and particles
of differing compositions can be utilized in this embodiment. The
hydrogel, the polymeric threads, and the particles can all be
utilized to deliver one or more biologically active agents, as
described below.
[0539] In a further embodiment, the hydrogel can be formed into a
variety of shapes and sizes for implantation into the fallopian
tubes. For example, the hydrogel can be shaped into a rod of the
desired length or subsequently cut to the appropriate length. The
hydrogel can be made into another shape and then further processed
to form a rod of the appropriate dimensions. The rods can be
cylindrical in shape or they can have a tapered shape or an
hourglass shape. The hydrogel can also be formed into a rectangular
shape by adding the appropriate reagents to a mould and then curing
the composition. A cork-borer type device of the appropriate
dimensions can be used to produce rods. The thickness of the
initial hydrogel can determine if these rods have to be further cut
into the appropriate lengths. These rods can be then dehydrated by
freeze drying or by air drying. The freeze-dried rods may have more
of a foam structure while the air dried rods may be of a more solid
nature. The particles and/or biologically active agents can be
incorporated into the hydrogel prior to the curing stage. The
particles can be applied to the surface by rolling the rods in the
particles or by applying the particles to the surface by dipping,
spraying or painting. The particles can be applied in combination
with a coating polymer that may dissolve or degrade. This coating
polymer may be gelatin, hydroxypropyl cellulose, MePEG-PLA,
MePEG-polyester, polyester-PEG-polyester, or the like.
[0540] The polymer threads can be added prior to the curing stage
or they can be added after the hydrogel has cured. The polymer
threads can be added before or after the drying stage of the rods.
The threads may be wrapped around the external surface of the rod.
The needle may be used to pass the threads through the rod in a
vertical, horizontal, diagonal manner or a combination thereof. The
threads may be placed such that they form loops protruding from the
surface of the rod.
[0541] One specific composition comprises rods prepared from a
methylated collagen-crosslinked poly(ethylene glycol) composition
such as described above which has powdered silk particles added to
the composition prior to curing. Once deployed, the rod can absorb
water and thereby occlude the fallopian tube. This expansion can
prevent the rod from moving, while the powdered silk can initiate a
fibroproliferative response. As the methylated collagen-crosslinked
poly(ethylene glycol) composition starts to degrade, the material
can support the fibrous tissue ingrowth that is initiated and
potentiated by the silk particles. To further increase the rate of
initiation of this fibroproliferative response, a sclerosant such
as a surfactant (SDS), ethanolamine oleate or DMSO can be added. In
addition, one may also add or replace all (or a portion) of the
4-armed thiol PEG with a 4-armed amino PEG. The amino PEG can
provide a gel that can take a longer time to degrade and can
provide some positive charge to further attract cellular
material.
[0542] A second specific embodiment consists of an implant composed
of silk fibers or from a polymerized version of the fibrosing agent
itself (i.e., repeating units of the fibrosing agent polymerized
together).
[0543] In addition to the hydrogels and related implants described
above, there are several other ways to practice this embodiment.
All involve the deployment of a biomaterial into the lumen of the
fallopian tube with or without the addition of a fibrosis-inducing
agent. The practice of this embodiment can be performed in several
ways including: (a) topical application of the fibrosing agent onto
the luminal surface of the fallopian tube (particularly useful for
this embodiment is the use of polymeric carriers which release the
fibrosing agent over a period ranging from several hours to several
weeks--fluids, suspensions, emulsions, microemulsions,
microspheres, pastes, gels, microparticulates, sprays, aerosols,
solid implants and other formulations which release a fibrosing
agent can be delivered into the fallopian tube via specialized
delivery catheters or other applicators); (b) microparticulate silk
and/or silk strands (linear, branched, and/or coiled), either
alone, or loaded with an additional fibrosis-inducing agent are
also useful for directed injection into the fallopian tube; (c)
sprayable collagen-containing formulations such as COSTASIS or
materials made from 4-armed thiol PEG (10K), a 4-armed NHS PEG(10K)
and methylated collagen such as described above, either alone, or
loaded with a fibrosis-inducing agent, applied to the lumen of the
fallopian tube; (d) sprayable PEG-containing formulations such as
COSEAL, FOCALSEAL, SPRAYGEL or DURASEAL, either alone, or loaded
with a fibrosis-inducing agent, applied to the lumen of the
fallopian tube; (e) fibrinogen-containing formulations such as
FLOSEAL or TISSEAL, either alone, or loaded with a
fibrosis-inducing agent, applied to the lumen of the fallopian
tube; (f) hyaluronic acid-containing formulations such as
RESTYLANE, HYLAFORM, PERLANE, SYNVISC, SEPRAFILM, SEPRACOAT loaded
with a fibrosis-inducing agent applied to the lumen of the
fallopian tube; (g) polymeric gels for surgical implantation such
as REPEL or FLOWGEL, either alone, or loaded with a
fibrosis-inducing agent applied to the lumen of the fallopian tube;
(h) orthopedic "cements" such as OSTEOBOND, LVC, SIMPLEX P,
PALACOS, CORTOSS, and ENDURANCE, either alone, or loaded with a
fibrosis-inducing agent applied to the luminal surface of the
fallopian tube; (i) surgical adhesives containing cyanoacrylates
such as DERMABOND, INDERMIL, GLUSTITCH, VETBOND, HISTOACRYL,
TISSUEMEND, TISSUMEND II, HISTOACRYL BLUE and ORABASE SOOTHE-N-SEAL
LIQUID PROTECTANT or as described above, either alone, or loaded
with a fibrosis-inducing agent, applied to the lumen of the
fallopian tube; (j) surgical implants containing hydroxyapatite,
calcium phosphate (e.g., VITOSS), or calcium sulfate, either alone,
or loaded with a fibrosis-inducing agent applied to the lumen of
the fallopian tube; (k) other biocompatible tissue fillers, such as
those made by BioCure, 3M Company and Neomend, either alone, or
loaded with a fibrosis-inducing agent, applied to the lumen of the
fallopian tube; (l) polysaccharide gels such as the ADCON series of
gels loaded with a fibrosis-inducing agent applied to the lumen of
the fallopian tube; (m) films, sponges or meshes such as INTERCEED,
VICRYL mesh, and GELFOAM, either alone, or loaded with a
fibrosis-inducing agent applied to the lumen of the fallopian tube
and/or (n) a hydrogel that is formed from an amino-functionalized
polyethylene glycol (e.g., 4-armed tetra-amino PEG [10k]) and a
4-armed NHS functionalized PEG (e.g., pentaerythritol poly(ethylene
glycol)ether tetra-succinimidyl glutarate [10K]). This hydrogel may
further contain collagen, methylated collagen and/or gelatin. This
hydrogel can further comprise the fibrosis-inducing agents
described above (e.g., silk powder or silk threads).
[0544] In many of the embodiments described above it may also be
useful to add a radio-opaque material (such as tantalum,
technetium, gadolinium, barium, other metal, or contrast material)
such that the injected material can be visualized radiographically
or MRI. The contrast agent may be a water soluble or water
insoluble radio-opaque material. Alternatively the gel or the
coated implant can contain air bubbles (e.g., ECHO-COAT) or air can
be injected into the tube such that visualization by ultrasound is
enhanced.
[0545] It should be apparent to one of skill in the art that
potentially any adhesion or fibrosis-inducing agent may be utilized
alone, or in combination, in the practice of this embodiment as
described above. Exemplary fibrosing agents for use in fallopian
tube implants and devices include talc, silk, wool, chitosan,
polylysine, fibronectin, bleomycin, and CTGF, as well as analogues
and derivatives of the aforementioned.
[0546] Optionally, the device may alone or additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone).
[0547] Furthermore, the device may alone or additionally comprise
an agent that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof.
[0548] The correct administration and dosage can be described
further in section (c) below.
[0549] (c) Fibrosing Agents for Fallopian Tube Implants
[0550] As fallopian tube implants are made in a variety of
configurations and sizes, the exact dose administered can vary with
device size, surface area and design. However, certain principles
can be applied in the application of this art. Drug dose can be
calculated as a function of dose per unit area (of the portion of
the device being coated), total drug dose administered can be
measured and appropriate surface concentrations of active drug can
be determined. Regardless of the method of application of the drug
to the sterilization device, the exemplary fibrosing agents, used
alone or in combination, should be administered under the following
dosing guidelines:
[0551] Utilizing talc as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, incorporated into
an injectable, or applied without a polymeric carrier, the total
dose of talc delivered from a sterilization device, or coated onto
the surface of a sterilization device, should not exceed 100 mg
(range of 1 .mu.g to 100 mg). In one embodiment, the total amount
of talc released from the prosthesis should be in the range of 10
.mu.g to 50 mg. The dose per unit area of the device (i.e., the
dosage of talc as a function of the surface area of the portion of
the device to which drug is applied and/or incorporated) should
fall within the range of 0.05 .mu.g-10 .mu.g per mm.sup.2 of
surface area coated. In another embodiment, talc should be applied
to a sterilization device surface at a dose of 0.05
.mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. In one
embodiment, talc is released from the surface of a sterilization
device such that fibrosis in the tissue is promoted for a period
ranging from several hours to several months. For example, talc may
be released in effective concentrations for a period ranging from 1
hour-30 days. It should be readily evident given the discussions
provided herein that analogues and derivatives of talc (as
described previously) with similar functional activity can be
utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound
(e.g., a compound twice as potent as talc is administered at half
the above parameters, a compound half as potent as talc is
administered at twice the above parameters, etc.).
[0552] Utilizing silk as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, incorporated into
an injectable, or applied without a polymeric carrier, the total
dose of silk delivered from a sterilization device, or coated onto
the surface of a sterilization device, should not exceed 100 mg
(range of 1 .mu.g to 100 mg). In one embodiment, the total amount
of silk released from the prosthesis should be in the range of 10
.mu.g to 50 mg. The dose per unit area of the device (i.e., the
dosage of silk as a function of the surface area of the portion of
the device to which drug is applied and/or incorporated) should
fall within the range of 0.05 .mu.g-10 .mu.g per mm.sup.2 of
surface area coated. In another embodiment, silk should be applied
to a sterilization device surface at a dose of 0.05
.mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. As
specific (polymeric and non-polymeric) drug delivery vehicles and
specific medical devices can release silk at differing rates, the
above dosing parameters should be utilized in combination with the
release rate of the drug from the sterilization device such that a
minimum concentration of 0.01 nM to 1000 .mu.M of silk is delivered
to the tissue. In one embodiment, silk is released from the surface
of a sterilization device such that fibrosis in the tissue is
promoted for a period ranging from several hours to several months.
For example, silk may be released in effective concentrations for a
period ranging from 1 hour-30 days. It should be readily evident
given the discussions provided herein that analogues and
derivatives of silk (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as silk is
administered at half the above parameters, a compound half as
potent as silk is administered at twice the above parameters,
etc.).
[0553] Utilizing chitosan as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, incorporated into
an injectable, or applied without a polymeric carrier, the total
dose of chitosan delivered from a sterilization device, or coated
onto the surface of a sterilization device, should not exceed 100
mg (range of 1 .mu.g to 100 mg). In one embodiment, the total
amount of chitosan released from the prosthesis should be in the
range of 10 .mu.g to 50 mg. The dose per unit area of the device
(i.e., the dosage of chitosan as a function of the surface area of
the portion of the device to which drug is applied and/or
incorporated) should fall within the range of 0.05 .mu.g-10 .mu.g
per mm.sup.2 of surface area coated. In another embodiment,
chitosan should be applied to a sterilization device surface at a
dose of 0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area
coated. As specific (polymeric and non-polymeric) drug delivery
vehicles and specific medical devices can release chitosan at
differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the
sterilization device such that a minimum concentration of 0.01 nM
to 1000 .mu.M of chitosan is delivered to the tissue. In one
embodiment, chitosan is released from the surface of a
sterilization device such that fibrosis in the tissue is promoted
for a period ranging from several hours to several months. For
example, chitosan may be released in effective concentrations for a
period ranging from 1 hour-30 days. It should be readily evident
given the discussions provided herein that analogues and
derivatives of chitosan (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
chitosan is administered at half the above parameters, a compound
half as potent as chitosan is administered at twice the above
parameters, etc.).
[0554] Utilizing polylysine as a exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, incorporated into
an injectable, or applied without a polymeric carrier, the total
dose of polylysine delivered from a sterilization device, or coated
onto the surface of a sterilization device, should not exceed 100
mg (range of 1 .mu.g to 100 mg). In one embodiment, the total
amount of polylysine released from the prosthesis should be in the
range of 10 .mu.g to 50 mg. The dose per unit area of the device
(i.e., the dosage of polylysine as a function of the surface area
of the portion of the device to which drug is applied and/or
incorporated) should fall within the range of 0.05 .mu.g-10 .mu.g
per mm.sup.2 of surface area coated. In another embodiment,
polylysine should be applied to a sterilization device surface at a
dose of 0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area
coated. As specific (polymeric and non-polymeric) drug delivery
vehicles and specific medical devices can release polylysine at
differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the
sterilization device such that a minimum concentration of 0.01 nM
to 1000 .mu.M of polylysine is delivered to the tissue. In one
embodiment, polylysine is released from the surface of a
sterilization device such that fibrosis in the tissue is promoted
for a period ranging from several hours to several months. For
example, polylysine may be released in effective concentrations for
a period ranging from 1 hour-30 days. It should be readily evident
given the discussions provided herein that analogues and
derivatives of polylysine (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
polylysine is administered at half the above parameters, a compound
half as potent as polylysine is administered at twice the above
parameters, etc.).
[0555] Utilizing fibronectin as an exemplary fibrosis-inducing
agent, whether it is applied using a polymer coating, incorporated
into the polymers which make up the device or implant, incorporated
into an injectable, or applied without a polymeric carrier, the
total dose of fibronectin delivered from a sterilization device, or
coated onto the surface of a sterilization device, should not
exceed 100 mg (range of 1 .mu.g to 100 mg). In one embodiment, the
total amount of fibronectin released from the prosthesis should be
in the range of 10 .mu.g to 50 mg. The dose per unit area of the
device (i.e., the dosage of fibronectin as a function of the
surface area of the portion of the device to which drug is applied
and/or incorporated) should fall within the range of 0.05 .mu.g-10
.mu.g per mm.sup.2 of surface area coated. In another embodiment,
fibronectin should be applied to a sterilization device surface at
a dose of 0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area
coated. As specific (polymeric and non-polymeric) drug delivery
vehicles and specific medical devices can release fibronectin at
differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the
sterilization device such that a minimum concentration of 0.01 nM
to 1000 .mu.M of fibronectin is delivered to the tissue. In one
embodiment, fibronectin is released from the surface of a
sterilization device such that fibrosis in the tissue is promoted
for a period ranging from several hours to several months. For
example, fibronectin may be released in effective concentrations
for a period ranging from 1 hour-30 days. It should be readily
evident given the discussions provided herein that analogues and
derivatives of fibronectin (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
fibronectin is administered at half the above parameters, a
compound half as potent as fibronectin is administered at twice the
above parameters, etc.).
[0556] Utilizing bleomycin as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, incorporated into
an injectable, or applied without a polymeric carrier, the total
dose of bleomycin delivered from a sterilization device, or coated
onto the surface of a sterilization device, should not exceed 100
mg (range of 0.01 .mu.g to 100 mg). In one embodiment, the total
amount of bleomycin released from the prosthesis should be in the
range of 0.10 .mu.g to 50 mg. The dose per unit area of the device
(i.e., the dosage of bleomycin as a function of the surface area of
the portion of the device to which drug is applied and/or
incorporated) should fall within the range of 0.005 .mu.g-10 .mu.g
per mm.sup.2 of surface area coated. In another embodiment,
bleomycin should be applied to a sterilization device surface at a
dose of 0.005 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area
coated. As specific (polymeric and non-polymeric) drug delivery
vehicles and specific medical devices can release bleomycin at
differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the
sterilization device such that a minimum concentration of 0.001 nM
to 1000 .mu.M of bleomycin is delivered to the tissue. In one
embodiment, bleomycin is released from the surface of a
sterilization device such that fibrosis in the tissue is promoted
for a period ranging from several hours to several months. For
example, bleomycin may be released in effective concentrations for
a period ranging from 1 hour-30 days. It should be readily evident
given the discussions provided herein that analogues and
derivatives of bleomycin (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
bleomycin is administered at half the above parameters, a compound
half as potent as bleomycin is administered at twice the above
parameters, etc.).
[0557] Utilizing CTGF as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, incorporated into
an injectable, or applied without a polymeric carrier, the total
dose of CTGF delivered from a sterilization device, or coated onto
the surface of a sterilization device, should not exceed 100 mg
(range of 0.01 .mu.g to 100 mg). In one embodiment, the total
amount of CTGF released from the prosthesis should be in the range
of 0.10 .mu.g to 50 mg. The dose per unit area of the device (i.e.,
the dosage of CTGF as a function of the surface area of the portion
of the device to which drug is applied and/or incorporated) should
fall within the range of 0.005 .mu.g-10 .mu.g per mm.sup.2 of
surface area coated. In another embodiment, CTGF should be applied
to a sterilization device surface at a dose of 0.005
.mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. As
specific (polymeric and non-polymeric) drug delivery vehicles and
specific medical devices can release CTGF at differing rates, the
above dosing parameters should be utilized in combination with the
release rate of the drug from the a sterilization device such that
a minimum concentration of 0.001 nM to 1000 .mu.M of CTGF is
delivered to the tissue. In one embodiment, CTGF is released from
the surface of a sterilization device such that fibrosis in the
tissue is promoted for a period ranging from several hours to
several months. For example, CTGF may be released in effective
concentrations for a period ranging from 1 hour-30 days. It should
be readily evident given the discussions provided herein that
analogues and derivatives of CTGF (as described previously) with
similar functional activity can be utilized for the purposes of
this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as CTGF is administered at half the above parameters, a compound
half as potent as CTGF is administered at twice the above
parameters, etc.).
[0558] Optionally, the device may alone or additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone). Inflammatory cytokines are to be used in
formulations at concentrations that range from 0.0001 .mu.g/ml to
approximately 20 mg/ml depending on the specific clinical
application, formulation type (e.g., gel, liquid, solid,
semi-solid), formulation chemistry, duration of required
application, type of medical device interface and formulation
volume and or surface area coverage required. Preferably, the
inflammatory cytokine is released in effective concentrations for a
period ranging from 1-180 days. The total dose for a single
application is typically not to exceed 500 mg (range of 0.0001
.mu.g to 100 mg); preferred 0.001 .mu.g to 50 mg. When used as a
device coating, the dose is per unit area of 0.0001 .mu.g-500 .mu.g
per mm.sup.2; with a preferred dose of 0.001 .mu.g/mm.sup.2-200
.mu.g/mm.sup.2. Minimum concentration of 10.sup.-10-10.sup.4 g/ml
of inflammatory cytokine is to be maintained on the device
surface.
[0559] Furthermore, the device may alone or additionally comprise
an agent that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof. Doses used are those
concentrations which are demonstrated to stimulate cell
proliferation (Example 16). The proliferative agents are to be used
in formulations at concentrations that range from 0.01 ng/ml to 25
mg/ml depending on the specific clinical application, formulation
type (e.g., gel, liquid, solid, semi-solid), formulation chemistry,
duration of required application, type of medical device interface
and formulation volume and or surface area coverage required.
Preferably, the proliferative agent is released in effective
concentrations for a period ranging from 1-180 days. The total dose
for a single application is typically not to exceed 500 mg (range
of 0.0001 .mu.g to 200 mg); preferred 0.001 .mu.g to 100 mg. When
used as a device coating, the dose is per unit area of 0.00001
.mu.g-500 .mu.g per mm.sup.2; with a preferred dose of 0.0001
.mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-11-10.sup.-6 M of proliferative agent is to be maintained
on the device surface.
[0560] It should be readily evident to one of skill in the art that
any of the previously described fibrosis inducing agents, or
derivatives and analogues thereof, can be utilized to create
variations of the above compositions without deviating from the
spirit and scope of the invention. It should also be apparent that
the agent can be utilized in a composition with or without polymer
carrier and that altering the carrier does not deviate from the
scope of this invention.
[0561] (ii) Male Permanent Contraceptive Devices
[0562] For permanent contraception in men, vasectomy is a commonly
used, highly effective method for the control of fertility. A
common vasectomy procedure involves injecting local anesthetic
alongside the vas deferens, opening the scrotum with pointed
dissecting forceps, pulling the vas through the puncture, and
occluding or cutting the vas deferens (e.g., using a ligation
technique in which the vas is ligatured at one or both ends with a
suture, application of an implantable clip, or by cutting and/or
cauterizing the vas).
[0563] (a) Deferens Implants
[0564] Several devices for male contraception have been disclosed
including valved sterilization devices for surgical insertion
within the vas deferens described in U.S. Pat. Nos. 3,704,704 and
3,777,737, a reversible male sterilization device described in U.S.
Pat. No. 4,682,592, and vasectomy and Intra-Vas devices described
in U.S. Pat. Nos. 3,589,355 and 4,200,088, 3,648,683, and
3,589,355. Commercially available vasectomy clips include those
produced by Advanced Meditech International, Inc. (Flushing, N.Y.)
and the VASCLIP from VMBC, LLC (Roseville, Minn.) In the present
invention, the incorporation of a fibrosis-inducing agent onto or
into vasectomy sutures, clips, or implantable devices (such as
those described above) can promote fibrosis of the vas deferens,
produce a more complete occlusion, and increase the success rate of
the procedure.
[0565] For clips, sutures, and other implanted devices, there are
several methods available for incorporating fibrosing compositions
onto or into the vas deferens implant, including: (a) directly
affixing to the device a fibrosing composition (e.g., by either a
spraying process or dipping process as described above, with or
without a carrier); (b) directly incorporating into the device a
fibrosing composition (e.g., by either a spraying process or
dipping process as described above, with or without a carrier); (c)
by coating the device with a substance such as a hydrogel which can
in turn absorb the fibrosing composition; (d) by interweaving into
the device structure a thread coated with a fibrosis-inducing agent
(or the fibrosis agent-polymer composition itself is formed into a
thread); (e) by inserting the device into a sleeve or mesh which is
comprised of, or coated with, a fibrosing composition; (f)
constructing the device itself (or a portion of the device) with a
fibrosing composition; or (g) by covalently binding the fibrosing
agent directly to the device surface or to a linker (small molecule
or polymer) that is coated or attached to the device surface.
[0566] In addition to coating the device with the fibrosing
composition, the fibrosing agent can be mixed with the materials
that are used to make the device such that the fibrosing agent is
incorporated into the final structure of device itself.
[0567] In another embodiment, a film or mesh that further comprises
a fibrosis-inducing agent can be wrapped around the vas deferens or
a cut portion of the vas deferens. This can promote fibrosis of the
cut vas deferens and can increase the success rate of the
procedure. In another embodiment, the fibrosis-inducing agent can
be incorporated into an in situ forming gel composition. Following
the application of a clip, ligation with a suture, or cutting of
the vas deferens, the in situ forming composition can be applied to
the treatment site (e.g., the cut end of the vas deferens) so as to
promote fibrosis and increase the success rate of the
procedure.
[0568] It should be apparent to one of skill in the art that
potentially any adhesion or fibrosis-inducing agent may be utilized
alone, or in combination, in the practice of this embodiment as
described above. Exemplary fibrosing agents for use in vas deferens
implants and devices include talc, silk, wool, chitosan,
polylysine, fibronectin, bleomycin, and CTGF, as well as analogues
and derivatives of the aforementioned.
[0569] Optionally, the device may alone or additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone).
[0570] Furthermore, the device may additionally comprise an agent
that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof.
[0571] The correct administration and dosage can be described
further in section (c) below.
[0572] (b) Injectable Vas Deferens Implants
[0573] A particularly preferred embodiment of the present invention
involves percutaneous delivery of a fibrosis-inducing agent in
combination with a biomaterial designed for injection into the vas
deferens to "plug" or obstruct the male reproductive tract. The vas
deferens is located by palpation (on both sides), a needle is
inserted into the lumen, a guidewire is advanced into the lumen of
the vas deferens, a dual lumen catheter (for many of the hydrogels
described below such as materials prepared from a 4-armed thiol PEG
(10K), a 4-armed NHS PEG(10K) and methylated collagen such as
described above, COSEAL, COSTASIS, FLOSEAL, TISSEAL) or a single
lumen catheter (for materials such as cyanoacrylate, hyaluronic
acid, proteins, carbohydrates, sclerosing agents etc.) is advanced
over the guidewire into the lumen of the vas deferens, the
guidewire is removed, and a composition containing a
fibrosis-inducing agent is injected via the catheter into the vas
deferens until the lumen is completely occluded. Techniques can be
used to enhance visualization of needle (or catheter) placement
within the vas deferens including, but not limited to, the use of a
needle coated with ECHO--COAT or the injection of air to enable
localization by ultrasound, or the addition of contrast agents
(e.g., barium, tantalum, technitium, gadolinium) for localization
by x-ray or MRI. The injectable implant can obstruct the vas
deferens from the inside (luminal surface) and can be implanted in
a conscious patient through a single (left and right) needle
puncture-reducing the time required to perform the procedure, the
invasiveness (a surgical incision is not required), and the risk of
infection. The biomaterial physically obstructs the lumen of the
tube, while the fibrosis-inducing agent encourages the formation of
scar tissue between adjacent walls of the vas deferens, leading to
permanent obstruction of the lumen. This prevents the movement of
sperm cells through the male reproductive tract, and can lower the
failure rate of the procedure (measured as the prevention of
unwanted pregnancies).
[0574] The injectable material may be composed of a hydrogel for
use in the sterilization of a mammalian male. The hydrogel can be
composed of a non-degradable or a degradable material.
Non-degradable materials can include crosslinked compositions that
comprise PVA, PVP, polyacrylamide, pHEMA, poly(vinyl PEG),
poly(styrene sulfonate), poly(acrylic acid), poly(methacrylic
acid), as well as other polymers that are known to form hydrogels.
Additional compositions include blends and copolymers of the agents
listed above. Degradable materials include, but are not limited to,
crosslinked materials of PEG, gelatin, collagen, hyaluronic acid,
hyaluronic acid derivatives, polysaccharides, carbohydrates,
proteins (e.g., albumin, casein, whey proteins, plant proteins, and
fish proteins), cellulose derivatives (e.g., HPC), chitosan,
chitosan derivatives, polyester-polyalkylene oxide block copolymers
(e.g., PLGA-PEG-PLGA and MePEG-PLGA, etc) and other low molecular
weight polymers that can be excreted. One material that is of
particular interest is prepared from a 4-armed thiol PEG (10K), a
4-armed NHS PEG(10K) and methylated collagen such as described
above. The hydrogel may also contain a biologically active agent
capable of inducing fibrosis in the vas deferens. Preferred,
biologically active, fibrosis-inducing, agents, their dosages and
their release kinetics, are all described in detail in section (c)
below.
[0575] In addition to, or in lieu of, fibrosis-inducing agents, the
hydrogel can be utilized to deliver a sclerosant to the vas
deferens. Sclerosants include compounds such as ethanol, DMSO,
surfactants, sucrose, NaCl, dextrose, glycerin, minocycline,
tetracycline, doxycycline, polidocanol, sodium tetradecyl sulfate,
sodium morrhuate, sotradecol and others. The hydrogel can further
comprise agents such as glycerol, glycerin, PEG 200, triethyl
citrate, and triacetin as plasticizers.
[0576] The hydrogels described above can further modified to be
comprised of, or contain, polymeric threads. Polymeric threads have
the ability to induce a fibroproliferative response from the
surrounding tissue in the vas deferens. These polymer threads can
be degradable or non-degradable. Degradable threads can be composed
of degradable polyesters, polyanhydrides, poly(anhydride esters),
poly(ester-amides), poly(ester-ureas), polyorthoesters,
polyphosphoesters, polyphosphazines, cyanoacrylate polymers,
collagen, chitosan, hyaluronic acid, chromic cat gut, alginates,
starch, cellulose, cellulose esters, blends and copolymers thereof,
as well as other known degradable polymers. Non-degradable polymers
that can be used include, but are not limited to, polyesters (e.g.,
PET), polyurethanes, silicones, PE, PP, PS, PAA, PMA, silk, blends,
copolymers thereof as well as other known polymers. The threads
used can be composed of a single composition or composed of a blend
of differing compositions. The polymeric threads themselves can be
further modified through the addition of a polymeric coating
applied to the threads. The polymer used for coating the thread can
be similar to that described above for the threads themselves. The
polymer coating may further comprise a biologically active agent
that has the ability to induce a fibroproliferative response. The
agents that can be used are further described in the section (c)
below.
[0577] The hydrogels described above can be utilized to deliver a
particulate material that has the ability to induce a
fibroproliferative response in the vas deferens. These particles
can be either degradable or non-degradable and are similar to those
described above for threads. In addition to those, particulate
materials useful for the practice of this embodiment include talc,
starch, glass, silicates, silica, silver nitrate, ceramic particles
and other inorganic particles known in the art to induce a
fibroproliferative response. The particles used in this embodiment
can be all of the same composition or a blend of differing
compositions. These particles can also be used as a coating applied
to the polymeric strands as described above.
[0578] The hydrogel can also be constructed such that it is
comprised of both polymeric threads and particles. The threads and
particles used are similar to those described above and may be of
uniform composition or blended composition. Virtually any
combination of threads of differing compositions and particles of
differing compositions can be utilized in this embodiment. The
hydrogel, the polymeric threads, and the particles can all be
utilized to deliver one or more biologically active agents, as
described below.
[0579] One specific composition comprises rods prepared from a
methylated collagen-crosslinked poly(ethylene glycol) composition
such as described above which has powdered silk particles added to
the composition prior to curing. Once deployed, the rod can absorb
water and thereby occlude the vas deferens. This expansion can
prevent the rod from moving, while the powdered silk can initiate a
fibroproliferative response. As the methylated collagen-crosslinked
poly(ethylene glycol) material starts to degrade, the material can
support the fibrous tissue ingrowth that is initiated and
potentiated by the silk particles. To further increase the rate of
initiation of this fibroproliferative response, a sclerosant such
as a surfactant (SDS), ethanolamine oleate or DMSO can be added. In
addition, one may also add or replace all (or a portion) of the
4-armed thiol PEG with a 4-armed amino PEG. The amino PEG can
provide a gel that can take a longer time to degrade and can
provide some positive charge to further attract cellular
material.
[0580] Another embodiment consists of an injectable implant
composed of silk fibers or from a polymerized version of the
fibrosing agent itself (i.e., repeating units of the fibrosing
agent polymerized together).
[0581] In addition to the hydrogels and related implants described
above, there are several other ways to practice this embodiment.
All involve the deployment of a biomaterial into the lumen of the
vas deferens, with or without, the addition of a fibrosis-inducing
agent. The practice of this embodiment can be performed in several
ways including: (a) injection of the fibrosing agent onto the
luminal surface of the vas deferens (particularly useful for this
embodiment is the use of polymeric carriers which release the
fibrosing agent over a period ranging from several hours to several
weeks-fluids, suspensions, emulsions, microemulsions, microspheres,
pastes, gels, microparticulates, sprays, aerosols, solid implants
and other formulations which release a fibrosing agent can be
delivered into the vas deferens via specialized delivery catheters
or other applicators); (b) microparticulate silk and/or silk
strands (linear, branched, and/or coiled) either alone, or loaded
with an additional fibrosis-inducing agent are also useful for
directed injection into the vas deferens; (c) injectable
collagen-containing formulations such as COSTASIS or materials
prepared from a 4-armed thiol PEG (10K), a 4-armed NHS PEG(10K) and
methylated collagen such as described above, either alone, or
loaded with a fibrosis-inducing agent, injected into the lumen of
the vas deferens; (d) injectable PEG-containing formulations such
as COSEAL, FOCALSEAL, SPRAYGEL or DURASEAL, either alone, or loaded
with a fibrosis-inducing agent, injected into the lumen of the vas
deferens; (e) fibrinogen-containing formulations such as FLOSEAL or
TISSEAL, either alone, or loaded with a fibrosis-inducing agent,
injected into the lumen of the vas deferens; (f) hyaluronic
acid-containing formulations such as RESTYLANE, HYLAFORM, PERLANE,
SYNVISC, SEPRAFILM, SEPRACOAT, either alone, or loaded with a
fibrosis-inducing agent injected into the lumen of the vas
deferens; (g) polymeric gels for surgical implantation such as
REPEL or FLOWGEL either alone, or loaded with a fibrosis-inducing
agent injected into the lumen of the vas deferens; (h) orthopedic
"cements" such as OSTEOBOND, LVC, SIMPLEX P, PALACOS, CORTOSS, and
ENDURANCE, either alone, or loaded with a fibrosis-inducing agent
injected into the luminal surface of the vas deferens; (i) surgical
adhesives containing cyanoacrylates such as DERMABOND, INDERMIL,
GLUSTITCH, VETBOND, HISTOACRYL, TISSUEMEND, TISSUMEND II,
HISTOACRYL BLUE and ORABASE SOOTHE-N-SEAL LIQUID PROTECTANT or as
described above, either alone, or loaded with a fibrosis-inducing
agent, injected into the lumen of the vas deferens; (j) surgical
implants containing hydroxyapatite such as VITOSS (Orthovita) or
calcium sulfate, alone or loaded with a fibrosis-inducing agent
injected into the lumen of the vas deferens; (k) other
biocompatible tissue fillers, such as those made by BioCure, 3M
Company and Neomend, either alone, or loaded with a
fibrosis-inducing agent, injected into the lumen of the vas
deferens; (l) polysaccharide gels such as the ADCON series of gels,
either alone, or loaded with a fibrosis-inducing agent injected
into the lumen of the vas deferens; (m) films, sponges or meshes
such as INTERCEED, VICRYL mesh, and GELFOAM either alone, or loaded
with a fibrosis-inducing agent injected into the lumen of the vas
deferens; and/or (n) a hydrogel that is formed from an
amino-functionalized polyethylene glycol (e.g., 4-armed tetra-amino
PEG [10k]) and a 4-armed NHS functionalized PEG (e.g.,
pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl
glutarate [10K]). This hydrogel may further contain collagen,
methylated collagen and/or gelatin. This hydrogel can further
comprise the fibrosis-inducing agents described above (e.g., silk
powder or silk threads).
[0582] In many of the embodiments described above it may also be
useful to add a radio-opaque material (such as tantalum, barium,
other metal, or contrast material) such that the injected material
can be visualized radiographically or by MRI. The contrast agent
may be a water soluble or water insoluble radio-opaque
material.
[0583] It should be apparent to one of skill in the art that
potentially any adhesion or fibrosis-inducing agent may be utilized
alone, or in combination, in the practice of this embodiment as
described above. Exemplary fibrosing agents for use in vas deferens
implants and devices include talc, silk, wool, chitosan,
polylysine, fibronectin, bleomycin, and CTGF, as well as analogues
and derivatives of the aforementioned.
[0584] Optionally, the device may alone or additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone).
[0585] Furthermore, the device may additionally comprise an agent
that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof.
[0586] The correct administration and dosage can be described
further in section (c) below.
[0587] (c) Fibrosing Agents for Vas Deferens Implants
[0588] As vas deferens implantables and injectables are made in a
variety of configurations and sizes, the exact dose administered
can vary with device size, surface area and design. However,
certain principles can be applied in the application of this art.
Drug dose can be calculated as a function of dose per unit area (of
the portion of the device being coated), total drug dose
administered can be measured and appropriate surface concentrations
of active drug can be determined. Regardless of the method of
application of the drug to the sterilization device, the exemplary
fibrosing agents, used alone or in combination, should be
administered under the following dosing guidelines:
[0589] Utilizing talc as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, incorporated into
an injectable, or applied without a polymeric carrier, the total
dose of talc delivered from a sterilization device, or coated onto
the surface of a sterilization device, should not exceed 100 mg
(range of 1 .mu.g to 100 mg). In one embodiment, the total amount
of talc released from the prosthesis should be in the range of 10
.mu.g to 50 mg. The dose per unit area of the device (i.e., the
dosage of talc as a function of the surface area of the portion of
the device to which drug is applied and/or incorporated) should
fall within the range of 0.05 .mu.g-10 .mu.g per mm.sup.2 of
surface area coated. In another embodiment, talc should be applied
to a sterilization device surface at a dose of 0.05
.mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. In one
embodiment, talc is released from the surface of a sterilization
device such that fibrosis in the tissue is promoted for a period
ranging from several hours to several months. For example, talc may
be released in effective concentrations for a period ranging from 1
hour-30 days. It should be readily evident given the discussions
provided herein that analogues and derivatives of talc (as
described previously) with similar functional activity can be
utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound
(e.g., a compound twice as potent as talc is administered at half
the above parameters, a compound half as potent as talc is
administered at twice the above parameters, etc.).
[0590] Utilizing silk as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, incorporated into
an injectable, or applied without a polymeric carrier, the total
dose of silk delivered from a sterilization device, or coated onto
the surface of a sterilization device, should not exceed 100 mg
(range of 1 .mu.g to 100 mg). In one embodiment, the total amount
of silk released from the prosthesis should be in the range of 10
.mu.g to 50 mg. The dose per unit area of the device (i.e., the
dosage of silk as a function of the surface area of the portion of
the device to which drug is applied and/or incorporated) should
fall within the range of 0.05 .mu.g-10 .mu.g per mm.sup.2 of
surface area coated. In another embodiment, silk should be applied
to a sterilization device surface at a dose of 0.05
.mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. As
specific (polymeric and non-polymeric) drug delivery vehicles and
specific medical devices can release silk at differing rates, the
above dosing parameters should be utilized in combination with the
release rate of the drug from the sterilization device such that a
minimum concentration of 0.01 nM to 1000 .mu.M of silk is delivered
to the tissue. In one embodiment, silk is released from the surface
of a sterilization device such that fibrosis in the tissue is
promoted for a period ranging from several hours to several months.
For example, silk may be released in effective concentrations for a
period ranging from 1 hour-30 days. It should be readily evident
given the discussions provided herein that analogues and
derivatives of silk (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as silk is
administered at half the above parameters, a compound half as
potent as silk is administered at twice the above parameters,
etc.).
[0591] Utilizing chitosan as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, incorporated into
an injectable, or applied without a polymeric carrier, the total
dose of chitosan delivered from a sterilization device, or coated
onto the surface of a sterilization device, should not exceed 100
mg (range of 1 .mu.g to 100 mg). In one embodiment, the total
amount of chitosan released from the prosthesis should be in the
range of 10 .mu.g to 50 mg. The dose per unit area of the device
(i.e., the dosage of chitosan as a function of the surface area of
the portion of the device to which drug is applied and/or
incorporated) should fall within the range of 0.05 .mu.g-10 .mu.g
per mm.sup.2 of surface area coated. In another embodiment,
chitosan should be applied to a sterilization device surface at a
dose of 0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area
coated. As specific (polymeric and non-polymeric) drug delivery
vehicles and specific medical devices can release chitosan at
differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the
sterilization device such that a minimum concentration of 0.01 nM
to 1000 .mu.M of chitosan is delivered to the tissue. In one
embodiment, chitosan is released from the surface of a
sterilization device such that fibrosis in the tissue is promoted
for a period ranging from several hours to several months. For
example, chitosan may be released in effective concentrations for a
period ranging from 1 hour-30 days. It should be readily evident
given the discussions provided herein that analogues and
derivatives of chitosan (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
chitosan is administered at half the above parameters, a compound
half as potent as chitosan is administered at twice the above
parameters, etc.).
[0592] Utilizing polylysine as a exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, incorporated into
an injectable, or applied without a polymeric carrier, the total
dose of polylysine delivered from a sterilization device, or coated
onto the surface of a sterilization device, should not exceed 100
mg (range of 1 .mu.g to 100 mg). In one embodiment, the total
amount of polylysine released from the prosthesis should be in the
range of 10 .mu.g to 50 mg. The dose per unit area of the device
(i.e., the dosage of polylysine as a function of the surface area
of the portion of the device to which drug is applied and/or
incorporated) should fall within the range of 0.05 .mu.g-10 .mu.g
per mm.sup.2 of surface area coated. In another embodiment,
polylysine should be applied to a sterilization device surface at a
dose of 0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area
coated. As specific (polymeric and non-polymeric) drug delivery
vehicles and specific medical devices can release polylysine at
differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the
sterilization device such that a minimum concentration of 0.01 nM
to 1000 .mu.M of polylysine is delivered to the tissue. In one
embodiment, polylysine is released from the surface of a
sterilization device such that fibrosis in the tissue is promoted
for a period ranging from several hours to several months. For
example, polylysine may be released in effective concentrations for
a period ranging from 1 hour-30 days. It should be readily evident
given the discussions provided herein that analogues and
derivatives of polylysine (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
polylysine is administered at half the above parameters, a compound
half as potent as polylysine is administered at twice the above
parameters, etc.).
[0593] Utilizing fibronectin as an exemplary fibrosis-inducing
agent, whether it is applied using a polymer coating, incorporated
into the polymers which make up the device or implant, incorporated
into an injectable, or applied without a polymeric carrier, the
total dose of fibronectin delivered from a sterilization device, or
coated onto the surface of a sterilization device, should not
exceed 100 mg (range of 1 .mu.g to 100 mg). In one embodiment, the
total amount of fibronectin released from the prosthesis should be
in the range of 10 .mu.g to 50 mg. The dose per unit area of the
device (i.e., the dosage of fibronectin as a function of the
surface area of the portion of the device to which drug is applied
and/or incorporated) should fall within the range of 0.05 .mu.g-10
.mu.g per mm.sup.2 of surface area coated. In another embodiment,
fibronectin should be applied to a sterilization device surface at
a dose of 0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area
coated. As specific (polymeric and non-polymeric) drug delivery
vehicles and specific medical devices can release fibronectin at
differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the
sterilization device such that a minimum concentration of 0.01 nM
to 1000 .mu.M of fibronectin is delivered to the tissue. In one
embodiment, fibronectin is released from the surface of a
sterilization device such that fibrosis in the tissue is promoted
for a period ranging from several hours to several months. For
example, fibronectin may be released in effective concentrations
for a period ranging from 1 hour-30 days. It should be readily
evident given the discussions provided herein that analogues and
derivatives of fibronectin (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
fibronectin is administered at half the above parameters, a
compound half as potent as fibronectin is administered at twice the
above parameters, etc.).
[0594] Utilizing bleomycin as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, incorporated into
an injectable, or applied without a polymeric carrier, the total
dose of bleomycin delivered from a sterilization device, or coated
onto the surface of a sterilization device, should not exceed 100
mg (range of 0.01 .mu.g to 100 mg). In one embodiment, the total
amount of bleomycin released from the prosthesis should be in the
range of 0.10 .mu.g to 50 mg. The dose per unit area of the device
(i.e., the dosage of bleomycin as a function of the surface area of
the portion of the device to which drug is applied and/or
incorporated) should fall within the range of 0.005 .mu.g-10 .mu.g
per mm.sup.2 of surface area coated. In another embodiment,
bleomycin should be applied to a sterilization device surface at a
dose of 0.005 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area
coated. As specific (polymeric and non-polymeric) drug delivery
vehicles and specific medical devices can release bleomycin at
differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the
sterilization device such that a minimum concentration of 0.001 nM
to 1000 .mu.M of bleomycin is delivered to the tissue. In one
embodiment, bleomycin is released from the surface of a
sterilization device such that fibrosis in the tissue is promoted
for a period ranging from several hours to several months. For
example, bleomycin may be released in effective concentrations for
a period ranging from 1 hour-30 days. It should be readily evident
given the discussions provided herein that analogues and
derivatives of bleomycin (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
bleomycin is administered at half the above parameters, a compound
half as potent as bleomycin is administered at twice the above
parameters, etc.).
[0595] Utilizing CTGF as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, incorporated into
an injectable, or applied without a polymeric carrier, the total
dose of CTGF delivered from a sterilization device, or coated onto
the surface of a sterilization device, should not exceed 100 mg
(range of 0.01 .mu.g to 100 mg). In one embodiment, the total
amount of CTGF released from the prosthesis should be in the range
of 0.10 .mu.g to 50 mg. The dose per unit area of the device (i.e.,
the dosage of CTGF as a function of the surface area of the portion
of the device to which drug is applied and/or incorporated) should
fall within the range of 0.005 .mu.g-10 .mu.g per mm.sup.2 of
surface area coated. In another embodiment, CTGF should be applied
to a sterilization device surface at a dose of 0.005
.mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. As
specific (polymeric and non-polymeric) drug delivery vehicles and
specific medical devices can release CTGF at differing rates, the
above dosing parameters should be utilized in combination with the
release rate of the drug from the a sterilization device such that
a minimum concentration of 0.001 nM to 1000 .mu.M of CTGF is
delivered to the tissue. In one embodiment, CTGF is released from
the surface of a sterilization device such that fibrosis in the
tissue is promoted for a period ranging from several hours to
several months. For example, CTGF may be released in effective
concentrations for a period ranging from 1 hour-30 days. It should
be readily evident given the discussions provided herein that
analogues and derivatives of CTGF (as described previously) with
similar functional activity can be utilized for the purposes of
this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as CTGF is administered at half the above parameters, a compound
half as potent as CTGF is administered at twice the above
parameters, etc.).
[0596] Optionally, the device may alone or additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone). Inflammatory cytokines are to be used in
formulations at concentrations that range from 0.0001 .mu.g/ml to
approximately 20 mg/ml depending on the specific clinical
application, formulation type (e.g., gel, liquid, solid,
semi-solid), formulation chemistry, duration of required
application, type of medical device interface and formulation
volume and or surface area coverage required. Preferably, the
inflammatory cytokine is released in effective concentrations for a
period ranging from 1-180 days. The total dose for a single
application is typically not to exceed 500 mg (range of 0.0001
.mu.g to 100 mg); preferred 0.001 .mu.g to 50 mg. When used as a
device coating, the dose is per unit area of 0.0001 .mu.g-500 .mu.g
per mm.sup.2; with a preferred dose of 0.001 .mu.g/mm.sup.2-200
.mu.g/mm.sup.2. Minimum concentration of 10.sup.-10-10.sup.-4 g/ml
of inflammatory cytokine is to be maintained on the device
surface.
[0597] Furthermore, the device may alone or additionally comprise
an agent that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof. Doses used are those
concentrations which are demonstrated to stimulate cell
proliferation (Example 16). The proliferative agents are to be used
in formulations at concentrations that range from 0.01 ng/ml to 25
mg/ml depending on the specific clinical application, formulation
type (e.g., gel, liquid, solid, semi-solid), formulation chemistry,
duration of required application, type of medical device interface
and formulation volume and or surface area coverage required.
Preferably, the proliferative agent is released in effective
concentrations for a period ranging from 1-180 days. The total dose
for a single application is typically not to exceed 500 mg (range
of 0.0001 .mu.g to 200 mg); preferred 0.001 .mu.g to 100 mg. When
used as a device coating, the dose is per unit area of 0.00001
.mu.g-500 .mu.g per mm.sup.2; with a preferred dose of 0.0001
.mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-11-10.sup.-6 M of proliferative agent is to be maintained
on the device surface.
[0598] It should be readily evident to one of skill in the art that
any of the previously described fibrosis inducing agents, or
derivatives and analogues thereof, can be utilized to create
variations of the above compositions without deviating from the
spirit and scope of the invention. It should also be apparent that
the agent can be utilized in a composition with or without polymer
carrier and that altering the carrier does not deviate from the
scope of this invention.
[0599] 6. Urinary Incontinence
[0600] The present invention provides compositions and devices for
use in the management of urinary incontinence. Urinary
incontinence, or the involuntary loss of urine, is a common medical
condition which affects 20% of women and 1-2% of men at some point
in their lifetime. The most common form of incontinence is stress
incontinence, or the inadvertent leakage of urine in response to
activities that cause an increase in intraabdominal pressure (such
as sneezing, coughing, or straining). This occurs when intravesical
pressure (pressure in the bladder) exceeds the pressure in the
urethra, forcing urine from the bladder and into the urethra in the
absence of detrusor (bladder muscle) contraction. Several
conditions are thought to result in stress incontinence, including:
(1) descent of the bladder neck and internal urethral sphincter out
of the abdomen; and (2) intrinsic urethral sphincter failure due to
trauma, surgery, childbirth or malignancy. Corrective measures are
aimed principally at supporting the proximal urethral and bladder
neck within the abdominal cavity by surgical or non-surgical means.
A second approach involves the use of urethral bulking agents
designed to increase urethral pressure and reduce stress
incontinence.
[0601] Regardless of their composition, urethral bulking agents are
designed to provide physical support for the urethra and prevent
the leakage of urine. Unfortunately, the symptomatic relief is
often only temporary for most patients and the procedure must be
repeated. Biodegradable injectable materials (such as collagen,
hyaluronic acid and others described below) are absorbed by the
body over time and lose their structural integrity--necessitating
replacement of the material via repeat injection. Non degradable
materials (such as acrylics, hydroxyapatite, polymeric beads, and
others described below) do not regenerate the normal structural
anatomy or biomechanics of the tissues surrounding the urethra. The
addition of a fibrosis-inducing agent to a urethral bulking agent
solves several of these problems. The fibrosis-inducing agent
encourages the formation of the body's own fibrous tissue
(including collagen) around the urethra. This results in the
formation of continuously sustainable connective tissue which
supports the urethra in a manner more closely approximating normal
pelvic anatomy and biomechanics. The result is a treatment that
lasts longer, provides better symptomatic relief and requires fewer
re-interventions.
[0602] (i) Injectable Urinary Bulking Agents Containing a Fibrosing
Agent
[0603] Bulking agents for use in treating urinary incontinence
which may be combined with one or more fibrosis-inducing agents
according to the present invention, include commercially available
products for the management of stress incontinence. CONTIGEN
(purified bovine dermal glutaraldehyde crosslinked collagen
dispersed in phosphate buffered physiologic saline at 35 mg/ml
available through C.R. Bard, Billerica, Mass.) is a widely used
urethral bulking agent. Other collagen based injectable products,
including those derived from non-bovine, human, or recombinant
sources can also be utilized in this embodiment. Other
representative examples of commercially available bulking agents
that can be used to treat urinary incontinence include
hydroxyapatite loaded gel (COAPATITE from BioForm Medical, Inc.,
San Mateo, Calif.), micronized alloderm acellular matrix (CYMETRA
from LifeCell Corporation, Branchburg, N.J.), non-animal stabilized
hyaluronic acid (NASHA and DEFLUX from Q-Med), pyrolytic
carbon-coated micro-beads in hydrogel containing beta-glucan
(DURASPHERE from Carbon Medical Technologies, Inc. St. Paul, Minn.
and Boston Scientific Corporation, Natick, Mass.), engineered
collagen fibrils (Organogenesis, Inc., Canton, Mass.), hylan
polymer (HYLAGEL URO from Genzyme), MACROPLASTIQUE
(polydimethylsiloxane in hydrogel carrier) from Uroplasty, Inc.
(Minneapolis, Minn.), microspheres (e.g., acrylic beads, such as
those available from Biosphere Medical, Inc. Marlborough, Mass.),
urethral bulking agents containing silk and elastin proteins
(Protein Polymer Technologies, San Diego, Calif.), cross-linked
silicon microballoon filled with biocompatible polymer (UROVIVE
from American Medical Systems, Minnetonka, Minn.), and URYX bulking
agent and Embolyx from Microtherapeutics, Inc., San Clemente,
Calif. and Genyx Medical, Inc., Aliso Viejo, Calif. Other
manufacturers of carriers suitable for use in bulking compositions
include C.R. Bard, Inc. (Murray Hill, N.J.), Collagenesis, Inc.
(Acton, Mass.), American Medical Systems, Mentor, Uromed
Corporation (Norwood, Mass.), Boston Scientific Corporation,
Johnson & Johnson (Ethicon, Inc.), Cook Group, Inc.
(Bloomington, Ind.), W.L. Gore & Associates, and SURX, Inc.
(Pleasonton, Calif.).
[0604] Administration of a fibrosis-agent loaded bulking agent may
typically be performed by transurethral injection. If the carrier
of the fibrosis-inducing agent contains collagen, the patient
should have completed two skin tests (conducted 2 weeks apart) to
test for an allergic response prior to administration. If these
tests are negative, the collagen injection containing a
fibrosis-inducing agent can be administered to the patient. A
refrigerated, single use, pre-loaded syringe agent with a fine
gauge needle (23 gauge transurethral injection needle with a
stabilizing cannula) containing 2.5 ml of the implant material (the
fibrosis-inducing agent and the urethral bulking agent) is used.
The patient is placed in the lithotomy position and 10 ml of 2%
lidocaine is inserted into the urethra for anesthesia. In women,
the bladder neck is visualized cystoscopically. Via the injection
port of the cystoscope, the needle is inserted at the 4 o'clock
position, at a sharp angle, 1-1.5 cm distal to the bladder neck
into the plane just beneath the bladder mucosa. The needle is then
advanced with the cystoscope parallel to the long axis of the
urethra until it lies just below the mucosa of the bladder neck.
The fibrosis-inducing agent and the urethral bulking agent is
injected slowly into this site. The procedure is then repeated at
the 8 o'clock position. Methylene blue, or other nontoxic coloring
agents, can be added to the implant to assist with visualization of
the injection.
[0605] Alternatively, periurethral injection of a fibrosis-inducing
agent loaded into a urethral bulking agent can also be used for the
treatment of incontinence. A refrigerated, single use, pre-loaded
syringe with a fine gauge needle (periurethral injection needle)
containing 2.5 ml of the implant material (the fibrosis-inducing
agent and the urethral bulking agent) is used. The patient is
placed in the lithotomy position, 10 ml of 2% lidocaine is inserted
into the urethra for anesthesia and the bladder neck is visualized
cystoscopically (in men the urethra can also be visualized via
suprapubic cystoscopic approach). The needle is inserted
transvaginally or suprapubically into the area immediately adjacent
and lateral to the urethra. When it reaches the appropriate
position near the bladder neck (as seen cystoscopically and
described above), the fibrosis-inducing agent loaded into a
urethral bulking agent is injected slowly into this site. Methylene
blue, or other nontoxic coloring agents, can be added to the
implant to assist with visualization of the injection.
[0606] It should be apparent to one of skill in the art that
potentially any adhesion or fibrosis-inducing agent may be utilized
(alone or in combination) with any injectable urethral bulking
agent in the practice of this invention. Exemplary fibrosing agents
for use in combination with injectable urethral bulking agents
include talc, silk, wool, chitosan, polylysine, fibronectin,
bleomycin, and CTGF, as well as analogues and derivatives of the
aforementioned.
[0607] Optionally, the device may alone or additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone) or an analogue or derivative thereof.
[0608] Furthermore, the device may alone or additionally comprise
an agent that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof.
[0609] The correct administration and dosage can be described
further in section (iii) below.
[0610] (ii) Urinary Slings Containing a Fibrosis-Inducing Agent
[0611] In another aspect, stress incontinence and weakening of the
urethra muscle may be treated with a pubovaginal sling procedure.
This operation can create enough compression on the urethra to help
the patient regain bladder control. Slings for treating urinary
incontinence are described in, e.g., U.S. Pat. Nos. 6,641,524;
6,592,610; 6,387,040; 6,328,686; 6,306,079; 6,221,005; 6,110,101;
6,056,687; 6,042,536; and 6,042,534 and U.S. Patent Application
Publication Nos. 2003/0199732A1; 2003/0149440A1; 2002/0183588A1;
2002/0058959A1; and 2002/0022841 A1.
[0612] Slings for use in treating urinary incontinence which may be
combined with one or more fibrosis-inducing agents according to the
present invention, include numerous commercially available
products. For example, the SUSPEND TUTOPLAST (Processed Fascia Lata
sling from Mentor) and REPLIFORM Tissue Regeneration Matrix (human
allograft dermal collagen fibers from Boston Scientific Corporation
(Natick, Mass.)) can be used. Products such as FORTAGEN Surgical
Mesh and GRAFTPATCH (both from Organogenesis Inc., Canton, Mass.),
and SURGISIS (Cook Biotech, Inc., West Lafayette, Ind.) consist of
a multilaminate sheet composed primarily of Type I collagen
(usually porcine or bovine) that is used to reinforce soft tissues
during operative repair. Indications include defects of the
abdominal and thoracic wall, muscle flap reinforcement, rectal and
vaginal prolapse, repair of tissue flap donor sites, ostomy
reinforcement, reconstruction of the pelvic floor, hernia repair,
suture line reinforcement and reconstructive purposes. Surgical
slings, such as the FORTAFLEX Surgical Sling (Organogenesis, Inc.)
and the SURGISIS Sling are also composed predominantly of Type I
Collagen (usually porcine or bovine) and are utilized in open
urological surgery procedures. Indications include pubourethral
support, prolapse repair (urethral, vaginal, rectal and colonic),
rectoceles, cystoceles, enteroceles, mastoplexy, reconstruction of
the pelvic floor, bladder support, sacrocolposuspension and other
reconstructive procedures. Other representative examples of slings
for use in the present invention include Tension-Free Vaginal Tape
(TVT) from Ethicon, Inc. (Somerville, N.J.), the SPARC Female Sling
System (a "vaginal tape" product from American Medical Systems),
the AMS Silicone-Coated Mesh Sling (American Medical Systems),
BIOSLING (InjecTx/ProSurg), VERITAS Collagen Matrix Urological
Sling (Synovis Life Technologies, Inc., St. Paul, Minn.), slings
made from PTFE, such as Gore-Tex MYCROMESH from Gore, the STRATESIS
Urethral Sling made from acellular porcine small intestine mucosa
(Cook, Inc.), slings made from allograph fascia, such as the
ALLOSLING (Alliant Medical), and slings made from human allograft
fascia, such as FASLATA Allograft Tissue (C.R. Bard). Slings can
also be prepared from, e.g., polypropylene mesh (C.R. Bard), and
MERSILENE polyester fiber mesh (Ethicon, Inc.).
[0613] Numerous polymeric and non-polymeric drug delivery systems
described above can be used to deliver fibrosis-inducing agents
from urological slings and implants. The methods for incorporating
fibrosing compositions onto or into the urinary incontinence
devices include: (a) directly affixing to the urinary incontinence
implant a fibrosing composition (e.g., by either a spraying process
or dipping process as described above, with or without a carrier);
(b) directly incorporating into the device a fibrosing composition
(e.g., by either a spraying process or dipping process as described
above, with or without a carrier); (c) by coating the device with a
substance such as a hydrogel which can in turn absorb the fibrosing
composition; (d) by interweaving fibrosing composition coated
thread (or the polymer itself formed into a thread) into the device
structure; (e) by inserting the device into a sleeve or mesh which
is comprised of or coated with a fibrosing composition; (f)
constructing the device itself or a portion of the device with a
fibrosing composition, or (g) by covalently binding the fibrosing
agent directly to the device surface or to a linker (small molecule
or polymer) that is coated or attached to the device surface. For
these devices, the coating process can be performed in such a
manner as to a) coat the exterior surfaces of the device, b) coat
the interior surfaces of the device or c) coat all or parts of both
external and internal surface of the device.
[0614] In addition to coating the device with the fibrosing
composition, the fibrosing agent can be mixed with the materials
that are used to make the device such that the fibrosing agent is
incorporated into the final device.
[0615] In one embodiment, fibrosis-inducing agents can be
incorporated directly into the formulation to produce a suspension
or a solution (e.g., silk powder, bleomycin) or it can be
incorporated into a secondary carrier (e.g., micelles, liposomes,
microspheres, microparticles, nanospheres, microparticulates,
emulsions and/or micromulsions) that is then incorporated into the
bulking composition. In another embodiment, the fibrosis-inducing
agent can be electrostatically or covalently bound to one or more
of the polymeric components of the in situ forming composition.
[0616] In another embodiment, the fibrosis-inducing agent can be
incorporated into the bulking agent during the manufacture of the
agent. For example, silk powder can be added as a reagent during
the manufacture of microspheres that are used as bulking
agents.
[0617] It should be apparent to one of skill in the art that
potentially any adhesion or fibrosis-inducing agents described
above may be utilized alone, or in combination, in the practice of
this embodiment. Exemplary fibrosing agents for use in urinary
incontinence devices and compositions include talc, silk, wool,
chitosan, polylysine, fibronectin, bleomycin, and CTGF, as well as
analogues and derivatives of the aforementioned.
[0618] Optionally, the device may alone or additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone) or an analogue or derivative thereof.
[0619] Furthermore, the device may additionally comprise an agent
that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof.
[0620] (iii) Fibrosing Agents for Use in Urinary Incontinence
Implants
[0621] As urinary incontinence devices are made in a variety of
configurations and sizes (including injectable bulking agents and
slings), the exact dose administered can vary with implant or
device size, surface area and design. However, certain principles
can be applied in the application of this art. Drug dose can be
calculated as a function of dose per unit area (of the portion of
the device being coated), total drug dose administered can be
measured and appropriate surface concentrations of active drug can
be determined. Regardless of the method of application of the drug
to the urinary incontinence implant or device, the exemplary
fibrosing agents, used alone or in combination, should be
administered under the following dosing guidelines:
[0622] Utilizing talc as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of talc delivered from
a urinary incontinence device, or coated onto the surface of a
urinary incontinence device, should not exceed 100 mg (range of 1
.mu.g to 100 mg). In one embodiment, the total amount of talc
released from the prosthesis should be in the range of 10 .mu.g to
50 mg. The dose per unit volume of the injectable urinary bulking
agent (i.e., the dosage of talc as a function of the volume of
urinary bulking agent injected) should fall within the range of
0.05 .mu.g-10 .mu.g per mm.sup.3. In another embodiment, talc
should be applied to a urinary sling incontinence device surface at
a dose of 0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area
coated. In one embodiment, talc is released from a urinary
incontinence bulking agent, implant or device such that fibrosis in
the tissue is promoted for a period ranging from several hours to
several months. For example, talc may be released in effective
concentrations for a period ranging from 1-9 months. It should be
readily evident given the discussions provided herein that
analogues and derivatives of talc (as described previously) with
similar functional activity can be utilized for the purposes of
this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as talc is administered at half the above parameters, a compound
half as potent as talc is administered at twice the above
parameters, etc.).
[0623] Utilizing silk as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of silk delivered from
a urinary incontinence device, or coated onto the surface of a
urinary incontinence device, should not exceed 100 mg (range of 1
.mu.g to 100 mg). In one embodiment, the total amount of silk
released from the prosthesis should be in the range of 10 .mu.g to
50 mg. The dose per unit volume of the injectable urinary bulking
agent (i.e., the dosage of silk as a function of the volume of
urinary bulking agent injected) should fall within the range of
0.05 .mu.g-10 .mu.g per mm.sup.3. In another embodiment, silk
should be applied to a urinary sling incontinence device surface at
a dose of 0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area
coated. As specific (polymeric and non-polymeric) drug delivery
vehicles and specific medical devices can release silk at differing
rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the urinary
incontinence bulking agent, implant or device such that a minimum
concentration of 0.01 nM to 1000 .mu.M of silk is delivered to the
tissue. In one embodiment, silk is released from a urinary
incontinence bulking agent, implant or device such that fibrosis in
the tissue is promoted for a period ranging from several hours to
several months. For example, silk may be released in effective
concentrations for a period ranging from 1-9 months. It should be
readily evident given the discussions provided herein that
analogues and derivatives of silk (as described previously) with
similar functional activity can be utilized for the purposes of
this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as silk is administered at half the above parameters, a compound
half as potent as silk is administered at twice the above
parameters, etc.).
[0624] Utilizing chitosan as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of chitosan delivered
from a urinary incontinence device, or coated onto the surface of a
urinary incontinence device, should not exceed 100 mg (range of 1
.mu.g to 100 mg). In one embodiment, the total amount of chitosan
released from the prosthesis should be in the range of 10 .mu.g to
50 mg. The dose per unit volume of the injectable urinary bulking
agent (i.e., the dosage of chitosan as a function of the volume of
urinary bulking agent injected) should fall within the range of
0.05 .mu.g-10 .mu.g per mm.sup.3. In another embodiment, chitosan
should be applied to a urinary sling incontinence device surface at
a dose of 0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area
coated. As specific (polymeric and non-polymeric) drug delivery
vehicles and specific medical devices can release chitosan at
differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the urinary
incontinence bulking agent, implant or device such that a minimum
concentration of 0.01 nM to 1000 .mu.M of chitosan is delivered to
the tissue. In one embodiment, chitosan is released from a urinary
incontinence bulking agent, implant or device such that fibrosis in
the tissue is promoted for a period ranging from several hours to
several months. For example, chitosan may be released in effective
concentrations for a period ranging from 1-9 months. It should be
readily evident given the discussions provided herein that
analogues and derivatives of chitosan (as described previously)
with similar functional activity can be utilized for the purposes
of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as chitosan is administered at half the above parameters, a
compound half as potent as chitosan is administered at twice the
above parameters, etc.).
[0625] Utilizing polylysine as an exemplary fibrosis-inducing
agent, whether it is applied using a polymer coating, incorporated
into the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of polylysine delivered
from a urinary incontinence device, or coated onto the surface of a
urinary incontinence device, should not exceed 100 mg (range of 1
.mu.g to 100 mg). In one embodiment, the total amount of polylysine
released from the prosthesis should be in the range of 10 .mu.g to
50 mg. The dose per unit volume of the injectable urinary bulking
agent (i.e., the dosage of polylysine as a function of the volume
of urinary bulking agent injected) should fall within the range of
0.05 .mu.g-10 .mu.g per mm.sup.3. In another embodiment, polylysine
should be applied to a urinary sling incontinence device surface at
a dose of 0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area
coated. As specific (polymeric and non-polymeric) drug delivery
vehicles and specific medical devices can release polylysine at
differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the urinary
incontinence bulking agent, implant or device such that a minimum
concentration of 0.01 nM to 1000 .mu.M of polylysine is delivered
to the tissue. In one embodiment, polylysine is released from a
urinary incontinence bulking agent, implant or device such that
fibrosis in the tissue is promoted for a period ranging from
several hours to several months. For example, polylysine may be
released in effective concentrations for a period ranging from 1-9
months. It should be readily evident given the discussions provided
herein that analogues and derivatives of polylysine (as described
previously) with similar functional activity can be utilized for
the purposes of this invention; the above dosing parameters are
then adjusted according to the relative potency of the analogue or
derivative as compared to the parent compound (e.g., a compound
twice as potent as polylysine is administered at half the above
parameters, a compound half as potent as polylysine is administered
at twice the above parameters, etc.).
[0626] Utilizing fibronectin as an exemplary fibrosis-inducing
agent, whether it is applied using a polymer coating, incorporated
into the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of fibronectin
delivered from a urinary incontinence device, or coated onto the
surface of a urinary incontinence device, should not exceed 100 mg
(range of 1 .mu.g to 100 mg). In one embodiment, the total amount
of fibronectin released from the prosthesis should be in the range
of 10 .mu.g to 50 mg. The dose per unit volume of the injectable
urinary bulking agent (i.e., the dosage of fibronectin as a
function of the volume of urinary bulking agent injected) should
fall within the range of 0.05 .mu.g-10 .mu.g per mm.sup.3. In
another embodiment, talc should be applied to a urinary sling
incontinence device surface at a dose of 0.05 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific medical devices
can release fibronectin at differing rates, the above dosing
parameters should be utilized in combination with the release rate
of the drug from the urinary incontinence bulking agent, implant or
device such that a minimum concentration of 0.01 nM to 1000 .mu.M
of fibronectin is delivered to the tissue. In one embodiment,
fibronectin is released from a urinary incontinence bulking agent,
implant or device such that fibrosis in the tissue is promoted for
a period ranging from several hours to several months. For example,
fibronectin may be released in effective concentrations for a
period ranging from 1-9 months. It should be readily evident given
the discussions provided herein that analogues and derivatives of
fibronectin (as described previously) with similar functional
activity can be utilized for the purposes of this invention; the
above dosing parameters are then adjusted according to the relative
potency of the analogue or derivative as compared to the parent
compound (e.g., a compound twice as potent as fibronectin is
administered at half the above parameters, a compound half as
potent as fibronectin is administered at twice the above
parameters, etc.).
[0627] Utilizing bleomycin as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of bleomycin delivered
from a urinary incontinence device, or coated onto the surface of a
urinary incontinence device, should not exceed 100 mg (range of
0.01 .mu.g to 100 mg). In one embodiment, the total amount of
bleomycin released from the prosthesis should be in the range of
0.10 .mu.g to 50 mg. The dose per unit volume of the injectable
urinary bulking agent (i.e., the dosage of bleomycin as a function
of the volume of urinary bulking agent injected) should fall within
the range of 0.005 .mu.g-10 .mu.g per mm.sup.3. In another
embodiment, bleomycin should be applied to a urinary sling
incontinence device surface at a dose of 0.005 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific medical devices
can release bleomycin at differing rates, the above dosing
parameters should be utilized in combination with the release rate
of the drug from the urinary incontinence bulking agent, implant or
device such that a minimum concentration of 0.001 nM to 1000 .mu.M
of bleomycin is delivered to the tissue. In one embodiment,
bleomycin is released from a urinary incontinence bulking agent,
implant or device such that fibrosis in the tissue is promoted for
a period ranging from several hours to several months. For example,
bleomycin may be released in effective concentrations for a period
ranging from 1-9 months. It should be readily evident given the
discussions provided herein that analogues and derivatives of
bleomycin (as described previously) with similar functional
activity can be utilized for the purposes of this invention; the
above dosing parameters are then adjusted according to the relative
potency of the analogue or derivative as compared to the parent
compound (e.g., a compound twice as potent as bleomycin is
administered at half the above parameters, a compound half as
potent as bleomycin is administered at twice the above parameters,
etc.).
[0628] Utilizing CTGF as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of CTGF delivered from
a urinary incontinence device, or coated onto the surface of a
urinary incontinence device, should not exceed 100 mg (range of
0.01 .mu.g to 100 mg). In one embodiment, the total amount of CTGF
released from the prosthesis should be in the range of 0.10 .mu.g
to 50 mg. The dose per unit volume of the injectable urinary
bulking agent (i.e., the dosage of CTGF as a function of the volume
of urinary bulking agent injected) should fall within the range of
0.005 .mu.g-10 .mu.g per mm.sup.3. In another embodiment, CTGF
should be applied to a urinary sling incontinence device surface at
a dose of 0.005 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area
coated. As specific (polymeric and non-polymeric) drug delivery
vehicles and specific medical devices can release CTGF at differing
rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the urinary
incontinence bulking agent, implant or device such that a minimum
concentration of 0.001 nM to 1000 .mu.M of CTGF is delivered to the
tissue. In one embodiment, CTGF is released from a urinary
incontinence bulking agent, implant or device such that fibrosis in
the tissue is promoted for a period ranging from several hours to
several months. For example, CTGF may be released in effective
concentrations for a period ranging from 1-9 months. It should be
readily evident given the discussions provided herein that
analogues and derivatives of CTGF (as described previously) with
similar functional activity can be utilized for the purposes of
this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as CTGF is administered at half the above parameters, a compound
half as potent as CTGF is administered at twice the above
parameters, etc.).
[0629] Optionally, the device may alone or additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone or an analogue or derivative thereof). Inflammatory
cytokines are to be used in formulations at concentrations that
range from 0.0001 .mu.g/ml to approximately 20 mg/ml depending on
the specific clinical application, formulation type (e.g., gel,
liquid, solid, semi-solid), formulation chemistry, duration of
required application, type of medical device interface and
formulation volume and or surface area coverage required.
Preferably, the inflammatory cytokine is released in effective
concentrations for a period ranging from 1-180 days. The total dose
for a single application is typically not to exceed 500 mg (range
of 0.0001 .mu.g to 100 mg); preferred 0.001 .mu.g to 50 mg. When
used as a device coating, the dose is per unit area of 0.0001
.mu.g-500 .mu.g per mm.sup.2; with a preferred dose of 0.001
.mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-10-10.sup.-4 g/ml of inflammatory cytokine is to be
maintained on the device surface.
[0630] Furthermore, the device may additionally comprise an agent
that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof. Doses used are those
concentrations which are demonstrated to stimulate cell
proliferation (Example 16). The proliferative agents are to be used
in formulations at concentrations that range from 0.1 ng/ml to 25
mg/ml depending on the specific clinical application, formulation
type (e.g., gel, liquid, solid, semi-solid), formulation chemistry,
duration of required application, type of medical device interface
and formulation volume and or surface area coverage required.
Preferably, the proliferative agent is released in effective
concentrations for a period ranging from 1-180 days. The total dose
for a single application is typically not to exceed 500 mg (range
of 0.0001 .mu.g to 200 mg); preferred 0.001 .mu.g to 100 mg. When
used as a device coating, the dose is per unit area of 0.00001
.mu.g-500 .mu.g per mm.sup.2; with a preferred dose of 0.0001
.mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-11-10.sup.-6 M of proliferative agent is to be maintained
on the device surface.
[0631] It should be readily evident to one of skill in the art that
any of the previously described fibrosis inducing agents, or
derivatives and analogues thereof, can be utilized to create
variations of the above compositions without deviating from the
spirit and scope of the invention. It should also be apparent that
the agent can be utilized in a composition with or without polymer
carrier and that altering the carrier does not deviate from the
scope of this invention.
[0632] 7. Venous Occluding Materials Containing Fibrosing
Agents
[0633] A variety of devices and injectable implants have been
developed for injection into veins for cosmetic purposes.
Typically, a needle or catheter is advanced into an unwanted vein
(primarily "spider" veins or varicose veins) and a sclerosing agent
is injected into the vessel to scar the vein shut. Unfortunately,
currently available agents often do not produce permanent fibrosis
(true luminal scarring where the walls of the vessel permanently
adhere to each other and fibrous tissue occludes the vessel)
leading to the possibility of recannulization, re-establishment of
venous flow, and ultimately recurrence of the vein (i.e., failure
of the procedure). The present invention describes the addition of
fibrosis-inducing agents to the materials injected into the vein
for the purpose of producing a permanent, obstructive scar in the
vascular lumen that results in regression and absorption of the
unwanted vein. If venous flow is permanently prevented in the vein
due to obstructive fibrosis, the body resorbs the non-functioning
vessel and eliminates the vein, leaving little or no chance for
recurrence.
[0634] There are several commercially available sclerosing agents
that are used to treat spider veins and varicose veins, which may
be combined with one or more fibrosis-inducing drugs according to
the present invention. For example, Wyeth Pharmaceuticals
(Collegeville, Pa.), a division of Wyeth (Madison, N.J.), sells
SOTRADECOL, which is a sodium tetradecyl sulfate injection. Other
sclerosing agents available for treating spider veins and varicose
veins (and may be suitable for delivery of a fibrosis-inducing
agent) include sodium morrhuate, ethanolamine oleate, compositions
containing ethanol, DMSO, surfactants, sucrose, NaCl, dextrose,
glycerin, minocycline, tetracycline, doxycycline, polidocanol,
sodium tetradecyl sulfate, sodium morrhuate, sotradecol and others.
Other examples of compositions suitable for cosmetic vascular
injection include silk (e.g., microparticulate silk), polymeric
gels composed of fibrosis-inducing agents (such as those available
from Polymerix Corporation) and fibrosis-inducing agents loaded
into vascular fillers.
[0635] A variety of polymer based products have been developed for
intra-vascular injection for the purposes of arterial embolization
(described in greater detail in the section 12(ii) on arterial
embolization below). Many of these intra-vascular polymer systems
are suitable for the treatment of spider veins and varicose veins
and can be made more efficacious through the addition of a
fibrosis-inducing agent. Examples of products suitable for
combining with a fibrosis-inducing agent include, for example,
TRUFILL n-butyl cyanoacrylate (n-BCA) Liquid Embolic System
(available from Cordis, a division of Johnson and Johnson, Miami,
Fla.); ONYX Liquid Embolic System (Micro Therapeutics, Irvine,
Calif.). Other examples of materials suitable for the delivery of a
fibrosis-inducing agent into the venous system include
polymer/solvent systems in which the solvent diffuses from the
polymer matrix once it has been injected into the vein (e.g.,
degradable polymeric systems from Atrix, non-degradable polymeric
compositions from ONYX and EMBOLYX, and in situ forming materials
from Biocure, Angiotech Pharmaceuticals, Inc., 3M Company, and
Neomend. Other types of commercially available embolic agents that
can be loaded or made with a fibrosis-inducing agent for venous
occlusion include PVA particles (from Cook, Inc. and Angiodynamics
Inc.), and microsphere formulations (e.g., EMBOSPHERE and EMBOGOLD
from Biosphere, Inc. (Rockland, Mass.) and BEAD BLOCK from
Biocompatibles Ltd., United Kingdom).
[0636] In one embodiment, the injectable vascular material is
composed of an injectable polymer system combined with a
fibrosis-inducing agent. One injectable polymer system that is of
particular interest is prepared from a 4-armed thiol PEG (10K), a
4-armed NHS PEG(10K) and methylated collagen such as described
above. The injectable vascular material may be combined with a
fibrosis-inducing agent (e.g., talc, silk, wool, chitosan,
polylysine, fibronectin, bleomycin, CTGF, bone morphogenic
proteins, transforming growth factor, platelet-derived growth
factor, fibroblast growth factor, as well as analogues and
derivatives of these compounds) and injected into a varicose vein
or spider vein. In addition to, or in lieu of, fibrosis-inducing
agents, bone morphogenic proteins and growth factors, the
injectable material can also be utilized to deliver a sclerosant to
the vein. Sclerosants include compounds such as ethanol, DMSO,
surfactants, sucrose, sodium morrhuate, ethanolamine oleate NaCl,
dextrose, glycerin, minocycline, tetracycline, doxycycline,
polidocanol, sodium tetradecyl sulfate, sodium morrhuate,
sotradecol and others. The injectable material can further comprise
agents such as glycerol, glycerin, PEG 200, triethyl citrate, and
triacetin as plasticizers.
[0637] In another embodiment, the injectable intra-vascular
materials described above can be further modified to be extruded
from the catheter (or needle) as a polymeric "thread" or contain
polymeric threads. Polymeric threads have the ability to induce
clotting as well as a fibroproliferative response from the vascular
wall. The injectable "threads" can be loaded with, coated with, or
comprised of a fibrosis-inducing agent (e.g., an injectable implant
composed of silk fibers or a polymerized version of the fibrosing
agent itself). These polymer threads can be degradable or
non-degradable. Degradable threads can be composed of degradable
polyesters, polyanhydrides, poly(anhydride esters),
poly(ester-amides), poly(ester-ureas), polyorthoesters,
polyphosphoesters, polyphosphazines, cyanoacrylate polymers,
collagen, chitosan, hyaluronic acid, chromic cat gut, alginates,
starch, cellulose, cellulose esters, blends and copolymers thereof,
as well as other known degradable polymers. Non-degradable polymers
that can be used include, but are not limited to, polyesters (e.g.,
PET), polyurethanes, silicones, PE, PP, PS, PAA, PMA, silk, blends,
copolymers thereof as well as other known polymers. The threads
used can be composed of a single composition or composed of a blend
of differing compositions. The polymeric threads themselves can be
further modified through the addition of a polymeric coating
applied to the threads. The polymer used for coating the thread can
be similar to that described above for the threads themselves. The
polymer coating may further comprise a biologically active
fibrosis-inducing agent.
[0638] In another embodiment, the intra-vascular injectable
materials described above can be formulated to be delivered from
the catheter (or needle) as a particulate material that has the
ability to induce clofting and fibrosis. The injectable particles
can be loaded with, coated with, or comprised of a
fibrosis-inducing agent. These particles can be either degradable
or non-degradable and are similar in composition to those described
above for threads. In addition to the aforementioned polymers,
particulate materials useful for the practice of this embodiment
include talc, starch, glass, silicates, silica, calcium phosphate,
calcium sulfate, calcium carbonate, hydroxyapatite, synthetic
mineral (VITOSS and CORTOSS), PMMA, silver nitrate, ceramic
particles and other inorganic particles known in the art to induce
a fibroproliferative response. The particles used in this
embodiment can be all of the same composition or a blend of
differing compositions. These particles can also be used as a
coating applied to the polymeric strands as described above.
[0639] As is readily apparent, the injectable intravascular
material can also be constructed such that it is comprised of both
polymeric threads and particles. The threads and particles used are
similar to those described above and may be of uniform composition
or blended composition. Virtually any combination of threads of
differing compositions and particles of differing compositions can
be utilized in this embodiment. The hydrogel, the polymeric
threads, and the particles can all be utilized to deliver one or
more fibrosis-inducing agents.
[0640] In addition to the injectable materials described above,
there are several other injectable compositions suitable for
intra-vascular administration in the treatment of spider veins and
varicose veins. All involve the deployment of a biomaterial into
the lumen of the vein, with or without, the addition of a
fibrosis-inducing agent, bone morphogenic protein(s), and/or a
suitable growth factor(s). The following compositions can be
delivered into the vein via specialized delivery catheters, an
endoscope (e.g., angioscope; typically the material is delivered
via a sideport in the device), a needle or other applicator, a
surgically placed access device, or other transdermal
intra-vascular access device and include administration of: (a)
fluids, suspensions, emulsions, microemulsions, microspheres,
pastes, gels, microparticulates, sprays, aerosols, solid implants
and other formulations which release a biologically active
agent(s); (b) microparticulate silk and/or silk strands (linear,
branched, and/or coiled) either alone, or loaded with an additional
fibrosis-inducing agent, bone morphogenic protein, and/or growth
factor injected into the vein; (c) injectable collagen-containing
formulations such as COSTASIS or materials made from 4-armed thiol
PEG (10K), a 4-armed NHS PEG (10K) and methylated collagen such as
described above, either alone, or loaded with a fibrosis-inducing
agent, bone morphogenic protein, and/or growth factor, injected
into the vein; (d) injectable PEG-containing formulations such as
COSEAL, FOCALSEAL, SPRAYGEL or DURASEAL, either alone, or loaded
with a fibrosis-inducing agent, bone morphogenic protein, and/or
growth factor, injected into the vein; (e) fibrinogen-containing
formulations such as FLOSEAL or TISSEAL, either alone, or loaded
with a fibrosis-inducing agent, bone morphogenic protein, and/or
growth factor, injected into the vein; (f) hyaluronic
acid-containing formulations such as RESTYLANE, HYLAFORM, PERLANE,
SYNVISC, SEPRAFILM, SEPRACOAT, either alone, or loaded with a
fibrosis-inducing agent, bone morphogenic protein, and/or growth
factor injected into the vein; (g) polymeric gels for surgical
implantation such as REPEL or FLOWGEL either alone, or loaded with
a fibrosis-inducing agent, bone morphogenic protein, and/or growth
factor injected into the vein; (h) orthopedic "cements" such as
OSTEOBOND, LVC, SIMPLEX P, PALACOS, CORTOSS, and ENDURANCE, either
alone, or loaded with a fibrosis-inducing agent, bone morphogenic
protein, and/or growth factor injected into the vein; (i) surgical
adhesives containing cyanoacrylates such as DERMABOND, INDERMIL,
GLUSTITCH, VETBOND, HISTOACRYL, TISSUEMEND, TISSUMEND II,
HISTOACRYL BLUE and ORABASE SOOTHE-N-SEAL LIQUID PROTECTANT or as
described above, either alone, or loaded with a fibrosis-inducing
agent, bone morphogenic protein, and/or growth factor, injected
into the vein; (j) surgical implants containing hydroxyapatite,
calcium phosphate (such as VITOSS), or calcium sulfate, alone or
loaded with a fibrosis-inducing agent, bone morphogenic protein,
and/or growth factor, injected into the vein; (k) other
biocompatible tissue fillers, such as those made by BioCure, 3M
Company and Neomend, either alone, or loaded with a
fibrosis-inducing agent, bone morphogenic protein, and/or growth
factor, injected into the vein; (l) polysaccharide gels such as the
ADCON series of gels, either alone, or loaded with a
fibrosis-inducing agent, bone morphogenic protein, and/or growth
factor, injected into the vein; (m) films, sponges or meshes such
as INTERCEED, VICRYL mesh, and GELFOAM either alone, or loaded with
a fibrosis-inducing agent, bone morphogenic protein, and/or growth
factor, injected into the vein; and/or (n) a hydrogel that is
formed from an amino-functionalized polyethylene glycol (e.g.,
4-armed tetra-amino PEG [10k]) and a 4-armed NHS functionalized PEG
(e.g., pentaerythritol poly(ethylene glycol)ether
tetra-succinimidyl glutarate [10K]). This hydrogel may further
contain collagen, methylated collagen and/or gelatin. This hydrogel
can further comprise the fibrosis-inducing agents described above
(e.g., silk powder or silk threads).
[0641] In many of these embodiments, it may also be useful to add a
radio-opaque material (such as tantalum, barium, other metal, or
contrast material) such that the injected material can be
visualized radiographically or MRI. Also, when performing direct
injection into the vein, techniques can be used to enhance
visualization of needle (or catheter) via ultrasound through the
use of a needle coated with ECHO--COAT or the injection of air
(microbubbles).
[0642] In one preferred method of administration for the treatment
of large varicose veins, the fibrosing agent is delivered under
direct vision during angioscopic evaluation of the vessel. Here the
composition containing the fibrosis-inducing agent, bone
morphogenic protein, and/or growth factor is injected into the
lumen of the varicose vein through the side port of an angioscope.
In some cases, the fibrosis-inducing agent may also be delivered
directly to the lumen of the vein (or the tissue surrounding the
vein) during open surgery.
[0643] It should be apparent to one of skill in the art that
potentially any adhesion or fibrosis-inducing agent may be utilized
alone, or in combination, in the practice of this embodiment as
described above. Exemplary fibrosing agents for use in venous
destruction procedures include talc, silk, wool, chitosan,
polylysine, fibronectin, bleomycin, CTGF, bone morphogenic
proteins, and/or osteogenic growth factors (such as transforming
growth factor, platelet-derived growth factor, fibroblast growth
factor) as well as analogues and derivatives of the aforementioned.
In some clinical situations, repeated injections of the active
agents described below may be required.
[0644] The exact dose administered can vary depending upon the
particular vein being treated. However, certain principles can be
applied in the application of this art. Drug dose can be calculated
as a function of dose per unit volume (of the amount being
injected), total drug dose administered can be measured and
appropriate surface concentrations of active drug can be
determined. Regardless of the method of application of the drug to
the vein, the exemplary fibrosing agents, bone morphogenic
proteins, and/or growth factors (such as transforming growth
factor, platelet-derived growth factor, fibroblast growth factor),
used alone or in combination, should be administered under the
following dosing guidelines:
[0645] Utilizing talc as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the injectable, or administered without
a polymeric carrier, the total dose of talc administered into the
venous system in any single injection should not exceed 100 mg
(range of 1 .mu.g to 100 mg). In one embodiment, the total amount
of talc administered should be in the range of 10 .mu.g to 50 mg.
The dose per unit volume injected should fall within the range of
0.05 .mu.g-10 .mu.g per mm.sup.3. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific implants can
release talc at differing rates, the above dosing parameters should
be utilized in combination with the release rate of the drug from
the carrier such that a minimum concentration of 0.01 nM to 1000
.mu.M of talc is continuously delivered to the vein over the
desired therapeutic period. In one embodiment, talc is released
from the injectable such that fibrosis in the vein is promoted for
a period ranging from several hours to several months. For example,
talc may be released in effective concentrations for a period
ranging from 2-12 weeks. It should be readily evident given the
discussions provided herein that analogues and derivatives of talc
(as described previously) with similar functional activity can be
utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound
(e.g., a compound twice as potent as talc is administered at half
the above parameters, a compound half as potent as talc is
administered at twice the above parameters, etc.).
[0646] Utilizing silk as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the injectable, or administered without
a polymeric carrier, the total dose of silk delivered to the venous
system in any single injection should not exceed 100 mg (range of 1
.mu.g to 100 mg). In one embodiment, the total amount of silk
administered to the vein should be in the range of 10 .mu.g to 50
mg. The dose per unit volume injected should fall within the range
of 0.05 .mu.g-10 .mu.g per mm.sup.3. As specific (polymeric and
non-polymeric) drug delivery vehicles can release silk at differing
rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the carrier such
that a minimum concentration of 0.01 nM to 1000 .mu.M of silk is
continuously delivered to the tissue over the desired therapeutic
time period. In one embodiment, silk is released into the lumen of
the vein such that fibrosis is promoted for a period ranging from
several hours to several months. For example, silk may be released
in effective concentrations for a period ranging from 2-12 weeks.
It should be readily evident given the discussions provided herein
that analogues and derivatives of silk (as described previously)
with similar functional activity can be utilized for the purposes
of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as silk is administered at half the above parameters, a compound
half as potent as silk is administered at twice the above
parameters, etc.).
[0647] Utilizing chitosan as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the injectable, or administered without
a polymeric carrier, the total dose of chitosan delivered into the
vein should not exceed 100 mg (range of 1 .mu.g to 100 mg). In one
embodiment, the total amount of chitosan administered into the vein
in any single injection should be in the range of 10 .mu.g to 50
mg. The dose per unit volume injected should fall within the range
of 0.05 .mu.g-10 .mu.g per mm.sup.3. As specific (polymeric and
non-polymeric) drug delivery vehicles can release chitosan at
differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the carrier such
that a minimum concentration of 0.01 nM to 1000 .mu.M of chitosan
is continuously delivered into the vein. In one embodiment,
chitosan is released into the lumen of the vein such that fibrosis
is promoted for a period ranging from several hours to several
months. For example, chitosan may be released in effective
concentrations for a period ranging from 2-12 weeks. It should be
readily evident given the discussions provided herein that
analogues and derivatives of chitosan (as described previously)
with similar functional activity can be utilized for the purposes
of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as chitosan is administered at half the above parameters, a
compound half as potent as chitosan is administered at twice the
above parameters, etc.).
[0648] Utilizing polylysine as a exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the injectable, or administered without
a polymeric carrier, the total dose of polylysine delivered into
the vein in a single injection should not exceed 100 mg (range of 1
.mu.g to 100 mg). In one embodiment, the total amount of polylysine
delivered to the vein should be in the range of 10 .mu.g to 50 mg.
The dose per unit volume injected should fall within the range of
0.05 .mu.g-10 .mu.g per mm.sup.3. In another embodiment, polylysine
should be injected into the vein at a dose of 0.05-10
.mu.g/mm.sup.3. As specific (polymeric and non-polymeric) drug
delivery vehicles can release polylysine at differing rates, the
above dosing parameters should be utilized in combination with the
release rate of the drug from the carrier such that a minimum
concentration of 0.01 nM to 1000 .mu.M of polylysine is
continuously delivered to the vein. In one embodiment, polylysine
is administered to the lumen of the vein such that fibrosis is
promoted for a period ranging from several hours to several months.
For example, polylysine may be released in effective concentrations
for a period ranging from 2-12 weeks. It should be readily evident
given the discussions provided herein that analogues and
derivatives of polylysine (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
polylysine is administered at half the above parameters, a compound
half as potent as polylysine is administered at twice the above
parameters, etc.).
[0649] Utilizing fibronectin as an exemplary fibrosis-inducing
agent, whether it is applied using a polymer coating, incorporated
into the polymers which make up the injectable, or administered
without a polymeric carrier, the total dose of fibronectin
delivered into the vein in a single injection should not exceed 100
mg (range of 1 .mu.g to 100 mg). In one embodiment, the total
amount of fibronectin injected into the vein should be in the range
of 10 .mu.g to 50 mg. The dose per unit volume of the injection
should fall within the range of 0.05 .mu.g-10 .mu.g per mm.sup.3.
In another embodiment, talc should be administered at a dose of
0.05-10 .mu.g/mm.sup.3 of injected material. As specific (polymeric
and non-polymeric) drug delivery vehicles can release fibronectin
at differing rates, the above dosing parameters should be utilized
in combination with the release rate of the drug from the carrier
such that a minimum concentration of 0.01 nM to 1000 .mu.M of
fibronectin is continuously delivered to the vein. In one
embodiment, fibronectin is released into the lumen of the vein such
that fibrosis is promoted for a period ranging from several hours
to several months. For example, fibronectin may be released in
effective concentrations for a period ranging from 2-12 weeks. It
should be readily evident given the discussions provided herein
that analogues and derivatives of fibronectin (as described
previously) with similar functional activity can be utilized for
the purposes of this invention; the above dosing parameters are
then adjusted according to the relative potency of the analogue or
derivative as compared to the parent compound (e.g., a compound
twice as potent as fibronectin is administered at half the above
parameters, a compound half as potent as fibronectin is
administered at twice the above parameters, etc.).
[0650] Utilizing bleomycin as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the injectable, or administered without
a polymeric carrier, the total dose of bleomycin administered to a
vein in a single injection should not exceed 100 mg (range of 0.01
.mu.g to 100 mg). In one embodiment, the total amount of bleomycin
injected into the vein should be in the range of 0.10 .mu.g to 50
mg. The dose per unit volume injected should fall within the range
of 0.005 .mu.g-10 .mu.g per mm.sup.3. As specific (polymeric and
non-polymeric) drug delivery vehicles can release bleomycin at
differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the carrier such
that a minimum concentration of 0.001 nM to 1000 .mu.M of bleomycin
is continuously delivered to the vein. In one embodiment, bleomycin
is released from the injection such that fibrosis in the vein is
promoted for a period ranging from several hours to several months.
For example, bleomycin may be released in effective concentrations
for a period ranging from 2-12 weeks. It should be readily evident
given the discussions provided herein that analogues and
derivatives of bleomycin (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
bleomycin is administered at half the above parameters, a compound
half as potent as bleomycin is administered at twice the above
parameters, etc.).
[0651] Utilizing CTGF as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the injectable, or administered without
a polymeric carrier, the total dose of CTGF administered to the
vein in a single injection should not exceed 100 mg (range of 0.01
.mu.g to 100 mg). In one embodiment, the total amount of CTGF
injected into the vein should be in the range of 0.10 .mu.g to 50
mg. The dose per unit volume of the injection should fall within
the range of 0.005 .mu.g-10 .mu.g per mm.sup.3. In another
embodiment, CTGF should be injected at a dose of 0.005-10
.mu.g/mm.sup.3. As specific (polymeric and non-polymeric) drug
delivery vehicles can release CTGF at differing rates, the above
dosing parameters should be utilized in combination with the
release rate of the drug from the carrier such that a minimum
concentration of 0.001 nM to 1000 .mu.M of CTGF is continuously
delivered to the vein. In one embodiment, CTGF is released from the
injectable such that fibrosis in the vein is promoted for a period
ranging from several hours to several months. For example, CTGF may
be released in effective concentrations for a period ranging from
2-12 weeks. It should be readily evident given the discussions
provided herein that analogues and derivatives of CTGF (as
described previously) with similar functional activity can be
utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound
(e.g., a compound twice as potent as CTGF is administered at half
the above parameters, a compound half as potent as CTGF is
administered at twice the above parameters, etc.).
[0652] Optionally, the device may alone or additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone). Inflammatory cytokines are to be used in
formulations at concentrations that range from 0.0001 .mu.g/ml to
approximately 20 mg/ml depending on the specific clinical
application, formulation type (e.g., gel, liquid, solid,
semi-solid), formulation chemistry, duration of required
application, type of medical device interface and formulation
volume and or surface area coverage required. Preferably, the
inflammatory cytokine is released in effective concentrations for a
period ranging from 1-180 days. The total dose for a single
application is typically not to exceed 500 mg (range of 0.0001
.mu.g to 100 mg); preferred 0.001 .mu.g to 50 mg. When used as a
device coating, the dose is per unit area of 0.0001 .mu.g-500 .mu.g
per mm.sup.2; with a preferred dose of 0.001 .mu.g/mm.sup.2-200
.mu.g/mm.sup.2. Minimum concentration of 10.sup.-10-10.sup.-4 g/ml
of inflammatory cytokine is to be maintained on the device
surface.
[0653] Furthermore, the device may alone or additionally comprise
an agent that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof. Doses used are those
concentrations which are demonstrated to stimulate cell
proliferation (see, e.g., Example 16). The proliferative agents are
to be used in formulations at concentrations that range from 0.1
ng/ml to 25 mg/ml depending on the specific clinical application,
formulation type (e.g., gel, liquid, solid, semi-solid),
formulation chemistry, duration of required application, type of
medical device interface and formulation volume and or surface area
coverage required. Preferably, the proliferative agent is released
in effective concentrations for a period ranging from 1-180 days.
The total dose for a single application is typically not to exceed
500 mg (range of 0.0001 .mu.g to 200 mg); preferred 0.001 .mu.g to
100 mg. When used as a device coating, the dose is per unit area of
0.00001 .mu.g-500 .mu.g per mm.sup.2; with a preferred dose of
0.0001 .mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-11-10.sup.-6 M of proliferative agent is to be maintained
on the device surface.
[0654] It should be readily evident to one of skill in the art that
any of the previously described fibrosis-inducing agents, bone
morphogenic proteins, or osteogenic growth factors, or derivatives
and analogues thereof, can be utilized to create variations of the
above compositions without deviating from the spirit and scope of
the invention.
[0655] It should also be apparent that the agent can be utilized in
a composition with or without polymer carrier and that altering the
carrier does not deviate from the scope of this invention.
[0656] 8. Fecal Incontinence
[0657] The present invention provides compositions and devices for
use in the management of fecal incontinence. Fecal incontinence is
the inability to control bowel movements. Reasons for fecal
incontinence include, e.g., damage to the nerves of the pelvic
floor, trauma to the anal and/or rectal area, a birth defect,
altered stool consistency, or abnormal rectal capacity, and
diseases such as diabetes, multiple sclerosis and colorectal
disease. In women, fecal incontinence can be the result of a
difficult childbirth.
[0658] (i) Anal Sphincter Bulking Agents
[0659] Fecal incontinence may be treated by injecting a bulking
agent close to the anal sphincter to reinforce closure of the anal
sphincter. Bulking agents which may be combined with one or more
fibrosis-inducing agents according to the present invention,
include numerous commercially available products. For example,
injectable microspheres from Artes Medical, Inc. (San Diego,
Calif.), ENTERYX (ethylene vinyl alcohol polymer implant from
Boston Scientific Corporation), and CONTIGEN (purified bovine
dermal glutaraldehyde crosslinked collagen dispersed in phosphate
buffered physiologic saline at 35 mg/ml available through C.R.
Bard, Billerica, Mass.) are widely used bulking agents. Other
collagen based injectable products, including those derived from
non-bovine, human, or recombinant sources can also be utilized in
this embodiment. Additional representative examples of commercially
available bulking agents that can be used to treat fecal
incontinence include hydroxyapatite loaded gel (COAPATITE),
micronized alloderm acellular matrix (CYMETRA), non-animal
stabilized hyaluronic acid (NASHA) (DEFLUX), pyrolytic
carbon-coated micro-beads in hydrogel containing beta-glucan
(DURASPHERE), engineered collagen fibrils (Organogenesis), hylan
polymer (HYLAGEL URO), MACROPLASTIQUE (polydimethylsiloxane in
hydrogel carrier), microspheres (e.g., acrylic beads, such as those
available from Biosphere Medical), urethral bulking agents
containing silk and elastin proteins (such as those available from
Protein Polymer Technologies), cross-linked silicon microballoon
filled with biocompatible polymer (UROVIVE), and URYX bulking agent
and Embolyx from Microtherapeutics, Inc., San Clemente, Calif. and
Genyx Medical, Inc., Aliso Viejo, Calif. Other manufacturers of
carriers suitable for use in bulking compositions include C.R.
Bard, Collagenesis, American Medical Systems, Mentor, Uromed,
Boston Scientific Corporation, Johnson & Johnson (Ethicon,
Inc.), Cook Urologic, W.L. Gore, and SURx.
[0660] Regardless of their composition, bulking agents are designed
to provide physical support for the anal sphincter and prevent the
leakage of feces. Unfortunately, the symptomatic relief is often
only temporary for most patients and the procedure must be
repeated. Biodegradable injectable materials (such as collagen,
hyaluronic acid and others described above) are absorbed by the
body over time and lose their structural integrity--necessitating
replacement of the material via repeat injection. Non-degradable
materials (such as acrylics, hydroxyapatite, polymeric beads, and
others described above) do not regenerate the normal structural
anatomy or biomechanics of the tissues surrounding the anal
sphincter. The addition of a fibrosis-inducing agent to a bulking
agent can solve several of these problems. The fibrosis-inducing
agent can encourage the formation of the body's own fibrous tissue
(including collagen) around the anal sphincter. This results in the
formation of continuously sustainable connective tissue which
supports the anal sphincter in a manner more closely approximating
normal rectal anatomy and biomechanics. The result is a treatment
that lasts longer, provides better symptomatic relief and requires
fewer re-interventions.
[0661] In one aspect, the present invention provides injectable
compositions (bulking agents) for use in treating fecal
incontinence. Specifically, the fibrosis-inducing agent can be
produced with or without a carrier (such as collagen, hyaluronic
acid, and/or another biocompatible polymer) which is then injected
in and around the anal sphincter to provide support and continence.
In one embodiment, fibrosis-inducing agents can be incorporated
directly into the formulation to produce a suspension or a solution
(e.g., silk powder, bleomycin) or it can be incorporated into a
secondary carrier (e.g., micelles, liposomes, microspheres,
microparticies, nanospheres, microparticulates, emulsions, and/or
microemulsions) that is then incorporated into the bulking
composition. In another embodiment, the fibrosis-inducing agent can
be electrostatically or covalently bound to one or more of the
polymeric components of the in situ forming composition. Injection
of the bulking agent (many commercial examples of which were
described above) containing the fibrosing agent into the
perimuscular space (alone or in combination with a polymeric
carrier) can enhance scarring and support to the anal sphincter and
may result in endogenous collagen production.
[0662] In another embodiment, the fibrosis-inducing agent can be
incorporated into the bulking agent during the manufacture of the
agent. For example, silk powder can be added as a reagent during
the manufacture of microspheres that are used as bulking
agents.
[0663] It should be apparent to one of skill in the art that
potentially any adhesion or fibrosis-inducing agents described
above may be utilized alone, or in combination, in the practice of
this embodiment. Exemplary fibrosing agents for use in fecal
incontinence devices and compositions include talc, silk, wool,
chitosan, polylysine, fibronectin, bleomycin, and CTGF, as well as
analogues and derivatives of the aforementioned.
[0664] Optionally, the device may alone or additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone) or an analogue or derivative thereof.
[0665] Furthermore, the device may additionally comprise an agent
that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof.
[0666] The appropriate agents and their dosages can be further
described below in section (iii).
[0667] (ii) Prosthetic Anal Sphincters
[0668] Another approach to treating fecal incontinence involves
implantation of prostheses or devices, such as ablation devices,
nerve stimulators, pumps, and stapling devices. Devices for
treating fecal incontinence are described in, e.g., U.S. Pat. Nos.
6,428,467; 6,013,023; 5,421,827; 4,428,365; and 4,351,322 and in
U.S. Published Patent Application Publication No.
2002/0120219A1.
[0669] Devices for treating fecal incontinence which may be
combined with one or more fibrosis-inducing drugs according to the
present invention include a variety of commercially available
products. For example, the SECCA system (Curon Medical) uses radio
frequency ablation to tighten the muscles of the anal sphincter.
The ACTICON Neosphincter (made by Acticon LLC and sold by American
Medical Systems) is an implantable prosthesis that contains hand
inflatable pump connected to an inflatable ring in an artificial
sphincter. The sacral nerve stimulator (Medtronic, Inc.,
Minneapolis, Minn.), is a device that addresses the neuropathy that
results in fecal incontinence. The PROXIMATE stapling device from
Ethicon EndoSurgery lifts up or repositions the mucosa or anal
canal tissue to its original position.
[0670] In the present invention, fibrosis-inducing agents are
combined with prosthetic anal sphincters to enhance scarring around
the device and to re-enforce rectal anatomy to restore fecal
continence. Numerous polymeric and non-polymeric carrier systems
described previously can be used to deliver one or more
fibrosis-inducing agents to promote the formation of granulation
tissue around the implanted device. The methods for incorporating
fibrosis-inducing agents onto or into the fecal incontinence
devices include: (a) directly affixing to the device a fibrosing
composition (e.g., by either a spraying process or dipping process
as described above, with or without a carrier); (b) directly
incorporating into the device a fibrosing composition (e.g., by
either a spraying process or dipping process as described above,
with or without a carrier); (c) by coating the device with a
substance such as a hydrogel which can in turn absorb the fibrosing
composition; (d) by interweaving fibrosing composition coated
thread (or the polymer itself formed into a thread) into the device
structure; (e) by inserting the device into a sleeve or mesh which
is comprised of or coated with a fibrosing composition; (f)
constructing the device itself or a portion of the device with a
fibrosing composition; or (g) by covalently binding the fibrosing
agent directly to the device surface or to a linker (small molecule
or polymer) that is coated or attached to the device surface. For
these devices, the coating process can be performed in such a
manner as to a) coat the exterior surfaces of the device, b) coat
the interior surfaces of the device or c) coat all or parts of both
external and internal surface of the device.
[0671] In addition to coating the device with the fibrosing
composition, the fibrosing agent can be mixed with the materials
that are used to make the device such that the fibrosing agent is
incorporated into the final device.
[0672] It should be apparent to one of skill in the art that
potentially any adhesion or fibrosis-inducing agents described
above may be utilized alone, or in combination, in the practice of
this embodiment. Exemplary fibrosing agents for use in fecal
incontinence devices and compositions include talc, silk, wool,
chitosan, polylysine, fibronectin, bleomycin, and CTGF, as well as
analogues and derivatives of the aforementioned.
[0673] Optionally, the device may alone or additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone) or an analogue or derivative thereof.
[0674] Furthermore, the device may additionally comprise an agent
that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof.
[0675] Preferred specific agents and dosages of use for coating
implantable, prosthetic devices used in the management of fecal
incontinence are described in section (iii) immediately below.
[0676] (iii) Fibrosis-Inducing Agents for Fecal Incontinence
[0677] As fecal incontinence devices are made in a variety of
configurations and sizes (including injectables and prosthetic
implants), the exact dose administered can vary with device or
implant size, surface area and design. However, certain principles
can be applied in the application of this art. Drug dose can be
calculated as a function of dose per unit volume/area (of the total
volume of bulking agent injected or of the surface area of the
portion of the prosthetic device being coated), total drug dose
administered can be measured and appropriate surface concentrations
of active drug can be determined. Regardless of the method of
application of the fibrosis-inducing agent in the management of
fecal incontinence, the exemplary fibrosing agents, used alone or
in combination, should be administered under the following dosing
guidelines:
[0678] Utilizing talc as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of talc delivered in a
bulking agent injection, or coated onto the surface of a fecal
incontinence implant or device, should not exceed 100 mg (range of
1 .mu.g to 100 mg). In one embodiment, the total amount of talc
released should be in the range of 10 .mu.g to 50 mg. The dose per
unit volume of the injectable bulking agent (i.e., the dosage of
talc as a function of the volume of bulking agent injected) should
fall within the range of 0.05 .mu.g-10 .mu.g per mm.sup.3. In
another embodiment, talc should be applied to a fecal incontinence
implant or device surface at a dose of 0.05 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. In one embodiment, talc is
released from a fecal incontinence bulking agent, implant or device
such that fibrosis in the tissue is promoted for a period ranging
from several hours to several months. For example, in a preferred
embodiment talc may be released in effective concentrations for a
period ranging from 3-12 months. It should be readily evident given
the discussions provided herein that analogues and derivatives of
talc (as described previously) with similar functional activity can
be utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound
(e.g., a compound twice as potent as talc is administered at half
the above parameters, a compound half as potent as talc is
administered at twice the above parameters, etc.).
[0679] Utilizing silk as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of silk delivered in a
bulking agent injection, or coated onto the surface of a fecal
incontinence implant or device, should not exceed 100 mg (range of
1 .mu.g to 100 mg). In one embodiment, the total amount of silk
released should be in the range of 10 .mu.g to 50 mg. The dose per
unit volume of the injectable bulking agent (i.e., the dosage of
silk as a function of the volume of bulking agent injected) should
fall within the range of 0.05 .mu.g-10 .mu.g per mm.sup.3. In
another embodiment, silk should be applied to a fecal incontinence
device surface at a dose of 0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2
of surface area coated. As specific (polymeric and non-polymeric)
drug delivery vehicles and specific bulking agents and prosthetic
devices can release silk at differing rates, the above dosing
parameters should be utilized in combination with the release rate
of the drug from the fecal incontinence bulking agent, implant or
device such that a minimum concentration of 0.01 nM to 1000 .mu.M
of silk is delivered to the tissue. In one embodiment, silk is
released from a fecal incontinence bulking agent, implant or device
such that fibrosis in the tissue is promoted for a period ranging
from several hours to several months. For example, in a preferred
embodiment silk may be released in effective concentrations for a
period ranging from 3-12 months. It should be readily evident given
the discussions provided herein that analogues and derivatives of
silk (as described previously) with similar functional activity can
be utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound
(e.g., a compound twice as potent as silk is administered at half
the above parameters, a compound half as potent as silk is
administered at twice the above parameters, etc.).
[0680] Utilizing chitosan as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of chitosan delivered
in a bulking agent injection, or coated onto the surface of a fecal
incontinence implant or device, should not exceed 100 mg (range of
1 .mu.g to 100 mg). In one embodiment, the total amount of chitosan
released should be in the range of 10 .mu.g to 50 mg. The dose per
unit volume of the injectable bulking agent (i.e., the dosage of
chitosan as a function of the volume of bulking agent injected)
should fall within the range of 0.05 .mu.g-10 .mu.g per mm.sup.3.
In another embodiment, chitosan should be applied to a fecal
incontinence device surface at a dose of 0.05 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific bulking agents
and prosthetic devices can release chitosan at differing rates, the
above dosing parameters should be utilized in combination with the
release rate of the drug from the fecal incontinence bulking agent,
implant or device such that a minimum concentration of 0.01 nM to
1000 .mu.M of chitosan is delivered to the tissue. In one
embodiment, chitosan is released from a fecal incontinence bulking
injection, implant or device such that fibrosis in the tissue is
promoted for a period ranging from several hours to several months.
For example, in a preferred embodiment chitosan may be released in
effective concentrations for a period ranging from 3-12 months. It
should be readily evident given the discussions provided herein
that analogues and derivatives of chitosan (as described
previously) with similar functional activity can be utilized for
the purposes of this invention; the above dosing parameters are
then adjusted according to the relative potency of the analogue or
derivative as compared to the parent compound (e.g., a compound
twice as potent as chitosan is administered at half the above
parameters, a compound half as potent as chitosan is administered
at twice the above parameters, etc.).
[0681] Utilizing polylysine as a exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of polylysine delivered
in a bulking agent injection, or coated onto the surface of a fecal
incontinence implant or device, should not exceed 100 mg (range of
1 .mu.g to 100 mg). In one embodiment, the total amount of
polylysine released should be in the range of 10 .mu.g to 50 mg.
The dose per unit volume of the injectable bulking agent (i.e., the
dosage of polylysine as a function of the volume of bulking agent
injected) should fall within the range of 0.05 .mu.g-10 .mu.g per
mm.sup.3. In another embodiment, polylysine should be applied to a
fecal incontinence device surface at a dose of 0.05
.mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. As
specific (polymeric and non-polymeric) drug delivery vehicles and
specific bulking agents and prosthetic devices can release
polylysine at differing rates, the above dosing parameters should
be utilized in combination with the release rate of the drug from
the fecal incontinence bulking agent, device or implant such that a
minimum concentration of 0.01 nM to 1000 .mu.M of polylysine is
delivered to the tissue. In one embodiment, polylysine is released
from a fecal incontinence bulking injection, implant or device such
that fibrosis in the tissue is promoted for a period ranging from
several hours to several months. For example, in a preferred
embodiment polylysine may be released in effective concentrations
for a period ranging from 3-12 months. It should be readily evident
given the discussions provided herein that analogues and
derivatives of polylysine (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
polylysine is administered at half the above parameters, a compound
half as potent as polylysine is administered at twice the above
parameters, etc.).
[0682] Utilizing fibronectin as an exemplary fibrosis-inducing
agent, whether it is applied using a polymer coating, incorporated
into the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of fibronectin
delivered from in a bulking agent injection, or coated onto the
surface of a fecal incontinence implant or device, should not
exceed 100 mg (range of 1 .mu.g to 100 mg). In one embodiment, the
total amount of fibronectin released should be in the range of 10
.mu.g to 50 mg. The dose per unit volume of the injectable bulking
agent (i.e., the dosage of fibronectin as a function of the volume
of bulking agent injected) should fall within the range of 0.05
.mu.g-10 .mu.g per mm.sup.3. In another embodiment, fibronectin
should be applied to a fecal incontinence device surface at a dose
of 0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. As
specific (polymeric and non-polymeric) drug delivery vehicles and
specific bulking agents and prosthetic devices can release
fibronectin at differing rates, the above dosing parameters should
be utilized in combination with the release rate of the drug from
the fecal incontinence bulking agent, implant or device such that a
minimum concentration of 0.01 nM to 1000 .mu.M of fibronectin is
delivered to the tissue. In one embodiment, fibronectin is released
from a fecal incontinence bulking injection, implant or device such
that fibrosis in the tissue is promoted for a period ranging from
several hours to several months. For example, in a preferred
embodiment fibronectin may be released in effective concentrations
for a period ranging from 3-12 months. It should be readily evident
given the discussions provided herein that analogues and
derivatives of fibronectin (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
fibronectin is administered at half the above parameters, a
compound half as potent as fibronectin is administered at twice the
above parameters, etc.).
[0683] Utilizing bleomycin as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of bleomycin delivered
in a bulking agent injection, or coated onto the surface of a fecal
incontinence implant or device, should not exceed 100 mg (range of
0.01 .mu.g to 100 mg). In one embodiment, the total amount of
bleomycin released should be in the range of 0.10 .mu.g to 50 mg.
The dose per unit volume of the injectable bulking agent (i.e., the
dosage of bleomycin as a function of the volume of bulking agent
injected) should fall within the range of 0.005 .mu.g-10 .mu.g per
mm.sup.3. In another embodiment, bleomycin should be applied to a
fecal incontinence device surface at a dose of 0.005
.mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. As
specific (polymeric and non-polymeric) drug delivery vehicles and
specific bulking agents and prosthetic devices can release
bleomycin at differing rates, the above dosing parameters should be
utilized in combination with the release rate of the drug from the
fecal incontinence bulking agent, implant or device such that a
minimum concentration of 0.001 nM to 1000 .mu.M of bleomycin is
delivered to the tissue. In one embodiment, bleomycin is released
from a fecal incontinence bulking injection, implant or device such
that fibrosis in the tissue is promoted for a period ranging from
several hours to several months. For example, in a preferred
embodiment bleomycin may be released in effective concentrations
for a period ranging from 3-12 months. It should be readily evident
given the discussions provided herein that analogues and
derivatives of bleomycin (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
bleomycin is administered at half the above parameters, a compound
half as potent as bleomycin is administered at twice the above
parameters, etc.).
[0684] Utilizing CTGF as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of CTGF delivered in a
bulking agent injection, or coated onto the surface of a fecal
incontinence implant or device, should not exceed 100 mg (range of
0.01 .mu.g to 100 mg). In one embodiment, the total amount of CTGF
released should be in the range of 0.10 .mu.g to 50 mg. The dose
per unit volume of the injectable bulking agent (i.e., the dosage
of CTGF as a function of the volume of bulking agent injected)
should fall within the range of 0.005 .mu.g-10 .mu.g per mm.sup.3.
In another embodiment, CTGF should be applied to a fecal
incontinence device surface at a dose of 0.005 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific bulking agents
and prosthetic devices can release CTGF at differing rates, the
above dosing parameters should be utilized in combination with the
release rate of the drug from the fecal incontinence bulking agent,
implant or device such that a minimum concentration of 0.001 nM to
1000 .mu.M of CTGF is delivered to the tissue. In one embodiment,
CTGF is released from a fecal incontinence bulking injection,
implant or device such that fibrosis in the tissue is promoted for
a period ranging from several hours to several months. For example,
in a preferred embodiment CTGF may be released in effective
concentrations for a period ranging from 3-12 months. It should be
readily evident given the discussions provided herein that
analogues and derivatives of CTGF (as described previously) with
similar functional activity can be utilized for the purposes of
this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as CTGF is administered at half the above parameters, a compound
half as potent as CTGF is administered at twice the above
parameters, etc.).
[0685] Optionally, the device may alone or additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone) or an analogue or derivative thereof. Inflammatory
cytokines are to be used in formulations at concentrations that
range from 0.0001 .mu.g/ml to approximately 20 mg/ml depending on
the specific clinical application, formulation type (e.g., gel,
liquid, solid, semi-solid), formulation chemistry, duration of
required application, type of medical device interface and
formulation volume and or surface area coverage required.
Preferably, the inflammatory cytokine is released in effective
concentrations for a period ranging from 1-180 days. The total dose
for a single application is typically not to exceed 500 mg (range
of 0.0001 .mu.g to 100 mg); preferred 0.001 .mu.g to 50 mg. When
used as a device coating, the dose is per unit area of 0.0001
.mu.g-500 .mu.g per mm.sup.2; with a preferred dose of 0.001
.mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-10-10.sup.-4 g/ml of inflammatory cytokine is to be
maintained on the device surface.
[0686] Furthermore, the device may additionally comprise an agent
that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof. Doses used are those
concentrations which are demonstrated to stimulate cell
proliferation (see, e.g., Example 16). The proliferative agents are
to be used in formulations at concentrations that range from 0.1
ng/ml to 25 mg/ml depending on the specific clinical application,
formulation type (e.g., gel, liquid, solid, semi-solid),
formulation chemistry, duration of required application, type of
medical device interface and formulation volume and or surface area
coverage required. Preferably, the proliferative agent is released
in effective concentrations for a period ranging from 1-180 days.
The total dose for a single application is typically not to exceed
500 mg (range of 0.0001 .mu.g to 200 mg); preferred 0.001 .mu.g to
100 mg. When used as a device coating, the dose is per unit area of
0.00001 .mu.g-500 .mu.g per mm.sup.2; with a preferred dose of
0.0001 .mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-11-10.sup.-6 M of proliferative agent is to be maintained
on the device surface.
[0687] It should be readily evident to one of skill in the art that
any of the previously described fibrosis inducing agents, or
derivatives and analogues thereof, can be utilized to create
variations of the above compositions without deviating from the
spirit and scope of the invention. It should also be apparent that
the agent can be utilized in a composition with or without polymer
carrier and that altering the carrier does not deviate from the
scope of this invention.
[0688] 9. Gastroesophageal Reflux Disease (GERD)
[0689] The present invention provides compositions and devices for
use in the management of gastroesophageal reflux disease (GERD).
GERD occurs when the lower esophageal sphincter (the muscle between
the stomach and the esophagus) is unable to prevent the contents of
the stomach from refluxing back into the esophagus. Gastric acid
and enzymes are quite corrosive to the epithelial lining of the
esophagus and can cause erosions, ulceration, scarring and
narrowing of the esophagus. Repetitive reflux into the esophagus
can result in irreversible injury and also predisposes the patient
to the development of esophageal cancer.
[0690] (i) GERD Bulking Agents
[0691] One approach to treating GERD involves lower esophageal
sphincter augmentation. One method for augmenting the lower
esophageal sphincter involves delivery (e.g., injection) of a
bulking agent (e.g., a collagen bulking agent) into the vicinity of
the lower esophageal sphincter (LES) (e.g., into the perimuscular
space of the LES) to restore the structure of the tissue and reduce
backflow into the esophagus. Another approach involves implantation
of bulking devices or devices that deliver expandable polymeric
compositions (e.g., hydrogel prostheses).
[0692] As mentioned above, GERD may be treated by injecting a
bulking agent close to the lower esophageal sphincter to reinforce
closure of the LES. Bulking agents which may be combined with one
or more fibrosis-inducing agents according to the present
invention, include numerous commercially available products. For
example, injectable microspheres from Artes Medical, ENTERYX and
CONTIGEN (purified bovine dermal glutaraldehyde crosslinked
collagen dispersed in phosphate buffered physiologic saline at 35
mg/ml available through C.R. Bard, Billerica, Mass.) are widely
used bulking agents. Other collagen based injectable products,
including those derived from non-bovine, human, or recombinant
sources can also be utilized in this embodiment. Additional
representative examples of commercially available bulking agents
that can be loaded with a fibrosis-inducing agent and used to treat
GERD include COAPATITE, CYMETRA, DEFLUX, DURASPHERE, engineered
collagen fibrils from Organogenesis, HYLAGEL URO, MACROPLASTIQUE,
microspheres (e.g., acrylic beads, such as those available from
Biosphere Medical), LES bulking agents containing silk and elastin
proteins (such as those available from Protein Polymer
Technologies), UROVIVE, and URYX bulking agent. Another device
suitable for use with a fibrosis-inducing agent in the management
of GERD includes the GATEKEEPER Reflux Repair System made by
Medtronic, Inc. (Minneapolis, Minn.). Other manufacturers of
carriers suitable for delivering a fibrosis-inducing agent for use
in GERD bulking compositions include C.R. Bard, Collagenesis,
American Medical Systems, Mentor, Uromed, BSX, Johnson &
Johnson (Ethicon, Inc.), Cook Inc., W.L. Gore & Associates, and
SURx. Examples of implantable lower esophageal bulking devices are
also described in WO 00/12027A1 and U.S. Pat. No. 6,401,718.
[0693] Regardless of their composition, bulking agents are designed
to provide physical support for the lower esophageal sphincter and
prevent the reflux of gastric contents into the esophagus.
Unfortunately, symptomatic relief is often only temporary for most
patients and the procedure must often be repeated. Biodegradable
injectable materials (such as collagen, hyaluronic acid and others
described above) are absorbed by the body over time and lose their
structural integrity--necessitating replacement of the material via
repeat injection. Non degradable materials (such as acrylics,
hydroxyapatite, polymeric beads, and others described above) do not
regenerate the normal structural anatomy or biomechanics of the
tissues surrounding the lower esophageal sphincter. The addition of
a fibrosis-inducing agent to a bulking agent solves several of
these problems. The fibrosis-inducing agent encourages the
formation of the body's own fibrous tissue (including collagen)
around the lower esophageal sphincter. This results in the
formation of continuously sustainable connective tissue which
supports the LES in a manner more closely approximating normal
gastroesophageal anatomy and biomechanics. The result is a
treatment that lasts longer, provides better symptomatic relief and
requires fewer re-interventions.
[0694] In one aspect, the present invention provides injectable
compositions (bulking agents) for use in treating GERD.
Specifically, the fibrosis-inducing agent can be produced with or
without a carrier (such as collagen, hyaluronic acid, and/or
another biocompatible polymer) which is then injected in and around
the anal sphincter to provide support and continence. In one
embodiment, fibrosis-inducing agents can be incorporated directly
into the formulation to produce a suspension or a solution (e.g.,
silk powder, bleomycin) or it can be incorporated into a secondary
carrier (e.g., micelles, liposomes, microspheres, microparticles,
nanospheres, microparticulates, emulsions and/or microemulsions)
that is then incorporated into the bulking composition. In another
embodiment, the fibrosis-inducing agent can be electrostatically or
covalently bound to one or more of the polymeric components of the
in situ forming composition. Injection of the bulking agent (many
commercial examples of which were described above) containing the
fibrosing agent into the perimuscular space (alone or in
combination with a polymeric carrier) can enhance scarring and
support to the lower esophageal sphincter and may result in
endogenous collagen production.
[0695] In another embodiment, the fibrosis-inducing agent can be
incorporated into the bulking agent during the manufacture of the
agent. For example, silk powder can be added as a reagent during
the manufacture of microspheres that are used as bulking
agents.
[0696] It should be apparent to one of skill in the art that
potentially any adhesion or fibrosis-inducing agents described
above may be utilized alone, or in combination, in the practice of
this embodiment. Exemplary fibrosing agents for use in GERD bulking
agents include talc, silk, wool, chitosan, polylysine, fibronectin,
bleomycin, and CTGF, as well as analogues and derivatives of the
aforementioned.
[0697] Optionally, the device may alone or additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone) or an analogue or derivative thereof.
[0698] Furthermore, the device may additionally comprise an agent
that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof.
[0699] The appropriate agents and their dosages can be further
described below in section (iii).
[0700] (ii) Devices Used in GERD
[0701] A variety of implantable devices and methods have been
described for use in treating GERD. Representative treatment
methods include, for example, suture-based treatments and the use
of energy based devices. Suture based treatments for GERD are
described in, e.g., U.S. Pat. No. 6,494,888, U.S. Patent
Application Publication No. 2002/0138075A1 describes a sphincter
electropotential mapping device. U.S. Pat. No. 6,321,121 describes
a lower esophageal sphincter tightening device. Other devices for
treating GERD are described in, e.g., U.S. Pat. Nos. 6,092,528,
6,159,146; 6,113,609; 5,571,116; 6,432,040; and 6,264,700; U.S.
Patent Application Publication No. 2003/0199731A1, and PCT
Publication Nos. WO 99/44520A1 and WO 01/24721A1.
[0702] Suture-based treatments for treating GERD may be combined
with one or more fibrosis-inducing agents according to the present
invention. Several commercially available products can be combined
with fibrosis-inducing agents including: (a) the ENDOCINCH AND
ENDOCINCH II Suturing System (C.R. Bard) which uses a procedure
that creates plications, or pleats, at the lower esophageal
sphincter; (b) the ENDOSCOPIC Suturing Device (ESD) (Wilson-Cook,
Winston-Salem, N.C.) which is composed of the Flexible SEW-RIGHT
device, the Flexible TI-KNOT device, and an external accessory
channel; (c) the PLICATOR SYSTEM (NDO Surgical, Mansfield Mass.)
which allows physicians to create a full-thickness plication at the
gastroesophageal junction, permitting serosa-to-serosa healing and
restructuring healing and restructuring of the LES; and (d) the
HISWIZ (Olympus, Inc.) suture-based device.
[0703] Another approach to treating GERD is through the use of
energy-based devices. Energy delivery devices for treating
esophageal sphincters are described, e.g., in U.S. Pat. Nos.
6,613,047 and 6,009,877. Tissue ablation devices are described
e.g., in U.S. Pat. Nos. 6,112,123 and 6,258,087. Energy-based
devices for treating GERD which may be combined with one or more
fibrosis-inducing agents according to the present invention include
several commercially available products, such as the STRETTA system
(Curon Medical) radio frequency (RF) ablation device.
[0704] In the present invention, fibrosis-inducing agents are
combined with suture-based and energy-based treatments of GERD to
enhance scarring around the device, re-enforce LES anatomy and
prevent gastroesophageal reflux. Numerous polymeric and
non-polymeric carrier systems described previously can be used to
deliver one or more fibrosis-inducing agents and promote the
formation of granulation tissue around the implanted device. The
methods for incorporating fibrosis-inducing agents onto or into the
implanted GERD devices include: (a) directly affixing to the
implanted suture a fibrosing composition (e.g., by either a
spraying process or dipping process as described previously, with
or without a carrier); (b) directly incorporating into the polymers
which compose the sutures themselves a fibrosing composition; (c)
by coating the sutures with a substance such as a hydrogel which
can in turn absorb the fibrosing composition, (d) by interweaving
fibrosing composition coated thread (or the polymer itself formed
into a thread) into the suturing material; (e) by constructing the
suture itself or a portion of the suture with a fibrosing
composition (particularly silk); or (f) by covalently binding the
fibrosing agent directly to the surface of the suture or the
surface of the gastric mucosa (or utilizing a linker small molecule
or polymer to accomplish this); (g) by applying (e.g., infusing,
spraying, injecting) the fibrosis-inducing agent into the LES or
the gastric mucosal (or serosal) surface, either alone or in a
polymeric carrier (e.g., collagen, COSTASIS, materials made from
4-armed thiol PEG (10K), a 4-armed NHS PEG(10K) and methylated
collagen such as described above, fibrin, PMMA, CORTOSS,
cyanoacrylate, hyaluronic acid, EVA, PLA and other polymers
described previously), to induce scarring in the sphincter or
across the plication created by the suture device; and/or (h)
applying (e.g., infusing, spraying, injecting) a fibrosis-inducing
agent, with or without a polymeric carrier, into the tissues into
which energy is being applied (to enhance scarring).
[0705] It should be apparent to one of skill in the art that
potentially any adhesion or fibrosis-inducing agents described
above may be utilized alone, or in combination, in the practice of
this embodiment. Exemplary fibrosing agents for use in the
treatment of GERD include talc, silk, wool, chitosan, polylysine,
fibronectin, bleomycin, and CTGF, as well as analogues and
derivatives of the aforementioned.
[0706] Optionally, the device may alone or additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone) or an analogue or derivative thereof.
[0707] Furthermore, the device may additionally comprise an agent
that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof.
[0708] Preferred specific agents and dosages of use for coating
implantable, prosthetic devices used in the management of GERD are
described in section (iii) immediately below.
[0709] (iii) Fibrosis-Inducing Agents for GERD
[0710] As GERD devices are made in a variety of configurations and
sizes (including injectables and implants), the exact dosage
administered can vary with the amount injected or the size, surface
area and design of the implant material. However, certain
principles can be applied in the application of this art. Drug dose
can be calculated as a function of dose per unit volume/area (of
the total volume of bulking agent injected or of the surface area
of the portion of the implant being coated), total drug dose
administered can be measured and appropriate surface concentrations
of active drug can be determined. Regardless of the method of
application of the fibrosis-inducing agent in the management of
GERD, the exemplary fibrosing agents, used alone or in combination,
should be administered under the following dosing guidelines:
[0711] Utilizing talc as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of talc delivered in
bulking agent injection, or coated onto the surface of a GERD
implant or device, should not exceed 100 mg (range of 1 .mu.g to
100 mg). In one embodiment, the total amount of talc released
should be in the range of 10 .mu.g to 50 mg. The dose per unit
volume of the injectable bulking agent (i.e., the dosage of talc as
a function of the volume of bulking agent injected) should fall
within the range of 0.05 .mu.g-10 .mu.g per mm.sup.3. In another
embodiment, talc should be applied to a GERD implant or device
surface at a dose of 0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of
surface area coated. In one embodiment, talc is released from a
GERD bulking agent, device or implant such that fibrosis in the
tissue is promoted for a period ranging from several hours to
several months. For example, in a preferred embodiment talc may be
released in effective concentrations for a period ranging from 3-12
months. It should be readily evident given the discussions provided
herein that analogues and derivatives of talc (as described
previously) with similar functional activity can be utilized for
the purposes of this invention; the above dosing parameters are
then adjusted according to the relative potency of the analogue or
derivative as compared to the parent compound (e.g., a compound
twice as potent as talc is administered at half the above
parameters, a compound half as potent as talc is administered at
twice the above parameters, etc.).
[0712] Utilizing silk as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of silk delivered in
bulking agent injection, or coated onto the surface of a GERD
implant or device, should not exceed 100 mg (range of 1 .mu.g to
100 mg). In one embodiment, the total amount of silk released
should be in the range of 10 .mu.g to 50 mg. The dose per unit
volume of the injectable bulking agent (i.e., the dosage of silk as
a function of the volume of bulking agent injected) should fall
within the range of 0.05 .mu.g-10 .mu.g per mm.sup.3. In another
embodiment, silk should be applied to a GERD implant or device
surface at a dose of 0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of
surface area coated. As specific (polymeric and non-polymeric) drug
delivery vehicles and specific bulking agents, implants and devices
can release silk at differing rates, the above dosing parameters
should be utilized in combination with the release rate of the drug
from the GERD bulking agent, implant or device such that a minimum
concentration of 0.01 nM to 1000 .mu.M of silk is delivered to the
tissue. In one embodiment, silk is released from a GERD bulking
injection, implant or device such that fibrosis in the tissue is
promoted for a period ranging from several hours to several months.
For example, in a preferred embodiment silk may be released in
effective concentrations for a period ranging from 3-12 months. It
should be readily evident given the discussions provided herein
that analogues and derivatives of silk (as described previously)
with similar functional activity can be utilized for the purposes
of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as silk is administered at half the above parameters, a compound
half as potent as silk is administered at twice the above
parameters, etc.).
[0713] Utilizing chitosan as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of chitosan delivered
in bulking agent injection, or coated onto the surface of a GERD
implant or device, should not exceed 100 mg (range of 1 .mu.g to
100 mg). In one embodiment, the total amount of chitosan released
should be in the range of 10 .mu.g to 50 mg. The dose per unit
volume of the injectable bulking agent (i.e., the dosage of
chitosan as a function of the volume of bulking agent injected)
should fall within the range of 0.05 .mu.g-10 .mu.g per mm.sup.3.
In another embodiment, chitosan should be applied to a GERD implant
or device surface at a dose of 0.05 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific bulking agents,
implants and devices can release chitosan at differing rates, the
above dosing parameters should be utilized in combination with the
release rate of the drug from the GERD bulking agent, implant or
device such that a minimum concentration of 0.01 nM to 1000 .mu.M
of chitosan is delivered to the tissue. In one embodiment, chitosan
is released from of a GERD bulking agent, implant or device such
that fibrosis in the tissue is promoted for a period ranging from
several hours to several months. For example, in a preferred
embodiment chitosan may be released in effective concentrations for
a period ranging from 3-12 months. It should be readily evident
given the discussions provided herein that analogues and
derivatives of chitosan (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
chitosan is administered at half the above parameters, a compound
half as potent as chitosan is administered at twice the above
parameters, etc.).
[0714] Utilizing polylysine as a exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of polylysine delivered
in bulking agent injection, or coated onto the surface of a GERD
implant or device, should not exceed 100 mg (range of 1 .mu.g to
100 mg). In one embodiment, the total amount of polylysine released
should be in the range of 10 .mu.g to 50 mg. The dose per unit
volume of the injectable bulking agent (i.e., the dosage of
polylysine as a function of the volume of bulking agent injected)
should fall within the range of 0.05 .mu.g-10 .mu.g per mm.sup.3.
In another embodiment, polylysine should be applied to a GERD
implant or device surface at a dose of 0.05 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific bulking agents,
implants and devices can release polylysine at differing rates, the
above dosing parameters should be utilized in combination with the
release rate of the drug from the GERD bulking agent, device or
implant such that a minimum concentration of 0.01 nM to 1000 .mu.M
of polylysine is delivered to the tissue. In one embodiment,
polylysine is released from a GERD bulking agent, implant or device
such that fibrosis in the tissue is promoted for a period ranging
from several hours to several months. For example, in a preferred
embodiment polylysine may be released in effective concentrations
for a period ranging from 3-12 months. It should be readily evident
given the discussions provided herein that analogues and
derivatives of polylysine (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
polylysine is administered at half the above parameters, a compound
half as potent as polylysine is administered at twice the above
parameters, etc.).
[0715] Utilizing fibronectin as an exemplary fibrosis-inducing
agent, whether it is applied using a polymer coating, incorporated
into the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of fibronectin
delivered in bulking agent injection, or coated onto the surface of
a GERD implant or device, should not exceed 100 mg (range of 1
.mu.g to 100 mg). In one embodiment, the total amount of
fibronectin released should be in the range of 10 .mu.g to 50 mg.
The dose per unit volume of the injectable bulking agent (i.e., the
dosage of fibronectin as a function of the volume of bulking agent
injected) should fall within the range of 0.05 .mu.g-10 .mu.g per
mm.sup.3. In another embodiment, fibronectin should be applied to a
GERD implant or device surface at a dose of 0.05 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific bulking agents,
implants and devices can release fibronectin at differing rates,
the above dosing parameters should be utilized in combination with
the release rate of the drug from the GERD bulking agent, implant
or device such that a minimum concentration of 0.01 nM to 1000
.mu.M of fibronectin is delivered to the tissue. In one embodiment,
fibronectin is released from a GERD bulking agent, implant or
device such that fibrosis in the tissue is promoted for a period
ranging from several hours to several months. For example, in a
preferred embodiment fibronectin may be released in effective
concentrations for a period ranging from 3-12 months. It should be
readily evident given the discussions provided herein that
analogues and derivatives of fibronectin (as described previously)
with similar functional activity can be utilized for the purposes
of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as fibronectin is administered at half the above parameters, a
compound half as potent as fibronectin is administered at twice the
above parameters, etc.).
[0716] Utilizing bleomycin as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of bleomycin delivered
in bulking agent injection, or coated onto the surface of a GERD
implant or device, should not exceed 100 mg (range of 0.01 .mu.g to
100 mg). In one embodiment, the total amount of bleomycin released
should be in the range of 0.10 .mu.g to 50 mg. The dose per unit
volume of the injectable bulking agent (i.e., the dosage of
bleomycin as a function of the volume of bulking agent injected)
should fall within the range of 0.005 .mu.g-10 .mu.g per mm.sup.3.
In another embodiment, bleomycin should be applied to a GERD
implant or device surface at a dose of 0.005 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific bulking agents,
implants and devices can release bleomycin at differing rates, the
above dosing parameters should be utilized in combination with the
release rate of the drug from the GERD bulking agent, implant or
device such that a minimum concentration of 0.001 nM to 1000 .mu.M
of bleomycin is delivered to the tissue. In one embodiment,
bleomycin is released from a GERD bulking agent, implant or device
such that fibrosis in the tissue is promoted for a period ranging
from several hours to several months. For example, in a preferred
embodiment bleomycin may be released in effective concentrations
for a period ranging from 3-12 months. It should be readily evident
given the discussions provided herein that analogues and
derivatives of bleomycin (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
bleomycin is administered at half the above parameters, a compound
half as potent as bleomycin is administered at twice the above
parameters, etc.).
[0717] Utilizing CTGF as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of CTGF delivered in
bulking agent injection, or coated onto the surface of a GERD
implant or device, should not exceed 100 mg (range of 0.01 .mu.g to
100 mg). In one embodiment, the total amount of CTGF released
should be in the range of 0.10 .mu.g to 50 mg. The dose per unit
volume of the injectable bulking agent (i.e., the dosage of CTGF as
a function of the volume of bulking agent injected) should fall
within the range of 0.005 .mu.g-10 .mu.g per mm.sup.3. In another
embodiment, CTGF should be applied to a GERD implant or device
surface at a dose of 0.005 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of
surface area coated. As specific (polymeric and non-polymeric) drug
delivery vehicles and specific bulking agents, implants and devices
can release CTGF at differing rates, the above dosing parameters
should be utilized in combination with the release rate of the drug
from the GERD bulking agent, implant or device such that a minimum
concentration of 0.001 nM to 1000 .mu.M of CTGF is delivered to the
tissue. In one embodiment, CTGF is released from a GERD bulking
agent, implant or device such that fibrosis in the tissue is
promoted for a period ranging from several hours to several months.
For example, in a preferred embodiment CTGF may be released in
effective concentrations for a period ranging from 3-12 months. It
should be readily evident given the discussions provided herein
that analogues and derivatives of CTGF (as described previously)
with similar functional activity can be utilized for the purposes
of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as CTGF is administered at half the above parameters, a compound
half as potent as CTGF is administered at twice the above
parameters, etc.).
[0718] Optionally, the device may alone or additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone) or an analogue or derivative thereof.
[0719] Inflammatory cytokines are to be used in formulations at
concentrations that range from 0.0001 .mu.g/ml to approximately 20
mg/ml depending on the specific clinical application, formulation
type (e.g., gel, liquid, solid, semi-solid), formulation chemistry,
duration of required application, type of medical device interface
and formulation volume and or surface area coverage required.
Preferably, the inflammatory cytokine is released in effective
concentrations for a period ranging from 1-180 days. The total dose
for a single application is typically not to exceed 500 mg (range
of 0.0001 .mu.g to 100 mg); preferred 0.001 .mu.g to 50 mg. When
used as a device coating, the dose is per unit area of 0.0001
.mu.g-500 .mu.g per mm.sup.2; with a preferred dose of 0.001
.mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-10-10.sup.-4 g/ml of inflammatory cytokine is to be
maintained on the device surface.
[0720] Furthermore, the device may alone or additionally comprise
an agent that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof. Doses used are those
concentrations which are demonstrated to stimulate cell
proliferation (see, e.g., Example 16). The proliferative agents are
to be used in formulations at concentrations that range from 0.1
ng/ml to 25 mg/ml depending on the specific clinical application,
formulation type (e.g., gel, liquid, solid, semi-solid),
formulation chemistry, duration of required application, type of
medical device interface and formulation volume and or surface area
coverage required. Preferably, the proliferative agent is released
in effective concentrations for a period ranging from 1-180 days.
The total dose for a single application is typically not to exceed
500 mg (range of 0.0001 .mu.g to 200 mg); preferred 0.001 .mu.g to
100 mg. When used as a device coating, the dose is per unit area of
0.00001 .mu.g-500 .mu.g per mm.sup.2; with a preferred dose of
0.0001 .mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-11-10.sup.-6 M of proliferative agent is to be maintained
on the device surface.
[0721] It should be readily evident to one of skill in the art that
any of the previously described fibrosis inducing agents, or
derivatives and analogues thereof, can be utilized to create
variations of the above compositions without deviating from the
spirit and scope of the invention. It should also be apparent that
the agent can be utilized in a composition with or without polymer
carrier and that altering the carrier does not deviate from the
scope of this invention.
[0722] 10. Morbid Obesity
[0723] The present invention provides fibrosis-inducing
compositions and devices for use in the management of morbid
obesity. Morbid obesity (people who are more than 50% above their
ideal body weight) is a significant public health problem that
affects a significant (and growing) percentage of the population in
the Western world. Morbid obesity predisposes the patient to a
variety of significant health problems including heart disease,
diabetes, stroke, kidney disease, joint disease and a shortened
lifespan. Numerous interventional procedures have been developed to
address the problem including strategies designed to surgically
decrease the size of the stomach. This physically limits the amount
of food that can be consumed, provides a sense of satiety and
ultimately leads to weight loss due to decreased food and caloric
intake. The present invention describes the addition of
fibrosis-inducing agents combined with gastric restriction devices
to improve the efficacy of the procedure.
[0724] An example of a gastric restriction device is a
laparoscopically installed inflatable cuff (referred to as a
lap-band) that is placed around the top of the stomach just below
the lower esophageal sphincter (LES). For a further description,
see, for example, U.S. Pat. Nos. 5,601,604; 5,226,429; and
5,074,868. Additional examples of restriction devices used for the
management of obesity are described in, e.g., U.S. Pat. Nos.
6,067,991; 6,454,699; 6,453,907; 6,450,946; 6,210,347; and
6,067,991. Other minimally invasive devices include, but are not
limited to, space occupying devices, suture-based endoluminal
devices for partitioning the stomach, electrostimulation devices
(e.g., neural and non-neural), and radio frequency antralplasty
devices. Space occupying devices (e.g., intragastric balloons) are
described, for example, in U.S. Pat. Nos. 5,259,399; 4,485,805;
5,129,915; 5,259,399; and 6,454,785. Electrostimulation devices for
the treatment of obesity are described in, e.g., U.S. Pat. Nos.
6,615,084; 6,129,685; 5,782,798, 6,535,764; and 6,606,523.
[0725] In one aspect, restriction devices can be combined with
fibrosis-inducing agents for the treatment of obesity.
Specifically, several commercially available restriction products
are suitable for the practice of this invention including: the
LAP-BAND Adjustable Gastric Banding System (made by Inamed) which
involves a small ring of inflatable silicone that can be inflated
or deflated from an attached tubing connected to a subcutaneous
port), the SWEDISH ADJUSTABLE GASTRIC BAND (by Ethicon-Endosurgery)
is a low pressure inflatable device reinforced with a DACRON net
that is fitted around the uppermost part of the stomach
laparoscopically and can be adjusted after placement by injecting
or removing fluid).
[0726] Also in the present invention, numerous commercially
available minimally invasive devices for treating obesity can be
combined with one or more fibrosis-inducing agents. Specifically,
space occupying minimally invasive devices suitable for use in the
practice of this invention include: the BARIATRIC INTRAGASTRIC
BALLOON (by Inamed) is a spherical silicon implant placed in the
stomach and expanded with saline to 400-800 ml that can be left in
place for 3-6 months), an intragastric balloon available from
Satiety, Inc., the BOWTIE space occupying device made from a
continuous ribbon of polyester (Wilson-Cook, Inc.), and a
suture-based endoluminal device for partitioning the stomach, such
as the EAGLE CLAW (Olympus America).
[0727] The addition of a fibrosis-inducing agent to a gastric band
device or a space occupying device can enhance efficacy and
longevity of the procedure in several ways. For example, inducing
fibrous tissue around the implant can secure the implant in place
allowing it to maintain the proper anatomical position in the
stomach. Also, fibrous tissue can form a permanent "band" in the
stomach that results in sustained, host tissue shrinkage of the
stomach. As the scar matures it can also contract, further reducing
the size of the stomach and improving the efficacy of the
procedure.
[0728] Numerous polymeric and non-polymeric carrier systems
described in detail previously can be used in the practice of this
invention. These compositions can further comprise one or more
fibrosis-inducing agents to promote the formation of granulation
tissue. The methods for incorporating fibrosing compositions onto
or into gastric restriction or space occupying obesity devices
include: (a) directly affixing to the device a fibrosing
composition (e.g., by either a spraying process or dipping process
as described above, with or without a carrier); (b) directly
incorporating into the device a fibrosing composition (e.g., by
either a spraying process or dipping process as described above,
with or without a carrier); (c) by coating the device with a
substance such as a hydrogel which can in turn absorb the fibrosing
composition; (d) by interweaving fibrosing composition coated
thread (or the polymer itself formed into a thread) into the device
structure; (e) by inserting the device into a sleeve or mesh which
is comprised of or coated with a fibrosing composition; (f)
constructing the device itself or a portion of the device with a
fibrosing composition; and/or (g) by covalently binding the
fibrosing agent directly to the device surface or to a linker
(small molecule or polymer) that is coated or attached to the
device surface. For these devices, the coating process can be
performed in such a manner as to a) coat the exterior surfaces of
the device, b) coat the interior surfaces of the device or c) coat
all or parts of both external and internal surface of the device.
In addition to coating the device with the fibrosing composition,
the fibrosing agent can be mixed with the materials that are used
to make the device such that the fibrosing agent is incorporated
into the final device.
[0729] In one embodiment fibrosis-inducing agents can be
incorporated directly into the formulation to produce a suspension
or a solution (e.g., silk powder, bleomycin) or it can be
incorporated into a secondary carrier (e.g., micelles, liposomes,
microspheres, microparticles, nanospheres, microparticulates,
emulsions and/or microemulsions) that is then incorporated into the
gastric restriction device or space occupying device. In another
embodiment, the fibrosis-inducing agent can be electrostatically or
covalently bound to one or more of the polymeric components of the
in situ forming composition.
[0730] It should be apparent to one of skill in the art that
potentially any adhesion or fibrosis-inducing agents described
above may be utilized alone, or in combination, in the practice of
this embodiment. Exemplary fibrosing agents for use in obesity
devices and compositions include talc, silk, wool, chitosan,
polylysine, fibronectin, bleomycin, and CTGF, as well as analogues
and derivatives of the aforementioned.
[0731] As obesity devices are made in a variety of configurations
and sizes, the exact dose administered can vary with device size,
surface area and design. However, certain principles can be applied
in the application of this art. Drug dose can be calculated as a
function of dose per unit area (of the portion of the device being
coated), total drug dose administered can be measured and
appropriate surface concentrations of active drug can be
determined. Regardless of the method of application of the drug to
the obesity device, the exemplary fibrosing agents, used alone or
in combination, should be administered under the following dosing
guidelines:
[0732] Utilizing talc as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of talc delivered from
a obesity device, or coated onto the surface of an obesity device,
should not exceed 100 mg (range of 1 .mu.g to 100 mg). In one
embodiment, the total amount of talc released from the prosthesis
should be in the range of 10 .mu.g to 50 mg. The dose per unit area
of the device (i.e., the dosage of talc as a function of the
surface area of the portion of the device to which drug is applied
and/or incorporated) should fall within the range of 0.05 .mu.g-10
.mu.g per mm.sup.2 of surface area coated. In another embodiment,
talc should be applied to an obesity device surface at a dose of
0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. In
one embodiment, talc is released from the surface of an obesity
device such that fibrosis in the tissue is promoted for a period
ranging from several hours to several months. For example, talc may
be released in effective concentrations for a period ranging from
1-9 months. It should be readily evident given the discussions
provided herein that analogues and derivatives of talc (as
described previously) with similar functional activity can be
utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound
(e.g., a compound twice as potent as talc is administered at half
the above parameters, a compound half as potent as talc is
administered at twice the above parameters, etc.).
[0733] Utilizing silk as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of silk delivered from
a obesity device, or coated onto the surface of an obesity device,
should not exceed 100 mg (range of 1 .mu.g to 100 mg). In one
embodiment, the total amount of silk released from the prosthesis
should be in the range of 10 .mu.g to 50 mg. The dose per unit area
of the device (i.e., the dosage of silk as a function of the
surface area of the portion of the device to which drug is applied
and/or incorporated) should fall within the range of 0.05 .mu.g-10
.mu.g per mm.sup.2 of surface area coated. In another embodiment,
silk should be applied to an obesity device surface at a dose of
0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. As
specific (polymeric and non-polymeric) drug delivery vehicles and
specific medical devices can release silk at differing rates, the
above dosing parameters should be utilized in combination with the
release rate of the drug from the obesity device such that a
minimum concentration of 0.01 nM to 1000 .mu.M of silk is delivered
to the tissue. In one embodiment, silk is released from the surface
of an obesity device such that fibrosis in the tissue is promoted
for a period ranging from several hours to several months. For
example, silk may be released in effective concentrations for a
period ranging from 1-9 months. It should be readily evident given
the discussions provided herein that analogues and derivatives of
silk (as described previously) with similar functional activity can
be utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound
(e.g., a compound twice as potent as silk is administered at half
the above parameters, a compound half as potent as silk is
administered at twice the above parameters, etc.).
[0734] Utilizing chitosan as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of chitosan delivered
from an obesity device, or coated onto the surface of an obesity
device, should not exceed 100 mg (range of 1 .mu.g to 100 mg). In
one embodiment, the total amount of chitosan released from the
prosthesis should be in the range of 10 .mu.g to 50 mg. The dose
per unit area of the device (i.e., the dosage of chitosan as a
function of the surface area of the portion of the device to which
drug is applied and/or incorporated) should fall within the range
of 0.05 .mu.g-10 .mu.g per mm.sup.2 of surface area coated. In
another embodiment, chitosan should be applied to an obesity device
surface at a dose of 0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of
surface area coated. As specific (polymeric and non-polymeric) drug
delivery vehicles and specific medical devices can release chitosan
at differing rates, the above dosing parameters should be utilized
in combination with the release rate of the drug from the obesity
device such that a minimum concentration of 0.01 nM to 1000 .mu.M
of chitosan is delivered to the tissue. In one embodiment, chitosan
is released from the surface of an obesity device such that
fibrosis in the tissue is promoted for a period ranging from
several hours to several months. For example, chitosan may be
released in effective concentrations for a period ranging from 1-9
months. It should be readily evident given the discussions provided
herein that analogues and derivatives of chitosan (as described
previously) with similar functional activity can be utilized for
the purposes of this invention; the above dosing parameters are
then adjusted according to the relative potency of the analogue or
derivative as compared to the parent compound (e.g., a compound
twice as potent as chitosan is administered at half the above
parameters, a compound half as potent as chitosan is administered
at twice the above parameters, etc.).
[0735] Utilizing polylysine as an exemplary fibrosis-inducing
agent, whether it is applied using a polymer coating, incorporated
into the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of polylysine delivered
from an obesity device, or coated onto the surface of an obesity
device, should not exceed 100 mg (range of 1 .mu.g to 100 mg). In
one embodiment, the total amount of polylysine released from the
prosthesis should be in the range of 10 .mu.g to 50 mg. The dose
per unit area of the device (i.e., the dosage of polylysine as a
function of the surface area of the portion of the device to which
drug is applied and/or incorporated) should fall within the range
of 0.05 .mu.g-10 .mu.g per mm.sup.2 of surface area coated. In
another embodiment, polylysine should be applied to an obesity
device surface at a dose of 0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2
of surface area coated. As specific (polymeric and non-polymeric)
drug delivery vehicles and specific medical devices can release
polylysine at differing rates, the above dosing parameters should
be utilized in combination with the release rate of the drug from
the obesity device such that a minimum concentration of 0.01 nM to
1000 .mu.M of polylysine is delivered to the tissue. In one
embodiment, polylysine is released from the surface of an obesity
device such that fibrosis in the tissue is promoted for a period
ranging from several hours to several months. For example,
polylysine may be released in effective concentrations for a period
ranging from 1-9 months. It should be readily evident given the
discussions provided herein that analogues and derivatives of
polylysine (as described previously) with similar functional
activity can be utilized for the purposes of this invention; the
above dosing parameters are then adjusted according to the relative
potency of the analogue or derivative as compared to the parent
compound (e.g., a compound twice as potent as polylysine is
administered at half the above parameters, a compound half as
potent as polylysine is administered at twice the above parameters,
etc.).
[0736] Utilizing fibronectin as an exemplary fibrosis-inducing
agent, whether it is applied using a polymer coating, incorporated
into the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of fibronectin
delivered from an obesity device, or coated onto the surface of an
obesity device, should not exceed 100 mg (range of 1 .mu.g to 100
mg). In one embodiment, the total amount of fibronectin released
from the prosthesis should be in the range of 10 .mu.g to 50 mg.
The dose per unit area of the device (i.e., the dosage of
fibronectin as a function of the surface area of the portion of the
device to which drug is applied and/or incorporated) should fall
within the range of 0.05 .mu.g-10 .mu.g per mm.sup.2 of surface
area coated. In another embodiment, fibronectin should be applied
to an obesity device surface at a dose of 0.05 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific medical devices
can release fibronectin at differing rates, the above dosing
parameters should be utilized in combination with the release rate
of the drug from the obesity device such that a minimum
concentration of 0.01 nM to 1000 .mu.M of fibronectin is delivered
to the tissue. In one embodiment, fibronectin is released from the
surface of an obesity device such that fibrosis in the tissue is
promoted for a period ranging from several hours to several months.
For example, fibronectin may be released in effective
concentrations for a period ranging from 1-9 months. It should be
readily evident given the discussions provided herein that
analogues and derivatives of fibronectin (as described previously)
with similar functional activity can be utilized for the purposes
of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as fibronectin is administered at half the above parameters, a
compound half as potent as fibronectin is administered at twice the
above parameters, etc.).
[0737] Utilizing bleomycin as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of bleomycin delivered
from an obesity device, or coated onto the surface of an obesity
device, should not exceed 100 mg (range of 0.01 .mu.g to 100 mg).
In one embodiment, the total amount of bleomycin released from the
prosthesis should be in the range of 0.10 .mu.g to 50 mg. The dose
per unit area of the device (i.e., the dosage of bleomycin as a
function of the surface area of the portion of the device to which
drug is applied and/or incorporated) should fall within the range
of 0.005 .mu.g-10 .mu.g per mm.sup.2 of surface area coated. In
another embodiment, bleomycin should be applied to an obesity
device surface at a dose of 0.005 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2
of surface area coated. As specific (polymeric and non-polymeric)
drug delivery vehicles and specific medical devices can release
bleomycin at differing rates, the above dosing parameters should be
utilized in combination with the release rate of the drug from the
obesity device such that a minimum concentration of 0.001 nM to
1000 .mu.M of bleomycin is delivered to the tissue. In one
embodiment, bleomycin is released from the surface of an obesity
device such that fibrosis in the tissue is promoted for a period
ranging from several hours to several months. For example,
bleomycin may be released in effective concentrations for a period
ranging from 1-9 months. It should be readily evident given the
discussions provided herein that analogues and derivatives of
bleomycin (as described previously) with similar functional
activity can be utilized for the purposes of this invention; the
above dosing parameters are then adjusted according to the relative
potency of the analogue or derivative as compared to the parent
compound (e.g., a compound twice as potent as bleomycin is
administered at half the above parameters, a compound half as
potent as bleomycin is administered at twice the above parameters,
etc.).
[0738] Utilizing CTGF as a exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of CTGF delivered from
an obesity device, or coated onto the surface of an obesity device,
should not exceed 100 mg (range of 0.01 .mu.g to 100 mg). In one
embodiment, the total amount of CTGF released from the prosthesis
should be in the range of 0.10 .mu.g to 50 mg. The dose per unit
area of the device (i.e., the dosage of CTGF as a function of the
surface area of the portion of the device to which drug is applied
and/or incorporated) should fall within the range of 0.005 .mu.g-10
.mu.g per mm.sup.2 of surface area coated. In another embodiment,
CTGF should be applied to an obesity device surface at a dose of
0.005 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. As
specific (polymeric and non-polymeric) drug delivery vehicles and
specific medical devices can release CTGF at differing rates, the
above dosing parameters should be utilized in combination with the
release rate of the drug from the obesity device such that a
minimum concentration of 0.001 nM to 1000 .mu.M of CTGF is
delivered to the tissue. In one embodiment, CTGF is released from
the surface of an obesity device such that fibrosis in the tissue
is promoted for a period ranging from several hours to several
months. For example, CTGF may be released in effective
concentrations for a period ranging from 1-9 months. It should be
readily evident given the discussions provided herein that
analogues and derivatives of CTGF (as described previously) with
similar functional activity can be utilized for the purposes of
this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as CTGF is administered at half the above parameters, a compound
half as potent as CTGF is administered at twice the above
parameters, etc.).
[0739] Optionally, the device may alone or additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone or an analogue or derivative thereof). Inflammatory
cytokines are to be used in formulations at concentrations that
range from 0.0001 .mu.g/ml to approximately 20 mg/ml depending on
the specific clinical application, formulation type (e.g., gel,
liquid, solid, semi-solid), formulation chemistry, duration of
required application, type of medical device interface and
formulation volume and or surface area coverage required.
Preferably, the inflammatory cytokine is released in effective
concentrations for a period ranging from 1-180 days. The total dose
for a single application is typically not to exceed 500 mg (range
of 0.0001 .mu.g to 100 mg); preferred 0.001 .mu.g to 50 mg. When
used as a device coating, the dose is per unit area of 0.0001
.mu.g-500 .mu.g per mm.sup.2; with a preferred dose of 0.001
.mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-11-10.sup.4 g/ml of inflammatory cytokine is to be
maintained on the device surface.
[0740] Furthermore, the device may alone or additionally comprise
an agent that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof. Doses used are those
concentrations which are demonstrated to stimulate cell
proliferation (see, e.g., Example 16). The proliferative agents are
to be used in formulations at concentrations that range from 0.1
ng/ml to 25 mg/ml depending on the specific clinical application,
formulation type (e.g., gel, liquid, solid, semi-solid),
formulation chemistry, duration of required application, type of
medical device interface and formulation volume and or surface area
coverage required. Preferably, the proliferative agent is released
in effective concentrations for a period ranging from 1-180 days.
The total dose for a single application is typically not to exceed
500 mg (range of 0.0001 .mu.g to 200 mg); preferred 0.001 .mu.g to
100 mg. When used as a device coating, the dose is per unit area of
0.00001 .mu.g-500 .mu.g per mm.sup.2; with a preferred dose of
0.0001 .mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-11-10.sup.-6 M of proliferative agent is to be maintained
on the device surface.
[0741] It should be readily evident to one of skill in the art that
any of the previously described fibrosis inducing agents, or
derivatives and analogues thereof, can be utilized to create
variations of the above compositions without deviating from the
spirit and scope of the invention. It should also be apparent that
the agent can be utilized in a composition with or without polymer
carrier and that altering the carrier does not deviate from the
scope of this invention.
[0742] 11. Soft Palate Implants
[0743] The present invention provides for the combination of a
fibrosis-inducing agent and soft palate implant devices for the
treatment of snoring and sleep apnea (also referred to as
obstructive sleep apnea (OSA)). Sleep apnea refers to the inability
to maintain normal respiration and oxygenation while sleeping.
Obstructive sleep apnea is characterized by frequent periods of
airway occlusion during sleep, with concomitant obstruction of
inspiratory airflow, drop in blood oxygen and interruption of sleep
when the patient awakes to use voluntary muscle contraction to open
the airway and take a few deep breaths. Also of consideration is
the impact that loud snoring (often reaching decibel levels equated
with the take-off of an airplane) has on the sleeping patterns and
lifestyle of the partner of a patient with obstructive sleep apnea.
Sleep apnea can arise from a mechanical obstruction of an airway
and can involve painful and/or insufficient breathing, an abnormal
heartbeat, and hypertension. The mechanical locations and
structural causes of obstruction are multiple. The most frequent
mechanisms include settling of the tongue, uvula, soft palate or
other tissues against the airway during the negative pressure
associated with inspiration. This may be related to adipose tissue
accumulation, lack of muscle tone or inadequate central respiratory
drive to the tongue and/or other accessory respiratory muscles
around the oropharyngeal airway. Treatment of sleep apnea includes
surgical procedures (such as uvulectomy or removal of the uvula,
surgical removal of soft tissue in the airway, or stiffening the
palate through the removal of tissue and the induction of
scarring), behavioral control of sleep posture, positive airway
pressure applied via a face mask, and the use of implantable sleep
apnea devices (such as soft palate implants).
[0744] The present invention describes soft palate implants
combined with a fibrosis-inducing agent to enhance scarring around
the implant and improve efficacy of the device. Injectable
compositions, with or without the addition of a fibrosis-inducing
agent, described in section (i), may be injected into the submucosa
of the palate to provide physical support of the tissue. The
combination of a fibrosis-inducing agent with soft palate
prosthesis (or solid implant) is described in section (ii).
[0745] Regardless of their design, soft palate injectables and
implants are designed to provide physical support for the uvula and
prevent the soft palate from obstructing the airway during sleep.
Unfortunately, the symptomatic relief can be only temporary for
many patients as support of the soft palate is incomplete or there
is insufficient scarring around the implant to create a permanent
result. The addition of a fibrosis-inducing agent to a palatal
implant can increase the amount of scar tissue surrounding the
implant and improve the long term outcome of the procedure. The
fibrosis-inducing agent encourages the formation of the body's own
fibrous tissue (including collagen) around the soft palate implant
to provide support; the natural contracture of the scar with time
further elevates the uvula and increases the size of the airway.
This results in the formation of continuously sustainable
connective tissue which supports the uvula in a manner more closely
approximating nasopharyngeal anatomy and biomechanics. The result
is a treatment that lasts longer, provides better symptomatic
relief and requires fewer re-interventions.
[0746] (i) Injectable Fibrosis-Inducing Palatal Implants
[0747] The present invention describes degradable and
non-degradable injectable biomaterials and implants, alone or
combined with a fibrosis-inducing agent, growth factor or
sclerosing agent, for injection into the soft palate for the
treatment of sleep apnea. Typically, a needle or catheter is
advanced into the submucosa of the soft palate and the injectable
implant is deployed. The addition of a fibrosis-inducing agent,
sclerosing agent and/or growth factor to the materials injected
into the soft palate produces a permanent scar that supports the
uvula and opens the airway.
[0748] A variety of injectable polymer-based products have been
developed that are suitable for the practice of this invention and
can be used alone or in combination with a fibrosis-inducing agent.
Examples of products suitable for injection into the soft palate,
alone or with a fibrosis-inducing agent, include: TRUFILL n-butyl
cyanoacrylate (n-BCA) Liquid Embolic System (Cordis, a division of
Johnson and Johnson, Miami, Fla.); EMBOSPHERE and EMBOGOLD
Microspheres; ONYX Liquid Embolic System; BEAD BLOCK; PVA particles
from Cook, Inc. and Angiodynamics, Inc.; and in situ forming
materials from Biocure, Angiotech Pharmaceuticals, Inc., 3M Company
and Neomend.
[0749] Several other injectable compositions are suitable for
injection into the soft palate for the treatment of sleep apnea.
All involve the deployment of a biomaterial into the tissues of the
soft palate, with or without the addition of a fibrosis-inducing
agent, sclerosing agent, and/or suitable growth factor(s). The
following compositions can be delivered via specialized delivery
catheters, a needle or other applicator, or a surgically placed
access device under direct or endoscopic vision. Examples of
appropriate injectable materials which may be injected into the
soft palate include: (a) fluids, suspensions, emulsions,
microemulsions, microspheres, pastes, gels, microparticulates,
sprays, aerosols, solid implants and other formulations which
release a biologically active agent(s); (b) microparticulate silk
and/or silk strands (linear, branched, and/or coiled) either alone,
or loaded with an additional fibrosis-inducing agent, sclerosing
agent, and/or growth factor injected into the soft palate; (c)
injectable collagen-containing formulations such as COSTASIS or
materials prepared from a 4-armed thiol PEG (10K), a 4-armed NHS
PEG(10K) and methylated collagen such as described above, either
alone, or loaded with a fibrosis-inducing agent, sclerosing agent,
and/or growth factor; (d) injectable PEG-containing formulations
such as COSEAL, FOCALSEAL, SPRAYGEL or DURASEAL, either alone, or
loaded with a fibrosis-inducing agent, sclerosing agent, and/or
growth factor; (e) fibrinogen-containing formulations such as
FLOSEAL or TISSEAL, either alone, or loaded with a
fibrosis-inducing agent, sclerosing agent, and/or growth factor;
(f) hyaluronic acid-containing formulations such as RESTYLANE,
HYLAFORM, PERLANE, SYNVISC, SEPRAFILM, SEPRACOAT, either alone, or
loaded with a fibrosis-inducing agent, sclerosing agent, and/or
growth factor; (g) polymeric gels for surgical implantation such as
REPEL or FLOWGEL either alone, or loaded with a fibrosis-inducing
agent, sclerosing agent, and/or growth factor; (h) orthopedic
"cements" such as OSTEOBOND, LVC, SIMPLEX P, PALACOS, CORTOSS, and
ENDURANCE, either alone, or loaded with a fibrosis-inducing agent,
sclerosing agent, and/or growth factor; (i) surgical adhesives
containing cyanoacrylates such as DERMABOND, INDERMIL, GLUSTITCH,
VETBOND, HISTOACRYL BLUE and ORABASE SOOTHE-N-SEAL LIQUID
PROTECTANT, either alone, or loaded with a fibrosis-inducing agent,
sclerosing agent, and/or growth factor, injected into the soft
palate; (j) surgical implants containing hydroxyapatite, calcium
phosphate (such as VITOSS), or calcium sulfate, alone or loaded
with a fibrosis-inducing agent, sclerosing agent, and/or growth
factor; (k) other biocompatible tissue fillers, such as those made
by BioCure, 3M Company and Neomend, either alone, or loaded with a
fibrosis-inducing agent, sclerosing agent, and/or growth factor;
(l) polysaccharide gels such as the ADCON series of gels, either
alone, or loaded with a fibrosis-inducing agent, sclerosing agent,
and/or growth factor; (m) films, sponges or meshes such as
INTERCEED, VICRYL mesh, and GELFOAM either alone, or loaded with a
fibrosis-inducing agent, sclerosing agent, and/or growth factor
and/or (n) a hydrogel that is formed from an amino-functionalized
polyethylene glycol (e.g., 4-armed tetra-amino PEG [10k]) and a
4-armed NHS functionalized PEG (e.g., pentaerythritol poly(ethylene
glycol)ether tetra-succinimidyl glutarate [10K]). This hydrogel may
further contain collagen, methylated collagen and/or gelatin. This
hydrogel can further comprise the fibrosis-inducing agents
described above (e.g., silk powder or silk threads). Films,
sponges, and meshes may be placed into the soft palate. Also of use
for injection into the soft palate are non-degradable polymers such
as polyesters (e.g., PET), polyurethanes, silicones, PE, PP, PS,
PAA, PMA, silk, blends, copolymers thereof as well as other known
non-degradable polymers that are known in the art. Degradable
polymers that can be injected into the soft palate to provide
tissue support include polyesters, polyanhydrides, poly(anhydride
esters), poly(ester-amides), poly(ester-ureas), polyorthoesters,
polyphosphoesters, polyphosphazines, cyanoacrylate polymers,
collagen, chitosan, hyaluronic acid, chromic cat gut, alginates,
starch, cellulose, cellulose esters, blends and copolymers thereof,
as well as other known degradable polymers.
[0750] In one embodiment, the injectable polymer system is prepared
from a 4-armed thiol PEG (10K), a 4-armed NHS PEG(10K) and
methylated collagen such as described above. The injectable polymer
system may be combined with a biologically active agent (e.g.,
fibrosis-inducing agents such as talc, silk, wool, chitosan,
polylysine, fibronectin, bleomycin, CTGF; sclerosing agents such as
ethanol, DMSO, surfactants, sucrose, sodium morrhuate, ethanolamine
oleate NaCl, dextrose, glycerin, minocycline, tetracycline,
doxycycline, polidocanol, sodium tetradecyl sulfate, sodium
morrhuate, sotradecol; growth factors such as transforming growth
factor, platelet-derived growth factor, fibroblast growth factor,
and bone morphogenic proteins; and/or analogues and derivatives of
these compounds) and injected into the soft palate. The injectable
polymer system can further comprise agents such as glycerol,
glycerin, PEG 200, triethyl citrate, and triacetin as
plasticizers.
[0751] In another embodiment, the injectable materials delivered to
the soft palate can be formulated to be delivered from the catheter
(or needle) as a particulate material that has the ability to
induce fibrosis. The injectable particles can be loaded with,
coated with, or comprised of a fibrosis-inducing agent. These
particles can be either degradable or non-degradable and are
similar in composition to those described above. In addition to the
aforementioned polymers, particulate materials useful for the
practice of this embodiment include talc, starch, glass, silicates,
silica, calcium phosphate, calcium sulfate, calcium carbonate,
hydroxyapatite, synthetic mineral (VITOSS and CORTOSS), PMMA,
silver nitrate, ceramic particles and other inorganic particles
known in the art to induce a fibroproliferative response. The
particles used in this embodiment can be all of the same
composition or a blend of differing compositions. These particles
can also be used in combination with the injectable polymeric
materials described above.
[0752] In many of the above embodiments, it may also be useful to
add a radio-opaque material (such as tantalum, barium, other metal,
or contrast material) such that the injected material can be
visualized radiographically. Also, when performing direct injection
into the soft palate, techniques can be used to enhance
visualization of needle (or catheter) via ultrasound through the
use of a needle coated with ECHO--COAT or the injection of air
(microbubbles).
[0753] It should be apparent to one of skill in the art that
potentially any adhesion or fibrosis-inducing agent, sclerosing
agent, or growth factor may be utilized alone, or in combination,
in the practice of this embodiment. Exemplary fibrosing agents for
use in injectable soft palate implant procedures include talc,
silk, wool, chitosan, polylysine, fibronectin, bleomycin, CTGF,
sclerosing agents, and/or growth factors (such as transforming
growth factor, platelet-derived growth factor, fibroblast growth
factor, bone morphogenic proteins) as well as analogues and
derivatives of the aforementioned.
[0754] Optionally, the device may alone or additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone) or a bone morphogenic protein (BMP) (e.g., BMP-2,
BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or an analogue or derivative
thereof).
[0755] Furthermore, the device may additionally comprise an agent
that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof.
[0756] In some clinical situations, repeated injections of the
active agents may be required. Specific agents and dosages for use
in injectable soft palate implants can be described in greater
detail in section (iii) below.
[0757] (ii) Soft Palate Implants Combined with a Fibrosis-Inducing
Agent
[0758] Soft palate implants are devices that are designed to be
inserted under the mucosa in the soft palate in the roof of the
mouth of a person with snoring or sleep apnea. Soft palate implants
are described in, e.g., U.S. Pat. Nos. 6,626,181; 6,571,798 and
6,578,580. Other medical devices used for treating sleep apnea
include soft palate implants that provide electrostimulation (see,
e.g., 6,240,316; 6,574,507; 5,284,161 and 5,792,067).
[0759] Soft palate implants, which may be combined with one or more
fibrosis-inducing agents, sclerosing agents and/or growth factors
according to the present invention, include several commercially
available products. For example, the PILLAR Palatal Implant System
from Restore Medical Inc. (St. Paul, Minn.) for the treatment of
snoring is a woven polyester material implanted into the soft
palate that stiffens and supports the palate (thereby reducing
vibration and the tendency for the soft palate to "flop down" and
obstruct the airway) without heating or removing tissue.
[0760] Numerous polymeric and non-polymeric carrier systems
described above may be used to deliver fibrosis-inducing agents,
sclerosing agents and growth factors from soft palate implants.
Methods for incorporating fibrosing, sclerosing and growth factor
compositions onto or into soft palate implants include: (a)
directly affixing to the palatal implant a fibrosing, sclerosing
and/or growth factor composition (e.g., by either spraying the
surface of the implant or dipping the implant into a solution
containing the active agent; the agent can be applied alone or with
a polymeric carrier); (b) directly incorporating into the
components or the polymers that make up the palatal implant a
fibrosing, sclerosing and/or growth factor composition (e.g., by
either a spraying process or dipping process with or without a
polymeric carrier; (c) by coating the palatal implant with a
substance such as a hydrogel which can in turn absorb the
fibrosing, sclerosing and/or growth factor composition; (d) by
interweaving a thread coated with (or composed of) a fibrosing,
sclerosing and/or growth factor into the structure of the palatal
implant; (e) by inserting the palatal implant into a sleeve or mesh
which is comprised of, or coated with, a fibrosing, sclerosing
and/or growth factor composition; (f) constructing the palatal
implant itself, or a portion of the implant, with a fibrosing,
sclerosing and/or growth factor composition (particularly effective
for silk); and/or (g) by covalently binding the fibrosing agent,
sclerosing agent, and/or growth factor directly to the palatal
implant surface or to a linker (small molecule or polymer) that is
coated or attached to the implant surface. For palatal implants,
the coating process can be performed in such a manner as to: a)
coat the exterior surfaces of the implant, b) coat the interior
surfaces of the implant or c) coat all or parts of both external
and internal surface of the implant. In addition to coating the
palatal implant with the fibrosing, sclerosing and/or growth factor
composition, the active agent can be mixed with the materials that
are used to make the implant such that the fibrosing, sclerosing
and/or growth factor is incorporated into the final implant.
[0761] It should be apparent to one of skill in the art that
potentially any fibrosis-inducing agent, sclerosing agent or growth
factor may be utilized alone, or in combination, in the practice of
this embodiment. Exemplary fibrosing agents for use in combination
with soft palate implants include talc, silk, wool, chitosan,
polylysine, fibronectin, bleomycin, CTGF; sclerosing agents such as
sodium morrhuate, ethanolamine oleate, ethanol, DMSO, surfactants,
sucrose, NaCl, dextrose, glycerin, minocycline, tetracycline,
doxycycline, polidocanol, sodium tetradecyl sulfate, sodium
morrhuate, sotradecol; and/or growth factors such as transforming
growth factor, platelet-derived growth factor, fibroblast growth
factor, and bone morphogenic proteins, as well as analogues and
derivatives of the aforementioned.
[0762] Optionally, the device may alone or additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone) or a bone morphogenic protein (BMP) (e.g., BMP-2,
BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or an analogue or derivative
thereof).
[0763] Furthermore, the device may additionally comprise an agent
that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof.
[0764] In some clinical situations, repeated injections of the
active agents may be required. Specific agents and dosages for use
in injectable soft palate implants can be described in greater
detail in section (iii) below.
[0765] (iii) Agents for Use in the Management Sleep Apnea
[0766] There are several commercially available sclerosing agents
which may be suitable for use according to the present invention.
One example available from Wyeth Pharmaceuticals (Collegeville,
Pa.), a division of Wyeth (Madison, N.J.), is SOTRADECOL, which is
sodium tetradecyl sulfate. Other sclerosing agents include sodium
morrhuate, ethanolamine oleate, compositions containing ethanol,
DMSO, surfactants, sucrose, NaCl, dextrose, glycerin, minocycline,
tetracycline, doxycycline, polidocanol, sodium morrhuate,
sotradecol and others. Other examples of compositions suitable for
injection into the soft palate or combining with a soft palate
implant include silk (e.g., microparticulate silk) and polymeric
gels (such as those available from Polymerix Corporation) composed
of fibrosis-inducing agents, sclerosing agents, and growth
factors.
[0767] Since palatal implants and devices are made in a variety of
configurations and sizes (including injectables and implants), the
exact dosage administered can vary with the amount injected, or the
size, surface area and design of the implant. However, certain
principles can be applied in the application of this art. Drug dose
can be calculated as a function of dose per unit volume/area (of
the total volume of material injected or of the surface area of the
portion of the palatal implant being coated), total drug dose
administered can be measured and appropriate surface concentrations
of active drug can be determined. Regardless of the method of
application of the fibrosis-inducing agent in the management of
sleep apnea, the exemplary fibrosing agents, used alone or in
combination, should be administered under the following dosing
guidelines:
[0768] Utilizing talc as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of talc delivered in a
soft palate injection, or coated onto the surface of a palatal
implant or device, should not exceed 100 mg (range of 1 .mu.g to
100 mg). In one embodiment, the total amount of talc released
should be in the range of 10 .mu.g to 50 mg. The dose per unit
volume of a soft palate injectable (i.e., the dosage of talc as a
function of the volume of material injected) should fall within the
range of 0.05 .mu.g-10 .mu.g per mm.sup.3. In another embodiment,
talc should be applied to a palatal implant or device surface at a
dose of 0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area
coated. In one embodiment, talc is released from a soft palate
injectable, device or implant such that fibrosis in the tissue is
promoted for a period ranging from several hours to several months.
For example, in a preferred embodiment talc may be released in
effective concentrations for a period ranging from 3-12 months. It
should be readily evident given the discussions provided herein
that analogues and derivatives of talc (as described previously)
with similar functional activity can be utilized for the purposes
of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as talc is administered at half the above parameters, a compound
half as potent as talc is administered at twice the above
parameters, etc.).
[0769] Utilizing silk as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of silk delivered in
soft palate injection, or coated onto the surface of a soft palate
implant or device, should not exceed 100 mg (range of 1 .mu.g to
100 mg). In one embodiment, the total amount of silk released
should be in the range of 10 .mu.g to 50 mg. The dose per unit
volume of a soft palate injectable (i.e., the dosage of silk as a
function of the volume of material injected) should fall within the
range of 0.05 .mu.g-10 .mu.g per mm.sup.3. In another embodiment,
silk should be applied to a soft palate implant or device surface
at a dose of 0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area
coated. As specific (polymeric and non-polymeric) drug delivery
vehicles and specific soft palate injectables, implants and devices
can release silk at differing rates, the above dosing parameters
should be utilized in combination with the release rate of the drug
from the soft palate injectable, implant or device such that a
minimum concentration of 0.01 nM to 1000 .mu.M of silk is delivered
to the tissue. In one embodiment, silk is released from a soft
palate injection, implant or device such that fibrosis in the
tissue is promoted for a period ranging from several hours to
several months. For example, in a preferred embodiment silk may be
released in effective concentrations for a period ranging from 3-12
months. It should be readily evident given the discussions provided
herein that analogues and derivatives of silk (as described
previously) with similar functional activity can be utilized for
the purposes of this invention; the above dosing parameters are
then adjusted according to the relative potency of the analogue or
derivative as compared to the parent compound (e.g., a compound
twice as potent as silk is administered at half the above
parameters, a compound half as potent as silk is administered at
twice the above parameters, etc.).
[0770] Utilizing chitosan as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of chitosan delivered
in soft palate injection, or coated onto the surface of a soft
palate implant or device, should not exceed 100 mg (range of 1
.mu.g to 100 mg). In one embodiment, the total amount of chitosan
released should be in the range of 10 .mu.g to 50 mg. The dose per
unit volume of the soft palate injectable (i.e., the dosage of
chitosan as a function of the volume of material injected) should
fall within the range of 0.05 .mu.g-10 .mu.g per mm.sup.3. In
another embodiment, chitosan should be applied to a soft palate
implant or device surface at a dose of 0.05 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific palatal
injectables, implants and devices can release chitosan at differing
rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the soft palate
injectable, implant or device such that a minimum concentration of
0.01 nM to 1000 .mu.M of chitosan is delivered to the tissue. In
one embodiment, chitosan is released from of a soft palate
injectable, implant or device such that fibrosis in the tissue is
promoted for a period ranging from several hours to several months.
For example, in a preferred embodiment chitosan may be released in
effective concentrations for a period ranging from 3-12 months. It
should be readily evident given the discussions provided herein
that analogues and derivatives of chitosan (as described
previously) with similar functional activity can be utilized for
the purposes of this invention; the above dosing parameters are
then adjusted according to the relative potency of the analogue or
derivative as compared to the parent compound (e.g., a compound
twice as potent as chitosan is administered at half the above
parameters, a compound half as potent as chitosan is administered
at twice the above parameters, etc.).
[0771] Utilizing polylysine as a exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of polylysine delivered
in soft palate injection, or coated onto the surface of a soft
palate implant or device, should not exceed 100 mg (range of 1
.mu.g to 100 mg). In one embodiment, the total amount of polylysine
released should be in the range of 10 .mu.g to 50 mg. The dose per
unit volume of the soft palate injectable (i.e., the dosage of
polylysine as a function of the volume of material injected) should
fall within the range of 0.05 .mu.g-10 .mu.g per mm.sup.3. In
another embodiment, polylysine should be applied to a soft palate
implant or device surface at a dose of 0.05 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific palatal
injectables, implants and devices can release polylysine at
differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the soft palate
injectable, device or implant such that a minimum concentration of
0.01 nM to 1000 .mu.M of polylysine is delivered to the tissue. In
one embodiment, polylysine is released from a soft palate
injectable, implant or device such that fibrosis in the tissue is
promoted for a period ranging from several hours to several months.
For example, in a preferred embodiment polylysine may be released
in effective concentrations for a period ranging from 3-12 months.
It should be readily evident given the discussions provided herein
that analogues and derivatives of polylysine (as described
previously) with similar functional activity can be utilized for
the purposes of this invention; the above dosing parameters are
then adjusted according to the relative potency of the analogue or
derivative as compared to the parent compound (e.g., a compound
twice as potent as polylysine is administered at half the above
parameters, a compound half as potent as polylysine is administered
at twice the above parameters, etc.).
[0772] Utilizing fibronectin as an exemplary fibrosis-inducing
agent, whether it is applied using a polymer coating, incorporated
into the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of fibronectin
delivered in soft palate injection, or coated onto the surface of a
soft palate implant or device, should not exceed 100 mg (range of 1
.mu.g to 100 mg). In one embodiment, the total amount of
fibronectin released should be in the range of 10 .mu.g to 50 mg.
The dose per unit volume of the soft palate injectable (i.e., the
dosage of fibronectin as a function of the volume of material
injected) should fall within the range of 0.05 .mu.g-10 .mu.g per
mm.sup.3. In another embodiment, fibronectin should be applied to a
soft palate implant or device surface at a dose of 0.05
.mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. As
specific (polymeric and non-polymeric) drug delivery vehicles and
specific soft palate injectables, implants and devices can release
fibronectin at differing rates, the above dosing parameters should
be utilized in combination with the release rate of the drug from
the soft palate injectable, implant or device such that a minimum
concentration of 0.01 nM to 1000 .mu.M of fibronectin is delivered
to the tissue. In one embodiment, fibronectin is released from a
soft palate injectable, implant or device such that fibrosis in the
tissue is promoted for a period ranging from several hours to
several months. For example, in a preferred embodiment fibronectin
may be released in effective concentrations for a period ranging
from 3-12 months. It should be readily evident given the
discussions provided herein that analogues and derivatives of
fibronectin (as described previously) with similar functional
activity can be utilized for the purposes of this invention; the
above dosing parameters are then adjusted according to the relative
potency of the analogue or derivative as compared to the parent
compound (e.g., a compound twice as potent as fibrohectin is
administered at half the above parameters, a compound half as
potent as fibronectin is administered at twice the above
parameters, etc.).
[0773] Utilizing bleomycin as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of bleomycin delivered
in soft palate injection, or coated onto the surface of a soft
palate implant or device, should not exceed 100 mg (range of 0.01
.mu.g to 100 mg). In one embodiment, the total amount of bleomycin
released should be in the range of 0.10 .mu.g to 50 mg. The dose
per unit volume of the soft palate injectable (i.e., the dosage of
bleomycin as a function of the volume of material injected) should
fall within the range of 0.005 .mu.g-10 .mu.g per mm.sup.3. In
another embodiment, bleomycin should be applied to a soft palate
implant or device surface at a dose of 0.005 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific soft palate
injectables, implants and devices can release bleomycin at
differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the soft palate
injectable, implant or device such that a minimum concentration of
0.001 nM to 1000 .mu.M of bleomycin is delivered to the tissue. In
one embodiment, bleomycin is released from a soft palate
injectable, implant or device such that fibrosis in the tissue is
promoted for a period ranging from several hours to several months.
For example, in a preferred embodiment bleomycin may be released in
effective concentrations for a period ranging from 3-12 months. It
should be readily evident given the discussions provided herein
that analogues and derivatives of bleomycin (as described
previously) with similar functional activity can be utilized for
the purposes of this invention; the above dosing parameters are
then adjusted according to the relative potency of the analogue or
derivative as compared to the parent compound (e.g., a compound
twice as potent as bleomycin is administered at half the above
parameters, a compound half as potent as bleomycin is administered
at twice the above parameters, etc.).
[0774] Utilizing CTGF as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of CTGF delivered in a
soft palate injection, or coated onto the surface of a soft palate
implant or device, should not exceed 100 mg (range of 0.01 .mu.g to
100 mg). In one embodiment, the total amount of CTGF released
should be in the range of 0.10 .mu.g to 50 mg. The dose per unit
volume of the soft palate injectable (i.e., the dosage of CTGF as a
function of the volume of material injected) should fall within the
range of 0.005 .mu.g-10 .mu.g per mm.sup.3. In another embodiment,
CTGF should be applied to a soft palate implant or device surface
at a dose of 0.005 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area
coated. As specific (polymeric and non-polymeric) drug delivery
vehicles and specific soft palate injectables, implants and devices
can release CTGF at differing rates, the above dosing parameters
should be utilized in combination with the release rate of the drug
from the soft palate injectable, implant or device such that a
minimum concentration of 0.001 nM to 1000 .mu.M of CTGF is
delivered to the tissue. In one embodiment, CTGF is released from a
soft palate injectable, implant or device such that fibrosis in the
tissue is promoted for a period ranging from several hours to
several months. For example, in a preferred embodiment CTGF may be
released in effective concentrations for a period ranging from 3-12
months. It should be readily evident given the discussions provided
herein that analogues and derivatives of CTGF (as described
previously) with similar functional activity can be utilized for
the purposes of this invention; the above dosing parameters are
then adjusted according to the relative potency of the analogue or
derivative as compared to the parent compound (e.g., a compound
twice as potent as CTGF is administered at half the above
parameters, a compound half as potent as CTGF is administered at
twice the above parameters, etc.).
[0775] Optionally, the device may alone or additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone) or a bone morphogenic protein (BMP) (e.g., BMP-2,
BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or an analogue or derivative
thereof. Bone morphogenic protein(s) (e.g., BMP-2, BMP-3, BMP-4,
BMP-5, BMP-6, or BMP-7 or an analogue or derivative thereof) are to
be used in formulations at concentrations that range from 0.001
.mu.g/ml to approximately 20 mg/ml depending on the specific
clinical application, formulation type (e.g., gel, liquid, solid,
semi-solid), formulation chemistry, duration of required
application, type of medical device interface and formulation
volume and or surface area coverage required. Preferably, the bone
morphogenic protein is released in effective concentrations for a
period ranging from 1-180 days. The total dose for a single
application is typically not to exceed 500 mg (range of 0.001 .mu.g
to 500 mg); preferred 1 .mu.g to 250 mg. When used as a device
coating, the dose is per unit area of 0.001 .mu.g-1000 .mu.g per
mm.sup.2; with a preferred dose of 0.01 .mu.g/mm.sup.2-200
.mu.g/mm.sup.2. Minimum concentration of 10.sup.-9-10.sup.-4 M of
bone morphogenic protein is to be maintained on the device
surface.
[0776] Inflammatory cytokines are to be used in formulations at
concentrations that range from 0.0001 .mu.g/ml to approximately 20
mg/ml depending on the specific clinical application, formulation
type (e.g., gel, liquid, solid, semi-solid), formulation chemistry,
duration of required application, type of medical device interface
and formulation volume and or surface area coverage required.
Preferably, the inflammatory cytokine is released in effective
concentrations for a period ranging from 1-180 days. The total dose
for a single application is typically not to exceed 500 mg (range
of 0.0001 .mu.g to 100 mg); preferred 0.001 .mu.g to 50 mg. When
used as a device coating, the dose is per unit area of 0.0001
.mu.g-500 .mu.g per mm.sup.2; with a preferred dose of 0.001
.mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-10-10.sup.-4 g/ml of inflammatory cytokine is to be
maintained on the device surface.
[0777] Furthermore, the device may alone or additionally comprise
an agent that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof. Doses used are those
concentrations which are demonstrated to stimulate cell
proliferation (see, e.g., Example 16). The proliferative agents are
to be used in formulations at concentrations that range from 0.1
ng/ml to 25 mg/ml depending on the specific clinical application,
formulation type (e.g., gel, liquid, solid, semi-solid),
formulation chemistry, duration of required application, type of
medical device interface and formulation volume and or surface area
coverage required. Preferably, the proliferative agent is released
in effective concentrations for a period ranging from 1-180 days.
The total dose for a single application is typically not to exceed
500 mg (range of 0.0001 .mu.g to 200 mg); preferred 0.001 .mu.g to
100 mg. When used as a device coating, the dose is per unit area of
0.00001 .mu.g-500 .mu.g per mm.sup.2; with a preferred dose of
0.0001 .mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-11-10.sup.-6 M of proliferative agent is to be maintained
on the device surface.
[0778] It should be readily evident to one of skill in the art that
any of the previously described fibrosis inducing agents, or
derivatives and analogues thereof, can be utilized to create
variations of the above compositions without deviating from the
spirit and scope of the invention. It should also be apparent that
the agent can be utilized in a composition with or without polymer
carrier and that altering the carrier does not deviate from the
scope of this invention.
[0779] 12. Embolic Agents and Embolization Devices
[0780] In one aspect, the present invention provides for the
combination of a fibrosing agent with embolization devices and
aneurysm coils. Embolization devices are designed to slow or
eliminate blood flow to a tissue and may be used to treat a variety
of medical conditions which include, without limitation,
uncontrolled vascular bleeding (such as menorrhagia), vascular
aneurysms (such as thoracic aortic aneurysm, abdominal aortic
aneurysms, cerebral aneurysms), benign tumor growth (such as
uterine fibroids), malignant tumor growth (particularly hepatic,
renal and other solid tumors) and vascular malformations (AV
malformations, vascular tumors).
[0781] Embolization devices refer to devices that are designed to
be placed within the vasculature (typically an artery) of the
patient such that the flow of blood through a vessel (or portion of
a vessel in the case of an aneurysm) is largely or completely
obstructed. The embolic agent or device can be inserted such that
it becomes physically lodged in the artery lumen causing
interruption of blood flow to a tissue. The embolic agent or device
can also induce clotting in the vessel (or portion of a vessel)
such that blood flow becomes obstructed by clot (or a combination
of the device and clot). In either case, blood supply to a
particular anatomical region (e.g., a tumor, an aneurysm sac, a
vascular malformation) is reduced, or eliminated, leading to
ischemic damage or complete destruction of the unwanted tissue.
[0782] Examples of embolization devices include, without
limitation, vascular coils, vaso-occlusion devices, vascular wires,
intravascular embolization devices, vascular occlusion apparatus,
microcoils, injectable embolic agents, polymeric embolic agents,
embolizing agents, embolic vascular implants, embolic plugs,
expandable implants, vascular plugs, vascular endoprostheses and
embolic microspheres.
[0783] In one aspect, the embolization device is a vascular
(vaso-)occlusive device. Vaso-occlusion devices can be inserted
into the vasculature or some other region which is to be occluded,
such as fallopian tubes and bile ducts. Vaso-occlusion devices may
be take a variety of forms. For example, the primary shape of a
vascular (vaso-)occlusive device may be a in the form of a coil
(e.g., a helical coil or spiral), also referred to herein as a
vaso-occlusive coil implant. Alternatively, the vaso-occlusive
device may be in a non-coil (i.e., non-helical or non-spiral) form.
Representative examples of non-coiled vaso-occlusive implants may
be in the form of a braid, a random shaped implant, a spherically
shaped, ovoid shaped, fibered (see, e.g., U.S. Pat. No. 5,226,911),
strands, flower-shaped, a sphere, threads, and other non-helical
forms. Helical and non-helical vaso-occlusive devices also may have
a variety of secondary shapes. Specific examples of embolization
coils and other types of embolization devices are described in
further detail in the following sections.
[0784] In one aspect, the vaso-occlusive device may be an
expandable vascular occlusion device. Expandable vaso-occlusive
devices may include a resilient or shape memory material which will
self-expand from its operative configuration by its own resilient
force or by undergoing a phase transformation when exposed and
warmed to body temperature. Alternatively, such devices may include
plastically deformable material which may be deformed from its
radially compact configuration to its operative configuration by
application of pressure or force. Alternatively, some of these
devices may be inflatable from their radially compact configuration
to their operative configuration. An example of an expandable
embolization device is a lumen blocking apparatus that includes a
blood vessel engaging portion which is operative to anchor the
apparatus to the surrounding wall of the blood vessel and a
radially expandable lumen blocking portion which is operative to
prevent the flow of blood in at least one direction, through the
lumen of the blood vessel. (see, e.g., U.S. Pat. No. 6,638,293)
Upon implantation of the device, the radially expandable portion
can expand to an operative configuration wherein the blood vessel
engaging portion of the apparatus will engage the blood vessel wall
and the lumen blocking portion of the apparatus will block the
lumen of the blood vessel to prevent blood flow in at least one
direction.
[0785] Unfortunately, in a significant number of cases blood flow
is re-established with time (a process called recanalization)
leading to treatment failure. This puts the patient back at risk
for the potentially life-threatening consequences of the condition
that was treated with the initial intervention such as bleeding,
aneurysm rupture, cerebral hemorrhage, or tumor growth. Treatment
failure occurs in some clinical situations in part because
currently available agents do not produce permanent fibrosis (true
luminal scarring where the walls of the vessel adhere to each other
and permanent fibrous tissue occludes the vessel) leading to the
possibility of recanalization, re-establishment of blood flow, and
ultimately disease recurrence. The present invention describes the
addition of fibrosis-inducing agents to the materials injected (or
devices implanted) into the vasculature for the purpose of
producing a permanent, obstructive scar in the vascular lumen (or
aneurysm sac) that results in regression and absorption of the
unwanted vessel (or portion of the vessel). If blood flow is
permanently prevented in the vessel due to obstructive fibrosis,
the body can resorb the non-functioning vascular tissue and can
eliminate the blood vessel, leaving little or no chance for
recurrence.
[0786] (i) Aneurysm "Coils" Combined with a Fibrosis-Inducing
Agent
[0787] Vascular aneurysms occur due to the focal weakening of a
portion of the arterial wall that eventually leads to bulging of
the vessel (called an aneurysm "sac"). The thin, weak wall of the
aneurysm sac is at an increased risk for rupturing under the
pressure of arterial blood flow; a risk that increases
progressively as the sac increases in size. Aneurysm rupture can
have catastrophic consequences including subarachnoid hemorrhage,
stroke, permanent neurological deficits, and death for cerebral
aneurysms and massive hemorrhage and death for aortic aneurysms.
Surgical procedures to treat this condition, especially if located
in the brain (known as aneurysm "clipping"), can be extremely risky
or even impossible, depending upon the anatomical location of the
aneurysm. As an alternative to surgery, minimally invasive
interventions have been developed whereby both ruptured and
unruptured aneurysms can be treated using embolization devices.
Embolization devices may be delivered to the aneurysm using a
catheter or guide-wire that is advanced from the groin to the area
of the aneurysm. The embolization device is then inserted through
the catheter and into the aneurysm. Once within the aneurysm, it
physically occupies space within the aneurysm sac, induces the
formation of clot, "fills" the aneurysm sac, and prevents arterial
blood flow from entering the aneurysm and thus, prevents further
damage. Numerous implants have been described for insertion into an
aneurysm sac and are suitable for combining with a
fibrosis-inducing agent. One of the most common treatments for
cerebral aneurysms involves the implantation of vascular "coils"
(i.e., aneurysm coil) into the aneurysm sac. The coil is advanced
into the sac via a delivery catheter under radiologic guidance,
detached (often by the induction of current in metal coils) from
the delivery catheter and released into the sac; the procedure is
then repeated until enough coils are "packed" into the aneurysm sac
to fill it completely. Although a significant advancement in the
treatment of aneurysms, detachable coils are not without their
limitations. Complications associated with these procedures include
inadvertent occlusion of the parent artery (occurs approximately
21% of the time), persistent filling of the aneurysm lumen
(incomplete occlusion), and recanalization (i.e., return of blood
flow into the aneurysm following initially successful occlusion)
rate of 2-5% per year. The consequences of incomplete occlusion
(occurring in 38% of cases for small necked aneurysms, 60-85% of
cases for broad necked aneurysms) and recanalization are that there
is an increased risk that the aneurysm can rebleed. Specifically,
the coil-thrombus complex formed after initial successful
deployment is thought to be unstable. Recanalization can be due to
compression of the coil bundle and rearrangement of individual coil
loops which have a tendency to revert back to their original
helical form (especially when not densely packed). The clinical
result of recanalization is that the patient is at risk for
aneurysm rupture and bleeding (subarachnoid hemorrhage), which is
associated with a high mortality rate (25-50%) and high morbidity
rate (50% of survivors have a significant neurologic deficit). In
contrast, completely occluded aneurysms are thought to have a low
(or no) risk of rebleeding. The addition of a fibrosis-inducing
agent to an aneurysm coil can help reduce the risk of failure by
stabilizing the coil-thrombus complex with fibrous tissue
(preventing incomplete occlusion) and filling the sac with
permanent scar tissue (preventing recanalization).
[0788] A variety of aneurysm coils can be combined with a
fibrosis-inducing agent for the purposes of this invention. It
should be obvious to one of skill in the art that the exact
physical shape of the coil is not critical to the practice of this
invention, however, numerous coil designs are presented by way of
illustration. In one aspect, the aneurysm coil may be composed of a
biocompatible metal alloy (e.g., platinum or tungsten) and/or a
biocompatible polymer, which may or may not be biodegradable. In
one aspect, aneurysm coils and wires are provided that are made
from a biodegradable material, such as a polymer, which is flexible
(malleable) and strong. The polymer may be capable of expanding in
size after deployment. Representative examples of expansible
polymers for use in aneurysm coils and wires are crosslinked
poly(vinyl alcohol), crosslinked poly(ethylene glycol),
poly(acrylic acid), poly(hydroxethyl methacrylate), as well as
copolymers and blends thereof. Degradation of the polymeric coil in
the days to weeks following deployment has several advantages. For
example, polymeric aneurysm coils, in contrast to metallic coils,
may reduce the risk of aneurysm performation during deployment.
Since the coils do not persist, they also may be less likely to
migrate into the parent vessel circulation. Further, degradable
coils can become incorporated into the thrombus-coil complex, thus
reducing the incidence of recanalization.
[0789] The vascular aneurysm coil may be coated or uncoated, and/or
may include other elements (e.g., strands, filaments, meshes and/or
other particles) along the coil. In one aspect, aneurysm coils can
be coated with or contain a non-thrombogenic substance (e.g.,
heparin, antithrombin, antithrombin-heparin complex), which
prevents thrombus from occurring prior to final placement of the
device. This temporary coating can be designed to persist for
minutes to hours depending upon the time required to deploy the
device.
[0790] The aneurysm coil may be composed of a porous, flexible PTFE
material, such as expanded PTFE (ePTFE). The PTFE material may take
a variety of forms. For example, the material may take the form of
a thin strand or ribbon and may be reinforced with a metallic
strand or a biodegradable polymeric strand. The PTFE material can
be coated with a water-soluble polymer that also may provide some
rigidity to the material for delivery purposes, but, upon
dissolution out of the material, the material becomes very
flexible. The material can be impregnated or coated, with or
without the use of a carrier, with one or a combination of
fibrosing agents and other biologically active agents (e.g., agents
to promote thrombosis or cellular growth). The material may be
delivered into the aneurysm using a catheter-based delivery system
as described above. With the appropriate design, the catheter could
deliver fixed lengths of the material or could deliver a continuous
strand of the material that could be cut to the desired length by a
cutting device at the end of the catheter. The material is
preferably thin enough so that it is very flexible and does not
exert significant pressure on the aneurysm wall once deployed. For
materials that do not have the structural strength to be delivered
through a catheter, a thin metallic strand can be incorporated into
the material to produce a more rigid material. The metallic strand
may be made from, for example, stainless steel, titanium, platinum,
gold, nickel, nitinol, or other alloy. A biodegradable polymeric
strand may be used in place of the metallic strand. Once deployed,
the polymeric strand can degrade, thereby eliminating the potential
for late strage perforation of the aneurysm. Polymeric strands may
be made from, e.g., a polyester (e.g., PLGA, PLA, PCL, PGA, and the
like), polyanhydrides, polyorthoesters, tyrosine based polymers,
polyphosphazines, polyamides (e.g., proteins such as gelatin),
carbohydrates, polysaccharides and blends thereof. The strands can
be incorporated into the material by threading them through the
material or by laminating them between two layers of the material
or by thermal fusion into the material. The strand may also be made
of a non-degradable polymer such as, for example, a polyurethane,
silicone, PE, PP, polyacrylate or poly(methacrylate) based polymer,
polyamide polymer, or vinyl based polymer. The material may also be
made more rigid by incorporating a polymer into the pores of the
material. This polymer may be either water-soluble or water
insoluble and may be biodegradable or non-degradable. An example of
a water-soluble, non-degradable polymer is PEG. A tyrosine based
polymer such as DTE is an example of a water-insoluble polymer that
has a relatively short degradation time. Polymers may be used to
supply some degree of structural rigidity for the deployment
process by filling the pores of the porous PTFE but would degrade
or dissolve rapidly after deployment, such that the material would
revert to its flexible state and can be packed into the aneurysm
sac more densely.
[0791] The vascular coil may be composed of a bioactive component
or may be biologically inert. Since vascular coils may be delivered
through a microcatheter to the vascular site, they may be designed
to have both a primary phase and a secondary phase. The phases of
the vascular coil may be characterized by a different shape or
configuration, composition, physical state and/or level of
bioactivity. Typically, these phases represent the state of the
vascular coil prior to insertion (i.e., primary phase) and then the
state of the vascular coil post-insertion (i.e., secondary phase).
For example, the vascular coil may be designed as an outer
helically wound device having a stretch-resistant polymeric
filament in which a secondary shape is formed and heat-treated to
preserve that form. See e.g., U.S. Pat. No. 6,193,728. The vascular
coil may be designed to be a linear helical configuration when
stretched, and a folded, convoluted configuration when relaxed. See
e.g., U.S. Pat. No. 4,994,069. The vascular coil may be composed of
a flexible, helically wound coil having two primary coil ends and a
primary diameter which in a relaxed secondary configuration
comprises at least two longitudinal focal axes. See e.g., U.S. Pat.
No. 5,639,277. The vascular coil may have attached fibrous elements
which extend in a sinusoidal fashion down the length of the coil
and thus, produce a variety of secondary shapes. See e.g., U.S.
Pat. No. 5,304,194. The vascular coil may be a metal coil that has
one or more fiber bundles having a serpentine configuration in
which the loops extend about the individual windings of the coil.
See e.g., U.S. Pat. No. 5,226,911. The embolization device (e.g.,
vascular coil) may be composed of a helical coil having a
multiplicity of windings that define a lumen and a plug of
thermoplastic biocompatible polymer that is located at the ends of
the coil into the lumen space. See e.g., U.S. Pat. No. 5,690,667.
The vascular coil may be composed of an elongated helical coil of a
biocompatible metal having a plurality of axial spaced windings and
a plurality of strands of a polymeric, bioactive, occlusion-causing
material extending axially through the coil. See e.g., U.S. Pat.
No. 5,658,308. The embolization device may be an expandable support
element having a relaxed expanded state and a stretched collapsed
state, and an embolization element which is mounted on the support
element which serves to substantially prevent the blood flow (e.g.,
polymer mesh). See e.g., U.S. Pat. No. 6,554,849. The embolization
device may be composed of an elongated, flexible filamentous
carrier and an embolizing element in the form of an expansile
polymer (e.g., porous hydrogel) which is fixed to the carrier. See
e.g., U.S. Pat. No. 6,602,261. The vascular coil may contain a
positive charge, electric current, or magnetic field on the coil
which promotes embolization. See e.g., U.S. Pat. Nos. 5,122,136,
6,066,133 and 6,603,994. Other vascular types of coils are
described in, e.g., U.S. Pat. Nos. 5,133,731; 5,312,415; 5,354,294;
5,382,259; 5,382,260; 5,417,708; 5,423,849; 5,476,472; 5,578,074;
5,582,619; 5,624,461; 5,645,558 and 5,718,711.
[0792] Aneurysm coils, which may be combined with one or more
fibrosis-inducing agents according to the present invention,
include several commercially available products. For example, the
GDC (GUGLIELMI DETACHABLE COIL) and the MATRIX detachable coils
(from Boston Scientific Corporation) are particularly useful for
the practice of this embodiment. The MICROPLEX and HYDROCOIL Coil
System (from MicroVention, Inc., Aliso Viejo, Calif.), TORNADO
Embolization Microcoils from Cook Diagnostic and Interventional
Products (Bloomington, Ind.), HELIPAQ helical and MICRUSPHERE
spherical coils from Micrus Corp. (Sunnyvale, Calif.), the GDC
Coils 2D and 3D from Target Therapeutics, Inc. (Fremont,
Calif.)/Boston Scientific Corporation, and the TRUFILL Pushable
Coils from Cordis Corporation (Miami Lakes, Fla.)/Johnson &
Johnson are also suitable.
[0793] Several injectable polymeric systems and embolization agents
have been described for injection into the aneurysm sac for the
treatment of cerebral and thoracic aneurysm. These vascular
"fillers" are further described in section (ii) below. Vascular
polymeric implants can be combined with a fibrosis-inducing agent
for the purposes of this invention in the treatment of aneurysms.
It should be obvious to one of skill in the art that the
composition of the polymeric aneurysm implant is not critical to
the practice of this invention.
[0794] Numerous polymeric and non-polymeric carrier systems
described above may be used to deliver fibrosis-inducing agents
from implantable aneurysm treatments such as coils and polymeric
implants. Methods for incorporating fibrosis-inducing compositions
onto or into aneurysm coils and implants include: (a) directly
affixing to the aneurysm coil or implant a fibrosing composition
(e.g., by either spraying the surface of the implant or dipping the
implant into a solution containing the active agent; the agent can
be applied alone or with a polymeric carrier); (b) directly
incorporating a fibrosing composition into the components or the
polymers that make up the aneurysm coil or implant (e.g., by either
a spraying process or dipping process with or without a polymeric
carrier--particularly effective for coils that have polymeric
components such as coatings, meshes and hydrogels described above);
(c) by coating the aneurysm coil or implant with a substance such
as a hydrogel which can in turn absorb the fibrosing composition;
the hydrogel can also swell to better fill the aneurysm sac; (d) by
interweaving or attaching "threads" coated with (or composed
of--particularly in the case of silk) a fibrosing agent into the
structure of the aneurysm coil or implant; the threads in turn can
be branched or "arborized" to increase the surface area; (e) by
inserting the aneurysm coil or implant into a sleeve or mesh which
is comprised of, or coated with, a fibrosing composition; (f)
constructing the aneurysm coil or implant itself, or a portion of
the coil or implant, with a fibrosing composition (particularly
effective for polymeric drug compositions, silk and EVA--e.g., to
create a silk and/or EVA aneurysm coil); this has the added benefit
of creating a "floppy coil" that can not perforate through the
weakened aneurysm wall (aneurysm perforation by metallic coils
occurs in 5% of cases); the floppy coil can be further coated with
hard polymer surface (to provide stiffness during deployment) that
dissipates quickly after deployment to leave behind a floppy coil;
in a particularly preferred embodiment, the aneurysm coil is
composed of silk and/or EVA backbone with multiple "branches" of
silk and/or EVA emanating from it to increase surface area (there
can be branches upon branches; i.e., multiple generations of
arborizations); or (g) by covalently binding the fibrosing agent
directly to the aneurysm coil or implant surface or to a linker
(small molecule or polymer) that is coated or attached to the
surface. For aneurysm coils and implants, the coating process can
be performed in such a manner as to: (a) coat the exterior surfaces
of the device; (b) coat the interior surfaces of the device, (c)
coat all or parts of both external and internal surface of the
device, or (d) coat the coil with a non-thrombogenic substance
(e.g., heparin, antithrombin, antithrombin-heparin complex) which
prevents thrombosis from occurring prior to final placement of the
device and then dissipates to allow thrombosis to occur. In
addition to coating the aneurysm coil or implant with the fibrosing
composition, the active agent can be mixed with the materials that
are used to make the coil or implant such that the fibrosing agent
is incorporated into the final implant.
[0795] In one embodiment, the aneurysm coil may include a starch
(e.g., corn starch or maize starch). The starch material may be
incorporated into the device as a coating and/or in combination
with polymeric threads (e.g., silk) that are attached to the
aneurysm coil. The starch or a starch-containing composition may be
coated onto the device by applying starch powder directly to the
device surface. Alternatively, the starch can be applied to the
device using a solvent process or an extrusion process. The entire
device or only a portion of the device may be coated with the
starch. For example, starch can be made into a solution (e.g., by
placing a 5% aqueous solution in an autoclave for 45 min.) which
can be coated onto the outer surface of the device. The solvent
then is removed to leave the starch coated on the device. In
another approach, the starch can be incorporated into a secondary
carrier (e.g., a degradable or non-degradable polymer, wax, lipid,
oil, and the like), which may, optionally, be cross-linked. The
secondary carrier (e.g., polymer) can be coated onto the device. In
another aspect, the starch may be incorporated into or onto a
non-degradable polymer (e.g., silk or DACRON) or biodegradable
polymer (e.g., PLGA) which is then coated onto the device. As the
polymer degrades, the starch is released to the surrounding tissue
where it may cause the desired biological response. Alternatively,
or in addition, the starch may be incorporated into the materials
used to make the device.
[0796] The aneurysm coil may include polymeric threads, such that
the presence of the polymeric threads results in an enhanced
cellular and extracellular matrix response to the exterior of the
device. The polymeric threads can be made from any polymer that
results in an enhanced cellular and/or fibrotic response. For
example, the threads may be a silk suture material or another type
of biocompatible polymer (e.g., starch) which is coated with a
polymer that results in an enhanced cellular response. The
polymeric threads can be attached to the aneurysm coil in various
configurations that may result in either partial or complete
coverage of the exterior of the aneurysm coil. Any combination of
the above methods may be used in the practice of this
embodiment.
[0797] The fibrosing agent containing threads may be attached to
the aneurysm coil using any appropriate method, e.g., an adhesive,
thermal welding, stitching, wrapping, weaving, knotting, or a
combination of any of these methods.
[0798] The threads can be coated with a material that delays the
time it takes for the thread material to come into contact with the
surrounding tissue. This allows for placement of the device without
concern of thrombotic events as a result of the polymeric threads.
Coatings may be from degradable materials that dissolve once
implanted (e.g., gelatin, polyesters, such as PLGA, PLA,
MePEG-PLGA, PLGA-PEG-PLGA, and copolymers and blends thereof,
lipids, fatty acids, sugar esters, nucleic acid esters,
polyanhydrides, polyorthoesters, PVA, and the like). These coatings
may include a fibrosis-inducing agent and/or an agent that reduces
the probability of an immediate thrombotic event (e.g., heparin and
heparin derivatives, such as hydrophobic quaternary amine heparin
complexes).
[0799] It should be apparent to one of skill in the art that
potentially any fibrosis-inducing agent may be utilized alone, or
in combination, in the practice of this embodiment. Exemplary
fibrosing agents for use in combination with aneurysm coils and
implants include talc, silk, wool, chitosan, polylysine,
fibronectin, bleomycin, and CTGF as well as analogues and
derivatives of the aforementioned. These can be further combined
with other agents such as sclerosing agents (sodium morrhuate,
ethanolamine oleate, ethanol, DMSO, surfactants, sucrose, NaCl,
dextrose, glycerin, minocycline, tetracycline, doxycycline,
polidocanol, sodium tetradecyl sulfate, sodium morrhuate,
sotradecol) and/or growth factors (transforming growth factor,
platelet-derived growth factor, fibroblast growth factor, and bone
morphogenic proteins) to further enhance efficacy.
[0800] Optionally, the device may additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone) and/or a bone morphogenic protein (BMP) (e.g.,
BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or an analogue or
derivative thereof).
[0801] Furthermore, the device may alone or additionally comprise
an agent that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof.
[0802] (ii) Embolization Agents Containing a Fibrosis-Inducing
Agent
[0803] Embolization products are used to reduce or eliminate blood
flow to a particular organ or tissue. Typically they are used in
the treatment of bleeding (e.g., embolization of the uterine artery
for the management of severe menorrhagia), benign tumor growth
(e.g., uterine fibroid embolization), malignant tumor growth
(hepatic tumors, renal cell carcinoma, solid tumors), varicoseals,
or to treat abnormal vascular structures (arterio-venous
malformations, vascular tumors). Classically the procedure is
performed by inserting a catheter into the vasculature (often the
femoral artery), advancing it under radiologic guidance to the
artery that supplies the tissue to be embolized, advancing a
delivery catheter over the guidewire, and delivering
particles/microspheres/gels into the lumen of the vessel that
travel in the blood stream until they become lodged in a downstream
vessel (whose caliber is smaller than that of the embolic
particle). This obstructs the blood flow to the target tissue,
starves it of oxygen and nutrients, leads to ischemia and, in some
cases, tissue necrosis and death.
[0804] Numerous particles, microspheres and injectable polymer
systems have been described for vascular injection as embolic
agents and are suitable for combining with a fibrosis-inducing
agent. Although initially successful in occluding blood flow, many
embolic agents are able to sustain their efficacy due to
recanalization of the treated vessel (i.e., return of blood flow
through the artery following initially successful occlusion). As a
consequence of recanalization, there is an increased risk that
bleeding can recur or tumor growth can resume. In contrast,
completely occluded blood vessels are thought to have a low (or no)
risk of rebleeding and force tumor cells to recruit new vasculature
to the tissue. The addition of a fibrosis-inducing agent to an
embolization agent can help reduce the risk of failure by filling
the arterial lumen with permanent scar tissue (preventing
recanalization). If blood flow is obstructed for a prolonged period
of time due to obstructive fibrosis, the vessel regresses, the body
resorbs the nonfunctioning vascular tissue, the blood vessel is
eliminated and the risk of recurrence is reduced.
[0805] Embolization agents, which may be combined with one or more
fibrosis-inducing agents according to the present invention,
include several commercially available products. For example, the
TRUFILL n-Butyl Cyanoacrylate (n-BCA) Liquid Embolic System
(Cordis, a division of Johnson and Johnson, Miami, Fla.);
EMBOSPHERE Microspheres and EMBOGOLD Microspheres (Biosphere,
Rockland, Mass.); and the ONYX Liquid Embolic System (Micro
Therapeutics, Irvine, Calif.) are all polymeric embolization
systems suitable for combining with a fibrosis-inducing agent.
Other examples of suitable embolization devices include
polymer/solvent systems containing a fibrosis-inducing agent in
which the solvent diffuses from the polymer matrix once it has been
injected at the treatment site (e.g., the degradable polymeric
systems from Atrix, non-degradable polymeric compositions such as
ONYX and EMBOLYX, and in situ forming materials such as those
available from Biocure, Angiotech Pharmaceuticals, Inc., 3M Company
and Neomend). Other types of commercially available embolic agents
that can be loaded or made with a fibrosis-inducing agent include
PVA particles (Cook, Inc. and Angiodynamics, Inc.) and microsphere
formulations (e.g., EMBOSPHERE from Biosphere, Inc., Contour SE
from Boston Scientific and BEAD BLOCK from Biocompatibles).
[0806] Numerous other vascular occlusion devices can be combined
with a fibrosis-inducing agent. The embolization device may be
composed of an expandable implant or plug that is guided into the
vascular site and detached at the desired location. For example,
the expandable implant may be a balloon delivered by an
intravascular catheter which acts as an embolization element when
it is inflated with solidifying fluid (e.g., polymerizing resin or
gel). See e.g., U.S. Pat. No. 4,819,637. The expandable vascular
implant can be composed of hydrogel stent that is guided to the
vascular site using a microcatheter and then hydrated and expanded
until it occludes the vessel. See e.g., U.S. Pat. No. 5,258,042.
Polymeric foams (e.g., polyvinyl alcohol, polyurethane foam or
polyethylene foam), pellets or particles that expand to induce
vascular occlusion upon exposure to blood fluids (see e.g., U.S.
Pat. No. 5,823,198) are also suitable for combining with
fibrosis-inducing agents. Another suitable expandable implant is
composed of a plurality of expansible embolizing elements and an
elongated filamentous carrier (formed from a flexible material with
an elastic memory shaped into a looped structure whereby the
elements are released from spaced intervals along the loop; see
e.g., U.S. Pat. No. 6,238,403).
[0807] Injectable liquid embolic agents that change their physical
properties (e.g., solidify and/or expand) in response to heating,
enzymatic reactions and/or chemical polymerization can be combined
with fibrosis-inducing agents. Injectable embolic agents that are
an emulsion of particles or microspheres and coagulate with blood
components and/or coalesce with each other at the vascular site can
also be utilized. For example, the embolic agent may be composed of
a cellulose diacetate polymer, a biocompatible solvent and a water
insoluble contrasting agent which, when delivered, the solvent
disperses into the bloodstream and leaves the remaining components
behind to form into a gel that embolizes the vessel. See e.g., U.S.
Pat. No. 5,580,568. Another suitable embolic agent is composed of a
polymer and a solvent that is a liquid at body temperature and
precipitates into a solid in situ in the presence of a
non-particulate agent (e.g., vascular coil). See e.g., U.S. Pat.
No. 6,017,977. Still another suitable embolic agent is composed of
a thermosensitive polymer delivered as an aqueous solution at one
temperature (i.e., above or below body temperature) that forms into
a solid after warming up to (or cooling down to) body temperature.
See e.g., U.S. Pat. No. 5,525,334. Still another suitable liquid
embolic agent is an emulsion (composed of an aqueous matrix base
and a liquid oil) which forms into an insoluble matrix by either
heating, an enzymatic reaction, or chemical polymerization. See
e.g., U.S. Pat. No. 5,894,022. The embolic agent may also be an
injectable solution of microspheres composed of a copolymer coated
with a cell adhesion promoter. See e.g., U.S. Pat. No. 5,648,100.
Additional materials that are used as injectable liquid embolic
agents are described in U.S. Pat. Nos. 4,551,132 and 4,795,741.
[0808] In one aspect, the present invention provides embolization
agents combined with a fibrosis-inducing agent directly, or a
composition (e.g., a polymeric or non-polymeric carrier) that
includes a fibrosing agent, for the purpose of permanently
occluding a blood vessel. The fibrosis-inducing agent can be
delivered with the embolization agent in several ways, including:
(a) fluids, suspensions, emulsions, microemulsions, microspheres,
pastes, gels, microparticulates, sprays, aerosols, solid implants
and other formulations (see those described above) which release a
fibrosis-inducing agent(s); (b) microparticulate silk and/or silk
strands (linear, branched, and/or coiled) either alone, or loaded
with an additional fibrosis-inducing agent (or embolic material)
and injected as an embolic agent; (c) gels, microspheres, or
microparticles formed from polymeric formulations of fibrosing
agents (e.g., polymeric drugs such as those described by Polymerix
Corporation); (d) fibrosis-inducing agents coated on the surface of
microspheres or microparticles, with or without a polymeric
carrier; (e) fibrosis-inducing agents loaded into one or more
phases of a liquid embolic system (see descriptions above); (f)
fibrosis-inducing agents delivered in the aqueous phase (i.e., as
an infusion into the treated tissue) in conjunction with (before,
during or after) an embolization procedure; (g) for in situ forming
embolic compositions, the fibrosis-inducing agents can be
incorporated directly into the formulation as a suspension or a
solution (e.g., silk powder, bleomycin), or loaded into a secondary
carrier (e.g., micelles, liposomes, microspheres, microparticles,
nanospheres, microparticulates, emulsions and/or micromulsions)
that is then incorporated into the in situ forming compositions;
(h) the fibrosis-inducing agent can be electrostatically or
covalently bound to one or more of the polymeric components of the
in situ forming embolization composition; and/or (i) the fibrosing
agent can be mixed with the materials that are used to make the
device such that the fibrosing agent is incorporated into the
embolic agent during manufacturing (for example, silk powder can be
added as a reagent during the manufacture of microspheres).
[0809] It should be apparent to one of skill in the art that
potentially any fibrosis-inducing agents described above may be
utilized alone, or in combination, in the practice of this
embodiment. Exemplary fibrosing agents for use in embolization
devices and compositions include talc, silk, wool, chitosan,
polylysine, fibronectin, bleomycin, and CTGF, as well as analogues
and derivatives of the aforementioned.
[0810] Optionally, the device may alone or additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone) or a bone morphogenic protein (BMP) (e.g., BMP-2,
BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or an analogue or derivative
thereof).
[0811] Furthermore, the device may alone or additionally comprise
an agent that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof.
[0812] In some clinical situations, repeated injections of the
active agents may be required. Specific agents and dosages for use
in aneurysm coils and implants can be described in greater detail
in section (iii) below.
[0813] (iii) Agents for Use in Embolic Agents and Aneurysm
Coils
[0814] As embolization agents and aneurysm treatment devices are
made in a variety of configurations and sizes, the exact dose
administered can vary with implant or device size, surface area and
design. However, certain principles can be applied in the
application of this art. Drug dose can be calculated as a function
of dose per unit area (of the portion of the embolic material or
aneurysm device being coated), total drug dose administered can be
measured and appropriate surface concentrations of active drug can
be determined. Regardless of the method of application of the drug
to the embolization or aneurysm device, the exemplary fibrosing
agents, used alone or in combination, should be administered under
the following dosing guidelines:
[0815] Utilizing talc as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of talc delivered from
an embolization agent or aneurysm device, or coated onto the
surface of an embolization or aneurysm device, should not exceed
100 mg (range of 1 .mu.g to 100 mg). In one embodiment, the total
amount of talc released from the embolization agent or aneurysm
coil should be in the range of 10 .mu.g to 50 mg. The dose per unit
area of the embolic agent or aneurysm device (i.e., the dosage of
talc as a function of the surface area of the portion of the
implant or device to which drug is applied and/or incorporated)
should fall within the range of 0.05 .mu.g-10 .mu.g per mm.sup.2 of
surface area coated. In another embodiment, talc should be applied
to an embolization agent or aneurysm device surface at a dose of
0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. In
one embodiment, talc is released from the surface of an
embolization or aneurysm device such that fibrosis in the tissue is
promoted for a period ranging from several hours to several months.
For example, talc may be released in effective concentrations for a
period ranging from 1-9 months. It should be readily evident given
the discussions provided herein that analogues and derivatives of
talc (as described previously) with similar functional activity can
be utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound
(e.g., a compound twice as potent as talc is administered at half
the above parameters, a compound half as potent as talc is
administered at twice the above parameters, etc.).
[0816] Utilizing silk as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of silk delivered from
an embolization agent or aneurysm device, or coated onto the
surface of an embolization agent or aneurysm device, should not
exceed 100 mg (range of 1 .mu.g to 100 mg). In one embodiment, the
total amount of silk released from the embolization agent or
aneurysm coil should be in the range of 10 .mu.g to 50 mg. The dose
per unit area of the implant or device (i.e., the dosage of silk as
a function of the surface area of the portion of the device to
which drug is applied and/or incorporated) should fall within the
range of 0.05 .mu.L-10 .mu.g per mm.sup.2 of surface area coated.
In another embodiment, silk should be applied to an embolization or
aneurysm device surface at a dose of 0.05 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific embolization
agents and aneurysm devices can release silk at differing rates,
the above dosing parameters should be utilized in combination with
the release rate of the drug from the embolization or aneurysm
device such that a minimum concentration of 0.01 nM to 1000 .mu.M
of silk is delivered to the tissue. In one embodiment, silk is
released from the surface of an embolization or aneurysm device
such that fibrosis in the tissue is promoted for a period ranging
from several hours to several months. For example, silk may be
released in effective concentrations for a period ranging from 1-9
months. It should be readily evident given the discussions provided
herein that analogues and derivatives of silk (as described
previously) with similar functional activity can be utilized for
the purposes of this invention; the above dosing parameters are
then adjusted according to the relative potency of the analogue or
derivative as compared to the parent compound (e.g., a compound
twice as potent as silk is administered at half the above
parameters, a compound half as potent as silk is administered at
twice the above parameters, etc.).
[0817] Utilizing chitosan as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of chitosan delivered
from an embolization agent or aneurysm device, or coated onto the
surface of an embolization agent or aneurysm device, should not
exceed 100 mg (range of 1 .mu.g to 100 mg). In one embodiment, the
total amount of chitosan released from the embolic agent or
aneurysm coil should be in the range of 10 .mu.g to 50 mg. The dose
per unit area of the device (i.e., the dosage of chitosan as a
function of the surface area of the portion of the implant or
device to which drug is applied and/or incorporated) should fall
within the range of 0.05 .mu.g-10 .mu.g per mm.sup.2 of surface
area coated. In another embodiment, chitosan should be applied to
an embolization or aneurysm device surface at a dose of 0.05
.mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. As
specific (polymeric and non-polymeric) drug delivery vehicles and
specific implants and devices can release chitosan at differing
rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the embolization
or aneurysm device such that a minimum concentration of 0.01 nM to
1000 .mu.M of chitosan is delivered to the tissue. In one
embodiment, chitosan is released from the surface of an
embolization or aneurysm device such that fibrosis in the tissue is
promoted for a period ranging from several hours to several months.
For example, chitosan may be released in effective concentrations
for a period ranging from 1-9 months. It should be readily evident
given the discussions provided herein that analogues and
derivatives of chitosan (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
chitosan is administered at half the above parameters, a compound
half as potent as chitosan is administered at twice the above
parameters, etc.).
[0818] Utilizing polylysine as an exemplary fibrosis-inducing
agent, whether it is applied using a polymer coating, incorporated
into the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of polylysine delivered
from an embolization agent or aneurysm device, or coated onto the
surface of an embolization agent or aneurysm device, should not
exceed 100 mg (range of 1 .mu.g to 100 mg). In one embodiment, the
total amount of polylysine released from the embolization agent or
aneurysm coil should be in the range of 10 .mu.g to 50 mg. The dose
per unit area of the device (i.e., the dosage of polylysine as a
function of the surface area of the portion of the implant or
device to which drug is applied and/or incorporated) should fall
within the range of 0.05 .mu.g-10 .mu.g per mm.sup.2 of surface
area coated. In another embodiment, polylysine should be applied to
an embolization or aneurysm device surface at a dose of 0.05
.mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. As
specific (polymeric and non-polymeric) drug delivery vehicles and
specific embolization agents and aneurysm devices can release
polylysine at differing rates, the above dosing parameters should
be utilized in combination with the release rate of the drug from
the embolization or aneurysm device such that a minimum
concentration of 0.01 nM to 1000 .mu.M of polylysine is delivered
to the tissue. In one embodiment, polylysine is released from the
surface of an embolization or aneurysm device such that fibrosis in
the tissue is promoted for a period ranging from several hours to
several months. For example, polylysine may be released in
effective concentrations for a period ranging from 1-9 months. It
should be readily evident given the discussions provided herein
that analogues and derivatives of polylysine (as described
previously) with similar functional activity can be utilized for
the purposes of this invention; the above dosing parameters are
then adjusted according to the relative potency of the analogue or
derivative as compared to the parent compound (e.g., a compound
twice as potent as polylysine is administered at half the above
parameters, a compound half as potent as polylysine is administered
at twice the above parameters, etc.).
[0819] Utilizing fibronectin as an exemplary fibrosis-inducing
agent, whether it is applied using a polymer coating, incorporated
into the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of fibronectin
delivered from an embolization agent or aneurysm device, or coated
onto the surface of an embolization agent or aneurysm device,
should not exceed 100 mg (range of 1 .mu.g to 100 mg). In one
embodiment, the total amount of fibronectin released from the
embolization agent or aneurysm coil should be in the range of 10
.mu.g to 50 mg. The dose per unit area of the device (i.e., the
dosage of fibronectin as a function of the surface area of the
portion of the implant or device to which drug is applied and/or
incorporated) should fall within the range of 0.05 .mu.g-10 .mu.g
per mm.sup.2 of surface area coated. In another embodiment, talc
should be applied to an embolization agent or aneurysm device
surface at a dose of 0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of
surface area coated. As specific (polymeric and non-polymeric) drug
delivery vehicles and specific embolization agents and aneurysm
devices can release fibronectin at differing rates, the above
dosing parameters should be utilized in combination with the
release rate of the drug from the embolization or aneurysm device
such that a minimum concentration of 0.01 nM to 1000 .mu.M of
fibronectin is delivered to the tissue. In one embodiment,
fibronectin is released from the surface of an embolization agent
or aneurysm device such that fibrosis in the tissue is promoted for
a period ranging from several hours to several months. For example,
fibronectin may be released in effective concentrations for a
period ranging from 1-9 months. It should be readily evident given
the discussions provided herein that analogues and derivatives of
fibronectin (as described previously) with similar functional
activity can be utilized for the purposes of this invention; the
above dosing parameters are then adjusted according to the relative
potency of the analogue or derivative as compared to the parent
compound (e.g., a compound twice as potent as fibronectin is
administered at half the above parameters, a compound half as
potent as fibronectin is administered at twice the above
parameters, etc.).
[0820] Utilizing bleomycin as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of bleomycin delivered
from an embolization agent or aneurysm device, or coated onto the
surface of an embolization agent or aneurysm device, should not
exceed 100 mg (range of 0.01 .mu.g to 100 mg). In one embodiment,
the total amount of bleomycin released from the embolization agent
or aneurysm coil should be in the range of 0.10 .mu.g to 50 mg. The
dose per unit area of the device (i.e., the dosage of bleomycin as
a function of the surface area of the portion of the implant or
device to which drug is applied and/or incorporated) should fall
within the range of 0.005 .mu.g-10 .mu.g per mm.sup.2 of surface
area coated. In another embodiment, bleomycin should be applied to
an embolization agent or aneurysm device surface at a dose of 0.005
.mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. As
specific (polymeric and non-polymeric) drug delivery vehicles and
specific embolization agents and aneurysm devices can release
bleomycin at differing rates, the above dosing parameters should be
utilized in combination with the release rate of the drug from the
an embolization or aneurysm device such that a minimum
concentration of 0.001 nM to 1000 .mu.M of bleomycin is delivered
to the tissue. In one embodiment, bleomycin is released from the
surface of an embolization or aneurysm device such that fibrosis in
the tissue is promoted for a period ranging from several hours to
several months. For example, bleomycin may be released in effective
concentrations for a period ranging from 1-9 months. It should be
readily evident given the discussions provided herein that
analogues and derivatives of bleomycin (as described previously)
with similar functional activity can be utilized for the purposes
of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as bleomycin is administered at half the above parameters, a
compound half as potent as bleomycin is administered at twice the
above parameters, etc.).
[0821] Utilizing CTGF as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of CTGF delivered from
an embolization agent or aneurysm device, or coated onto the
surface of an embolization agent or aneurysm device, should not
exceed 100 mg (range of 0.01 .mu.g to 100 mg). In one embodiment,
the total amount of CTGF released from the embolization agent or
aneurysm coil should be in the range of 0.10 .mu.g to 50 mg. The
dose per unit area of the implant or device (i.e., the dosage of
CTGF as a function of the surface area of the portion of the device
to which drug is applied and/or incorporated) should fall within
the range of 0.005 .mu.g-10 .mu.g per mm.sup.2 of surface area
coated. In another embodiment, CTGF should be applied to an
embolization agent or aneurysm device surface at a dose of 0.005
.mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. As
specific (polymeric and non-polymeric) drug delivery vehicles and
specific embolization agents and aneurysm devices can release CTGF
at differing rates, the above dosing parameters should be utilized
in combination with the release rate of the drug from the
embolization agent or aneurysm device such that a minimum
concentration of 0.001 nM to 1000 .mu.M of CTGF is delivered to the
tissue. In one embodiment, CTGF is released from the surface of an
embolization agent or aneurysm device such that fibrosis in the
tissue is promoted for a period ranging from several hours to
several months. For example, CTGF may be released in effective
concentrations for a period ranging from 1-9 months. It should be
readily evident given the discussions provided herein that
analogues and derivatives of CTGF (as described previously) with
similar functional activity can be utilized for the purposes of
this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as CTGF is administered at half the above parameters, a compound
half as potent as CTGF is administered at twice the above
parameters, etc.).
[0822] Optionally, the device may alone or additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone) or a bone morphogenic protein (BMP) (e.g., BMP-2,
BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or an analogue or derivative
thereof).
[0823] Bone morphogenic protein(s) (e.g., BMP-2, BMP-3, BMP-4,
BMP-5, BMP-6, or BMP-7 or an analogue or derivative thereof) are to
be used in formulations at concentrations that range from 0.001
.mu.g/ml to approximately 20 mg/ml depending on the specific
clinical application, formulation type (e.g., gel, liquid, solid,
semi-solid), formulation chemistry, duration of required
application, type of medical device interface and formulation
volume and or surface area coverage required. Preferably, the bone
morphogenic protein is released in effective concentrations for a
period ranging from 1-180 days. The total dose for a single
application is typically not to exceed 500 mg (range of 0.001 .mu.g
to 500 mg); preferred 1 .mu.g to 250 mg. When used as a device
coating, the dose is per unit area of 0.001 .mu.g-1000 .mu.g per
mm.sup.2; with a preferred dose of 0.01 .mu.g/mm.sup.2-200
.mu.g/mm.sup.2. Minimum concentration of 10.sup.-9-10.sup.-4 M of
bone morphogenic protein is to be maintained on the device
surface.
[0824] Inflammatory cytokines are to be used in formulations at
concentrations that range from 0.0001 .mu.g/ml to approximately 20
mg/ml depending on the specific clinical application, formulation
type (e.g., gel, liquid, solid, semi-solid), formulation chemistry,
duration of required application, type of medical device interface
and formulation volume and or surface area coverage required.
Preferably, the inflammatory cytokine is released in effective
concentrations for a period ranging from 1-180 days. The total dose
for a single application is typically not to exceed 500 mg (range
of 0.0001 .mu.g to 100 mg); preferred 0.001 .mu.g to 50 mg. When
used as a device coating, the dose is per unit area of 0.0001
.mu.g-500 .mu.g per mm.sup.2; with a preferred dose of 0.001
.mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-10-10.sup.-4 g/ml of inflammatory cytokine is to be
maintained on the device surface.
[0825] Furthermore, the device may alone or additionally comprise
an agent that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof. Doses used are those
concentrations which are demonstrated to stimulate cell
proliferation (Example 16). The proliferative agents are to be used
in formulations at concentrations that range from 0.01 ng/mL to 25
mg/ml depending on the specific clinical application, formulation
type (e.g., gel, liquid, solid, semi-solid), formulation chemistry,
duration of required application, type of medical device interface
and formulation volume and or surface area coverage required.
Preferably, the proliferative agent is released in effective
concentrations for a period ranging from 1-180 days. The total dose
for a single application is typically not to exceed 500 mg (range
of 0.0001 .mu.g to 200 mg); preferred 0.001 .mu.g to 100 mg. When
used as a device coating, the dose is per unit area of 0.00001
.mu.g-500 .mu.g per mm.sup.2; with a preferred dose of 0.0001
.mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-11-10.sup.-6 M of proliferative agent is to be maintained
on the device surface.
[0826] It should be readily evident to one of skill in the art that
any of the previously described fibrosis inducing agents, or
derivatives and analogues thereof, can be utilized to create
variations of the above compositions without deviating from the
spirit and scope of the invention. It should also be apparent that
the agent can be utilized in a composition with or without polymer
carrier and that altering the carrier does not deviate from the
scope of this invention.
[0827] 13. Pulmonary Sealants
[0828] The present invention provides compositions and devices for
use as pulmonary sealants during open or endoscopic lung reduction
surgeries. The primary clinical application for pulmonary sealants
is in the treatment of postoperative air leak in the lung. If air
is able to leak from the lung into the plural space via small holes
created during surgery, it can build up, exert pressure on the
lung, and prevent the lung from fully expanding during inhalation.
This prevents normal ventilation from occurring, and if severe, can
create a medical emergency that requires urgent drainage of the air
trapped in the plura via a chest tube inserted through the ribs and
into the air pocket. For example, persistent air leakage is a
frequent complication after open or endoscopic pulmonary resection
for lung cancer or emphysema and can cause serious complications,
such as empyema, chest tube insertion and prolonged
hospitalization. Surgical sealants of different types have been
developed for application to the lung surface to prevent or to
reduce postoperative air leaks. The addition of a fibrosis-inducing
agent to a pulmonary sealant can induce the formation of a stable,
fibrous scar that permanently seals the parietal surface of the
lung at the surgical location (or the alveolar surface of the lung
if delivered endoscopically during lung reduction surgery), reduces
hospitalization time and prevents recurrence of the air leak.
Clinically a fibrosis-inducing pulmonary sealant can be useful to
improve the outcomes in open lung surgery, endoscopic lung
reduction surgery for emphysema (severe COPD), esophageal leaks
after endoscopy or resection, complications of treatment of other
intra-thoracic malignancies, pleural effusion, haemothorax,
pneumothorax, chylothorax, complications of aspiration, and
tuberculosis.
[0829] As used herein, the term "sealant" refers to a material
which decreases or prevents the migration of fluid or air from one
tissue cavity (e.g., the lung) to another tissue cavity (e.g., the
plural space). Sealants are typically formed by the application of
precursor molecules to a tissue followed by local in situ
polymerization. The same sealant materials may also be used to
"glue" tissues together, both when applied between them and then
polymerized, or when used simultaneously and embedded between
tissues. Generally, surgical sealants are absorbable materials used
primarily to control internal bleeding and to seal tissue (to
prevent leakage).
[0830] Sealant material and devices for delivering sealant
materials for use in the present invention are described, e.g., in
U.S. Pat. Nos. 6,624,245; 6,534,591; 6,495,127; 6,482,179;
6,458,889; 6,323,278; 6,312,725; 6,280,727; 6,277,394; 6,166,130;
6,110,484; 6,096,309; 6,051,648; and 5,874,500; 6,063,061;
5,895,412; 5,900,245 and 6,379,373. The performance of these
materials may be enhanced through the addition of a
fibrosis-inducing agent.
[0831] In one aspect, the present invention provides lung sealants
that comprise a fibrosis-inducing agent. Numerous polymeric and
non-polymeric carrier systems described above may be used in the
practice of this embodiment. These compositions can further
comprise one or more fibrosis-inducing agents to promote the
formation of granulation tissue. One example of an appropriate
sealant is prepared from a 4-armed thiol PEG (10K), a 4-armed NHS
PEG(10K) and methylated collagen such as described above.
Commercially available sealants suitable for combining with one or
more fibrosis-inducing agents according to the present invention
include: COSEAL; FLOSEAL; SPRAYGEL or a variation thereof; and
FOCALSEAL.
[0832] In one aspect of the present invention, a fibrosing (i.e.,
scarring) agent can be included in a polymeric sealant spray which
solidifies into a film or coating to promote fibrosis and seal air
leaks. In another aspect, a sprayable fibrosis-inducing lung
sealant may be used to seal off pulmonary bullae in open and
endoscopic lung destruction procedures. In another embodiment, the
spray includes a tissue adherent polymer containing a
fibrosis-inducing agent and may be prepared from microspheres.
[0833] For sprayable in situ forming compositions, the
fibrosis-inducing agent can be incorporated directly into the
formulation to produce a suspension or a solution (e.g., silk
powder, bleomycin), or they can be incorporated into a secondary
carrier (e.g., micelles, liposomes, microspheres, microparticles,
nanospheres, microparticulates, emulsions and/or microemulsions)
that is then incorporated into the in situ forming
compositions.
[0834] In another embodiment, the fibrosis-inducing agent can be
electrostatically or covalently bound to one or more of the
polymeric components of the in situ forming composition.
[0835] In another embodiment, the fibrosis-inducing agent can be
incorporated directly, or via a secondary carrier, into a gel or
thermogel (e.g., hyaluronic acid, PLURONIC F127,
polyester-PEG-polyester (e.g., PLGA-PEG-PLGA)). These gels can then
be applied to the treatment site prior to, or after, the
application of a pulmonary sealant.
[0836] In another embodiment, the fibrosis-inducing agent can be
incorporated into a biodegradable or dissolvable film (or mesh)
that is then applied to the lung. An in situ forming composition
can then be sprayed over the film, thereby sealing the lung and the
film (or mesh) to the desired lung surface. In a variation of this
embodiment, the in situ sealant can be applied to the lung prior to
the application of a biodegradable film or mesh containing a
fibrosis-inducing agent to the treatment area. Exemplary materials
for the manufacture of these films or meshes are hyaluronic acid
(crosslinked or non-crosslinked), cellulose derivatives (e.g.,
hydroxypropyl cellulose) and crosslinked poly(ethylene glycol).
[0837] It should be apparent to one of skill in the art that
potentially any adhesion or fibrosis-inducing agents described
above may be utilized alone, or in combination, in the practice of
this embodiment. Exemplary fibrosing agents for use in pulmonary
sealants include talc, silk, wool, chitosan, polylysine,
fibronectin, bleomycin, and CTGF, as well as analogues and
derivatives of the aforementioned.
[0838] As pulmonary sealants are made in a variety of forms, the
exact dose administered can vary with the form. However, certain
principles can be applied in the application of this art. Drug dose
can be calculated as a function of dose per unit area (of the
amount of the sealant being applied), total drug dose administered
can be measured and appropriate surface concentrations of active
drug can be determined. Regardless of the method of incorporation
of the drug into the pulmonary sealants, the exemplary fibrosing
agents, used alone or in combination, should be administered under
the following dosing guidelines:
[0839] Utilizing talc as an exemplary fibrosis-inducing agent, the
total dose of talc delivered from a pulmonary sealant, or coated
onto the surface of a lung, should not exceed 100 mg (range of 1
.mu.g to 100 mg). In one embodiment, the total amount of talc
released from the sealant should be in the range of 10 .mu.g to 50
mg. The dose per unit area (i.e., the dosage of talc as a function
of the surface area of the lung to which drug is applied) should
fall within the range of 0.05 .mu.g-10 .mu.g per mm.sup.2 of
surface area coated. In another embodiment, talc should be applied
to a lung surface at a dose of 0.05 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. In one embodiment, talc is
released from the pulmonary sealant such that fibrosis in the
tissue is promoted for a period ranging from several hours to
several months. For example, talc may be released in effective
concentrations for a period ranging from 1 hour-30 days. It should
be readily evident given the discussions provided herein that
analogues and derivatives of talc (as described previously) with
similar functional activity can be utilized for the purposes of
this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as talc is administered at half the above parameters, a compound
half as potent as talc is administered at twice the above
parameters, etc.).
[0840] Utilizing silk as an exemplary fibrosis-inducing agent, the
total dose of silk delivered from a pulmonary sealant, or coated
onto the surface of a lung, should not exceed 100 mg (range of 1
.mu.g to 100 mg). In one embodiment, the total amount of silk
released from the sealant should be in the range of 10 .mu.g to 50
mg. The dose per unit area (i.e., the dosage of silk as a function
of the surface area of the lung to which drug is applied) should
fall within the range of 0.05 .mu.g-10 .mu.g per mm.sup.2 of
surface area coated. In another embodiment, silk should be applied
to a lung surface at a dose of 0.05 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific pulmonary
sealants can release silk at differing rates, the above dosing
parameters should be utilized in combination with the release rate
of the drug from the sealant such that a minimum concentration of
0.01 nM to 1000 .mu.M of silk is delivered to the tissue. In one
embodiment, silk is released from the pulmonary sealant such that
fibrosis in the tissue is promoted for a period ranging from
several hours to several months. For example, silk may be released
in effective concentrations for a period ranging from 1 hour-30
days. It should be readily evident given the discussions provided
herein that analogues and derivatives of silk (as described
previously) with similar functional activity can be utilized for
the purposes of this invention; the above dosing parameters are
then adjusted according to the relative potency of the analogue or
derivative as compared to the parent compound (e.g., a compound
twice as potent as silk is administered at half the above
parameters, a compound half as potent as silk is administered at
twice the above parameters, etc.).
[0841] Utilizing chitosan as an exemplary fibrosis-inducing agent,
the total dose of chitosan delivered from a pulmonary sealant, or
coated onto the surface of a lung, should not exceed 100 mg (range
of 1 .mu.g to 100 mg). In one embodiment, the total amount of
chitosan released from the sealant should be in the range of 10
.mu.g to 50 mg. The dose per unit area (i.e., the dosage of
chitosan as a function of the surface area of the lung to which
drug is applied) should fall within the range of 0.05 .mu.g-10
.mu.g per mm.sup.2 of surface area coated. In another embodiment,
chitosan should be applied to a lung surface at a dose of 0.05
.mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. As
specific (polymeric and non-polymeric) drug delivery vehicles and
specific pulmonary sealants can release chitosan at differing
rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the sealant such
that a minimum concentration of 0.01 nM to 1000 .mu.M of chitosan
is delivered to the tissue. In one embodiment, chitosan is released
from the pulmonary sealant such that fibrosis in the tissue is
promoted for a period ranging from several hours to several months.
For example, chitosan may be released in effective concentrations
for a period ranging from 1 hour-30 days. It should be readily
evident given the discussions provided herein that analogues and
derivatives of chitosan (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
chitosan is administered at half the above parameters, a compound
half as potent as chitosan is administered at twice the above
parameters, etc.).
[0842] Utilizing polylysine as an exemplary fibrosis-inducing
agent, the total dose of polylysine delivered from a pulmonary
sealant, or coated onto the surface of a lung, should not exceed
100 mg (range of 1 .mu.g to 100 mg). In one embodiment, the total
amount of polylysine released from the sealant should be in the
range of 10 .mu.g to 50 mg. The dose per unit area (i.e., the
dosage of polylysine as a function of the surface area of the lung
to which drug is applied) should fall within the range of 0.05
.mu.g-10 .mu.g per mm.sup.2 of surface area coated. In another
embodiment, polylysine should be applied to a lung surface at a
dose of 0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area
coated. As specific (polymeric and non-polymeric) drug delivery
vehicles and specific pulmonary sealants can release polylysine at
differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the pulmonary
sealant such that a minimum concentration of 0.01 nM to 1000 .mu.M
of polylysine is delivered to the tissue. In one embodiment,
polylysine is released from the pulmonary sealant such that
fibrosis in the tissue is promoted for a period ranging from
several hours to several months. For example, polylysine may be
released in effective concentrations for a period ranging from 1
hour-30 days. It should be readily evident given the discussions
provided herein that analogues and derivatives of polylysine (as
described previously) with similar functional activity can be
utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound
(e.g., a compound twice as potent as polylysine is administered at
half the above parameters, a compound half as potent as polylysine
is administered at twice the above parameters, etc.).
[0843] Utilizing fibronectin as an exemplary fibrosis-inducing
agent, the total dose of fibronectin delivered from a pulmonary
sealant, or coated onto the surface of a lung, should not exceed
100 mg (range of 1 .mu.g to 100 mg). In one embodiment, the total
amount of fibronectin released from the sealant should be in the
range of 10 .mu.g to 50 mg. The dose per unit area (i.e., the
dosage of fibronectin as a function of the surface area of the lung
to which drug is applied) should fall within the range of 0.05
.mu.g-10 .mu.g per mm.sup.2 of surface area coated. In another
embodiment, fibronectin should be applied to a lung surface at a
dose of 0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area
coated. As specific (polymeric and non-polymeric) drug delivery
vehicles and specific pulmonary sealants can release fibronectin at
differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the sealant such
that a minimum concentration of 0.01 nM to 1000 .mu.M of
fibronectin is delivered to the tissue. In one embodiment,
fibronectin is released from the pulmonary sealant such that
fibrosis in the tissue is promoted for a period ranging from
several hours to several months. For example, fibronectin may be
released in effective concentrations for a period ranging from 1
hour-30 days. It should be readily evident given the discussions
provided herein that analogues and derivatives of fibronectin (as
described previously) with similar functional activity can be
utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound
(e.g., a compound twice as potent as fibronectin is administered at
half the above parameters, a compound half as potent as fibronectin
is administered at twice the above parameters, etc.).
[0844] Utilizing bleomycin as an exemplary fibrosis-inducing agent,
the total dose of bleomycin delivered from a pulmonary sealant, or
coated onto the surface of a lung, should not exceed 100 mg (range
of 0.01 .mu.g to 100 mg). In one embodiment, the total amount of
bleomycin released from the sealant should be in the range of 0.10
.mu.g to 50 mg. The dose per unit area (i.e., the dosage of silk as
a function of the surface area of the lung to which drug is
applied) should fall within the range of 0.005 .mu.g-10 .mu.g per
mm.sup.2 of surface area coated. In another embodiment, bleomycin
should be applied to a lung surface at a dose of 0.005
.mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. As
specific (polymeric and non-polymeric) drug delivery vehicles and
specific pulmonary sealants can release bleomycin at differing
rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the sealant such
that a minimum concentration of 0.001 nM to 1000 .mu.M of bleomycin
is delivered to the tissue. In one embodiment, bleomycin is
released from the pulmonary sealant such that fibrosis in the
tissue is promoted for a period ranging from several hours to
several months. For example, bleomycin may be released in effective
concentrations for a period ranging from 1 hour-30 days. It should
be readily evident given the discussions provided herein that
analogues and derivatives of bleomycin (as described previously)
with similar functional activity can be utilized for the purposes
of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as bleomycin is administered at half the above parameters, a
compound half as potent as bleomycin is administered at twice the
above parameters, etc.).
[0845] Utilizing CTGF as an exemplary fibrosis-inducing agent, the
total dose of CTGF delivered from a pulmonary sealant, or coated
onto the surface of a lung, should not exceed 100 mg (range of 0.01
.mu.g to 100 mg). In one embodiment, the total amount of CTGF
released from the sealant should be in the range of 0.10 .mu.g to
50 mg. The dose per unit area (i.e., the dosage of CTGF as a
function of the surface area of the lung to which drug is applied)
should fall within the range of 0.005 .mu.g-10 .mu.g per mm.sup.2
of surface area coated. In another embodiment, CTGF should be
applied to a lung surface at a dose of 0.005 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific pulmonary
sealants can release CTGF at differing rates, the above dosing
parameters should be utilized in combination with the release rate
of the drug from the sealant such that a minimum concentration of
0.001 nM to 1000 .mu.M of CTGF is delivered to the tissue. In one
embodiment, CTGF is released from the pulmonary sealant such that
fibrosis in the tissue is promoted for a period ranging from
several hours to several months. For example, CTGF may be released
in effective concentrations for a period ranging from 1 hour-30
days. It should be readily evident given the discussions provided
herein that analogues and derivatives of CTGF (as described
previously) with similar functional activity can be utilized for
the purposes of this invention; the above dosing parameters are
then adjusted according to the relative potency of the analogue or
derivative as compared to the parent compound (e.g., a compound
twice as potent as CTGF is administered at half the above
parameters, a compound half as potent as CTGF is administered at
twice the above parameters, etc.).
[0846] Optionally, the sealant may alone or additionally comprise
an inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone) or an analogue or derivative thereof. Inflammatory
cytokines are to be used in formulations at concentrations that
range from 0.0001 .mu.g/ml to approximately 20 mg/ml depending on
the specific clinical application, formulation type (e.g., gel,
liquid, solid, semi-solid), formulation chemistry, duration of
required application, type of medical device interface and
formulation volume and or surface area coverage required.
Preferably, the inflammatory cytokine is released in effective
concentrations for a period ranging from 1-180 days. The total dose
for a single application is typically not to exceed 500 mg (range
of 0.0001 .mu.g to 100 mg); preferred 0.001 .mu.g to 50 mg. When
used as a device coating, the dose is per unit area of 0.0001
.mu.g-500 .mu.g per mm.sup.2; with a preferred dose of 0.001
.mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-10-10.sup.-4 g/ml of inflammatory cytokine is to be
maintained on the device surface.
[0847] Furthermore, the sealant may alone or additionally comprise
an agent that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof. Doses used are those
concentrations which are demonstrated to stimulate cell
proliferation (see, e.g., Example 16). The proliferative agents are
to be used in formulations at concentrations that range from
0.0000001 to 25 mg/ml depending on the specific clinical
application, formulation type (e.g., gel, liquid, solid,
semi-solid), formulation chemistry, duration of required
application, type of medical device interface and formulation
volume and or surface area coverage required. Preferably, the
proliferative agent is released in effective concentrations for a
period ranging from 1-180 days. The total dose for a single
application is typically not to exceed 500 mg (range of 0.0001
.mu.g to 200 mg); preferred 0.001 .mu.g to 100 mg. When used as a
device coating, the dose is per unit area of 0.00001 .mu.g-500
.mu.g per mm.sup.2; with a preferred dose of 0.0001
.mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-11-10.sup.-6 M of proliferative agent is to be maintained
on the device surface.
[0848] It should be readily evident to one of skill in the art that
any of the previously described fibrosis inducing agents, or
derivatives and analogues thereof, can be utilized to create
variations of the above compositions without deviating from the
spirit and scope of the invention. It should also be apparent that
the agent can be utilized in a composition with or without polymer
carrier and that altering the carrier does not deviate from the
scope of this invention.
[0849] 14. Hernia Meshes
[0850] The present invention provides for the combination of a
fibrosis-inducing agent and an implantable mesh used to reinforce
tissue wall defects such as hernias. Hernias are abnormal
protrusions (outpouchings) of an organ or other body structure
through a defect or natural opening in a covering membrane, muscle
or bone. Hernias are commonly caused by activities which result in
overstraining (activities that typically increase intra-abdominal
pressure), or they can occur as a result of childbirth. Conditions
in which a hernia mesh may need to be used include, without
limitation, the repair of inguinal (i.e., groin), umbilical,
ventral, femoral, abdominal, diaphragmatic, epigastric,
gastroesophageal, hiatal, intermuscular, mesenteric,
paraperitoneal, rectovaginal, rectocecal, uterine, and vesical
hernias.
[0851] Inguinal hernias are the most common type of hernias in
adults and develop as the result of a weakness, tear, gap or
opening in the muscle wall of the lower abdomen or groin (inguinal
canal). As a result, the contents of the abdomen, such as
intestine, may protrude through the opening creating, a bulge
and/or pain. Inguinal hernias may be congenital and may become
evident with pain or as a bulge at any time during life. They can
also be acquired as a result of repetitive pressure, strain or
injury to the muscles of the abdominal wall.
[0852] Umbilical hernias develop in and around the area of the
belly button (i.e., navel) and gradually affects those people
having a congenital weakness in the abdominal wall surrounding the
umbilicus (the area at which the vessels of the fetal umbilical
cord exited through the muscle of the abdominal wall). Hernias can
occur in this area of weakness at any time from birth through late
adulthood. The signs and symptoms include pain at or near the navel
area as well as the development of an associated bulge or navel
deformity. This bulge pushes out upon the skin beneath or around
the navel, distorting the normal contour and architecture in or
around the navel.
[0853] Incisional or ventral hernias may occur in the area of any
prior surgical incision, and can vary in size from very small, to
very large and complex. They develop as the result of disruption
along or adjacent to the area of abdominal wall suturing, often
subsequent tension placed on the tissue or other inhibition to
adequate healing (infection, poor nutrition, obesity, or metabolic
diseases). These hernias are present as a bulge or protrusion at or
near the area of the prior incision scar. Numerous types of
abdominal operations can subsequently develop an incisional hernia
at the scar area (e.g., intestinal surgery, vascular surgery,
appendectomy, or laparoscopy).
[0854] Femoral hernias, like inguinal hernias develop in the groin
area. These hernias develop at or very near the leg crease. The
defect itself occurs in between the inguinal ligament (a tendinous
cord that creates the leg crease), the lower side of the pubic
bone, and the femoral vein (the major vein of the leg). This gap is
somewhat larger in females due to the shape and angle of the
pelvis, therefore making femoral hernias more common in
females.
[0855] Hernias themselves are not dangerous, but can become
extremely problematic if they become incarcerated. In an
incarcerated hernia, the protruding viscera are unable to retract
back to their normal anatomical location and become "trapped" in
the hernia sac. If the incarcerated viscera swell, the organ
(typically the intestine) can become blocked (causing bowel
obstruction) and/or the blood supply to the organ can become
compromised, this can lead to necrosis and death of the
incarcerated portion. As such hernias are often repaired surgically
to prevent complications. In its simplest form, the viscera is
returned to its normal location and the defect in the wall is
primarily closed with sutures, but for bigger gaps, a mesh is
placed over the defect to close the hernia opening. Surgical
prostheses used in hernia repair (referred to herein as "hernia
meshes") include prosthetic mesh- or gauze-like materials, which
support the repaired hernia or other body structures during the
healing process. The addition of a fibrosis-inducing agent to the
implant can encourage the development and ingrowth of strong,
fibrous tissue in and around the mesh. This can reinforce the
tissue, form scar tissue over the abdominal wall defect and create
a lasting repair that can reduce the incidence of recurrence. For
smaller gaps, the fibrosis-inducing agent can be combined with the
suture material to produce the same effect.
[0856] In one aspect, the hernia mesh may comprise a biodegradable
or non-biodegradable material. In certain embodiments, the mesh
fabric may be susceptible to the formation of adhesions with the
surrounding tissue or organs and/or may promote enhanced tissue
ingrowth.
[0857] Representative examples of non-biodegradable material for
use in hernia repair meshes include the following: tantalum
metallic meshes, stainless steel meshes, polyamides, polyolefins
(e.g., polypropylene and polyethylene), polyurethanes,
polyester/polyether block copolymers, polyesters (PET,
polybutyleneterephthalate, and polyhexyleneterephthalate- ),
polyester cloth (such as DACRON), polyester sheeting (such as MYLAR
available from E. 1. DuPont De Nemours and Company, Wilmington,
Del.), nylon meshes, DACRON meshes (such as MERSILENE available
from Ethicon, Inc., a Johnson & Johnson Company, Somerville,
N.J.), acrylic cloth (ORLON available from E. 1. DuPont De Nemours
and Company), polyvinyl sponge (IVALON), polyvinyl cloth
(VINYON--N), polypropylene mesh (MARLEX or BARD mesh available from
CR Bard, Inc., Cranston, R.I.), and PROLENE available from Ethicon,
Inc., a Johnson & Johnson Company, Somerville, N.J.),
silicones, or fluoropolymers such as fluorinated ethylene propylene
(FEP) or polytetrafluoroethylene (PTFE; such as TEFLON mesh and
cloth available from E. 1. DuPont De Nemours and Company
(Wilmington, Del.) or expanded PTFE sold under the trade name
GORE-TEX available from W.L. Gore & Associates, Inc.).
[0858] Hernia repair meshes may comprise a biodegradable or
bioresorbable polymer such as polyglactin (VICRYL; Ethicon, Inc., a
Johnson & Johnson Company (Somerville, N.J.)), polyglycolic
acid (such as DEXON; United States Surgical/Syneture (Norwalk,
Conn.)), carbon fiber mesh, autogenous, heterogenous, and
xenogeneic tissue (e.g., pericardium or small intestine submucosa),
or oxidized, regenerated cellulose.
[0859] The surgical mesh used in hernia repairs may be produced by
knitting, weaving, braiding, or otherwise forming a plurality of
yarns (e.g., monofilament or multifilament yarns made of polymeric
materials such as polypropylene and polyester) into a support
trellis. Mesh fabrics for use in connection with hernia repairs are
disclosed in U.S. Pat. Nos. 6,638,284; 5,292,328; 4,769,038 and
2,671,444. Knitted and woven fabrics constructed from a variety of
synthetic fibers and the use of the fabrics, in surgical repair are
also discussed in U.S. Pat. Nos. 3,054,406; 3,124,136; 4,193,137;
4,347,847; 4,452,245; 4,520,821; 4,633,873; 4,652,264; 4,655,221;
4,838,884 and 5,002,551 and European Patent Application No.
334,046. Implantable hernia meshes are described in U.S. Pat. Nos.
6,610,006; 6,368,541 and 6,319,264. Hernia meshes for the repair of
hiatal hernias are described in, e.g., U.S. Pat. No. 6,436,030.
Hernia meshes for the repair of abdominal (e.g., ventral and
umbilical) hernias are described in U.S. Pat. No. 6,383,201.
Infection-resistant hernia meshes are described in, e.g., U.S. Pat.
No. 6,375,662. Hernia meshes such as those described in the patents
listed above are suitable for combining with a fibrosis-inducing
agent to create a mesh which promotes the growth of fibrous
tissue.
[0860] Commercially available hernia meshes can also be combined
with one or more fibrosis-inducing drugs according to the present
invention. Examples of commercially available meshes for use in
hernia repair (e.g., inguinal hernias and other hernias of the
abdominal wall) that can be combined with a fibrosis-inducing agent
include: (a) MARLEX or BARD mesh (CR Bard, Inc., Cranston, R.I.)),
which is a very dense knitted fabric structure with low porosity;
(b) monofilament polypropylene mesh such as PROLENE available from
Ethicon, Inc., a Johnson & Johnson Company, Somerville, N.J.
(see, e.g., U.S. Pat. Nos. 5,634,931 and 5,824,082)); (c) SURGISIS
GOLD and SURGISIS IHM soft tissue graft (both from Cook Surgical,
Inc.) which are devices specifically configured for use to
reinforce soft tissue in repair of inguinal hernias in open and
laparoscopic procedures; (d) thin walled polypropylene surgical
meshes such as are available from Atrium under the trade names
PROLITE, PROLITE ULTRA, and LITEMESH; (e) COMPOSIX hernia mesh
(C.R. Bard, Murray Hill, N.J.), which incorporates a mesh patch
(the patch includes two layers of an inert synthetic mesh,
generally made of polypropylene, and is described in U.S. Pat. No.
6,280,453) that includes a filament to stiffen and maintain the
device in a flat configuration; (f) VISILEX mesh (from C.R. Bard),
which is a polypropylene mesh that is constructed with monofilament
polypropylene; (g) other hernia meshes available from C.R. Bard,
Inc. which include PERFIX Plug, KUGEL Hernia Patch, 3D MAX mesh,
LHI mesh, DULEX mesh, and the VENTRALEX Hernia Patch; and (h) other
types of polypropylene monofilament hernia mesh and plug products
include HERTRA mesh 1, 2, and 2A, HERMESH 3, 4 & 5 and
3-dimensional Plugs T1, T2, and T3 from Herniamesh USA, Inc (Great
Neck, N.Y.). Another implant suitable for use in this embodiment is
a prosthetic polypropylene mesh with a bioresorbable coating called
SEPRAMESH Biosurgical Composite (Genzyme Corporation, Cambridge,
Mass.). One side of the mesh is coated with a bioresorbable layer
of sodium hyaluronate and carboxymethylcellulose, providing a
temporary physical barrier that separates the underlying tissue and
organ surfaces from the mesh. The other side of the mesh is
uncoated, allowing for complete tissue ingrowth similar to bare
polypropylene mesh. In one embodiment, the fibrosis-inducing agent
may be applied only to the uncoated side of SEPRAMESH and not to
the sodium hyaluronate/carboxymethylcellulose coated side.
[0861] Other commercially available materials may also be used as
hernia meshes. Boston Scientific Corporation (Natick, Mass.) sells
the TRELEX NATURAL Mesh which is composed of a unique knitted
polypropylene material. Atrium Medical Corporation (Hudson, N.H.)
sells the PROLITE Mesh and the PROLITE Ultra Mesh made of thin wall
polypropylene and the 3-dimensional PROLOOP Plug composed of
monofilament loops of polypropylene for the treatment of hernia
repairs. Ethicon, Inc. makes the absorbable VICRYL (polyglactin
910) meshes (knitted and woven), PROLENE Polypropylene Hernia
Meshes and MERSILENE Polyester Fiber Mesh. Dow Corning Corporation
(Midland, Mich.) sells a mesh material formed from silicone
elastomer known as SILASTIC Rx Medical Grade Sheeting (Platinum
Cured). United States Surgical/Syneture (Norwalk, Conn.) sells a
mesh made from absorbable polyglycolic acid under the trade name
DEXON Mesh Products. Membrana Accurel Systems (Obernburg, Germany)
sells the CELGARD microporous polypropylene fiber and membrane.
Gynecare Worldwide, a division of Ethicon, Inc., a Johnson &
Johnson Company (Somerville, N.J.) sells a mesh material made from
oxidized, regenerated cellulose known as INTERCEED TC7.
[0862] In one aspect, the present invention provides a hernia
repair mesh that includes a fibrosis-inducing agent to promote
scarring and closure of an abdominal wall defect. The hernia mesh
may be coated with the fibrosing agent (with or without a carrier).
For example, a fibrosis-inducing drug may be applied to the surface
of the mesh or woven into the fabric. Alternatively, or in
addition, the hernia mesh may be composed either entirely or
partially of fibers that are capable of inducing fibrosis. For
example, silk strands or silk can be woven into the hernia mesh or
the hernia mesh can be composed entirely of silk.
[0863] In another aspect, the present invention provides a
sprayable composition that includes a fibrosis-inducing agent that
can be used in endoscopic hernia repair procedures to promote
scarring and closure of an abdominal wall defect.
[0864] Numerous polymeric and non-polymeric carrier systems
described above may be used in the practice of this embodiment.
These compositions can further comprise one or more
fibrosis-inducing agents to promote the formation of fibrous scar
tissue. Methods for incorporating fibrosing compositions onto or
into hernia meshes include: (a) directly affixing to the implant a
fibrosing composition (e.g., by either a spraying process or
dipping process as described above, with or without a carrier); (b)
directly incorporating into the device a fibrosing composition
(e.g., by either a spraying process or dipping process as described
above, with or without a carrier); (c) by coating the device with a
substance such as a hydrogel which can in turn absorb the fibrosing
composition; (d) by interweaving fibrosing composition coated
thread (or the polymer itself formed into a thread) into the device
structure; (e) by binding a film or mesh which is comprised of, or
coated with, a fibrosing composition to the hernia mesh; (f)
constructing the device itself or a portion of the device with a
fibrosing composition; and/or (g) by covalently binding the
fibrosing agent directly to the hernia mesh surface or to a linker
(small molecule or polymer) that is coated or attached to the mesh
surface. For hernia meshes, the coating process can be performed in
such a manner as to (a) coat the exterior surfaces of the mesh, (b)
coat the interior surfaces of the mesh, or (c) coat all or parts of
both external and internal surface of the device.
[0865] In addition to coating the device with a fibrosis-inducing
composition, the fibrosing agent can be mixed with the materials
that are used to make the device such that the fibrosing agent is
incorporated into the final device.
[0866] In addition to (or as an alternative to) applying the
fibrosis agent to the hernia mesh, an in situ forming composition,
gel or thermogel composition containing a fibrosis-inducing agent
can be applied to (as a gel, solid implant, liquid or spray) the
placement site of the hernia mesh, either: (a) prior to placement
of the mesh; (b) after placement of the hernia mesh; (c) during the
placement of the mesh; or (d) any combination of those three. For
the in situ forming thermogel and gel compositions, the
fibrosis-inducing agent(s) (e.g., silk powder, bleomycin) can be
incorporated directly into the formulation to produce a suspension
or a solution or it can be incorporated into a secondary carrier
(e.g., micelles, liposomes, microspheres, microparticles,
nanospheres, microparticulates, emulsions and/or microemulsions)
that is then incorporated into the in situ forming compositions. In
another embodiment, the fibrosis-inducing agent can be
electrostatically or covalently bound to one or more of the
polymeric components of the in-situ in situ forming
composition.
[0867] In a particularly preferred embodiment, the composition may
be prepared from a 4-armed thiol PEG (10K), a 4-armed NHS PEG(10K)
and methylated collagen such as described above and contains a
fibrosis-inducing agent that is sprayed onto the surgical site to
affix the hernia mesh in place and induce fibrosis into the
mesh.
[0868] In another embodiment, the fibrosis-inducing agent can be
incorporated into a biodegradable or dissolvable film or mesh that
is then applied to the treatment site prior to, or post,
implantation of the hernia mesh. Exemplary materials for the
manufacture of these films or meshes are hyaluronic acid
(crosslinked or non-crosslinked), cellulose derivatives (e.g.,
hydroxypropyl cellulose), collagen and crosslinked poly(ethylene
glycol).
[0869] It should be apparent to one of skill in the art that
potentially any adhesion or fibrosis-inducing agents described
above may be utilized alone, or in combination, in the practice of
this embodiment. Exemplary fibrosing agents for use in hernia
repair meshes include talc, silk, wool, chitosan, polylysine,
fibronectin, bleomycin, and CTGF, as well as analogues and
derivatives of the aforementioned.
[0870] As hernia meshes and compositions for use with hernia meshes
are made in a variety of configurations and sizes, the exact dose
administered can vary with mesh size, surface area and design.
However, certain principles can be applied in the application of
this art. Drug dose can be calculated as a function of dose per
unit area (of the portion of the mesh being coated), total drug
dose administered can be measured and appropriate surface
concentrations of active drug can be determined. Regardless of the
method of application of the drug to the hernia mesh, the exemplary
fibrosing agents, used alone or in combination, should be
administered under the following dosing guidelines:
[0871] Utilizing talc as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the hernia mesh, or applied without a
polymeric carrier, the total dose of talc delivered from a hernia
mesh, or coated onto the surface of a hernia mesh, should not
exceed 100 mg (range of 1 .mu.g to 100 mg). In one embodiment, the
total amount of talc released from the prosthesis should be in the
range of 10 .mu.g to 50 mg. The dose per unit area of the implanted
mesh (i.e., the dosage of talc as a function of the surface area of
the portion of the mesh to which drug is applied and/or
incorporated) should fall within the range of 0.05 .mu.g-10 .mu.g
per mm.sup.2 of surface area coated. In another embodiment, talc
should be applied to a hernia mesh surface at a dose of 0.05
.mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. In one
embodiment, talc is released from the surface of a hernia mesh such
that fibrosis in the tissue is promoted for a period ranging from
several hours to several months. For example, talc may be released
in effective concentrations for a period ranging from 1 week to 9
months. It should be readily evident given the discussions provided
herein that analogues and derivatives of talc (as described
previously) with similar functional activity can be utilized for
the purposes of this invention; the above dosing parameters are
then adjusted according to the relative potency of the analogue or
derivative as compared to the parent compound (e.g., a compound
twice as potent as talc is administered at half the above
parameters, a compound half as potent as talc is administered at
twice the above parameters, etc.).
[0872] Utilizing silk as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the hernia mesh, or applied without a
polymeric carrier, the total dose of silk delivered from a hernia
mesh, or coated onto the surface of a hernia mesh, should not
exceed 100 mg (range of 1 .mu.g to 100 mg). In one embodiment, the
total amount of silk released from the hernia mesh should be in the
range of 10 .mu.g to 50 mg. The dose per unit area of the implanted
mesh (i.e., the dosage of silk as a function of the surface area of
the portion of the mesh to which drug is applied and/or
incorporated) should fall within the range of 0.05 .mu.g-10 .mu.g
per mm.sup.2 of surface area coated. In another embodiment, silk
should be applied to a hernia mesh surface at a dose of 0.05
.mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. As
specific (polymeric and non-polymeric) drug delivery vehicles and
specific hernia meshes can release silk at differing rates, the
above dosing parameters should be utilized in combination with the
release rate of the drug from the hernia mesh such that a minimum
concentration of 0.01 nM to 1000 .mu.M of silk is delivered to the
tissue. In one embodiment, silk is released from the surface of a
hernia mesh such that fibrosis in the tissue is promoted for a
period ranging from several hours to several months. For example,
silk may be released in effective concentrations for a period
ranging from 1 week-9 months. It should be readily evident given
the discussions provided herein that analogues and derivatives of
silk (as described previously) with similar functional activity can
be utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound
(e.g., a compound twice as potent as silk is administered at half
the above parameters, a compound half as potent as silk is
administered at twice the above parameters, etc.).
[0873] Utilizing chitosan as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the hernia mesh, or applied without a
polymeric carrier, the total dose of chitosan delivered from a
hernia mesh, or coated onto the surface of a hernia mesh, should
not exceed 100 mg (range of 1 .mu.g to 100 mg). In one embodiment,
the total amount of chitosan released from the hernia mesh should
be in the range of 10 .mu.g to 50 mg. The dose per unit area of the
implanted mesh (i.e., the dosage of chitosan as a function of the
surface area of the portion of the mesh to which drug is applied
and/or incorporated) should fall within the range of 0.05 .mu.g-10
.mu.g per mm.sup.2 of surface area coated. In another embodiment,
chitosan should be applied to a hernia mesh surface at a dose of
0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. As
specific (polymeric and non-polymeric) drug delivery vehicles and
specific hernia meshes can release chitosan at differing rates, the
above dosing parameters should be utilized in combination with the
release rate of the drug from the hernia mesh such that a minimum
concentration of 0.01 nM to 1000 .mu.M of chitosan is delivered to
the tissue. In one embodiment, chitosan is released from the
surface of a hernia mesh such that fibrosis in the tissue is
promoted for a period ranging from several hours to several months.
For example, chitosan may be released in effective concentrations
for a period ranging from 1 week to 9 months. It should be readily
evident given the discussions provided herein that analogues and
derivatives of chitosan (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
chitosan is administered at half the above parameters, a compound
half as potent as chitosan is administered at twice the above
parameters, etc.).
[0874] Utilizing polylysine as an exemplary fibrosis-inducing
agent, whether it is applied using a polymer coating, incorporated
into the polymers which make up the hernia mesh, or applied without
a polymeric carrier, the total dose of polylysine delivered from a
hernia mesh, or coated onto the surface of a hernia mesh, should
not exceed 100 mg (range of 1 .mu.g to 100 mg). In one embodiment,
the total amount of polylysine released from the hernia mesh should
be in the range of 10 .mu.g to 50 mg. The dose per unit area of the
implanted mesh (i.e., the dosage of polylysine as a function of the
surface area of the portion of the mesh to which drug is applied
and/or incorporated) should fall within the range of 0.05 .mu.g-10
.mu.g per mm.sup.2 of surface area coated. In another embodiment,
polylysine should be applied to a hernia mesh surface at a dose of
0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. As
specific (polymeric and non-polymeric) drug delivery vehicles and
specific hernia meshes can release polylysine at differing rates,
the above dosing parameters should be utilized in combination with
the release rate of the drug from the hernia mesh such that a
minimum concentration of 0.01 nM to 1000 .mu.M of polylysine is
delivered to the tissue. In one embodiment, polylysine is released
from the surface of a hernia mesh such that fibrosis in the tissue
is promoted for a period ranging from several hours to several
months. For example, polylysine may be released in effective
concentrations for a period ranging from 1 week to 9 months. It
should be readily evident given the discussions provided herein
that analogues and derivatives of polylysine (as described
previously) with similar functional activity can be utilized for
the purposes of this invention; the above dosing parameters are
then adjusted according to the relative potency of the analogue or
derivative as compared to the parent compound (e.g., a compound
twice as potent as polylysine is administered at half the above
parameters, a compound half as potent as polylysine is administered
at twice the above parameters, etc.).
[0875] Utilizing fibronectin as an exemplary fibrosis-inducing
agent, whether it is applied using a polymer coating, incorporated
into the polymers which make up the hernia mesh, or applied without
a polymeric carrier, the total dose of fibronectin delivered from a
hernia mesh, or coated onto the surface of a hernia mesh, should
not exceed 100 mg (range of 1 .mu.g to 100 mg). In one embodiment,
the total amount of fibronectin released from the hernia mesh
should be in the range of 10 .mu.g to 50 mg. The dose per unit area
of the implanted mesh (i.e., the dosage of fibronectin as a
function of the surface area of the portion of the mesh to which
drug is applied and/or incorporated) should fall within the range
of 0.05 .mu.g-10 .mu.g per mm.sup.2 of surface area coated. In
another embodiment, fibronectin should be applied to a hernia mesh
surface at a dose of 0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of
surface area coated. As specific (polymeric and non-polymeric) drug
delivery vehicles and specific hernia meshes can release
fibronectin at differing rates, the above dosing parameters should
be utilized in combination with the release rate of the drug from
the hernia mesh such that a minimum concentration of 0.01 nM to
1000 .mu.M of fibronectin is delivered to the tissue. In one
embodiment, fibronectin is released from the surface of a hernia
mesh such that fibrosis in the tissue is promoted for a period
ranging from several hours to several months. For example,
fibronectin may be released in effective concentrations for a
period ranging from 1 week to 9 months. It should be readily
evident given the discussions provided herein that analogues and
derivatives of fibronectin (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
fibronectin is administered at half the above parameters, a
compound half as potent as fibronectin is administered at twice the
above parameters, etc.).
[0876] Utilizing bleomycin as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the hernia mesh, or applied without a
polymeric carrier, the total dose of bleomycin delivered from a
hernia mesh, or coated onto the surface of a hernia mesh, should
not exceed 100 mg (range of 0.01 .mu.g to 100 mg). In one
embodiment, the total amount of bleomycin released from the hernia
mesh should be in the range of 0.10 .mu.g to 50 mg. The dose per
unit area of the implanted mesh (i.e., the dosage of bleomycin as a
function of the surface area of the portion of the mesh to which
drug is applied and/or incorporated) should fall within the range
of 0.005 .mu.g-10 .mu.g per mm.sup.2 of surface area coated. In
another embodiment, bleomycin should be applied to a hernia mesh
surface at a dose of 0.005 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of
surface area coated. As specific (polymeric and non-polymeric) drug
delivery vehicles and specific hernia meshes can release bleomycin
at differing rates, the above dosing parameters should be utilized
in combination with the release rate of the drug from the hernia
mesh such that a minimum concentration of 0.001 nM to 1000 .mu.M of
bleomycin is delivered to the tissue. In one embodiment, bleomycin
is released from the surface of a hernia mesh such that fibrosis in
the tissue is promoted for a period ranging from several hours to
several months. For example, bleomycin may be released in effective
concentrations for a period ranging from 1 week to 9 months. It
should be readily evident given the discussions provided herein
that analogues and derivatives of bleomycin (as described
previously) with similar functional activity can be utilized for
the purposes of this invention; the above dosing parameters are
then adjusted according to the relative potency of the analogue or
derivative as compared to the parent compound (e.g., a compound
twice as potent as bleomycin is administered at half the above
parameters, a compound half as potent as bleomycin is administered
at twice the above parameters, etc.).
[0877] Utilizing CTGF as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the hernia mesh, or applied without a
polymeric carrier, the total dose of CTGF delivered from a hernia
mesh, or coated onto the surface of a hernia mesh, should not
exceed 100 mg (range of 0.01 .mu.g to 100 mg). In one embodiment,
the total amount of CTGF released from the hernia mesh should be in
the range of 0.10 .mu.g to 50 mg. The dose per unit area of the
implanted mesh (i.e., the dosage of CTGF as a function of the
surface area of the portion of the mesh to which drug is applied
and/or incorporated) should fall within the range of 0.005 .mu.g-10
.mu.g per mm.sup.2 of surface area coated. In another embodiment,
CTGF should be applied to a hernia mesh surface at a dose of 0.005
.mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. As
specific (polymeric and non-polymeric) drug delivery vehicles and
specific hernia meshes can release CTGF at differing rates, the
above dosing parameters should be utilized in combination with the
release rate of the drug from the hernia mesh such that a minimum
concentration of 0.001 nM to 1000 .mu.M of CTGF is delivered to the
tissue. In one embodiment, CTGF is released from the surface of a
hernia mesh such that fibrosis in the tissue is promoted for a
period ranging from several hours to several months. For example,
CTGF may be released in effective concentrations for a period
ranging from 1 week to 9 months. It should be readily evident given
the discussions provided herein that analogues and derivatives of
CTGF (as described previously) with similar functional activity can
be utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound
(e.g., a compound twice as potent as CTGF is administered at half
the above parameters, a compound half as potent as CTGF is
administered at twice the above parameters, etc.).
[0878] Optionally, the device or composition may alone or
additionally comprise an inflammatory cytokine (e.g., TGF.beta.,
PDGF, VEGF, bFGF, TNF.alpha., NGF, GM-CSF, IGF-a, IL-1,
IL-1-.beta., IL-8, IL-6, and growth hormone) or an analogue or
derivative thereof. Inflammatory cytokines are to be used in
formulations at concentrations that range from 0.0001 .mu.g/ml to
approximately 20 mg/ml depending on the specific clinical
application, formulation type (e.g., gel, liquid, solid,
semi-solid), formulation chemistry, duration of required
application, type of medical device interface and formulation
volume and or surface area coverage required. Preferably, the
inflammatory cytokine is released in effective concentrations for a
period ranging from 1-180 days. The total dose for a single
application is typically not to exceed 500 mg (range of 0.0001
.mu.g to 100 mg); preferred 0.001 .mu.g to 50 mg. When used as a
device coating, the dose is per unit area of 0.0001 .mu.g-500 .mu.g
per mm.sup.2; with a preferred dose of 0.001 .mu.g/mm.sup.2-200
.mu.g/mm.sup.2. Minimum concentration of 10.sup.-10-10.sup.-4 g/ml
of inflammatory cytokine is to be maintained on the device
surface.
[0879] Furthermore, the device or composition may alone or
additionally comprise an agent that stimulates cellular
proliferation. Examples include: dexamethasone, isotretinoin
(13-cis retinoic acid), 17-.beta.-estradiol, estradiol, 1-a-25
dihydroxyvitamin D.sub.3, diethylstibesterol, cyclosporine A,
L-NAME, all-trans retinoic acid (ATRA), and analogues and
derivatives thereof. Doses used are those concentrations which are
demonstrated to stimulate cell proliferation (see, e.g., Example
16). The proliferative agents are to be used in formulations at
concentrations that range from 0.1 ng/ml to 25 mg/ml depending on
the specific clinical application, formulation type (e.g., gel,
liquid, solid, semi-solid), formulation chemistry, duration of
required application, type of medical device interface and
formulation volume and or surface area coverage required.
Preferably, the proliferative agent is released in effective
concentrations for a period ranging from 1-180 days. The total dose
for a single application is typically not to exceed 500 mg (range
of 0.0001 .mu.g to 200 mg); preferred 0.001 .mu.g to 100 mg. When
used as a device coating, the dose is per unit area of 0.00001
.mu.g-500 .mu.g per mm.sup.2; with a preferred dose of 0.0001
.mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-11-10.sup.-6 M of proliferative agent is to be maintained
on the device surface.
[0880] It should be readily evident to one of skill in the art that
any of the previously described fibrosis inducing agents, or
derivatives and analogues thereof, can be utilized to create
variations of the above compositions without deviating from the
spirit and scope of the invention. It should also be apparent that
the agent can be utilized in a composition with or without polymer
carrier and that altering the carrier does not deviate from the
scope of this invention.
[0881] 15. Shoulder Capsule, Ligament and Tendon Repairs
[0882] In one aspect, the present invention provides compositions
and devices for use in shoulder capsule, ligament, and tendon
repair surgeries. The term "ligament" refers to a band of fibrous
connective tissue that connects bones to cartilage, which serves to
support and strengthen a joint. The term "tendon" refers to a
fibrous cord of connective tissue in which the fibers of a muscle
end and by which the muscle is attached to a bone or other
structure. Over 700,000 ligament and tendon repairs are performed
annually in the United States including: repairs of the foot and
ankle (11% of the total; particularly the Achilles tendon, but also
the peroneal tendons, plantar fascia repair, extensor digitorum
tendons, anterior tibial tendon, lateral stabilizing ligaments of
the ankle, anterior inferior tibial fibular ligament, medial
deltoid ligament), knee (38% of the total; particularly the medial
collateral ligament, lateral collateral ligament, anterior cruciate
ligament, posterior cruciate ligament, and meniscal repair, but
also chondral surface repair, patellar tendon repair, bicep femoris
tendon repair), hip (rectus femoris origin, gracilis tendon,
avulsion of the hamstring muscle origins), pelvis (gracilis muscle
origin, adductor muscle origins, rectus femoris insertion, pubic
symphysis cartilage), shoulder (25% of the total; particularly the
rotator cuff tendons; also acromioclavicular stabilizing ligaments,
biceps tendons), back (sacroiliac stabilizing ligaments), elbow
(biceps tendons, lateral epicondyle--extensor origins, medial
epicondyle--flexor origins, triceps complex), and hand (26% of the
total; flexor and extensor tendons of the wrist and hand). The
addition of a fibrosis-inducing agent to a soft tissue repair
procedure (such as those listed above) can increase scarring and
lead to a more durable, sustainable and functional outcome for the
patient.
[0883] Several collagen-based surgical meshes have been produced to
function as tissue repair products for use during open surgery and
are suitable for the delivery of a fibrosis-inducing agent. For
example, collagen surgical patches, such as the FORTAFLEX Patch
(Organogenesis Inc., Canton, Mass.), are used in tendon, ligament
and cartilage repair surgeries to reinforce the tissue during
surgical repair and healing. Tendon and ligament repair surgeries
typically involve the use of suture anchors or suture-passing
devices to secure the damaged tendons to the bone. Depending on the
size of the tear, a collagen patch may be used to fill a defect in
the tendon or ligament. The collagen implant serves as a resorbable
scaffold that provides biomechanical strength, support and
reinforcement of soft tissues that are surgically repaired.
Eventually the collagen becomes infiltrated and replaced by host
tissue cells (primarily fibroblasts) which are able to repair and
regenerate the damaged tissue (primarily organized connective
tissue).
[0884] Unfortunately, for many of these surgical interventions,
durability of the collagen implant becomes an important clinical
issue. In tendon and ligament repairs, it is desirable for the
collagen implant to provide structural integrity until full healing
and native tissue replacement can occur. In the case of large
tissue defects, which can take several months to over a year to
heal, limited durability of the collagen implant can become a
clinical problem if it completely absorbs prior to the completion
of healing. In an attempt to address this problem, manufacturers
have sought to produce a collagen implant with improved durability
through by increasing the amount crosslinking between the collagen
fibers. However highly crosslinked collagen material has different
scaffolding and degradation profiles than native collagen and does
not function optimally in the healing process. The addition of one
or more fibrosis-inducing agents to a collagen patch has several
important clinical implications. First, since it does not require
alteration of the collagen material itself, the collagen scaffold
remains in its native state and is able to support the normal
ingrowth of reparative fibrous connective tissue. Secondly, the
fibrosis-inducing agent stimulates the ingrowth of the body's own
fibrous connective tissue, speeding the healing process and
allowing repair to occur prior to failure of the implant. The
result is a more rapid, stronger, longer-lasting repair composed of
the body's own connective tissue which leads to a better clinical
outcome and a lower risk of failure.
[0885] In one aspect, the present invention provides compositions
and devices that include a fibrosis-inducing agent, where the agent
may encourage scar formation to strengthen the surgically repaired
ligament (e.g., anterior or posterior cruciate ligament), tendon
(e.g., Achilles tendon), or joint capsule (e.g., the anterior
capsule to prevent recurrent shoulder dislocation). A variety of
embodiments are suitable for the practice of this invention,
including delivering to the soft tissue operative site: (1) a
"thermopaste" containing a fibrosis-inducing agent that is applied
to a desired site as a fluid, and hardens to a solid of the desired
shape at a specified temperature (e.g., body temperature); (2) as a
spray (i.e., "nanospray") containing a fibrosis-inducing agent that
can be delivered to a desired site either directly in open surgery,
or through a specialized surgical apparatus (e.g., an endoscope),
and which subsequently hardens to a solid that adheres to the
tissue it is applied to; (3) as an adherent, pliable, resilient,
polymer film containing a fibrosis-inducing agent applied to a
desired site either directly or through a specialized apparatus,
and which preferably adheres to the site to which it is applied;
and/or (4) as a fluid composed of a suspension of microspheres
containing a fibrosis-inducing agent in an appropriate carrier
medium, which is applied to a desired site either directly or via a
specialized apparatus, and which leaves a layer of microspheres at
the application site. Representative examples of each of the above
embodiments are set forth in more detail below.
[0886] In another embodiment, tendons, ligaments or the shoulder
capsule can be treated with a fibrosis-inducing agent combined with
a composition that forms a gel in situ. These can be crosslinked
gels, thermogels, or traditional gel compositions. For the in situ
forming gels, thermogel and gel compositions, the fibrosis-inducing
agent(s) can be incorporated directly into the formulation to
produce a suspension or a solution (e.g., silk powder, bleomycin)
or it can be incorporated into a secondary carrier (e.g., micelles,
liposomes, microspheres, microparticles, nanospheres,
microparticulates, emulsions and/or micromulsions) that is then
incorporated into the in situ forming gel compositions. In certain
embodiments, the fibrosis-inducing agent can be electrostatically
or covalently bound to one or more of the polymeric components of
the in situ forming gel composition.
[0887] In yet another embodiment, the fibrosis-inducing agent can
be incorporated into a biodegradable or dissolvable film or mesh
that is then applied to the treatment site prior to, during, or
post treatment. The film or mesh can be applied to the entire
treatment site, used to bridge or fill tissue defects, or they can
be applied as a patch to a very specific location within the
treatment site. Preferred materials for the manufacture of these
films or meshes are hyaluronic acid (crosslinked or
non-crosslinked), cellulose derivatives (e.g., hydroxypropyl
cellulose), collagen and crosslinked poly(ethylene glycol).
[0888] In yet another embodiment, the fibrosis-inducing agent can
be in an injectable or sprayable form (particularly useful for
endoscopic delivery) that can be delivered directly into the
treatment site, applied over the surgically repaired tendon,
ligament or capsule, used to patch tissue defects, or applied to
the tissue surrounding the treatment site. The compositions may be
readily applied as a "spray", which subsequently solidifies into a
film or coating. A sprayable formulation of a fibrosing agent may
be used in, for example, knee surgery (e.g., MCL and ACL) repairs
to reinforce the ligament or in ankle surgery to reinforce a tendon
(e.g., Achilles' tendon). The compositions also may be used for
cosmetic purposes, such as, reinforcement or augmentation of the
Cooper's ligament (e.g., for support or lifting of the breast). For
example, the ligament may be coated with a scarring fibrosing agent
in order to cause the ligament to contract (i.e., shorten) and lift
the breast tissue. The fibrosis-inducing agent(s) (e.g., silk
powder, bleomycin) can be incorporated directly into the
formulation to produce a suspension or a solution or incorporated
into a secondary carrier (e.g., micelles, liposomes, microspheres,
microparticles, nanospheres, microparticulates, emulsions and/or
micromulsions) that is then incorporated into the injectable or
sprayable composition. The spray, which includes a tissue adherent
polymer containing a fibrosis-inducing agent, may be prepared from
microspheres of a wide array of sizes. In another embodiment, the
fibrosis-inducing agent can be electrostatically or covalently
bound to one or more of the polymeric components of the injectable
or sprayable composition.
[0889] The injectable and sprayable compositions can further
comprise a polymer to enhance the viscosity of the solution.
Polymers that can be used for this purpose include hyaluronic acid,
CMC, PLURONICS, such as PLURONIC F127, and gels (including thermo
gels) of the form X--Y, X--Y--X, or Y--X--Y (where X is a
degradable polyester and Y is a polyalkylene oxide, preferably
polyethylene glycol or the mono-methyl ether thereof). In another
embodiment, the injectable or sprayable formulation can further
comprise one or more biocompatible solvents. These can include
ethanol, DMSO, NMP, poly(ethylene glycol)-200, and/or poly(ethylene
glycol)-300.
[0890] One material that is of particular interest for the practice
of this embodiment is prepared from a 4-armed thiol PEG (10K), a
4-armed NHS PEG(10K) and methylated collagen such as described
above. In one embodiment, a material made from 4-armed thiol PEG
(10K), a 4-armed NHS PEG(10K) and methylated collagen is loaded
with a fibrosis-inducing agent and sprayed (directly or via
endoscope) directly onto the treatment site, used to patch a tissue
defect, applied to the tissue surrounding the treatment site, or
applied over a damaged tendon, ligament or capsule to adhere the
tissues together and induce fibrosis.
[0891] It should be apparent to one of skill in the art that
potentially any fibrosis-inducing agents described above may be
utilized alone, or in combination, in the practice of this
embodiment. Exemplary fibrosing agents for use in capsule,
ligament, and tendon repair devices and implants include talc,
silk, wool, chitosan, polylysine, fibronectin, bleomycin, and CTGF,
as well as analogues and derivatives of the aforementioned.
[0892] As shoulder capsule, ligament, and tendon repair devices and
compositions are made in a variety of configurations and sizes
depending upon the location and the degree of the injury, the exact
dose administered can vary with implant size, surface area and
design. However, certain principles can be applied in the
application of this art. Drug dose can be calculated as a function
of dose per unit area (or volume) of the implant, total drug dose
administered can be measured and appropriate surface concentrations
of active drug can be determined. Regardless of the method of
application of the drug to the joint capsule, ligament, or tendon
repair device or implant, the exemplary fibrosing agents, used
alone or in combination, should be administered under the following
dosing guidelines:
[0893] Utilizing talc as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of talc delivered from
a joint capsule, ligament, or tendon repair implant, or coated onto
the surface of a joint capsule, ligament, or tendon repair implant,
should not exceed 100 mg (range of 1 .mu.g to 100 mg). In one
embodiment, the total amount of talc released from the implant
should be in the range of 10 .mu.g to 50 mg. The dose per unit
volume of the implant (i.e., the dosage of talc as a function of
the volume of the portion of the implant to which drug is applied
and/or incorporated) should fall within the range of 0.05 .mu.g-10
.mu.g per mm.sup.3 of material implanted. In another embodiment,
talc should be applied to a joint capsule, ligament, or tendon
repair implant surface at a dose of 0.05 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. In one embodiment, talc is
released from the surface of a joint capsule, ligament, or tendon
repair implant such that fibrosis in the tissue is promoted for a
period ranging from several hours to several months. For example,
talc may be released in effective concentrations for a period
ranging from 1 to 12 months. It should be readily evident given the
discussions provided herein that analogues and derivatives of talc
(as described previously) with similar functional activity can be
utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound
(e.g., a compound twice as potent as talc is administered at half
the above parameters, a compound half as potent as talc is
administered at twice the above parameters, etc.).
[0894] Utilizing silk as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of silk delivered from
a joint capsule, ligament, or tendon repair implant, or coated onto
the surface of a joint capsule, ligament, or tendon repair implant,
should not exceed 100 mg (range of 1 .mu.g to 100 mg). In one
embodiment, the total amount of silk released from the implant
should be in the range of 10 .mu.g to 50 mg. The dose per unit
volume of the implant (i.e., the dosage of silk as a function of
the volume of the portion of the implant to which drug is applied
and/or incorporated) should fall within the range of 0.05 .mu.g-10
.mu.g per mm.sup.3 of material implanted. In another embodiment,
silk should be applied to a joint capsule, ligament, or tendon
repair implant surface at a dose of 0.05 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific medical implants
can release silk at differing rates, the above dosing parameters
should be utilized in combination with the release rate of the drug
from the joint capsule, ligament, or tendon repair implant such
that a minimum concentration of 0.01 nM to 1000 .mu.M of silk is
delivered to the tissue. In one embodiment, silk is released from
the surface of a joint capsule, ligament, or tendon repair implant
such that fibrosis in the tissue is promoted for a period ranging
from several hours to several months. For example, silk may be
released in effective concentrations for a period ranging from 1 to
12 months. It should be readily evident given the discussions
provided herein that analogues and derivatives of silk (as
described previously) with similar functional activity can be
utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound
(e.g., a compound twice as potent as silk is administered at half
the above parameters, a compound half as potent as silk is
administered at twice the above parameters, etc.).
[0895] Utilizing chitosan as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of chitosan delivered
from a joint capsule, ligament, or tendon repair implant, or coated
onto the surface of a joint capsule, ligament, or tendon repair
implant, should not exceed 100 mg (range of 1 .mu.g to 100 mg). In
one embodiment, the total amount of chitosan released from the
implant should be in the range of 10 .mu.g to 50 mg. The dose per
unit volume of the implant (i.e., the dosage of chitosan as a
function of the volume of the portion of the implant to which drug
is applied and/or incorporated) should fall within the range of
0.05 .mu.g-10 .mu.g per mm.sup.3 of material implanted. In another
embodiment, chitosan should be applied to a joint capsule,
ligament, or tendon repair implant surface at a dose of 0.05
.mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. As
specific (polymeric and non-polymeric) drug delivery vehicles and
specific medical implants can release chitosan at differing rates,
the above dosing parameters should be utilized in combination with
the release rate of the drug from the joint capsule, ligament, or
tendon repair implant such that a minimum concentration of 0.01 nM
to 1000 .mu.M of chitosan is delivered to the tissue. In one
embodiment, chitosan is released from the surface of a joint
capsule, ligament, or tendon repair implant such that fibrosis in
the tissue is promoted for a period ranging from several hours to
several months. For example, chitosan may be released in effective
concentrations for a period ranging from 1 to 12 months. It should
be readily evident given the discussions provided herein that
analogues and derivatives of chitosan (as described previously)
with similar functional activity can be utilized for the purposes
of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as chitosan is administered at half the above parameters, a
compound half as potent as chitosan is administered at twice the
above parameters, etc.).
[0896] Utilizing polylysine as an exemplary fibrosis-inducing
agent, whether it is applied using a polymer coating, incorporated
into the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of polylysine delivered
from a joint capsule, ligament, or tendon repair implant, or coated
onto the surface of a joint capsule, ligament, or tendon repair
implant, should not exceed 100 mg (range of 1 .mu.g to 100 mg). In
one embodiment, the total amount of polylysine released from the
implant should be in the range of 10 .mu.g to 50 mg. The dose per
unit volume of the implant (i.e., the dosage of polylysine as a
function of the volume of the portion of the implant to which drug
is applied and/or incorporated) should fall within the range of
0.05 .mu.g-10 .mu.g per mm.sup.3 of material implanted. In another
embodiment, polylysine should be applied to a joint capsule,
ligament, or tendon repair implant surface at a dose of 0.05
.mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. As
specific (polymeric and non-polymeric) drug delivery vehicles and
specific medical implants can release polylysine at differing
rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the joint
capsule, ligament, or tendon repair implant such that a minimum
concentration of 0.01 nM to 1000 .mu.M of polylysine is delivered
to the tissue. In one embodiment, polylysine is released from the
surface of a joint capsule, ligament, or tendon repair implant such
that fibrosis in the tissue is promoted for a period ranging from
several hours to several months. For example, polylysine may be
released in effective concentrations for a period ranging from 1 to
12 months. It should be readily evident given the discussions
provided herein that analogues and derivatives of polylysine (as
described previously) with similar functional activity can be
utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound
(e.g., a compound twice as potent as polylysine is administered at
half the above parameters, a compound half as potent as polylysine
is administered at twice the above parameters, etc.).
[0897] Utilizing fibronectin as an exemplary fibrosis-inducing
agent, whether it is applied using a polymer coating, incorporated
into the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of fibronectin
delivered from a joint capsule, ligament, or tendon repair implant,
or coated onto the surface of a joint capsule, ligament, or tendon
repair implant, should not exceed 100 mg (range of 1 .mu.g to 100
mg). In one embodiment, the total amount of fibronectin released
from the implant should be in the range of 10 .mu.g to 50 mg. The
dose per unit volume of the implant (i.e., the dosage of
fibronectin as a function of the volume of the portion of the
implant to which drug is applied and/or incorporated) should fall
within the range of 0.05 .mu.g-10 .mu.g per mm.sup.3 of material
implanted. In another embodiment, fibronectin should be applied to
a joint capsule, ligament, or tendon repair implant surface at a
dose of 0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area
coated. As specific (polymeric and non-polymeric) drug delivery
vehicles and specific medical implants can release fibronectin at
differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the joint
capsule, ligament, or tendon repair implant such that a minimum
concentration of 0.01 nM to 1000 .mu.M of fibronectin is delivered
to the tissue. In one embodiment, fibronectin is released from the
surface of a joint capsule, ligament, or tendon repair implant such
that fibrosis in the tissue is promoted for a period ranging from
several hours to several months. For example, fibronectin may be
released in effective concentrations for a period ranging from 1 to
12 months. It should be readily evident given the discussions
provided herein that analogues and derivatives of fibronectin (as
described previously) with similar functional activity can be
utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound
(e.g., a compound twice as potent as fibronectin is administered at
half the above parameters, a compound half as potent as fibronectin
is administered at twice the above parameters, etc.).
[0898] Utilizing bleomycin as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of bleomycin delivered
from a joint capsule, ligament, or tendon repair implant, or coated
onto the surface of a joint capsule, ligament, or tendon repair
implant, should not exceed 100 mg (range of 0.01 .mu.g to 100 mg).
In one embodiment, the total amount of bleomycin released from the
implant should be in the range of 0.10 .mu.g to 50 mg. The dose per
unit volume of the implant (i.e., the dosage of bleomycin as a
function of the volume of the portion of the implant to which drug
is applied and/or incorporated) should fall within the range of
0.005 .mu.g-10 .mu.g per mm.sup.3 of material implanted. In another
embodiment, bleomycin should be applied to a joint capsule,
ligament, or tendon repair implant surface at a dose of 0.005
.mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. As
specific (polymeric and non-polymeric) drug delivery vehicles and
specific medical implants can release bleomycin at differing rates,
the above dosing parameters should be utilized in combination with
the release rate of the drug from the joint capsule, ligament, or
tendon repair implant such that a minimum concentration of 0.001 nM
to 1000 .mu.M of bleomycin is delivered to the tissue. In one
embodiment, bleomycin is released from the surface of a joint
capsule, ligament, or tendon repair implant such that fibrosis in
the tissue is promoted for a period ranging from several hours to
several months. For example, bleomycin may be released in effective
concentrations for a period ranging from 1 to 12 months. It should
be readily evident given the discussions provided herein that
analogues and derivatives of bleomycin (as described previously)
with similar functional activity can be utilized for the purposes
of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as bleomycin is administered at half the above parameters, a
compound half as potent as bleomycin is administered at twice the
above parameters, etc.).
[0899] Utilizing CTGF as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the device or implant, or applied
without a polymeric carrier, the total dose of CTGF delivered from
a joint capsule, ligament, or tendon repair implant, or coated onto
the surface of a joint capsule, ligament, or tendon repair implant,
should not exceed 100 mg (range of 0.01 .mu.g to 100 mg). In one
embodiment, the total amount of CTGF released from the implant
should be in the range of 0.10 .mu.g to 50 mg. The dose per unit
volume of the implant (i.e., the dosage of CTGF as a function of
the volume of the portion of the implant to which drug is applied
and/or incorporated) should fall within the range of 0.005 .mu.g-10
.mu.g per mm.sup.3 of material implanted. In another embodiment,
CTGF should be applied to a joint capsule, ligament, or tendon
repair implant surface at a dose of 0.005 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific medical implants
can release CTGF at differing rates, the above dosing parameters
should be utilized in combination with the release rate of the drug
from the joint capsule, ligament, or tendon repair implant such
that a minimum concentration of 0.001 nM to 1000 .mu.M of CTGF is
delivered to the tissue. In one embodiment, CTGF is released from
the surface of a joint capsule, ligament, or tendon repair implant
such that fibrosis in the tissue is promoted for a period ranging
from several hours to several months. For example, CTGF may be
released in effective concentrations for a period ranging from 1 to
12 months. It should be readily evident given the discussions
provided herein that analogues and derivatives of CTGF (as
described previously) with similar functional activity can be
utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound
(e.g., a compound twice as potent as CTGF is administered at half
the above parameters, a compound half as potent as CTGF is
administered at twice the above parameters, etc.).
[0900] Optionally, the device may alone or additionally comprise an
inflammatory cytokine (e.g., TGF.beta., PDGF, VEGF, bFGF,
TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8, IL-6, and
growth hormone) or a bone morphogenic protein (BMP) (e.g., BMP-2,
BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or an analogue or derivative
thereof).
[0901] Bone morphogenic protein(s) (e.g., BMP-2, BMP-3, BMP-4,
BMP-5, BMP-6, or BMP-7 or an analogue or derivative thereof) are to
be used in formulations at concentrations that range from 0.001
.mu.g/ml to approximately 20 mg/ml depending on the specific
clinical application, formulation type (e.g., gel, liquid, solid,
semi-solid), formulation chemistry, duration of required
application, type of medical device interface and formulation
volume and or surface area coverage required. Preferably, the bone
morphogenic protein is released in effective concentrations for a
period ranging from 1-180 days. The total dose for a single
application is typically not to exceed 500 mg (range of 0.001 .mu.g
to 500 mg); preferred 1 .mu.g to 250 mg. When used as a device
coating, the dose is per unit area of 0.001 .mu.g-1000 .mu.g per
mm.sup.2; with a preferred dose of 0.01 .mu.g/mm.sup.2-200
.mu.g/mm.sup.2. Minimum concentration of 10.sup.-9-10.sup.4 M of
bone morphogenic protein is to be maintained on the device
surface.
[0902] Inflammatory cytokines are to be used in formulations at
concentrations that range from 0.0001 .mu.g/ml to approximately 20
mg/ml depending on the specific clinical application, formulation
type (e.g., gel, liquid, solid, semi-solid), formulation chemistry,
duration of required application, type of medical device interface
and formulation volume and or surface area coverage required.
Preferably, the inflammatory cytokine is released in effective
concentrations for a period ranging from 1-180 days. The total dose
for a single application is typically not to exceed 500 mg (range
of 0.0001 .mu.g to 100 mg); preferred 0.001 .mu.g to 50 mg. When
used as a device coating, the dose is per unit area of 0.0001
.mu.g-500 .mu.g per mm.sup.2; with a preferred dose of 0.001
.mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-10-10.sup.-4 g/ml of inflammatory cytokine is to be
maintained on the device surface.
[0903] Furthermore, the device may alone or additionally comprise
an agent that stimulates cellular proliferation. Examples include:
dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof. Doses used are those
concentrations which are demonstrated to stimulate cell
proliferation (see, e.g., Example 16). The proliferative agents are
to be used in formulations at concentrations that range from
0.0000001 to 25 mg/ml depending on the specific clinical
application, formulation type (e.g., gel, liquid, solid,
semi-solid), formulation chemistry, duration of required
application, type of medical device interface and formulation
volume and or surface area coverage required. Preferably, the
proliferative agent is released in effective concentrations for a
period ranging from 1-180 days. The total dose for a single
application is typically not to exceed 500 mg (range of 0.0001
.mu.g to 200 mg); preferred 0.001 .mu.g to 100 mg. When used as a
device coating, the dose is per unit area of 0.00001 .mu.g-500
.mu.g per mm.sup.2; with a preferred dose of 0.0001
.mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-11-10.sup.-6 M of proliferative agent is to be maintained
on the device surface.
[0904] It should be readily evident to one of skill in the art that
any of the previously described fibrosis inducing agents, or
derivatives and analogues thereof, can be utilized to create
variations of the above compositions without deviating from the
spirit and scope of the invention. It should also be apparent that
the agent can be utilized in a composition with or without polymer
carrier and that altering the carrier does not deviate from the
scope of this invention.
[0905] 16. Septal Occlusion Patches
[0906] The present invention provides for the combination of a
fibrosis-inducing agent and a septal occlusion patch. Incorporation
of a fibrosing agent into or onto a septal occlusion patch can
promote tissue growth that will anchor the device to the septum and
provide a better seal, thus reducing the incidence of leaks.
[0907] Approximately half of congenital cardiovascular defects let
blood flow between the right and left chambers of the heart. The
two most common types of defects are atrial septal defects
involving an opening in the wall between the two atria and
ventricular septal defects involving an opening in the wall between
the ventricles. Other similar cardiac defects are patent foramen
ovale and patent ductus arteriosus. In the United States alone,
about 20,000 babies are born each year with one of these
malformations. In addition approximately 1 million Americans with
congenital cardiovascular defects are alive today and will develop
complications, such as pulmonary hypertension, congestive heart
failure, atrial arrhythmia, impaired aerobic capacity and stroke,
which will require treatment.
[0908] Transcatheter closure of cardiac defects is becoming an
attractive alternative to surgical closure because it reduces the
risks and morbidity inherent to cardiac surgery. Several
transcatheter techniques and septal occlusion devices have been
developed and are used clinically. The latest generation of devices
is composed of two disks joined by a center stalk. The stalk
occludes the defect and the disks adhere to each side of the wall.
The collapsed device is positioned via a catheter and released
under fluoroscopy guidance. The size of these devices, however,
limits the use of this technology in small patients. Further,
patients with large defects and patients having an insufficient
septal rim around the defect typically cannot be treated with
septal occlusion devices. In addition, adverse complications
associated with septal occlusion devices include incomplete closure
(leaks), friction lesions and cardiac perforation.
[0909] The addition of a fibrosis-inducing agent to the implant can
encourage the development and ingrowth of strong, fibrous tissue in
and around the septal occlusion device. This can reinforce the
tissue, form scar tissue over the implant and create a lasting
repair. Tissue growth can anchor the device to the septum and
provide an improved seal, thus minimizing the occurrence of leaks.
Further, incorporation of the device by cardiac tissue can prevent
friction fracture and cardiac perforation. Tissue growth in and/or
on the device can strengthen the device and allow the use of
thinner devices, thus reducing bulkiness and allowing inclusion of
a wider patient population. Increased strength of the device can
also allow for the treatment of larger defects. Finally, patients
having a small septal rim that generally would be insufficient for
transcatheter treatment will become eligible for this procedure
because tissue growth will anchor the device in place.
[0910] The term septal occlusion patches refer to devices that are
designed to be placed within or near the vasculature of the host to
block the flow of blood through a vascular defect. Examples of
septal occlusion patches include, without limitation, defect
closure devices, shunt closure apparatus, intracardiac occluders,
occluding disks, defect occluding systems, and intravascular shunt
devices.
[0911] Septal occlusion patches may be composed of a variety of
configurations. For example, the septal occlusion patch may center
itself elastically against a margin of an opening by being shaped
to form a closed loop with at least two spaced apart windings. See
e.g., U.S. Pat. No. 6,355,052. The septal occlusion patch may be
composed of a delivery shaft and a patch releasably held at the
distal end whereby the patch has a collapsed configuration for
positioning through the lumen of a sleeve and a deployment
configuration for positioning across a septal defect. See e.g.,
U.S. Pat. No. 6,346,074. The septal occlusion patch may be composed
of two flexible membranes having an elastically deformable frame
extending along the periphery to allow the membranes to collapse
for passage through a catheter while returning to their
predetermined shape following implantation. See e.g., U.S. Pat.
Nos. 6,077,291 and 5,334,217. The septal occlusion patch may be
composed of an occlusion bag with two sacs connected to each other
and an unattached super-elastic wire frame having two sets of
multiple loops contained within the occlusion bag. See e.g., U.S.
Pat. No. 5,861,003. The septal occlusion patch may be composed of
at least two clips with fastening means that firmly grip the
peripheral portions of the opening as well as a flat fabric
occluder which is used to close the opening of the septum. See
e.g., U.S. Pat. No. 5,507,811. The septal occlusion patch may be
composed of two occluders connected by a fastener with a pivot for
allowing rotation of the occluders when in an expanded
configuration. See e.g., U.S. Pat. No. 5,451,235. The septal
occlusion patch may be composed of two foldable foam resin or
polyurethane discs with sutured wire skeletons whereby the discs
are secured to each other using a buttoning technique through the
heart defect. See e.g., U.S. Pat. Nos. 5,433,727; 5,284,488 and
4,917,089. The septal occlusion patch may be an umbrella-like
expansive device composed of a plurality of struts movably mounted
on a hub such that the patch has a first collapsed position and a
second expanded position. See e.g., U.S. Pat. No. 4,007,743. The
septal occlusion patch may be composed of a mechanical expansion
means that has a dual set of umbrella-like structures with a
central hub for placement on opposite sides of the shunt defect.
See e.g., U.S. Pat. No. 3,874,388.
[0912] Commercially available septal occlusion patches can also be
combined with one or more fibrosis-inducing drugs according to the
present invention. For example, W. L. Gore and Associates, Inc.
(Newark, Del.) sells its HELEX Septal Occluder which is used as a
minimally invasive closure of atrial septal defects. NMT Medical,
Inc. (Boston, Mass.) sells their CARDIOSEAL and STARFLEX which are
designed for minimally invasive procedures. AGA Medical Corp.
(Golden Valley, Minn.) sells their AMPLATZER Septal Occluder.
[0913] In one aspect, the present invention provides a septal
occlusion patch that includes a fibrosis-inducing agent to promote
scarring and closure of a cardiac defect. The septal occlusion
patch may be coated with the fibrosing agent (with or without a
carrier). For example, a fibrosis-inducing drug may be applied to
the surface of the patch or woven into the fabric. Alternatively,
or in addition, the septal occlusion patch may be composed either
entirely or partially of fibers that are capable of inducing
fibrosis. For example, silk strands or silk can be woven into the
septal occlusion patch or the septal occlusion patch can be
composed entirely of silk.
[0914] In another aspect, the present invention provides a
sprayable composition that includes a fibrosis-inducing agent that
can be used in transcatheter repair procedures to promote scarring
and closure of a cardiac defect.
[0915] Numerous polymeric and non-polymeric carrier systems
described above may be used in the practice of this embodiment.
These compositions can further comprise one or more
fibrosis-inducing agents to promote the formation of fibrous scar
tissue. Methods for incorporating fibrosing compositions onto or
into septal occlusion patch include: (a) directly affixing to the
implant a fibrosing composition (e.g., by either a spraying process
or dipping process as described above, with or without a carrier);
(b) directly incorporating into the device a fibrosing composition
(e.g., by either a spraying process or dipping process as described
above, with or without a carrier); (c) by coating the device with a
substance such as a hydrogel which can in turn absorb the fibrosing
composition; (d) by interweaving fibrosing composition coated
thread (or the polymer itself formed into a thread) into the device
structure; (e) by binding a film or mesh which is comprised of, or
coated with, a fibrosing composition to the septal occlusion patch;
(f) constructing the device itself or a portion of the device with
a fibrosing composition; and/or (g) by covalently binding the
fibrosing agent directly to the septal occlusion patch surface or
to a linker (small molecule or polymer) that is coated or attached
to the patch surface. For septal occlusion patch, the coating
process can be performed in such a manner as to (a) coat the
exterior surfaces of the patch, (b) coat the interior surfaces of
the patch, or (c) coat all or parts of both external and internal
surface of the patch.
[0916] In addition to coating the device with a fibrosis-inducing
composition, the fibrosing agent can be mixed with the materials
that are used to make the device such that the fibrosing agent is
incorporated into the final device.
[0917] In addition to (or as an alternative to) applying the
fibrosis agent to the septal occlusion patch, an in situ forming
composition, gel or thermogel composition containing a
fibrosis-inducing agent can be applied to (as a gel, solid implant,
liquid or spray) the placement site of the septal occlusion patch,
either: (a) prior to placement of the patch; (b) after placement of
the patch; (c) during the placement of the patch; or (d) any
combination of those three. For the in situ forming thermogel and
gel compositions, the fibrosis-inducing agent(s) (e.g., silk
powder, bleomycin) can be incorporated directly into the
formulation to produce a suspension or a solution or it can be
incorporated into a secondary carrier (e.g., micelles, liposomes,
microspheres, microparticles, nanospheres, microparticulates,
emulsions and/or microemulsions) that is then incorporated into the
in situ forming compositions. In another embodiment, the
fibrosis-inducing agent can be electrostatically or covalently
bound to one or more of the polymeric components of the in-situ in
situ forming composition.
[0918] In a particularly preferred embodiment, the composition may
be prepared from a 4-armed thiol PEG (10K), a 4-armed NHS PEG(10K)
and methylated collagen such as described above and contains a
fibrosis-inducing agent that is sprayed onto the surgical site to
affix the septal occlusion patch in place and induce fibrosis into
the patch.
[0919] In another embodiment, the fibrosis-inducing agent can be
incorporated into a biodegradable or dissolvable film or mesh that
is then applied to the treatment site prior to, or post,
implantation of the septal occlusion patch. Exemplary materials for
the manufacture of these films or meshes are hyaluronic acid
(crosslinked or non-crosslinked), cellulose derivatives (e.g.,
hydroxypropyl cellulose), collagen and crosslinked poly(ethylene
glycol).
[0920] It should be apparent to one of skill in the art that
potentially any adhesion or fibrosis-inducing agents described
above may be utilized alone, or in combination, in the practice of
this embodiment. Exemplary fibrosing agents for use in septal
occlusion patches include talc, silk, wool, chitosan, polylysine,
fibronectin, bleomycin, and CTGF, as well as analogues and
derivatives of the aforementioned.
[0921] As septal occlusion patches and compositions for use with
septal occlusion patches are made in a variety of configurations
and sizes, the exact dose administered can vary with patch size,
surface area and design. However, certain principles can be applied
in the application of this art. Drug dose can be calculated as a
function of dose per unit area (of the portion of the patch being
coated), total drug dose administered can be measured and
appropriate surface concentrations of active drug can be
determined. Regardless of the method of application of the drug to
the septal occlusion patch, the exemplary fibrosing agents, used
alone or in combination, should be administered under the following
dosing guidelines:
[0922] Utilizing talc as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the septal occlusion patch, or applied
without a polymeric carrier, the total dose of talc delivered from
a septal occlusion patch, or coated onto the surface of a septal
occlusion patch, should not exceed 100 mg (range of 1 .mu.g to 100
mg). In one embodiment, the total amount of talc released from the
prosthesis should be in the range of 10 .mu.g to 50 mg. The dose
per unit area of the implanted septal occlusion patch (i.e., the
dosage of talc as a function of the surface area of the portion of
the septal occlusion patch to which drug is applied and/or
incorporated) should fall within the range of 0.05 .mu.g-10 .mu.g
per mm.sup.2 of surface area coated. In another embodiment, talc
should be applied to a septal occlusion patch surface at a dose of
0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. In
one embodiment, talc is released from the surface of a septal
occlusion patch such that fibrosis in the tissue is promoted for a
period ranging from several hours to several months. For example,
talc may be released in effective concentrations for a period
ranging from 1 week to 9 months. It should be readily evident given
the discussions provided herein that analogues and derivatives of
talc (as described previously) with similar functional activity can
be utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound
(e.g., a compound twice as potent as talc is administered at half
the above parameters, a compound half as potent as talc is
administered at twice the above parameters, etc.).
[0923] Utilizing silk as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the septal occlusion patch, or applied
without a polymeric carrier, the total dose of silk delivered from
a septal occlusion patch, or coated onto the surface of a septal
occlusion patch, should not exceed 100 mg (range of 1 .mu.g to 100
mg). In one embodiment, the total amount of silk released from the
septal occlusion patch should be in the range of 10 .mu.g to 50 mg.
The dose per unit area of the implanted septal occlusion patch
(i.e., the dosage of silk as a function of the surface area of the
portion of the septal occlusion patch to which drug is applied
and/or incorporated) should fall within the range of 0.05 .mu.g-10
.mu.g per mm.sup.2 of surface area coated. In another embodiment,
silk should be applied to a septal occlusion patch surface at a
dose of 0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area
coated. As specific (polymeric and non-polymeric) drug delivery
vehicles and specific septal occlusion patch can release silk at
differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the septal
occlusion patch such that a minimum concentration of 0.01 nM to
1000 .mu.M of silk is delivered to the tissue. In one embodiment,
silk is released from the surface of a septal occlusion patch such
that fibrosis in the tissue is promoted for a period ranging from
several hours to several months. For example, silk may be released
in effective concentrations for a period ranging from 1 week-9
months. It should be readily evident given the discussions provided
herein that analogues and derivatives of silk (as described
previously) with similar functional activity can be utilized for
the purposes of this invention; the above dosing parameters are
then adjusted according to the relative potency of the analogue or
derivative as compared to the parent compound (e.g., a compound
twice as potent as silk is administered at half the above
parameters, a compound half as potent as silk is administered at
twice the above parameters, etc.).
[0924] Utilizing chitosan as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the septal occlusion patch, or applied
without a polymeric carrier, the total dose of chitosan delivered
from a septal occlusion patch, or coated onto the surface of a
septal occlusion patch, should not exceed 100 mg (range of 1 .mu.g
to 100 mg). In one embodiment, the total amount of chitosan
released from the septal occlusion patch should be in the range of
10 .mu.g to 50 mg. The dose per unit area of the implanted septal
occlusion patch (i.e., the dosage of chitosan as a function of the
surface area of the portion of the septal occlusion patch to which
drug is applied and/or incorporated) should fall within the range
of 0.05 .mu.g-10 .mu.g per mm.sup.2 of surface area coated. In
another embodiment, chitosan should be applied to a septal
occlusion patch surface at a dose of 0.05 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific septal occlusion
patches can release chitosan at differing rates, the above dosing
parameters should be utilized in combination with the release rate
of the drug from the septal occlusion patch such that a minimum
concentration of 0.01 nM to 1000 .mu.M of chitosan is delivered to
the tissue. In one embodiment, chitosan is released from the
surface of a septal occlusion patch such that fibrosis in the
tissue is promoted for a period ranging from several hours to
several months. For example, chitosan may be released in effective
concentrations for a period ranging from 1 week to 9 months. It
should be readily evident given the discussions provided herein
that analogues and derivatives of chitosan (as described
previously) with similar functional activity can be utilized for
the purposes of this invention; the above dosing parameters are
then adjusted according to the relative potency of the analogue or
derivative as compared to the parent compound (e.g., a compound
twice as potent as chitosan is administered at half the above
parameters, a compound half as potent as chitosan is administered
at twice the above parameters, etc.).
[0925] Utilizing polylysine as an exemplary fibrosis-inducing
agent, whether it is applied using a polymer coating, incorporated
into the polymers which make up the septal occlusion patch, or
applied without a polymeric carrier, the total dose of polylysine
delivered from a septal occlusion patch, or coated onto the surface
of a septal occlusion patch, should not exceed 100 mg (range of 1
.mu.g to 100 mg). In one embodiment, the total amount of polylysine
released from the septal occlusion patch should be in the range of
10 .mu.g to 50 mg. The dose per unit area of the implanted septal
occlusion patch (i.e., the dosage of polylysine as a function of
the surface area of the portion of the septal occlusion patch to
which drug is applied and/or incorporated) should fall within the
range of 0.05 .mu.g-10 .mu.g per mm.sup.2 of surface area coated.
In another embodiment, polylysine should be applied to a septal
occlusion patch surface at a dose of 0.05 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific septal occlusion
patches can release polylysine at differing rates, the above dosing
parameters should be utilized in combination with the release rate
of the drug from the septal occlusion patch such that a minimum
concentration of 0.01 nM to 1000 .mu.M of polylysine is delivered
to the tissue. In one embodiment, polylysine is released from the
surface of a septal occlusion patch such that fibrosis in the
tissue is promoted for a period ranging from several hours to
several months. For example, polylysine may be released in
effective concentrations for a period ranging from 1 week to 9
months. It should be readily evident given the discussions provided
herein that analogues and derivatives of polylysine (as described
previously) with similar functional activity can be utilized for
the purposes of this invention; the above dosing parameters are
then adjusted according to the relative potency of the analogue or
derivative as compared to the parent compound (e.g., a compound
twice as potent as polylysine is administered at half the above
parameters, a compound half as potent as polylysine is administered
at twice the above parameters, etc.).
[0926] Utilizing fibronectin as an exemplary fibrosis-inducing
agent, whether it is applied using a polymer coating, incorporated
into the polymers which make up the septal occlusion patch, or
applied without a polymeric carrier, the total dose of fibronectin
delivered from a septal occlusion patch, or coated onto the surface
of a septal occlusion patch, should not exceed 100 mg (range of 1
.mu.g to 100 mg). In one embodiment, the total amount of
fibronectin released from the septal occlusion patch should be in
the range of 10 .mu.g to 50 mg. The dose per unit area of the
implanted septal occlusion patch (i.e., the dosage of fibronectin
as a function of the surface area of the portion of the septal
occlusion patch to which drug is applied and/or incorporated)
should fall within the range of 0.05 .mu.g-10 .mu.g per mm.sup.2 of
surface area coated. In another embodiment, fibronectin should be
applied to a septal occlusion patch surface at a dose of 0.05
.mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. As
specific (polymeric and non-polymeric) drug delivery vehicles and
specific septal occlusion patches can release fibronectin at
differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the septal
occlusion patch such that a minimum concentration of 0.01 nM to
1000 .mu.M of fibronectin is delivered to the tissue. In one
embodiment, fibronectin is released from the surface of a septal
occlusion patch such that fibrosis in the tissue is promoted for a
period ranging from several hours to several months. For example,
fibronectin may be released in effective concentrations for a
period ranging from 1 week to 9 months. It should be readily
evident given the discussions provided herein that analogues and
derivatives of fibronectin (as described previously) with similar
functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according
to the relative potency of the analogue or derivative as compared
to the parent compound (e.g., a compound twice as potent as
fibronectin is administered at half the above parameters, a
compound half as potent as fibronectin is administered at twice the
above parameters, etc.).
[0927] Utilizing bleomycin as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the septal occlusion patch, or applied
without a polymeric carrier, the total dose of bleomycin delivered
from a septal occlusion patch, or coated onto the surface of a
septal occlusion patch, should not exceed 100 mg (range of 0.01
.mu.g to 100 mg). In one embodiment, the total amount of bleomycin
released from the septal occlusion patch should be in the range of
0.10 .mu.g to 50 mg. The dose per unit area of the implanted septal
occlusion patch (i.e., the dosage of bleomycin as a function of the
surface area of the portion of the patch to which drug is applied
and/or incorporated) should fall within the range of 0.005 .mu.g-10
.mu.g per mm.sup.2 of surface area coated. In another embodiment,
bleomycin should be applied to a septal occlusion patch surface at
a dose of 0.005 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area
coated. As specific (polymeric and non-polymeric) drug delivery
vehicles and specific septal occlusion patches can release
bleomycin at differing rates, the above dosing parameters should be
utilized in combination with the release rate of the drug from the
septal occlusion patch such that a minimum concentration of 0.001
nM to 1000 .mu.M of bleomycin is delivered to the tissue. In one
embodiment, bleomycin is released from the surface of a septal
occlusion patch such that fibrosis in the tissue is promoted for a
period ranging from several hours to several months. For example,
bleomycin may be released in effective concentrations for a period
ranging from 1 week to 9 months. It should be readily evident given
the discussions provided herein that analogues and derivatives of
bleomycin (as described previously) with similar functional
activity can be utilized for the purposes of this invention; the
above dosing parameters are then adjusted according to the relative
potency of the analogue or derivative as compared to the parent
compound (e.g., a compound twice as potent as bleomycin is
administered at half the above parameters, a compound half as
potent as bleomycin is administered at twice the above parameters,
etc.).
[0928] Utilizing CTGF as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the septal occlusion patch, or applied
without a polymeric carrier, the total dose of CTGF delivered from
a septal occlusion patch, or coated onto the surface of a septal
occlusion patch, should not exceed 100 mg (range of 0.01 .mu.g to
100 mg). In one embodiment, the total amount of CTGF released from
the septal occlusion patch should be in the range of 0.10 .mu.g to
50 mg. The dose per unit area of the implanted septal occlusion
patch (i.e., the dosage of CTGF as a function of the surface area
of the portion of the septal occlusion patch to which drug is
applied and/or incorporated) should fall within the range of 0.005
.mu.g-10 .mu.g per mm.sup.2 of surface area coated. In another
embodiment, CTGF should be applied to a septal occlusion patch
surface at a dose of 0.005 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of
surface area coated. As specific (polymeric and non-polymeric) drug
delivery vehicles and specific septal occlusion patches can release
CTGF at differing rates, the above dosing parameters should be
utilized in combination with the release rate of the drug from the
septal occlusion patch such that a minimum concentration of 0.001
nM to 1000 .mu.M of CTGF is delivered to the tissue. In one
embodiment, CTGF is released from the surface of a septal occlusion
patch such that fibrosis in the tissue is promoted for a period
ranging from several hours to several months. For example, CTGF may
be released in effective concentrations for a period ranging from 1
week to 9 months. It should be readily evident given the
discussions provided herein that analogues and derivatives of CTGF
(as described previously) with similar functional activity can be
utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound
(e.g., a compound twice as potent as CTGF is administered at half
the above parameters, a compound half as potent as CTGF is
administered at twice the above parameters, etc.).
[0929] Optionally, the device or composition may alone or
additionally comprise an inflammatory cytokine (e.g., TGF.beta.,
PDGF, VEGF, bFGF, TNF.alpha., NGF, GM-CSF, IGF-a, IL-1,
IL-1-.beta., IL-8, IL-6, and growth hormone) or an analogue or
derivative thereof. Inflammatory cytokines are to be used in
formulations at concentrations that range from 0.0001 .mu.g/ml to
approximately 20 mg/ml depending on the specific clinical
application, formulation type (e.g., gel, liquid, solid,
semi-solid), formulation chemistry, duration of required
application, type of medical device interface and formulation
volume and or surface area coverage required. Preferably, the
inflammatory cytokine is released in effective concentrations for a
period ranging from 1-180 days. The total dose for a single
application is typically not to exceed 500 mg (range of 0.0001
.mu.g to 100 mg); preferred 0.001 .mu.g to 50 mg. When used as a
device coating, the dose is per unit area of 0.0001 .mu.g-500 .mu.g
per mm.sup.2; with a preferred dose of 0.001 .mu.g/mm.sup.2-200
.mu.g/mm.sup.2. Minimum concentration of 10.sup.-10-10.sup.-4 g/ml
of inflammatory cytokine is to be maintained on the device
surface.
[0930] Furthermore, the device or composition may alone or
additionally comprise an agent that stimulates cellular
proliferation. Examples include: dexamethasone, isotretinoin
(13-cis retinoic acid), 17-.beta.-estradiol, estradiol, 1-a-25
dihydroxyvitamin D.sub.3, diethylstibesterol, cyclosporine A,
L-NAME, all-trans retinoic acid (ATRA), and analogues and
derivatives thereof. Doses used are those concentrations which are
demonstrated to stimulate cell proliferation (see, e.g., Example
16). The proliferative agents are to be used in formulations at
concentrations that range from 0.0000001 to 25 mg/ml depending on
the specific clinical application, formulation type (e.g., gel,
liquid, solid, semi-solid), formulation chemistry, duration of
required application, type of medical device interface and
formulation volume and or surface area coverage required.
Preferably, the proliferative agent is released in effective
concentrations for a period ranging from 1-180 days. The total dose
for a single application is typically not to exceed 500 mg (range
of 0.0001 .mu.g to 200 mg); preferred 0.001 .mu.g to 100 mg. When
used as a device coating, the dose is per unit area of 0.00001
.mu.g-500 .mu.g per mm.sup.2; with a preferred dose of 0.0001
.mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-11-10.sup.-6 M of proliferative agent is to be maintained
on the device surface.
[0931] It should be readily evident to one of skill in the art that
any of the previously described fibrosis inducing agents, or
derivatives and analogues thereof, can be utilized to create
variations of the above compositions without deviating from the
spirit and scope of the invention. It should also be apparent that
the agent can be utilized in a composition with or without polymer
carrier and that altering the carrier does not deviate from the
scope of this invention.
[0932] 17. Endoluminal Fasteners
[0933] The present invention provides for the combination of a
fibrosis-inducing agent and an endoluminal fastener. Endoluminal
fasteners may include, but are not limited to, staples (e.g.,
endostaples), sutures, wires, filaments, cords, pins, clips and
other connector devices and materials.
[0934] Endoluminal fasteners are devices that act like ribets to
increase the integrity of a damaged or perforated bodily tube or to
secure an endoluminal graft to the wall of a bodily tube (e.g.,
blood vessel). Endoluminal fasteners may also be used in a variety
of endoluminal surgeries, such as, but not limited to, transmural
polypectomies, resections of submucosal lesions, bowel resections,
resections of processes such as ulcers, controlling of bleeding,
closing perforations, prophylactic or therapeutical appendectomies,
resection of bleeding diverticuli or Meckel's diverticulum,
anchoring tubes or grafts (e.g., anastomosis of a vascular artery
to a graft), securing time-released medications, performing
gastroplasty, fallopian tubal ligation, solid organ biopsies, bowel
structuring or partial lung resectioning.
[0935] Endoluminal fasteners may be used by loading them into a
delivery catheter and then introducing them percutaneously into a
bodily lumen. The catheter is then guided through the bodily tube
to the site to be repaired. The fastener is delivered from the tip
of the delivery catheter so that it penetrates the desired site
whereby the endoluminal fastener becomes secured to the wall of the
bodily tube. The addition of a fibrosis-inducing agent to the
endoluminal fastener may encourage the development and ingrowth of
strong, fibrous tissue in and around the device. Incorporation of a
fibrosing agent into or onto an endoluminal fastener can promote
tissue growth that can help anchor the device to the wall of the
lumen. Once the endoluminal fastener has been positioned across the
wall, part of it remains in the lumen, exposed to the constituents
of the bodily tube. For example, if the bodily tube was a blood
vessel, the endoluminal fastener would be exposed to blood flow
which can cause a thrombotic event. Thus, in another aspect of the
invention, the endoluminal fastener may further comprise an
anti-thrombotic agent to prevent thrombus formation.
[0936] Endoluminal fasteners may be composed of biocompatible
metals, including, but not limited to, nitinol, tantalum, stainless
steel or metallic alloys such as nickel, gold, silver, titanium
nitride and chromium. Metallic fasteners have advantages when using
them in a minimally invasive manner as the metal enables
visualization during endoscopic delivery via catheter. However,
endoluminal fasteners may also be composed of biocompatible
polymers and other synthetic or natural materials either alone or
in combination with metallic materials. These may include
magnesium-based materials, plastics, ceramics, resin, protein-based
materials, collagen and other similar materials. Non-metallic
fasteners may be preferred in certain procedures, for example, if
there is a need for a bioabsorbable fastener or to reduce the
scattering of x-rays which occurs with metallic fasteners.
Endoluminal fasteners may be made out of rigid, pliable, elastic,
nonelastic, malleable, nonmalleable, retractable, or nonretractable
material such that the fastener exerts the desired amount of
pulling force required to attach to the luminal wall.
[0937] The endoluminal fasteners may be generally configured in a
"T", "H" or "U" shape. Metallic endoluminal fasteners are often
secured in place by crimping the fastener structure since they
possess strength and ductility. Endoluminal fasteners made of
polymers and/or other materials often do not possess the same
physical characteristics of the metallic fasteners. Therefore,
fasteners made of polymers, for example, are often made of
two-parts, including a general U-shape fastener portion which
engages and interlocks its legs with a retainer portion.
[0938] In one aspect, the endoluminal fastener may be of a variety
of configurations and materials. For example, the endoluminal
fastener may be a single-tipped device having a curved
configuration with a sharpened end. See e.g., U.S. Pat. No.
6,491,707. The endoluminal fastener may have a stressed elongated
shape and a second unstressed shape with a plurality of coils
around a spring axis upon release from the delivery element. See
e.g., U.S. Pat. No. 6,113,611. The endoluminal fastener may be a
suturing staple for passing through and securing tissue together
whereby the staple is positioned between lips of an endoluminal
apparatus that aids in positioning, resecting and securing
remaining tissue. See e.g., U.S. Pat. Nos. 6,264,086 and 5,868,760.
The endoluminal fastener may be adapted to incorporate a radiation
source such that it provides radiation to a wound repair site. See
e.g., U.S. Pat. No. 5,906,573. The endoluminal fastener may be
composed of a fastener and a retainer member made of resinous
material which is absorbable and exhibits improved hemostasis. See
e.g., U.S. Pat. No. 4,667,674. The endoluminal fastener may be
composed of a shape-memory surgical staple which may be formed as
an open shape or closed shape based on a transition temperature,
whereby the heating of the staple by an electric current elevates
the temperature of the staple which causes it to close and thus,
join abutting tissue. See e.g., U.S. Pat. No. 4,485,816. The
endoluminal fastener may be a helical fastener having a penetrating
end and a limiting end. See e.g., U.S. Pat. No. 6,592,593. The
endoluminal fastener may be a pinned retainer surgical fastener
that may be composed of a needle and a retainer that may be used to
attach a graft to a vascular artery. See e.g., U.S. Pat. No.
6,074,401. The endoluminal fastener may be of a general U-shape
having parallel prongs and a retainer portion with apertures to
retain the tips of respective prongs. See e.g., U.S. Pat. No.
5,292,334.
[0939] Commercially available endoluminal fasteners may also be
combined with one or more fibrosis-inducing drugs according to the
present invention. Examples of commercially available endoluminal
fasteners are often sold with an associated stapling device or
endoscopic instrumentation. For example, Johnson & Johnson
Gateway (Piscataway, N.J.) sells their PROXIMATE ILS and ENDOPATH
STEALTH Intraluminal Staplers which are used for anastomotic
repair. Angiolink Corporation (Taunton, Mass.) sells their EVS
Vascular Closure System. U.S. Surgical (Norwalk, Conn.) also sells
surgical stapling and endoscopic instrumentation.
[0940] In one aspect, the present invention provides an endoluminal
fastener that includes a fibrosis-inducing agent to promote
scarring between the endoluminal fastener and the blood vessel
wall. The endoluminal fastener may be coated with the fibrosing
agent (with or without a carrier). For example, a fibrosis-inducing
drug may be applied to the surface of the endoluminal fastener.
Alternatively, or in addition, the endoluminal fastener may be
composed either entirely or partially of a material that is capable
of inducing fibrosis. For example, silk strands or silk can be
affixed to the endoluminal fastener or the endoluminal fastener can
be composed partially or entirely of a fibrosing material (e.g., a
fibrosing polymer).
[0941] In another aspect, the present invention provides a
sprayable composition that includes a fibrosis-inducing agent that
can be used in fastening procedures to promote scarring and
attachment of an endoluminal fastener to a vessel wall.
[0942] Numerous polymeric and non-polymeric carrier systems
described above may be used in the practice of this embodiment.
These compositions can further comprise one or more
fibrosis-inducing agents to promote the formation of fibrous scar
tissue. Methods for incorporating fibrosing compositions onto or
into endoluminal fasteners include: (a) directly affixing to the
implant a fibrosing composition (e.g., by either a spraying process
or dipping process as described above, with or without a carrier);
(b) directly incorporating into the device a fibrosing composition
(e.g., by either a spraying process or dipping process as described
above, with or without a carrier); (c) by coating the device with a
substance such as a hydrogel which can in turn absorb the fibrosing
composition; (d) by interweaving fibrosing composition coated
thread (or the polymer itself formed into a thread) into the device
structure; (e) by binding a film or mesh which is comprised of, or
coated with, a fibrosing composition to the endoluminal fastener;
(f) constructing the device itself or a portion of the device with
a fibrosing composition; and/or (g) by covalently binding the
fibrosing agent directly to the endoluminal fastener surface or to
a linker (small molecule or polymer) that is coated or attached to
the endoluminal fastener surface.
[0943] In addition to coating the device with a fibrosis-inducing
composition, the fibrosing agent can be mixed with the materials
that are used to make the device such that the fibrosing agent is
incorporated into the final device.
[0944] In addition to (or as an alternative to) applying the
fibrosis agent to the endoluminal fastener, an in situ forming
composition, gel or thermogel composition containing a
fibrosis-inducing agent can be applied to (as a gel, solid implant,
liquid or spray) the placement site of the endoluminal fastener,
either: (a) prior to placement of the fastener; (b) after placement
of the fastener; (c) during the placement of the fastener; or (d)
any combination of these. For the in situ forming thermogel and gel
compositions, the fibrosis-inducing agent(s) (e.g., silk powder,
bleomycin) can be incorporated directly into the formulation to
produce a suspension or a solution or it can be incorporated into a
secondary carrier (e.g., micelles, liposomes, microspheres,
microparticles, nanospheres, microparticulates, emulsions and/or
microemulsions) that is then incorporated into the in situ forming
compositions. In another embodiment, the fibrosis-inducing agent
can be electrostatically or covalently bound to one or more of the
polymeric components of the in-situ forming composition.
[0945] In a particularly preferred embodiment, the composition may
be prepared from a 4-armed thiol PEG (10K), a 4-armed NHS PEG(10K)
and methylated collagen such as described above and contains a
fibrosis-inducing agent that is sprayed onto the surgical site to
affix the endoluminal fastener in place and induce fibrosis between
the fastener and the vessel wall.
[0946] In another embodiment, the fibrosis-inducing agent can be
incorporated into a biodegradable or dissolvable film or mesh that
is then applied to the treatment site prior to, or post,
implantation of the endoluminal fastener. Exemplary materials for
the manufacture of these films or meshes are hyaluronic acid
(crosslinked or non-crosslinked), cellulose derivatives (e.g.,
hydroxypropyl cellulose), collagen and crosslinked poly(ethylene
glycol).
[0947] It should be apparent to one of skill in the art that
potentially any adhesion or fibrosis-inducing agents described
above may be utilized alone, or in combination, in the practice of
this embodiment. Exemplary fibrosing agents for use with
endoluminal fasteners include talc, silk, wool, chitosan,
polylysine, fibronectin, bleomycin, and CTGF, as well as analogues
and derivatives of the aforementioned.
[0948] As endoluminal fasteners and compositions for use with
endoluminal fasteners are made in a variety of configurations and
sizes, the exact dose administered can vary with staple size,
surface area and design. However, certain principles can be applied
in the application of this art. Drug dose can be calculated as a
function of dose per unit area (of the portion of the patch being
coated), total drug dose administered can be measured and
appropriate surface concentrations of active drug can be
determined. Regardless of the method of application of the drug to
the endoluminal fastener, the exemplary fibrosing agents, used
alone or in combination, should be administered under the following
dosing guidelines:
[0949] Utilizing talc as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the endostaples, or applied without a
polymeric carrier, the total dose of talc delivered from an
endostaple, or coated onto the surface of an endostaple, should not
exceed 100 mg (range of 1 .mu.g to 100 mg). In one embodiment, the
total amount of talc released from the prosthesis should be in the
range of 10 .mu.g to 50 mg. The dose per unit area of the implanted
endostaple (i.e., the dosage of talc as a function of the surface
area of the portion of the endostaple to which drug is applied
and/or incorporated) should fall within the range of 0.05 .mu.g-10
.mu.g per mm.sup.2 of surface area coated. In another embodiment,
talc should be applied to an endostaple surface at a dose of 0.05
.mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. In one
embodiment, talc is released from the surface of an endostaple such
that fibrosis in the tissue is promoted for a period ranging from
several hours to several months. For example, talc may be released
in effective concentrations for a period ranging from 1 week to 9
months. It should be readily evident given the discussions provided
herein that analogues and derivatives of talc (as described
previously) with similar functional activity can be utilized for
the purposes of this invention; the above dosing parameters are
then adjusted according to the relative potency of the analogue or
derivative as compared to the parent compound (e.g., a compound
twice as potent as talc is administered at half the above
parameters, a compound half as potent as talc is administered at
twice the above parameters, etc.).
[0950] Utilizing silk as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the endostaple, or applied without a
polymeric carrier, the total dose of silk delivered from an
endostaple, or coated onto the surface of an endostaple, should not
exceed 100 mg (range of 1 .mu.g to 100 mg). In one embodiment, the
total amount of silk released from the endostaple should be in the
range of 10 .mu.g to 50 mg. The dose per unit area of the implanted
endostaple (i.e., the dosage of silk as a function of the surface
area of the portion of the endostaple to which drug is applied
and/or incorporated) should fall within the range of 0.05 .mu.g-10
.mu.g per mm.sup.2 of surface area coated. In another embodiment,
silk should be applied to an endostaple surface at a dose of 0.05
.mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area coated. As
specific (polymeric and non-polymeric) drug delivery vehicles and
specific endostaple can release silk at differing rates, the above
dosing parameters should be utilized in combination with the
release rate of the drug from the endostaple such that a minimum
concentration of 0.01 nM to 1000 .mu.M of silk is delivered to the
tissue. In one embodiment, silk is released from the surface of an
endostaple such that fibrosis in the tissue is promoted for a
period ranging from several hours to several months. For example,
silk may be released in effective concentrations for a period
ranging from 1 week-9 months. It should be readily evident given
the discussions provided herein that analogues and derivatives of
silk (as described previously) with similar functional activity can
be utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound
(e.g., a compound twice as potent as silk is administered at half
the above parameters, a compound half as potent as silk is
administered at twice the above parameters, etc.).
[0951] Utilizing chitosan as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the endostaple, or applied without a
polymeric carrier, the total dose of chitosan delivered from an
endostaple, or coated onto the surface of an endostaple, should not
exceed 100 mg (range of 1 .mu.g to 100 mg). In one embodiment, the
total amount of chitosan released from the endostaple should be in
the range of 10 .mu.g to 50 mg. The dose per unit area of the
implanted endostaple (i.e., the dosage of chitosan as a function of
the surface area of the portion of the endostaple to which drug is
applied and/or incorporated) should fall within the range of 0.05
.mu.g-10 .mu.g per mm.sup.2 of surface area coated. In another
embodiment, chitosan should be applied to an endostaple surface at
a dose of 0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area
coated. As specific (polymeric and non-polymeric) drug delivery
vehicles and specific endostaples can release chitosan at differing
rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the endostaple
such that a minimum concentration of 0.01 nM to 1000 .mu.M of
chitosan is delivered to the tissue. In one embodiment, chitosan is
released from the surface of an endostaple such that fibrosis in
the tissue is promoted for a period ranging from several hours to
several months. For example, chitosan may be released in effective
concentrations for a period ranging from 1 week to 9 months. It
should be readily evident given the discussions provided herein
that analogues and derivatives of chitosan (as described
previously) with similar functional activity can be utilized for
the purposes of this invention; the above dosing parameters are
then adjusted according to the relative potency of the analogue or
derivative as compared to the parent compound (e.g., a compound
twice as potent as chitosan is administered at half the above
parameters, a compound half as potent as chitosan is administered
at twice the above parameters, etc.).
[0952] Utilizing polylysine as an exemplary fibrosis-inducing
agent, whether it is applied using a polymer coating, incorporated
into the polymers which make up the endostaple, or applied without
a polymeric carrier, the total dose of polylysine delivered from an
endostaple, or coated onto the surface of an endostaple, should not
exceed 100 mg (range of 1 .mu.g to 100 mg). In one embodiment, the
total amount of polylysine released from the endostaple should be
in the range of 10 .mu.g to 50 mg. The dose per unit area of the
implanted endostaple (i.e., the dosage of polylysine as a function
of the surface area of the portion of the endostaple to which drug
is applied and/or incorporated) should fall within the range of
0.05 .mu.g-10 .mu.g per mm.sup.2 of surface area coated. In another
embodiment, polylysine should be applied to an endostaple surface
at a dose of 0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area
coated. As specific (polymeric and non-polymeric) drug delivery
vehicles and specific endostaples can release polylysine at
differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the endostaple
such that a minimum concentration of 0.01 nM to 1000 .mu.M of
polylysine is delivered to the tissue. In one embodiment,
polylysine is released from the surface of an endostaple such that
fibrosis in the tissue is promoted for a period ranging from
several hours to several months. For example, polylysine may be
released in effective concentrations for a period ranging from 1
week to 9 months. It should be readily evident given the
discussions provided herein that analogues and derivatives of
polylysine (as described previously) with similar functional
activity can be utilized for the purposes of this invention; the
above dosing parameters are then adjusted according to the relative
potency of the analogue or derivative as compared to the parent
compound (e.g., a compound twice as potent as polylysine is
administered at half the above parameters, a compound half as
potent as polylysine is administered at twice the above parameters,
etc.).
[0953] Utilizing fibronectin as an exemplary fibrosis-inducing
agent, whether it is applied using a polymer coating, incorporated
into the polymers which make up the endostaple, or applied without
a polymeric carrier, the total dose of fibronectin delivered from
an endostaple, or coated onto the surface of an endostaple, should
not exceed 100 mg (range of 1 .mu.g to 100 mg). In one embodiment,
the total amount of fibronectin released from the endostaple should
be in the range of 10 .mu.g to 50 mg. The dose per unit area of the
implanted endostaple (i.e., the dosage of fibronectin as a function
of the surface area of the portion of the endostaple to which drug
is applied and/or incorporated) should fall within the range of
0.05 .mu.g-10 .mu.g per mm.sup.2 of surface area coated. In another
embodiment, fibronectin should be applied to an endostaple surface
at a dose of 0.05 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of surface area
coated. As specific (polymeric and non-polymeric) drug delivery
vehicles and specific endostaples can release fibronectin at
differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the endostaple
such that a minimum concentration of 0.01 nM to 1000 .mu.M of
fibronectin is delivered to the tissue. In one embodiment,
fibronectin is released from the surface of an endostaple such that
fibrosis in the tissue is promoted for a period ranging from
several hours to several months. For example, fibronectin may be
released in effective concentrations for a period ranging from 1
week to 9 months. It should be readily evident given the
discussions provided herein that analogues and derivatives of
fibronectin (as described previously) with similar functional
activity can be utilized for the purposes of this invention; the
above dosing parameters are then adjusted according to the relative
potency of the analogue or derivative as compared to the parent
compound (e.g., a compound twice as potent as fibronectin is
administered at half the above parameters, a compound half as
potent as fibronectin is administered at twice the above
parameters, etc.).
[0954] Utilizing bleomycin as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the endostaple, or applied without a
polymeric carrier, the total dose of bleomycin delivered from an
endostaple, or coated onto the surface of an endostaple, should not
exceed 100 25 mg (range of 0.01 .mu.g to 100 25 mg). In one
embodiment, the total amount of bleomycin released from the
endostaple should be in the range of 0.10 .mu.g to 50 25 mg. The
dose per unit area of the implanted endostaple (i.e., the dosage of
bleomycin as a function of the surface area of the portion of the
patch to which drug is applied and/or incorporated) should fall
within the range of 0.005 .mu.g-10 .mu.g per mm.sup.2 of surface
area coated. In another embodiment, bleomycin should be applied to
an endostaple surface at a dose of 0.005 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2 of surface area coated. As specific (polymeric and
non-polymeric) drug delivery vehicles and specific endostaples can
release bleomycin at differing rates, the above dosing parameters
should be utilized in combination with the release rate of the drug
from the endostaple such that a minimum concentration of 0.001 nM
to 1000 .mu.M of bleomycin is delivered to the tissue. In one
embodiment, bleomycin is released from the surface of an endostaple
such that fibrosis in the tissue is promoted for a period ranging
from several hours to several months. For example, bleomycin may be
released in effective concentrations for a period ranging from 1
week to 9 months. It should be readily evident given the
discussions provided herein that analogues and derivatives of
bleomycin (as described previously) with similar functional
activity can be utilized for the purposes of this invention; the
above dosing parameters are then adjusted according to the relative
potency of the analogue or derivative as compared to the parent
compound (e.g., a compound twice as potent as bleomycin is
administered at half the above parameters, a compound half as
potent as bleomycin is administered at twice the above parameters,
etc.).
[0955] Utilizing CTGF as an exemplary fibrosis-inducing agent,
whether it is applied using a polymer coating, incorporated into
the polymers which make up the endostaple, or applied without a
polymeric carrier, the total dose of CTGF delivered from an
endostaple, or coated onto the surface of an endostaple, should not
exceed 100 25 mg (range of 0.01 .mu.g to 100 mg). In one
embodiment, the total amount of CTGF released from the endostaple
should be in the range of 0.10 .mu.g to 50 25 mg. The dose per unit
area of the implanted endostaple (i.e., the dosage of CTGF as a
function of the surface area of the portion of the endostaple to
which drug is applied and/or incorporated) should fall within the
range of 0.005 .mu.g-10 .mu.g per mm.sup.2 of surface area coated.
In another embodiment, CTGF should be applied to an endostaple
surface at a dose of 0.005 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2 of
surface area coated. As specific (polymeric and non-polymeric) drug
delivery vehicles and specific endostaples can release CTGF at
differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the endostaple
such that a minimum concentration of 0.001 nM to 1000 .mu.M of CTGF
is delivered to the tissue. In one embodiment, CTGF is released
from the surface of an endostaple such that fibrosis in the tissue
is promoted for a period ranging from several hours to several
months. For example, CTGF may be released in effective
concentrations for a period ranging from 1 week to 9 months. It
should be readily evident given the discussions provided herein
that analogues and derivatives of CTGF (as described previously)
with similar functional activity can be utilized for the purposes
of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g., a compound twice as potent
as CTGF is administered at half the above parameters, a compound
half as potent as CTGF is administered at twice the above
parameters, etc.).
[0956] Optionally, the device or composition may alone or
additionally comprise an inflammatory cytokine (e.g., TGF.beta.,
PDGF, VEGF, bFGF, TNF.alpha., NGF, GM-CSF, IGF-a, IL-1,
IL-1-.beta., IL-8, IL-6, and growth hormone) or an analogue or
derivative thereof. Inflammatory cytokines are to be used in
formulations at concentrations that range from 0.0001 .mu.g/ml to
approximately 20 mg/ml depending on the specific clinical
application, formulation type (e.g., gel, liquid, solid,
semi-solid), formulation chemistry, duration of required
application, type of medical device interface and formulation
volume and or surface area coverage required. Preferably, the
inflammatory cytokine is released in effective concentrations for a
period ranging from 1-180 days. The total dose for a single
application is typically not to exceed 500 mg (range of 0.0001
.mu.g to 100 mg); preferred 0.001 .mu.g to 50 mg. When used as a
device coating, the dose is per unit area of 0.0001 .mu.g-500 .mu.g
per mm.sup.2; with a preferred dose of 0.001 .mu.g/mm.sup.2-200
.mu.g/mm.sup.2. Minimum concentration of 10.sup.-10-10.sup.-4 g/ml
of inflammatory cytokine is to be maintained on the device
surface.
[0957] Furthermore, the device or composition may alone or
additionally comprise an agent that stimulates cellular
proliferation. Examples include: dexamethasone, isotretinoin
(13-cis retinoic acid), 17-.beta.-estradiol, estradiol, 1-a-25
dihydroxyvitamin D.sub.3, diethylstibesterol, cyclosporine A,
L-NAME, all-trans retinoic acid (ATRA), and analogues and
derivatives thereof. Doses used are those concentrations which are
demonstrated to stimulate cell proliferation (see, e.g., Example
16). The proliferative agents are to be used in formulations at
concentrations that range from 0.0000001 to 25 mg/ml depending on
the specific clinical application, formulation type (e.g., gel,
liquid, solid, semi-solid), formulation chemistry, duration of
required application, type of medical device interface and
formulation volume and or surface area coverage required.
Preferably, the proliferative agent is released in effective
concentrations for a period ranging from 1-180 days. The total dose
for a single application is typically not to exceed 500 mg (range
of 0.0001 .mu.g to 200 mg); preferred 0.001 .mu.g to 100 mg. When
used as a device coating, the dose is per unit area of 0.00001
.mu.g-500 .mu.g per mm.sup.2; with a preferred dose of 0.0001
.mu.g/mm.sup.2-200 .mu.g/mm.sup.2. Minimum concentration of
10.sup.-11-10.sup.-6 M of proliferative agent is to be maintained
on the device surface.
[0958] It should be readily evident to one of skill in the art that
any of the previously described fibrosis inducing agents, or
derivatives and analogues thereof, can be utilized to create
variations of the above compositions without deviating from the
spirit and scope of the invention. It should also be apparent that
the agent can be utilized in a composition with or without polymer
carrier and that altering the carrier does not deviate from the
scope of this invention.
[0959] For all the previously described embodiments, suitable
fibrosis-inducing agents include tissue irritants such tissue as
silk, silica, bleomycin, neomycin, talcum powder, metallic
beryllium, and copper are particularly suitable for the practice of
this invention. Other agents which may be incorporated into or onto
the implant or device or released from the implant or device
include extracellular matrix components such as fibrous structural
proteins (e.g., fibrillar collagens, nonfibrillar collagen and
elastins), adhesive glycoproteins (e.g., laminin and fibronectin),
proteoglycans (e.g., heparin sulfate, chondroitin sulfate, dermatan
sulfate), hyaluronan (e.g., hyaluronic acid), secreted protein
acidic and rich in cysteine (SPARC), thrombospondins, tenacin,
inhibitors of matrix metalloproteinases (e.g., TIMPs and synthetic
TIMPs such as marimistat, batimistat, doxycycline, tetracycline,
minocycline, TROCADE, Ro-1130830, CGS 27023A, BMS-275291) and
polylysine. Growth factors and inflammatory cytokines involved in
angiogenesis, fibroblast migration, fibroblast proliferation, ECM
synthesis and tissue remodeling such as epidermal growth factor
(EGF) family, transforming growth factor-.alpha. (TGF-.alpha.),
transforming growth factor-.beta. (TGF-9-1, TGF-9-2, TGF-9-3),
platelet-derived growth factor (PDGF), fibroblast growth factor
(acidic--aFGF; and basic--bFGF), bone morphogenic proteins,
activins, vascular endothelial growth factor (VEGF, VEGF-B, VEGF-C,
placental growth factor--PIGF), angiopoietins, insulin-like growth
factors (IGF), hepatocyte growth factor (HGF), connective tissue
growth factor (CTGF), myeloid colony-stimulating factors (CSFs),
granulocyte-macrophage colony-stimulating factors (GM-CSF),
granulocyte colony-stimulating factor (G-CSF), macrophage
colony-stimulating factor (M-CSF), erythropoietin, interleukins
(particularly IL-1, IL-8, IL-6), tumor necrosis factor-.alpha.
(TNF9), nerve growth factor (NGF), interferon-.alpha.,
interferon-.beta., and growth hormone (GH) are also suitable for
release from specific implants and devices. Other agents which may
be coated onto or released by the implant or device include
adhesives such as cyanoacrylate or materials made from 4-armed
thiol PEG (10K), a 4-armed NHS PEG(10K) and methylated collagen
such as described above.
[0960] Within related aspects of the present invention, orthopaedic
implants (artificial joints, artificial ligaments and tendons,
screws, plates, and the like), dental implants, intravascular
implants (particularly arterial and venous occlusion, vascular
destructive implants), male and female contraceptive or
sterilization devices and implants, implantable tissue bulking
agents for incontinence (esophageal, urethral, anal), soft palate
implants, embolization agents, pulmonary sealants, surgical meshes
(e.g., hernia repair meshes, tissue scaffolds), and spinal implants
(e.g., artificial discs) are provided comprising an implant or
device, wherein the implant or device releases an agent which
induces fibrosis in vivo.
[0961] In one aspect, methods are provided for manufacturing a
medical device or implant that release a fibrosis agent. Within yet
other aspects of the present invention, methods are provided for
manufacturing a medical device or implant, comprising the step of
coating (e.g., spraying, dipping, wrapping, or administering drug
through) a medical device or implant. Additionally, the implant or
medical device can be constructed so that the device itself is
comprised of materials, which induce fibrosis in or around the
implant. A wide variety of medical devices and implants may be
utilized within the context of the present invention, depending on
the site and nature of treatment desired.
[0962] Within various embodiments of the invention, the implant or
device is further coated with a composition or compound, which
delays the onset of activity of the fibrosis-inducing agent for a
period of time after implantation. Representative examples of such
agents include heparin, PLGA/MePEG, PLA, and polyethylene glycol.
Within further embodiments the fibrosis-inducing implant or device
is activated before, during, or after deployment (e.g., an inactive
agent on the device is first activated to one that induces or
accelerates an in vivo fibrotic reaction).
[0963] Within various embodiments of the invention, a device or
implant is coated one one aspect, portion or surface with a
composition which promotes fibrosis, as well as being coated with a
composition or compound which prevents scarring on another aspect,
potion or surface of the device. Representative examples of agents
that inhibit fibrosis and scarring include paclitaxel, sirolimus,
everolimus, as well as analogues and derivatives thereof. Other
examples are described in co-pending application entitled, "Medical
Implants and Anti-Scarring Agents" (U.S. Ser. No. 60/523,908),
filed Nov. 20, 2003 and (U.S. Ser. No. 60/586,861), filed Jul. 9,
2004.
[0964] Also provided by the present invention are methods for
treating patients undergoing surgical, endoscopic or minimally
invasive therapies where a medical device or implant is placed as
part of the procedure. As utilized herein, it should be understood
that "induces fibrosis" refers to a statistically significant
increase in the amount of scar tissue around the device or an
improvement in the incorporation of the device/implant into the
surrounding tissue and not to a permanent prohibition of any
complications or failures of the device/implant.
[0965] The present invention also provides the following itemized
embodiments.
[0966] 1. A method comprising introducing into an intervertebral
disc space of a patient in need thereof, a therapeutically
effective amount of a fibrosing agent or a composition comprising a
fibrosing agent, where the fibrosing agent induces a fibrotic
response at the intervertebral disc space of the patient, thereby
providing the patient with a beneficial result.
[0967] 2. The method of item 1 wherein beneficial result is the
repair of a spinal disc.
[0968] 3. The method of item 1 wherein the beneficial result is
fibrous ankylosis.
[0969] 4. The method of item 1 wherein the beneficial result is
bony ankylosis.
[0970] 5. The method of item 1 wherein the fibrosing agent promotes
regeneration.
[0971] 6. The method of item 1 wherein the fibrosing agent promotes
angiogenesis.
[0972] 7. The method of item 1 wherein the fibrosing agent promotes
fibroblast migration.
[0973] 8. The method of item 1 wherein the fibrosing agent promotes
fibroblast proliferation.
[0974] 9. The method of item 1 wherein the fibrosing agent promotes
deposition of extracellular matrix (ECM).
[0975] 10. The method of item 1 wherein the fibrosing agent
promotes tissue remodeling.
[0976] 11. The method of item 1 wherein the fibrosing agent is an
arterial vessel wall irritant.
[0977] 12. The method of item 1 wherein the fibrosing agent is or
comprises silk.
[0978] 13. The method of item 1 wherein the fibrosing agent is or
comprises silkworm silk.
[0979] 14. The method of item 1 wherein the fibrosing agent is or
comprises spider silk.
[0980] 15. The method of item 1 wherein the fibrosing agent is or
comprises recombinant silk.
[0981] 16. The method of item 1 wherein the fibrosing agent is or
comprises raw silk.
[0982] 17. The method of item 1 wherein the fibrosing agent is or
comprises hydrolyzed silk.
[0983] 18. The method of item 1 wherein the fibrosing agent is or
comprises acid-treated silk.
[0984] 19. The method of item 1 wherein the fibrosing agent is or
comprises acylated silk.
[0985] 20. The method of item 1 wherein the fibrosing agent is in
the form of strands.
[0986] 21. The method of item 1 wherein the fibrosing agent is in
the form of tufts.
[0987] 22. The method of item 1 wherein the fibrosing agent is in
the form of microparticulates.
[0988] 23. The method of item 1 wherein the fibrosing agent is or
comprises mineral particles.
[0989] 24. The method of item 1 wherein the fibrosing agent is or
comprises talc.
[0990] 25. The method of item 1 wherein the fibrosing agent is or
comprises chitosan.
[0991] 26. The method of item 1 wherein the fibrosing agent is or
comprises polylysine.
[0992] 27. The method of item 1 wherein the fibrosing agent is or
comprises fibronectin.
[0993] 28. The method of item 1 wherein the fibrosing agent is or
comprises bleomycin.
[0994] 29. The method of item 1 wherein the fibrosing agent is or
comprises CTGF.
[0995] 30. The method of item 1 wherein the fibrosing agent is in
the form of a thread, or is in contact with a thread.
[0996] 31. The method of item 30 wherein the thread is
biodegradable.
[0997] 32. The method of item 31 wherein the biodegradable thread
comprises a material selected from the group consisting of
polyester, polyanhydride, poly(anhydride ester), poly(ester-amide),
poly(ester-urea), polyorthoester, polyphosphoester,
polyphosphazine, polycyanoacrylate, collagen, chitosan, hyaluronic
acid, chromic cat gut, alginate, starch, cellulose and cellulose
ester.
[0998] 33. The method of item 30 wherein the thread is
non-biodegradable.
[0999] 34. The method of item 33 wherein the non-biodegradable
thread comprises a material selected from the group consisting of
polyester, polyurethane, silicone, polyethylene, polypropylene,
polystyrene, polyacrylate, polymethacrylate, and silk.
[1000] 35. The method of item 30 wherein the thread is coated with
a polymer.
[1001] 36. The method of item 30 wherein the thread is coated with
a pharmaceutical agent that induces a fibrotic response in the
patient.
[1002] 37. The method of item 30 wherein the thread is coated with
a pharmaceutical agent that induces an osteogenic response in the
patient.
[1003] 38. The method of item 30 wherein the fibrosing agent is in
the form of a particulate.
[1004] 39. The method of item 38 wherein the particulate is a
biodegradable particulate.
[1005] 40. The method of item 39 wherein the biodegradable
particulate comprises a material selected from the group consisting
of polyester, polyanhydride, poly(anhydride ester),
poly(ester-amide), poly(ester-urea), polyorthoester,
polyphosphoester, polyphosphazine, polycyanoacrylate, collagen,
chitosan, hyaluronic acid, chromic cat gut, alginate, starch,
cellulose and cellulose ester.
[1006] 41. The method of item 38 wherein the particulate is
non-biodegradable.
[1007] 42. The method of item 41 wherein the non-biodegradable
particulate comprises a material selected from the group consisting
of polyester, polyurethane, silicone, polyethylene, polypropylene,
polystyrene, polyacrylate, polymethacrylate, and silk.
[1008] 43. The method of item 38 wherein the particulate is a
particulate form of a member selected from the group consisting of
silk, talc, starch, glass, silicate, silica, calcium phosphate,
calcium sulfate, calcium carbonate, hydroxyapatite, synthetic
mineral, polymethylmethacrylate, silver nitrate, ceramic and other
inorganic particles.
[1009] 44. The method of item 38 wherein the particulate is coated
with a polymer.
[1010] 45. The method of item 38 wherein the particulate is coated
with a pharmaceutical agent that induces a fibrotic response in the
patient.
[1011] 46. The method of item 38 wherein the particulate is coated
with a member selected from the group consisting of silk, talc,
starch, glass, silicate, silica, calcium phosphate, calcium
sulfate, calcium carbonate, hydroxyapatite, synthetic mineral,
polymethylmethacrylate, silver nitrate, ceramic and other inorganic
particles.
[1012] 47. The method of item 38 wherein the particulate is coated
with a pharmaceutical agent that induces an osteogenic response in
the patient.
[1013] 48. The method of item 1 wherein the composition further
comprises an agent that promotes bone growth.
[1014] 49. The method of item 48 wherein the fibrosing agent that
promotes bone growth is a bone morphogenic protein.
[1015] 50. The method of item 48 wherein the fibrosing agent that
promotes bone growth is an osteogenic growth factor.
[1016] 51. The method of item 50 wherein the osteogenic growth
factor is selected from transforming growth factor,
platelet-derived growth factor, and fibroblast growth factor.
[1017] 52. The method of item 1 wherein the composition further
comprises a pharmaceutical agent that induces sclerosis (a
sclerosant).
[1018] 53. The method of item 52 wherein the sclerosant is selected
from the group consisting of ethanol, dimethyl sulfoxide, sucrose,
sodium chloride, dextrose, glycerin, minocycline, tetracycline,
doxycycline, polidocanol, sodium tetradecyl sulfate, sodium
morrhuate, and sotradecol.
[1019] 54. The method of item 52 wherein the sclerosant is a
surfactant.
[1020] 55. The method of item 1 wherein the composition further
comprises an inflammatory cytokine.
[1021] 56. The method of item 55 wherein the inflammatory cytokine
is selected from the group consisting of TGF.beta., PDGF, VEGF,
bFGF, TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-1-.beta., IL-8,
IL-6, and growth hormone.
[1022] 57. The method of item 1 wherein the composition further
comprises an agent that stimulates cell proliferation.
[1023] 58. The method of item 57 wherein the fibrosing agent that
stimulates cell proliferation is selected from the group consisting
of dexamethasone, isotretinoin (13-cis retinoic acid),
17-.beta.-estradiol, estradiol, 1-a-25 dihydroxyvitamin D.sub.3,
diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid
(ATRA), and analogues and derivatives thereof.
[1024] 59. The method of item 1 wherein the composition further
comprises a bulking agent.
[1025] 60. The method of item 1 wherein the composition further
comprises a sealant.
[1026] 61. The method of item 1 wherein the composition further
comprises a polymeric carrier.
[1027] 62. The method of item 61 wherein the polymeric carrier
provides sustained release for an active component of the
composition.
[1028] 63. The method of item 61 wherein the polymeric carrier is a
non-biodegradable material.
[1029] 64. The method of item 63 wherein the non-biodegradable
material is crosslinked.
[1030] 65. The method of item 64 wherein the crosslinked
non-biodegradable material comprises a crosslinked form of
polyvinylalcohol, polyvinylpyrrolidone, polyacrylamide, methyl
methacrylate or methyl methacrylate-styrene copolymer.
[1031] 66. The method of item 63 wherein the non-biodegradable
material is a hydogel.
[1032] 67. The method of item 61 wherein the polymeric carrier is a
biodegradable material.
[1033] 68. The method of item 67 wherein the biodegradable material
is a crosslinked material prepared from, or incorporating units of,
polyethyleneglycol, gelatin, collagen, bone allografts, mesenchymal
stem cells, hyaluronic acid, hyaluronic acid derivatives,
polysaccharides, carbohydrates, proteins, autologous bone,
demineralized bone matrix, cellulose derivatives, chitosan,
chitosan derivatives, and polyester-polyalkylene oxide block
copolymers.
[1034] 69. The method of item 61 wherein the polymeric carrier is
prepared from a 4-armed thiol PEG, a 4-armed NHS PEG, and
methylated collagen.
[1035] 70. The method of item 1 wherein the composition further
comprises a resorbable ceramic.
[1036] 71. The method of item 70 wherein the resorbable ceramic
comprises, or is prepared from, a material selected from the group
consisting of .quadrature.-tricalcium phosphate, hydroxyapatite,
Ca.sub.10(PO.sub.4).sub.6OH, calcium carbonate, calcium sulfate and
calcium phosphate.
[1037] 72. The method of item 1 wherein the composition further
comprises a contrast agent.
[1038] 73. The method of item 72 wherein the contrast agent
responds to x-ray.
[1039] 74. The method of item 73 wherein the contrast agent is
barium, tantalum, technetium, or gadolinium.
[1040] 75. The method of item 1 wherein the composition further
comprises a thread.
[1041] 76. The method of item 75 wherein the thread is
biodegradable.
[1042] 77. The method of item 76 wherein the biodegradable thread
comprises a material selected from the group consisting of
polyester, polyanhydride, poly(anhydride ester), poly(ester-amide),
poly(ester-urea), polyorthoester, polyphosphoester,
polyphosphazine, polycyanoacrylate, collagen, chitosan, hyaluronic
acid, chromic cat gut, alginate, starch, cellulose and cellulose
ester.
[1043] 78. The method of item 75 wherein the thread is
non-biodegradable.
[1044] 79. The method of item 78 wherein the non-biodegradable
thread comprises a material selected from the group consisting of
polyester, polyurethane, silicone, polyethylene, polypropylene,
polystyrene, polyacrylate, polymethacrylate, and silk.
[1045] 80. The method of item 75 wherein the thread is coated with
a polymer.
[1046] 81. The method of item 75 wherein the thread is coated with
a pharmaceutical agent that induces a fibrotic response in the
patient.
[1047] 82. The method of item 75 were in wherein the thread is
coated with a pharmaceutical agent that induces a osteogenic
response in the patient.
[1048] 83. The method of item 1 wherein the composition is in the
form of a gel.
[1049] 84. The method of item 1 wherein the composition is in the
form of a paste.
[1050] 85. The method of item 1 wherein the composition is in the
form of a spray.
[1051] 86. The method of item 1 wherein the composition is in the
form of an aerosol.
[1052] 87. The method of item 1 wherein the composition is in the
form of a suspension.
[1053] 88. The method of item 1 wherein the composition is in the
form of an emulsion or microemulsion.
[1054] 89. The method of item 1 wherein the composition is in the
form of a microsphere.
[1055] 90. The method of item 1 wherein the composition is in the
form of a microparticulate.
[1056] 91. The method of item 1 wherein the composition is in the
form of a solid implant.
[1057] 92. An injectable composition comprising a fibrosing agent
and a bulking agent.
[1058] 93. The composition of item 92 wherein the fibrosing agent
promotes fibrosis and promotes regeneration.
[1059] 94. The composition of item 92 wherein the fibrosing agent
promotes angiogenesis.
[1060] 95. The composition of item 92 wherein the fibrosing agent
promotes fibroblast migration.
[1061] 96. The composition of item 92 wherein the fibrosing agent
promotes fibroblast proliferation.
[1062] 97. The composition of item 92 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[1063] 98. The composition of item 92 wherein the fibrosing agent
promotes tissue remodeling.
[1064] 99. The composition of item 92 wherein the fibrosing agent
is an arterial vessel wall irritant.
[1065] 100. The composition of item 92 wherein the fibrosing agent
is or comprises silk.
[1066] 101. The composition of item 92 wherein the fibrosing agent
is or comprises silkworm silk.
[1067] 102. The composition of item 92 wherein the fibrosing agent
is or comprises spider silk.
[1068] 103. The composition of item 92 wherein the fibrosing agent
is or comprises recombinant silk.
[1069] 104. The composition of item 92 wherein the fibrosing agent
is or comprises raw silk.
[1070] 105. The composition of item 92 wherein the fibrosing agent
is or comprises hydrolyzed silk.
[1071] 106. The composition of item 92 wherein the fibrosing agent
is or comprises acid-treated silk.
[1072] 107. The composition of item 92 wherein the fibrosing agent
is or comprises acylated silk.
[1073] 108. The composition of item 92 wherein the fibrosing agent
is in the form of strands.
[1074] 109. The composition of item 92 wherein the fibrosing agent
is in the form of tufts.
[1075] 110. The composition of item 92 wherein the fibrosing agent
is in the form of microparticulates.
[1076] 111. The composition of item 92 wherein the fibrosing agent
is or comprises mineral particles.
[1077] 112. The composition of item 92 wherein the fibrosing agent
is or comprises talc.
[1078] 113. The composition of item 92 wherein the fibrosing agent
is or comprises chitosan.
[1079] 114. The composition of item 92 wherein the fibrosing agent
is or comprises polylysine.
[1080] 115. The composition of item 92 wherein the fibrosing agent
is or comprises fibronectin.
[1081] 116. The composition of item 92 wherein the fibrosing agent
is or comprises bleomycin.
[1082] 117. The composition of item 92 wherein the fibrosing agent
is or comprises CTGF.
[1083] 118. The composition of item 92 wherein the fibrosing agent
is in the form of a thread, or is in contact with a thread.
[1084] 119. The composition of item 118 wherein the thread is
biodegradable.
[1085] 120. The composition of item 119 wherein the biodegradable
thread comprises a material selected from the group consisting of
polyester, polyanhydride, poly(anhydride ester), poly(ester-amide),
poly(ester-urea), polyorthoester, polyphosphoester,
polyphosphazine, polycyanoacrylate, collagen, chitosan, hyaluronic
acid, chromic cat gut, alginate, starch, cellulose and cellulose
ester.
[1086] 121. The composition of item 118 wherein the thread is
non-biodegradable.
[1087] 122. The composition of item 121 wherein the
non-bioderadable thread comprises a material selected from the
group consisting of polyester, polyurethane, silicone,
polyethylene, polypropylene, polystyrene, polyacrylate,
polymethacrylate, and silk.
[1088] 123. The composition of item 118 wherein the thread is
coated with a polymer.
[1089] 124. The composition of item 118 wherein the thread is
coated with a pharmaceutical agent that induces a fibrotic response
in the patient.
[1090] 125. The composition of item 118 wherein the thread is
coated with a pharmaceutical agent that induces an osteogenic
response in the patient.
[1091] 126. The composition of item 92 wherein the fibrosing agent
is in the form of a particulate.
[1092] 127. The composition of item 126 wherein the particulate is
a biodegradable particulate.
[1093] 128. The composition of item 127 wherein the biodegradable
particulate comprises a material selected from the group consisting
of polyester, polyanhydride, poly(anhydride ester),
poly(ester-amide), poly(ester-urea), polyorthoester,
polyphosphoester, polyphosphazine, polycyanoacrylate, collagen,
chitosan, hyaluronic acid, chromic cat gut, alginate, starch,
cellulose and cellulose ester.
[1094] 129. The composition of item 126 wherein the particulate is
non-biodegradable.
[1095] 130. The composition of item 129 wherein the
non-biodegradable particulate comprises a material selected from
the group consisting of polyester, polyurethane, silicone,
polyethylene, polypropylene, polystyrene, polyacrylate,
polymethacrylate, and silk.
[1096] 131. The composition of item 126 wherein the particulate is
a particulate form of a member selected from the group consisting
of silk, talc, starch, glass, silicate, silica, calcium phosphate,
calcium sulfate, calcium carbonate, hydroxyapatite, synthetic
mineral, polymethylmethacrylate, silver nitrate, ceramic and other
inorganic particles.
[1097] 132. The composition of item 126 wherein the particulate is
coated with a polymer.
[1098] 133. The composition of item 126 wherein the particulate is
coated with a pharmaceutical agent that induces a fibrotic response
in the patient.
[1099] 134. The composition of item 126 wherein the particulate is
coated with a member selected from the group consisting of silk,
talc, starch, glass, silicate, silica, calcium phosphate, calcium
sulfate, calcium carbonate, hydroxyapatite, synthetic mineral,
polymethylmethacrylate, silver nitrate, ceramic and other inorganic
particles.
[1100] 135. The composition of item 126 wherein the particulate is
coated with a pharmaceutical agent that induces an osteogenic
response in the patient.
[1101] 136. The composition of item 92 wherein the composition
further comprises an agent that promotes bone growth.
[1102] 137. The composition of item 136 wherein the fibrosing agent
that promotes bone growth is a bone morphogenic protein.
[1103] 138. The composition of item 136 wherein the fibrosing agent
that promotes bone growth is an osteogenic growth factor.
[1104] 139. The composition of item 138 wherein the osteogenic
growth factor is selected from transforming growth factor,
platelet-derived growth factor, and fibroblast growth factor.
[1105] 140. A method comprising introducing into a patient in need
thereof, a therapeutically effective amount of a fibrosing agent or
a composition comprising a fibrosing agent, where the fibrosing
agent induces a fibrotic response at a specific site within the
patient, thereby providing the patient with treatment of a shoulder
capsule injury.
[1106] 141. The method of item 140 wherein the agent promotes
regeneration.
[1107] 142. The method of item 140 wherein the agent promotes
angiogenesis.
[1108] 143. The method of item 140 wherein the agent promotes
fibroblast migration.
[1109] 144. The method of item 140 wherein the agent promotes
fibroblast proliferation.
[1110] 145. The method of item 140 wherein the agent promotes
deposition of extracellular matrix (ECM).
[1111] 146. The method of item 140 wherein the agent promotes
tissue remodeling.
[1112] 147. The method of item 140 wherein the agent is an arterial
vessel wall irritant.
[1113] 148. The method of item 140 wherein the fibrosing agent is
or comprises silk.
[1114] 149. The method of item 140 wherein the fibrosing agent is
in the form of tufts.
[1115] 150. The method of item 140 wherein the fibrosing agent is
or comprises mineral particles.
[1116] 151. The method of item 140 wherein the fibrosing agent is
or comprises chitosan.
[1117] 152. The method of item 140 wherein the fibrosing agent is
or comprises polylysine.
[1118] 153. The method of item 140 wherein the fibrosing agent is
or comprises fibronectin.
[1119] 154. The method of item 140 wherein the fibrosing agent is
or comprises bleomycin.
[1120] 155. The method of item 140 wherein the fibrosing agent is
or comprises CTGF.
[1121] 156. The method of item 140 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[1122] 157. The method of item 140 wherein the fibrosing agent is
in the form of a particulate.
[1123] 158. The method of item 140, wherein the composition
comprises a polymer.
[1124] 159. The method of item 140, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
copolymer.
[1125] 160. The method of item 140, wherein the composition
comprises a polymer, and the polymer is, or comprises, a block
copolymer.
[1126] 161. The method of item 140, wherein the composition
comprises a polymer, and the polymer is, or comprises, a random
copolymer.
[1127] 162. The method of item 140, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
biodegradable polymer.
[1128] 163. The method of item 140, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
non-biodegradable polymer.
[1129] 164. The method of item 140, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrophilic polymer.
[1130] 165. The method of item 140, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrophobic polymer.
[1131] 166. The method of item 140, wherein the composition
comprises a polymer, and the polymer is, or comprises, a polymer
having hydrophilic domains.
[1132] 167. The method of item 140, wherein the composition
comprises a polymer, and the polymer is, or comprises, a polymer
having hydrophobic domains.
[1133] 168. The method of item 140, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
non-conductive polymer.
[1134] 169. The method of item 140, wherein the composition
comprises a polymer, and the polymer is, or comprises, an
elastomer.
[1135] 170. The method of item 140, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrogel.
[1136] 171. The method of item 140, wherein the composition
comprises a polymer, and the polymer is, or comprises, a silicone
polymer.
[1137] 172. The method of item 140, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrocarbon polymer.
[1138] 173. The method of item 140, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
styrene-derived polymer.
[1139] 174. The method of item 140, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
butadiene-derived polymer.
[1140] 175. The method of item 140, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
macromer.
[1141] 176. The method of item 140, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
poly(ethylene glycol) polymer.
[1142] 177. The method of item 140, wherein the composition
comprises a polymer, and the polymer is, or comprises, an amorphous
polymer.
[1143] 178. The method of item 140, wherein the composition further
comprises a second pharmaceutically active agent.
[1144] 179. The method of item 140, wherein the composition further
comprises an anti-inflammatory agent.
[1145] 180. The method of item 140, wherein the composition further
comprises an agent that inhibits infection.
[1146] 181. The method of item 140, wherein the composition further
comprises an anthracycline.
[1147] 182. The method of item 140, wherein the composition further
comprises doxorubicin.
[1148] 183. The method of item 140 wherein the composition further
comprises mitoxantrone.
[1149] 184. The method of item 140 wherein the composition further
comprises a fluoropyrimidine.
[1150] 185. The method of item 140, wherein the composition further
comprises 5-fluorouracil (5-FU).
[1151] 186. The method of item 140, wherein the composition further
comprises a folic acid antagonist.
[1152] 187. The method of item 140, wherein the composition further
comprises methotrexate.
[1153] 188. The method of item 140, wherein the composition further
comprises a podophylotoxin.
[1154] 189. The method of item 140, wherein the composition further
comprises etoposide.
[1155] 190. The method of item 140, wherein the composition further
comprises camptothecin.
[1156] 191. The method of item 140, wherein the composition further
comprises a hydroxyurea.
[1157] 192. The method of item 140, wherein the composition further
comprises a platinum complex.
[1158] 193. The method of item 140, wherein the composition further
comprises cisplatin.
[1159] 194. The method of item 140 wherein the composition further
comprises an anti-thrombotic agent.
[1160] 195. The method of item 140, wherein the composition further
comprises a visualization agent.
[1161] 196. The method of item 140, wherein the composition further
comprises a visualization agent, and the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[1162] 197. The method of item 140, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, barium, tantalum, or technetium.
[1163] 198. The method of item 140, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, an MRI responsive material.
[1164] 199. The method of item 140, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, a gadolinium chelate.
[1165] 200. The method of item 140, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, iron, magnesium, manganese, copper, or chromium.
[1166] 201. The method of item 140, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, iron oxide compound.
[1167] 202. The method of item 140, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, a dye, pigment, or colorant.
[1168] 203. The method of item 140 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of administration to about 90 days.
[1169] 204. The method of item 140 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of administration to about 90
days.
[1170] 205. The method of item 140 wherein the composition further
comprises an inflammatory cytokine.
[1171] 206. The method of item 140 wherein the composition further
comprises an agent that stimulates cell proliferation.
[1172] 207. The method of item 140 wherein the composition further
comprises a polymeric carrier.
[1173] 208. The method of item 140 wherein the composition is in
the form of a gel, paste, or spray.
[1174] 209. The method of item 140 wherein the agent is delivered
from a device, and the device delivers the fibrosing agent locally
to tissue proximate to the device.
[1175] 210. The method of item 140 wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating comprises the fibrosing agent.
[1176] 211. The method of item 140 wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is disposed on a surface of the device.
[1177] 212. The method of item 140, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating directly contacts the device.
[1178] 213. The method of item 140, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating indirectly contacts the device.
[1179] 214. The method of item 140 wherein the agent is delivered
from a device, wherein the device further comprises a coating,
wherein the coating partially covers the device.
[1180] 215. The method of item 140, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating completely covers the device.
[1181] 216. The method of item 140 wherein the agent is delivered
from a device, wherein the fibrosing agent is located within pores
or holes of the device.
[1182] 217. The method of item 140 wherein the agent is delivered
from a device, wherein the fibrosing agent is located within a
channel, lumen, or divet of the device.
[1183] 218. The method of item 140 wherein the agent is delivered
from a device, wherein the device further comprising an echogenic
material.
[1184] 219. The method of item 140 wherein the agent is delivered
from a device, wherein the device further comprises an echogenic
material, wherein the echogenic material is in the form of a
coating.
[1185] 220. The method of item 140 wherein the agent is delivered
from a device, wherein the device is sterile.
[1186] 221. The method of item 140 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device.
[1187] 222. The method of item 140 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is connective tissue.
[1188] 223. The method of item 140 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is muscle tissue.
[1189] 224. The method of item 140 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is nerve tissue.
[1190] 225. The method of item 140 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is epithelium tissue.
[1191] 226. The method of item 140 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from the time
of deployment of the device to about 1 year.
[1192] 227. The method of item 140 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from about 1
month to 6 months.
[1193] 228. The method of item 140 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from about
1-90 days.
[1194] 229. The method of item 140 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device at a constant rate.
[1195] 230. The method of item 140 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[1196] 231. The method of item 140 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device at a decreasing rate.
[1197] 232. The method of item 140 wherein the agent is delivered
from a device, wherein the device comprises about 0.01 .mu.g to
about 10 .mu.g of the fibrosing agent.
[1198] 233. The method of item 140 wherein the agent is delivered
from a device, wherein the device comprises about 10 .mu.g to about
10 mg of the fibrosing agent.
[1199] 234. The method of item 140 wherein the agent is delivered
from a device, wherein the device comprises about 10 mg to about
250 mg of the fibrosing agent.
[1200] 235. The method of item 140 wherein the agent is delivered
from a device, wherein the device comprises about 250 mg to about
1000 mg of the fibrosing agent.
[1201] 236. The method of item 140 wherein the agent is delivered
from a device, wherein the device comprises about 1000 mg to about
2500 mg of the fibrosing agent.
[1202] 237. The method of item 140 wherein the agent is delivered
from a device, wherein a surface of the device comprises less than
0.01 .mu.g of the fibrosing agent per mm.sup.2 of device surface to
which the fibrosing agent is applied.
[1203] 238. The method of item 140 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 0.01
.mu.g to about 1 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[1204] 239. The method of item 140 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 1
.mu.g to about 10 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[1205] 240. The method of item 140 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 10
.mu.g to about 250 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[1206] 241. The method of item 140 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 250
.mu.g to about 1000 .mu.g of the fibrosing agent of fibrosing agent
per mm.sup.2 of device surface to which the fibrosing agent is
applied.
[1207] 242. The method of item 140 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 1000
.mu.g to about 2500 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[1208] 243. The method of item 140, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is a uniform coating.
[1209] 244. The method of item 140, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is a non-uniform coating.
[1210] 245. The method of item 140, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is a discontinuous coating.
[1211] 246. The method of item 140, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is a patterned coating.
[1212] 247. The method of item 140, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating has a thickness of 100 .mu.m or less.
[1213] 248. The method of item 140, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating has a thickness of 10 .mu.m or less.
[1214] 249. The method of item 140, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating adheres to the surface of the device upon deployment of
the device.
[1215] 250. The method of item 140, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is stable at room temperature for a period of at least
1 year.
[1216] 251. The method of item 140, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the fibrosing agent is present in the coating in an amount ranging
between about 0.0001% to about 1% by weight.
[1217] 252. The method of item 140, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the fibrosing agent is present in the coating in an amount ranging
between about 1% to about 10% by weight.
[1218] 253. The method of item 140, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the fibrosing agent is present in the coating in an amount ranging
between about 10% to about 25% by weight.
[1219] 254. The method of item 140, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the fibrosing agent is present in the coating in an amount ranging
between about 25% to about 70% by weight.
[1220] 255. The method of item 140, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating comprises a polymer.
[1221] 256. The method of item 140, wherein the agent is delivered
from a device, wherein the device comprises a first coating having
a first composition and a second coating having a second
composition.
[1222] 257. The method of item 140, wherein the agent is delivered
from a device, wherein the device comprises a first coating having
a first composition and a second coating having a second
composition, wherein the first composition and the second
composition are different.
[1223] 258. A method comprising introducing into a patient in need
thereof, a therapeutically effective amount of a fibrosing agent or
a composition comprising a fibrosing agent, where the fibrosing
agent induces a fibrotic response at a specific site within the
patient, thereby providing the patient with ligament repair.
[1224] 259. The method of item 258 wherein the agent promotes
regeneration.
[1225] 260. The method of item 258 wherein the agent promotes
angiogenesis.
[1226] 261. The method of item 258 wherein the agent promotes
fibroblast migration.
[1227] 262. The method of item 258 wherein the agent promotes
fibroblast proliferation.
[1228] 263. The method of item 258 wherein the agent promotes
deposition of extracellular matrix (ECM).
[1229] 264. The method of item 258 wherein the agent promotes
tissue remodeling.
[1230] 265. The method of item 258 wherein the agent is an arterial
vessel wall irritant.
[1231] 266. The method of item 258 wherein the fibrosing agent is
or comprises silk.
[1232] 267. The method of item 258 wherein the fibrosing agent is
in the form of tufts.
[1233] 268. The method of item 258 wherein the fibrosing agent is
or comprises mineral particles.
[1234] 269. The method of item 258 wherein the fibrosing agent is
or comprises chitosan.
[1235] 270. The method of item 258 wherein the fibrosing agent is
or comprises polylysine.
[1236] 271. The method of item 258 wherein the fibrosing agent is
or comprises fibronectin.
[1237] 272. The method of item 258 wherein the fibrosing agent is
or comprises bleomycin.
[1238] 273. The method of item 258 wherein the fibrosing agent is
or comprises CTGF.
[1239] 274. The method of item 258 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[1240] 275. The method of item 258 wherein the fibrosing agent is
in the form of a particulate.
[1241] 276. The method of item 258, wherein the composition
comprises a polymer.
[1242] 277. The method of item 258, wherein the composition
comprises a polymer, and the polymer is or comprises, a
copolymer.
[1243] 278. The method of item 258, wherein the composition
comprises a polymer, and the polymer is, or comprises, a block
copolymer.
[1244] 279. The method of item 258, wherein the composition
comprises a polymer, and the polymer is, or comprises, a random
copolymer.
[1245] 280. The method of item 258, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
biodegradable polymer.
[1246] 281. The method of item 258, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
non-biodegradable polymer.
[1247] 282. The method of item 258, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrophilic polymer.
[1248] 283. The method of item 258, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrophobic polymer.
[1249] 284. The method of item 258, wherein the composition
comprises a polymer, and the polymer is, or comprises, a polymer
having hydrophilic domains.
[1250] 285. The method of item 258, wherein the composition
comprises a polymer, and the polymer is, or comprises, a polymer
having hydrophobic domains.
[1251] 286. The method of item 258, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
non-conductive polymer.
[1252] 287. The method of item 258, wherein the composition
comprises a polymer, and the polymer is, or comprises, an
elastomer.
[1253] 288. The method of item 258, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrogel.
[1254] 289. The method of item 258, wherein the composition
comprises a polymer, and the polymer is, or comprises, a silicone
polymer.
[1255] 290. The method of item 258, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrocarbon polymer.
[1256] 291. The method of item 258, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
styrene-derived polymer.
[1257] 292. The method of item 258, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
butadiene-derived polymer.
[1258] 293. The method of item 258, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
macromer.
[1259] 294. The method of item 258, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
poly(ethylene glycol) polymer.
[1260] 295. The method of item 258, wherein the composition
comprises a polymer, and the polymer is, or comprises, an amorphous
polymer.
[1261] 296. The method of item 258, wherein the composition further
comprises a second pharmaceutically active agent.
[1262] 297. The method of item 258, wherein the composition further
comprises an anti-inflammatory agent.
[1263] 298. The method of item 258, wherein the composition further
comprises an agent that inhibits infection.
[1264] 299. The method of item 258, wherein the composition further
comprises an anthracycline.
[1265] 300. The method of item 258, wherein the composition further
comprises doxorubicin.
[1266] 301. The method of item 258 wherein the composition further
comprises mitoxantrone.
[1267] 302. The method of item 258 wherein the composition further
comprises a fluoropyrimidine.
[1268] 303. The method of item 258, wherein the composition further
comprises 5-fluorouracil (5-FU).
[1269] 304. The method of item 258, wherein the composition further
comprises a folic acid antagonist.
[1270] 305. The method of item 258, wherein the composition further
comprises methotrexate.
[1271] 306. The method of item 258, wherein the composition further
comprises a podophylotoxin.
[1272] 307. The method of item 258, wherein the composition further
comprises etoposide.
[1273] 308. The method of item 258, wherein the composition further
comprises camptothecin.
[1274] 309. The method of item 258, wherein the composition further
comprises a hydroxyurea.
[1275] 310. The method of item 258, wherein the composition further
comprises a platinum complex.
[1276] 311. The method of item 258, wherein the composition further
comprises cisplatin.
[1277] 312. The method of item 258 wherein the composition further
comprises an anti-thrombotic agent.
[1278] 313. The method of item 258, wherein the composition further
comprises a visualization agent.
[1279] 314. The method of item 258, wherein the composition further
comprises a visualization agent, and the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[1280] 315. The method of item 258, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, barium, tantalum, or technetium.
[1281] 316. The method of item 258, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, an MRI responsive material.
[1282] 317. The method of item 258, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, a gadolinium chelate.
[1283] 318. The method of item 258, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, iron, magnesium, manganese, copper, or chromium.
[1284] 319. The method of item 258, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, iron oxide compound.
[1285] 320. The method of item 258, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, a dye, pigment, or colorant.
[1286] 321. The method of item 258 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of administration to about 90 days.
[1287] 322. The method of item 258 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of administration to about 90
days.
[1288] 323. The method of item 258 wherein the composition further
comprises an inflammatory cytokine.
[1289] 324. The method of item 258 wherein the composition further
comprises an agent that stimulates cell proliferation.
[1290] 325. The method of item 258 wherein the composition further
comprises a polymeric carrier.
[1291] 326. The method of item 258 wherein the composition is in
the form of a gel, paste, or spray.
[1292] 327. The method of item 258 wherein the agent is delivered
from a device, and the device delivers the fibrosing agent locally
to tissue proximate to the device.
[1293] 328. The method of item 258 wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating comprises the fibrosing agent.
[1294] 329. The method of item 258 wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is disposed on a surface of the device.
[1295] 330. The method of item 258, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating directly contacts the device.
[1296] 331. The method of item 258, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating indirectly contacts the device.
[1297] 332. The method of item 258 wherein the agent is delivered
from a device, wherein the device further comprises a coating,
wherein the coating partially covers the device.
[1298] 333. The method of item 258, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating completely covers the device.
[1299] 334. The method of item 258 wherein the agent is delivered
from a device, wherein the fibrosing agent is located within pores
or holes of the device.
[1300] 335. The method of item 258 wherein the agent is delivered
from a device, wherein the fibrosing agent is located within a
channel, lumen, or divet of the device.
[1301] 336. The method of item 258 wherein the agent is delivered
from a device, wherein the device further comprising an echogenic
material.
[1302] 337. The method of item 258 wherein the agent is delivered
from a device, wherein the device further comprises an echogenic
material, wherein the echogenic material is in the form of a
coating.
[1303] 338. The method of item 258 wherein the agent is delivered
from a device, wherein the device is sterile.
[1304] 339. The method of item 258 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device.
[1305] 340. The method of item 258 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is connective tissue.
[1306] 341. The method of item 258 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is muscle tissue.
[1307] 342. The method of item 258 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is nerve tissue.
[1308] 343. The method of item 258 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is epithelium tissue.
[1309] 344. The method of item 258 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from the time
of deployment of the device to about 1 year.
[1310] 345. The method of item 258 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from about 1
month to 6 months.
[1311] 346. The method of item 258 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from about
1-90 days.
[1312] 347. The method of item 258 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device at a constant rate.
[1313] 348. The method of item 258 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[1314] 349. The method of item 258 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device at a decreasing rate.
[1315] 350. The method of item 258 wherein the agent is delivered
from a device, wherein the device comprises about 0.01 .mu.g to
about 10 .mu.g of the fibrosing agent.
[1316] 351. The method of item 258 wherein the agent is delivered
from a device, wherein the device comprises about 10 .mu.g to about
10 mg of the fibrosing agent.
[1317] 352. The method of item 258 wherein the agent is delivered
from a device, wherein the device comprises about 10 mg to about
250 mg of the fibrosing agent.
[1318] 353. The method of item 258 wherein the agent is delivered
from a device, wherein the device comprises about 250 mg to about
1000 mg of the fibrosing agent.
[1319] 354. The method of item 258 wherein the agent is delivered
from a device, wherein the device comprises about 1000 mg to about
2500 mg of the fibrosing agent.
[1320] 355. The method of item 258 wherein the agent is delivered
from a device, wherein a surface of the device comprises less than
0.01 .mu.g of the fibrosing agent per mm.sup.2 of device surface to
which the fibrosing agent is applied.
[1321] 356. The method of item 258 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 0.01
.mu.g to about 1 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[1322] 357. The method of item 258 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 1
.mu.g to about 10 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[1323] 358. The method of item 258 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 10
.mu.g to about 250 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[1324] 359. The method of item 258 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 250
.mu.g to about 1000 .mu.g of the fibrosing agent of fibrosing agent
per mm.sup.2 of device surface to which the fibrosing agent is
applied.
[1325] 360. The method of item 258 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 1000
.mu.g to about 2500 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[1326] 361. The method of item 258, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is a uniform coating.
[1327] 362. The method of item 258, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is a non-uniform coating.
[1328] 363. The method of item 258, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is a discontinuous coating.
[1329] 364. The method of item 258, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is a patterned coating.
[1330] 365. The method of item 258, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating has a thickness of 100 .mu.m or less.
[1331] 366. The method of item 258, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating has a thickness of 10 .mu.m or less.
[1332] 367. The method of item 258, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating adheres to the surface of the device upon deployment of
the device.
[1333] 368. The method of item 258, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is stable at room temperature for a period of at least
1 year.
[1334] 369. The method of item 258, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the fibrosing agent is present in the coating in an amount ranging
between about 0.0001% to about 1% by weight.
[1335] 370. The method of item 258, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the fibrosing agent is present in the coating in an amount ranging
between about 1% to about 10% by weight.
[1336] 371. The method of item 258, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the fibrosing agent is present in the coating in an amount ranging
between about 10% to about 25% by weight.
[1337] 372. The method of item 258, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the fibrosing agent is present in the coating in an amount ranging
between about 25% to about 70% by weight.
[1338] 373. The method of item 258, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating comprises a polymer.
[1339] 374. The method of item 258, wherein the agent is delivered
from a device, wherein the device comprises a first coating having
a first composition and a second coating having a second
composition.
[1340] 375. The method of item 258, wherein the agent is delivered
from a device, wherein the device comprises a first coating having
a first composition and a second coating having a second
composition, wherein the first composition and the second
composition are different.
[1341] 376. A method comprising introducing into a patient in need
thereof, a therapeutically effective amount of a fibrosing agent or
a composition comprising a fibrosing agent, where the fibrosing
agent induces a fibrotic response at a specific site within the
patient, thereby providing the patient with tendon repair.
[1342] 377. The method of item 376 wherein the agent promotes
regeneration.
[1343] 378. The method of item 376 wherein the agent promotes
angiogenesis.
[1344] 379. The method of item 376 wherein the agent promotes
fibroblast migration.
[1345] 380. The method of item 376 wherein the agent promotes
fibroblast proliferation.
[1346] 381. The method of item 376 wherein the agent promotes
deposition of extracellular matrix (ECM).
[1347] 382. The method of item 376 wherein the agent promotes
tissue remodeling.
[1348] 383. The method of item 376 wherein the agent is an arterial
vessel wall irritant.
[1349] 384. The method of item 376 wherein the fibrosing agent is
or comprises silk.
[1350] 385. The method of item 376 wherein the fibrosing agent is
in the form of tufts.
[1351] 386. The method of item 376 wherein the fibrosing agent is
or comprises mineral particles.
[1352] 387. The method of item 376 wherein the fibrosing agent is
or comprises chitosan.
[1353] 388. The method of item 376 wherein the fibrosing agent is
or comprises polylysine.
[1354] 389. The method of item 376 wherein the fibrosing agent is
or comprises fibronectin.
[1355] 390. The method of item 376 wherein the fibrosing agent is
or comprises bleomycin.
[1356] 391. The method of item 376 wherein the fibrosing agent is
or comprises CTGF.
[1357] 392. The method of item 376 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[1358] 393. The method of item 376 wherein the fibrosing agent is
in the form of a particulate.
[1359] 394. The method of item 376, wherein the composition
comprises a polymer.
[1360] 395. The method of item 376, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
copolymer.
[1361] 396. The method of item 376, wherein the composition
comprises a polymer, and the polymer is, or comprises, a block
copolymer.
[1362] 397. The method of item 376, wherein the composition
comprises a polymer, and the polymer is, or comprises, a random
copolymer.
[1363] 398. The method of item 376, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
biodegradable polymer.
[1364] 399. The method of item 376, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
non-biodegradable polymer.
[1365] 400. The method of item 376, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrophilic polymer.
[1366] 401. The method of item 376, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrophobic polymer.
[1367] 402. The method of item 376, wherein the composition
comprises a polymer, and the polymer is, or comprises, a polymer
having hydrophilic domains.
[1368] 403. The method of item 376, wherein the composition
comprises a polymer, and the polymer is, or comprises, a polymer
having hydrophobic domains.
[1369] 404. The method of item 376, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
non-conductive polymer.
[1370] 405. The method of item 376, wherein the composition
comprises a polymer, and the polymer is, or comprises, an
elastomer.
[1371] 406. The method of item 376, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrogel.
[1372] 407. The method of item 376, wherein the composition
comprises a polymer, and the polymer is, or comprises, a silicone
polymer.
[1373] 408. The method of item 376, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrocarbon polymer.
[1374] 409. The method of item 376, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
styrene-derived polymer.
[1375] 410. The method of item 376, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
butadiene-derived polymer.
[1376] 411. The method of item 376, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
macromer.
[1377] 412. The method of item 376, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
poly(ethylene glycol) polymer.
[1378] 413. The method of item 376, wherein the composition
comprises a polymer, and the polymer is, or comprises, an amorphous
polymer.
[1379] 414. The method of item 376, wherein the composition further
comprises a second pharmaceutically active agent.
[1380] 415. The method of item 376, wherein the composition further
comprises an anti-inflammatory agent.
[1381] 416. The method of item 376, wherein the composition further
comprises an agent that inhibits infection.
[1382] 417. The method of item 376, wherein the composition further
comprises an anthracycline.
[1383] 418. The method of item 376, wherein the composition further
comprises doxorubicin.
[1384] 419. The method of item 376 wherein the composition further
comprises mitoxantrone.
[1385] 420. The method of item 376 wherein the composition further
comprises a fluoropyrimidine.
[1386] 421. The method of item 376, wherein the composition further
comprises 5-fluorouracil (5-FU).
[1387] 422. The method of item 376, wherein the composition further
comprises a folic acid antagonist.
[1388] 423. The method of item 376, wherein the composition further
comprises methotrexate.
[1389] 424. The method of item 376, wherein the composition further
comprises a podophylotoxin.
[1390] 425. The method of item 376, wherein the composition further
comprises etoposide.
[1391] 426. The method of item 376, wherein the composition further
comprises camptothecin.
[1392] 427. The method of item 376, wherein the composition further
comprises a hydroxyurea.
[1393] 428. The method of item 376, wherein the composition further
comprises a platinum complex.
[1394] 429. The method of item 376, wherein the composition further
comprises cisplatin.
[1395] 430. The method of item 376 wherein the composition further
comprises an anti-thrombotic agent.
[1396] 431. The method of item 376, wherein the composition further
comprises a visualization agent.
[1397] 432. The method of item 376, wherein the composition further
comprises a visualization agent, and the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[1398] 433. The method of item 376, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, barium, tantalum, or technetium.
[1399] 434. The method of item 376, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, an MRI responsive material.
[1400] 435. The method of item 376, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, a gadolinium chelate.
[1401] 436. The method of item 376, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, iron, magnesium, manganese, copper, or chromium.
[1402] 437. The method of item 376, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, iron oxide compound.
[1403] 438. The method of item 376, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, a dye, pigment, or colorant.
[1404] 439. The method of item 376 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of administration to about 90 days.
[1405] 440. The method of item 376 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of administration to about 90
days.
[1406] 441. The method of item 376 wherein the composition further
comprises an inflammatory cytokine.
[1407] 442. The method of item 376 wherein the composition further
comprises an agent that stimulates cell proliferation.
[1408] 443. The method of item 376 wherein the composition further
comprises a polymeric carrier.
[1409] 444. The method of item 376 wherein the composition is in
the form of a gel, paste, or spray.
[1410] 445. The method of item 376 wherein the agent is delivered
from a device, and the device delivers the fibrosing agent locally
to tissue proximate to the device.
[1411] 446. The method of item 376 wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating comprises the fibrosing agent.
[1412] 447. The method of item 376 wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is disposed on a surface of the device.
[1413] 448. The method of item 376, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating directly contacts the device.
[1414] 449. The method of item 376, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating indirectly contacts the device.
[1415] 450. The method of item 376 wherein the agent is delivered
from a device, wherein the device further comprises a coating,
wherein the coating partially covers the device.
[1416] 451. The method of item 376, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating completely covers the device.
[1417] 452. The method of item 376 wherein the agent is delivered
from a device, wherein the fibrosing agent is located within pores
or holes of the device.
[1418] 453. The method of item 376 wherein the agent is delivered
from a device, wherein the fibrosing agent is located within a
channel, lumen, or divet of the device.
[1419] 454. The method of item 376 wherein the agent is delivered
from a device, wherein the device further comprising an echogenic
material.
[1420] 455. The method of item 376 wherein the agent is delivered
from a device, wherein the device further comprises an echogenic
material, wherein the echogenic material is in the form of a
coating.
[1421] 456. The method of item 376 wherein the agent is delivered
from a device, wherein the device is sterile.
[1422] 457. The method of item 376 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device.
[1423] 458. The method of item 376 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is connective tissue.
[1424] 459. The method of item 376 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is muscle tissue.
[1425] 460. The method of item 376 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is nerve tissue.
[1426] 461. The method of item 376 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is epithelium tissue.
[1427] 462. The method of item 376 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from the time
of deployment of the device to about 1 year.
[1428] 463. The method of item 376 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from about 1
month to 6 months.
[1429] 464. The method of item 376 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from about
1-90 days.
[1430] 465. The method of item 376 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device at a constant rate.
[1431] 466. The method of item 376 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[1432] 467. The method of item 376 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device at a decreasing rate.
[1433] 468. The method of item 376 wherein the agent is delivered
from a device, wherein the device comprises about 0.01 .mu.g to
about 10 .mu.g of the fibrosing agent.
[1434] 469. The method of item 376 wherein the agent is delivered
from a device, wherein the device comprises about 10 .mu.g to about
10 mg of the fibrosing agent.
[1435] 470. The method of item 376 wherein the agent is delivered
from a device, wherein the device comprises about 10 mg to about
250 mg of the fibrosing agent.
[1436] 471. The method of item 376 wherein the agent is delivered
from a device, wherein the device comprises about 250 mg to about
1000 mg of the fibrosing agent.
[1437] 472. The method of item 376 wherein the agent is delivered
from a device, wherein the device comprises about 1000 mg to about
2500 mg of the fibrosing agent.
[1438] 473. The method of item 376 wherein the agent is delivered
from a device, wherein a surface of the device comprises less than
0.01 .mu.g of the fibrosing agent per mm.sup.2 of device surface to
which the fibrosing agent is applied.
[1439] 474. The method of item 376 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 0.01
.mu.g to about 1 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[1440] 475. The method of item 376 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 1
.mu.g to about 10 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[1441] 476. The method of item 376 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 10
.mu.g to about 250 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[1442] 477. The method of item 376 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 250
.mu.g to about 1000 .mu.g of the fibrosing agent of fibrosing agent
per mm.sup.2 of device surface to which the fibrosing agent is
applied.
[1443] 478. The method of item 376 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 1000
.mu.g to about 2500 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[1444] 479. The method of item 376, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is a uniform coating.
[1445] 480. The method of item 376, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is a non-uniform coating.
[1446] 481. The method of item 376, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is a discontinuous coating.
[1447] 482. The method of item 376, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is a patterned coating.
[1448] 483. The method of item 376, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating has a thickness of 100 .mu.m or less.
[1449] 484. The method of item 376, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating has a thickness of 10 .mu.m or less.
[1450] 485. The method of item 376, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating adheres to the surface of the device upon deployment of
the device.
[1451] 486. The method of item 376, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is stable at room temperature for a period of at least
1 year.
[1452] 487. The method of item 376, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the fibrosing agent is present in the coating in an amount ranging
between about 0.0001% to about 1% by weight.
[1453] 488. The method of item 376, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the fibrosing agent is present in the coating in an amount ranging
between about 1% to about 10% by weight.
[1454] 489. The method of item 376, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the fibrosing agent is present in the coating in an amount ranging
between about 10% to about 25% by weight.
[1455] 490. The method of item 376, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the fibrosing agent is present in the coating in an amount ranging
between about 25% to about 70% by weight.
[1456] 491. The method of item 376, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating comprises a polymer.
[1457] 492. The method of item 376, wherein the agent is delivered
from a device, wherein the device comprises a first coating having
a first composition and a second coating having a second
composition.
[1458] 493. The method of item 376, wherein the agent is delivered
from a device, wherein the device comprises a first coating having
a first composition and a second coating having a second
composition, wherein the first composition and the second
composition are different.
[1459] 494. A method comprising introducing into a patient in need
thereof, a therapeutically effective amount of a fibrosing agent or
a composition comprising a fibrosing agent, where the fibrosing
agent induces a fibrotic response at a specific site within the
patient, thereby providing the patient with hernia repair.
[1460] 495. The method of item 494 wherein the agent promotes
regeneration.
[1461] 496. The method of item 494 wherein the agent promotes
angiogenesis.
[1462] 497. The method of item 494 wherein the agent promotes
fibroblast migration.
[1463] 498. The method of item 494 wherein the agent promotes
fibroblast proliferation.
[1464] 499. The method of item 494 wherein the agent promotes
deposition of extracellular matrix (ECM).
[1465] 500. The method of item 494 wherein the agent promotes
tissue remodeling.
[1466] 501. The method of item 494 wherein the agent is an arterial
vessel wall irritant.
[1467] 502. The method of item 494 wherein the fibrosing agent is
or comprises silk.
[1468] 503. The method of item 494 wherein the fibrosing agent is
in the form of tufts.
[1469] 504. The method of item 494 wherein the fibrosing agent is
or comprises mineral particles.
[1470] 505. The method of item 494 wherein the fibrosing agent is
or comprises chitosan.
[1471] 506. The method of item 494 wherein the fibrosing agent is
or comprises polylysine.
[1472] 507. The method of item 494 wherein the fibrosing agent is
or comprises fibronectin.
[1473] 508. The method of item 494 wherein the fibrosing agent is
or comprises bleomycin.
[1474] 509. The method of item 494 wherein the fibrosing agent is
or comprises CTGF.
[1475] 510. The method of item 494 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[1476] 511. The method of item 494 wherein the fibrosing agent is
in the form of a particulate.
[1477] 512. The method of item 494, wherein the composition
comprises a polymer.
[1478] 513. The method of item 494, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
copolymer.
[1479] 514. The method of item 494, wherein the composition
comprises a polymer, and the polymer is, or comprises, a block
copolymer.
[1480] 515. The method of item 494, wherein the composition
comprises a polymer, and the polymer is, or comprises, a random
copolymer.
[1481] 516. The method of item 494, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
biodegradable polymer.
[1482] 517. The method of item 494, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
non-biodegradable polymer.
[1483] 518. The method of item 494, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrophilic polymer.
[1484] 519. The method of item 494, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrophobic polymer.
[1485] 520. The method of item 494, wherein the composition
comprises a polymer, and the polymer is, or comprises, a polymer
having hydrophilic domains.
[1486] 521. The method of item 494, wherein the composition
comprises a polymer, and the polymer is, or comprises, a polymer
having hydrophobic domains.
[1487] 522. The method of item 494, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
non-conductive polymer.
[1488] 523. The method of item 494, wherein the composition
comprises a polymer, and the polymer is, or comprises, an
elastomer.
[1489] 524. The method of item 494, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrogel.
[1490] 525. The method of item 494, wherein the composition
comprises a polymer, and the polymer is, or comprises, a silicone
polymer.
[1491] 526. The method of item 494, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrocarbon polymer.
[1492] 527. The method of item 494, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
styrene-derived polymer.
[1493] 528. The method of item 494, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
butadiene-derived polymer.
[1494] 529. The method of item 494, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
macromer.
[1495] 530. The method of item 494, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
poly(ethylene glycol) polymer.
[1496] 531. The method of item 494, wherein the composition
comprises a polymer, and the polymer is, or comprises, an amorphous
polymer.
[1497] 532. The method of item 494, wherein the composition further
comprises a second pharmaceutically active agent.
[1498] 533. The method of item 494, wherein the composition further
comprises an anti-inflammatory agent.
[1499] 534. The method of item 494, wherein the composition further
comprises an agent that inhibits infection.
[1500] 535. The method of item 494, wherein the composition further
comprises an anthracycline.
[1501] 536. The method of item 494, wherein the composition further
comprises doxorubicin.
[1502] 537. The method of item 494 wherein the composition further
comprises mitoxantrone.
[1503] 538. The method of item 494 wherein the composition further
comprises a fluoropyrimidine.
[1504] 539. The method of item 494, wherein the composition further
comprises 5-fluorouracil (5-FU).
[1505] 540. The method of item 494, wherein the composition further
comprises a folic acid antagonist.
[1506] 541. The method of item 494, wherein the composition further
comprises methotrexate.
[1507] 542. The method of item 494, wherein the composition further
comprises a podophylotoxin.
[1508] 543. The method of item 494, wherein the composition further
comprises etoposide.
[1509] 544. The method of item 494, wherein the composition further
comprises camptothecin.
[1510] 545. The method of item 494, wherein the composition further
comprises a hydroxyurea.
[1511] 546. The method of item 494, wherein the composition further
comprises a platinum complex.
[1512] 547. The method of item 494, wherein the composition further
comprises cisplatin.
[1513] 548. The method of item 494 wherein the composition further
comprises an anti-thrombotic agent.
[1514] 549. The method of item 494, wherein the composition further
comprises a visualization agent.
[1515] 550. The method of item 494, wherein the composition further
comprises a visualization agent, and the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[1516] 551. The method of item 494, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, barium, tantalum, or technetium.
[1517] 552. The method of item 494, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, an MRI responsive material.
[1518] 553. The method of item 494, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, a gadolinium chelate.
[1519] 554. The method of item 494, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, iron, magnesium, manganese, copper, or chromium.
[1520] 555. The method of item 494, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, iron oxide compound.
[1521] 556. The method of item 494, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, a dye, pigment, or colorant.
[1522] 557. The method of item 494 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of administration to about 90 days.
[1523] 558. The method of item 494 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of administration to about 90
days.
[1524] 559. The method of item 494 wherein the composition further
comprises an inflammatory cytokine.
[1525] 560. The method of item 494 wherein the composition further
comprises an agent that stimulates cell proliferation.
[1526] 561. The method of item 494 wherein the composition further
comprises a polymeric carrier.
[1527] 562. The method of item 494 wherein the composition is in
the form of a gel, paste, or spray.
[1528] 563. The method of item 494 wherein the agent is delivered
from a device, and the device delivers the fibrosing agent locally
to tissue proximate to the device.
[1529] 564. The method of item 494 wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating comprises the fibrosing agent.
[1530] 565. The method of item 494 wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is disposed on a surface of the device.
[1531] 566. The method of item 494, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating directly contacts the device.
[1532] 567. The method of item 494, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating indirectly contacts the device.
[1533] 568. The method of item 494 wherein the agent is delivered
from a device, wherein the device further comprises a coating,
wherein the coating partially covers the device.
[1534] 569. The method of item 494, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating completely covers the device.
[1535] 570. The method of item 494 wherein the agent is delivered
from a device, wherein the fibrosing agent is located within pores
or holes of the device.
[1536] 571. The method of item 494 wherein the agent is delivered
from a device, wherein the fibrosing agent is located within a
channel, lumen, or divet of the device.
[1537] 572. The method of item 494 wherein the agent is delivered
from a device, wherein the device further comprising an echogenic
material.
[1538] 573. The method of item 494 wherein the agent is delivered
from a device, wherein the device further comprises an echogenic
material, wherein the echogenic material is in the form of a
coating.
[1539] 574. The method of item 494 wherein the agent is delivered
from a device, wherein the device is sterile.
[1540] 575. The method of item 494 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device.
[1541] 576. The method of item 494 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is connective tissue.
[1542] 577. The method of item 494 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is muscle tissue.
[1543] 578. The method of item 494 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is nerve tissue.
[1544] 579. The method of item 494 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is epithelium tissue.
[1545] 580. The method of item 494 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from the time
of deployment of the device to about 1 year.
[1546] 581. The method of item 494 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from about 1
month to 6 months.
[1547] 582. The method of item 494 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from about
1-90 days.
[1548] 583. The method of item 494 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device at a constant rate.
[1549] 584. The method of item 494 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[1550] 585. The method of item 494 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device at a decreasing rate.
[1551] 586. The method of item 494 wherein the agent is delivered
from a device, wherein the device comprises about 0.01 .mu.g to
about 10 .mu.g of the fibrosing agent.
[1552] 587. The method of item 494 wherein the agent is delivered
from a device, wherein the device comprises about 10 .mu.g to about
10 mg of the fibrosing agent.
[1553] 588. The method of item 494 wherein the agent is delivered
from a device, wherein the device comprises about 10 mg to about
250 mg of the fibrosing agent.
[1554] 589. The method of item 494 wherein the agent is delivered
from a device, wherein the device comprises about 250 mg to about
1000 mg of the fibrosing agent.
[1555] 590. The method of item 494 wherein the agent is delivered
from a device, wherein the device comprises about 1000 mg to about
2500 mg of the fibrosing agent.
[1556] 591. The method of item 494 wherein the agent is delivered
from a device, wherein a surface of the device comprises less than
0.01 .mu.g of the fibrosing agent per mm.sup.2 of device surface to
which the fibrosing agent is applied.
[1557] 592. The method of item 494 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 0.01
.mu.g to about 1 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[1558] 593. The method of item 494 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 1
.mu.g to about 10 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[1559] 594. The method of item 494 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 10
.mu.g to about 250 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[1560] 595. The method of item 494 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 250
.mu.g to about 1000 .mu.g of the fibrosing agent of fibrosing agent
per mm.sup.2 of device surface to which the fibrosing agent is
applied.
[1561] 596. The method of item 494 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 1000
.mu.g to about 2500 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[1562] 597. The method of item 494, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is a uniform coating.
[1563] 598. The method of item 494, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is a non-uniform coating.
[1564] 599. The method of item 494, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is a discontinuous coating.
[1565] 600. The method of item 494, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is a patterned coating.
[1566] 601. The method of item 494, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating has a thickness of 100 .mu.m or less.
[1567] 602. The method of item 494, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating has a thickness of 10 .mu.m or less.
[1568] 603. The method of item 494, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating adheres to the surface of the device upon deployment of
the device.
[1569] 604. The method of item 494, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is stable at room temperature for a period of at least
1 year.
[1570] 605. The method of item 494, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the fibrosing agent is present in the coating in an amount ranging
between about 0.0001% to about 1% by weight.
[1571] 606. The method of item 494, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the fibrosing agent is present in the coating in an amount ranging
between about 1% to about 10% by weight.
[1572] 607. The method of item 494, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the fibrosing agent is present in the coating in an amount ranging
between about 10% to about 25% by weight.
[1573] 608. The method of item 494, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the fibrosing agent is present in the coating in an amount ranging
between about 25% to about 70% by weight.
[1574] 609. The method of item 494, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating comprises a polymer.
[1575] 610. The method of item 494, wherein the agent is delivered
from a device, wherein the device comprises a first coating having
a first composition and a second coating having a second
composition.
[1576] 611. The method of item 494, wherein the agent is delivered
from a device, wherein the device comprises a first coating having
a first composition and a second coating having a second
composition, wherein the first composition and the second
composition are different.
[1577] 612. A method comprising introducing into a patient in need
thereof, a therapeutically effective amount of a fibrosing agent or
a composition comprising a fibrosing agent, where the fibrosing
agent induces a fibrotic response at a specific site within the
patient, thereby providing the patient with pulmonary sealing.
[1578] 613. The method of item 612 wherein the agent promotes
regeneration.
[1579] 614. The method of item 612 wherein the agent promotes
angiogenesis.
[1580] 615. The method of item 612 wherein the agent promotes
fibroblast migration.
[1581] 616. The method of item 612 wherein the agent promotes
fibroblast proliferation.
[1582] 617. The method of item 612 wherein the agent promotes
deposition of extracellular matrix (ECM).
[1583] 618. The method of item 612 wherein the agent promotes
tissue remodeling.
[1584] 619. The method of item 612 wherein the agent is an arterial
vessel wall irritant.
[1585] 620. The method of item 612 wherein the fibrosing agent is
or comprises silk.
[1586] 621. The method of item 612 wherein the fibrosing agent is
in the form of tufts.
[1587] 622. The method of item 612 wherein the fibrosing agent is
or comprises mineral particles.
[1588] 623. The method of item 612 wherein the fibrosing agent is
or comprises chitosan.
[1589] 624. The method of item 612 wherein the fibrosing agent is
or comprises polylysine.
[1590] 625. The method of item 612 wherein the fibrosing agent is
or comprises fibronectin.
[1591] 626. The method of item 612 wherein the fibrosing agent is
or comprises bleomycin.
[1592] 627. The method of item 612 wherein the fibrosing agent is
or comprises CTGF.
[1593] 628. The method of item 612 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[1594] 629. The method of item 612 wherein the fibrosing agent is
in the form of a particulate.
[1595] 630. The method of item 612, wherein the composition
comprises a polymer.
[1596] 631. The method of item 612, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
copolymer.
[1597] 632. The method of item 612, wherein the composition
comprises a polymer, and the polymer is, or comprises, a block
copolymer.
[1598] 633. The method of item 612, wherein the composition
comprises a polymer, and the polymer is, or comprises, a random
copolymer.
[1599] 634. The method of item 612, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
biodegradable polymer.
[1600] 635. The method of item 612, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
non-biodegradable polymer.
[1601] 636. The method of item 612, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrophilic polymer.
[1602] 637. The method of item 612, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrophobic polymer.
[1603] 638. The method of item 612, wherein the composition
comprises a polymer, and the polymer is, or comprises, a polymer
having hydrophilic domains.
[1604] 639. The method of item 612, wherein the composition
comprises a polymer, and the polymer is, or comprises, a polymer
having hydrophobic domains.
[1605] 640. The method of item 612, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
non-conductive polymer.
[1606] 641. The method of item 612, wherein the composition
comprises a polymer, and the polymer is, or comprises, an
elastomer.
[1607] 642. The method of item 612, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrogel.
[1608] 643. The method of item 612, wherein the composition
comprises a polymer, and the polymer is, or comprises, a silicone
polymer.
[1609] 644. The method of item 612, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrocarbon polymer.
[1610] 645. The method of item 612, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
styrene-derived polymer.
[1611] 646. The method of item 612, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
butadiene-derived polymer.
[1612] 647. The method of item 612, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
macromer.
[1613] 648. The method of item 612, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
poly(ethylene glycol) polymer.
[1614] 649. The method of item 612, wherein the composition
comprises a polymer, and the polymer is, or comprises, an amorphous
polymer.
[1615] 650. The method of item 612, wherein the composition further
comprises a second pharmaceutically active agent.
[1616] 651. The method of item 612, wherein the composition further
comprises an anti-inflammatory agent.
[1617] 652. The method of item 612, wherein the composition further
comprises an agent that inhibits infection.
[1618] 653. The method of item 612, wherein the composition further
comprises an anthracycline.
[1619] 654. The method of item 612, wherein the composition further
comprises doxorubicin.
[1620] 655. The method of item 612 wherein the composition further
comprises mitoxantrone.
[1621] 656. The method of item 612 wherein the composition further
comprises a fluoropyrimidine.
[1622] 657. The method of item 612, wherein the composition further
comprises 5-fluorouracil (5-FU).
[1623] 658. The method of item 612, wherein the composition further
comprises a folic acid antagonist.
[1624] 659. The method of item 612, wherein the composition further
comprises methotrexate.
[1625] 660. The method of item 612, wherein the composition further
comprises a podophylotoxin.
[1626] 661. The method of item 612, wherein the composition further
comprises etoposide.
[1627] 662. The method of item 612, wherein the composition further
comprises camptothecin.
[1628] 663. The method of item 612, wherein the composition further
comprises a hydroxyurea.
[1629] 664. The method of item 612, wherein the composition further
comprises a platinum complex.
[1630] 665. The method of item 612, wherein the composition further
comprises cisplatin.
[1631] 666. The method of item 612 wherein the composition further
comprises an anti-thrombotic agent.
[1632] 667. The method of item 612, wherein the composition further
comprises a visualization agent.
[1633] 668. The method of item 612, wherein the composition further
comprises a visualization agent, and the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[1634] 669. The method of item 612, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, barium, tantalum, or technetium.
[1635] 670. The method of item 612, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, an MRI responsive material.
[1636] 671. The method of item 612, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, a gadolinium chelate.
[1637] 672. The method of item 612, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, iron, magnesium, manganese, copper, or chromium.
[1638] 673. The method of item 612, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, iron oxide compound.
[1639] 674. The method of item 612, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, a dye, pigment, or colorant.
[1640] 675. The method of item 612 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of administration to about 90 days.
[1641] 676. The method of item 612 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of administration to about 90
days.
[1642] 677. The method of item 612 wherein the composition further
comprises an inflammatory cytokine.
[1643] 678. The method of item 612 wherein the composition further
comprises an agent that stimulates cell proliferation.
[1644] 679. The method of item 612 wherein the composition further
comprises a polymeric carrier.
[1645] 680. The method of item 612 wherein the composition is in
the form of a gel, paste, or spray.
[1646] 681. The method of item 612 wherein the agent is delivered
from a device, and the device delivers the fibrosing agent locally
to tissue proximate to the device.
[1647] 682. The method of item 612 wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating comprises the fibrosing agent.
[1648] 683. The method of item 612 wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is disposed on a surface of the device.
[1649] 684. The method of item 612, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating directly contacts the device.
[1650] 685. The method of item 612, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating indirectly contacts the device.
[1651] 686. The method of item 612 wherein the agent is delivered
from a device, wherein the device further comprises a coating,
wherein the coating partially covers the device.
[1652] 687. The method of item 612, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating completely covers the device.
[1653] 688. The method of item 612 wherein the agent is delivered
from a device, wherein the fibrosing agent is located within pores
or holes of the device.
[1654] 689. The method of item 612 wherein the agent is delivered
from a device, wherein the fibrosing agent is located within a
channel, lumen, or divet of the device.
[1655] 690. The method of item 612 wherein the agent is delivered
from a device, wherein the device further comprising an echogenic
material.
[1656] 691. The method of item 612 wherein the agent is delivered
from a device, wherein the device further comprises an echogenic
material, wherein the echogenic material is in the form of a
coating.
[1657] 692. The method of item 612 wherein the agent is delivered
from a device, wherein the device is sterile.
[1658] 693. The method of item 612 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device.
[1659] 694. The method of item 612 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is connective tissue.
[1660] 695. The method of item 612 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is muscle tissue.
[1661] 696. The method of item 612 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is nerve tissue.
[1662] 697. The method of item 612 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is epithelium tissue.
[1663] 698. The method of item 612 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from the time
of deployment of the device to about 1 year.
[1664] 699. The method of item 612 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from about 1
month to 6 months.
[1665] 700. The method of item 612 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from about
1-90 days.
[1666] 701. The method of item 612 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device at a constant rate.
[1667] 702. The method of item 612 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[1668] 703. The method of item 612 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device at a decreasing rate.
[1669] 704. The method of item 612 wherein the agent is delivered
from a device, wherein the device comprises about 0.01 .mu.g to
about 10 .mu.g of the fibrosing agent.
[1670] 705. The method of item 612 wherein the agent is delivered
from a device, wherein the device comprises about 10 .mu.g to about
10 mg of the fibrosing agent.
[1671] 706. The method of item 612 wherein the agent is delivered
from a device, wherein the device comprises about 10 mg to about
250 mg of the fibrosing agent.
[1672] 707. The method of item 612 wherein the agent is delivered
from a device, wherein the device comprises about 250 mg to about
1000 mg of the fibrosing agent.
[1673] 708. The method of item 612 wherein the agent is delivered
from a device, wherein the device comprises about 1000 mg to about
2500 mg of the fibrosing agent.
[1674] 709. The method of item 612 wherein the agent is delivered
from a device, wherein a surface of the device comprises less than
0.01 .mu.g of the fibrosing agent per mm.sup.2 of device surface to
which the fibrosing agent is applied.
[1675] 710. The method of item 612 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 0.01
.mu.g to about 1 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[1676] 711. The method of item 612 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 1
.mu.g to about 10 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[1677] 712. The method of item 612 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 10
.mu.g to about 250 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[1678] 713. The method of item 612 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 250
.mu.g to about 1000 .mu.g of the fibrosing agent of fibrosing agent
per mm.sup.2 of device surface to which the fibrosing agent is
applied.
[1679] 714. The method of item 612 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 1000
.mu.g to about 2500 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[1680] 715. The method of item 612, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is a uniform coating.
[1681] 716. The method of item 612, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is a non-uniform coating.
[1682] 717. The method of item 612, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is a discontinuous coating.
[1683] 718. The method of item 612, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is a patterned coating.
[1684] 719. The method of item 612, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating has a thickness of 100 .mu.m or less.
[1685] 720. The method of item 612, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating has a thickness of 10 .mu.m or less.
[1686] 721. The method of item 612, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating adheres to the surface of the device upon deployment of
the device.
[1687] 722. The method of item 612, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is stable at room temperature for a period of at least
1 year.
[1688] 723. The method of item 612, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the fibrosing agent is present in the coating in an amount ranging
between about 0.0001% to about 1% by weight.
[1689] 724. The method of item 612, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the fibrosing agent is present in the coating in an amount ranging
between about 1% to about 10% by weight.
[1690] 725. The method of item 612, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the fibrosing agent is present in the coating in an amount ranging
between about 10% to about 25% by weight.
[1691] 726. The method of item 612, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the fibrosing agent is present in the coating in an amount ranging
between about 25% to about 70% by weight.
[1692] 727. The method of item 612, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating comprises a polymer.
[1693] 728. The method of item 612, wherein the agent is delivered
from a device, wherein the device comprises a first coating having
a first composition and a second coating having a second
composition.
[1694] 729. The method of item 612, wherein the agent is delivered
from a device, wherein the device comprises a first coating having
a first composition and a second coating having a second
composition, wherein the first composition and the second
composition are different.
[1695] 730. A method comprising introducing into a patient in need
thereof, a therapeutically effective amount of a fibrosing agent or
a composition comprising a fibrosing agent, where the fibrosing
agent induces a fibrotic response at a specific site within the
patient, thereby providing the patient with treatment or prevention
of an aneurysm.
[1696] 731. The method of item 730 wherein the agent promotes
regeneration.
[1697] 732. The method of item 730 wherein the agent promotes
angiogenesis.
[1698] 733. The method of item 730 wherein the agent promotes
fibroblast migration.
[1699] 734. The method of item 730 wherein the agent promotes
fibroblast proliferation.
[1700] 735. The method of item 730 wherein the agent promotes
deposition of extracellular matrix (ECM).
[1701] 736. The method of item 730 wherein the agent promotes
tissue remodeling.
[1702] 737. The method of item 730 wherein the agent is an arterial
vessel wall irritant.
[1703] 738. The method of item 730 wherein the fibrosing agent is
or comprises silk.
[1704] 739. The method of item 730 wherein the fibrosing agent is
in the form of tufts.
[1705] 740. The method of item 730 wherein the fibrosing agent is
or comprises mineral particles.
[1706] 741. The method of item 730 wherein the fibrosing agent is
or comprises chitosan.
[1707] 742. The method of item 730 wherein the fibrosing agent is
or comprises polylysine.
[1708] 743. The method of item 730 wherein the fibrosing agent is
or comprises fibronectin.
[1709] 744. The method of item 730 wherein the fibrosing agent is
or comprises bleomycin.
[1710] 745. The method of item 730 wherein the fibrosing agent is
or comprises CTGF.
[1711] 746. The method of item 730 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[1712] 747. The method of item 730 wherein the fibrosing agent is
in the form of a particulate.
[1713] 748. The method of item 730, wherein the composition
comprises a polymer.
[1714] 749. The method of item 730, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
copolymer.
[1715] 750. The method of item 730, wherein the composition
comprises a polymer, and the polymer is, or comprises, a block
copolymer.
[1716] 751. The method of item 730, wherein the composition
comprises a polymer, and the polymer is, or comprises, a random
copolymer.
[1717] 752. The method of item 730, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
biodegradable polymer.
[1718] 753. The method of item 730, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
non-biodegradable polymer.
[1719] 754. The method of item 730, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrophilic polymer.
[1720] 755. The method of item 730, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrophobic polymer.
[1721] 756. The method of item 730, wherein the composition
comprises a polymer, and the polymer is, or comprises, a polymer
having hydrophilic domains.
[1722] 757. The method of item 730, wherein the composition
comprises a polymer, and the polymer is, or comprises, a polymer
having hydrophobic domains.
[1723] 758. The method of item 730, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
non-conductive polymer.
[1724] 759. The method of item 730, wherein the composition
comprises a polymer, and the polymer is, or comprises, an
elastomer.
[1725] 760. The method of item 730, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrogel.
[1726] 761. The method of item 730, wherein the composition
comprises a polymer, and the polymer is, or comprises, a silicone
polymer.
[1727] 762. The method of item 730, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrocarbon polymer.
[1728] 763. The method of item 730, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
styrene-derived polymer.
[1729] 764. The method of item 730, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
butadiene-derived polymer.
[1730] 765. The method of item 730, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
macromer.
[1731] 766. The method of item 730, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
poly(ethylene glycol) polymer.
[1732] 767. The method of item 730, wherein the composition
comprises a polymer, and the polymer is, or comprises, an amorphous
polymer.
[1733] 768. The method of item 730, wherein the composition further
comprises a second pharmaceutically active agent.
[1734] 769. The method of item 730, wherein the composition further
comprises an anti-inflammatory agent.
[1735] 770. The method of item 730, wherein the composition further
comprises an agent that inhibits infection.
[1736] 771. The method of item 730, wherein the composition further
comprises an anthracycline.
[1737] 772. The method of item 730, wherein the composition further
comprises doxorubicin.
[1738] 773. The method of item 730 wherein the composition further
comprises mitoxantrone.
[1739] 774. The method of item 730 wherein the composition further
comprises a fluoropyrimidine.
[1740] 775. The method of item 730, wherein the composition further
comprises 5-fluorouracil (5-FU).
[1741] 776. The method of item 730, wherein the composition further
comprises a folic acid antagonist.
[1742] 777. The method of item 730, wherein the composition further
comprises methotrexate.
[1743] 778. The method of item 730, wherein the composition further
comprises a podophylotoxin.
[1744] 779. The method of item 730, wherein the composition further
comprises etoposide.
[1745] 780. The method of item 730, wherein the composition further
comprises camptothecin.
[1746] 781. The method of item 730, wherein the composition further
comprises a hydroxyurea.
[1747] 782. The method of item 730, wherein the composition further
comprises a platinum complex.
[1748] 783. The method of item 730, wherein the composition further
comprises cisplatin.
[1749] 784. The method of item 730 wherein the composition further
comprises an anti-thrombotic agent.
[1750] 785. The method of item 730, wherein the composition further
comprises a visualization agent.
[1751] 786. The method of item 730, wherein the composition further
comprises a visualization agent, and the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[1752] 787. The method of item 730, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, barium, tantalum, or technetium.
[1753] 788. The method of item 730, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, an MRI responsive material.
[1754] 789. The method of item 730, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, a gadolinium chelate.
[1755] 790. The method of item 730, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, iron, magnesium, manganese, copper, or chromium.
[1756] 791. The method of item 730, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, iron oxide compound.
[1757] 792. The method of item 730, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, a dye, pigment, or colorant.
[1758] 793. The method of item 730 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of administration to about 90 days.
[1759] 794. The method of item 730 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of administration to about 90
days.
[1760] 795. The method of item 730 wherein the composition further
comprises an inflammatory cytokine.
[1761] 796. The method of item 730 wherein the composition further
comprises an agent that stimulates cell proliferation.
[1762] 797. The method of item 730 wherein the composition further
comprises a polymeric carrier.
[1763] 798. The method of item 730 wherein the composition is in
the form of a gel, paste, or spray.
[1764] 799. The method of item 730 wherein the agent is delivered
from a device, and the device delivers the fibrosing agent locally
to tissue proximate to the device.
[1765] 800. The method of item 730 wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating comprises the fibrosing agent.
[1766] 801. The method of item 730 wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is disposed on a surface of the device.
[1767] 802. The method of item 730, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating directly contacts the device.
[1768] 803. The method of item 730, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating indirectly contacts the device.
[1769] 804. The method of item 730 wherein the agent is delivered
from a device, wherein the device further comprises a coating,
wherein the coating partially covers the device.
[1770] 805. The method of item 730, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating completely covers the device.
[1771] 806. The method of item 730 wherein the agent is delivered
from a device, wherein the fibrosing agent is located within pores
or holes of the device.
[1772] 807. The method of item 730 wherein the agent is delivered
from a device, wherein the fibrosing agent is located within a
channel, lumen, or divet of the device.
[1773] 808. The method of item 730 wherein the agent is delivered
from a device, wherein the device further comprising an echogenic
material.
[1774] 809. The method of item 730 wherein the agent is delivered
from a device, wherein the device further comprises an echogenic
material, wherein the echogenic material is in the form of a
coating.
[1775] 810. The method of item 730 wherein the agent is delivered
from a device, wherein the device is sterile.
[1776] 811. The method of item 730 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device.
[1777] 812. The method of item 730 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is connective tissue.
[1778] 813. The method of item 730 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is muscle tissue.
[1779] 814. The method of item 730 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is nerve tissue.
[1780] 815. The method of item 730 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is epithelium tissue.
[1781] 816. The method of item 730 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from the time
of deployment of the device to about 1 year.
[1782] 817. The method of item 730 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from about 1
month to 6 months.
[1783] 818. The method of item 730 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from about
1-90 days.
[1784] 819. The method of item 730 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device at a constant rate.
[1785] 820. The method of item 730 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[1786] 821. The method of item 730 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device at a decreasing rate.
[1787] 822. The method of item 730 wherein the agent is delivered
from a device, wherein the device comprises about 0.01 .mu.g to
about 10 .mu.g of the fibrosing agent.
[1788] 823. The method of item 730 wherein the agent is delivered
from a device, wherein the device comprises about 10 .mu.g to about
10 mg of the fibrosing agent.
[1789] 824. The method of item 730 wherein the agent is delivered
from a device, wherein the device comprises about 10 mg to about
250 mg of the fibrosing agent.
[1790] 825. The method of item 730 wherein the agent is delivered
from a device, wherein the device comprises about 250 mg to about
1000 mg of the fibrosing agent.
[1791] 826. The method of item 730 wherein the agent is delivered
from a device, wherein the device comprises about 1000 mg to about
2500 mg of the fibrosing agent.
[1792] 827. The method of item 730 wherein the agent is delivered
from a device, wherein a surface of the device comprises less than
0.01 .mu.g of the fibrosing agent per mm.sup.2 of device surface to
which the fibrosing agent is applied.
[1793] 828. The method of item 730 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 0.01
.mu.g to about 1 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[1794] 829. The method of item 730 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 1
.mu.g to about 10 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[1795] 830. The method of item 730 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 10
.mu.g to about 250 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[1796] 831. The method of item 730 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 250
.mu.g to about 1000 .mu.g of the fibrosing agent of fibrosing agent
per mm.sup.2 of device surface to which the fibrosing agent is
applied.
[1797] 832. The method of item 730 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 1000
.mu.g to about 2500 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[1798] 833. The method of item 730, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is a uniform coating.
[1799] 834. The method of item 730, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is a non-uniform coating.
[1800] 835. The method of item 730, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is a discontinuous coating.
[1801] 836. The method of item 730, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is a patterned coating.
[1802] 837. The method of item 730, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating has a thickness of 100 .mu.m or less.
[1803] 838. The method of item 730, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating has a thickness of 10 .mu.m or less.
[1804] 839. The method of item 730, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating adheres to the surface of the device upon deployment of
the device.
[1805] 840. The method of item 730, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is stable at room temperature for a period of at least
1 year.
[1806] 841. The method of item 730, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the fibrosing agent is present in the coating in an amount ranging
between about 0.0001% to about 1% by weight.
[1807] 842. The method of item 730, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the fibrosing agent is present in the coating in an amount ranging
between about 1% to about 10% by weight.
[1808] 843. The method of item 730, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the fibrosing agent is present in the coating in an amount ranging
between about 10% to about 25% by weight.
[1809] 844. The method of item 730, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the fibrosing agent is present in the coating in an amount ranging
between about 25% to about 70% by weight.
[1810] 845. The method of item 730, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating comprises a polymer.
[1811] 846. The method of item 730, wherein the agent is delivered
from a device, wherein the device comprises a first coating having
a first composition and a second coating having a second
composition.
[1812] 847. The method of item 730, wherein the agent is delivered
from a device, wherein the device comprises a first coating having
a first composition and a second coating having a second
composition, wherein the first composition and the second
composition are different.
[1813] 848. A method comprising introducing into a patient in need
thereof, a therapeutically effective amount of a fibrosing agent or
a composition comprising a fibrosing agent, where the fibrosing
agent induces a fibrotic response at a specific site within the
patient, thereby providing the patient with embolization.
[1814] 849. The method of item 848 wherein the agent promotes
regeneration.
[1815] 850. The method of item 848 wherein the agent promotes
angiogenesis.
[1816] 851. The method of item 848 wherein the agent promotes
fibroblast migration.
[1817] 852. The method of item 848 wherein the agent promotes
fibroblast proliferation.
[1818] 853. The method of item 848 wherein the agent promotes
deposition of extracellular matrix (ECM).
[1819] 854. The method of item 848 wherein the agent promotes
tissue remodeling.
[1820] 855. The method of item 848 wherein the agent is an arterial
vessel wall irritant.
[1821] 856. The method of item 848 wherein the fibrosing agent is
or comprises silk.
[1822] 857. The method of item 848 wherein the fibrosing agent is
in the form of tufts.
[1823] 858. The method of item 848 wherein the fibrosing agent is
or comprises mineral particles.
[1824] 859. The method of item 848 wherein the fibrosing agent is
or comprises chitosan.
[1825] 860. The method of item 848 wherein the fibrosing agent is
or comprises polylysine.
[1826] 861. The method of item 848 wherein the fibrosing agent is
or comprises fibronectin.
[1827] 862. The method of item 848 wherein the fibrosing agent is
or comprises bleomycin.
[1828] 863. The method of item 848 wherein the fibrosing agent is
or comprises CTGF.
[1829] 864. The method of item 848 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[1830] 865. The method of item 848 wherein the fibrosing agent is
in the form of a particulate.
[1831] 866. The method of item 848, wherein the composition
comprises a polymer.
[1832] 867. The method of item 848, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
copolymer.
[1833] 868. The method of item 848, wherein the composition
comprises a polymer, and the polymer is, or comprises, a block
copolymer.
[1834] 869. The method of item 848, wherein the composition
comprises a polymer, and the polymer is, or comprises, a random
copolymer.
[1835] 870. The method of item 848, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
biodegradable polymer.
[1836] 871. The method of item 848, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
non-biodegradable polymer.
[1837] 872. The method of item 848, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrophilic polymer.
[1838] 873. The method of item 848, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrophobic polymer.
[1839] 874. The method of item 848, wherein the composition
comprises a polymer, and the polymer is, or comprises, a polymer
having hydrophilic domains.
[1840] 875. The method of item 848, wherein the composition
comprises a polymer, and the polymer is, or comprises, a polymer
having hydrophobic domains.
[1841] 876. The method of item 848, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
non-conductive polymer.
[1842] 877. The method of item 848, wherein the composition
comprises a polymer, and the polymer is, or comprises, an
elastomer.
[1843] 878. The method of item 848, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrogel.
[1844] 879. The method of item 848, wherein the composition
comprises a polymer, and the polymer is, or comprises, a silicone
polymer.
[1845] 880. The method of item 848, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrocarbon polymer.
[1846] 881. The method of item 848, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
styrene-derived polymer.
[1847] 882. The method of item 848, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
butadiene-derived polymer.
[1848] 883. The method of item 848, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
macromer.
[1849] 884. The method of item 848, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
poly(ethylene glycol) polymer.
[1850] 885. The method of item 848, wherein the composition
comprises a polymer, and the polymer is, or comprises, an amorphous
polymer.
[1851] 886. The method of item 848, wherein the composition further
comprises a second pharmaceutically active agent.
[1852] 887. The method of item 848, wherein the composition further
comprises an anti-inflammatory agent.
[1853] 888. The method of item 848, wherein the composition further
comprises an agent that inhibits infection.
[1854] 889. The method of item 848, wherein the composition further
comprises an anthracycline.
[1855] 890. The method of item 848, wherein the composition further
comprises doxorubicin.
[1856] 891. The method of item 848 wherein the composition further
comprises mitoxantrone.
[1857] 892. The method of item 848 wherein the composition further
comprises a fluoropyrimidine.
[1858] 893. The method of item 848, wherein the composition further
comprises 5-fluorouracil (5-FU).
[1859] 894. The method of item 848, wherein the composition further
comprises a folic acid antagonist.
[1860] 895. The method of item 848, wherein the composition further
comprises methotrexate.
[1861] 896. The method of item 848, wherein the composition further
comprises a podophylotoxin.
[1862] 897. The method of item 848, wherein the composition further
comprises etoposide.
[1863] 898. The method of item 848, wherein the composition further
comprises camptothecin.
[1864] 899. The method of item 848, wherein the composition further
comprises a hydroxyurea.
[1865] 900. The method of item 848, wherein the composition further
comprises a platinum complex.
[1866] 901. The method of item 848, wherein the composition further
comprises cisplatin.
[1867] 902. The method of item 848 wherein the composition further
comprises an anti-thrombotic agent.
[1868] 903. The method of item 848, wherein the composition further
comprises a visualization agent.
[1869] 904. The method of item 848, wherein the composition further
comprises a visualization agent, and the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[1870] 905. The method of item 848, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, barium, tantalum, or technetium.
[1871] 906. The method of item 848, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, an MRI responsive material.
[1872] 907. The method of item 848, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, a gadolinium chelate.
[1873] 908. The method of item 848, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, iron, magnesium, manganese, copper, or chromium.
[1874] 909. The method of item 848, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, iron oxide compound.
[1875] 910. The method of item 848, wherein the composition further
comprises a visualization agent, and the visualization agent is, or
comprises, a dye, pigment, or colorant.
[1876] 911. The method of item 848 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of administration to about 90 days.
[1877] 912. The method of item 848 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of administration to about 90
days.
[1878] 913. The method of item 848 wherein the composition further
comprises an inflammatory cytokine.
[1879] 914. The method of item 848 wherein the composition further
comprises an agent that stimulates cell proliferation.
[1880] 915. The method of item 848 wherein the composition further
comprises a polymeric carrier.
[1881] 916. The method of item 848 wherein the composition is in
the form of a gel, paste, or spray.
[1882] 917. The method of item 848 wherein the agent is delivered
from a device, and the device delivers the fibrosing agent locally
to tissue proximate to the device.
[1883] 918. The method of item 848 wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating comprises the fibrosing agent.
[1884] 919. The method of item 848 wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is disposed on a surface of the device.
[1885] 920. The method of item 848, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating directly contacts the device.
[1886] 921. The method of item 848, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating indirectly contacts the device.
[1887] 922. The method of item 848 wherein the agent is delivered
from a device, wherein the device further comprises a coating,
wherein the coating partially covers the device.
[1888] 923. The method of item 848, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating completely covers the device.
[1889] 924. The method of item 848 wherein the agent is delivered
from a device, wherein the fibrosing agent is located within pores
or holes of the device.
[1890] 925. The method of item 848 wherein the agent is delivered
from a device, wherein the fibrosing agent is located within a
channel, lumen, or divet of the device.
[1891] 926. The method of item 848 wherein the agent is delivered
from a device, wherein the device further comprising an echogenic
material.
[1892] 927. The method of item 848 wherein the agent is delivered
from a device, wherein the device further comprises an echogenic
material, wherein the echogenic material is in the form of a
coating.
[1893] 928. The method of item 848 wherein the agent is delivered
from a device, wherein the device is sterile.
[1894] 929. The method of item 848 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device.
[1895] 930. The method of item 848 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is connective tissue.
[1896] 931. The method of item 848 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is muscle tissue.
[1897] 932. The method of item 848 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is nerve tissue.
[1898] 933. The method of item 848 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is epithelium tissue.
[1899] 934. The method of item 848 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from the time
of deployment of the device to about 1 year.
[1900] 935. The method of item 848 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from about 1
month to 6 months.
[1901] 936. The method of item 848 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from about
1-90 days.
[1902] 937. The method of item 848 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device at a constant rate.
[1903] 938. The method of item 848 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[1904] 939. The method of item 848 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device at a decreasing rate.
[1905] 940. The method of item 848 wherein the agent is delivered
from a device, wherein the device comprises about 0.01 .mu.g to
about 10 .mu.g of the fibrosing agent.
[1906] 941. The method of item 848 wherein the agent is delivered
from a device, wherein the device comprises about 10 .mu.g to about
10 mg of the fibrosing agent.
[1907] 942. The method of item 848 wherein the agent is delivered
from a device, wherein the device comprises about 10 mg to about
250 mg of the fibrosing agent.
[1908] 943, The method of item 848 wherein the agent is delivered
from a device, wherein the device comprises about 250 mg to about
1000 mg of the fibrosing agent.
[1909] 944. The method of item 848 wherein the agent is delivered
from a device, wherein the device comprises about 1000 mg to about
2500 mg of the fibrosing agent.
[1910] 945. The method of item 848 wherein the agent is delivered
from a device, wherein a surface of the device comprises less than
0.01 .mu.g of the fibrosing agent per mm.sup.2 of device surface to
which the fibrosing agent is applied.
[1911] 946. The method of item 848 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 0.01
.mu.g to about 1 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[1912] 947. The method of item 848 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 1
.mu.g to about 10 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[1913] 948. The method of item 848 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 10
.mu.g to about 250 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[1914] 949. The method of item 848 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 250
.mu.g to about 1000 .mu.g of the fibrosing agent of fibrosing agent
per mm.sup.2 of device surface to which the fibrosing agent is
applied.
[1915] 950. The method of item 848 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 1000
.mu.g to about 2500 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[1916] 951. The method of item 848, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is a uniform coating.
[1917] 952. The method of item 848, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is a non-uniform coating.
[1918] 953. The method of item 848, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is a discontinuous coating.
[1919] 954. The method of item 848, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is a patterned coating.
[1920] 955. The method of item 848, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating has a thickness of 100 .mu.m or less.
[1921] 956. The method of item 848, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating has a thickness of 10 .mu.m or less.
[1922] 957. The method of item 848, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating adheres to the surface of the device upon deployment of
the device.
[1923] 958. The method of item 848, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is stable at room temperature for a period of at least
1 year.
[1924] 959. The method of item 848, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the fibrosing agent is present in the coating in an amount ranging
between about 0.0001% to about 1% by weight.
[1925] 960. The method of item 848, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the fibrosing agent is present in the coating in an amount ranging
between about 1% to about 10% by weight.
[1926] 961. The method of item 848, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the fibrosing agent is present in the coating in an amount ranging
between about 10% to about 25% by weight.
[1927] 962. The method of item 848, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the fibrosing agent is present in the coating in an amount ranging
between about 25% to about 70% by weight.
[1928] 963. The method of item 848, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating comprises a polymer.
[1929] 964. The method of item 848, wherein the agent is delivered
from a device, wherein the device comprises a first coating having
a first composition and a second coating having a second
composition.
[1930] 965. The method of item 848, wherein the agent is delivered
from a device, wherein the device comprises a first coating having
a first composition and a second coating having a second
composition, wherein the first composition and the second
composition are different.
[1931] 966. A method comprising introducing into a patient in need
thereof, a therapeutically effective amount of a fibrosing agent or
a composition comprising a fibrosing agent, where the fibrosing
agent induces a fibrotic response at a specific site within the
patient, thereby providing the patient with a fibrotic response
between the patient and a soft palate implant.
[1932] 967. The method of item 966 wherein the agent promotes
regeneration.
[1933] 968. The method of item 966 wherein the agent promotes
angiogenesis.
[1934] 969. The method of item 966 wherein the agent promotes
fibroblast migration.
[1935] 970. The method of item 966 wherein the agent promotes
fibroblast proliferation.
[1936] 971. The method of item 966 wherein the agent promotes
deposition of extracellular matrix (ECM).
[1937] 972. The method of item 966 wherein the agent promotes
tissue remodeling.
[1938] 973. The method of item 966 wherein the agent is an arterial
vessel wall irritant.
[1939] 974. The method of item 966 wherein the fibrosing agent is
or comprises silk.
[1940] 975. The method of item 966 wherein the fibrosing agent is
in the form of tufts.
[1941] 976. The method of item 966 wherein the fibrosing agent is
or comprises mineral particles.
[1942] 977. The method of item 966 wherein the fibrosing agent is
or comprises chitosan.
[1943] 978. The method of item 966 wherein the fibrosing agent is
or comprises polylysine.
[1944] 979. The method of item 966 wherein the fibrosing agent is
or comprises fibronectin.
[1945] 980. The method of item 966 wherein the fibrosing agent is
or comprises bleomycin.
[1946] 981. The method of item 966 wherein the fibrosing agent is
or comprises CTGF.
[1947] 982. The method of item 966 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[1948] 983. The method of item 966 wherein the fibrosing agent is
in the form of a particulate.
[1949] 984. The method of item 966, wherein the composition
comprises a polymer.
[1950] 985. The method of item 966, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
copolymer.
[1951] 986. The method of item 966, wherein the composition
comprises a polymer, and the polymer is, or comprises, a block
copolymer.
[1952] 987. The method of item 966, wherein the composition
comprises a polymer, and the polymer is, or comprises, a random
copolymer.
[1953] 988. The method of item 966, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
biodegradable polymer.
[1954] 989. The method of item 966, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
non-biodegradable polymer.
[1955] 990. The method of item 966, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrophilic polymer.
[1956] 991. The method of item 966, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrophobic polymer.
[1957] 992. The method of item 966, wherein the composition
comprises a polymer, and the polymer is, or comprises, a polymer
having hydrophilic domains.
[1958] 993. The method of item 966, wherein the composition
comprises a polymer, and the polymer is, or comprises, a polymer
having hydrophobic domains.
[1959] 994. The method of item 966, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
non-conductive polymer.
[1960] 995. The method of item 966, wherein the composition
comprises a polymer, and the polymer is, or comprises, an
elastomer.
[1961] 996. The method of item 966, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrogel.
[1962] 997. The method of item 966, wherein the composition
comprises a polymer, and the polymer is, or comprises, a silicone
polymer.
[1963] 998. The method of item 966, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrocarbon polymer.
[1964] 999. The method of item 966, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
styrene-derived polymer.
[1965] 1000. The method of item 966, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
butadiene-derived polymer.
[1966] 1001. The method of item 966, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
macromer.
[1967] 1002. The method of item 966, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
poly(ethylene glycol) polymer.
[1968] 1003. The method of item 966, wherein the composition
comprises a polymer, and the polymer is, or comprises, an amorphous
polymer.
[1969] 1004. The method of item 966, wherein the composition
further comprises a second pharmaceutically active agent.
[1970] 1005. The method of item 966, wherein the composition
further comprises an anti-inflammatory agent.
[1971] 1006. The method of item 966, wherein the composition
further comprises an agent that inhibits infection.
[1972] 1007. The method of item 966, wherein the composition
further comprises an anthracycline.
[1973] 1008. The method of item 966, wherein the composition
further comprises doxorubicin.
[1974] 1009. The method of item 966 wherein the composition further
comprises mitoxantrone.
[1975] 1010. The method of item 966 wherein the composition further
comprises a fluoropyrimidine.
[1976] 1011. The method of item 966, wherein the composition
further comprises 5-fluorouracil (5-FU).
[1977] 1012. The method of item 966, wherein the composition
further comprises a folic acid antagonist.
[1978] 1013. The method of item 966, wherein the composition
further comprises methotrexate.
[1979] 1014. The method of item 966, wherein the composition
further comprises a podophylotoxin.
[1980] 1015. The method of item 966, wherein the composition
further comprises etoposide.
[1981] 1016. The method of item 966, wherein the composition
further comprises camptothecin.
[1982] 1017. The method of item 966, wherein the composition
further comprises a hydroxyurea.
[1983] 1018. The method of item 966, wherein the composition
further comprises a platinum complex.
[1984] 1019. The method of item 966, wherein the composition
further comprises cisplatin.
[1985] 1020. The method of item 966 wherein the composition further
comprises an anti-thrombotic agent.
[1986] 1021. The method of item 966, wherein the composition
further comprises a visualization agent.
[1987] 1022. The method of item 966, wherein the composition
further comprises a visualization agent, and the visualization
agent is a radiopaque material, wherein the radiopaque material
comprises a metal, a halogenated compound, or a barium containing
compound.
[1988] 1023. The method of item 966, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, barium, tantalum, or technetium.
[1989] 1024. The method of item 966, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, an MRI responsive material.
[1990] 1025. The method of item 966, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, a gadolinium chelate.
[1991] 1026. The method of item 966, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, iron, magnesium, manganese, copper, or
chromium.
[1992] 1027. The method of item 966, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, iron oxide compound.
[1993] 1028. The method of item 966, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, a dye, pigment, or colorant.
[1994] 1029. The method of item 966 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of administration to about 90 days.
[1995] 1030. The method of item 966 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of administration to about 90
days.
[1996] 1031. The method of item 966 wherein the composition further
comprises an inflammatory cytokine.
[1997] 1032. The method of item 966 wherein the composition further
comprises an agent that stimulates cell proliferation.
[1998] 1033. The method of item 966 wherein the composition further
comprises a polymeric carrier.
[1999] 1034. The method of item 966 wherein the composition is in
the form of a gel, paste, or spray.
[2000] 1035. The method of item 966 wherein the agent is delivered
from a device, and the device delivers the fibrosing agent locally
to tissue proximate to the device.
[2001] 1036. The method of item 966 wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating comprises the fibrosing agent.
[2002] 1037. The method of item 966 wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is disposed on a surface of the device.
[2003] 1038. The method of item 966, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating directly contacts the device.
[2004] 1039. The method of item 966, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating indirectly contacts the device.
[2005] 1040. The method of item 966 wherein the agent is delivered
from a device, wherein the device further comprises a coating,
wherein the coating partially covers the device.
[2006] 1041. The method of item 966, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating completely covers the device.
[2007] 1042. The method of item 966 wherein the agent is delivered
from a device, wherein the fibrosing agent is located within pores
or holes of the device.
[2008] 1043. The method of item 966 wherein the agent is delivered
from a device, wherein the fibrosing agent is located within a
channel, lumen, or divet of the device.
[2009] 1044. The method of item 966 wherein the agent is delivered
from a device, wherein the device further comprising an echogenic
material.
[2010] 1045. The method of item 966 wherein the agent is delivered
from a device, wherein the device further comprises an echogenic
material, wherein the echogenic material is in the form of a
coating.
[2011] 1046. The method of item 966 wherein the agent is delivered
from a device, wherein the device is sterile.
[2012] 1047. The method of item 966 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device.
[2013] 1048. The method of item 966 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is connective tissue.
[2014] 1049. The method of item 966 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is muscle tissue.
[2015] 1050. The method of item 966 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is nerve tissue.
[2016] 1051. The method of item 966 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is epithelium tissue.
[2017] 1052. The method of item 966 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from the time
of deployment of the device to about 1 year.
[2018] 1053. The method of item 966 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from about 1
month to 6 months.
[2019] 1054. The method of item 966 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from about
1-90 days.
[2020] 1055. The method of item 966 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device at a constant rate.
[2021] 1056. The method of item 966 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[2022] 1057. The method of item 966 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device at a decreasing rate.
[2023] 1058. The method of item 966 wherein the agent is delivered
from a device, wherein the device comprises about 0.01 .mu.g to
about 10 .mu.g of the fibrosing agent.
[2024] 1059. The method of item 966 wherein the agent is delivered
from a device, wherein the device comprises about 10 .mu.g to about
10 mg of the fibrosing agent.
[2025] 1060. The method of item 966 wherein the agent is delivered
from a device, wherein the device comprises about 10 mg to about
250 mg of the fibrosing agent.
[2026] 1061. The method of item 966 wherein the agent is delivered
from a device, wherein the device comprises about 250 mg to about
1000 mg of the fibrosing agent.
[2027] 1062. The method of item 966 wherein the agent is delivered
from a device, wherein the device comprises about 1000 mg to about
2500 mg of the fibrosing agent.
[2028] 1063. The method of item 966 wherein the agent is delivered
from a device, wherein a surface of the device comprises less than
0.01 .mu.g of the fibrosing agent per mm.sup.2 of device surface to
which the fibrosing agent is applied.
[2029] 1064. The method of item 966 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 0.01
.mu.g to about 1 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2030] 1065. The method of item 966 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 1
.mu.g to about 10 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2031] 1066. The method of item 966 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 10
.mu.g to about 250 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2032] 1067. The method of item 966 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 250
.mu.g to about 1000 .mu.g of the fibrosing agent of fibrosing agent
per mm.sup.2 of device surface to which the fibrosing agent is
applied.
[2033] 1068. The method of item 966 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 1000
.mu.g to about 2500 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2034] 1069. The method of item 966, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is a uniform coating.
[2035] 1070. The method of item 966, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is a non-uniform coating.
[2036] 1071. The method of item 966, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is a discontinuous coating.
[2037] 1072. The method of item 966, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is a patterned coating.
[2038] 1073. The method of item 966, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating has a thickness of 100 .mu.m or less.
[2039] 1074. The method of item 966, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating has a thickness of 10 .mu.m or less.
[2040] 1075. The method of item 966, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating adheres to the surface of the device upon deployment of
the device.
[2041] 1076. The method of item 966, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is stable at room temperature for a period of at least
1 year.
[2042] 1077. The method of item 966, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the fibrosing agent is present in the coating in an amount ranging
between about 0.0001% to about 1% by weight.
[2043] 1078. The method of item 966, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the fibrosing agent is present in the coating in an amount ranging
between about 1% to about 10% by weight.
[2044] 1079. The method of item 966, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the fibrosing agent is present in the coating in an amount ranging
between about 10% to about 25% by weight.
[2045] 1080. The method of item 966, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the fibrosing agent is present in the coating in an amount ranging
between about 25% to about 70% by weight.
[2046] 1081. The method of item 966, wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating comprises a polymer.
[2047] 1082. The method of item 966, wherein the agent is delivered
from a device, wherein the device comprises a first coating having
a first composition and a second coating having a second
composition.
[2048] 1083. The method of item 966, wherein the agent is delivered
from a device, wherein the device comprises a first coating having
a first composition and a second coating having a second
composition, wherein the first composition and the second
composition are different.
[2049] 1084. A method comprising introducing into a patient in need
thereof, a therapeutically effective amount of a fibrosing agent or
a composition comprising a fibrosing agent, where the fibrosing
agent induces a fibrotic response at a specific site within the
patient, thereby providing the patient with treatment for
obesity.
[2050] 1085. The method of item 1084 wherein the agent promotes
regeneration.
[2051] 1086. The method of item 1084 wherein the agent promotes
angiogenesis.
[2052] 1087. The method of item 1084 wherein the agent promotes
fibroblast migration.
[2053] 1088. The method of item 1084 wherein the agent promotes
fibroblast proliferation.
[2054] 1089. The method of item 1084 wherein the agent promotes
deposition of extracellular matrix (ECM).
[2055] 1090. The method of item 1084 wherein the agent promotes
tissue remodeling.
[2056] 1091. The method of item 1084 wherein the agent is an
arterial vessel wall irritant.
[2057] 1092. The method of item 1084 wherein the fibrosing agent is
or comprises silk.
[2058] 1093. The method of item 1084 wherein the fibrosing agent is
in the form of tufts.
[2059] 1094. The method of item 1084 wherein the fibrosing agent is
or comprises mineral particles.
[2060] 1095. The method of item 1084 wherein the fibrosing agent is
or comprises chitosan.
[2061] 1096. The method of item 1084 wherein the fibrosing agent is
or comprises polylysine.
[2062] 1097. The method of item 1084 wherein the fibrosing agent is
or comprises fibronectin.
[2063] 1098. The method of item 1084 wherein the fibrosing agent is
or comprises bleomycin.
[2064] 1099. The method of item 1084 wherein the fibrosing agent is
or comprises CTGF.
[2065] 1100. The method of item 1084 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[2066] 1101. The method of item 1084 wherein the fibrosing agent is
in the form of a particulate.
[2067] 1102. The method of item 1084, wherein the composition
comprises a polymer.
[2068] 1103. The method of item 1084, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
copolymer.
[2069] 1104. The method of item 1084, wherein the composition
comprises a polymer, and the polymer is, or comprises, a block
copolymer.
[2070] 1105. The method of item 1084, wherein the composition
comprises a polymer, and the polymer is, or comprises, a random
copolymer.
[2071] 1106. The method of item 1084, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
biodegradable polymer.
[2072] 1107. The method of item 1084, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
non-biodegradable polymer.
[2073] 1108. The method of item 1084, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrophilic polymer.
[2074] 1109. The method of item 1084, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrophobic polymer.
[2075] 1110. The method of item 1084, wherein the composition
comprises a polymer, and the polymer is, or comprises, a polymer
having hydrophilic domains.
[2076] 1111. The method of item 1084, wherein the composition
comprises a polymer, and the polymer is, or comprises, a polymer
having hydrophobic domains.
[2077] 1112. The method of item 1084, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
non-conductive polymer.
[2078] 1113. The method of item 1084, wherein the composition
comprises a polymer, and the polymer is, or comprises, an
elastomer.
[2079] 1114. The method of item 1084, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrogel.
[2080] 1115. The method of item 1084, wherein the composition
comprises a polymer, and the polymer is, or comprises, a silicone
polymer.
[2081] 1116. The method of item 1084, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrocarbon polymer.
[2082] 1117. The method of item 1084, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
styrene-derived polymer.
[2083] 1118. The method of item 1084, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
butadiene-derived polymer.
[2084] 1119. The method of item 1084, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
macromer.
[2085] 1120. The method of item 1084, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
poly(ethylene glycol) polymer.
[2086] 1121. The method of item 1084, wherein the composition
comprises a polymer, and the polymer is, or comprises, an amorphous
polymer.
[2087] 1122. The method of item 1084, wherein the composition
further comprises a second pharmaceutically active agent.
[2088] 1123. The method of item 1084, wherein the composition
further comprises an anti-inflammatory agent.
[2089] 1124. The method of item 1084, wherein the composition
further comprises an agent that inhibits infection.
[2090] 1125. The method of item 1084, wherein the composition
further comprises an anthracycline.
[2091] 1126. The method of item 1084, wherein the composition
further comprises doxorubicin.
[2092] 1127. The method of item 1084 wherein the composition
further comprises mitoxantrone.
[2093] 1128. The method of item 1084 wherein the composition
further comprises a fluoropyrimidine.
[2094] 1129. The method of item 1084, wherein the composition
further comprises 5-fluorouracil (5-FU).
[2095] 1130. The method of item 1084, wherein the composition
further comprises a folic acid antagonist.
[2096] 1131. The method of item 1084, wherein the composition
further comprises methotrexate.
[2097] 1132. The method of item 1084, wherein the composition
further comprises a podophylotoxin.
[2098] 1133. The method of item 1084, wherein the composition
further comprises etoposide.
[2099] 1134. The method of item 1084, wherein the composition
further comprises camptothecin.
[2100] 1135. The method of item 1084, wherein the composition
further comprises a hydroxyurea.
[2101] 1136. The method of item 1084, wherein the composition
further comprises a platinum complex.
[2102] 1137. The method of item 1084, wherein the composition
further comprises cisplatin.
[2103] 1138. The method of item 1084 wherein the composition
further comprises an anti-thrombotic agent.
[2104] 1139. The method of item 1084, wherein the composition
further comprises a visualization agent.
[2105] 1140. The method of item 1084, wherein the composition
further comprises a visualization agent, and the visualization
agent is a radiopaque material, wherein the radiopaque material
comprises a metal, a halogenated compound, or a barium containing
compound.
[2106] 1141. The method of item 1084, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, barium, tantalum, or technetium.
[2107] 1142. The method of item 1084, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, an MRI responsive material.
[2108] 1143. The method of item 1084, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, a gadolinium chelate.
[2109] 1144. The method of item 1084, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, iron, magnesium, manganese, copper, or
chromium.
[2110] 1145. The method of item 1084, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, iron oxide compound.
[2111] 1146. The method of item 1084, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, a dye, pigment, or colorant.
[2112] 1147. The method of item 1084 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of administration to about 90 days.
[2113] 1148. The method of item 1084 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of administration to about 90
days.
[2114] 1149. The method of item 1084 wherein the composition
further comprises an inflammatory cytokine.
[2115] 1150. The method of item 1084 wherein the composition
further comprises an agent that stimulates cell proliferation.
[2116] 1151. The method of item 1084 wherein the composition
further comprises a polymeric carrier.
[2117] 1152. The method of item 1084 wherein the composition is in
the form of a gel, paste, or spray.
[2118] 1153. The method of item 1084 wherein the agent is delivered
from a device, and the device delivers the fibrosing agent locally
to tissue proximate to the device.
[2119] 1154. The method of item 1084 wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating comprises the fibrosing agent.
[2120] 1155. The method of item 1084 wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is disposed on a surface of the device.
[2121] 1156. The method of item 1084, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating directly contacts the device.
[2122] 1157. The method of item 1084, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating indirectly contacts the device.
[2123] 1158. The method of item 1084 wherein the agent is delivered
from a device, wherein the device further comprises a coating,
wherein the coating partially covers the device.
[2124] 1159. The method of item 1084, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating completely covers the device.
[2125] 1160. The method of item 1084 wherein the agent is delivered
from a device, wherein the fibrosing agent is located within pores
or holes of the device.
[2126] 1161. The method of item 1084 wherein the agent is delivered
from a device, wherein the fibrosing agent is located within a
channel, lumen, or divet of the device.
[2127] 1162. The method of item 1084 wherein the agent is delivered
from a device, wherein the device further comprising an echogenic
material.
[2128] 1163. The method of item 1084 wherein the agent is delivered
from a device, wherein the device further comprises an echogenic
material, wherein the echogenic material is in the form of a
coating.
[2129] 1164. The method of item 1084 wherein the agent is delivered
from a device, wherein the device is sterile.
[2130] 1165. The method of item 1084 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device.
[2131] 1166. The method of item 1084 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is connective tissue.
[2132] 1167. The method of item 1084 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is muscle tissue.
[2133] 1168. The method of item 1084 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is nerve tissue.
[2134] 1169. The method of item 1084 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is epithelium tissue.
[2135] 1170. The method of item 1084 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from the time
of deployment of the device to about 1 year.
[2136] 1171. The method of item 1084 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from about 1
month to 6 months.
[2137] 1172. The method of item 1084 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from about
1-90 days.
[2138] 1173. The method of item 1084 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device at a constant rate.
[2139] 1174. The method of item 1084 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[2140] 1175. The method of item 1084 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device at a decreasing rate.
[2141] 1176. The method of item 1084 wherein the agent is delivered
from a device, wherein the device comprises about 0.01 .mu.g to
about 10 .mu.g of the fibrosing agent.
[2142] 1177. The method of item 1084 wherein the agent is delivered
from a device, wherein the device comprises about 10 .mu.g to about
10 mg of the fibrosing agent.
[2143] 1178. The method of item 1084 wherein the agent is delivered
from a device, wherein the device comprises about 10 mg to about
250 mg of the fibrosing agent.
[2144] 1179. The method of item 1084 wherein the agent is delivered
from a device, wherein the device comprises about 250 mg to about
1000 mg of the fibrosing agent.
[2145] 1180. The method of item 1084 wherein the agent is delivered
from a device, wherein the device comprises about 1000 mg to about
2500 mg of the fibrosing agent.
[2146] 1181. The method of item 1084 wherein the agent is delivered
from a device, wherein a surface of the device comprises less than
0.01 .mu.g of the fibrosing agent per mm.sup.2 of device surface to
which the fibrosing agent is applied.
[2147] 1182. The method of item 1084 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 0.01
.mu.g to about 1 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2148] 1183. The method of item 1084 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 1
.mu.g to about 10 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2149] 1184. The method of item 1084 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 10
.mu.g to about 250 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2150] 1185. The method of item 1084 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 250
.mu.g to about 1000 .mu.g of the fibrosing agent of fibrosing agent
per mm.sup.2 of device surface to which the fibrosing agent is
applied.
[2151] 1186. The method of item 1084 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 1000
.mu.g to about 2500 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2152] 1187. The method of item 1084, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is a uniform coating.
[2153] 1188. The method of item 1084, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is a non-uniform coating.
[2154] 1189. The method of item 1084, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is a discontinuous coating.
[2155] 1190. The method of item 1084, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is a patterned coating.
[2156] 1191. The method of item 1084, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating has a thickness of 100 .mu.m or less.
[2157] 1192. The method of item 1084, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating has a thickness of 10 .mu.m or less.
[2158] 1193. The method of item 1084, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating adheres to the surface of the device upon
deployment of the device.
[2159] 1194. The method of item 1084, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is stable at room temperature for a period
of at least 1 year.
[2160] 1195. The method of item 1084, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the fibrosing agent is present in the coating in an
amount ranging between about 0.0001% to about 1% by weight.
[2161] 1196. The method of item 1084, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the fibrosing agent is present in the coating in an
amount ranging between about 1% to about 10% by weight.
[2162] 1197. The method of item 1084, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the fibrosing agent is present in the coating in an
amount ranging between about 10% to about 25% by weight.
[2163] 1198. The method of item 1084, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the fibrosing agent is present in the coating in an
amount ranging between about 25% to about 70% by weight.
[2164] 1199. The method of item 1084, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating comprises a polymer.
[2165] 1200. The method of item 1084, wherein the agent is
delivered from a device, wherein the device comprises a first
coating having a first composition and a second coating having a
second composition.
[2166] 1201. The method of item 1084, wherein the agent is
delivered from a device, wherein the device comprises a first
coating having a first composition and a second coating having a
second composition, wherein the first composition and the second
composition are different.
[2167] 1202. A method comprising introducing into a patient in need
thereof, a therapeutically effective amount of a fibrosing agent or
a composition comprising a fibrosing agent, where the fibrosing
agent induces a fibrotic response at a specific site within the
patient, thereby providing the patient with treatment for GERD.
[2168] 1203. The method of item 1202 wherein the agent promotes
regeneration.
[2169] 1204. The method of item 1202 wherein the agent promotes
angiogenesis.
[2170] 1205. The method of item 1202 wherein the agent promotes
fibroblast migration.
[2171] 1206. The method of item 1202 wherein the agent promotes
fibroblast proliferation.
[2172] 1207. The method of item 1202 wherein the agent promotes
deposition of extracellular matrix (ECM).
[2173] 1208. The method of item 1202 wherein the agent promotes
tissue remodeling.
[2174] 1209. The method of item 1202 wherein the agent is an
arterial vessel wall irritant.
[2175] 1210. The method of item 1202 wherein the fibrosing agent is
or comprises silk.
[2176] 1211. The method of item 1202 wherein the fibrosing agent is
in the form of tufts.
[2177] 1212. The method of item 1202 wherein the fibrosing agent is
or comprises mineral particles.
[2178] 1213. The method of item 1202 wherein the fibrosing agent is
or comprises chitosan.
[2179] 1214. The method of item 1202 wherein the fibrosing agent is
or comprises polylysine.
[2180] 1215. The method of item 1202 wherein the fibrosing agent is
or comprises fibronectin.
[2181] 1216. The method of item 1202 wherein the fibrosing agent is
or comprises bleomycin.
[2182] 1217. The method of item 1202 wherein the fibrosing agent is
or comprises CTGF.
[2183] 1218. The method of item 1202 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[2184] 1219. The method of item 1202 wherein the fibrosing agent is
in the form of a particulate.
[2185] 1220. The method of item 1202, wherein the composition
comprises a polymer.
[2186] 1221. The method of item 1202, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
copolymer.
[2187] 1222. The method of item 1202, wherein the composition
comprises a polymer, and the polymer is, or comprises, a block
copolymer.
[2188] 1223. The method of item 1202, wherein the composition
comprises a polymer, and the polymer is, or comprises, a random
copolymer.
[2189] 1224. The method of item 1202, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
biodegradable polymer.
[2190] 1225. The method of item 1202, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
non-biodegradable polymer.
[2191] 1226. The method of item 1202, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrophilic polymer.
[2192] 1227. The method of item 1202, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrophobic polymer.
[2193] 1228. The method of item 1202, wherein the composition
comprises a polymer, and the polymer is, or comprises, a polymer
having hydrophilic domains.
[2194] 1229. The method of item 1202, wherein the composition
comprises a polymer, and the polymer is, or comprises, a polymer
having hydrophobic domains.
[2195] 1230. The method of item 1202, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
non-conductive polymer.
[2196] 1231. The method of item 1202, wherein the composition
comprises a polymer, and the polymer is, or comprises, an
elastomer.
[2197] 1232. The method of item 1202, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrogel.
[2198] 1233. The method of item 1202, wherein the composition
comprises a polymer, and the polymer is, or comprises, a silicone
polymer.
[2199] 1234. The method of item 1202, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrocarbon polymer.
[2200] 1235. The method of item 1202, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
styrene-derived polymer.
[2201] 1236. The method of item 1202, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
butadiene-derived polymer.
[2202] 1237. The method of item 1202, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
macromer.
[2203] 1238. The method of item 1202, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
poly(ethylene glycol) polymer.
[2204] 1239. The method of item 1202, wherein the composition
comprises a polymer, and the polymer is, or comprises, an amorphous
polymer.
[2205] 1240. The method of item 1202, wherein the composition
further comprises a second pharmaceutically active agent.
[2206] 1241. The method of item 1202, wherein the composition
further comprises an anti-inflammatory agent.
[2207] 1242. The method of item 1202, wherein the composition
further comprises an agent that inhibits infection.
[2208] 1243. The method of item 1202, wherein the composition
further comprises an anthracycline.
[2209] 1244. The method of item 1202, wherein the composition
further comprises doxorubicin.
[2210] 1245. The method of item 1202 wherein the composition
further comprises mitoxantrone.
[2211] 1246. The method of item 1202 wherein the composition
further comprises a fluoropyrimidine.
[2212] 1247. The method of item 1202, wherein the composition
further comprises 5-fluorouracil (5-FU).
[2213] 1248. The method of item 1202, wherein the composition
further comprises a folic acid antagonist.
[2214] 1249. The method of item 1202, wherein the composition
further comprises methotrexate.
[2215] 1250. The method of item 1202, wherein the composition
further comprises a podophylotoxin.
[2216] 1251. The method of item 1202, wherein the composition
further comprises etoposide.
[2217] 1252. The method of item 1202, wherein the composition
further comprises camptothecin.
[2218] 1253. The method of item 1202, wherein the composition
further comprises a hydroxyurea.
[2219] 1254. The method of item 1202, wherein the composition
further comprises a platinum complex.
[2220] 1255. The method of item 1202, wherein the composition
further comprises cisplatin.
[2221] 1256. The method of item 1202 wherein the composition
further comprises an anti-thrombotic agent.
[2222] 1257. The method of item 1202, wherein the composition
further comprises a visualization agent.
[2223] 1258. The method of item 1202, wherein the composition
further comprises a visualization agent, and the visualization
agent is a radiopaque material, wherein the radiopaque material
comprises a metal, a halogenated compound, or a barium containing
compound.
[2224] 1259. The method of item 1202, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, barium, tantalum, or technetium.
[2225] 1260. The method of item 1202, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, an MRI responsive material.
[2226] 1261. The method of item 1202, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, a gadolinium chelate.
[2227] 1262. The method of item 1202, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, iron, magnesium, manganese, copper, or
chromium.
[2228] 1263. The method of item 1202, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, iron oxide compound.
[2229] 1264. The method of item 1202, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, a dye, pigment, or colorant.
[2230] 1265. The method of item 1202 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of administration to about 90 days.
[2231] 1266. The method of item 1202 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of administration to about 90
days.
[2232] 1267. The method of item 1202 wherein the composition
further comprises an inflammatory cytokine.
[2233] 1268. The method of item 1202 wherein the composition
further comprises an agent that stimulates cell proliferation.
[2234] 1269. The method of item 1202 wherein the composition
further comprises a polymeric carrier.
[2235] 1270. The method of item 1202 wherein the composition is in
the form of a gel, paste, or spray.
[2236] 1271. The method of item 1202 wherein the agent is delivered
from a device, and the device delivers the fibrosing agent locally
to tissue proximate to the device.
[2237] 1272. The method of item 1202 wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating comprises the fibrosing agent.
[2238] 1273. The method of item 1202 wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is disposed on a surface of the device.
[2239] 1274. The method of item 1202, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating directly contacts the device.
[2240] 1275. The method of item 1202, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating indirectly contacts the device.
[2241] 1276. The method of item 1202 wherein the agent is delivered
from a device, wherein the device further comprises a coating,
wherein the coating partially covers the device.
[2242] 1277. The method of item 1202, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating completely covers the device.
[2243] 1278. The method of item 1202 wherein the agent is delivered
from a device, wherein the fibrosing agent is located within pores
or holes of the device.
[2244] 1279. The method of item 1202 wherein the agent is delivered
from a device, wherein the fibrosing agent is located within a
channel, lumen, or divet of the device.
[2245] 1280. The method of item 1202 wherein the agent is delivered
from a device, wherein the device further comprising an echogenic
material.
[2246] 1281. The method of item 1202 wherein the agent is delivered
from a device, wherein the device further comprises an echogenic
material, wherein the echogenic material is in the form of a
coating.
[2247] 1282. The method of item 1202 wherein the agent is delivered
from a device, wherein the device is sterile.
[2248] 1283. The method of item 1202 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device.
[2249] 1284. The method of item 1202 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is connective tissue.
[2250] 1285. The method of item 1202 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is muscle tissue.
[2251] 1286. The method of item 1202 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is nerve tissue.
[2252] 1287. The method of item 1202 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is epithelium tissue.
[2253] 1288. The method of item 1202 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from the time
of deployment of the device to about 1 year.
[2254] 1289. The method of item 1202 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from about 1
month to 6 months.
[2255] 1290. The method of item 1202 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from about
1-90 days.
[2256] 1291. The method of item 1202 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device at a constant rate.
[2257] 1292. The method of item 1202 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[2258] 1293. The method of item 1202 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device at a decreasing rate.
[2259] 1294. The method of item 1202 wherein the agent is delivered
from a device, wherein the device comprises about 0.01 .mu.g to
about 10 .mu.g of the fibrosing agent.
[2260] 1295. The method of item 1202 wherein the agent is delivered
from a device, wherein the device comprises about 10 .mu.g to about
10 mg of the fibrosing agent.
[2261] 1296. The method of item 1202 wherein the agent is delivered
from a device, wherein the device comprises about 10 mg to about
250 mg of the fibrosing agent.
[2262] 1297. The method of item 1202 wherein the agent is delivered
from a device, wherein the device comprises about 250 mg to about
1000 mg of the fibrosing agent.
[2263] 1298. The method of item 1202 wherein the agent is delivered
from a device, wherein the device comprises about 1000 mg to about
2500 mg of the fibrosing agent.
[2264] 1299. The method of item 1202 wherein the agent is delivered
from a device, wherein a surface of the device comprises less than
0.01 .mu.g of the fibrosing agent per mm.sup.2 of device surface to
which the fibrosing agent is applied.
[2265] 1300. The method of item 1202 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 0.01
.mu.g to about 1 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2266] 1301. The method of item 1202 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 1
.mu.g to about 10 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2267] 1302. The method of item 1202 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 10
.mu.g to about 250 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2268] 1303. The method of item 1202 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 250
.mu.g to about 1000 .mu.g of the fibrosing agent of fibrosing agent
per mm.sup.2 of device surface to which the fibrosing agent is
applied.
[2269] 1304. The method of item 1202 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 1000
.mu.g to about 2500 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2270] 1305. The method of item 1202, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is a uniform coating.
[2271] 1306. The method of item 1202, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is a non-uniform coating.
[2272] 1307. The method of item 1202, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is a discontinuous coating.
[2273] 1308. The method of item 1202, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is a patterned coating.
[2274] 1309. The method of item 1202, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating has a thickness of 100 .mu.m or less.
[2275] 1310. The method of item 1202, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating has a thickness of 10 .mu.m or less.
[2276] 1311. The method of item 1202, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating adheres to the surface of the device upon
deployment of the device.
[2277] 1312. The method of item 1202, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is stable at room temperature for a period
of at least 1 year.
[2278] 1313. The method of item 1202, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the fibrosing agent is present in the coating in an
amount ranging between about 0.0001% to about 1% by weight.
[2279] 1314. The method of item 1202, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the fibrosing agent is present in the coating in an
amount ranging between about 1% to about 10% by weight.
[2280] 1315. The method of item 1202, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the fibrosing agent is present in the coating in an
amount ranging between about 10% to about 25% by weight.
[2281] 1316. The method of item 1202, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the fibrosing agent is present in the coating in an
amount ranging between about 25% to about 70% by weight.
[2282] 1317. The method of item 1202, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating comprises a polymer.
[2283] 1318. The method of item 1202, wherein the agent is
delivered from a device, wherein the device comprises a first
coating having a first composition and a second coating having a
second composition.
[2284] 1319. The method of item 1202, wherein the agent is
delivered from a device, wherein the device comprises a first
coating having a first composition and a second coating having a
second composition, wherein the first composition and the second
composition are different.
[2285] 1320. A method comprising introducing into a patient in need
thereof, a therapeutically effective amount of a fibrosing agent or
a composition comprising a fibrosing agent, where the fibrosing
agent induces a fibrotic response at a specific site within the
patient, thereby providing the patient with treatment or prevention
of fecal incontinence.
[2286] 1321. The method of item 1320 wherein the agent promotes
regeneration.
[2287] 1322. The method of item 1320 wherein the agent promotes
angiogenesis.
[2288] 1323. The method of item 1320 wherein the agent promotes
fibroblast migration.
[2289] 1324. The method of item 1320 wherein the agent promotes
fibroblast proliferation.
[2290] 1325. The method of item 1320 wherein the agent promotes
deposition of extracellular matrix (ECM).
[2291] 1326. The method of item 1320 wherein the agent promotes
tissue remodeling.
[2292] 1327. The method of item 1320 wherein the agent is an
arterial vessel wall irritant.
[2293] 1328. The method of item 1320 wherein the fibrosing agent is
or comprises silk.
[2294] 1329. The method of item 1320 wherein the fibrosing agent is
in the form of tufts.
[2295] 1330. The method of item 1320 wherein the fibrosing agent is
or comprises mineral particles.
[2296] 1331. The method of item 1320 wherein the fibrosing agent is
or comprises chitosan.
[2297] 1332. The method of item 1320 wherein the fibrosing agent is
or comprises polylysine.
[2298] 1333. The method of item 1320 wherein the fibrosing agent is
or comprises fibronectin.
[2299] 1334. The method of item 1320 wherein the fibrosing agent is
or comprises bleomycin.
[2300] 1335. The method of item 1320 wherein the fibrosing agent is
or comprises CTGF.
[2301] 1336. The method of item 1320 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[2302] 1337. The method of item 1320 wherein the fibrosing agent is
in the form of a particulate.
[2303] 1338. The method of item 1320, wherein the composition
comprises a polymer.
[2304] 1339. The method of item 1320, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
copolymer.
[2305] 1340. The method of item 1320, wherein the composition
comprises a polymer, and the polymer is, or comprises, a block
copolymer.
[2306] 1341. The method of item 1320, wherein the composition
comprises a polymer, and the polymer is, or comprises, a random
copolymer.
[2307] 1342. The method of item 1320, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
biodegradable polymer.
[2308] 1343. The method of item 1320, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
non-biodegradable polymer.
[2309] 1344. The method of item 1320, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrophilic polymer.
[2310] 1345. The method of item 1320, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrophobic polymer.
[2311] 1346. The method of item 1320, wherein the composition
comprises a polymer, and the polymer is, or comprises, a polymer
having hydrophilic domains.
[2312] 1347. The method of item 1320, wherein the composition
comprises a polymer, and the polymer is, or comprises, a polymer
having hydrophobic domains.
[2313] 1348. The method of item 1320, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
non-conductive polymer.
[2314] 1349. The method of item 1320, wherein the composition
comprises a polymer, and the polymer is, or comprises, an
elastomer.
[2315] 1350. The method of item 1320, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrogel.
[2316] 1351. The method of item 1320, wherein the composition
comprises a polymer, and the polymer is, or comprises, a silicone
polymer.
[2317] 1352. The method of item 1320, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrocarbon polymer.
[2318] 1353. The method of item 1320, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
styrene-derived polymer.
[2319] 1354. The method of item 1320, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
butadiene-derived polymer.
[2320] 1355. The method of item 1320, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
macromer.
[2321] 1356. The method of item 1320, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
poly(ethylene glycol) polymer.
[2322] 1357. The method of item 1320, wherein the composition
comprises a polymer, and the polymer is, or comprises, an amorphous
polymer.
[2323] 1358. The method of item 1320, wherein the composition
further comprises a second pharmaceutically active agent.
[2324] 1359. The method of item 1320, wherein the composition
further comprises an anti-inflammatory agent.
[2325] 1360. The method of item 1320, wherein the composition
further comprises an agent that inhibits infection.
[2326] 1361. The method of item 1320, wherein the composition
further comprises an anthracycline.
[2327] 1362. The method of item 1320, wherein the composition
further comprises doxorubicin.
[2328] 1363. The method of item 1320 wherein the composition
further comprises mitoxantrone.
[2329] 1364. The method of item 1320 wherein the composition
further comprises a fluoropyrimidine.
[2330] 1365. The method of item 1320, wherein the composition
further comprises 5-fluorouracil (5-FU).
[2331] 1366. The method of item 1320, wherein the composition
further comprises a folic acid antagonist.
[2332] 1367. The method of item 1320, wherein the composition
further comprises methotrexate.
[2333] 1368. The method of item 1320, wherein the composition
further comprises a podophylotoxin.
[2334] 1369. The method of item 1320, wherein the composition
further comprises etoposide.
[2335] 1370. The method of item 1320, wherein the composition
further comprises camptothecin.
[2336] 1371. The method of item 1320, wherein the composition
further comprises a hydroxyurea.
[2337] 1372. The method of item 1320, wherein the composition
further comprises a platinum complex.
[2338] 1373. The method of item 1320, wherein the composition
further comprises cisplatin.
[2339] 1374. The method of item 1320 wherein the composition
further comprises an anti-thrombotic agent.
[2340] 1375. The method of item 1320, wherein the composition
further comprises a visualization agent.
[2341] 1376. The method of item 1320, wherein the composition
further comprises a visualization agent, and the visualization
agent is a radiopaque material, wherein the radiopaque material
comprises a metal, a halogenated compound, or a barium containing
compound.
[2342] 1377. The method of item 1320, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, barium, tantalum, or technetium.
[2343] 1378. The method of item 1320, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, an MRI responsive material.
[2344] 1379. The method of item 1320, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, a gadolinium chelate.
[2345] 1380. The method of item 1320, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, iron, magnesium, manganese, copper, or
chromium.
[2346] 1381. The method of item 1320, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, iron oxide compound.
[2347] 1382. The method of item 1320, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, a dye, pigment, or colorant.
[2348] 1383. The method of item 1320 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of administration to about 90 days.
[2349] 1384. The method of item 1320 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of administration to about 90
days.
[2350] 1385. The method of item 1320 wherein the composition
further comprises an inflammatory cytokine.
[2351] 1386. The method of item 1320 wherein the composition
further comprises an agent that stimulates cell proliferation.
[2352] 1387. The method of item 1320 wherein the composition
further comprises a polymeric carrier.
[2353] 1388. The method of item 1320 wherein the composition is in
the form of a gel, paste, or spray.
[2354] 1389. The method of item 1320 wherein the agent is delivered
from a device, and the device delivers the fibrosing agent locally
to tissue proximate to the device.
[2355] 1390. The method of item 1320 wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating comprises the fibrosing agent.
[2356] 1391. The method of item 1320 wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is disposed on a surface of the device.
[2357] 1392. The method of item 1320, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating directly contacts the device.
[2358] 1393. The method of item 1320, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating indirectly contacts the device.
[2359] 1394. The method of item 1320 wherein the agent is delivered
from a device, wherein the device further comprises a coating,
wherein the coating partially covers the device.
[2360] 1395. The method of item 1320, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating completely covers the device.
[2361] 1396. The method of item 1320 wherein the agent is delivered
from a device, wherein the fibrosing agent is located within pores
or holes of the device.
[2362] 1397. The method of item 1320 wherein the agent is delivered
from a device, wherein the fibrosing agent is located within a
channel, lumen, or divet of the device.
[2363] 1398. The method of item 1320 wherein the agent is delivered
from a device, wherein the device further comprising an echogenic
material.
[2364] 1399. The method of item 1320 wherein the agent is delivered
from a device, wherein the device further comprises an echogenic
material, wherein the echogenic material is in the form of a
coating.
[2365] 1400. The method of item 1320 wherein the agent is delivered
from a device, wherein the device is sterile.
[2366] 1401. The method of item 1320 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device.
[2367] 1402. The method of item 1320 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is connective tissue.
[2368] 1403. The method of item 1320 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is muscle tissue.
[2369] 1404. The method of item 1320 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is nerve tissue.
[2370] 1405. The method of item 1320 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is epithelium tissue.
[2371] 1406. The method of item 1320 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from the time
of deployment of the device to about 1 year.
[2372] 1407. The method of item 1320 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from about 1
month to 6 months.
[2373] 1408. The method of item 1320 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from about
1-90 days.
[2374] 1409. The method of item 1320 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device at a constant rate.
[2375] 1410. The method of item 1320 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[2376] 1411. The method of item 1320 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device at a decreasing rate.
[2377] 1412. The method of item 1320 wherein the agent is delivered
from a device, wherein the device comprises about 0.01 .mu.g to
about 10 .mu.g of the fibrosing agent.
[2378] 1413. The method of item 1320 wherein the agent is delivered
from a device, wherein the device comprises about 10 .mu.g to about
10 mg of the fibrosing agent.
[2379] 1414. The method of item 1320 wherein the agent is delivered
from a device, wherein the device comprises about 10 mg to about
250 mg of the fibrosing agent.
[2380] 1415. The method of item 1320 wherein the agent is delivered
from a device, wherein the device comprises about 250 mg to about
1000 mg of the fibrosing agent.
[2381] 1416. The method of item 1320 wherein the agent is delivered
from a device, wherein the device comprises about 1000 mg to about
2500 mg of the fibrosing agent.
[2382] 1417. The method of item 1320 wherein the agent is delivered
from a device, wherein a surface of the device comprises less than
0.01 .mu.g of the fibrosing agent per mm.sup.2 of device surface to
which the fibrosing agent is applied.
[2383] 1418. The method of item 1320 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 0.01
.mu.g to about 1 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2384] 1419. The method of item 1320 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 1
.mu.g to about 10 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2385] 1420. The method of item 1320 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 10
.mu.g to about 250 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2386] 1421. The method of item 1320 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 250
.mu.g to about 1000 .mu.g of the fibrosing agent of fibrosing agent
per mm.sup.2 of device surface to which the fibrosing agent is
applied.
[2387] 1422. The method of item 1320 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 1000
.mu.g to about 2500 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2388] 1423. The method of item 1320, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is a uniform coating.
[2389] 1424. The method of item 1320, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is a non-uniform coating.
[2390] 1425. The method of item 1320, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is a discontinuous coating.
[2391] 1426. The method of item 1320, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is a patterned coating.
[2392] 1427. The method of item 1320, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating has a thickness of 100 .mu.m or less.
[2393] 1428. The method of item 1320, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating has a thickness of 10 .mu.m or less.
[2394] 1429. The method of item 1320, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating adheres to the surface of the device upon
deployment of the device.
[2395] 1430. The method of item 1320, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is stable at room temperature for a period
of at least 1 year.
[2396] 1431. The method of item 1320, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the fibrosing agent is present in the coating in an
amount ranging between about 0.0001% to about 1% by weight.
[2397] 1432. The method of item 1320, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the fibrosing agent is present in the coating in an
amount ranging between about 1% to about 10% by weight.
[2398] 1433. The method of item 1320, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the fibrosing agent is present in the coating in an
amount ranging between about 10% to about 25% by weight.
[2399] 1434. The method of item 1320, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the fibrosing agent is present in the coating in an
amount ranging between about 25% to about 70% by weight.
[2400] 1435. The method of item 1320, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating comprises a polymer.
[2401] 1436. The method of item 1320, wherein the agent is
delivered from a device, wherein the device comprises a first
coating having a first composition and a second coating having a
second composition.
[2402] 1437. The method of item 1320, wherein the agent is
delivered from a device, wherein the device comprises a first
coating having a first composition and a second coating having a
second composition, wherein the first composition and the second
composition are different.
[2403] 1438. A method comprising introducing into a patient in need
thereof, a therapeutically effective amount of a fibrosing agent or
a composition comprising a fibrosing agent, where the fibrosing
agent induces a fibrotic response at a specific site within the
patient, thereby providing the patient with treatment or prevention
of varicose veins.
[2404] 1439. The method of item 1438 wherein the agent promotes
regeneration.
[2405] 1440. The method of item 1438 wherein the agent promotes
angiogenesis.
[2406] 1441. The method of item 1438 wherein the agent promotes
fibroblast migration.
[2407] 1442. The method of item 1438 wherein the agent promotes
fibroblast proliferation.
[2408] 1443. The method of item 1438 wherein the agent promotes
deposition of extracellular matrix (ECM).
[2409] 1444. The method of item 1438 wherein the agent promotes
tissue remodeling.
[2410] 1445. The method of item 1438 wherein the agent is an
arterial vessel wall irritant.
[2411] 1446. The method of item 1438 wherein the fibrosing agent is
or comprises silk.
[2412] 1447. The method of item 1438 wherein the fibrosing agent is
in the form of tufts.
[2413] 1448. The method of item 1438 wherein the fibrosing agent is
or comprises mineral particles.
[2414] 1449. The method of item 1438 wherein the fibrosing agent is
or comprises chitosan.
[2415] 1450. The method of item 1438 wherein the fibrosing agent is
or comprises polylysine.
[2416] 1451. The method of item 1438 wherein the fibrosing agent is
or comprises fibronectin.
[2417] 1452. The method of item 1438 wherein the fibrosing agent is
or comprises bleomycin.
[2418] 1453. The method of item 1438 wherein the fibrosing agent is
or comprises CTGF.
[2419] 1454. The method of item 1438 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[2420] 1455. The method of item 1438 wherein the fibrosing agent is
in the form of a particulate.
[2421] 1456. The method of item 1438, wherein the composition
comprises a polymer.
[2422] 1457. The method of item 1438, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
copolymer.
[2423] 1458. The method of item 1438, wherein the composition
comprises a polymer, and the polymer is, or comprises, a block
copolymer.
[2424] 1459. The method of item 1438, wherein the composition
comprises a polymer, and the polymer is, or comprises, a random
copolymer.
[2425] 1460. The method of item 1438, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
biodegradable polymer.
[2426] 1461. The method of item 1438, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
non-biodegradable polymer.
[2427] 1462. The method of item 1438, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrophilic polymer.
[2428] 1463. The method of item 1438, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrophobic polymer.
[2429] 1464. The method of item 1438, wherein the composition
comprises a polymer, and the polymer is, or comprises, a polymer
having hydrophilic domains.
[2430] 1465. The method of item 1438, wherein the composition
comprises a polymer, and the polymer is, or comprises, a polymer
having hydrophobic domains.
[2431] 1466. The method of item 1438, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
non-conductive polymer.
[2432] 1467. The method of item 1438, wherein the composition
comprises a polymer, and the polymer is, or comprises, an
elastomer.
[2433] 1468. The method of item 1438, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrogel.
[2434] 1469. The method of item 1438, wherein the composition
comprises a polymer, and the polymer is, or comprises, a silicone
polymer.
[2435] 1470. The method of item 1438, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrocarbon polymer.
[2436] 1471. The method of item 1438, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
styrene-derived polymer.
[2437] 1472. The method of item 1438, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
butadiene-derived polymer.
[2438] 1473. The method of item 1438, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
macromer.
[2439] 1474. The method of item 1438, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
poly(ethylene glycol) polymer.
[2440] 1475. The method of item 1438, wherein the composition
comprises a polymer, and the polymer is, or comprises, an amorphous
polymer.
[2441] 1476. The method of item 1438, wherein the composition
further comprises a second pharmaceutically active agent.
[2442] 1477. The method of item 1438, wherein the composition
further comprises an anti-inflammatory agent.
[2443] 1478. The method of item 1438, wherein the composition
further comprises an agent that inhibits infection.
[2444] 1479. The method of item 1438, wherein the composition
further comprises an anthracycline.
[2445] 1480. The method of item 1438, wherein the composition
further comprises doxorubicin.
[2446] 1481. The method of item 1438 wherein the composition
further comprises mitoxantrone.
[2447] 1482. The method of item 1438 wherein the composition
further comprises a fluoropyrimidine.
[2448] 1483. The method of item 1438, wherein the composition
further comprises 5-fluorouracil (5-FU).
[2449] 1484. The method of item 1438, wherein the composition
further comprises a folic acid antagonist.
[2450] 1485. The method of item 1438, wherein the composition
further comprises methotrexate.
[2451] 1486. The method of item 1438, wherein the composition
further comprises a podophylotoxin.
[2452] 1487. The method of item 1438, wherein the composition
further comprises etoposide.
[2453] 1488. The method of item 1438, wherein the composition
further comprises camptothecin.
[2454] 1489. The method of item 1438, wherein the composition
further comprises a hydroxyurea.
[2455] 1490. The method of item 1438, wherein the composition
further comprises a platinum complex.
[2456] 1491. The method of item 1438, wherein the composition
further comprises cisplatin.
[2457] 1492. The method of item 1438 wherein the composition
further comprises an anti-thrombotic agent.
[2458] 1493. The method of item 1438, wherein the composition
further comprises a visualization agent.
[2459] 1494. The method of item 1438, wherein the composition
further comprises a visualization agent, and the visualization
agent is a radiopaque material, wherein the radiopaque material
comprises a metal, a halogenated compound, or a barium containing
compound.
[2460] 1495. The method of item 1438, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, barium, tantalum, or technetium.
[2461] 1496. The method of item 1438, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, an MRI responsive material.
[2462] 1497. The method of item 1438, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, a gadolinium chelate.
[2463] 1498. The method of item 1438, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, iron, magnesium, manganese, copper, or
chromium.
[2464] 1499. The method of item 1438, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, iron oxide compound.
[2465] 1500. The method of item 1438, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, a dye, pigment, or colorant.
[2466] 1501. The method of item 1438 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of administration to about 90 days.
[2467] 1502. The method of item 1438 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of administration to about 90
days.
[2468] 1503. The method of item 1438 wherein the composition
further comprises an inflammatory cytokine.
[2469] 1504. The method of item 1438 wherein the composition
further comprises an agent that stimulates cell proliferation.
[2470] 1505. The method of item 1438 wherein the composition
further comprises a polymeric carrier.
[2471] 1506. The method of item 1438 wherein the composition is in
the form of a gel, paste, or spray.
[2472] 1507. The method of item 1438 wherein the agent is delivered
from a device, and the device delivers the fibrosing agent locally
to tissue proximate to the device.
[2473] 1508. The method of item 1438 wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating comprises the fibrosing agent.
[2474] 1509. The method of item 1438 wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is disposed on a surface of the device.
[2475] 1510. The method of item 1438, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating directly contacts the device.
[2476] 1511. The method of item 1438, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating indirectly contacts the device.
[2477] 1512. The method of item 1438 wherein the agent is delivered
from a device, wherein the device further comprises a coating,
wherein the coating partially covers the device.
[2478] 1513. The method of item 1438, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating completely covers the device.
[2479] 1514. The method of item 1438 wherein the agent is delivered
from a device, wherein the fibrosing agent is located within pores
or holes of the device.
[2480] 1515. The method of item 1438 wherein the agent is delivered
from a device, wherein the fibrosing agent is located within a
channel, lumen, or divet of the device.
[2481] 1516. The method of item 1438 wherein the agent is delivered
from a device, wherein the device further comprising an echogenic
material.
[2482] 1517. The method of item 1438 wherein the agent is delivered
from a device, wherein the device further comprises an echogenic
material, wherein the echogenic material is in the form of a
coating.
[2483] 1518. The method of item 1438 wherein the agent is delivered
from a device, wherein the device is sterile.
[2484] 1519. The method of item 1438 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device.
[2485] 1520. The method of item 1438 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is connective tissue.
[2486] 1521. The method of item 1438 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is muscle tissue.
[2487] 1522. The method of item 1438 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is nerve tissue.
[2488] 1523. The method of item 1438 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is epithelium tissue.
[2489] 1524. The method of item 1438 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from the time
of deployment of the device to about 1 year.
[2490] 1525. The method of item 1438 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from about 1
month to 6 months.
[2491] 1526. The method of item 1438 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from about
1-90 days.
[2492] 1527. The method of item 1438 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device at a constant rate.
[2493] 1528. The method of item 1438 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[2494] 1529. The method of item 1438 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device at a decreasing rate.
[2495] 1530. The method of item 1438 wherein the agent is delivered
from a device, wherein the device comprises about 0.01 .mu.g to
about 10 .mu.g of the fibrosing agent.
[2496] 1531. The method of item 1438 wherein the agent is delivered
from a device, wherein the device comprises about 10 .mu.g to about
10 mg of the fibrosing agent.
[2497] 1532. The method of item 1438 wherein the agent is delivered
from a device, wherein the device comprises about 10 mg to about
250 mg of the fibrosing agent.
[2498] 1533. The method of item 1438 wherein the agent is delivered
from a device, wherein the device comprises about 250 mg to about
1000 mg of the fibrosing agent.
[2499] 1534. The method of item 1438 wherein the agent is delivered
from a device, wherein the device comprises about 1000 mg to about
2500 mg of the fibrosing agent.
[2500] 1535. The method of item 1438 wherein the agent is delivered
from a device, wherein a surface of the device comprises less than
0.01 .mu.g of the fibrosing agent per mm.sup.2 of device surface to
which the fibrosing agent is applied.
[2501] 1536. The method of item 1438 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 0.01
.mu.g to about 1 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2502] 1537. The method of item 1438 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 1
.mu.g to about 10 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2503] 1538. The method of item 1438 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 10
.mu.g to about 250 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2504] 1539. The method of item 1438 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 250
.mu.g to about 1000 .mu.g of the fibrosing agent of fibrosing agent
per mm.sup.2 of device surface to which the fibrosing agent is
applied.
[2505] 1540. The method of item 1438 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 1000
.mu.g to about 2500 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2506] 1541. The method of item 1438, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is a uniform coating.
[2507] 1542. The method of item 1438, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is a non-uniform coating.
[2508] 1543. The method of item 1438, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is a discontinuous coating.
[2509] 1544. The method of item 1438, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is a patterned coating.
[2510] 1545. The method of item 1438, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating has a thickness of 100 .mu.m or less.
[2511] 1546. The method of item 1438, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating has a thickness of 10 .mu.m or less.
[2512] 1547. The method of item 1438, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating adheres to the surface of the device upon
deployment of the device.
[2513] 1548. The method of item 1438, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is stable at room temperature for a period
of at least 1 year.
[2514] 1549. The method of item 1438, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the fibrosing agent is present in the coating in an
amount ranging between about 0.0001% to about 1% by weight.
[2515] 1550. The method of item 1438, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the fibrosing agent is present in the coating in an
amount ranging between about 1% to about 10% by weight.
[2516] 1551. The method of item 1438, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the fibrosing agent is present in the coating in an
amount ranging between about 10% to about 25% by weight.
[2517] 1552. The method of item 1438, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the fibrosing agent is present in the coating in an
amount ranging between about 25% to about 70% by weight.
[2518] 1553. The method of item 1438, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating comprises a polymer.
[2519] 1554. The method of item 1438, wherein the agent is
delivered from a device, wherein the device comprises a first
coating having a first composition and a second coating having a
second composition.
[2520] 1555. The method of item 1438, wherein the agent is
delivered from a device, wherein the device comprises a first
coating having a first composition and a second coating having a
second composition, wherein the first composition and the second
composition are different.
[2521] 1556. A method comprising introducing into a patient in need
thereof, a therapeutically effective amount of a fibrosing agent or
a composition comprising a fibrosing agent, where the fibrosing
agent induces a fibrotic response at a specific site within the
patient, thereby providing the patient with treatment for urinary
incontinence.
[2522] 1557. The method of item 1556 wherein the agent promotes
regeneration.
[2523] 1558. The method of item 1556 wherein the agent promotes
angiogenesis.
[2524] 1559. The method of item 1556 wherein the agent promotes
fibroblast migration.
[2525] 1560. The method of item 1556 wherein the agent promotes
fibroblast proliferation.
[2526] 1561. The method of item 1556 wherein the agent promotes
deposition of extracellular matrix (ECM).
[2527] 1562. The method of item 1556 wherein the agent promotes
tissue remodeling.
[2528] 1563. The method of item 1556 wherein the agent is an
arterial vessel wall irritant.
[2529] 1564. The method of item 1556 wherein the fibrosing agent is
or comprises silk.
[2530] 1565. The method of item 1556 wherein the fibrosing agent is
in the form of tufts.
[2531] 1566. The method of item 1556 wherein the fibrosing agent is
or comprises mineral particles.
[2532] 1567. The method of item 1556 wherein the fibrosing agent is
or comprises chitosan.
[2533] 1568. The method of item 1556 wherein the fibrosing agent is
or comprises polylysine.
[2534] 1569. The method of item 1556 wherein the fibrosing agent is
or comprises fibronectin.
[2535] 1570. The method of item 1556 wherein the fibrosing agent is
or comprises bleomycin.
[2536] 1571. The method of item 1556 wherein the fibrosing agent is
or comprises CTGF.
[2537] 1572. The method of item 1556 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[2538] 1573. The method of item 1556 wherein the fibrosing agent is
in the form of a particulate.
[2539] 1574. The method of item 1556, wherein the composition
comprises a polymer.
[2540] 1575. The method of item 1556, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
copolymer.
[2541] 1576. The method of item 1556, wherein the composition
comprises a polymer, and the polymer is, or comprises, a block
copolymer.
[2542] 1577. The method of item 1556, wherein the composition
comprises a polymer, and the polymer is, or comprises, a random
copolymer.
[2543] 1578. The method of item 1556, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
biodegradable polymer.
[2544] 1579. The method of item 1556, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
non-biodegradable polymer.
[2545] 1580. The method of item 1556, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrophilic polymer.
[2546] 1581. The method of item 1556, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrophobic polymer.
[2547] 1582. The method of item 1556, wherein the composition
comprises a polymer, and the polymer is, or comprises, a polymer
having hydrophilic domains.
[2548] 1583. The method of item 1556, wherein the composition
comprises a polymer, and the polymer is, or comprises, a polymer
having hydrophobic domains.
[2549] 1584. The method of item 1556, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
non-conductive polymer.
[2550] 1585. The method of item 1556, wherein the composition
comprises a polymer, and the polymer is, or comprises, an
elastomer.
[2551] 1586. The method of item 1556, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrogel.
[2552] 1587. The method of item 1556, wherein the composition
comprises a polymer, and the polymer is, or comprises, a silicone
polymer.
[2553] 1588. The method of item 1556, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrocarbon polymer.
[2554] 1589. The method of item 1556, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
styrene-derived polymer.
[2555] 1590. The method of item 1556, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
butadiene-derived polymer.
[2556] 1591. The method of item 1556, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
macromer.
[2557] 1592. The method of item 1556, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
poly(ethylene glycol) polymer.
[2558] 1593. The method of item 1556, wherein the composition
comprises a polymer, and the polymer is, or comprises, an amorphous
polymer.
[2559] 1594. The method of item 1556, wherein the composition
further comprises a second pharmaceutically active agent.
[2560] 1595. The method of item 1556, wherein the composition
further comprises an anti-inflammatory agent.
[2561] 1596. The method of item 1556, wherein the composition
further comprises an agent that inhibits infection.
[2562] 1597. The method of item 1556, wherein the composition
further comprises an anthracycline.
[2563] 1598. The method of item 1556, wherein the composition
further comprises doxorubicin.
[2564] 1599. The method of item 1556 wherein the composition
further comprises mitoxantrone.
[2565] 1600. The method of item 1556 wherein the composition
further comprises a fluoropyrimidine.
[2566] 1601. The method of item 1556, wherein the composition
further comprises 5-fluorouracil (5-FU).
[2567] 1602. The method of item 1556, wherein the composition
further comprises a folic acid antagonist.
[2568] 1603. The method of item 1556, wherein the composition
further comprises methotrexate.
[2569] 1604. The method of item 1556, wherein the composition
further comprises a podophylotoxin.
[2570] 1605. The method of item 1556, wherein the composition
further comprises etoposide.
[2571] 1606. The method of item 1556, wherein the composition
further comprises camptothecin.
[2572] 1607. The method of item 1556, wherein the composition
further comprises a hydroxyurea.
[2573] 1608. The method of item 1556, wherein the composition
further comprises a platinum complex.
[2574] 1609. The method of item 1556, wherein the composition
further comprises cisplatin.
[2575] 1610. The method of item 1556 wherein the composition
further comprises an anti-thrombotic agent.
[2576] 1611. The method of item 1556, wherein the composition
further comprises a visualization agent.
[2577] 1612. The method of item 1556, wherein the composition
further comprises a visualization agent, and the visualization
agent is a radiopaque material, wherein the radiopaque material
comprises a metal, a halogenated compound, or a barium containing
compound.
[2578] 1613. The method of item 1556, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, barium, tantalum, or technetium.
[2579] 1614. The method of item 1556, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, an MRI responsive material.
[2580] 1615. The method of item 1556, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, a gadolinium chelate.
[2581] 1616. The method of item 1556, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, iron, magnesium, manganese, copper, or
chromium.
[2582] 1617. The method of item 1556, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, iron oxide compound.
[2583] 1618. The method of item 1556, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, a dye, pigment, or colorant.
[2584] 1619. The method of item 1556 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of administration to about 90 days.
[2585] 1620. The method of item 1556 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of administration to about 90
days.
[2586] 1621. The method of item 1556 wherein the composition
further comprises an inflammatory cytokine.
[2587] 1622. The method of item 1556 wherein the composition
further comprises an agent that stimulates cell proliferation.
[2588] 1623. The method of item 1556 wherein the composition
further comprises a polymeric carrier.
[2589] 1624. The method of item 1556 wherein the composition is in
the form of a gel, paste, or spray.
[2590] 1625. The method of item 1556 wherein the agent is delivered
from a device, and the device delivers the fibrosing agent locally
to tissue proximate to the device.
[2591] 1626. The method of item 1556 wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating comprises the fibrosing agent.
[2592] 1627. The method of item 1556 wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is disposed on a surface of the device.
[2593] 1628. The method of item 1556, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating directly contacts the device.
[2594] 1629. The method of item 1556, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating indirectly contacts the device.
[2595] 1630. The method of item 1556 wherein the agent is delivered
from a device, wherein the device further comprises a coating,
wherein the coating partially covers the device.
[2596] 1631. The method of item 1556, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating completely covers the device.
[2597] 1632. The method of item 1556 wherein the agent is delivered
from a device, wherein the fibrosing agent is located within pores
or holes of the device.
[2598] 1633. The method of item 1556 wherein the agent is delivered
from a device, wherein the fibrosing agent is located within a
channel, lumen, or divet of the device.
[2599] 1634. The method of item 1556 wherein the agent is delivered
from a device, wherein the device further comprising an echogenic
material.
[2600] 1635. The method of item 1556 wherein the agent is delivered
from a device, wherein the device further comprises an echogenic
material, wherein the echogenic material is in the form of a
coating.
[2601] 1636. The method of item 1556 wherein the agent is delivered
from a device, wherein the device is sterile.
[2602] 1637. The method of item 1556 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device.
[2603] 1638. The method of item 1556 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is connective tissue.
[2604] 1639. The method of item 1556 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is muscle tissue.
[2605] 1640. The method of item 1556 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is nerve tissue.
[2606] 1641. The method of item 1556 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is epithelium tissue.
[2607] 1642. The method of item 1556 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from the time
of deployment of the device to about 1 year.
[2608] 1643. The method of item 1556 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from about 1
month to 6 months.
[2609] 1644. The method of item 1556 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from about
1-90 days.
[2610] 1645. The method of item 1556 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device at a constant rate.
[2611] 1646. The method of item 1556 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[2612] 1647. The method of item 1556 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device at a decreasing rate.
[2613] 1648. The method of item 1556 wherein the agent is delivered
from a device, wherein the device comprises about 0.01 .mu.g to
about 10 .mu.g of the fibrosing agent.
[2614] 1649. The method of item 1556 wherein the agent is delivered
from a device, wherein the device comprises about 10 .mu.g to about
10 mg of the fibrosing agent.
[2615] 1650. The method of item 1556 wherein the agent is delivered
from a device, wherein the device comprises about 10 mg to about
250 mg of the fibrosing agent.
[2616] 1651. The method of item 1556 wherein the agent is delivered
from a device, wherein the device comprises about 250 mg to about
1000 mg of the fibrosing agent.
[2617] 1652. The method of item 1556 wherein the agent is delivered
from a device, wherein the device comprises about 1000 mg to about
2500 mg of the fibrosing agent.
[2618] 1653. The method of item 1556 wherein the agent is delivered
from a device, wherein a surface of the device comprises less than
0.01 .mu.g of the fibrosing agent per mm.sup.2 of device surface to
which the fibrosing agent is applied.
[2619] 1654. The method of item 1556 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 0.01
.mu.g to about 1 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2620] 1655. The method of item 1556 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 1
.mu.g to about 10 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2621] 1656. The method of item 1556 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 10
.mu.g to about 250 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2622] 1657. The method of item 1556 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 250
.mu.g to about 1000 .mu.g of the fibrosing agent of fibrosing agent
per mm.sup.2 of device surface to which the fibrosing agent is
applied.
[2623] 1658. The method of item 1556 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 1000
.mu.g to about 2500 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2624] 1659. The method of item 1556, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is a uniform coating.
[2625] 1660. The method of item 1556, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is a non-uniform coating.
[2626] 1661. The method of item 1556, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is a discontinuous coating.
[2627] 1662. The method of item 1556, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is a patterned coating.
[2628] 1663. The method of item 1556, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating has a thickness of 100 .mu.m or less.
[2629] 1664. The method of item 1556, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating has a thickness of 10 .mu.m or less.
[2630] 1665. The method of item 1556, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating adheres to the surface of the device upon
deployment of the device.
[2631] 1666. The method of item 1556, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is stable at room temperature for a period
of at least 1 year.
[2632] 1667. The method of item 1556, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the fibrosing agent is present in the coating in an
amount ranging between about 0.0001% to about 1% by weight.
[2633] 1668. The method of item 1556, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the fibrosing agent is present in the coating in an
amount ranging between about 1% to about 10% by weight.
[2634] 1669. The method of item 1556, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the fibrosing agent is present in the coating in an
amount ranging between about 10% to about 25% by weight.
[2635] 1670. The method of item 1556, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the fibrosing agent is present in the coating in an
amount ranging between about 25% to about 70% by weight.
[2636] 1671. The method of item 1556, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating comprises a polymer.
[2637] 1672. The method of item 1556, wherein the agent is
delivered from a device, wherein the device comprises a first
coating having a first composition and a second coating having a
second composition.
[2638] 1673. The method of item 1556, wherein the agent is
delivered from a device, wherein the device comprises a first
coating having a first composition and a second coating having a
second composition, wherein the first composition and the second
composition are different.
[2639] 1674. A method comprising introducing into a patient in need
thereof, a therapeutically effective amount of a fibrosing agent or
a composition comprising a fibrosing agent, where the fibrosing
agent induces a fibrotic response at a specific site within the
patient, thereby providing the patient with contraception.
[2640] 1675. The method of item 1674 wherein the agent promotes
regeneration.
[2641] 1676. The method of item 1674 wherein the agent promotes
angiogenesis.
[2642] 1677. The method of item 1674 wherein the agent promotes
fibroblast migration.
[2643] 1678. The method of item 1674 wherein the agent promotes
fibroblast proliferation.
[2644] 1679. The method of item 1674 wherein the agent promotes
deposition of extracellular matrix (ECM).
[2645] 1680. The method of item 1674 wherein the agent promotes
tissue remodeling.
[2646] 1681. The method of item 1674 wherein the agent is an
arterial vessel wall irritant.
[2647] 1682. The method of item 1674 wherein the fibrosing agent is
or comprises silk.
[2648] 1683. The method of item 1674 wherein the fibrosing agent is
in the form of tufts.
[2649] 1684. The method of item 1674 wherein the fibrosing agent is
or comprises mineral particles.
[2650] 1685. The method of item 1674 wherein the fibrosing agent is
or comprises chitosan.
[2651] 1686. The method of item 1674 wherein the fibrosing agent is
or comprises polylysine.
[2652] 1687. The method of item 1674 wherein the fibrosing agent is
or comprises fibronectin.
[2653] 1688. The method of item 1674 wherein the fibrosing agent is
or comprises bleomycin.
[2654] 1689. The method of item 1674 wherein the fibrosing agent is
or comprises CTGF.
[2655] 1690. The method of item 1674 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[2656] 1691. The method of item 1674 wherein the fibrosing agent is
in the form of a particulate.
[2657] 1692. The method of item 1674, wherein the composition
comprises a polymer.
[2658] 1693. The method of item 1674, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
copolymer.
[2659] 1694. The method of item 1674, wherein the composition
comprises a polymer, and the polymer is, or comprises, a block
copolymer.
[2660] 1695. The method of item 1674, wherein the composition
comprises a polymer, and the polymer is, or comprises, a random
copolymer.
[2661] 1696. The method of item 1674, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
biodegradable polymer.
[2662] 1697. The method of item 1674, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
non-biodegradable polymer.
[2663] 1698. The method of item 1674, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrophilic polymer.
[2664] 1699. The method of item 1674, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrophobic polymer.
[2665] 1700. The method of item 1674, wherein the composition
comprises a polymer, and the polymer is, or comprises, a polymer
having hydrophilic domains.
[2666] 1701. The method of item 1674, wherein the composition
comprises a polymer, and the polymer is, or comprises, a polymer
having hydrophobic domains.
[2667] 1702. The method of item 1674, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
non-conductive polymer.
[2668] 1703. The method of item 1674, wherein the composition
comprises a polymer, and the polymer is, or comprises, an
elastomer.
[2669] 1704. The method of item 1674, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrogel.
[2670] 1705. The method of item 1674, wherein the composition
comprises a polymer, and the polymer is, or comprises, a silicone
polymer.
[2671] 1706. The method of item 1674, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrocarbon polymer.
[2672] 1707. The method of item 1674, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
styrene-derived polymer.
[2673] 1708. The method of item 1674, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
butadiene-derived polymer.
[2674] 1709. The method of item 1674, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
macromer.
[2675] 1710. The method of item 1674, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
poly(ethylene glycol) polymer.
[2676] 1711. The method of item 1674, wherein the composition
comprises a polymer, and the polymer is, or comprises, an amorphous
polymer.
[2677] 1712. The method of item 1674, wherein the composition
further comprises a second pharmaceutically active agent.
[2678] 1713. The method of item 1674, wherein the composition
further comprises an anti-inflammatory agent.
[2679] 1714. The method of item 1674, wherein the composition
further comprises an agent that inhibits infection.
[2680] 1715. The method of item 1674, wherein the composition
further comprises an anthracycline.
[2681] 1716. The method of item 1674, wherein the composition
further comprises doxorubicin.
[2682] 1717. The method of item 1674 wherein the composition
further comprises mitoxantrone.
[2683] 1718. The method of item 1674 wherein the composition
further comprises a fluoropyrimidine.
[2684] 1719. The method of item 1674, wherein the composition
further comprises 5-fluorouracil (5-FU).
[2685] 1720. The method of item 1674, wherein the composition
further comprises a folic acid antagonist.
[2686] 1721. The method of item 1674, wherein the composition
further comprises methotrexate.
[2687] 1722. The method of item 1674, wherein the composition
further comprises a podophylotoxin.
[2688] 1723. The method of item 1674, wherein the composition
further comprises etoposide.
[2689] 1724. The method of item 1674, wherein the composition
further comprises camptothecin.
[2690] 1725. The method of item 1674, wherein the composition
further comprises a hydroxyurea.
[2691] 1726. The method of item 1674, wherein the composition
further comprises a platinum complex.
[2692] 1727. The method of item 1674, wherein the composition
further comprises cisplatin.
[2693] 1728. The method of item 1674 wherein the composition
further comprises an anti-thrombotic agent.
[2694] 1729. The method of item 1674, wherein the composition
further comprises a visualization agent.
[2695] 1730. The method of item 1674, wherein the composition
further comprises a visualization agent, and the visualization
agent is a radiopaque material, wherein the radiopaque material
comprises a metal, a halogenated compound, or a barium containing
compound.
[2696] 1731. The method of item 1674, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, barium, tantalum, or technetium.
[2697] 1732. The method of item 1674, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, an MRI responsive material.
[2698] 1733. The method of item 1674, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, a gadolinium chelate.
[2699] 1734. The method of item 1674, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, iron, magnesium, manganese, copper, or
chromium.
[2700] 1735. The method of item 1674, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, iron oxide compound.
[2701] 1736. The method of item 1674, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, a dye, pigment, or colorant.
[2702] 1737. The method of item 1674 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of administration to about 90 days.
[2703] 1738. The method of item 1674 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of administration to about 90
days.
[2704] 1739. The method of item 1674 wherein the composition
further comprises an inflammatory cytokine.
[2705] 1740. The method of item 1674 wherein the composition
further comprises an agent that stimulates cell proliferation.
[2706] 1741. The method of item 1674 wherein the composition
further comprises a polymeric carrier.
[2707] 1742. The method of item 1674 wherein the composition is in
the form of a gel, paste, or spray.
[2708] 1743. The method of item 1674 wherein the agent is delivered
from a device, and the device delivers the fibrosing agent locally
to tissue proximate to the device.
[2709] 1744. The method of item 1674 wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating comprises the fibrosing agent.
[2710] 1745. The method of item 1674 wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is disposed on a surface of the device.
[2711] 1746. The method of item 1674, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating directly contacts the device.
[2712] 1747. The method of item 1674, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating indirectly contacts the device.
[2713] 1748. The method of item 1674 wherein the agent is delivered
from a device, wherein the device further comprises a coating,
wherein the coating partially covers the device.
[2714] 1749. The method of item 1674, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating completely covers the device.
[2715] 1750. The method of item 1674 wherein the agent is delivered
from a device, wherein the fibrosing agent is located within pores
or holes of the device.
[2716] 1751. The method of item 1674 wherein the agent is delivered
from a device, wherein the fibrosing agent is located within a
channel, lumen, or divet of the device.
[2717] 1752. The method of item 1674 wherein the agent is delivered
from a device, wherein the device further comprising an echogenic
material.
[2718] 1753. The method of item 1674 wherein the agent is delivered
from a device, wherein the device further comprises an echogenic
material, wherein the echogenic material is in the form of a
coating.
[2719] 1754. The method of item 1674 wherein the agent is delivered
from a device, wherein the device is sterile.
[2720] 1755. The method of item 1674 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device.
[2721] 1756. The method of item 1674 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is connective tissue.
[2722] 1757. The method of item 1674 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is muscle tissue.
[2723] 1758. The method of item 1674 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is nerve tissue.
[2724] 1759. The method of item 1674 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is epithelium tissue.
[2725] 1760. The method of item 1674 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from the time
of deployment of the device to about 1 year.
[2726] 1761. The method of item 1674 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from about 1
month to 6 months.
[2727] 1762. The method of item 1674 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from about
1-90 days.
[2728] 1763. The method of item 1674 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device at a constant rate.
[2729] 1764. The method of item 1674 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[2730] 1765. The method of item 1674 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device at a decreasing rate.
[2731] 1766. The method of item 1674 wherein the agent is delivered
from a device, wherein the device comprises about 0.01 .mu.g to
about 10 .mu.g of the fibrosing agent.
[2732] 1767. The method of item 1674 wherein the agent is delivered
from a device, wherein the device comprises about 10 .mu.g to about
10 mg of the fibrosing agent.
[2733] 1768. The method of item 1674 wherein the agent is delivered
from a device, wherein the device comprises about 10 mg to about
250 mg of the fibrosing agent.
[2734] 1769. The method of item 1674 wherein the agent is delivered
from a device, wherein the device comprises about 250 mg to about
1000 mg of the fibrosing agent.
[2735] 1770. The method of item 1674 wherein the agent is delivered
from a device, wherein the device comprises about 1000 mg to about
2500 mg of the fibrosing agent.
[2736] 1771. The method of item 1674 wherein the agent is delivered
from a device, wherein a surface of the device comprises less than
0.01 .mu.g of the fibrosing agent per mm.sup.2 of device surface to
which the fibrosing agent is applied.
[2737] 1772. The method of item 1674 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 0.01
.mu.g to about 1 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2738] 1773. The method of item 1674 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 1
.mu.g to about 10 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2739] 1774. The method of item 1674 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 10
.mu.g to about 250 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2740] 1775. The method of item 1674 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 250
.mu.g to about 1000 .mu.g of the fibrosing agent of fibrosing agent
per mm.sup.2 of device surface to which the fibrosing agent is
applied.
[2741] 1776. The method of item 1674 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 1000
.mu.g to about 2500 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2742] 1777. The method of item 1674, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is a uniform coating.
[2743] 1778. The method of item 1674, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is a non-uniform coating.
[2744] 1779. The method of item 1674, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is a discontinuous coating.
[2745] 1780. The method of item 1674, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is a patterned coating.
[2746] 1781. The method of item 1674, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating has a thickness of 100 .mu.m or less.
[2747] 1782. The method of item 1674, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating has a thickness of 10 .mu.m or less.
[2748] 1783. The method of item 1674, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating adheres to the surface of the device upon
deployment of the device.
[2749] 1784. The method of item 1674, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is stable at room temperature for a period
of at least 1 year.
[2750] 1785. The method of item 1674, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the fibrosing agent is present in the coating in an
amount ranging between about 0.0001% to about 1% by weight.
[2751] 1786. The method of item 1674, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the fibrosing agent is present in the coating in an
amount ranging between about 1% to about 10% by weight.
[2752] 1787. The method of item 1674, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the fibrosing agent is present in the coating in an
amount ranging between about 10% to about 25% by weight.
[2753] 1788. The method of item 1674, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the fibrosing agent is present in the coating in an
amount ranging between about 25% to about 70% by weight.
[2754] 1789. The method of item 1674, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating comprises a polymer.
[2755] 1790. The method of item 1674, wherein the agent is
delivered from a device, wherein the device comprises a first
coating having a first composition and a second coating having a
second composition.
[2756] 1791. The method of item 1674, wherein the agent is
delivered from a device, wherein the device comprises a first
coating having a first composition and a second coating having a
second composition, wherein the first composition and the second
composition are different.
[2757] 1792. A method comprising introducing into a patient in need
thereof, a therapeutically effective amount of a fibrosing agent or
a composition comprising a fibrosing agent, where the fibrosing
agent induces a fibrotic response at a specific site within the
patient, thereby providing the patient with treatment for an
orthopedic condition.
[2758] 1793. The method of item 1792 wherein the agent promotes
regeneration.
[2759] 1794. The method of item 1792 wherein the agent promotes
angiogenesis.
[2760] 1795. The method of item 1792 wherein the agent promotes
fibroblast migration.
[2761] 1796. The method of item 1792 wherein the agent promotes
fibroblast proliferation.
[2762] 1797. The method of item 1792 wherein the agent promotes
deposition of extracellular matrix (ECM).
[2763] 1798. The method of item 1792 wherein the agent promotes
tissue remodeling.
[2764] 1799. The method of item 1792 wherein the agent is an
arterial vessel wall irritant.
[2765] 1800. The method of item 1792 wherein the fibrosing agent is
or comprises silk.
[2766] 1801. The method of item 1792 wherein the fibrosing agent is
in the form of tufts.
[2767] 1802. The method of item 1792 wherein the fibrosing agent is
or comprises mineral particles.
[2768] 1803. The method of item 1792 wherein the fibrosing agent is
or comprises chitosan.
[2769] 1804. The method of item 1792 wherein the fibrosing agent is
or comprises polylysine.
[2770] 1805. The method of item 1792 wherein the fibrosing agent is
or comprises fibronectin.
[2771] 1806. The method of item 1792 wherein the fibrosing agent is
or comprises bleomycin.
[2772] 1807. The method of item 1792 wherein the fibrosing agent is
or comprises CTGF.
[2773] 1808. The method of item 1792 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[2774] 1809. The method of item 1792 wherein the fibrosing agent is
in the form of a particulate.
[2775] 1810. The method of item 1792, wherein the composition
comprises a polymer.
[2776] 1811. The method of item 1792, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
copolymer.
[2777] 1812. The method of item 1792, wherein the composition
comprises a polymer, and the polymer is, or comprises, a block
copolymer.
[2778] 1813. The method of item 1792, wherein the composition
comprises a polymer, and the polymer is, or comprises, a random
copolymer.
[2779] 1814. The method of item 1792, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
biodegradable polymer.
[2780] 1815. The method of item 1792, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
non-biodegradable polymer.
[2781] 1816. The method of item 1792, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrophilic polymer.
[2782] 1817. The method of item 1792, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrophobic polymer.
[2783] 1818. The method of item 1792, wherein the composition
comprises a polymer, and the polymer is, or comprises, a polymer
having hydrophilic domains.
[2784] 1819. The method of item 1792, wherein the composition
comprises a polymer, and the polymer is, or comprises, a polymer
having hydrophobic domains.
[2785] 1820. The method of item 1792, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
non-conductive polymer.
[2786] 1821. The method of item 1792, wherein the composition
comprises a polymer, and the polymer is, or comprises, an
elastomer.
[2787] 1822. The method of item 1792, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrogel.
[2788] 1823. The method of item 1792, wherein the composition
comprises a polymer, and the polymer is, or comprises, a silicone
polymer.
[2789] 1824. The method of item 1792, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrocarbon polymer.
[2790] 1825. The method of item 1792, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
styrene-derived polymer.
[2791] 1826. The method of item 1792, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
butadiene-derived polymer.
[2792] 1827. The method of item 1792, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
macromer.
[2793] 1828. The method of item 1792, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
poly(ethylene glycol) polymer.
[2794] 1829. The method of item 1792, wherein the composition
comprises a polymer, and the polymer is, or comprises, an amorphous
polymer.
[2795] 1830. The method of item 1792, wherein the composition
further comprises a second pharmaceutically active agent.
[2796] 1831. The method of item 1792, wherein the composition
further comprises an anti-inflammatory agent.
[2797] 1832. The method of item 1792, wherein the composition
further comprises an agent that inhibits infection.
[2798] 1833. The method of item 1792, wherein the composition
further comprises an anthracycline.
[2799] 1834. The method of item 1792, wherein the composition
further comprises doxorubicin.
[2800] 1835. The method of item 1792 wherein the composition
further comprises mitoxantrone.
[2801] 1836. The method of item 1792 wherein the composition
further comprises a fluoropyrimidine.
[2802] 1837. The method of item 1792, wherein the composition
further comprises 5-fluorouracil (5-FU).
[2803] 1838. The method of item 1792, wherein the composition
further comprises a folic acid antagonist.
[2804] 1839. The method of item 1792, wherein the composition
further comprises methotrexate.
[2805] 1840. The method of item 1792, wherein the composition
further comprises a podophylotoxin.
[2806] 1841. The method of item 1792, wherein the composition
further comprises etoposide.
[2807] 1842. The method of item 1792, wherein the composition
further comprises camptothecin.
[2808] 1843. The method of item 1792, wherein the composition
further comprises a hydroxyurea.
[2809] 1844. The method of item 1792, wherein the composition
further comprises a platinum complex.
[2810] 1845. The method of item 1792, wherein the composition
further comprises cisplatin.
[2811] 1846. The method of item 1792 wherein the composition
further comprises an anti-thrombotic agent.
[2812] 1847. The method of item 1792, wherein the composition
further comprises a visualization agent.
[2813] 1848. The method of item 1792, wherein the composition
further comprises a visualization agent, and the visualization
agent is a radiopaque material, wherein the radiopaque material
comprises a metal, a halogenated compound, or a barium containing
compound.
[2814] 1849. The method of item 1792, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, barium, tantalum, or technetium.
[2815] 1850. The method of item 1792, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, an MRI responsive material.
[2816] 1851. The method of item 1792, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, a gadolinium chelate.
[2817] 1852. The method of item 1792, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, iron, magnesium, manganese, copper, or
chromium.
[2818] 1853. The method of item 1792, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, iron oxide compound.
[2819] 1854. The method of item 1792, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, a dye, pigment, or colorant.
[2820] 1855. The method of item 1792 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of administration to about 90 days.
[2821] 1856. The method of item 1792 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of administration to about 90
days.
[2822] 1857. The method of item 1792 wherein the composition
further comprises an inflammatory cytokine.
[2823] 1858. The method of item 1792 wherein the composition
further comprises an agent that stimulates cell proliferation.
[2824] 1859. The method of item 1792 wherein the composition
further comprises a polymeric carrier.
[2825] 1860. The method of item 1792 wherein the composition is in
the form of a gel, paste, or spray.
[2826] 1861. The method of item 1792 wherein the agent is delivered
from a device, and the device delivers the fibrosing agent locally
to tissue proximate to the device.
[2827] 1862. The method of item 1792 wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating comprises the fibrosing agent.
[2828] 1863. The method of item 1792 wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is disposed on a surface of the device.
[2829] 1864. The method of item 1792, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating directly contacts the device.
[2830] 1865. The method of item 1792, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating indirectly contacts the device.
[2831] 1866. The method of item 1792 wherein the agent is delivered
from a device, wherein the device further comprises a coating,
wherein the coating partially covers the device.
[2832] 1867. The method of item 1792, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating completely covers the device.
[2833] 1868. The method of item 1792 wherein the agent is delivered
from a device, wherein the fibrosing agent is located within pores
or holes of the device.
[2834] 1869. The method of item 1792 wherein the agent is delivered
from a device, wherein the fibrosing agent is located within a
channel, lumen, or divet of the device.
[2835] 1870. The method of item 1792 wherein the agent is delivered
from a device, wherein the device further comprising an echogenic
material.
[2836] 1871. The method of item 1792 wherein the agent is delivered
from a device, wherein the device further comprises an echogenic
material, wherein the echogenic material is in the form of a
coating.
[2837] 1872. The method of item 1792 wherein the agent is delivered
from a device, wherein the device is sterile.
[2838] 1873. The method of item 1792 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device.
[2839] 1874. The method of item 1792 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is connective tissue.
[2840] 1875. The method of item 1792 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is muscle tissue.
[2841] 1876. The method of item 1792 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is nerve tissue.
[2842] 1877. The method of item 1792 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is epithelium tissue.
[2843] 1878. The method of item 1792 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from the time
of deployment of the device to about 1 year.
[2844] 1879. The method of item 1792 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from about 1
month to 6 months.
[2845] 1880. The method of item 1792 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from about
1-90 days.
[2846] 1881. The method of item 1792 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device at a constant rate.
[2847] 1882. The method of item 1792 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[2848] 1883. The method of item 1792 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device at a decreasing rate.
[2849] 1884. The method of item 1792 wherein the agent is delivered
from a device, wherein the device comprises about 0.01 .mu.g to
about 10 .mu.g of the fibrosing agent.
[2850] 1885. The method of item 1792 wherein the agent is delivered
from a device, wherein the device comprises about 10 .mu.g to about
10 mg of the fibrosing agent.
[2851] 1886. The method of item 1792 wherein the agent is delivered
from a device, wherein the device comprises about 10 mg to about
250 mg of the fibrosing agent.
[2852] 1887. The method of item 1792 wherein the agent is delivered
from a device, wherein the device comprises about 250 mg to about
1000 mg of the fibrosing agent.
[2853] 1888. The method of item 1792 wherein the agent is delivered
from a device, wherein the device comprises about 1000 mg to about
2500 mg of the fibrosing agent.
[2854] 1889. The method of item 1792 wherein the agent is delivered
from a device, wherein a surface of the device comprises less than
0.01 .mu.g of the fibrosing agent per mm.sup.2 of device surface to
which the fibrosing agent is applied.
[2855] 1890. The method of item 1792 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 0.01
.mu.g to about 1 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2856] 1891. The method of item 1792 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 1
.mu.g to about 10 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2857] 1892. The method of item 1792 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 10
.mu.g to about 250 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2858] 1893. The method of item 1792 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 250
.mu.g to about 1000 .mu.g of the fibrosing agent of fibrosing agent
per mm.sup.2 of device surface to which the fibrosing agent is
applied.
[2859] 1894. The method of item 1792 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 1000
.mu.g to about 2500 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2860] 1895. The method of item 1792, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is a uniform coating.
[2861] 1896. The method of item 1792, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is a non-uniform coating.
[2862] 1897. The method of item 1792, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is a discontinuous coating.
[2863] 1898. The method of item 1792, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is a patterned coating.
[2864] 1899. The method of item 1792, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating has a thickness of 100 .mu.m or less.
[2865] 1900. The method of item 1792, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating has a thickness of 10 .mu.m or less.
[2866] 1901. The method of item 1792, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating adheres to the surface of the device upon
deployment of the device.
[2867] 1902. The method of item 1792, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is stable at room temperature for a period
of at least 1 year.
[2868] 1903. The method of item 1792, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the fibrosing agent is present in the coating in an
amount ranging between about 0.0001% to about 1% by weight.
[2869] 1904. The method of item 1792, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the fibrosing agent is present in the coating in an
amount ranging between about 1% to about 10% by weight.
[2870] 1905. The method of item 1792, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the fibrosing agent is present in the coating in an
amount ranging between about 10% to about 25% by weight.
[2871] 1906. The method of item 1792, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the fibrosing agent is present in the coating in an
amount ranging between about 25% to about 70% by weight.
[2872] 1907. The method of item 1792, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating comprises a polymer.
[2873] 1908. The method of item 1792, wherein the agent is
delivered from a device, wherein the device comprises a first
coating having a first composition and a second coating having a
second composition.
[2874] 1909. The method of item 1792, wherein the agent is
delivered from a device, wherein the device comprises a first
coating having a first composition and a second coating having a
second composition, wherein the first composition and the second
composition are different.
[2875] 1910. A method comprising introducing into a patient in need
thereof, a therapeutically effective amount of a fibrosing agent or
a composition comprising a fibrosing agent, where the fibrosing
agent induces a fibrotic response at a specific site within the
patient, thereby providing the patient with treatment for a dental
condition.
[2876] 1911. The method of item 1910 wherein the agent promotes
regeneration.
[2877] 1912. The method of item 1910 wherein the agent promotes
angiogenesis.
[2878] 1913. The method of item 1910 wherein the agent promotes
fibroblast migration.
[2879] 1914. The method of item 1910 wherein the agent promotes
fibroblast proliferation.
[2880] 1915. The method of item 1910 wherein the agent promotes
deposition of extracellular matrix (ECM).
[2881] 1916. The method of item 1910 wherein the agent promotes
tissue remodeling.
[2882] 1917. The method of item 1910 wherein the agent is an
arterial vessel wall irritant.
[2883] 1918. The method of item 1910 wherein the fibrosing agent is
or comprises silk.
[2884] 1919. The method of item 1910 wherein the fibrosing agent is
in the form of tufts.
[2885] 1920. The method of item 1910 wherein the fibrosing agent is
or comprises mineral particles.
[2886] 1921. The method of item 1910 wherein the fibrosing agent is
or comprises chitosan.
[2887] 1922. The method of item 1910 wherein the fibrosing agent is
or comprises polylysine.
[2888] 1923. The method of item 1910 wherein the fibrosing agent is
or comprises fibronectin.
[2889] 1924. The method of item 1910 wherein the fibrosing agent is
or comprises bleomycin.
[2890] 1925. The method of item 1910 wherein the fibrosing agent is
or comprises CTGF.
[2891] 1926. The method of item 1910 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[2892] 1927. The method of item 1910 wherein the fibrosing agent is
in the form of a particulate.
[2893] 1928. The method of item 1910, wherein the composition
comprises a polymer.
[2894] 1929. The method of item 1910, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
copolymer.
[2895] 1930. The method of item 1910, wherein the composition
comprises a polymer, and the polymer is, or comprises, a block
copolymer.
[2896] 1931. The method of item 1910, wherein the composition
comprises a polymer, and the polymer is, or comprises, a random
copolymer.
[2897] 1932. The method of item 1910, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
biodegradable polymer.
[2898] 1933. The method of item 1910, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
non-biodegradable polymer.
[2899] 1934. The method of item 1910, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrophilic polymer.
[2900] 1935. The method of item 1910, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrophobic polymer.
[2901] 1936. The method of item 1910, wherein the composition
comprises a polymer, and the polymer is, or comprises, a polymer
having hydrophilic domains.
[2902] 1937. The method of item 1910, wherein the composition
comprises a polymer, and the polymer is, or comprises, a polymer
having hydrophobic domains.
[2903] 1938. The method of item 1910, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
non-conductive polymer.
[2904] 1939. The method of item 1910, wherein the composition
comprises a polymer, and the polymer is, or comprises, an
elastomer.
[2905] 1940. The method of item 1910, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrogel.
[2906] 1941. The method of item 1910, wherein the composition
comprises a polymer, and the polymer is, or comprises, a silicone
polymer.
[2907] 1942. The method of item 1910, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
hydrocarbon polymer.
[2908] 1943. The method of item 1910, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
styrene-derived polymer.
[2909] 1944. The method of item 1910, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
butadiene-derived polymer.
[2910] 1945. The method of item 1910, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
macromer.
[2911] 1946. The method of item 1910, wherein the composition
comprises a polymer, and the polymer is, or comprises, a
poly(ethylene glycol) polymer.
[2912] 1947. The method of item 1910, wherein the composition
comprises a polymer, and the polymer is, or comprises, an amorphous
polymer.
[2913] 1948. The method of item 1910, wherein the composition
further comprises a second pharmaceutically active agent.
[2914] 1949. The method of item 1910, wherein the composition
further comprises an anti-inflammatory agent.
[2915] 1950. The method of item 1910, wherein the composition
further comprises an agent that inhibits infection.
[2916] 1951. The method of item 1910, wherein the composition
further comprises an anthracycline.
[2917] 1952. The method of item 1910, wherein the composition
further comprises doxorubicin.
[2918] 1953. The method of item 1910 wherein the composition
further comprises mitoxantrone.
[2919] 1954. The method of item 1910 wherein the composition
further comprises a fluoropyrimidine.
[2920] 1955. The method of item 1910, wherein the composition
further comprises 5-fluorouracil (5-FU).
[2921] 1956. The method of item 1910, wherein the composition
further comprises a folic acid antagonist.
[2922] 1957. The method of item 1910, wherein the composition
further comprises methotrexate.
[2923] 1958. The method of item 1910, wherein the composition
further comprises a podophylotoxin.
[2924] 1959. The method of item 1910, wherein the composition
further comprises etoposide.
[2925] 1960. The method of item 1910, wherein the composition
further comprises camptothecin.
[2926] 1961. The method of item 1910, wherein the composition
further comprises a hydroxyurea.
[2927] 1962. The method of item 1910, wherein the composition
further comprises a platinum complex.
[2928] 1963. The method of item 1910, wherein the composition
further comprises cisplatin.
[2929] 1964. The method of item 1910 wherein the composition
further comprises an anti-thrombotic agent.
[2930] 1965. The method of item 1910, wherein the composition
further comprises a visualization agent.
[2931] 1966. The method of item 1910, wherein the composition
further comprises a visualization agent, and the visualization
agent is a radiopaque material, wherein the radiopaque material
comprises a metal, a halogenated compound, or a barium containing
compound.
[2932] 1967. The method of item 1910, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, barium, tantalum, or technetium.
[2933] 1968. The method of item 1910, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, an MRI responsive material.
[2934] 1969. The method of item 1910, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, a gadolinium chelate.
[2935] 1970. The method of item 1910, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, iron, magnesium, manganese, copper, or
chromium.
[2936] 1971. The method of item 1910, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, iron oxide compound.
[2937] 1972. The method of item 1910, wherein the composition
further comprises a visualization agent, and the visualization
agent is, or comprises, a dye, pigment, or colorant.
[2938] 1973. The method of item 1910 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of administration to about 90 days.
[2939] 1974. The method of item 1910 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of administration to about 90
days.
[2940] 1975. The method of item 1910 wherein the composition
further comprises an inflammatory cytokine.
[2941] 1976. The method of item 1910 wherein the composition
further comprises an agent that stimulates cell proliferation.
[2942] 1977. The method of item 1910 wherein the composition
further comprises a polymeric carrier.
[2943] 1978. The method of item 1910 wherein the composition is in
the form of a gel, paste, or spray.
[2944] 1979. The method of item 1910 wherein the agent is delivered
from a device, and the device delivers the fibrosing agent locally
to tissue proximate to the device.
[2945] 1980. The method of item 1910 wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating comprises the fibrosing agent.
[2946] 1981. The method of item 1910 wherein the agent is delivered
from a device, wherein the device further comprises a coating, and
the coating is disposed on a surface of the device.
[2947] 1982. The method of item 1910, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating directly contacts the device.
[2948] 1983. The method of item 1910, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating indirectly contacts the device.
[2949] 1984. The method of item 1910 wherein the agent is delivered
from a device, wherein the device further comprises a coating,
wherein the coating partially covers the device.
[2950] 1985. The method of item 1910, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating completely covers the device.
[2951] 1986. The method of item 1910 wherein the agent is delivered
from a device, wherein the fibrosing agent is located within pores
or holes of the device.
[2952] 1987. The method of item 1910 wherein the agent is delivered
from a device, wherein the fibrosing agent is located within a
channel, lumen, or divet of the device.
[2953] 1988. The method of item 1910 wherein the agent is delivered
from a device, wherein the device further comprising an echogenic
material.
[2954] 1989. The method of item 1910 wherein the agent is delivered
from a device, wherein the device further comprises an echogenic
material, wherein the echogenic material is in the form of a
coating.
[2955] 1990. The method of item 1910 wherein the agent is delivered
from a device, wherein the device is sterile.
[2956] 1991. The method of item 1910 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device.
[2957] 1992. The method of item 1910 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is connective tissue.
[2958] 1993. The method of item 1910 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is muscle tissue.
[2959] 1994. The method of item 1910 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is nerve tissue.
[2960] 1995. The method of item 1910 wherein the agent is delivered
from a device, wherein the fibrosing agent is released into tissue
in the vicinity of the device after deployment of the device,
wherein the tissue is epithelium tissue.
[2961] 1996. The method of item 1910 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from the time
of deployment of the device to about 1 year.
[2962] 1997. The method of item 1910 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from about 1
month to 6 months.
[2963] 1998. The method of item 1910 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device over a period ranging from about
1-90 days.
[2964] 1999. The method of item 1910 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device at a constant rate.
[2965] 2000. The method of item 1910 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[2966] 2001. The method of item 1910 wherein the agent is delivered
from a device, wherein the fibrosing agent is released in effective
concentrations from the device at a decreasing rate.
[2967] 2002. The method of item 1910 wherein the agent is delivered
from a device, wherein the device comprises about 0.01 .mu.g to
about 10 .mu.g of the fibrosing agent.
[2968] 2003. The method of item 1910 wherein the agent is delivered
from a device, wherein the device comprises about 10 .mu.g to about
10 mg of the fibrosing agent.
[2969] 2004. The method of item 1910 wherein the agent is delivered
from a device, wherein the device comprises about 10 mg to about
250 mg of the fibrosing agent.
[2970] 2005. The method of item 1910 wherein the agent is delivered
from a device, wherein the device comprises about 250 mg to about
1000 mg of the fibrosing agent.
[2971] 2006. The method of item 1910 wherein the agent is delivered
from a device, wherein the device comprises about 1000 mg to about
2500 mg of the fibrosing agent.
[2972] 2007. The method of item 1910 wherein the agent is delivered
from a device, wherein a surface of the device comprises less than
0.01 .mu.g of the fibrosing agent per mm.sup.2 of device surface to
which the fibrosing agent is applied.
[2973] 2008. The method of item 1910 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 0.01
.mu.g to about 1 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2974] 2009. The method of item 1910 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 1
.mu.g to about 10 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2975] 2010. The method of item 1910 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 10
.mu.g to about 250 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2976] 2011. The method of item 1910 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 250
.mu.g to about 1000 .mu.g of the fibrosing agent of fibrosing agent
per mm.sup.2 of device surface to which the fibrosing agent is
applied.
[2977] 2012. The method of item 1910 wherein the agent is delivered
from a device, wherein a surface of the device comprises about 1000
.mu.g to about 2500 .mu.g of the fibrosing agent per mm.sup.2 of
device surface to which the fibrosing agent is applied.
[2978] 2013. The method of item 1910, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is a uniform coating.
[2979] 2014. The method of item 1910, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is a non-uniform coating.
[2980] 2015. The method of item 1910, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is a discontinuous coating.
[2981] 2016. The method of item 1910, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is a patterned coating.
[2982] 2017. The method of item 1910, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating has a thickness of 100 .mu.m or less.
[2983] 2018. The method of item 1910, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating has a thickness of 10 .mu.m or less.
[2984] 2019. The method of item 1910, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating adheres to the surface of the device upon
deployment of the device.
[2985] 2020. The method of item 1910, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating is stable at room temperature for a period
of at least 1 year.
[2986] 2021. The method of item 1910, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the fibrosing agent is present in the coating in an
amount ranging between about 0.0001% to about 1% by weight.
[2987] 2022. The method of item 1910, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the fibrosing agent is present in the coating in an
amount ranging between about 1% to about 10% by weight.
[2988] 2023. The method of item 1910, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the fibrosing agent is present in the coating in an
amount ranging between about 10% to about 25% by weight.
[2989] 2024. The method of item 1910, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the fibrosing agent is present in the coating in an
amount ranging between about 25% to about 70% by weight.
[2990] 2025. The method of item 1910, wherein the agent is
delivered from a device, wherein the device further comprises a
coating, and the coating comprises a polymer.
[2991] 2026. The method of item 1910, wherein the agent is
delivered from a device, wherein the device comprises a first
coating having a first composition and a second coating having a
second composition.
[2992] 2027. The method of item 1910, wherein the agent is
delivered from a device, wherein the device comprises a first
coating having a first composition and a second coating having a
second composition, wherein the first composition and the second
composition are different.
[2993] 2028. A medical device comprising an orthopedic implant and
a fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
[2994] 2029. The device of item 2028 wherein the fibrosing agent
promotes regeneration.
[2995] 2030. The device of item 2028 wherein the fibrosing agent
promotes angiogenesis.
[2996] 2031. The device of item 2028 wherein the fibrosing agent
promotes fibroblast migration.
[2997] 2032. The device of item 2028 wherein the fibrosing agent
promotes fibroblast proliferation.
[2998] 2033. The device of item 2028 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[2999] 2034. The device of item 2028 wherein the fibrosing agent
promotes tissue remodeling.
[3000] 2035. The device of item 2028 wherein the fibrosing agent is
an arterial vessel wall irritant.
[3001] 2036. The device of item 2028 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[3002] 2037. The device of item 2028 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[3003] 2038. The device of item 2028 wherein the fibrosing agent is
or comprises silk.
[3004] 2039. The device of item 2028 wherein the fibrosing agent is
or comprises mineral particles.
[3005] 2040. The device of item 2028 wherein the fibrosing agent is
or comprises chitosan.
[3006] 2041. The device of item 2028 wherein the fibrosing agent is
or comprises polylysine.
[3007] 2042. The device of item 2028 wherein the fibrosing agent is
or comprises fibronectin.
[3008] 2043. The device of item 2028 wherein the fibrosing agent is
or comprises bleomycin.
[3009] 2044. The device of item 2028 wherein the fibrosing agent is
or comprises CTGF.
[3010] 2045. The device of item 2028 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[3011] 2046. The device of item 2028 wherein the fibrosing agent is
in the form of a particulate.
[3012] 2047. The device of item 2028 wherein the composition
further comprises an inflammatory cytokine.
[3013] 2048. The device of item 2028 wherein the composition
further comprises an agent that stimulates cell proliferation.
[3014] 2049. The device of item 2028 wherein the composition is in
the form of a gel, paste, or spray.
[3015] 2050. The device of item 2028 wherein the fibrosing agent is
in the form of tufts.
[3016] 2051. The device of item 2028, further comprising a
polymer.
[3017] 2052. The device of item 2028, further comprising a
polymeric carrier.
[3018] 2053. The device of item 2028 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[3019] 2054. The device of item 2028 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[3020] 2055. The device of item 2028, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[3021] 2056. The device of item 2028, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[3022] 2057. The device of item 2028, further comprising a coating,
wherein the coating directly contacts the device.
[3023] 2058. The device of item 2028, further comprising a coating,
wherein the coating indirectly contacts the device.
[3024] 2059. The device of item 2028, further comprising a coating,
wherein the coating partially covers the device.
[3025] 2060. The device of item 2028, further comprising a coating,
wherein the coating completely covers the device.
[3026] 2061. The device of item 2028, further comprising a coating,
wherein the coating is a uniform coating.
[3027] 2062. The device of item 2028, further comprising a coating,
wherein the coating is a non-uniform coating.
[3028] 2063. The device of item 2028, further comprising a coating,
wherein the coating is a discontinuous coating.
[3029] 2064. The device of item 2028, further comprising a coating,
wherein the coating is a patterned coating.
[3030] 2065. The device of item 2028, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[3031] 2066. The device of item 2028, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[3032] 2067. The device of item 2028, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[3033] 2068. The device of item 2028, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[3034] 2069. The device of item 2028, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[3035] 2070. The device of item 2028, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[3036] 2071. The device of item 2028, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[3037] 2072. The device of item 2028, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[3038] 2073. The device of item 2028, further comprising a coating,
wherein the coating further comprises a polymer.
[3039] 2074. The device of item 2028, further comprising a first
coating having a first composition and the second coating having a
second composition.
[3040] 2075. The device of item 2028, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[3041] 2076. The device of item 2028, further comprising a
polymer.
[3042] 2077. The device of item 2028, further comprising a
polymeric carrier.
[3043] 2078. The device of item 2028, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[3044] 2079. The device of item 2028, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[3045] 2080. The device of item 2028, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[3046] 2081. The device of item 2028, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[3047] 2082. The device of item 2028, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[3048] 2083. The device of item 2028, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[3049] 2084. The device of item 2028, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[3050] 2085. The device of item 2028, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[3051] 2086. The device of item 2028, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[3052] 2087. The device of item 2028, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[3053] 2088. The device of item 2028, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[3054] 2089. The device of item 2028, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[3055] 2090. The device of item 2028, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[3056] 2091. The device of item 2028, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[3057] 2092. The device of item 2028, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[3058] 2093. The device of item 2028, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[3059] 2094. The device of item 2028, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[3060] 2095. The device of item 2028, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[3061] 2096. The device of item 2028, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[3062] 2097. The device of item 2028, further comprising a
lubricious coating.
[3063] 2098. The device of item 2028 wherein the fibrosing agent is
located within pores or holes of the device.
[3064] 2099. The device of item 2028 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[3065] 2100. The device of item 2028, further comprising a second
pharmaceutically active agent.
[3066] 2101. The device of item 2028, further comprising an
anti-inflammatory agent.
[3067] 2102. The device of item 2028, further comprising an agent
that inhibits infection.
[3068] 2103. The device of item 2028, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[3069] 2104. The device of item 2028, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[3070] 2105. The device of item 2028, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[3071] 2106. The device of item 2028, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[3072] 2107. The device of item 2028, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[3073] 2108. The device of item 2028, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[3074] 2109. The device of item 2028, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[3075] 2110. The device of item 2028, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[3076] 2111. The device of item 2028, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[3077] 2112. The device of item 2028, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[3078] 2113. The device of item 2028, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[3079] 2114. The device of item 2028, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[3080] 2115. The device of item 2028, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[3081] 2116. The device of item 2028, further comprising an
anti-thrombotic agent.
[3082] 2117. The device of item 2028, further comprising a
visualization agent.
[3083] 2118. The device of item 2028, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[3084] 2119. The device of item 2028, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[3085] 2120. The device of item 2028, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[3086] 2121. The device of item 2028, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[3087] 2122. The device of item 2028, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[3088] 2123. The device of item 2028, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[3089] 2124. The device of item 2028, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[3090] 2125. The device of item 2028, further comprising an
echogenic material.
[3091] 2126. The device of item 2028, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[3092] 2127. The device of item 2028 wherein the device is
sterile.
[3093] 2128. The device of item 2028 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[3094] 2129. The device of item 2028 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[3095] 2130. The device of item 2028 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[3096] 2131. The device of item 2028 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[3097] 2132. The device of item 2028 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[3098] 2133. The device of item 2028 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[3099] 2134. The device of item 2028 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[3100] 2135. The device of item 2028 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[3101] 2136. The device of item 2028 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[3102] 2137. The device of item 2028 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[3103] 2138. The device of item 2028 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[3104] 2139. The device of item 2028 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[3105] 2140. The device of item 2028 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[3106] 2141. The device of item 2028 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[3107] 2142. The device of item 2028 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[3108] 2143. The device of item 2028 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[3109] 2144. The device of item 2028 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[3110] 2145. The device of item 2028 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[3111] 2146. The device of item 2028 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[3112] 2147. The device of item 2028 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[3113] 2148. The device of item 2028 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[3114] 2149. The device of item 2028 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[3115] 2150. The device of item 2028 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[3116] 2151. The device of item 2028 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[3117] 2152. The device of item 2028 wherein the orthopedic implant
is used as a substitute for a bone graft.
[3118] 2153. The device of item 2028 wherein the orthopedic implant
is an orthopedic pin implant.
[3119] 2154. The device of item 2028 wherein the orthopedic implant
is an orthopedic nail implant.
[3120] 2155. A medical device comprising an orthopedic prosthesis
and a fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
[3121] 2156. The device of item 2155 wherein the fibrosing agent
promotes regeneration.
[3122] 2157. The device of item 2155 wherein the fibrosing agent
promotes angiogenesis.
[3123] 2158. The device of item 2155 wherein the fibrosing agent
promotes fibroblast migration.
[3124] 2159. The device of item 2155 wherein the fibrosing agent
promotes fibroblast proliferation.
[3125] 2160. The device of item 2155 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[3126] 2161. The device of item 2155 wherein the fibrosing agent
promotes tissue remodeling.
[3127] 2162. The device of item 2155 wherein the fibrosing agent is
an arterial vessel wall irritant.
[3128] 2163. The device of item 2155 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[3129] 2164. The device of item 2155 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[3130] 2165. The device of item 2155 wherein the fibrosing agent is
or comprises silk.
[3131] 2166. The device of item 2155 wherein the fibrosing agent is
or comprises mineral particles.
[3132] 2167. The device of item 2155 wherein the fibrosing agent is
or comprises chitosan.
[3133] 2168. The device of item 2155 wherein the fibrosing agent is
or comprises polylysine.
[3134] 2169. The device of item 2155 wherein the fibrosing agent is
or comprises fibronectin.
[3135] 2170. The device of item 2155 wherein the fibrosing agent is
or comprises bleomycin.
[3136] 2171. The device of item 2155 wherein the fibrosing agent is
or comprises CTGF.
[3137] 2172. The device of item 2155 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[3138] 2173. The device of item 2155 wherein the fibrosing agent is
in the form of a particulate.
[3139] 2174. The device of item 2155 wherein the composition
further comprises an inflammatory cytokine.
[3140] 2175. The device of item 2155 wherein the composition
further comprises an agent that stimulates cell proliferation.
[3141] 2176. The device of item 2155 wherein the composition is in
the form of a gel, paste, or spray.
[3142] 2177. The device of item 2155 wherein the fibrosing agent is
in the form of tufts.
[3143] 2178. The device of item 2155, further comprising a
polymer.
[3144] 2179. The device of item 2155, further comprising a
polymeric carrier.
[3145] 2180. The device of item 2155 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[3146] 2181. The device of item 2155 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[3147] 2182. The device of item 2155, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[3148] 2183. The device of item 2155, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[3149] 2184. The device of item 2155, further comprising a coating,
wherein the coating directly contacts the device.
[3150] 2185. The device of item 2155, further comprising a coating,
wherein the coating indirectly contacts the device.
[3151] 2186. The device of item 2155, further comprising a coating,
wherein the coating partially covers the device.
[3152] 2187. The device of item 2155, further comprising a coating,
wherein the coating completely covers the device.
[3153] 2188. The device of item 2155, further comprising a coating,
wherein the coating is a uniform coating.
[3154] 2189. The device of item 2155, further comprising a coating,
wherein the coating is a non-uniform coating.
[3155] 2190. The device of item 2155, further comprising a coating,
wherein the coating is a discontinuous coating.
[3156] 2191. The device of item 2155, further comprising a coating,
wherein the coating is a patterned coating.
[3157] 2192. The device of item 2155, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[3158] 2193. The device of item 2155, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[3159] 2194. The device of item 2155, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[3160] 2195. The device of item 2155, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[3161] 2196. The device of item 2155, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[3162] 2197. The device of item 2155, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[3163] 2198. The device of item 2155, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[3164] 2199. The device of item 2155, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[3165] 2200. The device of item 2155, further comprising a coating,
wherein the coating further comprises a polymer.
[3166] 2201. The device of item 2155, further comprising a first
coating having a first composition and the second coating having a
second composition.
[3167] 2202. The device of item 2155, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[3168] 2203. The device of item 2155, further comprising a
polymer.
[3169] 2204. The device of item 2155, further comprising a
polymeric carrier.
[3170] 2205. The device of item 2155, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[3171] 2206. The device of item 2155, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[3172] 2207. The device of item 2155, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[3173] 2208. The device of item 2155, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[3174] 2209. The device of item 2155, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[3175] 2210. The device of item 2155, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[3176] 2211. The device of item 2155, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[3177] 2212. The device of item 2155, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[3178] 2213. The device of item 2155, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[3179] 2214. The device of item 2155, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[3180] 2215. The device of item 2155, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[3181] 2216. The device of item 2155, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[3182] 2217. The device of item 2155, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[3183] 2218. The device of item 2155, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[3184] 2219. The device of item 2155, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[3185] 2220. The device of item 2155, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[3186] 2221. The device of item 2155, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[3187] 2222. The device of item 2155, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[3188] 2223. The device of item 2155, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[3189] 2224. The device of item 2155, further comprising a
lubricious coating.
[3190] 2225. The device of item 2155 wherein the fibrosing agent is
located within pores or holes of the device.
[3191] 2226. The device of item 2155 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[3192] 2227. The device of item 2155, further comprising a second
pharmaceutically active agent.
[3193] 2228. The device of item 2155, further comprising an
anti-inflammatory agent.
[3194] 2229. The device of item 2155, further comprising an agent
that inhibits infection.
[3195] 2230. The device of item 2155, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[3196] 2231. The device of item 2155, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[3197] 2232. The device of item 2155, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[3198] 2233. The device of item 2155, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[3199] 2234. The device of item 2155, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[3200] 2235. The device of item 2155, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[3201] 2236. The device of item 2155, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[3202] 2237. The device of item 2155, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[3203] 2238. The device of item 2155, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[3204] 2239. The device of item 2155, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[3205] 2240. The device of item 2155, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[3206] 2241. The device of item 2155, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[3207] 2242. The device of item 2155, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[3208] 2243. The device of item 2155, further comprising an
anti-thrombotic agent.
[3209] 2244. The device of item 2155, further comprising a
visualization agent.
[3210] 2245. The device of item 2155, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[3211] 2246. The device of item 2155, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[3212] 2247. The device of item 2155, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[3213] 2248. The device of item 2155, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[3214] 2249. The device of item 2155, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[3215] 2250. The device of item 2155, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[3216] 2251. The device of item 2155, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[3217] 2252. The device of item 2155, further comprising an
echogenic material.
[3218] 2253. The device of item 2155, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[3219] 2254. The device of item 2155 wherein the device is
sterile.
[3220] 2255. The device of item 2155 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[3221] 2256. The device of item 2155 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[3222] 2257. The device of item 2155 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[3223] 2258. The device of item 2155 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[3224] 2259. The device of item 2155 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[3225] 2260. The device of item 2155 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[3226] 2261. The device of item 2155 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[3227] 2262. The device of item 2155 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[3228] 2263. The device of item 2155 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[3229] 2264. The device of item 2155 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[3230] 2265. The device of item 2155 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[3231] 2266. The device of item 2155 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[3232] 2267. The device of item 2155 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[3233] 2268. The device of item 2155 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[3234] 2269. The device of item 2155 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[3235] 2270. The device of item 2155 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[3236] 2271. The device of item 2155 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[3237] 2272. The device of item 2155 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[3238] 2273. The device of item 2155 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[3239] 2274. The device of item 2155 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[3240] 2275. The device of item 2155 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[3241] 2276. The device of item 2155 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[3242] 2277. The device of item 2155 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[3243] 2278. The device of item 2155 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[3244] 2279. A medical device comprising a modular implant and a
fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
[3245] 2280. The device of item 2279 wherein the fibrosing agent
promotes regeneration.
[3246] 2281. The device of item 2279 wherein the fibrosing agent
promotes angiogenesis.
[3247] 2282. The device of item 2279 wherein the fibrosing agent
promotes fibroblast migration.
[3248] 2283. The device of item 2279 wherein the fibrosing agent
promotes fibroblast proliferation.
[3249] 2284. The device of item 2279 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[3250] 2285. The device of item 2279 wherein the fibrosing agent
promotes tissue remodeling.
[3251] 2286. The device of item 2279 wherein the fibrosing agent is
an arterial vessel wall irritant.
[3252] 2287. The device of item 2279 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[3253] 2288. The device of item 2279 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[3254] 2289. The device of item 2279 wherein the fibrosing agent is
or comprises silk.
[3255] 2290. The device of item 2279 wherein the fibrosing agent is
or comprises mineral particles.
[3256] 2291. The device of item 2279 wherein the fibrosing agent is
or comprises chitosan.
[3257] 2292. The device of item 2279 wherein the fibrosing agent is
or comprises polylysine.
[3258] 2293. The device of item 2279 wherein the fibrosing agent is
or comprises fibronectin.
[3259] 2294. The device of item 2279 wherein the fibrosing agent is
or comprises bleomycin.
[3260] 2295. The device of item 2279 wherein the fibrosing agent is
or comprises CTGF.
[3261] 2296. The device of item 2279 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[3262] 2297. The device of item 2279 wherein the fibrosing agent is
in the form of a particulate.
[3263] 2298. The device of item 2279 wherein the composition
further comprises an inflammatory cytokine.
[3264] 2299. The device of item 2279 wherein the composition
further comprises an agent that stimulates cell proliferation.
[3265] 2300. The device of item 2279 wherein the composition is in
the form of a gel, paste, or spray.
[3266] 2301. The device of item 2279 wherein the fibrosing agent is
in the form of tufts.
[3267] 2302. The device of item 2279, further comprising a
polymer.
[3268] 2303. The device of item 2279, further comprising a
polymeric carrier.
[3269] 2304. The device of item 2279 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[3270] 2305. The device of item 2279 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[3271] 2306. The device of item 2279, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[3272] 2307. The device of item 2279, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[3273] 2308. The device of item 2279, further comprising a coating,
wherein the coating directly contacts the device.
[3274] 2309. The device of item 2279, further comprising a coating,
wherein the coating indirectly contacts the device.
[3275] 2310. The device of item 2279, further comprising a coating,
wherein the coating partially covers the device.
[3276] 2311. The device of item 2279, further comprising a coating,
wherein the coating completely covers the device.
[3277] 2312. The device of item 2279, further comprising a coating,
wherein the coating is a uniform coating.
[3278] 2313. The device of item 2279, further comprising a coating,
wherein the coating is a non-uniform coating.
[3279] 2314. The device of item 2279, further comprising a coating,
wherein the coating is a discontinuous coating.
[3280] 2315. The device of item 2279, further comprising a coating,
wherein the coating is a patterned coating.
[3281] 2316. The device of item 2279, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[3282] 2317. The device of item 2279, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[3283] 2318. The device of item 2279, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[3284] 2319. The device of item 2279, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[3285] 2320. The device of item 2279, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[3286] 2321. The device of item 2279, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[3287] 2322. The device of item 2279, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[3288] 2323. The device of item 2279, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[3289] 2324. The device of item 2279, further comprising a coating,
wherein the coating further comprises a polymer.
[3290] 2325. The device of item 2279, further comprising a first
coating having a first composition and the second coating having a
second composition.
[3291] 2326. The device of item 2279, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[3292] 2327. The device of item 2279, further comprising a
polymer.
[3293] 2328. The device of item 2279, further comprising a
polymeric carrier.
[3294] 2329. The device of item 2279, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[3295] 2330. The device of item 2279, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[3296] 2331. The device of item 2279, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[3297] 2332. The device of item 2279, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[3298] 2333. The device of item 2279, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[3299] 2334. The device of item 2279, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[3300] 2335. The device of item 2279, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[3301] 2336. The device of item 2279, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[3302] 2337. The device of item 2279, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[3303] 2338. The device of item 2279, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[3304] 2339. The device of item 2279, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[3305] 2340. The device of item 2279, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[3306] 2341. The device of item 2279, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[3307] 2342. The device of item 2279, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[3308] 2343. The device of item 2279, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[3309] 2344. The device of item 2279, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[3310] 2345. The device of item 2279, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[3311] 2346. The device of item 2279, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[3312] 2347. The device of item 2279, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[3313] 2348. The device of item 2279, further comprising a
lubricious coating.
[3314] 2349. The device of item 2279 wherein the fibrosing agent is
located within pores or holes of the device.
[3315] 2350. The device of item 2279 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[3316] 2351. The device of item 2279, further comprising a second
pharmaceutically active agent.
[3317] 2352. The device of item 2279, further comprising an
anti-inflammatory agent.
[3318] 2353. The device of item 2279, further comprising an agent
that inhibits infection.
[3319] 2354. The device of item 2279, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[3320] 2355. The device of item 2279, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[3321] 2356. The device of item 2279, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[3322] 2357. The device of item 2279, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[3323] 2358. The device of item 2279, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[3324] 2359. The device of item 2279, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[3325] 2360. The device of item 2279, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[3326] 2361. The device of item 2279, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[3327] 2362. The device of item 2279, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[3328] 2363. The device of item 2279, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[3329] 2364. The device of item 2279, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[3330] 2365. The device of item 2279, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[3331] 2366. The device of item 2279, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[3332] 2367. The device of item 2279, further comprising an
anti-thrombotic agent.
[3333] 2368. The device of item 2279, further comprising a
visualization agent.
[3334] 2369. The device of item 2279, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[3335] 2370. The device of item 2279, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[3336] 2371. The device of item 2279, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[3337] 2372. The device of item 2279, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[3338] 2373. The device of item 2279, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[3339] 2374. The device of item 2279, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[3340] 2375. The device of item 2279, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[3341] 2376. The device of item 2279, further comprising an
echogenic material.
[3342] 2377. The device of item 2279, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[3343] 2378. The device of item 2279 wherein the device is
sterile.
[3344] 2379. The device of item 2279 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[3345] 2380. The device of item 2279 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[3346] 2381. The device of item 2279 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[3347] 2382. The device of item 2279 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[3348] 2383. The device of item 2279 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[3349] 2384. The device of item 2279 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[3350] 2385. The device of item 2279 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[3351] 2386. The device of item 2279 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[3352] 2387. The device of item 2279 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[3353] 2388. The device of item 2279 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[3354] 2389. The device of item 2279 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[3355] 2390. The device of item 2279 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[3356] 2391. The device of item 2279 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[3357] 2392. The device of item 2279 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[3358] 2393. The device of item 2279 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[3359] 2394. The device of item 2279 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[3360] 2395. The device of item 2279 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[3361] 2396. The device of item 2279 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[3362] 2397. The device of item 2279 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[3363] 2398. The device of item 2279 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[3364] 2399. The device of item 2279 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[3365] 2400. The device of item 2279 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[3366] 2401. The device of item 2279 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[3367] 2402. The device of item 2279 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[3368] 2403. A medical device comprising a urinary sling and a
fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
[3369] 2404. The device of item 2403 wherein the fibrosing agent
promotes regeneration.
[3370] 2405. The device of item 2403 wherein the fibrosing agent
promotes angiogenesis.
[3371] 2406. The device of item 2403 wherein the fibrosing agent
promotes fibroblast migration.
[3372] 2407. The device of item 2403 wherein the fibrosing agent
promotes fibroblast proliferation.
[3373] 2408. The device of item 2403 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[3374] 2409. The device of item 2403 wherein the fibrosing agent
promotes tissue remodeling.
[3375] 2410. The device of item 2403 wherein the fibrosing agent is
an arterial vessel wall irritant.
[3376] 2411. The device of item 2403 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[3377] 2412. The device of item 2403 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[3378] 2413. The device of item 2403 wherein the fibrosing agent is
or comprises silk.
[3379] 2414. The device of item 2403 wherein the fibrosing agent is
or comprises mineral particles.
[3380] 2415. The device of item 2403 wherein the fibrosing agent is
or comprises chitosan.
[3381] 2416. The device of item 2403 wherein the fibrosing agent is
or comprises polylysine.
[3382] 2417. The device of item 2403 wherein the fibrosing agent is
or comprises fibronectin.
[3383] 2418. The device of item 2403 wherein the fibrosing agent is
or comprises bleomycin.
[3384] 2419. The device of item 2403 wherein the fibrosing agent is
or comprises CTGF.
[3385] 2420. The device of item 2403 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[3386] 2421. The device of item 2403 wherein the fibrosing agent is
in the form of a particulate.
[3387] 2422. The device of item 2403 wherein the composition
further comprises an inflammatory cytokine.
[3388] 2423. The device of item 2403 wherein the composition
further comprises an agent that stimulates cell proliferation.
[3389] 2424. The device of item 2403 wherein the composition is in
the form of a gel, paste, or spray.
[3390] 2425. The device of item 2403 wherein the fibrosing agent is
in the form of tufts.
[3391] 2426. The device of item 2403, further comprising a
polymer.
[3392] 2427. The device of item 2403, further comprising a
polymeric carrier.
[3393] 2428. The device of item 2403 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[3394] 2429. The device of item 2403 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[3395] 2430. The device of item 2403, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[3396] 2431. The device of item 2403, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[3397] 2432. The device of item 2403, further comprising a coating,
wherein the coating directly contacts the device.
[3398] 2433. The device of item 2403, further comprising a coating,
wherein the coating indirectly contacts the device.
[3399] 2434. The device of item 2403, further comprising a coating,
wherein the coating partially covers the device.
[3400] 2435. The device of item 2403, further comprising a coating,
wherein the coating completely covers the device.
[3401] 2436. The device of item 2403, further comprising a coating,
wherein the coating is a uniform coating.
[3402] 2437. The device of item 2403, further comprising a coating,
wherein the coating is a non-uniform coating.
[3403] 2438. The device of item 2403, further comprising a coating,
wherein the coating is a discontinuous coating.
[3404] 2439. The device of item 2403, further comprising a coating,
wherein the coating is a patterned coating.
[3405] 2440. The device of item 2403, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[3406] 2441. The device of item 2403, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[3407] 2442. The device of item 2403, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[3408] 2443. The device of item 2403, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[3409] 2444. The device of item 2403, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[3410] 2445. The device of item 2403, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[3411] 2446. The device of item 2403, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[3412] 2447. The device of item 2403, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[3413] 2448. The device of item 2403, further comprising a coating,
wherein the coating further comprises a polymer.
[3414] 2449. The device of item 2403, further comprising a first
coating having a first composition and the second coating having a
second composition.
[3415] 2450. The device of item 2403, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[3416] 2451. The device of item 2403, further comprising a
polymer.
[3417] 2452. The device of item 2403, further comprising a
polymeric carrier.
[3418] 2453. The device of item 2403, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[3419] 2454. The device of item 2403, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[3420] 2455. The device of item 2403, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[3421] 2456. The device of item 2403, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[3422] 2457. The device of item 2403, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[3423] 2458. The device of item 2403, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[3424] 2459. The device of item 2403, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[3425] 2460. The device of item 2403, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[3426] 2461. The device of item 2403, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[3427] 2462. The device of item 2403, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[3428] 2463. The device of item 2403, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[3429] 2464. The device of item 2403, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[3430] 2465. The device of item 2403, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[3431] 2466. The device of item 2403, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[3432] 2467. The device of item 2403, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[3433] 2468. The device of item 2403, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[3434] 2469. The device of item 2403, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[3435] 2470. The device of item 2403, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[3436] 2471. The device of item 2403, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[3437] 2472. The device of item 2403, further comprising a
lubricious coating.
[3438] 2473. The device of item 2403 wherein the fibrosing agent is
located within pores or holes of the device.
[3439] 2474. The device of item 2403 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[3440] 2475. The device of item 2403, further comprising a second
pharmaceutically active agent.
[3441] 2476. The device of item 2403, further comprising an
anti-inflammatory agent.
[3442] 2477. The device of item 2403, further comprising an agent
that inhibits infection.
[3443] 2478. The device of item 2403, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[3444] 2479. The device of item 2403, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[3445] 2480. The device of item 2403, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[3446] 2481. The device of item 2403, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[3447] 2482. The device of item 2403, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[3448] 2483. The device of item 2403, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[3449] 2484. The device of item 2403, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[3450] 2485. The device of item 2403, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[3451] 2486. The device of item 2403, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[3452] 2487. The device of item 2403, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[3453] 2488. The device of item 2403, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[3454] 2489. The device of item 2403, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[3455] 2490. The device of item 2403, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[3456] 2491. The device of item 2403, further comprising an
anti-thrombotic agent.
[3457] 2492. The device of item 2403, further comprising a
visualization agent.
[3458] 2493. The device of item 2403, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[3459] 2494. The device of item 2403, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[3460] 2495. The device of item 2403, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[3461] 2496. The device of item 2403, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[3462] 2497. The device of item 2403, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[3463] 2498. The device of item 2403, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[3464] 2499. The device of item 2403, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[3465] 2500. The device of item 2403, further comprising an
echogenic material.
[3466] 2501. The device of item 2403, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[3467] 2502. The device of item 2403 wherein the device is
sterile.
[3468] 2503. The device of item 2403 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[3469] 2504. The device of item 2403 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[3470] 2505. The device of item 2403 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[3471] 2506. The device of item 2403 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[3472] 2507. The device of item 2403 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[3473] 2508. The device of item 2403 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[3474] 2509. The device of item 2403 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[3475] 2510. The device of item 2403 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[3476] 2511. The device of item 2403 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[3477] 2512. The device of item 2403 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[3478] 2513. The device of item 2403 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[3479] 2514. The device of item 2403 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[3480] 2515. The device of item 2403 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[3481] 2516. The device of item 2403 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[3482] 2517. The device of item 2403 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[3483] 2518. The device of item 2403 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[3484] 2519. The device of item 2403 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[3485] 2520. The device of item 2403 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[3486] 2521. The device of item 2403 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[3487] 2522. The device of item 2403 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[3488] 2523. The device of item 2403 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[3489] 2524. The device of item 2403 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[3490] 2525. The device of item 2403 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[3491] 2526. The device of item 2403 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[3492] 2527. A medical device comprising a prosthetic joint and a
fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
[3493] 2528. The device of item 2527 wherein the fibrosing agent
promotes regeneration.
[3494] 2529. The device of item 2527 wherein the fibrosing agent
promotes angiogenesis.
[3495] 2530. The device of item 2527 wherein the fibrosing agent
promotes fibroblast migration.
[3496] 2531. The device of item 2527 wherein the fibrosing agent
promotes fibroblast proliferation.
[3497] 2532. The device of item 2527 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[3498] 2533. The device of item 2527 wherein the fibrosing agent
promotes tissue remodeling.
[3499] 2534. The device of item 2527 wherein the fibrosing agent is
an arterial vessel wall irritant.
[3500] 2535. The device of item 2527 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[3501] 2536. The device of item 2527 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[3502] 2537. The device of item 2527 wherein the fibrosing agent is
or comprises silk.
[3503] 2538. The device of item 2527 wherein the fibrosing agent is
or comprises mineral particles.
[3504] 2539. The device of item 2527 wherein the fibrosing agent is
or comprises chitosan.
[3505] 2540. The device of item 2527 wherein the fibrosing agent is
or comprises polylysine.
[3506] 2541. The device of item 2527 wherein the fibrosing agent is
or comprises fibronectin.
[3507] 2542. The device of item 2527 wherein the fibrosing agent is
or comprises bleomycin.
[3508] 2543. The device of item 2527 wherein the fibrosing agent is
or comprises CTGF.
[3509] 2544. The device of item 2527 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[3510] 2545. The device of item 2527 wherein the fibrosing agent is
in the form of a particulate.
[3511] 2546. The device of item 2527 wherein the composition
further comprises an inflammatory cytokine.
[3512] 2547. The device of item 2527 wherein the composition
further comprises an agent that stimulates cell proliferation.
[3513] 2548. The device of item 2527 wherein the composition is in
the form of a gel, paste, or spray.
[3514] 2549. The device of item 2527 wherein the fibrosing agent is
in the form of tufts.
[3515] 2550. The device of item 2527, further comprising a
polymer.
[3516] 2551. The device of item 2527, further comprising a
polymeric carrier.
[3517] 2552. The device of item 2527 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[3518] 2553. The device of item 2527 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[3519] 2554. The device of item 2527, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[3520] 2555. The device of item 2527, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[3521] 2556. The device of item 2527, further comprising a coating,
wherein the coating directly contacts the device.
[3522] 2557. The device of item 2527, further comprising a coating,
wherein the coating indirectly contacts the device.
[3523] 2558. The device of item 2527, further comprising a coating,
wherein the coating partially covers the device.
[3524] 2559. The device of item 2527, further comprising a coating,
wherein the coating completely covers the device.
[3525] 2560. The device of item 2527, further comprising a coating,
wherein the coating is a uniform coating.
[3526] 2561. The device of item 2527, further comprising a coating,
wherein the coating is a non-uniform coating.
[3527] 2562. The device of item 2527, further comprising a coating,
wherein the coating is a discontinuous coating.
[3528] 2563. The device of item 2527, further comprising a coating,
wherein the coating is a patterned coating.
[3529] 2564. The device of item 2527, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[3530] 2565. The device of item 2527, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[3531] 2566. The device of item 2527, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[3532] 2567. The device of item 2527, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[3533] 2568. The device of item 2527, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[3534] 2569. The device of item 2527, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[3535] 2570. The device of item 2527, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[3536] 2571. The device of item 2527, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[3537] 2572. The device of item 2527, further comprising a coating,
wherein the coating further comprises a polymer.
[3538] 2573. The device of item 2527, further comprising a first
coating having a first composition and the second coating having a
second composition.
[3539] 2574. The device of item 2527, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[3540] 2575. The device of item 2527, further comprising a
polymer.
[3541] 2576. The device of item 2527, further comprising a
polymeric carrier.
[3542] 2577. The device of item 2527, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[3543] 2578. The device of item 2527, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[3544] 2579. The device of item 2527, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[3545] 2580. The device of item 2527, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[3546] 2581. The device of item 2527, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[3547] 2582. The device of item 2527, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[3548] 2583. The device of item 2527, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[3549] 2584. The device of item 2527, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[3550] 2585. The device of item 2527, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[3551] 2586. The device of item 2527, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[3552] 2587. The device of item 2527, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[3553] 2588. The device of item 2527, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[3554] 2589. The device of item 2527, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[3555] 2590. The device of item 2527, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[3556] 2591. The device of item 2527, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[3557] 2592. The device of item 2527, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[3558] 2593. The device of item 2527, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[3559] 2594. The device of item 2527, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[3560] 2595. The device of item 2527, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[3561] 2596. The device of item 2527, further comprising a
lubricious coating.
[3562] 2597. The device of item 2527 wherein the fibrosing agent is
located within pores or holes of the device.
[3563] 2598. The device of item 2527 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[3564] 2599. The device of item 2527, further comprising a second
pharmaceutically active agent.
[3565] 2600. The device of item 2527, further comprising an
anti-inflammatory agent.
[3566] 2601. The device of item 2527, further comprising an agent
that inhibits infection.
[3567] 2602. The device of item 2527, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[3568] 2603. The device of item 2527, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[3569] 2604. The device of item 2527, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[3570] 2605. The device of item 2527, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[3571] 2606. The device of item 2527, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[3572] 2607. The device of item 2527, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[3573] 2608. The device of item 2527, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[3574] 2609. The device of item 2527, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[3575] 2610. The device of item 2527, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[3576] 2611. The device of item 2527, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[3577] 2612. The device of item 2527, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[3578] 2613. The device of item 2527, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[3579] 2614. The device of item 2527, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[3580] 2615. The device of item 2527, further comprising an
anti-thrombotic agent.
[3581] 2616. The device of item 2527, further comprising a
visualization agent.
[3582] 2617. The device of item 2527, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[3583] 2618. The device of item 2527, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[3584] 2619. The device of item 2527, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[3585] 2620. The device of item 2527, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[3586] 2621. The device of item 2527, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[3587] 2622. The device of item 2527, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[3588] 2623. The device of item 2527, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[3589] 2624. The device of item 2527, further comprising an
echogenic material.
[3590] 2625. The device of item 2527, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[3591] 2626. The device of item 2527 wherein the device is
sterile.
[3592] 2627. The device of item 2527 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[3593] 2628. The device of item 2527 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[3594] 2629. The device of item 2527 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[3595] 2630. The device of item 2527 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[3596] 2631. The device of item 2527 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[3597] 2632. The device of item 2527 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[3598] 2633. The device of item 2527 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[3599] 2634. The device of item 2527 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[3600] 2635. The device of item 2527 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[3601] 2636. The device of item 2527 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[3602] 2637. The device of item 2527 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[3603] 2638. The device of item 2527 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[3604] 2639. The device of item 2527 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[3605] 2640. The device of item 2527 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[3606] 2641. The device of item 2527 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[3607] 2642. The device of item 2527 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[3608] 2643. The device of item 2527 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[3609] 2644. The device of item 2527 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[3610] 2645. The device of item 2527 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[3611] 2646. The device of item 2527 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[3612] 2647. The device of item 2527 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[3613] 2648. The device of item 2527 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[3614] 2649. The device of item 2527 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[3615] 2650. The device of item 2527 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[3616] 2651. A medical device comprising a modular prosthesis and a
fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
[3617] 2652. The device of item 2651 wherein the fibrosing agent
promotes regeneration.
[3618] 2653. The device of item 2651 wherein the fibrosing agent
promotes angiogenesis.
[3619] 2654. The device of item 2651 wherein the fibrosing agent
promotes fibroblast migration.
[3620] 2655. The device of item 2651 wherein the fibrosing agent
promotes fibroblast proliferation.
[3621] 2656. The device of item 2651 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[3622] 2657. The device of item 2651 wherein the fibrosing agent
promotes tissue remodeling.
[3623] 2658. The device of item 2651 wherein the fibrosing agent is
an arterial vessel wall irritant.
[3624] 2659. The device of item 2651 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[3625] 2660. The device of item 2651 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[3626] 2661. The device of item 2651 wherein the fibrosing agent is
or comprises silk.
[3627] 2662. The device of item 2651 wherein the fibrosing agent is
or comprises mineral particles.
[3628] 2663. The device of item 2651 wherein the fibrosing agent is
or comprises chitosan.
[3629] 2664. The device of item 2651 wherein the fibrosing agent is
or comprises polylysine.
[3630] 2665. The device of item 2651 wherein the fibrosing agent is
or comprises fibronectin.
[3631] 2666. The device of item 2651 wherein the fibrosing agent is
or comprises bleomycin.
[3632] 2667. The device of item 2651 wherein the fibrosing agent is
or comprises CTGF.
[3633] 2668. The device of item 2651 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[3634] 2669. The device of item 2651 wherein the fibrosing agent is
in the form of a particulate.
[3635] 2670. The device of item 2651 wherein the composition
further comprises an inflammatory cytokine.
[3636] 2671. The device of item 2651 wherein the composition
further comprises an agent that stimulates cell proliferation.
[3637] 2672. The device of item 2651 wherein the composition is in
the form of a gel, paste, or spray.
[3638] 2673. The device of item 2651 wherein the fibrosing agent is
in the form of tufts.
[3639] 2674. The device of item 2651, further comprising a
polymer.
[3640] 2675. The device of item 2651, further comprising a
polymeric carrier.
[3641] 2676. The device of item 2651 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[3642] 2677. The device of item 2651 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[3643] 2678. The device of item 2651, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[3644] 2679. The device of item 2651, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[3645] 2680. The device of item 2651, further comprising a coating,
wherein the coating directly contacts the device.
[3646] 2681. The device of item 2651, further comprising a coating,
wherein the coating indirectly contacts the device.
[3647] 2682. The device of item 2651, further comprising a coating,
wherein the coating partially covers the device.
[3648] 2683. The device of item 2651, further comprising a coating,
wherein the coating completely covers the device.
[3649] 2684. The device of item 2651, further comprising a coating,
wherein the coating is a uniform coating.
[3650] 2685. The device of item 2651, further comprising a coating,
wherein the coating is a non-uniform coating.
[3651] 2686. The device of item 2651, further comprising a coating,
wherein the coating is a discontinuous coating.
[3652] 2687. The device of item 2651, further comprising a coating,
wherein the coating is a patterned coating.
[3653] 2688. The device of item 2651, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[3654] 2689. The device of item 2651, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[3655] 2690. The device of item 2651, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[3656] 2691. The device of item 2651, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[3657] 2692. The device of item 2651, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[3658] 2693. The device of item 2651, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[3659] 2694. The device of item 2651, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[3660] 2695. The device of item 2651, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[3661] 2696. The device of item 2651, further comprising a coating,
wherein the coating further comprises a polymer.
[3662] 2697. The device of item 2651, further comprising a first
coating having a first composition and the second coating having a
second composition.
[3663] 2698. The device of item 2651, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[3664] 2699. The device of item 2651, further comprising a
polymer.
[3665] 2700. The device of item 2651, further comprising a
polymeric carrier.
[3666] 2701. The device of item 2651, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[3667] 2702. The device of item 2651, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[3668] 2703. The device of item 2651, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[3669] 2704. The device of item 2651, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[3670] 2705. The device of item 2651, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[3671] 2706. The device of item 2651, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[3672] 2707. The device of item 2651, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[3673] 2708. The device of item 2651, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[3674] 2709. The device of item 2651, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[3675] 2710. The device of item 2651, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[3676] 2711. The device of item 2651, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[3677] 2712. The device of item 2651, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[3678] 2713. The device of item 2651, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[3679] 2714. The device of item 2651, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[3680] 2715. The device of item 2651, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[3681] 2716. The device of item 2651, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[3682] 2717. The device of item 2651, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[3683] 2718. The device of item 2651, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[3684] 2719. The device of item 2651, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[3685] 2720. The device of item 2651, further comprising a
lubricious coating.
[3686] 2721. The device of item 2651 wherein the fibrosing agent is
located within pores or holes of the device.
[3687] 2722. The device of item 2651 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[3688] 2723. The device of item 2651, further comprising a second
pharmaceutically active agent.
[3689] 2724. The device of item 2651, further comprising an
anti-inflammatory agent.
[3690] 2725. The device of item 2651, further comprising an agent
that inhibits infection.
[3691] 2726. The device of item 2651, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[3692] 2727. The device of item 2651, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[3693] 2728. The device of item 2651, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[3694] 2729. The device of item 2651, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[3695] 2730. The device of item 2651, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[3696] 2731. The device of item 2651, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[3697] 2732. The device of item 2651, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[3698] 2733. The device of item 2651, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[3699] 2734. The device of item 2651, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[3700] 2735. The device of item 2651, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[3701] 2736. The device of item 2651, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[3702] 2737. The device of item 2651, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[3703] 2738. The device of item 2651, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[3704] 2739. The device of item 2651, further comprising an
anti-thrombotic agent.
[3705] 2740. The device of item 2651, further comprising a
visualization agent.
[3706] 2741. The device of item 2651, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[3707] 2742. The device of item 2651, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[3708] 2743. The device of item 2651, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[3709] 2744. The device of item 2651, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[3710] 2745. The device of item 2651, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[3711] 2746. The device of item 2651, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[3712] 2747. The device of item 2651, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[3713] 2748. The device of item 2651, further comprising an
echogenic material.
[3714] 2749. The device of item 2651, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[3715] 2750. The device of item 2651 wherein the device is
sterile.
[3716] 2751. The device of item 2651 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[3717] 2752. The device of item 2651 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[3718] 2753. The device of item 2651 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[3719] 2754. The device of item 2651 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[3720] 2755. The device of item 2651 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[3721] 2756. The device of item 2651 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[3722] 2757. The device of item 2651 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[3723] 2758. The device of item 2651 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[3724] 2759. The device of item 2651 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[3725] 2760. The device of item 2651 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[3726] 2761. The device of item 2651 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[3727] 2762. The device of item 2651 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[3728] 2763. The device of item 2651 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[3729] 2764. The device of item 2651 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[3730] 2765. The device of item 2651 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[3731] 2766. The device of item 2651 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[3732] 2767. The device of item 2651 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[3733] 2768. The device of item 2651 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[3734] 2769. The device of item 2651 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[3735] 2770. The device of item 2651 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[3736] 2771. The device of item 2651 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[3737] 2772. The device of item 2651 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[3738] 2773. The device of item 2651 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[3739] 2774. The device of item 2651 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[3740] 2775. A medical device comprising a joint prosthesis and a
fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
[3741] 2776. The device of item 2775 wherein the fibrosing agent
promotes regeneration.
[3742] 2777. The device of item 2775 wherein the fibrosing agent
promotes angiogenesis.
[3743] 2778. The device of item 2775 wherein the fibrosing agent
promotes fibroblast migration.
[3744] 2779. The device of item 2775 wherein the fibrosing agent
promotes fibroblast proliferation.
[3745] 2780. The device of item 2775 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[3746] 2781. The device of item 2775 wherein the fibrosing agent
promotes tissue remodeling.
[3747] 2782. The device of item 2775 wherein the fibrosing agent is
an arterial vessel wall irritant.
[3748] 2783. The device of item 2775 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[3749] 2784. The device of item 2775 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[3750] 2785. The device of item 2775 wherein the fibrosing agent is
or comprises silk.
[3751] 2786. The device of item 2775 wherein the fibrosing agent is
or comprises mineral particles.
[3752] 2787. The device of item 2775 wherein the fibrosing agent is
or comprises chitosan.
[3753] 2788. The device of item 2775 wherein the fibrosing agent is
or comprises polylysine.
[3754] 2789. The device of item 2775 wherein the fibrosing agent is
or comprises fibronectin.
[3755] 2790. The device of item 2775 wherein the fibrosing agent is
or comprises bleomycin.
[3756] 2791. The device of item 2775 wherein the fibrosing agent is
or comprises CTGF.
[3757] 2792. The device of item 2775 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[3758] 2793. The device of item 2775 wherein the fibrosing agent is
in the form of a particulate.
[3759] 2794. The device of item 2775 wherein the composition
further comprises an inflammatory cytokine.
[3760] 2795. The device of item 2775 wherein the composition
further comprises an agent that stimulates cell proliferation.
[3761] 2796. The device of item 2775 wherein the composition is in
the form of a gel, paste, or spray.
[3762] 2797. The device of item 2775 wherein the fibrosing agent is
in the form of tufts.
[3763] 2798. The device of item 2775, further comprising a
polymer.
[3764] 2799. The device of item 2775, further comprising a
polymeric carrier.
[3765] 2800. The device of item 2775 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[3766] 2801. The device of item 2775 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[3767] 2802. The device of item 2775, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[3768] 2803. The device of item 2775, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[3769] 2804. The device of item 2775, further comprising a coating,
wherein the coating directly contacts the device.
[3770] 2805. The device of item 2775, further comprising a coating,
wherein the coating indirectly contacts the device.
[3771] 2806. The device of item 2775, further comprising a coating,
wherein the coating partially covers the device.
[3772] 2807. The device of item 2775, further comprising a coating,
wherein the coating completely covers the device.
[3773] 2808. The device of item 2775, further comprising a coating,
wherein the coating is a uniform coating.
[3774] 2809. The device of item 2775, further comprising a coating,
wherein the coating is a non-uniform coating.
[3775] 2810. The device of item 2775, further comprising a coating,
wherein the coating is a discontinuous coating.
[3776] 2811. The device of item 2775, further comprising a coating,
wherein the coating is a patterned coating.
[3777] 2812. The device of item 2775, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[3778] 2813. The device of item 2775, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[3779] 2814. The device of item 2775, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[3780] 2815. The device of item 2775, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[3781] 2816. The device of item 2775, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[3782] 2817. The device of item 2775, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[3783] 2818. The device of item 2775, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[3784] 2819. The device of item 2775, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[3785] 2820. The device of item 2775, further comprising a coating,
wherein the coating further comprises a polymer.
[3786] 2821. The device of item 2775, further comprising a first
coating having a first composition and the second coating having a
second composition.
[3787] 2822. The device of item 2775, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[3788] 2823. The device of item 2775, further comprising a
polymer.
[3789] 2824. The device of item 2775, further comprising a
polymeric carrier.
[3790] 2825. The device of item 2775, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[3791] 2826. The device of item 2775, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[3792] 2827. The device of item 2775, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[3793] 2828. The device of item 2775, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[3794] 2829. The device of item 2775, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[3795] 2830. The device of item 2775, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[3796] 2831. The device of item 2775, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[3797] 2832. The device of item 2775, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[3798] 2833. The device of item 2775, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[3799] 2834. The device of item 2775, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[3800] 2835. The device of item 2775, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[3801] 2836. The device of item 2775, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[3802] 2837. The device of item 2775, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[3803] 2838. The device of item 2775, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[3804] 2839. The device of item 2775, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[3805] 2840. The device of item 2775, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[3806] 2841. The device of item 2775, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[3807] 2842. The device of item 2775, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[3808] 2843. The device of item 2775, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[3809] 2844. The device of item 2775, further comprising a
lubricious coating.
[3810] 2845. The device of item 2775 wherein the fibrosing agent is
located within pores or holes of the device.
[3811] 2846. The device of item 2775 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[3812] 2847. The device of item 2775, further comprising a second
pharmaceutically active agent.
[3813] 2848. The device of item 2775, further comprising an
anti-inflammatory agent.
[3814] 2849. The device of item 2775, further comprising an agent
that inhibits infection.
[3815] 2850. The device of item 2775, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[3816] 2851. The device of item 2775, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[3817] 2852. The device of item 2775, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[3818] 2853. The device of item 2775, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[3819] 2854. The device of item 2775, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[3820] 2855. The device of item 2775, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[3821] 2856. The device of item 2775, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[3822] 2857. The device of item 2775, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[3823] 2858. The device of item 2775, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[3824] 2859. The device of item 2775, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[3825] 2860. The device of item 2775, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[3826] 2861. The device of item 2775, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[3827] 2862. The device of item 2775, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[3828] 2863. The device of item 2775, further comprising an
anti-thrombotic agent.
[3829] 2864. The device of item 2775, further comprising a
visualization agent.
[3830] 2865. The device of item 2775, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[3831] 2866. The device of item 2775, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[3832] 2867. The device of item 2775, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[3833] 2868. The device of item 2775, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[3834] 2869. The device of item 2775, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[3835] 2870. The device of item 2775, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[3836] 2871. The device of item 2775, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[3837] 2872. The device of item 2775, further comprising an
echogenic material.
[3838] 2873. The device of item 2775, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[3839] 2874. The device of item 2775 wherein the device is
sterile.
[3840] 2875. The device of item 2775 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[3841] 2876. The device of item 2775 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[3842] 2877. The device of item 2775 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[3843] 2878. The device of item 2775 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[3844] 2879. The device of item 2775 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[3845] 2880. The device of item 2775 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[3846] 2881. The device of item 2775 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[3847] 2882. The device of item 2775 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[3848] 2883. The device of item 2775 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[3849] 2884. The device of item 2775 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[3850] 2885. The device of item 2775 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[3851] 2886. The device of item 2775 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[3852] 2887. The device of item 2775 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[3853] 2888. The device of item 2775 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[3854] 2889. The device of item 2775 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[3855] 2890. The device of item 2775 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[3856] 2891. The device of item 2775 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[3857] 2892. The device of item 2775 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[3858] 2893. The device of item 2775 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[3859] 2894. The device of item 2775 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[3860] 2895. The device of item 2775 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[3861] 2896. The device of item 2775 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[3862] 2897. The device of item 2775 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[3863] 2898. The device of item 2775 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[3864] 2899. A medical device comprising a partial prosthesis and a
fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
[3865] 2900. The device of item 2899 wherein the fibrosing agent
promotes regeneration.
[3866] 2901. The device of item 2899 wherein the fibrosing agent
promotes angiogenesis.
[3867] 2902. The device of item 2899 wherein the fibrosing agent
promotes fibroblast migration.
[3868] 2903. The device of item 2899 wherein the fibrosing agent
promotes fibroblast proliferation.
[3869] 2904. The device of item 2899 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[3870] 2905. The device of item 2899 wherein the fibrosing agent
promotes tissue remodeling.
[3871] 2906. The device of item 2899 wherein the fibrosing agent is
an arterial vessel wall irritant.
[3872] 2907. The device of item 2899 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[3873] 2908. The device of item 2899 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[3874] 2909. The device of item 2899 wherein the fibrosing agent is
or comprises silk.
[3875] 2910. The device of item 2899 wherein the fibrosing agent is
or comprises mineral particles.
[3876] 2911. The device of item 2899 wherein the fibrosing agent is
or comprises chitosan.
[3877] 2912. The device of item 2899 wherein the fibrosing agent is
or comprises polylysine.
[3878] 2913. The device of item 2899 wherein the fibrosing agent is
or comprises fibronectin.
[3879] 2914. The device of item 2899 wherein the fibrosing agent is
or comprises bleomycin.
[3880] 2915. The device of item 2899 wherein the fibrosing agent is
or comprises CTGF.
[3881] 2916. The device of item 2899 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[3882] 2917. The device of item 2899 wherein the fibrosing agent is
in the form of a particulate.
[3883] 2918. The device of item 2899 wherein the composition
further comprises an inflammatory cytokine.
[3884] 2919. The device of item 2899 wherein the composition
further comprises an agent that stimulates cell proliferation.
[3885] 2920. The device of item 2899 wherein the composition is in
the form of a gel, paste, or spray.
[3886] 2921. The device of item 2899 wherein the fibrosing agent is
in the form of tufts.
[3887] 2922. The device of item 2899, further comprising a
polymer.
[3888] 2923. The device of item 2899, further comprising a
polymeric carrier.
[3889] 2924. The device of item 2899 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[3890] 2925. The device of item 2899 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[3891] 2926. The device of item 2899, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[3892] 2927. The device of item 2899, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[3893] 2928. The device of item 2899, further comprising a coating,
wherein the coating directly contacts the device.
[3894] 2929. The device of item 2899, further comprising a coating,
wherein the coating indirectly contacts the device.
[3895] 2930. The device of item 2899, further comprising a coating,
wherein the coating partially covers the device.
[3896] 2931. The device of item 2899, further comprising a coating,
wherein the coating completely covers the device.
[3897] 2932. The device of item 2899, further comprising a coating,
wherein the coating is a uniform coating.
[3898] 2933. The device of item 2899, further comprising a coating,
wherein the coating is a non-uniform coating.
[3899] 2934. The device of item 2899, further comprising a coating,
wherein the coating is a discontinuous coating.
[3900] 2935. The device of item 2899, further comprising a coating,
wherein the coating is a patterned coating.
[3901] 2936. The device of item 2899, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[3902] 2937. The device of item 2899, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[3903] 2938. The device of item 2899, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[3904] 2939. The device of item 2899, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[3905] 2940. The device of item 2899, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[3906] 2941. The device of item 2899, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[3907] 2942. The device of item 2899, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[3908] 2943. The device of item 2899, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[3909] 2944. The device of item 2899, further comprising a coating,
wherein the coating further comprises a polymer.
[3910] 2945. The device of item 2899, further comprising a first
coating having a first composition and the second coating having a
second composition.
[3911] 2946. The device of item 2899, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[3912] 2947. The device of item 2899, further comprising a
polymer.
[3913] 2948. The device of item 2899, further comprising a
polymeric carrier.
[3914] 2949. The device of item 2899, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[3915] 2950. The device of item 2899, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[3916] 2951. The device of item 2899, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[3917] 2952. The device of item 2899, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[3918] 2953. The device of item 2899, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[3919] 2954. The device of item 2899, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[3920] 2955. The device of item 2899, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[3921] 2956. The device of item 2899, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[3922] 2957. The device of item 2899, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[3923] 2958. The device of item 2899, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[3924] 2959. The device of item 2899, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[3925] 2960. The device of item 2899, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[3926] 2961. The device of item 2899, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[3927] 2962. The device of item 2899, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[3928] 2963. The device of item 2899, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[3929] 2964. The device of item 2899, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[3930] 2965. The device of item 2899, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[3931] 2966. The device of item 2899, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[3932] 2967. The device of item 2899, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[3933] 2968. The device of item 2899, further comprising a
lubricious coating.
[3934] 2969. The device of item 2899 wherein the fibrosing agent is
located within pores or holes of the device.
[3935] 2970. The device of item 2899 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[3936] 2971. The device of item 2899, further comprising a second
pharmaceutically active agent.
[3937] 2972. The device of item 2899, further comprising an
anti-inflammatory agent.
[3938] 2973. The device of item 2899, further comprising an agent
that inhibits infection.
[3939] 2974. The device of item 2899, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[3940] 2975. The device of item 2899, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[3941] 2976. The device of item 2899, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[3942] 2977. The device of item 2899, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[3943] 2978. The device of item 2899, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[3944] 2979. The device of item 2899, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[3945] 2980. The device of item 2899, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[3946] 2981. The device of item 2899, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[3947] 2982. The device of item 2899, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[3948] 2983. The device of item 2899, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[3949] 2984. The device of item 2899, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[3950] 2985. The device of item 2899, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[3951] 2986. The device of item 2899, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[3952] 2987. The device of item 2899, further comprising an
anti-thrombotic agent.
[3953] 2988. The device of item 2899, further comprising a
visualization agent.
[3954] 2989. The device of item 2899, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[3955] 2990. The device of item 2899, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[3956] 2991. The device of item 2899, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[3957] 2992. The device of item 2899, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[3958] 2993. The device of item 2899, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[3959] 2994. The device of item 2899, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[3960] 2995. The device of item 2899, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[3961] 2996. The device of item 2899, further comprising an
echogenic material.
[3962] 2997. The device of item 2899, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[3963] 2998. The device of item 2899 wherein the device is
sterile.
[3964] 2999. The device of item 2899 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[3965] 3000. The device of item 2899 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[3966] 3001. The device of item 2899 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[3967] 3002. The device of item 2899 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[3968] 3003. The device of item 2899 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[3969] 3004. The device of item 2899 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[3970] 3005. The device of item 2899 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[3971] 3006. The device of item 2899 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[3972] 3007. The device of item 2899 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[3973] 3008. The device of item 2899 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[3974] 3009. The device of item 2899 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[3975] 3010. The device of item 2899 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[3976] 3011. The device of item 2899 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[3977] 3012. The device of item 2899 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[3978] 3013. The device of item 2899 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[3979] 3014. The device of item 2899 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[3980] 3015. The device of item 2899 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[3981] 3016. The device of item 2899 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[3982] 3017. The device of item 2899 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[3983] 3018. The device of item 2899 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[3984] 3019. The device of item 2899 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[3985] 3020. The device of item 2899 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[3986] 3021. The device of item 2899 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[3987] 3022. The device of item 2899 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[3988] 3023. A medical device comprising a hip implant and a
fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
[3989] 3024. The device of item 3023 wherein the fibrosing agent
promotes regeneration.
[3990] 3025. The device of item 3023 wherein the fibrosing agent
promotes angiogenesis.
[3991] 3026. The device of item 3023 wherein the fibrosing agent
promotes fibroblast migration.
[3992] 3027. The device of item 3023 wherein the fibrosing agent
promotes fibroblast proliferation.
[3993] 3028. The device of item 3023 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[3994] 3029. The device of item 3023 wherein the fibrosing agent
promotes tissue remodeling.
[3995] 3030. The device of item 3023 wherein the fibrosing agent is
an arterial vessel wall irritant.
[3996] 3031. The device of item 3023 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[3997] 3032. The device of item 3023 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[3998] 3033. The device of item 3023 wherein the fibrosing agent is
or comprises silk.
[3999] 3034. The device of item 3023 wherein the fibrosing agent is
or comprises mineral particles.
[4000] 3035. The device of item 3023 wherein the fibrosing agent is
or comprises chitosan.
[4001] 3036. The device of item 3023 wherein the fibrosing agent is
or comprises polylysine.
[4002] 3037. The device of item 3023 wherein the fibrosing agent is
or comprises fibronectin.
[4003] 3038. The device of item 3023 wherein the fibrosing agent is
or comprises bleomycin.
[4004] 3039. The device of item 3023 wherein the fibrosing agent is
or comprises CTGF.
[4005] 3040. The device of item 3023 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[4006] 3041. The device of item 3023 wherein the fibrosing agent is
in the form of a particulate.
[4007] 3042. The device of item 3023 wherein the composition
further comprises an inflammatory cytokine.
[4008] 3043. The device of item 3023 wherein the composition
further comprises an agent that stimulates cell proliferation.
[4009] 3044. The device of item 3023 wherein the composition is in
the form of a gel, paste, or spray.
[4010] 3045. The device of item 3023 wherein the fibrosing agent is
in the form of tufts.
[4011] 3046. The device of item 3023, further comprising a
polymer.
[4012] 3047. The device of item 3023, further comprising a
polymeric carrier.
[4013] 3048. The device of item 3023 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[4014] 3049. The device of item 3023 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[4015] 3050. The device of item 3023, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[4016] 3051. The device of item 3023, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[4017] 3052. The device of item 3023, further comprising a coating,
wherein the coating directly contacts the device.
[4018] 3053. The device of item 3023, further comprising a coating,
wherein the coating indirectly contacts the device.
[4019] 3054. The device of item 3023, further comprising a coating,
wherein the coating partially covers the device.
[4020] 3055. The device of item 3023, further comprising a coating,
wherein the coating completely covers the device.
[4021] 3056. The device of item 3023, further comprising a coating,
wherein the coating is a uniform coating.
[4022] 3057. The device of item 3023, further comprising a coating,
wherein the coating is a non-uniform coating.
[4023] 3058. The device of item 3023, further comprising a coating,
wherein the coating is a discontinuous coating.
[4024] 3059. The device of item 3023, further comprising a coating,
wherein the coating is a patterned coating.
[4025] 3060. The device of item 3023, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[4026] 3061. The device of item 3023, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[4027] 3062. The device of item 3023, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[4028] 3063. The device of item 3023, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[4029] 3064. The device of item 3023, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[4030] 3065. The device of item 3023, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[4031] 3066. The device of item 3023, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[4032] 3067. The device of item 3023, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[4033] 3068. The device of item 3023, further comprising a coating,
wherein the coating further comprises a polymer.
[4034] 3069. The device of item 3023, further comprising a first
coating having a first composition and the second coating having a
second composition.
[4035] 3070. The device of item 3023, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[4036] 3071. The device of item 3023, further comprising a
polymer.
[4037] 3072. The device of item 3023, further comprising a
polymeric carrier.
[4038] 3073. The device of item 3023, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[4039] 3074. The device of item 3023, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[4040] 3075. The device of item 3023, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[4041] 3076. The device of item 3023, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[4042] 3077. The device of item 3023, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[4043] 3078. The device of item 3023, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[4044] 3079. The device of item 3023, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[4045] 3080. The device of item 3023, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[4046] 3081. The device of item 3023, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[4047] 3082. The device of item 3023, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[4048] 3083. The device of item 3023, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[4049] 3084. The device of item 3023, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[4050] 3085. The device of item 3023, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[4051] 3086. The device of item 3023, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[4052] 3087. The device of item 3023, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[4053] 3088. The device of item 3023, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[4054] 3089. The device of item 3023, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[4055] 3090. The device of item 3023, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[4056] 3091. The device of item 3023, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[4057] 3092. The device of item 3023, further comprising a
lubricious coating.
[4058] 3093. The device of item 3023 wherein the fibrosing agent is
located within pores or holes of the device.
[4059] 3094. The device of item 3023 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[4060] 3095. The device of item 3023, further comprising a second
pharmaceutically active agent.
[4061] 3096. The device of item 3023, further comprising an
anti-inflammatory agent.
[4062] 3097. The device of item 3023, further comprising an agent
that inhibits infection.
[4063] 3098. The device of item 3023, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[4064] 3099. The device of item 3023, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[4065] 3100. The device of item 3023, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[4066] 3101. The device of item 3023, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[4067] 3102. The device of item 3023, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[4068] 3103. The device of item 3023, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[4069] 3104. The device of item 3023, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[4070] 3105. The device of item 3023, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[4071] 3106. The device of item 3023, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[4072] 3107. The device of item 3023, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[4073] 3108. The device of item 3023, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[4074] 3109. The device of item 3023, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[4075] 3110. The device of item 3023, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[4076] 3111. The device of item 3023, further comprising an
anti-thrombotic agent.
[4077] 3112. The device of item 3023, further comprising a
visualization agent.
[4078] 3113. The device of item 3023, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[4079] 3114. The device of item 3023, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[4080] 3115. The device of item 3023, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[4081] 3116. The device of item 3023, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[4082] 3117. The device of item 3023, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[4083] 3118. The device of item 3023, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[4084] 3119. The device of item 3023, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[4085] 3120. The device of item 3023, further comprising an
echogenic material.
[4086] 3121. The device of item 3023, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[4087] 3122. The device of item 3023 wherein the device is
sterile.
[4088] 3123. The device of item 3023 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[4089] 3124. The device of item 3023 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[4090] 3125. The device of item 3023 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[4091] 3126. The device of item 3023 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[4092] 3127. The device of item 3023 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[4093] 3128. The device of item 3023 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[4094] 3129. The device of item 3023 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[4095] 3130. The device of item 3023 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[4096] 3131. The device of item 3023 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[4097] 3132. The device of item 3023 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[4098] 3133. The device of item 3023 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[4099] 3134. The device of item 3023 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[4100] 3135. The device of item 3023 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[4101] 3136. The device of item 3023 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[4102] 3137. The device of item 3023 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[4103] 3138. The device of item 3023 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[4104] 3139. The device of item 3023 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[4105] 3140. The device of item 3023 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[4106] 3141. The device of item 3023 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[4107] 3142. The device of item 3023 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[4108] 3143. The device of item 3023 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[4109] 3144. The device of item 3023 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[4110] 3145. The device of item 3023 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[4111] 3146. The device of item 3023 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[4112] 3147. The device of item 3023 wherein the hip implant is a
full hip replacement.
[4113] 3148. The device of item 3023 wherein the hip implant is a
partial hip replacement.
[4114] 3149. The device of item 3023 wherein the hip implant is
modular.
[4115] 3150. A medical device comprising a knee implant and a
fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
[4116] 3151. The device of item 3150 wherein the fibrosing agent
promotes regeneration.
[4117] 3152. The device of item 3150 wherein the fibrosing agent
promotes angiogenesis.
[4118] 3153. The device of item 3150 wherein the fibrosing agent
promotes fibroblast migration.
[4119] 3154. The device of item 3150 wherein the fibrosing agent
promotes fibroblast proliferation.
[4120] 3155. The device of item 3150 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[4121] 3156. The device of item 3150 wherein the fibrosing agent
promotes tissue remodeling.
[4122] 3157. The device of item 3150 wherein the fibrosing agent is
an arterial vessel wall irritant.
[4123] 3158. The device of item 3150 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[4124] 3159. The device of item 3150 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[4125] 3160. The device of item 3150 wherein the fibrosing agent is
or comprises silk.
[4126] 3161. The device of item 3150 wherein the fibrosing agent is
or comprises mineral particles.
[4127] 3162. The device of item 3150 wherein the fibrosing agent is
or comprises chitosan.
[4128] 3163. The device of item 3150 wherein the fibrosing agent is
or comprises polylysine.
[4129] 3164. The device of item 3150 wherein the fibrosing agent is
or comprises fibronectin.
[4130] 3165. The device of item 3150 wherein the fibrosing agent is
or comprises bleomycin.
[4131] 3166. The device of item 3150 wherein the fibrosing agent is
or comprises CTGF.
[4132] 3167. The device of item 3150 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[4133] 3168. The device of item 3150 wherein the fibrosing agent is
in the form of a particulate.
[4134] 3169. The device of item 3150 wherein the composition
further comprises an inflammatory cytokine.
[4135] 3170. The device of item 3150 wherein the composition
further comprises an agent that stimulates cell proliferation.
[4136] 3171. The device of item 3150 wherein the composition is in
the form of a gel, paste, or spray.
[4137] 3172. The device of item 3150 wherein the fibrosing agent is
in the form of tufts.
[4138] 3173. The device of item 3150, further comprising a
polymer.
[4139] 3174. The device of item 3150, further comprising a
polymeric carrier.
[4140] 3175. The device of item 3150 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[4141] 3176. The device of item 3150 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[4142] 3177. The device of item 3150, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[4143] 3178. The device of item 3150, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[4144] 3179. The device of item 3150, further comprising a coating,
wherein the coating directly contacts the device.
[4145] 3180. The device of item 3150, further comprising a coating,
wherein the coating indirectly contacts the device.
[4146] 3181. The device of item 3150, further comprising a coating,
wherein the coating partially covers the device.
[4147] 3182. The device of item 3150, further comprising a coating,
wherein the coating completely covers the device.
[4148] 3183. The device of item 3150, further comprising a coating,
wherein the coating is a uniform coating.
[4149] 3184. The device of item 3150, further comprising a coating,
wherein the coating is a non-uniform coating.
[4150] 3185. The device of item 3150, further comprising a coating,
wherein the coating is a discontinuous coating.
[4151] 3186. The device of item 3150, further comprising a coating,
wherein the coating is a patterned coating.
[4152] 3187. The device of item 3150, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[4153] 3188. The device of item 3150, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[4154] 3189. The device of item 3150, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[4155] 3190. The device of item 3150, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[4156] 3191. The device of item 3150, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[4157] 3192. The device of item 3150, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[4158] 3193. The device of item 3150, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[4159] 3194. The device of item 3150, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[4160] 3195. The device of item 3150, further comprising a coating,
wherein the coating further comprises a polymer.
[4161] 3196. The device of item 3150, further comprising a first
coating having a first composition and the second coating having a
second composition.
[4162] 3197. The device of item 3150, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[4163] 3198. The device of item 3150, further comprising a
polymer.
[4164] 3199. The device of item 3150, further comprising a
polymeric carrier.
[4165] 3200. The device of item 3150, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[4166] 3201. The device of item 3150, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[4167] 3202. The device of item 3150, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[4168] 3203. The device of item 3150, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[4169] 3204. The device of item 3150, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[4170] 3205. The device of item 3150, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[4171] 3206. The device of item 3150, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[4172] 3207. The device of item 3150, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[4173] 3208. The device of item 3150, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[4174] 3209. The device of item 3150, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[4175] 3210. The device of item 3150, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[4176] 3211. The device of item 3150, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[4177] 3212. The device of item 3150, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[4178] 3213. The device of item 3150, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[4179] 3214. The device of item 3150, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[4180] 3215. The device of item 3150, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[4181] 3216. The device of item 3150, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[4182] 3217. The device of item 3150, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[4183] 3218. The device of item 3150, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[4184] 3219. The device of item 3150, further comprising a
lubricious coating.
[4185] 3220. The device of item 3150 wherein the fibrosing agent is
located within pores or holes of the device.
[4186] 3221. The device of item 3150 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[4187] 3222. The device of item 3150, further comprising a second
pharmaceutically active agent.
[4188] 3223. The device of item 3150, further comprising an
anti-inflammatory agent.
[4189] 3224. The device of item 3150, further comprising an agent
that inhibits infection.
[4190] 3225. The device of item 3150, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[4191] 3226. The device of item 3150, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[4192] 3227. The device of item 3150, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[4193] 3228. The device of item 3150, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[4194] 3229. The device of item 3150, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[4195] 3230. The device of item 3150, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[4196] 3231. The device of item 3150, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[4197] 3232. The device of item 3150, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[4198] 3233. The device of item 3150, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[4199] 3234. The device of item 3150, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[4200] 3235. The device of item 3150, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[4201] 3236. The device of item 3150, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[4202] 3237. The device of item 3150, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[4203] 3238. The device of item 3150, further comprising an
anti-thrombotic agent.
[4204] 3239. The device of item 3150, further comprising a
visualization agent.
[4205] 3240. The device of item 3150, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[4206] 3241. The device of item 3150, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[4207] 3242. The device of item 3150, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[4208] 3243. The device of item 3150, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[4209] 3244. The device of item 3150, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[4210] 3245. The device of item 3150, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[4211] 3246. The device of item 3150, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[4212] 3247. The device of item 3150, further comprising an
echogenic material.
[4213] 3248. The device of item 3150, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[4214] 3249. The device of item 3150 wherein the device is
sterile.
[4215] 3250. The device of item 3150 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[4216] 3251. The device of item 3150 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[4217] 3252. The device of item 3150 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[4218] 3253. The device of item 3150 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[4219] 3254. The device of item 3150 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[4220] 3255. The device of item 3150 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[4221] 3256. The device of item 3150 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[4222] 3257. The device of item 3150 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[4223] 3258. The device of item 3150 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[4224] 3259. The device of item 3150 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[4225] 3260. The device of item 3150 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[4226] 3261. The device of item 3150 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[4227] 3262. The device of item 3150 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[4228] 3263. The device of item 3150 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[4229] 3264. The device of item 3150 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[4230] 3265. The device of item 3150 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[4231] 3266. The device of item 3150 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[4232] 3267. The device of item 3150 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[4233] 3268. The device of item 3150 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[4234] 3269. The device of item 3150 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[4235] 3270. The device of item 3150 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[4236] 3271. The device of item 3150 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[4237] 3272. The device of item 3150 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[4238] 3273. The device of item 3150 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[4239] 3274. A medical device comprising a shoulder implant and a
fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
[4240] 3275. The device of item 3274 wherein the fibrosing agent
promotes regeneration.
[4241] 3276. The device of item 3274 wherein the fibrosing agent
promotes angiogenesis.
[4242] 3277. The device of item 3274 wherein the fibrosing agent
promotes fibroblast migration.
[4243] 3278. The device of item 3274 wherein the fibrosing agent
promotes fibroblast proliferation.
[4244] 3279. The device of item 3274 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[4245] 3280. The device of item 3274 wherein the fibrosing agent
promotes tissue remodeling.
[4246] 3281. The device of item 3274 wherein the fibrosing agent is
an arterial vessel wall irritant.
[4247] 3282. The device of item 3274 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[4248] 3283. The device of item 3274 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[4249] 3284. The device of item 3274 wherein the fibrosing agent is
or comprises silk.
[4250] 3285. The device of item 3274 wherein the fibrosing agent is
or comprises mineral particles.
[4251] 3286. The device of item 3274 wherein the fibrosing agent is
or comprises chitosan.
[4252] 3287. The device of item 3274 wherein the fibrosing agent is
or comprises polylysine.
[4253] 3288. The device of item 3274 wherein the fibrosing agent is
or comprises fibronectin.
[4254] 3289. The device of item 3274 wherein the fibrosing agent is
or comprises bleomycin.
[4255] 3290. The device of item 3274 wherein the fibrosing agent is
or comprises CTGF.
[4256] 3291. The device of item 3274 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[4257] 3292. The device of item 3274 wherein the fibrosing agent is
in the form of a particulate.
[4258] 3293. The device of item 3274 wherein the composition
further comprises an inflammatory cytokine.
[4259] 3294. The device of item 3274 wherein the composition
further comprises an agent that stimulates cell proliferation.
[4260] 3295. The device of item 3274 wherein the composition is in
the form of a gel, paste, or spray.
[4261] 3296. The device of item 3274 wherein the fibrosing agent is
in the form of tufts.
[4262] 3297. The device of item 3274, further comprising a
polymer.
[4263] 3298. The device of item 3274, further comprising a
polymeric carrier.
[4264] 3299. The device of item 3274 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[4265] 3300. The device of item 3274 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[4266] 3301. The device of item 3274, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[4267] 3302. The device of item 3274, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[4268] 3303. The device of item 3274, further comprising a coating,
wherein the coating directly contacts the device.
[4269] 3304. The device of item 3274, further comprising a coating,
wherein the coating indirectly contacts the device.
[4270] 3305. The device of item 3274, further comprising a coating,
wherein the coating partially covers the device.
[4271] 3306. The device of item 3274, further comprising a coating,
wherein the coating completely covers the device.
[4272] 3307. The device of item 3274, further comprising a coating,
wherein the coating is a uniform coating.
[4273] 3308. The device of item 3274, further comprising a coating,
wherein the coating is a non-uniform coating.
[4274] 3309. The device of item 3274, further comprising a coating,
wherein the coating is a discontinuous coating.
[4275] 3310. The device of item 3274, further comprising a coating,
wherein the coating is a patterned coating.
[4276] 3311. The device of item 3274, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[4277] 3312. The device of item 3274, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[4278] 3313. The device of item 3274, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[4279] 3314. The device of item 3274, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[4280] 3315. The device of item 3274, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[4281] 3316. The device of item 3274, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[4282] 3317. The device of item 3274, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[4283] 3318. The device of item 3274, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[4284] 3319. The device of item 3274, further comprising a coating,
wherein the coating further comprises a polymer.
[4285] 3320. The device of item 3274, further comprising a first
coating having a first composition and the second coating having a
second composition.
[4286] 3321. The device of item 3274, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[4287] 3322. The device of item 3274, further comprising a
polymer.
[4288] 3323. The device of item 3274, further comprising a
polymeric carrier.
[4289] 3324. The device of item 3274, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[4290] 3325. The device of item 3274, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[4291] 3326. The device of item 3274, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[4292] 3327. The device of item 3274, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[4293] 3328. The device of item 3274, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[4294] 3329. The device of item 3274, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[4295] 3330. The device of item 3274, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[4296] 3331. The device of item 3274, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[4297] 3332. The device of item 3274, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[4298] 3333. The device of item 3274, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[4299] 3334. The device of item 3274, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[4300] 3335. The device of item 3274, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[4301] 3336. The device of item 3274, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[4302] 3337. The device of item 3274, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[4303] 3338. The device of item 3274, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[4304] 3339. The device of item 3274, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[4305] 3340. The device of item 3274, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[4306] 3341. The device of item 3274, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[4307] 3342. The device of item 3274, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[4308] 3343. The device of item 3274, further comprising a
lubricious coating.
[4309] 3344. The device of item 3274 wherein the fibrosing agent is
located within pores or holes of the device.
[4310] 3345. The device of item 3274 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[4311] 3346. The device of item 3274, further comprising a second
pharmaceutically active agent.
[4312] 3347. The device of item 3274, further comprising an
anti-inflammatory agent.
[4313] 3348. The device of item 3274, further comprising an agent
that inhibits infection.
[4314] 3349. The device of item 3274, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[4315] 3350. The device of item 3274, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[4316] 3351. The device of item 3274, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[4317] 3352. The device of item 3274, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[4318] 3353. The device of item 3274, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[4319] 3354. The device of item 3274, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[4320] 3355. The device of item 3274, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[4321] 3356. The device of item 3274, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[4322] 3357. The device of item 3274, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[4323] 3358. The device of item 3274, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[4324] 3359. The device of item 3274, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[4325] 3360. The device of item 3274, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[4326] 3361. The device of item 3274, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[4327] 3362. The device of item 3274, further comprising an
anti-thrombotic agent.
[4328] 3363. The device of item 3274, further comprising a
visualization agent.
[4329] 3364. The device of item 3274, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[4330] 3365. The device of item 3274, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[4331] 3366. The device of item 3274, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[4332] 3367. The device of item 3274, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[4333] 3368. The device of item 3274, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[4334] 3369. The device of item 3274, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[4335] 3370. The device of item 3274, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[4336] 3371. The device of item 3274, further comprising an
echogenic material.
[4337] 3372. The device of item 3274, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[4338] 3373. The device of item 3274 wherein the device is
sterile.
[4339] 3374. The device of item 3274 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[4340] 3375. The device of item 3274 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[4341] 3376. The device of item 3274 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[4342] 3377. The device of item 3274 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[4343] 3378. The device of item 3274 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[4344] 3379. The device of item 3274 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[4345] 3380. The device of item 3274 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[4346] 3381. The device of item 3274 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[4347] 3382. The device of item 3274 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[4348] 3383. The device of item 3274 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[4349] 3384. The device of item 3274 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[4350] 3385. The device of item 3274 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[4351] 3386. The device of item 3274 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[4352] 3387. The device of item 3274 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[4353] 3388. The device of item 3274 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[4354] 3389. The device of item 3274 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[4355] 3390. The device of item 3274 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[4356] 3391. The device of item 3274 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[4357] 3392. The device of item 3274 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[4358] 3393. The device of item 3274 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[4359] 3394. The device of item 3274 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[4360] 3395. The device of item 3274 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[4361] 3396. The device of item 3274 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[4362] 3397. The device of item 3274 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[4363] 3398. The device of item 3274 wherein the shoulder implant
is a hemiarthroplasty.
[4364] 3399. The device of item 3274 wherein the shoulder implant
is a total shoulder replacement.
[4365] 3400. A medical device comprising a digit implant and a
fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
[4366] 3401. The device of item 3400 wherein the fibrosing agent
promotes regeneration.
[4367] 3402. The device of item 3400 wherein the fibrosing agent
promotes angiogenesis.
[4368] 3403. The device of item 3400 wherein the fibrosing agent
promotes fibroblast migration.
[4369] 3404. The device of item 3400 wherein the fibrosing agent
promotes fibroblast proliferation.
[4370] 3405. The device of item 3400 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[4371] 3406. The device of item 3400 wherein the fibrosing agent
promotes tissue remodeling.
[4372] 3407. The device of item 3400 wherein the fibrosing agent is
an arterial vessel wall irritant.
[4373] 3408. The device of item 3400 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[4374] 3409. The device of item 3400 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[4375] 3410. The device of item 3400 wherein the fibrosing agent is
or comprises silk.
[4376] 3411. The device of item 3400 wherein the fibrosing agent is
or comprises mineral particles.
[4377] 3412. The device of item 3400 wherein the fibrosing agent is
or comprises chitosan.
[4378] 3413. The device of item 3400 wherein the fibrosing agent is
or comprises polylysine.
[4379] 3414. The device of item 3400 wherein the fibrosing agent is
or comprises fibronectin.
[4380] 3415. The device of item 3400 wherein the fibrosing agent is
or comprises bleomycin.
[4381] 3416. The device of item 3400 wherein the fibrosing agent is
or comprises CTGF.
[4382] 3417. The device of item 3400 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[4383] 3418. The device of item 3400 wherein the fibrosing agent is
in the form of a particulate.
[4384] 3419. The device of item 3400 wherein the composition
further comprises an inflammatory cytokine.
[4385] 3420. The device of item 3400 wherein the composition
further comprises an agent that stimulates cell proliferation.
[4386] 3421. The device of item 3400 wherein the composition is in
the form of a gel, paste, or spray.
[4387] 3422. The device of item 3400 wherein the fibrosing agent is
in the form of tufts.
[4388] 3423. The device of item 3400, further comprising a
polymer.
[4389] 3424. The device of item 3400, further comprising a
polymeric carrier.
[4390] 3425. The device of item 3400 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[4391] 3426. The device of item 3400 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[4392] 3427. The device of item 3400, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[4393] 3428. The device of item 3400, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[4394] 3429. The device of item 3400, further comprising a coating,
wherein the coating directly contacts the device.
[4395] 3430. The device of item 3400, further comprising a coating,
wherein the coating indirectly contacts the device.
[4396] 3431. The device of item 3400, further comprising a coating,
wherein the coating partially covers the device.
[4397] 3432. The device of item 3400, further comprising a coating,
wherein the coating completely covers the device.
[4398] 3433. The device of item 3400, further comprising a coating,
wherein the coating is a uniform coating.
[4399] 3434. The device of item 3400, further comprising a coating,
wherein the coating is a non-uniform coating.
[4400] 3435. The device of item 3400, further comprising a coating,
wherein the coating is a discontinuous coating.
[4401] 3436. The device of item 3400, further comprising a coating,
wherein the coating is a patterned coating.
[4402] 3437. The device of item 3400, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[4403] 3438. The device of item 3400, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[4404] 3439. The device of item 3400, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[4405] 3440. The device of item 3400, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[4406] 3441. The device of item 3400, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[4407] 3442. The device of item 3400, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[4408] 3443. The device of item 3400, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[4409] 3444. The device of item 3400, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[4410] 3445. The device of item 3400, further comprising a coating,
wherein the coating further comprises a polymer.
[4411] 3446. The device of item 3400, further comprising a first
coating having a first composition and the second coating having a
second composition.
[4412] 3447. The device of item 3400, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[4413] 3448. The device of item 3400, further comprising a
polymer.
[4414] 3449. The device of item 3400, further comprising a
polymeric carrier.
[4415] 3450. The device of item 3400, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[4416] 3451. The device of item 3400, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[4417] 3452. The device of item 3400, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[4418] 3453. The device of item 3400, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[4419] 3454. The device of item 3400, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[4420] 3455. The device of item 3400, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[4421] 3456. The device of item 3400, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[4422] 3457. The device of item 3400, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[4423] 3458. The device of item 3400, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[4424] 3459. The device of item 3400, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[4425] 3460. The device of item 3400, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[4426] 3461. The device of item 3400, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[4427] 3462. The device of item 3400, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[4428] 3463. The device of item 3400, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[4429] 3464. The device of item 3400, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[4430] 3465. The device of item 3400, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[4431] 3466. The device of item 3400, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[4432] 3467. The device of item 3400, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[4433] 3468. The device of item 3400, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[4434] 3469. The device of item 3400, further comprising a
lubricious coating.
[4435] 3470. The device of item 3400 wherein the fibrosing agent is
located within pores or holes of the device.
[4436] 3471. The device of item 3400 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[4437] 3472. The device of item 3400, further comprising a second
pharmaceutically active agent.
[4438] 3473. The device of item 3400, further comprising an
anti-inflammatory agent.
[4439] 3474. The device of item 3400, further comprising an agent
that inhibits infection.
[4440] 3475. The device of item 3400, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[4441] 3476. The device of item 3400, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[4442] 3477. The device of item 3400, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[4443] 3478. The device of item 3400, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[4444] 3479. The device of item 3400, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[4445] 3480. The device of item 3400, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[4446] 3481. The device of item 3400, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[4447] 3482. The device of item 3400, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[4448] 3483. The device of item 3400, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[4449] 3484. The device of item 3400, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[4450] 3485. The device of item 3400, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[4451] 3486. The device of item 3400, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[4452] 3487. The device of item 3400, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[4453] 3488. The device of item 3400, further comprising an
anti-thrombotic agent.
[4454] 3489. The device of item 3400, further comprising a
visualization agent.
[4455] 3490. The device of item 3400, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[4456] 3491. The device of item 3400, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[4457] 3492. The device of item 3400, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[4458] 3493. The device of item 3400, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[4459] 3494. The device of item 3400, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[4460] 3495. The device of item 3400, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[4461] 3496. The device of item 3400, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[4462] 3497. The device of item 3400, further comprising an
echogenic material.
[4463] 3498. The device of item 3400, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[4464] 3499. The device of item 3400 wherein the device is
sterile.
[4465] 3500. The device of item 3400 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[4466] 3501. The device of item 3400 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[4467] 3502. The device of item 3400 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[4468] 3503. The device of item 3400 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[4469] 3504. The device of item 3400 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[4470] 3505. The device of item 3400 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[4471] 3506. The device of item 3400 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[4472] 3507. The device of item 3400 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[4473] 3508. The device of item 3400 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[4474] 3509. The device of item 3400 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[4475] 3510. The device of item 3400 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[4476] 3511. The device of item 3400 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[4477] 3512. The device of item 3400 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[4478] 3513. The device of item 3400 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[4479] 3514. The device of item 3400 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[4480] 3515. The device of item 3400 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[4481] 3516. The device of item 3400 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[4482] 3517. The device of item 3400 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[4483] 3518. The device of item 3400 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[4484] 3519. The device of item 3400 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[4485] 3520. The device of item 3400 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[4486] 3521. The device of item 3400 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[4487] 3522. The device of item 3400 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[4488] 3523. The device of item 3400 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[4489] 3524. A medical device comprising a titanium fixture for
replacement of the root portion of a missing natural tooth and a
fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
[4490] 3525. The device of item 3524 wherein the fibrosing agent
promotes regeneration.
[4491] 3526. The device of item 3524 wherein the fibrosing agent
promotes angiogenesis.
[4492] 3527. The device of item 3524 wherein the fibrosing agent
promotes fibroblast migration.
[4493] 3528. The device of item 3524 wherein the fibrosing agent
promotes fibroblast proliferation.
[4494] 3529. The device of item 3524 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[4495] 3530. The device of item 3524 wherein the fibrosing agent
promotes tissue remodeling.
[4496] 3531. The device of item 3524 wherein the fibrosing agent is
an arterial vessel wall irritant.
[4497] 3532. The device of item 3524 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[4498] 3533. The device of item 3524 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[4499] 3534. The device of item 3524 wherein the fibrosing agent is
or comprises silk.
[4500] 3535. The device of item 3524 wherein the fibrosing agent is
or comprises mineral particles.
[4501] 3536. The device of item 3524 wherein the fibrosing agent is
or comprises chitosan.
[4502] 3537. The device of item 3524 wherein the fibrosing agent is
or comprises polylysine.
[4503] 3538. The device of item 3524 wherein the fibrosing agent is
or comprises fibronectin.
[4504] 3539. The device of item 3524 wherein the fibrosing agent is
or comprises bleomycin.
[4505] 3540. The device of item 3524 wherein the fibrosing agent is
or comprises CTGF.
[4506] 3541. The device of item 3524 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[4507] 3542. The device of item 3524 wherein the fibrosing agent is
in the form of a particulate.
[4508] 3543. The device of item 3524 wherein the composition
further comprises an inflammatory cytokine.
[4509] 3544. The device of item 3524 wherein the composition
further comprises an agent that stimulates cell proliferation.
[4510] 3545. The device of item 3524 wherein the composition is in
the form of a gel, paste, or spray.
[4511] 3546. The device of item 3524 wherein the fibrosing agent is
in the form of tufts.
[4512] 3547. The device of item 3524, further comprising a
polymer.
[4513] 3548. The device of item 3524, further comprising a
polymeric carrier.
[4514] 3549. The device of item 3524 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[4515] 3550. The device of item 3524 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[4516] 3551. The device of item 3524, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[4517] 3552. The device of item 3524, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[4518] 3553. The device of item 3524, further comprising a coating,
wherein the coating directly contacts the device.
[4519] 3554. The device of item 3524, further comprising a coating,
wherein the coating indirectly contacts the device.
[4520] 3555. The device of item 3524, further comprising a coating,
wherein the coating partially covers the device.
[4521] 3556. The device of item 3524, further comprising a coating,
wherein the coating completely covers the device.
[4522] 3557. The device of item 3524, further comprising a coating,
wherein the coating is a uniform coating.
[4523] 3558. The device of item 3524, further comprising a coating,
wherein the coating is a non-uniform coating.
[4524] 3559. The device of item 3524, further comprising a coating,
wherein the coating is a discontinuous coating.
[4525] 3560. The device of item 3524, further comprising a coating,
wherein the coating is a patterned coating.
[4526] 3561. The device of item 3524, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[4527] 3562. The device of item 3524, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[4528] 3563. The device of item 3524, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[4529] 3564. The device of item 3524, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[4530] 3565. The device of item 3524, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[4531] 3566. The device of item 3524, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[4532] 3567. The device of item 3524, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[4533] 3568. The device of item 3524, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[4534] 3569. The device of item 3524, further comprising a coating,
wherein the coating further comprises a polymer.
[4535] 3570. The device of item 3524, further comprising a first
coating having a first composition and the second coating having a
second composition.
[4536] 3571. The device of item 3524, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[4537] 3572. The device of item 3524, further comprising a
polymer.
[4538] 3573. The device of item 3524, further comprising a
polymeric carrier.
[4539] 3574. The device of item 3524, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[4540] 3575. The device of item 3524, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[4541] 3576. The device of item 3524, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[4542] 3577. The device of item 3524, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[4543] 3578. The device of item 3524, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[4544] 3579. The device of item 3524, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[4545] 3580. The device of item 3524, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[4546] 3581. The device of item 3524, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[4547] 3582. The device of item 3524, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[4548] 3583. The device of item 3524, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[4549] 3584. The device of item 3524, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[4550] 3585. The device of item 3524, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[4551] 3586. The device of item 3524, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[4552] 3587. The device of item 3524, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[4553] 3588. The device of item 3524, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[4554] 3589. The device of item 3524, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[4555] 3590. The device of item 3524, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[4556] 3591. The device of item 3524, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[4557] 3592. The device of item 3524, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[4558] 3593. The device of item 3524, further comprising a
lubricious coating.
[4559] 3594. The device of item 3524 wherein the fibrosing agent is
located within pores or holes of the device.
[4560] 3595. The device of item 3524 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[4561] 3596. The device of item 3524, further comprising a second
pharmaceutically active agent.
[4562] 3597. The device of item 3524, further comprising an
anti-inflammatory agent.
[4563] 3598. The device of item 3524, further comprising an agent
that inhibits infection.
[4564] 3599. The device of item 3524, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[4565] 3600. The device of item 3524, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[4566] 3601. The device of item 3524, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[4567] 3602. The device of item 3524, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[4568] 3603. The device of item 3524, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[4569] 3604. The device of item 3524, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[4570] 3605. The device of item 3524, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[4571] 3606. The device of item 3524, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[4572] 3607. The device of item 3524, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[4573] 3608. The device of item 3524, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[4574] 3609. The device of item 3524, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[4575] 3610. The device of item 3524, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[4576] 3611. The device of item 3524, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[4577] 3612. The device of item 3524, further comprising an
anti-thrombotic agent.
[4578] 3613. The device of item 3524, further comprising a
visualization agent.
[4579] 3614. The device of item 3524, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[4580] 3615. The device of item 3524, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[4581] 3616. The device of item 3524, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[4582] 3617. The device of item 3524, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[4583] 3618. The device of item 3524, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[4584] 3619. The device of item 3524, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[4585] 3620. The device of item 3524, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[4586] 3621. The device of item 3524, further comprising an
echogenic material.
[4587] 3622. The device of item 3524, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[4588] 3623. The device of item 3524 wherein the device is
sterile.
[4589] 3624. The device of item 3524 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[4590] 3625. The device of item 3524 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[4591] 3626. The device of item 3524 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[4592] 3627. The device of item 3524 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[4593] 3628. The device of item 3524 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[4594] 3629. The device of item 3524 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[4595] 3630. The device of item 3524 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[4596] 3631. The device of item 3524 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[4597] 3632. The device of item 3524 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[4598] 3633. The device of item 3524 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[4599] 3634. The device of item 3524 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[4600] 3635. The device of item 3524 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[4601] 3636. The device of item 3524 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[4602] 3637. The device of item 3524 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[4603] 3638. The device of item 3524 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[4604] 3639. The device of item 3524 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[4605] 3640. The device of item 3524 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[4606] 3641. The device of item 3524 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[4607] 3642. The device of item 3524 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[4608] 3643. The device of item 3524 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[4609] 3644. The device of item 3524 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[4610] 3645. The device of item 3524 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[4611] 3646. The device of item 3524 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[4612] 3647. The device of item 3524 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[4613] 3648. A medical device comprising an endosteal implant and a
fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
[4614] 3649. The device of item 3648 wherein the fibrosing agent
promotes regeneration.
[4615] 3650. The device of item 3648 wherein the fibrosing agent
promotes angiogenesis.
[4616] 3651. The device of item 3648 wherein the fibrosing agent
promotes fibroblast migration.
[4617] 3652. The device of item 3648 wherein the fibrosing agent
promotes fibroblast proliferation.
[4618] 3653. The device of item 3648 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[4619] 3654. The device of item 3648 wherein the fibrosing agent
promotes tissue remodeling.
[4620] 3655. The device of item 3648 wherein the fibrosing agent is
an arterial vessel wall irritant.
[4621] 3656. The device of item 3648 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[4622] 3657. The device of item 3648 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[4623] 3658. The device of item 3648 wherein the fibrosing agent is
or comprises silk.
[4624] 3659. The device of item 3648 wherein the fibrosing agent is
or comprises mineral particles.
[4625] 3660. The device of item 3648 wherein the fibrosing agent is
or comprises chitosan.
[4626] 3661. The device of item 3648 wherein the fibrosing agent is
or comprises polylysine.
[4627] 3662. The device of item 3648 wherein the fibrosing agent is
or comprises fibronectin.
[4628] 3663. The device of item 3648 wherein the fibrosing agent is
or comprises bleomycin.
[4629] 3664. The device of item 3648 wherein the fibrosing agent is
or comprises CTGF.
[4630] 3665. The device of item 3648 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[4631] 3666. The device of item 3648 wherein the fibrosing agent is
in the form of a particulate.
[4632] 3667. The device of item 3648 wherein the composition
further comprises an inflammatory cytokine.
[4633] 3668. The device of item 3648 wherein the composition
further comprises an agent that stimulates cell proliferation.
[4634] 3669. The device of item 3648 wherein the composition is in
the form of a gel, paste, or spray.
[4635] 3670. The device of item 3648 wherein the fibrosing agent is
in the form of tufts.
[4636] 3671. The device of item 3648, further comprising a
polymer.
[4637] 3672. The device of item 3648, further comprising a
polymeric carrier.
[4638] 3673. The device of item 3648 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[4639] 3674. The device of item 3648 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[4640] 3675. The device of item 3648, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[4641] 3676. The device of item 3648, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[4642] 3677. The device of item 3648, further comprising a coating,
wherein the coating directly contacts the device.
[4643] 3678. The device of item 3648, further comprising a coating,
wherein the coating indirectly contacts the device.
[4644] 3679. The device of item 3648, further comprising a coating,
wherein the coating partially covers the device.
[4645] 3680. The device of item 3648, further comprising a coating,
wherein the coating completely covers the device.
[4646] 3681. The device of item 3648, further comprising a coating,
wherein the coating is a uniform coating.
[4647] 3682. The device of item 3648, further comprising a coating,
wherein the coating is a non-uniform coating.
[4648] 3683. The device of item 3648, further comprising a coating,
wherein the coating is a discontinuous coating.
[4649] 3684. The device of item 3648, further comprising a coating,
wherein the coating is a patterned coating.
[4650] 3685. The device of item 3648, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[4651] 3686. The device of item 3648, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[4652] 3687. The device of item 3648, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[4653] 3688. The device of item 3648, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[4654] 3689. The device of item 3648, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[4655] 3690. The device of item 3648, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[4656] 3691. The device of item 3648, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[4657] 3692. The device of item 3648, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[4658] 3693. The device of item 3648, further comprising a coating,
wherein the coating further comprises a polymer.
[4659] 3694. The device of item 3648, further comprising a first
coating having a first composition and the second coating having a
second composition.
[4660] 3695. The device of item 3648, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[4661] 3696. The device of item 3648, further comprising a
polymer.
[4662] 3697. The device of item 3648, further comprising a
polymeric carrier.
[4663] 3698. The device of item 3648, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[4664] 3699. The device of item 3648, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[4665] 3700. The device of item 3648, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[4666] 3701. The device of item 3648, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[4667] 3702. The device of item 3648, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[4668] 3703. The device of item 3648, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[4669] 3704. The device of item 3648, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[4670] 3705. The device of item 3648, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[4671] 3706. The device of item 3648, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[4672] 3707. The device of item 3648, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[4673] 3708. The device of item 3648, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[4674] 3709. The device of item 3648, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[4675] 3710. The device of item 3648, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[4676] 3711. The device of item 3648, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[4677] 3712. The device of item 3648, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[4678] 3713. The device of item 3648, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[4679] 3714. The device of item 3648, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[4680] 3715. The device of item 3648, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[4681] 3716. The device of item 3648, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[4682] 3717. The device of item 3648, further comprising a
lubricious coating.
[4683] 3718. The device of item 3648 wherein the fibrosing agent is
located within pores or holes of the device.
[4684] 3719. The device of item 3648 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[4685] 3720. The device of item 3648, further comprising a second
pharmaceutically active agent.
[4686] 3721. The device of item 3648, further comprising an
anti-inflammatory agent.
[4687] 3722. The device of item 3648, further comprising an agent
that inhibits infection.
[4688] 3723. The device of item 3648, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[4689] 3724. The device of item 3648, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[4690] 3725. The device of item 3648, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[4691] 3726. The device of item 3648, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[4692] 3727. The device of item 3648, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[4693] 3728. The device of item 3648, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[4694] 3729. The device of item 3648, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[4695] 3730. The device of item 3648, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[4696] 3731. The device of item 3648, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[4697] 3732. The device of item 3648, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[4698] 3733. The device of item 3648, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[4699] 3734. The device of item 3648, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[4700] 3735. The device of item 3648, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[4701] 3736. The device of item 3648, further comprising an
anti-thrombotic agent.
[4702] 3737. The device of item 3648, further comprising a
visualization agent.
[4703] 3738. The device of item 3648, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[4704] 3739. The device of item 3648, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[4705] 3740. The device of item 3648, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[4706] 3741. The device of item 3648, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[4707] 3742. The device of item 3648, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[4708] 3743. The device of item 3648, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[4709] 3744. The device of item 3648, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[4710] 3745. The device of item 3648, further comprising an
echogenic material.
[4711] 3746. The device of item 3648, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[4712] 3747. The device of item 3648 wherein the device is
sterile.
[4713] 3748. The device of item 3648 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[4714] 3749. The device of item 3648 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[4715] 3750. The device of item 3648 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[4716] 3751. The device of item 3648 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[4717] 3752. The device of item 3648 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[4718] 3753. The device of item 3648 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[4719] 3754. The device of item 3648 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[4720] 3755. The device of item 3648 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[4721] 3756. The device of item 3648 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[4722] 3757. The device of item 3648 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[4723] 3758. The device of item 3648 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[4724] 3759. The device of item 3648 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[4725] 3760. The device of item 3648 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[4726] 3761. The device of item 3648 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[4727] 3762. The device of item 3648 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[4728] 3763. The device of item 3648 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[4729] 3764. The device of item 3648 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[4730] 3765. The device of item 3648 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[4731] 3766. The device of item 3648 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[4732] 3767. The device of item 3648 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[4733] 3768. The device of item 3648 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[4734] 3769. The device of item 3648 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[4735] 3770. The device of item 3648 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[4736] 3771. The device of item 3648 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[4737] 3772. A medical device comprising a subperiosteal implant
and a fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
[4738] 3773. The device of item 3772 wherein the fibrosing agent
promotes regeneration.
[4739] 3774. The device of item 3772 wherein the fibrosing agent
promotes angiogenesis.
[4740] 3775. The device of item 3772 wherein the fibrosing agent
promotes fibroblast migration.
[4741] 3776. The device of item 3772 wherein the fibrosing agent
promotes fibroblast proliferation.
[4742] 3777. The device of item 3772 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[4743] 3778. The device of item 3772 wherein the fibrosing agent
promotes tissue remodeling.
[4744] 3779. The device of item 3772 wherein the fibrosing agent is
an arterial vessel wall irritant.
[4745] 3780. The device of item 3772 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[4746] 3781. The device of item 3772 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[4747] 3782. The device of item 3772 wherein the fibrosing agent is
or comprises silk.
[4748] 3783. The device of item 3772 wherein the fibrosing agent is
or comprises mineral particles.
[4749] 3784. The device of item 3772 wherein the fibrosing agent is
or comprises chitosan.
[4750] 3785. The device of item 3772 wherein the fibrosing agent is
or comprises polylysine.
[4751] 3786. The device of item 3772 wherein the fibrosing agent is
or comprises fibronectin.
[4752] 3787. The device of item 3772 wherein the fibrosing agent is
or comprises bleomycin.
[4753] 3788. The device of item 3772 wherein the fibrosing agent is
or comprises CTGF.
[4754] 3789. The device of item 3772 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[4755] 3790. The device of item 3772 wherein the fibrosing agent is
in the form of a particulate.
[4756] 3791. The device of item 3772 wherein the composition
further comprises an inflammatory cytokine.
[4757] 3792. The device of item 3772 wherein the composition
further comprises an agent that stimulates cell proliferation.
[4758] 3793. The device of item 3772 wherein the composition is in
the form of a gel, paste, or spray.
[4759] 3794. The device of item 3772 wherein the fibrosing agent is
in the form of tufts.
[4760] 3795. The device of item 3772, further comprising a
polymer.
[4761] 3796. The device of item 3772, further comprising a
polymeric carrier.
[4762] 3797. The device of item 3772 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[4763] 3798. The device of item 3772 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[4764] 3799. The device of item 3772, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[4765] 3800. The device of item 3772, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[4766] 3801. The device of item 3772, further comprising a coating,
wherein the coating directly contacts the device.
[4767] 3802. The device of item 3772, further comprising a coating,
wherein the coating indirectly contacts the device.
[4768] 3803. The device of item 3772, further comprising a coating,
wherein the coating partially covers the device.
[4769] 3804. The device of item 3772, further comprising a coating,
wherein the coating completely covers the device.
[4770] 3805. The device of item 3772, further comprising a coating,
wherein the coating is a uniform coating.
[4771] 3806. The device of item 3772, further comprising a coating,
wherein the coating is a non-uniform coating.
[4772] 3807. The device of item 3772, further comprising a coating,
wherein the coating is a discontinuous coating.
[4773] 3808. The device of item 3772, further comprising a coating,
wherein the coating is a patterned coating.
[4774] 3809. The device of item 3772, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[4775] 3810. The device of item 3772, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[4776] 3811. The device of item 3772, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[4777] 3812. The device of item 3772, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[4778] 3813. The device of item 3772, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[4779] 3814. The device of item 3772, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[4780] 3815. The device of item 3772, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[4781] 3816. The device of item 3772, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[4782] 3817. The device of item 3772, further comprising a coating,
wherein the coating further comprises a polymer.
[4783] 3818. The device of item 3772, further comprising a first
coating having a first composition and the second coating having a
second composition.
[4784] 3819. The device of item 3772, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[4785] 3820. The device of item 3772, further comprising a
polymer.
[4786] 3821. The device of item 3772, further comprising a
polymeric carrier.
[4787] 3822. The device of item 3772, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[4788] 3823. The device of item 3772, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[4789] 3824. The device of item 3772, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[4790] 3825. The device of item 3772, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[4791] 3826. The device of item 3772, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[4792] 3827. The device of item 3772, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[4793] 3828. The device of item 3772, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[4794] 3829. The device of item 3772, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[4795] 3830. The device of item 3772, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[4796] 3831. The device of item 3772, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[4797] 3832. The device of item 3772, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[4798] 3833. The device of item 3772, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[4799] 3834. The device of item 3772, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[4800] 3835. The device of item 3772, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[4801] 3836. The device of item 3772, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[4802] 3837. The device of item 3772, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[4803] 3838. The device of item 3772, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[4804] 3839. The device of item 3772, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[4805] 3840. The device of item 3772, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[4806] 3841. The device of item 3772, further comprising a
lubricious coating.
[4807] 3842. The device of item 3772 wherein the fibrosing agent is
located within pores or holes of the device.
[4808] 3843. The device of item 3772 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[4809] 3844. The device of item 3772, further comprising a second
pharmaceutically active agent.
[4810] 3845. The device of item 3772, further comprising an
anti-inflammatory agent.
[4811] 3846. The device of item 3772, further comprising an agent
that inhibits infection.
[4812] 3847. The device of item 3772, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[4813] 3848. The device of item 3772, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[4814] 3849. The device of item 3772, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[4815] 3850. The device of item 3772, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[4816] 3851. The device of item 3772, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[4817] 3852. The device of item 3772, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[4818] 3853. The device of item 3772, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[4819] 3854. The device of item 3772, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[4820] 3855. The device of item 3772, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[4821] 3856. The device of item 3772, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[4822] 3857. The device of item 3772, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[4823] 3858. The device of item 3772, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[4824] 3859. The device of item 3772, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[4825] 3860. The device of item 3772, further comprising an
anti-thrombotic agent.
[4826] 3861. The device of item 3772, further comprising a
visualization agent.
[4827] 3862. The device of item 3772, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[4828] 3863. The device of item 3772, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[4829] 3864. The device of item 3772, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[4830] 3865. The device of item 3772, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[4831] 3866. The device of item 3772, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[4832] 3867. The device of item 3772, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[4833] 3868. The device of item 3772, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[4834] 3869. The device of item 3772, further comprising an
echogenic material.
[4835] 3870. The device of item 3772, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[4836] 3871. The device of item 3772 wherein the device is
sterile.
[4837] 3872. The device of item 3772 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[4838] 3873. The device of item 3772 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[4839] 3874. The device of item 3772 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[4840] 3875. The device of item 3772 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[4841] 3876. The device of item 3772 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[4842] 3877. The device of item 3772 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[4843] 3878. The device of item 3772 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[4844] 3879. The device of item 3772 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[4845] 3880. The device of item 3772 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[4846] 3881. The device of item 3772 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[4847] 3882. The device of item 3772 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[4848] 3883. The device of item 3772 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[4849] 3884. The device of item 3772 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[4850] 3885. The device of item 3772 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[4851] 3886. The device of item 3772 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[4852] 3887. The device of item 3772 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[4853] 3888. The device of item 3772 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[4854] 3889. The device of item 3772 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[4855] 3890. The device of item 3772 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[4856] 3891. The device of item 3772 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[4857] 3892. The device of item 3772 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[4858] 3893. The device of item 3772 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[4859] 3894. The device of item 3772 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[4860] 3895. The device of item 3772 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[4861] 3896. A medical device comprising a guided bone regeneration
(GBR) implant and a fibrosing agent, where the fibrosing agent
induces a fibrotic response between the device and a patient in
which the device is implanted.
[4862] 3897. The device of item 3896 wherein the fibrosing agent
promotes regeneration.
[4863] 3898. The device of item 3896 wherein the fibrosing agent
promotes angiogenesis.
[4864] 3899. The device of item 3896 wherein the fibrosing agent
promotes fibroblast migration.
[4865] 3900. The device of item 3896 wherein the fibrosing agent
promotes fibroblast proliferation.
[4866] 3901. The device of item 3896 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[4867] 3902. The device of item 3896 wherein the fibrosing agent
promotes tissue remodeling.
[4868] 3903. The device of item 3896 wherein the fibrosing agent is
an arterial vessel wall irritant.
[4869] 3904. The device of item 3896 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[4870] 3905. The device of item 3896 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[4871] 3906. The device of item 3896 wherein the fibrosing agent is
or comprises silk.
[4872] 3907. The device of item 3896 wherein the fibrosing agent is
or comprises mineral particles.
[4873] 3908. The device of item 3896 wherein the fibrosing agent is
or comprises chitosan.
[4874] 3909. The device of item 3896 wherein the fibrosing agent is
or comprises polylysine.
[4875] 3910. The device of item 3896 wherein the fibrosing agent is
or comprises fibronectin.
[4876] 3911. The device of item 3896 wherein the fibrosing agent is
or comprises bleomycin.
[4877] 3912. The device of item 3896 wherein the fibrosing agent is
or comprises CTGF.
[4878] 3913. The device of item 3896 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[4879] 3914. The device of item 3896 wherein the fibrosing agent is
in the form of a particulate.
[4880] 3915. The device of item 3896 wherein the composition
further comprises an inflammatory cytokine.
[4881] 3916. The device of item 3896 wherein the composition
further comprises an agent that stimulates cell proliferation.
[4882] 3917. The device of item 3896 wherein the composition is in
the form of a gel, paste, or spray.
[4883] 3918. The device of item 3896 wherein the fibrosing agent is
in the form of tufts.
[4884] 3919. The device of item 3896, further comprising a
polymer.
[4885] 3920. The device of item 3896, further comprising a
polymeric carrier.
[4886] 3921. The device of item 3896 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[4887] 3922. The device of item 3896 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[4888] 3923. The device of item 3896, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[4889] 3924. The device of item 3896, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[4890] 3925. The device of item 3896, further comprising a coating,
wherein the coating directly contacts the device.
[4891] 3926. The device of item 3896, further comprising a coating,
wherein the coating indirectly contacts the device.
[4892] 3927. The device of item 3896, further comprising a coating,
wherein the coating partially covers the device.
[4893] 3928. The device of item 3896, further comprising a coating,
wherein the coating completely covers the device.
[4894] 3929. The device of item 3896, further comprising a coating,
wherein the coating is a uniform coating.
[4895] 3930. The device of item 3896, further comprising a coating,
wherein the coating is a non-uniform coating.
[4896] 3931. The device of item 3896, further comprising a coating,
wherein the coating is a discontinuous coating.
[4897] 3932. The device of item 3896, further comprising a coating,
wherein the coating is a patterned coating.
[4898] 3933. The device of item 3896, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[4899] 3934. The device of item 3896, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[4900] 3935. The device of item 3896, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[4901] 3936. The device of item 3896, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[4902] 3937. The device of item 3896, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[4903] 3938. The device of item 3896, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[4904] 3939. The device of item 3896, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[4905] 3940. The device of item 3896, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[4906] 3941. The device of item 3896, further comprising a coating,
wherein the coating further comprises a polymer.
[4907] 3942. The device of item 3896, further comprising a first
coating having a first composition and the second coating having a
second composition.
[4908] 3943. The device of item 3896, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[4909] 3944. The device of item 3896, further comprising a
polymer.
[4910] 3945. The device of item 3896, further comprising a
polymeric carrier.
[4911] 3946. The device of item 3896, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[4912] 3947. The device of item 3896, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[4913] 3948. The device of item 3896, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[4914] 3949. The device of item 3896, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[4915] 3950. The device of item 3896, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[4916] 3951. The device of item 3896, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[4917] 3952. The device of item 3896, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[4918] 3953. The device of item 3896, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[4919] 3954. The device of item 3896, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[4920] 3955. The device of item 3896, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[4921] 3956. The device of item 3896, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[4922] 3957. The device of item 3896, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[4923] 3958. The device of item 3896, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[4924] 3959. The device of item 3896, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[4925] 3960. The device of item 3896, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[4926] 3961. The device of item 3896, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[4927] 3962. The device of item 3896, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[4928] 3963. The device of item 3896, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[4929] 3964. The device of item 3896, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[4930] 3965. The device of item 3896, further comprising a
lubricious coating.
[4931] 3966. The device of item 3896 wherein the fibrosing agent is
located within pores or holes of the device.
[4932] 3967. The device of item 3896 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[4933] 3968. The device of item 3896, further comprising a second
pharmaceutically active agent.
[4934] 3969. The device of item 3896, further comprising an
anti-inflammatory agent.
[4935] 3970. The device of item 3896, further comprising an agent
that inhibits infection.
[4936] 3971. The device of item 3896, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[4937] 3972. The device of item 3896, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[4938] 3973. The device of item 3896, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[4939] 3974. The device of item 3896, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[4940] 3975. The device of item 3896, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[4941] 3976. The device of item 3896, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[4942] 3977. The device of item 3896, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[4943] 3978. The device of item 3896, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[4944] 3979. The device of item 3896, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[4945] 3980. The device of item 3896, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[4946] 3981. The device of item 3896, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[4947] 3982. The device of item 3896, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[4948] 3983. The device of item 3896, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[4949] 3984. The device of item 3896, further comprising an
anti-thrombotic agent.
[4950] 3985. The device of item 3896, further comprising a
visualization agent.
[4951] 3986. The device of item 3896, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[4952] 3987. The device of item 3896, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[4953] 3988. The device of item 3896, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[4954] 3989. The device of item 3896, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[4955] 3990. The device of item 3896, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[4956] 3991. The device of item 3896, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[4957] 3992. The device of item 3896, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[4958] 3993. The device of item 3896, further comprising an
echogenic material.
[4959] 3994. The device of item 3896, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[4960] 3995. The device of item 3896 wherein the device is
sterile.
[4961] 3996. The device of item 3896 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[4962] 3997. The device of item 3896 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[4963] 3998. The device of item 3896 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[4964] 3999. The device of item 3896 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[4965] 4000. The device of item 3896 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[4966] 4001. The device of item 3896 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[4967] 4002. The device of item 3896 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[4968] 4003. The device of item 3896 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[4969] 4004. The device of item 3896 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[4970] 4005. The device of item 3896 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[4971] 4006. The device of item 3896 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[4972] 4007. The device of item 3896 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[4973] 4008. The device of item 3896 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[4974] 4009. The device of item 3896 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[4975] 4010. The device of item 3896 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[4976] 4011. The device of item 3896 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[4977] 4012. The device of item 3896 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[4978] 4013. The device of item 3896 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[4979] 4014. The device of item 3896 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[4980] 4015. The device of item 3896 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[4981] 4016. The device of item 3896 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[4982] 4017. The device of item 3896 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[4983] 4018. The device of item 3896 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[4984] 4019. The device of item 3896 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[4985] 4020. The medical device of claqim 3896 wherein the GBR is
resorbable bone substitutes for filing bony defects.
[4986] 4021. A medical device comprising a dental implant to
control the healing process subsequent to periodontal disease and a
fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
[4987] 4022. The device of item 4021 wherein the fibrosing agent
promotes regeneration.
[4988] 4023. The device of item 4021 wherein the fibrosing agent
promotes angiogenesis.
[4989] 4024. The device of item 4021 wherein the fibrosing agent
promotes fibroblast migration.
[4990] 4025. The device of item 4021 wherein the fibrosing agent
promotes fibroblast proliferation.
[4991] 4026. The device of item 4021 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[4992] 4027. The device of item 4021 wherein the fibrosing agent
promotes tissue remodeling.
[4993] 4028. The device of item 4021 wherein the fibrosing agent is
an arterial vessel wall irritant.
[4994] 4029. The device of item 4021 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[4995] 4030. The device of item 4021 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[4996] 4031. The device of item 4021 wherein the fibrosing agent is
or comprises silk.
[4997] 4032. The device of item 4021 wherein the fibrosing agent is
or comprises mineral particles.
[4998] 4033. The device of item 4021 wherein the fibrosing agent is
or comprises chitosan.
[4999] 4034. The device of item 4021 wherein the fibrosing agent is
or comprises polylysine.
[5000] 4035. The device of item 4021 wherein the fibrosing agent is
or comprises fibronectin.
[5001] 4036. The device of item 4021 wherein the fibrosing agent is
or comprises bleomycin.
[5002] 4037. The device of item 4021 wherein the fibrosing agent is
or comprises CTGF.
[5003] 4038. The device of item 4021 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[5004] 4039. The device of item 4021 wherein the fibrosing agent is
in the form of a particulate.
[5005] 4040. The device of item 4021 wherein the composition
further comprises an inflammatory cytokine.
[5006] 4041. The device of item 4021 wherein the composition
further comprises an agent that stimulates cell proliferation.
[5007] 4042. The device of item 4021 wherein the composition is in
the form of a gel, paste, or spray.
[5008] 4043. The device of item 4021 wherein the fibrosing agent is
in the form of tufts.
[5009] 4044. The device of item 4021, further comprising a
polymer.
[5010] 4045. The device of item 4021, further comprising a
polymeric carrier.
[5011] 4046. The device of item 4021 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[5012] 4047. The device of item 4021 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[5013] 4048. The device of item 4021, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[5014] 4049. The device of item 4021, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[5015] 4050. The device of item 4021, further comprising a coating,
wherein the coating directly contacts the device.
[5016] 4051. The device of item 4021, further comprising a coating,
wherein the coating indirectly contacts the device.
[5017] 4052. The device of item 4021, further comprising a coating,
wherein the coating partially covers the device.
[5018] 4053. The device of item 4021, further comprising a coating,
wherein the coating completely covers the device.
[5019] 4054. The device of item 4021, further comprising a coating,
wherein the coating is a uniform coating.
[5020] 4055. The device of item 4021, further comprising a coating,
wherein the coating is a non-uniform coating.
[5021] 4056. The device of item 4021, further comprising a coating,
wherein the coating is a discontinuous coating.
[5022] 4057. The device of item 4021, further comprising a coating,
wherein the coating is a patterned coating.
[5023] 4058. The device of item 4021, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[5024] 4059. The device of item 4021, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[5025] 4060. The device of item 4021, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[5026] 4061. The device of item 4021, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[5027] 4062. The device of item 4021, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[5028] 4063. The device of item 4021, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[5029] 4064. The device of item 4021, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[5030] 4065. The device of item 4021, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[5031] 4066. The device of item 4021, further comprising a coating,
wherein the coating further comprises a polymer.
[5032] 4067. The device of item 4021, further comprising a first
coating having a first composition and the second coating having a
second composition.
[5033] 4068. The device of item 4021, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[5034] 4069. The device of item 4021, further comprising a
polymer.
[5035] 4070. The device of item 4021, further comprising a
polymeric carrier.
[5036] 4071. The device of item 4021, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[5037] 4072. The device of item 4021, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[5038] 4073. The device of item 4021, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[5039] 4074. The device of item 4021, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[5040] 4075. The device of item 4021, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[5041] 4076. The device of item 4021, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[5042] 4077. The device of item 4021, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[5043] 4078. The device of item 4021, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[5044] 4079. The device of item 4021, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[5045] 4080. The device of item 4021, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[5046] 4081. The device of item 4021, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[5047] 4082. The device of item 4021, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[5048] 4083. The device of item 4021, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[5049] 4084. The device of item 4021, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[5050] 4085. The device of item 4021, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[5051] 4086. The device of item 4021, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[5052] 4087. The device of item 4021, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[5053] 4088. The device of item 4021, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[5054] 4089. The device of item 4021, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[5055] 4090. The device of item 4021, further comprising a
lubricious coating.
[5056] 4091. The device of item 4021 wherein the fibrosing agent is
located within pores or holes of the device.
[5057] 4092. The device of item 4021 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[5058] 4093. The device of item 4021, further comprising a second
pharmaceutically active agent.
[5059] 4094. The device of item 4021, further comprising an
anti-inflammatory agent.
[5060] 4095. The device of item 4021, further comprising an agent
that inhibits infection.
[5061] 4096. The device of item 4021, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[5062] 4097. The device of item 4021, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[5063] 4098. The device of item 4021, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[5064] 4099. The device of item 4021, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[5065] 4100. The device of item 4021, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[5066] 4101. The device of item 4021, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[5067] 4102. The device of item 4021, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[5068] 4103. The device of item 4021, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[5069] 4104. The device of item 4021, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[5070] 4105. The device of item 4021, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[5071] 4106. The device of item 4021, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[5072] 4107. The device of item 4021, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[5073] 4108. The device of item 4021, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[5074] 4109. The device of item 4021, further comprising an
anti-thrombotic agent.
[5075] 4110. The device of item 4021, further comprising a
visualization agent.
[5076] 4111. The device of item 4021, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[5077] 4112. The device of item 4021, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[5078] 4113. The device of item 4021, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[5079] 4114. The device of item 4021, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[5080] 4115. The device of item 4021, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[5081] 4116. The device of item 4021, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[5082] 4117. The device of item 4021, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[5083] 4118. The device of item 4021, further comprising an
echogenic material.
[5084] 4119. The device of item 4021, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[5085] 4120. The device of item 4021 wherein the device is
sterile.
[5086] 4121. The device of item 4021 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[5087] 4122. The device of item 4021 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[5088] 4123. The device of item 4021 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[5089] 4124. The device of item 4021 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[5090] 4125. The device of item 4021 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[5091] 4126. The device of item 4021 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[5092] 4127. The device of item 4021 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[5093] 4128. The device of item 4021 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[5094] 4129. The device of item 4021 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[5095] 4130. The device of item 4021 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[5096] 4131. The device of item 4021 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[5097] 4132. The device of item 4021 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[5098] 4133. The device of item 4021 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[5099] 4134. The device of item 4021 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[5100] 4135. The device of item 4021 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[5101] 4136. The device of item 4021 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[5102] 4137. The device of item 4021 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[5103] 4138. The device of item 4021 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[5104] 4139. The device of item 4021 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[5105] 4140. The device of item 4021 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[5106] 4141. The device of item 4021 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[5107] 4142. The device of item 4021 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[5108] 4143. The device of item 4021 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[5109] 4144. The device of item 4021 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[5110] 4145. A medical device comprising an internal fixation
implant and a fibrosing agent, where the fibrosing agent induces a
fibrotic response between the device and a patient in which the
device is implanted.
[5111] 4146. The device of item 4145 wherein the fibrosing agent
promotes regeneration.
[5112] 4147. The device of item 4145 wherein the fibrosing agent
promotes angiogenesis.
[5113] 4148. The device of item 4145 wherein the fibrosing agent
promotes fibroblast migration.
[5114] 4149. The device of item 4145 wherein the fibrosing agent
promotes fibroblast proliferation.
[5115] 4150. The device of item 4145 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[5116] 4151. The device of item 4145 wherein the fibrosing agent
promotes tissue remodeling.
[5117] 4152. The device of item 4145 wherein the fibrosing agent is
an arterial vessel wall irritant.
[5118] 4153. The device of item 4145 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[5119] 4154. The device of item 4145 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[5120] 4155. The device of item 4145 wherein the fibrosing agent is
or comprises silk.
[5121] 4156. The device of item 4145 wherein the fibrosing agent is
or comprises mineral particles.
[5122] 4157. The device of item 4145 wherein the fibrosing agent is
or comprises chitosan.
[5123] 4158. The device of item 4145 wherein the fibrosing agent is
or comprises polylysine.
[5124] 4159. The device of item 4145 wherein the fibrosing agent is
or comprises fibronectin.
[5125] 4160. The device of item 4145 wherein the fibrosing agent is
or comprises bleomycin.
[5126] 4161. The device of item 4145 wherein the fibrosing agent is
or comprises CTGF.
[5127] 4162. The device of item 4145 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[5128] 4163. The device of item 4145 wherein the fibrosing agent is
in the form of a particulate.
[5129] 4164. The device of item 4145 wherein the composition
further comprises an inflammatory cytokine.
[5130] 4165. The device of item 4145 wherein the composition
further comprises an agent that stimulates cell proliferation.
[5131] 4166. The device of item 4145 wherein the composition is in
the form of a gel, paste, or spray.
[5132] 4167. The device of item 4145 wherein the fibrosing agent is
in the form of tufts.
[5133] 4168. The device of item 4145, further comprising a
polymer.
[5134] 4169. The device of item 4145, further comprising a
polymeric carrier.
[5135] 4170. The device of item 4145 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[5136] 4171. The device of item 4145 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[5137] 4172. The device of item 4145, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[5138] 4173. The device of item 4145, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[5139] 4174. The device of item 4145, further comprising a coating,
wherein the coating directly contacts the device.
[5140] 4175. The device of item 4145, further comprising a coating,
wherein the coating indirectly contacts the device.
[5141] 4176. The device of item 4145, further comprising a coating,
wherein the coating partially covers the device.
[5142] 4177. The device of item 4145, further comprising a coating,
wherein the coating completely covers the device.
[5143] 4178. The device of item 4145, further comprising a coating,
wherein the coating is a uniform coating.
[5144] 4179. The device of item 4145, further comprising a coating,
wherein the coating is a non-uniform coating.
[5145] 4180. The device of item 4145, further comprising a coating,
wherein the coating is a discontinuous coating.
[5146] 4181. The device of item 4145, further comprising a coating,
wherein the coating is a patterned coating.
[5147] 4182. The device of item 4145, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[5148] 4183. The device of item 4145, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[5149] 4184. The device of item 4145, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[5150] 4185. The device of item 4145, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[5151] 4186. The device of item 4145, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[5152] 4187. The device of item 4145, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[5153] 4188. The device of item 4145, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[5154] 4189. The device of item 4145, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[5155] 4190. The device of item 4145, further comprising a coating,
wherein the coating further comprises a polymer.
[5156] 4191. The device of item 4145, further comprising a first
coating having a first composition and the second coating having a
second composition.
[5157] 4192. The device of item 4145, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[5158] 4193. The device of item 4145, further comprising a
polymer.
[5159] 4194. The device of item 4145, further comprising a
polymeric carrier.
[5160] 4195. The device of item 4145, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[5161] 4196. The device of item 4145, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[5162] 4197. The device of item 4145, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[5163] 4198. The device of item 4145, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[5164] 4199. The device of item 4145, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[5165] 4200. The device of item 4145, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[5166] 4201. The device of item 4145, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[5167] 4202. The device of item 4145, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[5168] 4203. The device of item 4145, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[5169] 4204. The device of item 4145, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[5170] 4205. The device of item 4145, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[5171] 4206. The device of item 4145, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[5172] 4207. The device of item 4145, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[5173] 4208. The device of item 4145, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[5174] 4209. The device of item 4145, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[5175] 4210. The device of item 4145, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[5176] 4211. The device of item 4145, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[5177] 4212. The device of item 4145, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[5178] 4213. The device of item 4145, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[5179] 4214. The device of item 4145, further comprising a
lubricious coating.
[5180] 4215. The device of item 4145 wherein the fibrosing agent is
located within pores or holes of the device.
[5181] 4216. The device of item 4145 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[5182] 4217. The device of item 4145, further comprising a second
pharmaceutically active agent.
[5183] 4218. The device of item 4145, further comprising an
anti-inflammatory agent.
[5184] 4219. The device of item 4145, further comprising an agent
that inhibits infection.
[5185] 4220. The device of item 4145, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[5186] 4221. The device of item 4145, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[5187] 4222. The device of item 4145, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[5188] 4223. The device of item 4145, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[5189] 4224. The device of item 4145, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[5190] 4225. The device of item 4145, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[5191] 4226. The device of item 4145, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[5192] 4227. The device of item 4145, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[5193] 4228. The device of item 4145, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[5194] 4229. The device of item 4145, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[5195] 4230. The device of item 4145, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[5196] 4231. The device of item 4145, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[5197] 4232. The device of item 4145, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[5198] 4233. The device of item 4145, further comprising an
anti-thrombotic agent.
[5199] 4234. The device of item 4145, further comprising a
visualization agent.
[5200] 4235. The device of item 4145, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[5201] 4236. The device of item 4145, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[5202] 4237. The device of item 4145, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[5203] 4238. The device of item 4145, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[5204] 4239. The device of item 4145, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[5205] 4240. The device of item 4145, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[5206] 4241. The device of item 4145, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[5207] 4242. The device of item 4145, further comprising an
echogenic material.
[5208] 4243. The device of item 4145, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[5209] 4244. The device of item 4145 wherein the device is
sterile.
[5210] 4245. The device of item 4145 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[5211] 4246. The device of item 4145 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[5212] 4247. The device of item 4145 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[5213] 4248. The device of item 4145 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[5214] 4249. The device of item 4145 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[5215] 4250. The device of item 4145 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[5216] 4251. The device of item 4145 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[5217] 4252. The device of item 4145 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[5218] 4253. The device of item 4145 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[5219] 4254. The device of item 4145 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[5220] 4255. The device of item 4145 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[5221] 4256. The device of item 4145 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[5222] 4257. The device of item 4145 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[5223] 4258. The device of item 4145 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[5224] 4259. The device of item 4145 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[5225] 4260. The device of item 4145 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[5226] 4261. The device of item 4145 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[5227] 4262. The device of item 4145 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[5228] 4263. The device of item 4145 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[5229] 4264. The device of item 4145 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[5230] 4265. The device of item 4145 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[5231] 4266. The device of item 4145 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[5232] 4267. The device of item 4145 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[5233] 4268. The device of item 4145 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[5234] 4269. A medical device comprising an external fixation
implant and a fibrosing agent, where the fibrosing agent induces a
fibrotic response between the device and a patient in which the
device is implanted.
[5235] 4270. The device of item 4269 wherein the fibrosing agent
promotes regeneration.
[5236] 4271. The device of item 4269 wherein the fibrosing agent
promotes angiogenesis.
[5237] 4272. The device of item 4269 wherein the fibrosing agent
promotes fibroblast migration.
[5238] 4273. The device of item 4269 wherein the fibrosing agent
promotes fibroblast proliferation.
[5239] 4274. The device of item 4269 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[5240] 4275. The device of item 4269 wherein the fibrosing agent
promotes tissue remodeling.
[5241] 4276. The device of item 4269 wherein the fibrosing agent is
an arterial vessel wall irritant.
[5242] 4277. The device of item 4269 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[5243] 4278. The device of item 4269 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[5244] 4279. The device of item 4269 wherein the fibrosing agent is
or comprises silk.
[5245] 4280. The device of item 4269 wherein the fibrosing agent is
or comprises mineral particles.
[5246] 4281. The device of item 4269 wherein the fibrosing agent is
or comprises chitosan.
[5247] 4282. The device of item 4269 wherein the fibrosing agent is
or comprises polylysine.
[5248] 4283. The device of item 4269 wherein the fibrosing agent is
or comprises fibronectin.
[5249] 4284. The device of item 4269 wherein the fibrosing agent is
or comprises bleomycin.
[5250] 4285. The device of item 4269 wherein the fibrosing agent is
or comprises CTGF.
[5251] 4286. The device of item 4269 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[5252] 4287. The device of item 4269 wherein the fibrosing agent is
in the form of a particulate.
[5253] 4288. The device of item 4269 wherein the composition
further comprises an inflammatory cytokine.
[5254] 4289. The device of item 4269 wherein the composition
further comprises an agent that stimulates cell proliferation.
[5255] 4290. The device of item 4269 wherein the composition is in
the form of a gel, paste, or spray.
[5256] 4291. The device of item 4269 wherein the fibrosing agent is
in the form of tufts.
[5257] 4292. The device of item 4269, further comprising a
polymer.
[5258] 4293. The device of item 4269, further comprising a
polymeric carrier.
[5259] 4294. The device of item 4269 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[5260] 4295. The device of item 4269 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[5261] 4296. The device of item 4269, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[5262] 4297. The device of item 4269, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[5263] 4298. The device of item 4269, further comprising a coating,
wherein the coating directly contacts the device.
[5264] 4299. The device of item 4269, further comprising a coating,
wherein the coating indirectly contacts the device.
[5265] 4300. The device of item 4269, further comprising a coating,
wherein the coating partially covers the device.
[5266] 4301. The device of item 4269, further comprising a coating,
wherein the coating completely covers the device.
[5267] 4302. The device of item 4269, further comprising a coating,
wherein the coating is a uniform coating.
[5268] 4303. The device of item 4269, further comprising a coating,
wherein the coating is a non-uniform coating.
[5269] 4304. The device of item 4269, further comprising a coating,
wherein the coating is a discontinuous coating.
[5270] 4305. The device of item 4269, further comprising a coating,
wherein the coating is a patterned coating.
[5271] 4306. The device of item 4269, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[5272] 4307. The device of item 4269, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[5273] 4308. The device of item 4269, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[5274] 4309. The device of item 4269, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[5275] 4310. The device of item 4269, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[5276] 4311. The device of item 4269, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[5277] 4312. The device of item 4269, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[5278] 4313. The device of item 4269, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[5279] 4314. The device of item 4269, further comprising a coating,
wherein the coating further comprises a polymer.
[5280] 4315. The device of item 4269, further comprising a first
coating having a first composition and the second coating having a
second composition.
[5281] 4316. The device of item 4269, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[5282] 4317. The device of item 4269, further comprising a
polymer.
[5283] 4318. The device of item 4269, further comprising a
polymeric carrier.
[5284] 4319. The device of item 4269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[5285] 4320. The device of item 4269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[5286] 4321. The device of item 4269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[5287] 4322. The device of item 4269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[5288] 4323. The device of item 4269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[5289] 4324. The device of item 4269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[5290] 4325. The device of item 4269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[5291] 4326. The device of item 4269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[5292] 4327. The device of item 4269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[5293] 4328. The device of item 4269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[5294] 4329. The device of item 4269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[5295] 4330. The device of item 4269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[5296] 4331. The device of item 4269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[5297] 4332. The device of item 4269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[5298] 4333. The device of item 4269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[5299] 4334. The device of item 4269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[5300] 4335. The device of item 4269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[5301] 4336. The device of item 4269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[5302] 4337. The device of item 4269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[5303] 4338. The device of item 4269, further comprising a
lubricious coating.
[5304] 4339. The device of item 4269 wherein the fibrosing agent is
located within pores or holes of the device.
[5305] 4340. The device of item 4269 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[5306] 4341. The device of item 4269, further comprising a second
pharmaceutically active agent.
[5307] 4342. The device of item 4269, further comprising an
anti-inflammatory agent.
[5308] 4343. The device of item 4269, further comprising an agent
that inhibits infection.
[5309] 4344. The device of item 4269, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[5310] 4345. The device of item 4269, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[5311] 4346. The device of item 4269, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[5312] 4347. The device of item 4269, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[5313] 4348. The device of item 4269, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[5314] 4349. The device of item 4269, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[5315] 4350. The device of item 4269, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[5316] 4351. The device of item 4269, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[5317] 4352. The device of item 4269, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[5318] 4353. The device of item 4269, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[5319] 4354. The device of item 4269, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[5320] 4355. The device of item 4269, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[5321] 4356. The device of item 4269, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[5322] 4357. The device of item 4269, further comprising an
anti-thrombotic agent.
[5323] 4358. The device of item 4269, further comprising a
visualization agent.
[5324] 4359. The device of item 4269, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[5325] 4360. The device of item 4269, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[5326] 4361. The device of item 4269, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[5327] 4362. The device of item 4269, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[5328] 4363. The device of item 4269, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[5329] 4364. The device of item 4269, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[5330] 4365. The device of item 4269, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[5331] 4366. The device of item 4269, further comprising an
echogenic material.
[5332] 4367. The device of item 4269, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[5333] 4368. The device of item 4269 wherein the device is
sterile.
[5334] 4369. The device of item 4269 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[5335] 4370. The device of item 4269 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[5336] 4371. The device of item 4269 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[5337] 4372. The device of item 4269 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[5338] 4373. The device of item 4269 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[5339] 4374. The device of item 4269 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[5340] 4375. The device of item 4269 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[5341] 4376. The device of item 4269 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[5342] 4377. The device of item 4269 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[5343] 4378. The device of item 4269 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[5344] 4379. The device of item 4269 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[5345] 4380. The device of item 4269 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[5346] 4381. The device of item 4269 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[5347] 4382. The device of item 4269 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[5348] 4383. The device of item 4269 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[5349] 4384. The device of item 4269 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[5350] 4385. The device of item 4269 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[5351] 4386. The device of item 4269 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[5352] 4387. The device of item 4269 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[5353] 4388. The device of item 4269 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[5354] 4389. The device of item 4269 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[5355] 4390. The device of item 4269 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[5356] 4391. The device of item 4269 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[5357] 4392. The device of item 4269 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[5358] 4393. A medical device comprising a fixation screw and a
fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
[5359] 4394. The device of item 4393 wherein the fibrosing agent
promotes regeneration.
[5360] 4395. The device of item 4393 wherein the fibrosing agent
promotes angiogenesis.
[5361] 4396. The device of item 4393 wherein the fibrosing agent
promotes fibroblast migration.
[5362] 4397. The device of item 4393 wherein the fibrosing agent
promotes fibroblast proliferation.
[5363] 4398. The device of item 4393 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[5364] 4399. The device of item 4393 wherein the fibrosing agent
promotes tissue remodeling.
[5365] 4400. The device of item 4393 wherein the fibrosing agent is
an arterial vessel wall irritant.
[5366] 4401. The device of item 4393 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[5367] 4402. The device of item 4393 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[5368] 4403. The device of item 4393 wherein the fibrosing agent is
or comprises silk.
[5369] 4404. The device of item 4393 wherein the fibrosing agent is
or comprises mineral particles.
[5370] 4405. The device of item 4393 wherein the fibrosing agent is
or comprises chitosan.
[5371] 4406. The device of item 4393 wherein the fibrosing agent is
or comprises polylysine.
[5372] 4407. The device of item 4393 wherein the fibrosing agent is
or comprises fibronectin.
[5373] 4408. The device of item 4393 wherein the fibrosing agent is
or comprises bleomycin.
[5374] 4409. The device of item 4393 wherein the fibrosing agent is
or comprises CTGF.
[5375] 4410. The device of item 4393 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[5376] 4411. The device of item 4393 wherein the fibrosing agent is
in the form of a particulate.
[5377] 4412. The device of item 4393 wherein the composition
further comprises an inflammatory cytokine.
[5378] 4413. The device of item 4393 wherein the composition
further comprises an agent that stimulates cell proliferation.
[5379] 4414. The device of item 4393 wherein the composition is in
the form of a gel, paste, or spray.
[5380] 4415. The device of item 4393 wherein the fibrosing agent is
in the form of tufts.
[5381] 4416. The device of item 4393, further comprising a
polymer.
[5382] 4417. The device of item 4393, further comprising a
polymeric carrier.
[5383] 4418. The device of item 4393 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[5384] 4419. The device of item 4393 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[5385] 4420. The device of item 4393, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[5386] 4421. The device of item 4393, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[5387] 4422. The device of item 4393, further comprising a coating,
wherein the coating directly contacts the device.
[5388] 4423. The device of item 4393, further comprising a coating,
wherein the coating indirectly contacts the device.
[5389] 4424. The device of item 4393, further comprising a coating,
wherein the coating partially covers the device.
[5390] 4425. The device of item 4393, further comprising a coating,
wherein the coating completely covers the device.
[5391] 4426. The device of item 4393, further comprising a coating,
wherein the coating is a uniform coating.
[5392] 4427. The device of item 4393, further comprising a coating,
wherein the coating is a non-uniform coating.
[5393] 4428. The device of item 4393, further comprising a coating,
wherein the coating is a discontinuous coating.
[5394] 4429. The device of item 4393, further comprising a coating,
wherein the coating is a patterned coating.
[5395] 4430. The device of item 4393, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[5396] 4431. The device of item 4393, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[5397] 4432. The device of item 4393, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[5398] 4433. The device of item 4393, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[5399] 4434. The device of item 4393, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[5400] 4435. The device of item 4393, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[5401] 4436. The device of item 4393, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[5402] 4437. The device of item 4393, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[5403] 4438. The device of item 4393, further comprising a coating,
wherein the coating further comprises a polymer.
[5404] 4439. The device of item 4393, further comprising a first
coating having a first composition and the second coating having a
second composition.
[5405] 4440. The device of item 4393, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[5406] 4441. The device of item 4393, further comprising a
polymer.
[5407] 4442. The device of item 4393, further comprising a
polymeric carrier.
[5408] 4443. The device of item 4393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[5409] 4444. The device of item 4393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[5410] 4445. The device of item 4393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[5411] 4446. The device of item 4393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[5412] 4447. The device of item 4393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[5413] 4448. The device of item 4393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[5414] 4449. The device of item 4393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[5415] 4450. The device of item 4393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[5416] 4451. The device of item 4393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[5417] 4452. The device of item 4393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[5418] 4453. The device of item 4393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[5419] 4454. The device of item 4393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[5420] 4455. The device of item 4393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[5421] 4456. The device of item 4393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[5422] 4457. The device of item 4393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[5423] 4458. The device of item 4393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[5424] 4459. The device of item 4393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[5425] 4460. The device of item 4393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[5426] 4461. The device of item 4393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[5427] 4462. The device of item 4393, further comprising a
lubricious coating.
[5428] 4463. The device of item 4393 wherein the fibrosing agent is
located within pores or holes of the device.
[5429] 4464. The device of item 4393 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[5430] 4465. The device of item 4393, further comprising a second
pharmaceutically active agent.
[5431] 4466. The device of item 4393, further comprising an
anti-inflammatory agent.
[5432] 4467. The device of item 4393, further comprising an agent
that inhibits infection.
[5433] 4468. The device of item 4393, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[5434] 4469. The device of item 4393, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[5435] 4470. The device of item 4393, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[5436] 4471. The device of item 4393, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[5437] 4472. The device of item 4393, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[5438] 4473. The device of item 4393, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[5439] 4474. The device of item 4393, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[5440] 4475. The device of item 4393, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[5441] 4476. The device of item 4393, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[5442] 4477. The device of item 4393, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[5443] 4478. The device of item 4393, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[5444] 4479. The device of item 4393, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[5445] 4480. The device of item 4393, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[5446] 4481. The device of item 4393, further comprising an
anti-thrombotic agent.
[5447] 4482. The device of item 4393, further comprising a
visualization agent.
[5448] 4483. The device of item 4393, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[5449] 4484. The device of item 4393, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[5450] 4485. The device of item 4393, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[5451] 4486. The device of item 4393, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[5452] 4487. The device of item 4393, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[5453] 4488. The device of item 4393, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[5454] 4489. The device of item 4393, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[5455] 4490. The device of item 4393, further comprising an
echogenic material.
[5456] 4491. The device of item 4393, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[5457] 4492. The device of item 4393 wherein the device is
sterile.
[5458] 4493. The device of item 4393 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[5459] 4494. The device of item 4393 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[5460] 4495. The device of item 4393 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[5461] 4496. The device of item 4393 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[5462] 4497. The device of item 4393 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[5463] 4498. The device of item 4393 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[5464] 4499. The device of item 4393 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[5465] 4500. The device of item 4393 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[5466] 4501. The device of item 4393 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[5467] 4502. The device of item 4393 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[5468] 4503. The device of item 4393 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[5469] 4504. The device of item 4393 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[5470] 4505. The device of item 4393 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[5471] 4506. The device of item 4393 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[5472] 4507. The device of item 4393 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[5473] 4508. The device of item 4393 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[5474] 4509. The device of item 4393 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[5475] 4510. The device of item 4393 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[5476] 4511. The device of item 4393 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[5477] 4512. The device of item 4393 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[5478] 4513. The device of item 4393 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[5479] 4514. The device of item 4393 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[5480] 4515. The device of item 4393 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[5481] 4516. The device of item 4393 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[5482] 4517. The device of item 4393 wherein the fixation screw is
biodegradable.
[5483] 4518. The device of item 4393 wherein the fixation screw is
non-biodegradable.
[5484] 4519. A medical device comprising an interferential screw
and a fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
[5485] 4520. The device of item 4519 wherein the fibrosing agent
promotes regeneration.
[5486] 4521. The device of item 4519 wherein the fibrosing agent
promotes angiogenesis.
[5487] 4522. The device of item 4519 wherein the fibrosing agent
promotes fibroblast migration.
[5488] 4523. The device of item 4519 wherein the fibrosing agent
promotes fibroblast proliferation.
[5489] 4524. The device of item 4519 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[5490] 4525. The device of item 4519 wherein the fibrosing agent
promotes tissue remodeling.
[5491] 4526. The device of item 4519 wherein the fibrosing agent is
an arterial vessel wall irritant.
[5492] 4527. The device of item 4519 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[5493] 4528. The device of item 4519 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[5494] 4529. The device of item 4519 wherein the fibrosing agent is
or comprises silk.
[5495] 4530. The device of item 4519 wherein the fibrosing agent is
or comprises mineral particles.
[5496] 4531. The device of item 4519 wherein the fibrosing agent is
or comprises chitosan.
[5497] 4532. The device of item 4519 wherein the fibrosing agent is
or comprises polylysine.
[5498] 4533. The device of item 4519 wherein the fibrosing agent is
or comprises fibronectin.
[5499] 4534. The device of item 4519 wherein the fibrosing agent is
or comprises bleomycin.
[5500] 4535. The device of item 4519 wherein the fibrosing agent is
or comprises CTGF.
[5501] 4536. The device of item 4519 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[5502] 4537. The device of item 4519 wherein the fibrosing agent is
in the form of a particulate.
[5503] 4538. The device of item 4519 wherein the composition
further comprises an inflammatory cytokine.
[5504] 4539. The device of item 4519 wherein the composition
further comprises an agent that stimulates cell proliferation.
[5505] 4540. The device of item 4519 wherein the composition is in
the form of a gel, paste, or spray.
[5506] 4541. The device of item 4519 wherein the fibrosing agent is
in the form of tufts.
[5507] 4542. The device of item 4519, further comprising a
polymer.
[5508] 4543. The device of item 4519, further comprising a
polymeric carrier.
[5509] 4544. The device of item 4519 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[5510] 4545. The device of item 4519 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[5511] 4546. The device of item 4519, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[5512] 4547. The device of item 4519, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[5513] 4548. The device-of item 4519, further comprising a coating,
wherein the coating directly contacts the device.
[5514] 4549. The device of item 4519, further comprising a coating,
wherein the coating indirectly contacts the device.
[5515] 4550. The device of item 4519, further comprising a coating,
wherein the coating partially covers the device.
[5516] 4551. The device of item 4519, further comprising a coating,
wherein the coating completely covers the device.
[5517] 4552. The device of item 4519, further comprising a coating,
wherein the coating is a uniform coating.
[5518] 4553. The device of item 4519, further comprising a coating,
wherein the coating is a non-uniform coating.
[5519] 4554. The device of item 4519, further comprising a coating,
wherein the coating is a discontinuous coating.
[5520] 4555. The device of item 4519, further comprising a coating,
wherein the coating is a patterned coating.
[5521] 4556. The device of item 4519, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[5522] 4557. The device of item 4519, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[5523] 4558. The device of item 4519, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[5524] 4559. The device of item 4519, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[5525] 4560. The device of item 4519, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[5526] 4561. The device of item 4519, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[5527] 4562. The device of item 4519, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[5528] 4563. The device of item 4519, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[5529] 4564. The device of item 4519, further comprising a coating,
wherein the coating further comprises a polymer.
[5530] 4565. The device of item 4519, further comprising a first
coating having a first composition and the second coating having a
second composition.
[5531] 4566. The device of item 4519, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[5532] 4567. The device of item 4519, further comprising a
polymer.
[5533] 4568. The device of item 4519, further comprising a
polymeric carrier.
[5534] 4569. The device of item 4519, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[5535] 4570. The device of item 4519, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[5536] 4571. The device of item 4519, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[5537] 4572. The device of item 4519, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[5538] 4573. The device of item 4519, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[5539] 4574. The device of item 4519, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[5540] 4575. The device of item 4519, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[5541] 4576. The device of item 4519, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[5542] 4577. The device of item 4519, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[5543] 4578. The device of item 4519, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[5544] 4579. The device of item 4519, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[5545] 4580. The device of item 4519, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[5546] 4581. The device of item 4519, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[5547] 4582. The device of item 4519, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[5548] 4583. The device of item 4519, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[5549] 4584. The device of item 4519, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[5550] 4585. The device of item 4519, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[5551] 4586. The device of item 4519, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[5552] 4587. The device of item 4519, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[5553] 4588. The device of item 4519, further comprising a
lubricious coating.
[5554] 4589. The device of item 4519 wherein the fibrosing agent is
located within pores or holes of the device.
[5555] 4590. The device of item 4519 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[5556] 4591. The device of item 4519, further comprising a second
pharmaceutically active agent.
[5557] 4592. The device of item 4519, further comprising an
anti-inflammatory agent.
[5558] 4593. The device of item 4519, further comprising an agent
that inhibits infection.
[5559] 4594. The device of item 4519, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[5560] 4595. The device of item 4519, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[5561] 4596. The device of item 4519, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[5562] 4597. The device of item 4519, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[5563] 4598. The device of item 4519, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[5564] 4599. The device of item 4519, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[5565] 4600. The device of item 4519, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[5566] 4601. The device of item 4519, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[5567] 4602. The device of item 4519, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[5568] 4603. The device of item 4519, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[5569] 4604. The device of item 4519, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[5570] 4605. The device of item 4519, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[5571] 4606. The device of item 4519, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[5572] 4607. The device of item 4519, further comprising an
anti-thrombotic agent.
[5573] 4608. The device of item 4519, further comprising a
visualization agent.
[5574] 4609. The device of item 4519, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[5575] 4610. The device of item 4519, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[5576] 4611. The device of item 4519, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[5577] 4612. The device of item 4519, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[5578] 4613. The device of item 4519, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[5579] 4614. The device of item 4519, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[5580] 4615. The device of item 4519, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[5581] 4616. The device of item 4519, further comprising an
echogenic material.
[5582] 4617. The device of item 4519, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[5583] 4618. The device of item 4519 wherein the device is
sterile.
[5584] 4619. The device of item 4519 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[5585] 4620. The device of item 4519 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[5586] 4621. The device of item 4519 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[5587] 4622. The device of item 4519 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[5588] 4623. The device of item 4519 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[5589] 4624. The device of item 4519 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[5590] 4625. The device of item 4519 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[5591] 4626. The device of item 4519 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[5592] 4627. The device of item 4519 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[5593] 4628. The device of item 4519 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[5594] 4629. The device of item 4519 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[5595] 4630. The device of item 4519 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[5596] 4631. The device of item 4519 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[5597] 4632. The device of item 4519 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[5598] 4633. The device of item 4519 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[5599] 4634. The device of item 4519 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[5600] 4635. The device of item 4519 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[5601] 4636. The device of item 4519 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[5602] 4637. The device of item 4519 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[5603] 4638. The device of item 4519 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[5604] 4639. The device of item 4519 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[5605] 4640. The device of item 4519 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[5606] 4641. The device of item 4519 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[5607] 4642. The device of item 4519 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[5608] 4643. The device of item 4519 wherein the interferential
screw is degradable.
[5609] 4644. The device of item 4519 wherein the interferential
screw is non-degradable.
[5610] 4645. A medical device comprising a trochanteric screw and a
fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
[5611] 4646. The device of item 4645 wherein the fibrosing agent
promotes regeneration.
[5612] 4647. The device of item 4645 wherein the fibrosing agent
promotes angiogenesis.
[5613] 4648. The device of item 4645 wherein the fibrosing agent
promotes fibroblast migration.
[5614] 4649. The device of item 4645 wherein the fibrosing agent
promotes fibroblast proliferation.
[5615] 4650. The device of item 4645 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[5616] 4651. The device of item 4645 wherein the fibrosing agent
promotes tissue remodeling.
[5617] 4652. The device of item 4645 wherein the fibrosing agent is
an arterial vessel wall irritant.
[5618] 4653. The device of item 4645 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[5619] 4654. The device of item 4645 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[5620] 4655. The device of item 4645 wherein the fibrosing agent is
or comprises silk.
[5621] 4656. The device of item 4645 wherein the fibrosing agent is
or comprises mineral particles.
[5622] 4657. The device of item 4645 wherein the fibrosing agent is
or comprises chitosan.
[5623] 4658. The device of item 4645 wherein the fibrosing agent is
or comprises polylysine.
[5624] 4659. The device of item 4645 wherein the fibrosing agent is
or comprises fibronectin.
[5625] 4660. The device of item 4645 wherein the fibrosing agent is
or comprises bleomycin.
[5626] 4661. The device of item 4645 wherein the fibrosing agent is
or comprises CTGF.
[5627] 4662. The device of item 4645 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[5628] 4663. The device of item 4645 wherein the fibrosing agent is
in the form of a particulate.
[5629] 4664. The device of item 4645 wherein the composition
further comprises an inflammatory cytokine.
[5630] 4665. The device of item 4645 wherein the composition
further comprises an agent that stimulates cell proliferation.
[5631] 4666. The device of item 4645 wherein the composition is in
the form of a gel, paste, or spray.
[5632] 4667. The device of item 4645 wherein the fibrosing agent is
in the form of tufts.
[5633] 4668. The device of item 4645, further comprising a
polymer.
[5634] 4669. The device of item 4645, further comprising a
polymeric carrier.
[5635] 4670. The device of item 4645 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[5636] 4671. The device of item 4645 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[5637] 4672. The device of item 4645, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[5638] 4673. The device of item 4645, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[5639] 4674. The device of item 4645, further comprising a coating,
wherein the coating directly contacts the device.
[5640] 4675. The device of item 4645, further comprising a coating,
wherein the coating indirectly contacts the device.
[5641] 4676. The device of item 4645, further comprising a coating,
wherein the coating partially covers the device.
[5642] 4677. The device of item 4645, further comprising a coating,
wherein the coating completely covers the device.
[5643] 4678. The device of item 4645, further comprising a coating,
wherein the coating is a uniform coating.
[5644] 4679. The device of item 4645, further comprising a coating,
wherein the coating is a non-uniform coating.
[5645] 4680. The device of item 4645, further comprising a coating,
wherein the coating is a discontinuous coating.
[5646] 4681. The device of item 4645, further comprising a coating,
wherein the coating is a patterned coating.
[5647] 4682. The device of item 4645, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[5648] 4683. The device of item 4645, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[5649] 4684. The device of item 4645, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[5650] 4685. The device of item 4645, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[5651] 4686. The device of item 4645, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[5652] 4687. The device of item 4645, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[5653] 4688. The device of item 4645, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[5654] 4689. The device of item 4645, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[5655] 4690. The device of item 4645, further comprising a coating,
wherein the coating further comprises a polymer.
[5656] 4691. The device of item 4645, further comprising a first
coating having a first composition and the second coating having a
second composition.
[5657] 4692. The device of item 4645, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[5658] 4693. The device of item 4645, further comprising a
polymer.
[5659] 4694. The device of item 4645, further comprising a
polymeric carrier.
[5660] 4695. The device of item 4645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[5661] 4696. The device of item 4645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[5662] 4697. The device of item 4645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[5663] 4698. The device of item 4645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[5664] 4699. The device of item 4645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[5665] 4700. The device of item 4645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[5666] 4701. The device of item 4645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[5667] 4702. The device of item 4645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[5668] 4703. The device of item 4645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[5669] 4704. The device of item 4645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[5670] 4705. The device of item 4645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[5671] 4706. The device of item 4645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[5672] 4707. The device of item 4645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[5673] 4708. The device of item 4645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[5674] 4709. The device of item 4645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[5675] 4710. The device of item 4645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[5676] 4711. The device of item 4645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[5677] 4712. The device of item 4645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[5678] 4713. The device of item 4645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[5679] 4714. The device of item 4645, further comprising a
lubricious coating.
[5680] 4715. The device of item 4645 wherein the fibrosing agent is
located within pores or holes of the device.
[5681] 4716. The device of item 4645 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[5682] 4717. The device of item 4645, further comprising a second
pharmaceutically active agent.
[5683] 4718. The device of item 4645, further comprising an
anti-inflammatory agent.
[5684] 4719. The device of item 4645, further comprising an agent
that inhibits infection.
[5685] 4720. The device of item 4645, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[5686] 4721. The device of item 4645, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[5687] 4722. The device of item 4645, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[5688] 4723. The device of item 4645, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[5689] 4724. The device of item 4645, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[5690] 4725. The device of item 4645, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[5691] 4726. The device of item 4645, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[5692] 4727. The device of item 4645, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[5693] 4728. The device of item 4645, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[5694] 4729. The device of item 4645, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[5695] 4730. The device of item 4645, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[5696] 4731. The device of item 4645, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[5697] 4732. The device of item 4645, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[5698] 4733. The device of item 4645, further comprising an
anti-thrombotic agent.
[5699] 4734. The device of item 4645, further comprising a
visualization agent.
[5700] 4735. The device of item 4645, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[5701] 4736. The device of item 4645, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[5702] 4737. The device of item 4645, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[5703] 4738. The device of item 4645, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[5704] 4739. The device of item 4645, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[5705] 4740. The device of item 4645, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[5706] 4741. The device of item 4645, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[5707] 4742. The device of item 4645, further comprising an
echogenic material.
[5708] 4743. The device of item 4645, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[5709] 4744. The device of item 4645 wherein the device is
sterile.
[5710] 4745. The device of item 4645 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[5711] 4746. The device of item 4645 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[5712] 4747. The device of item 4645 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[5713] 4748. The device of item 4645 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[5714] 4749. The device of item 4645 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[5715] 4750. The device of item 4645 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[5716] 4751. The device of item 4645 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[5717] 4752. The device of item 4645 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[5718] 4753. The device of item 4645 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[5719] 4754. The device of item 4645 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[5720] 4755. The device of item 4645 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[5721] 4756. The device of item 4645 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[5722] 4757. The device of item 4645 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[5723] 4758. The device of item 4645 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[5724] 4759. The device of item 4645 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[5725] 4760. The device of item 4645 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[5726] 4761. The device of item 4645 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[5727] 4762. The device of item 4645 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[5728] 4763. The device of item 4645 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[5729] 4764. The device of item 4645 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[5730] 4765. The device of item 4645 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[5731] 4766. The device of item 4645 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[5732] 4767. The device of item 4645 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[5733] 4768. The device of item 4645 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[5734] 4769. A medical device comprising a plate implant and a
fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
[5735] 4770. The device of item 4769 wherein the fibrosing agent
promotes regeneration.
[5736] 4771. The device of item 4769 wherein the fibrosing agent
promotes angiogenesis.
[5737] 4772. The device of item 4769 wherein the fibrosing agent
promotes fibroblast migration.
[5738] 4773. The device of item 4769 wherein the fibrosing agent
promotes fibroblast proliferation.
[5739] 4774. The device of item 4769 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[5740] 4775. The device of item 4769 wherein the fibrosing agent
promotes tissue remodeling.
[5741] 4776. The device of item 4769 wherein the fibrosing agent is
an arterial vessel wall irritant.
[5742] 4777. The device of item 4769 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[5743] 4778. The device of item 4769 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[5744] 4779. The device of item 4769 wherein the fibrosing agent is
or comprises silk.
[5745] 4780. The device of item 4769 wherein the fibrosing agent is
or comprises mineral particles.
[5746] 4781. The device of item 4769 wherein the fibrosing agent is
or comprises chitosan.
[5747] 4782. The device of item 4769 wherein the fibrosing agent is
or comprises polylysine.
[5748] 4783. The device of item 4769 wherein the fibrosing agent is
or comprises fibronectin.
[5749] 4784. The device of item 4769 wherein the fibrosing agent is
or comprises bleomycin.
[5750] 4785. The device of item 4769 wherein the fibrosing agent is
or comprises CTGF.
[5751] 4786. The device of item 4769 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[5752] 4787. The device of item 4769 wherein the fibrosing agent is
in the form of a particulate.
[5753] 4788. The device of item 4769 wherein the composition
further comprises an inflammatory cytokine.
[5754] 4789. The device of item 4769 wherein the composition
further comprises an agent that stimulates cell proliferation.
[5755] 4790. The device of item 4769 wherein the composition is in
the form of a gel, paste, or spray.
[5756] 4791. The device of item 4769 wherein the fibrosing agent is
in the form of tufts.
[5757] 4792. The device of item 4769, further comprising a
polymer.
[5758] 4793. The device of item 4769, further comprising a
polymeric carrier.
[5759] 4794. The device of item 4769 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[5760] 4795. The device of item 4769 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[5761] 4796. The device of item 4769, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[5762] 4797. The device of item 4769, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[5763] 4798. The device of item 4769, further comprising a coating,
wherein the coating directly contacts the device.
[5764] 4799. The device of item 4769, further comprising a coating,
wherein the coating indirectly contacts the device.
[5765] 4800. The device of item 4769, further comprising a coating,
wherein the coating partially covers the device.
[5766] 4801. The device of item 4769, further comprising a coating,
wherein the coating completely covers the device.
[5767] 4802. The device of item 4769, further comprising a coating,
wherein the coating is a uniform coating.
[5768] 4803. The device of item 4769, further comprising a coating,
wherein the coating is a non-uniform coating.
[5769] 4804. The device of item 4769, further comprising a coating,
wherein the coating is a discontinuous coating.
[5770] 4805. The device of item 4769, further comprising a coating,
wherein the coating is a patterned coating.
[5771] 4806. The device of item 4769, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[5772] 4807. The device of item 4769, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[5773] 4808. The device of item 4769, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[5774] 4809. The device of item 4769, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[5775] 4810. The device of item 4769, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[5776] 4811. The device of item 4769, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[5777] 4812. The device of item 4769, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[5778] 4813. The device of item 4769, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[5779] 4814. The device of item 4769, further comprising a coating,
wherein the coating further comprises a polymer.
[5780] 4815. The device of item 4769, further comprising a first
coating having a first composition and the second coating having a
second composition.
[5781] 4816. The device of item 4769, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[5782] 4817. The device of item 4769, further comprising a
polymer.
[5783] 4818. The device of item 4769, further comprising a
polymeric carrier.
[5784] 4819. The device of item 4769, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[5785] 4820. The device of item 4769, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[5786] 4821. The device of item 4769, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[5787] 4822. The device of item 4769, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[5788] 4823. The device of item 4769, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[5789] 4824. The device of item 4769, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[5790] 4825. The device of item 4769, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[5791] 4826. The device of item 4769, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[5792] 4827. The device of item 4769, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[5793] 4828. The device of item 4769, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[5794] 4829. The device of item 4769, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[5795] 4830. The device of item 4769, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[5796] 4831. The device of item 4769, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[5797] 4832. The device of item 4769, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[5798] 4833. The device of item 4769, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[5799] 4834. The device of item 4769, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[5800] 4835. The device of item 4769, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[5801] 4836. The device of item 4769, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[5802] 4837. The device of item 4769, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[5803] 4838. The device of item 4769, further comprising a
lubricious coating.
[5804] 4839. The device of item 4769 wherein the fibrosing agent is
located within pores or holes of the device.
[5805] 4840. The device of item 4769 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[5806] 4841. The device of item 4769, further comprising a second
pharmaceutically active agent.
[5807] 4842. The device of item 4769, further comprising an
anti-inflammatory agent.
[5808] 4843. The device of item 4769, further comprising an agent
that inhibits infection.
[5809] 4844. The device of item 4769, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[5810] 4845. The device of item 4769, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[5811] 4846. The device of item 4769, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[5812] 4847. The device of item 4769, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[5813] 4848. The device of item 4769, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[5814] 4849. The device of item 4769, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[5815] 4850. The device of item 4769, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[5816] 4851. The device of item 4769, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[5817] 4852. The device of item 4769, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[5818] 4853. The device of item 4769, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[5819] 4854. The device of item 4769, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[5820] 4855. The device of item 4769, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[5821] 4856. The device of item 4769, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[5822] 4857. The device of item 4769, further comprising an
anti-thrombotic agent.
[5823] 4858. The device of item 4769, further comprising a
visualization agent.
[5824] 4859. The device of item 4769, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[5825] 4860. The device of item 4769, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[5826] 4861. The device of item 4769, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[5827] 4862. The device of item 4769, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[5828] 4863. The device of item 4769, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[5829] 4864. The device of item 4769, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[5830] 4865. The device of item 4769, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[5831] 4866. The device of item 4769, further comprising an
echogenic material.
[5832] 4867. The device of item 4769, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[5833] 4868. The device of item 4769 wherein the device is
sterile.
[5834] 4869. The device of item 4769 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[5835] 4870. The device of item 4769 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[5836] 4871. The device of item 4769 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[5837] 4872. The device of item 4769 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[5838] 4873. The device of item 4769 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[5839] 4874. The device of item 4769 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[5840] 4875. The device of item 4769 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[5841] 4876. The device of item 4769 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 190 days.
[5842] 4877. The device of item 4769 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[5843] 4878. The device of item 4769 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[5844] 4879. The device of item 4769 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[5845] 4880. The device of item 4769 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[5846] 4881. The device of item 4769 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[5847] 4882. The device of item 4769 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[5848] 4883. The device of item 4769 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[5849] 4884. The device of item 4769 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[5850] 4885. The device of item 4769 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[5851] 4886. The device of item 4769 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[5852] 4887. The device of item 4769 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[5853] 4888. The device of item 4769 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[5854] 4889. The device of item 4769 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[5855] 4890. The device of item 4769 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[5856] 4891. The device of item 4769 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[5857] 4892. The device of item 4769 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[5858] 4893. A medical device comprising a wire implant and a
fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
[5859] 4894. The device of item 4893 wherein the fibrosing agent
promotes regeneration.
[5860] 4895. The device of item 4893 wherein the fibrosing agent
promotes angiogenesis.
[5861] 4896. The device of item 4893 wherein the fibrosing agent
promotes fibroblast migration.
[5862] 4897. The device of item 4893 wherein the fibrosing agent
promotes fibroblast proliferation.
[5863] 4898. The device of item 4893 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[5864] 4899. The device of item 4893 wherein the fibrosing agent
promotes tissue remodeling.
[5865] 4900. The device of item 4893 wherein the fibrosing agent is
an arterial vessel wall irritant.
[5866] 4901. The device of item 4893 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[5867] 4902. The device of item 4893 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[5868] 4903. The device of item 4893 wherein the fibrosing agent is
or comprises silk.
[5869] 4904. The device of item 4893 wherein the fibrosing agent is
or comprises mineral particles.
[5870] 4905. The device of item 4893 wherein the fibrosing agent is
or comprises chitosan.
[5871] 4906. The device of item 4893 wherein the fibrosing agent is
or comprises polylysine.
[5872] 4907. The device of item 4893 wherein the fibrosing agent is
or comprises fibronectin.
[5873] 4908. The device of item 4893 wherein the fibrosing agent is
or comprises bleomycin.
[5874] 4909. The device of item 4893 wherein the fibrosing agent is
or comprises CTGF.
[5875] 4910. The device of item 4893 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[5876] 4911. The device of item 4893 wherein the fibrosing agent is
in the form of a particulate.
[5877] 4912. The device of item 4893 wherein the composition
further comprises an inflammatory cytokine.
[5878] 4913. The device of item 4893 wherein the composition
further comprises an agent that stimulates cell proliferation.
[5879] 4914. The device of item 4893 wherein the composition is in
the form of a gel, paste, or spray.
[5880] 4915. The device of item 4893 wherein the fibrosing agent is
in the form of tufts.
[5881] 4916. The device of item 4893, further comprising a
polymer.
[5882] 4917. The device of item 4893, further comprising a
polymeric carrier.
[5883] 4918. The device of item 4893 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[5884] 4919. The device of item 4893 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[5885] 4920. The device of item 4893, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[5886] 4921. The device of item 4893, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[5887] 4922. The device of item 4893, further comprising a coating,
wherein the coating directly contacts the device.
[5888] 4923. The device of item 4893, further comprising a coating,
wherein the coating indirectly contacts the device.
[5889] 4924. The device of item 4893, further comprising a coating,
wherein the coating partially covers the device.
[5890] 4925. The device of item 4893, further comprising a coating,
wherein the coating completely covers the device.
[5891] 4926. The device of item 4893, further comprising a coating,
wherein the coating is a uniform coating.
[5892] 4927. The device of item 4893, further comprising a coating,
wherein the coating is a non-uniform coating.
[5893] 4928. The device of item 4893, further comprising a coating,
wherein the coating is a discontinuous coating.
[5894] 4929. The device of item 4893, further comprising a coating,
wherein the coating is a patterned coating.
[5895] 4930. The device of item 4893, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[5896] 4931. The device of item 4893, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[5897] 4932. The device of item 4893, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[5898] 4933. The device of item 4893, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[5899] 4934. The device of item 4893, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[5900] 4935. The device of item 4893, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[5901] 4936. The device of item 4893, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[5902] 4937. The device of item 4893, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[5903] 4938. The device of item 4893, further comprising a coating,
wherein the coating further comprises a polymer.
[5904] 4939. The device of item 4893, further comprising a first
coating having a first composition and the second coating having a
second composition.
[5905] 4940. The device of item 4893, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[5906] 4941. The device of item 4893, further comprising a
polymer.
[5907] 4942. The device of item 4893, further comprising a
polymeric carrier.
[5908] 4943. The device of item 4893, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[5909] 4944. The device of item 4893, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[5910] 4945. The device of item 4893, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[5911] 4946. The device of item 4893, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[5912] 4947. The device of item 4893, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[5913] 4948. The device of item 4893, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[5914] 4949. The device of item 4893, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[5915] 4950. The device of item 4893, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[5916] 4951. The device of item 4893, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[5917] 4952. The device of item 4893, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[5918] 4953. The device of item 4893, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[5919] 4954. The device of item 4893, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[5920] 4955. The device of item 4893, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[5921] 4956. The device of item 4893, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[5922] 4957. The device of item 4893, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[5923] 4958. The device of item 4893, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[5924] 4959. The device of item 4893, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[5925] 4960. The device of item 4893, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[5926] 4961. The device of item 4893, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[5927] 4962. The device of item 4893, further comprising a
lubricious coating.
[5928] 4963. The device of item 4893 wherein the fibrosing agent is
located within pores or holes of the device.
[5929] 4964. The device of item 4893 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[5930] 4965. The device of item 4893, further comprising a second
pharmaceutically active agent.
[5931] 4966. The device of item 4893, further comprising an
anti-inflammatory agent.
[5932] 4967. The device of item 4893, further comprising an agent
that inhibits infection.
[5933] 4968. The device of item 4893, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[5934] 4969. The device of item 4893, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[5935] 4970. The device of item 4893, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[5936] 4971. The device of item 4893, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[5937] 4972. The device of item 4893, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[5938] 4973. The device of item 4893, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[5939] 4974. The device of item 4893, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[5940] 4975. The device of item 4893, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[5941] 4976. The device of item 4893, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[5942] 4977. The device of item 4893, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[5943] 4978. The device of item 4893, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[5944] 4979. The device of item 4893, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[5945] 4980. The device of item 4893, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[5946] 4981. The device of item 4893, further comprising an
anti-thrombotic agent.
[5947] 4982. The device of item 4893, further comprising a
visualization agent.
[5948] 4983. The device of item 4893, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[5949] 4984. The device of item 4893, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[5950] 4985. The device of item 4893, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[5951] 4986. The device of item 4893, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[5952] 4987. The device of item 4893, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[5953] 4988. The device of item 4893, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[5954] 4989. The device of item 4893, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[5955] 4990. The device of item 4893, further comprising an
echogenic material.
[5956] 4991. The device of item 4893, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[5957] 4992. The device of item 4893 wherein the device is
sterile.
[5958] 4993. The device of item 4893 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[5959] 4994. The device of item 4893 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[5960] 4995. The device of item 4893 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[5961] 4996. The device of item 4893 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[5962] 4997. The device of item 4893 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[5963] 4998. The device of item 4893 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[5964] 4999. The device of item 4893 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[5965] 5000. The device of item 4893 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[5966] 5001. The device of item 4893 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[5967] 5002. The device of item 4893 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[5968] 5003. The device of item 4893 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[5969] 5004. The device of item 4893 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[5970] 5005. The device of item 4893 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[5971] 5006. The device of item 4893 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[5972] 5007. The device of item 4893 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[5973] 5008. The device of item 4893 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[5974] 5009. The device of item 4893 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[5975] 5010. The device of item 4893 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[5976] 5011. The device of item 4893 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[5977] 5012. The device of item 4893 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[5978] 5013. The device of item 4893 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[5979] 5014. The device of item 4893 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[5980] 5015. The device of item 4893 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[5981] 5016. The device of item 4893 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[5982] 5017. A medical device comprising a collagen implant and a
fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
[5983] 5018. The device of item 5017 wherein the fibrosing agent
promotes regeneration.
[5984] 5019. The device of item 5017 wherein the fibrosing agent
promotes angiogenesis.
[5985] 5020. The device of item 5017 wherein the fibrosing agent
promotes fibroblast migration.
[5986] 5021. The device of item 5017 wherein the fibrosing agent
promotes fibroblast proliferation.
[5987] 5022. The device of item 5017 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[5988] 5023. The device of item 5017 wherein the fibrosing agent
promotes tissue remodeling.
[5989] 5024. The device of item 5017 wherein the fibrosing agent is
an arterial vessel wall irritant.
[5990] 5025. The device of item 5017 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[5991] 5026. The device of item 5017 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[5992] 5027. The device of item 5017 wherein the fibrosing agent is
or comprises silk.
[5993] 5028. The device of item 5017 wherein the fibrosing agent is
or comprises mineral particles.
[5994] 5029. The device of item 5017 wherein the fibrosing agent is
or comprises chitosan.
[5995] 5030. The device of item 5017 wherein the fibrosing agent is
or comprises polylysine.
[5996] 5031. The device of item 5017 wherein the fibrosing agent is
or comprises fibronectin.
[5997] 5032. The device of item 5017 wherein the fibrosing agent is
or comprises bleomycin.
[5998] 5033. The device of item 5017 wherein the fibrosing agent is
or comprises CTGF.
[5999] 5034. The device of item 5017 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[6000] 5035. The device of item 5017 wherein the fibrosing agent is
in the form of a particulate.
[6001] 5036. The device of item 5017 wherein the composition
further comprises an inflammatory cytokine.
[6002] 5037. The device of item 5017 wherein the composition
further comprises an agent that stimulates cell proliferation.
[6003] 5038. The device of item 5017 wherein the composition is in
the form of a gel, paste, or spray.
[6004] 5039. The device of item 5017 wherein the fibrosing agent is
in the form of tufts.
[6005] 5040. The device of item 5017, further comprising a
polymer.
[6006] 5041. The device of item 5017, further comprising a
polymeric carrier.
[6007] 5042. The device of item 5017 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[6008] 5043. The device of item 5017 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[6009] 5044. The device of item 5017, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[6010] 5045. The device of item 5017, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[6011] 5046. The device of item 5017, further comprising a coating,
wherein the coating directly contacts the device.
[6012] 5047. The device of item 5017, further comprising a coating,
wherein the coating indirectly contacts the device.
[6013] 5048. The device of item 5017, further comprising a coating,
wherein the coating partially covers the device.
[6014] 5049. The device of item 5017, further comprising a coating,
wherein the coating completely covers the device.
[6015] 5050. The device of item 5017, further comprising a coating,
wherein the coating is a uniform coating.
[6016] 5051. The device of item 5017, further comprising a coating,
wherein the coating is a non-uniform coating.
[6017] 5052. The device of item 5017, further comprising a coating,
wherein the coating is a discontinuous coating.
[6018] 5053. The device of item 5017, further comprising a coating,
wherein the coating is a patterned coating.
[6019] 5054. The device of item 5017, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[6020] 5055. The device of item 5017, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[6021] 5056. The device of item 5017, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[6022] 5057. The device of item 5017, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[6023] 5058. The device of item 5017, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[6024] 5059. The device of item 5017, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[6025] 5060. The device of item 5017, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[6026] 5061. The device of item 5017, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[6027] 5062. The device of item 5017, further comprising a coating,
wherein the coating further comprises a polymer.
[6028] 5063. The device of item 5017, further comprising a first
coating having a first composition and the second coating having a
second composition.
[6029] 5064. The device of item 5017, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[6030] 5065. The device of item 5017, further comprising a
polymer.
[6031] 5066. The device of item 5017, further comprising a
polymeric carrier.
[6032] 5067. The device of item 5017, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[6033] 5068. The device of item 5017, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[6034] 5069. The device of item 5017, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[6035] 5070. The device of item 5017, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[6036] 5071. The device of item 5017, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[6037] 5072. The device of item 5017, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[6038] 5073. The device of item 5017, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[6039] 5074. The device of item 5017, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[6040] 5075. The device of item 5017, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[6041] 5076. The device of item 5017, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[6042] 5077. The device of item 5017, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[6043] 5078. The device of item 5017, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[6044] 5079. The device of item 5017, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[6045] 5080. The device of item 5017, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[6046] 5081. The device of item 5017, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[6047] 5082. The device of item 5017, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[6048] 5083. The device of item 5017, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[6049] 5084. The device of item 5017, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[6050] 5085. The device of item 5017, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[6051] 5086. The device of item 5017, further comprising a
lubricious coating.
[6052] 5087. The device of item 5017 wherein the fibrosing agent is
located within pores or holes of the device.
[6053] 5088. The device of item 5017 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[6054] 5089. The device of item 5017, further comprising a second
pharmaceutically active agent.
[6055] 5090. The device of item 5017, further comprising an
anti-inflammatory agent.
[6056] 5091. The device of item 5017, further comprising an agent
that inhibits infection.
[6057] 5092. The device of item 5017, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[6058] 5093. The device of item 5017, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[6059] 5094. The device of item 5017, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[6060] 5095. The device of item 5017, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[6061] 5096. The device of item 5017, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[6062] 5097. The device of item 5017, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[6063] 5098. The device of item 5017, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[6064] 5099. The device of item 5017, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[6065] 5100. The device of item 5017, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[6066] 5101. The device of item 5017, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[6067] 5102. The device of item 5017, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[6068] 5103. The device of item 5017, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[6069] 5104. The device of item 5017, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[6070] 5105. The device of item 5017, further comprising an
anti-thrombotic agent.
[6071] 5106. The device of item 5017, further comprising a
visualization agent.
[6072] 5107. The device of item 5017, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[6073] 5108. The device of item 5017, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[6074] 5109. The device of item 5017, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[6075] 5110. The device of item 5017, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[6076] 5111. The device of item 5017, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[6077] 5112. The device of item 5017, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[6078] 5113. The device of item 5017, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[6079] 5114. The device of item 5017, further comprising an
echogenic material.
[6080] 5115. The device of item 5017, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[6081] 5116. The device of item 5017 wherein the device is
sterile.
[6082] 5117. The device of item 5017 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[6083] 5118. The device of item 5017 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[6084] 5119. The device of item 5017 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[6085] 5120. The device of item 5017 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[6086] 5121. The device of item 5017 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[6087] 5122. The device of item 5017 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[6088] 5123. The device of item 5017 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[6089] 5124. The device of item 5017 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[6090] 5125. The device of item 5017 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[6091] 5126. The device of item 5017 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[6092] 5127. The device of item 5017 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[6093] 5128. The device of item 5017 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[6094] 5129. The device of item 5017 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[6095] 5130. The device of item 5017 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[6096] 5131. The device of item 5017 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[6097] 5132. The device of item 5017 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[6098] 5133. The device of item 5017 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[6099] 5134. The device of item 5017 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[6100] 5135. The device of item 5017 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[6101] 5136. The device of item 5017 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[6102] 5137. The device of item 5017 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[6103] 5138. The device of item 5017 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[6104] 5139. The device of item 5017 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[6105] 5140. The device of item 5017 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[6106] 5141. A medical device comprising a Fallopian tube implant
and a fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
[6107] 5142. The device of item 5141 wherein the fibrosing agent
promotes regeneration.
[6108] 5143. The device of item 5141 wherein the fibrosing agent
promotes angiogenesis.
[6109] 5144. The device of item 5141 wherein the fibrosing agent
promotes fibroblast migration.
[6110] 5145. The device of item 5141 wherein the fibrosing agent
promotes fibroblast proliferation.
[6111] 5146. The device of item 5141 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[6112] 5147. The device of item 5141 wherein the fibrosing agent
promotes tissue remodeling.
[6113] 5148. The device of item 5141 wherein the fibrosing agent is
an arterial vessel wall irritant.
[6114] 5149. The device of item 5141 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[6115] 5150. The device of item 5141 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[6116] 5151. The device of item 5141 wherein the fibrosing agent is
or comprises silk.
[6117] 5152. The device of item 5141 wherein the fibrosing agent is
or comprises mineral particles.
[6118] 5153. The device of item 5141 wherein the fibrosing agent is
or comprises chitosan.
[6119] 5154. The device of item 5141 wherein the fibrosing agent is
or comprises polylysine.
[6120] 5155. The device of item 5141 wherein the fibrosing agent is
or comprises fibronectin.
[6121] 5156. The device of item 5141 wherein the fibrosing agent is
or comprises bleomycin.
[6122] 5157. The device of item 5141 wherein the fibrosing agent is
or comprises CTGF.
[6123] 5158. The device of item 5141 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[6124] 5159. The device of item 5141 wherein the fibrosing agent is
in the form of a particulate.
[6125] 5160. The device of item 5141 wherein the composition
further comprises an inflammatory cytokine.
[6126] 5161. The device of item 5141 wherein the composition
further comprises an agent that stimulates cell proliferation.
[6127] 5162. The device of item 5141 wherein the composition is in
the form of a gel, paste, or spray.
[6128] 5163. The device of item 5141 wherein the fibrosing agent is
in the form of tufts.
[6129] 5164. The device of item 5141, further comprising a
polymer.
[6130] 5165. The device of item 5141, further comprising a
polymeric carrier.
[6131] 5166. The device of item 5141 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[6132] 5167. The device of item 5141 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[6133] 5168. The device of item 5141, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[6134] 5169. The device of item 5141, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[6135] 5170. The device of item 5141, further comprising a coating,
wherein the coating directly contacts the device.
[6136] 5171. The device of item 5141, further comprising a coating,
wherein the coating indirectly contacts the device.
[6137] 5172. The device of item 5141, further comprising a coating,
wherein the coating partially covers the device.
[6138] 5173. The device of item 5141, further comprising a coating,
wherein the coating completely covers the device.
[6139] 5174. The device of item 5141, further comprising a coating,
wherein the coating is a uniform coating.
[6140] 5175. The device of item 5141, further comprising a coating,
wherein the coating is a non-uniform coating.
[6141] 5176. The device of item 5141, further comprising a coating,
wherein the coating is a discontinuous coating.
[6142] 5177. The device of item 5141, further comprising a coating,
wherein the coating is a patterned coating.
[6143] 5178. The device of item 5141, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[6144] 5179. The device of item 5141, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[6145] 5180. The device of item 5141, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[6146] 5181. The device of item 5141, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[6147] 5182. The device of item 5141, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[6148] 5183. The device of item 5141, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[6149] 5184. The device of item 5141, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[6150] 5185. The device of item 5141, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[6151] 5186. The device of item 5141, further comprising a coating,
wherein the coating further comprises a polymer.
[6152] 5187. The device of item 5141, further comprising a first
coating having a first composition and the second coating having a
second composition.
[6153] 5188. The device of item 5141, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[6154] 5189. The device of item 5141, further comprising a
polymer.
[6155] 5190. The device of item 5141, further comprising a
polymeric carrier.
[6156] 5191. The device of item 5141, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[6157] 5192. The device of item 5141, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[6158] 5193. The device of item 5141, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[6159] 5194. The device of item 5141, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[6160] 5195. The device of item 5141, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[6161] 5196. The device of item 5141, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[6162] 5197. The device of item 5141, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[6163] 5198. The device of item 5141, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[6164] 5199. The device of item 5141, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[6165] 5200. The device of item 5141, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[6166] 5201. The device of item 5141, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[6167] 5202. The device of item 5141, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[6168] 5203. The device of item 5141, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[6169] 5204. The device of item 5141, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[6170] 5205. The device of item 5141, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[6171] 5206. The device of item 5141, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[6172] 5207. The device of item 5141, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[6173] 5208. The device of item 5141, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[6174] 5209. The device of item 5141, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[6175] 5210. The device of item 5141, further comprising a
lubricious coating.
[6176] 5211. The device of item 5141 wherein the fibrosing agent is
located within pores or holes of the device.
[6177] 5212. The device of item 5141 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[6178] 5213. The device of item 5141, further comprising a second
pharmaceutically active agent.
[6179] 5214. The device of item 5141, further comprising an
anti-inflammatory agent.
[6180] 5215. The device of item 5141, further comprising an agent
that inhibits infection.
[6181] 5216. The device of item 5141, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[6182] 5217. The device of item 5141, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[6183] 5218. The device of item 5141, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[6184] 5219. The device of item 5141, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[6185] 5220. The device of item 5141, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[6186] 5221. The device of item 5141, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[6187] 5222. The device of item 5141, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[6188] 5223. The device of item 5141, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[6189] 5224. The device of item 5141, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[6190] 5225. The device of item 5141, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[6191] 5226. The device of item 5141, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[6192] 5227. The device of item 5141, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[6193] 5228. The device of item 5141, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[6194] 5229. The device of item 5141, further comprising an
anti-thrombotic agent.
[6195] 5230. The device of item 5141, further comprising a
visualization agent.
[6196] 5231. The device of item 5141, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[6197] 5232. The device of item 5141, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[6198] 5233. The device of item 5141, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[6199] 5234. The device of item 5141, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[6200] 5235. The device of item 5141, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[6201] 5236. The device of item 5141, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[6202] 5237. The device of item 5141, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[6203] 5238. The device of item 5141, further comprising an
echogenic material.
[6204] 5239. The device of item 5141, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[6205] 5240. The device of item 5141 wherein the device is
sterile.
[6206] 5241. The device of item 5141 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[6207] 5242. The device of item 5141 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[6208] 5243. The device of item 5141 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[6209] 5244. The device of item 5141 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[6210] 5245. The device of item 5141 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[6211] 5246. The device of item 5141 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[6212] 5247. The device of item 5141 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[6213] 5248. The device of item 5141 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[6214] 5249. The device of item 5141 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[6215] 5250. The device of item 5141 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[6216] 5251. The device of item 5141 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[6217] 5252. The device of item 5141 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[6218] 5253. The device of item 5141 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[6219] 5254. The device of item 5141 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[6220] 5255. The device of item 5141 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[6221] 5256. The device of item 5141 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[6222] 5257. The device of item 5141 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[6223] 5258. The device of item 5141 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[6224] 5259. The device of item 5141 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[6225] 5260. The device of item 5141 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[6226] 5261. The device of item 5141 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[6227] 5262. The device of item 5141 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[6228] 5263. The device of item 5141 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[6229] 5264. The device of item 5141 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[6230] 5265. The device of item 5141 wherein the fallopian tube
implant is injectable.
[6231] 5266. The device of item 5141 wherein the fallopian tube
implant is an fallopian tumbe occlusive wire.
[6232] 5267. The device of item 5141 wherein the fallopian tube
implant is a coil fallopian tube implants.
[6233] 5268. The device of item 5141 wherein the fallopian tube
implant is a contraceptive uterine implant.
[6234] 5269. A medical device comprising a transcatheter occluding
implant and a fibrosing agent, where the fibrosing agent induces a
fibrotic response between the device and a patient in which the
device is implanted.
[6235] 5270. The device of item 5269 wherein the fibrosing agent
promotes regeneration.
[6236] 5271. The device of item 5269 wherein the fibrosing agent
promotes angiogenesis.
[6237] 5272. The device of item 5269 wherein the fibrosing agent
promotes fibroblast migration.
[6238] 5273. The device of item 5269 wherein the fibrosing agent
promotes fibroblast proliferation.
[6239] 5274. The device of item 5269 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[6240] 5275. The device of item 5269 wherein the fibrosing agent
promotes tissue remodeling.
[6241] 5276. The device of item 5269 wherein the fibrosing agent is
an arterial vessel wall irritant.
[6242] 5277. The device of item 5269 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[6243] 5278. The device of item 5269 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[6244] 5279. The device of item 5269 wherein the fibrosing agent is
or comprises silk.
[6245] 5280. The device of item 5269 wherein the fibrosing agent is
or comprises mineral particles.
[6246] 5281. The device of item 5269 wherein the fibrosing agent is
or comprises chitosan.
[6247] 5282. The device of item 5269 wherein the fibrosing agent is
or comprises polylysine.
[6248] 5283. The device of item 5269 wherein the fibrosing agent is
or comprises fibronectin.
[6249] 5284. The device of item 5269 wherein the fibrosing agent is
or comprises bleomycin.
[6250] 5285. The device of item 5269 wherein the fibrosing agent is
or comprises CTGF.
[6251] 5286. The device of item 5269 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[6252] 5287. The device of item 5269 wherein the fibrosing agent is
in the form of a particulate.
[6253] 5288. The device of item 5269 wherein the composition
further comprises an inflammatory cytokine.
[6254] 5289. The device of item 5269 wherein the composition
further comprises an agent that stimulates cell proliferation.
[6255] 5290. The device of item 5269 wherein the composition is in
the form of a gel, paste, or spray.
[6256] 5291. The device of item 5269 wherein the fibrosing agent is
in the form of tufts.
[6257] 5292. The device of item 5269, further comprising a
polymer.
[6258] 5293. The device of item 5269, further comprising a
polymeric carrier.
[6259] 5294. The device of item 5269 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[6260] 5295. The device of item 5269 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[6261] 5296. The device of item 5269, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[6262] 5297. The device of item 5269, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[6263] 5298. The device of item 5269, further comprising a coating,
wherein the coating directly contacts the device.
[6264] 5299. The device of item 5269, further comprising a coating,
wherein the coating indirectly contacts the device.
[6265] 5300. The device of item 5269, further comprising a coating,
wherein the coating partially covers the device.
[6266] 5301. The device of item 5269, further comprising a coating,
wherein the coating completely covers the device.
[6267] 5302. The device of item 5269, further comprising a coating,
wherein the coating is a uniform coating.
[6268] 5303. The device of item 5269, further comprising a coating,
wherein the coating is a non-uniform coating.
[6269] 5304. The device of item 5269, further comprising a coating,
wherein the coating is a discontinuous coating.
[6270] 5305. The device of item 5269, further comprising a coating,
wherein the coating is a patterned coating.
[6271] 5306. The device of item 5269, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[6272] 5307. The device of item 5269, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[6273] 5308. The device of item 5269, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[6274] 5309. The device of item 5269, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[6275] 5310. The device of item 5269, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[6276] 5311. The device of item 5269, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[6277] 5312. The device of item 5269, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[6278] 5313. The device of item 5269, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[6279] 5314. The device of item 5269, further comprising a coating,
wherein the coating further comprises a polymer.
[6280] 5315. The device of item 5269, further comprising a first
coating having a first composition and the second coating having a
second composition.
[6281] 5316. The device of item 5269, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[6282] 5317. The device of item 5269, further comprising a
polymer.
[6283] 5318. The device of item 5269, further comprising a
polymeric carrier.
[6284] 5319. The device of item 5269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[6285] 5320. The device of item 5269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[6286] 5321. The device of item 5269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[6287] 5322. The device of item 5269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[6288] 5323. The device of item 5269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[6289] 5324. The device of item 5269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[6290] 5325. The device of item 5269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[6291] 5326. The device of item 5269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[6292] 5327. The device of item 5269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[6293] 5328. The device of item 5269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[6294] 5329. The device of item 5269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[6295] 5330. The device of item 5269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[6296] 5331. The device of item 5269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[6297] 5332. The device of item 5269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[6298] 5333. The device of item 5269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[6299] 5334. The device of item 5269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[6300] 5335. The device of item 5269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[6301] 5336. The device of item 5269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[6302] 5337. The device of item 5269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[6303] 5338. The device of item 5269, further comprising a
lubricious coating.
[6304] 5339. The device of item 5269 wherein the fibrosing agent is
located within pores or holes of the device.
[6305] 5340. The device of item 5269 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[6306] 5341. The device of item 5269, further comprising a second
pharmaceutically active agent.
[6307] 5342. The device of item 5269, further comprising an
anti-inflammatory agent.
[6308] 5343. The device of item 5269, further comprising an agent
that inhibits infection.
[6309] 5344. The device of item 5269, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[6310] 5345. The device of item 5269, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[6311] 5346. The device of item 5269, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[6312] 5347. The device of item 5269, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[6313] 5348. The device of item 5269, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[6314] 5349. The device of item 5269, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[6315] 5350. The device of item 5269, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[6316] 5351. The device of item 5269, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[6317] 5352. The device of item 5269, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[6318] 5353. The device of item 5269, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[6319] 5354. The device of item 5269, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[6320] 5355. The device of item 5269, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[6321] 5356. The device of item 5269, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[6322] 5357. The device of item 5269, further comprising an
anti-thrombotic agent.
[6323] 5358. The device of item 5269, further comprising a
visualization agent.
[6324] 5359. The device of item 5269, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[6325] 5360. The device of item 5269, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[6326] 5361. The device of item 5269, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[6327] 5362. The device of item 5269, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[6328] 5363. The device of item 5269, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[6329] 5364. The device of item 5269, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[6330] 5365. The device of item 5269, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[6331] 5366. The device of item 5269, further comprising an
echogenic material.
[6332] 5367. The device of item 5269, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[6333] 5368. The device of item 5269 wherein the device is
sterile.
[6334] 5369. The device of item 5269 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[6335] 5370. The device of item 5269 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[6336] 5371. The device of item 5269 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[6337] 5372. The device of item 5269 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[6338] 5373. The device of item 5269 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[6339] 5374. The device of item 5269 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[6340] 5375. The device of item 5269 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[6341] 5376. The device of item 5269 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[6342] 5377. The device of item 5269 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[6343] 5378. The device of item 5269 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[6344] 5379. The device of item 5269 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[6345] 5380. The device of item 5269 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[6346] 5381. The device of item 5269 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[6347] 5382. The device of item 5269 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[6348] 5383. The device of item 5269 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[6349] 5384. The device of item 5269 wherein the device comprises
about 10 mg to about 0.250 mg of the fibrosing agent.
[6350] 5385. The device of item 5269 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[6351] 5386. The device of item 5269 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[6352] 5387. The device of item 5269 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[6353] 5388. The device of item 5269 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[6354] 5389. The device of item 5269 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[6355] 5390. The device of item 5269 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[6356] 5391. The device of item 5269 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[6357] 5392. The device of item 5269 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[6358] 5393. A medical device comprising a prosthetic anal
sphincter and a fibrosing agent, where the fibrosing agent induces
a fibrotic response between the device and a patient in which the
device is implanted.
[6359] 5394. The device of item 5393 wherein the fibrosing agent
promotes regeneration.
[6360] 5395. The device of item 5393 wherein the fibrosing agent
promotes angiogenesis.
[6361] 5396. The device of item 5393 wherein the fibrosing agent
promotes fibroblast migration.
[6362] 5397. The device of item 5393 wherein the fibrosing agent
promotes fibroblast proliferation.
[6363] 5398. The device of item 5393 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[6364] 5399. The device of item 5393 wherein the fibrosing agent
promotes tissue remodeling.
[6365] 5400. The device of item 5393 wherein the fibrosing agent is
an arterial vessel wall irritant.
[6366] 5401. The device of item 5393 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[6367] 5402. The device of item 5393 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[6368] 5403. The device of item 5393 wherein the fibrosing agent is
or comprises silk.
[6369] 5404. The device of item 5393 wherein the fibrosing agent is
or comprises mineral particles.
[6370] 5405. The device of item 5393 wherein the fibrosing agent is
or comprises chitosan.
[6371] 5406. The device of item 5393 wherein the fibrosing agent is
or comprises polylysine.
[6372] 5407. The device of item 5393 wherein the fibrosing agent is
or comprises fibronectin.
[6373] 5408. The device of item 5393 wherein the fibrosing agent is
or comprises bleomycin.
[6374] 5409. The device of item 5393 wherein the fibrosing agent is
or comprises CTGF.
[6375] 5410. The device of item 5393 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[6376] 5411. The device of item 5393 wherein the fibrosing agent is
in the form of a particulate.
[6377] 5412. The device of item 5393 wherein the composition
further comprises an inflammatory cytokine.
[6378] 5413. The device of item 5393 wherein the composition
further comprises an agent that stimulates cell proliferation.
[6379] 5414. The device of item 5393 wherein the composition is in
the form of a gel, paste, or spray.
[6380] 5415. The device of item 5393 wherein the fibrosing agent is
in the form of tufts.
[6381] 5416. The device of item 5393, further comprising a
polymer.
[6382] 5417. The device of item 5393, further comprising a
polymeric carrier.
[6383] 5418. The device of item 5393 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[6384] 5419. The device of item 5393 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[6385] 5420. The device of item 5393, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[6386] 5421. The device of item 5393, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[6387] 5422. The device of item 5393, further comprising a coating,
wherein the coating directly contacts the device.
[6388] 5423. The device of item 5393, further comprising a coating,
wherein the coating indirectly contacts the device.
[6389] 5424. The device of item 5393, further comprising a coating,
wherein the coating partially covers the device.
[6390] 5425. The device of item 5393, further comprising a coating,
wherein the coating completely covers the device.
[6391] 5426. The device of item 5393, further comprising a coating,
wherein the coating is a uniform coating.
[6392] 5427. The device of item 5393, further comprising a coating,
wherein the coating is a non-uniform coating.
[6393] 5428. The device of item 5393, further comprising a coating,
wherein the coating is a discontinuous coating.
[6394] 5429. The device of item 5393, further comprising a coating,
wherein the coating is a patterned coating.
[6395] 5430. The device of item 5393, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[6396] 5431. The device of item 5393, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[6397] 5432. The device of item 5393, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[6398] 5433. The device of item 5393, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[6399] 5434. The device of item 5393, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[6400] 5435. The device of item 5393, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[6401] 5436. The device of item 5393, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[6402] 5437. The device of item 5393, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[6403] 5438. The device of item 5393, further comprising a coating,
wherein the coating further comprises a polymer.
[6404] 5439. The device of item 5393, further comprising a first
coating having a first composition and the second coating having a
second composition.
[6405] 5440. The device of item 5393, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[6406] 5441. The device of item 5393, further comprising a
polymer.
[6407] 5442. The device of item 5393, further comprising a
polymeric carrier.
[6408] 5443. The device of item 5393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[6409] 5444. The device of item 5393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[6410] 5445. The device of item 5393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[6411] 5446. The device of item 5393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[6412] 5447. The device of item 5393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[6413] 5448. The device of item 5393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[6414] 5449. The device of item 5393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[6415] 5450. The device of item 5393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[6416] 5451. The device of item 5393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[6417] 5452. The device of item 5393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[6418] 5453. The device of item 5393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[6419] 5454. The device of item 5393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[6420] 5455. The device of item 5393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[6421] 5456. The device of item 5393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[6422] 5457. The device of item 5393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[6423] 5458. The device of item 5393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[6424] 5459. The device of item 5393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[6425] 5460. The device of item 5393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[6426] 5461. The device of item 5393, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[6427] 5462. The device of item 5393, further comprising a
lubricious coating.
[6428] 5463. The device of item 5393 wherein the fibrosing agent is
located within pores or holes of the device.
[6429] 5464. The device of item 5393 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[6430] 5465. The device of item 5393, further comprising a second
pharmaceutically active agent.
[6431] 5466. The device of item 5393, further comprising an
anti-inflammatory agent.
[6432] 5467. The device of item 5393, further comprising an agent
that inhibits infection.
[6433] 5468. The device of item 5393, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[6434] 5469. The device of item 5393, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[6435] 5470. The device of item 5393, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[6436] 5471. The device of item 5393, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[6437] 5472. The device of item 5393, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[6438] 5473. The device of item 5393, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[6439] 5474. The device of item 5393, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[6440] 5475. The device of item 5393, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[6441] 5476. The device of item 5393, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[6442] 5477. The device of item 5393, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[6443] 5478. The device of item 5393, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[6444] 5479. The device of item 5393, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[6445] 5480. The device of item 5393, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[6446] 5481. The device of item 5393, further comprising an
anti-thrombotic agent.
[6447] 5482. The device of item 5393, further comprising a
visualization agent.
[6448] 5483. The device of item 5393, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[6449] 5484. The device of item 5393, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[6450] 5485. The device of item 5393, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[6451] 5486. The device of item 5393, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[6452] 5487. The device of item 5393, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[6453] 5488. The device of item 5393, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[6454] 5489. The device of item 5393, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[6455] 5490. The device of item 5393, further comprising an
echogenic material.
[6456] 5491. The device of item 5393, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[6457] 5492. The device of item 5393 wherein the device is
sterile.
[6458] 5493. The device of item 5393 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[6459] 5494. The device of item 5393 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[6460] 5495. The device of item 5393 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[6461] 5496. The device of item 5393 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[6462] 5497. The device of item 5393 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[6463] 5498. The device of item 5393 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[6464] 5499. The device of item 5393 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[6465] 5500. The device of item 5393 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[6466] 5501. The device of item 5393 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[6467] 5502. The device of item 5393 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[6468] 5503. The device of item 5393 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[6469] 5504. The device of item 5393 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[6470] 5505. The device of item 5393 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[6471] 5506. The device of item 5393 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[6472] 5507. The device of item 5393 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[6473] 5508. The device of item 5393 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[6474] 5509. The device of item 5393 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[6475] 5510. The device of item 5393 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[6476] 5511. The device of item 5393 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[6477] 5512. The device of item 5393 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[6478] 5513. The device of item 5393 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[6479] 5514. The device of item 5393 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[6480] 5515. The device of item 5393 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[6481] 5516. The device of item 5393 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[6482] 5517. A medical device comprising a Fallopian tube stent and
a fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
[6483] 5518. The device of item 5517 wherein the fibrosing agent
promotes regeneration.
[6484] 5519. The device of item 5517 wherein the fibrosing agent
promotes angiogenesis.
[6485] 5520. The device of item 5517 wherein the fibrosing agent
promotes fibroblast migration.
[6486] 5521. The device of item 5517 wherein the fibrosing agent
promotes fibroblast proliferation.
[6487] 5522. The device of item 5517 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[6488] 5523. The device of item 5517 wherein the fibrosing agent
promotes tissue remodeling.
[6489] 5524. The device of item 5517 wherein the fibrosing agent is
an arterial vessel wall irritant.
[6490] 5525. The device of item 5517 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[6491] 5526. The device of item 5517 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[6492] 5527. The device of item 5517 wherein the fibrosing agent is
or comprises silk.
[6493] 5528. The device of item 5517 wherein the fibrosing agent is
or comprises mineral particles.
[6494] 5529. The device of item 5517 wherein the fibrosing agent is
or comprises chitosan.
[6495] 5530. The device of item 5517 wherein the fibrosing agent is
or comprises polylysine.
[6496] 5531. The device of item 5517 wherein the fibrosing agent is
or comprises fibronectin.
[6497] 5532. The device of item 5517 wherein the fibrosing agent is
or comprises bleomycin.
[6498] 5533. The device of item 5517 wherein the fibrosing agent is
or comprises CTGF.
[6499] 5534. The device of item 5517 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[6500] 5535. The device of item 5517 wherein the fibrosing agent is
in the form of a particulate.
[6501] 5536. The device of item 5517 wherein the composition
further comprises an inflammatory cytokine.
[6502] 5537. The device of item 5517 wherein the composition
further comprises an agent that stimulates cell proliferation.
[6503] 5538. The device of item 5517 wherein the composition is in
the form of a gel, paste, or spray.
[6504] 5539. The device of item 5517 wherein the fibrosing agent is
in the form of tufts.
[6505] 5540. The device of item 5517, further comprising a
polymer.
[6506] 5541. The device of item 5517, further comprising a
polymeric carrier.
[6507] 5542. The device of item 5517 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[6508] 5543. The device of item 5517 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[6509] 5544. The device of item 5517, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[6510] 5545. The device of item 5517, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[6511] 5546. The device of item 5517, further comprising a coating,
wherein the coating directly contacts the device.
[6512] 5547. The device of item 5517, further comprising a coating,
wherein the coating indirectly contacts the device.
[6513] 5548. The device of item 5517, further comprising a coating,
wherein the coating partially covers the device.
[6514] 5549. The device of item 5517, further comprising a coating,
wherein the coating completely covers the device.
[6515] 5550. The device of item 5517, further comprising a coating,
wherein the coating is a uniform coating.
[6516] 5551. The device of item 5517, further comprising a coating,
wherein the coating is a non-uniform coating.
[6517] 5552. The device of item 5517, further comprising a coating,
wherein the coating is a discontinuous coating.
[6518] 5553. The device of item 5517, further comprising a coating,
wherein the coating is a patterned coating.
[6519] 5554. The device of item 5517, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[6520] 5555. The device of item 5517, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[6521] 5556. The device of item 5517, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[6522] 5557. The device of item 5517, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[6523] 5558. The device of item 5517, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[6524] 5559. The device of item 5517, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[6525] 5560. The device of item 5517, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[6526] 5561. The device of item 5517, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[6527] 5562. The device of item 5517, further comprising a coating,
wherein the coating further comprises a polymer.
[6528] 5563. The device of item 5517, further comprising a first
coating having a first composition and the second coating having a
second composition.
[6529] 5564. The device of item 5517, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[6530] 5565. The device of item 5517, further comprising a
polymer.
[6531] 5566. The device of item 5517, further comprising a
polymeric carrier.
[6532] 5567. The device of item 5517, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[6533] 5568. The device of item 5517, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[6534] 5569. The device of item 5517, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[6535] 5570. The device of item 5517, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[6536] 5571. The device of item 5517, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[6537] 5572. The device of item 5517, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[6538] 5573. The device of item 5517, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[6539] 5574. The device of item 5517, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[6540] 5575. The device of item 5517, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[6541] 5576. The device of item 5517, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[6542] 5577. The device of item 5517, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[6543] 5578. The device of item 5517, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[6544] 5579. The device of item 5517, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[6545] 5580. The device of item 5517, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[6546] 5581. The device of item 5517, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[6547] 5582. The device of item 5517, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[6548] 5583. The device of item 5517, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[6549] 5584. The device of item 5517, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[6550] 5585. The device of item 5517, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[6551] 5586. The device of item 5517, further comprising a
lubricious coating.
[6552] 5587. The device of item 5517 wherein the fibrosing agent is
located within pores or holes of the device.
[6553] 5588. The device of item 5517 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[6554] 5589. The device of item 5517, further comprising a second
pharmaceutically active agent.
[6555] 5590. The device of item 5517, further comprising an
anti-inflammatory agent.
[6556] 5591. The device of item 5517, further comprising an agent
that inhibits infection.
[6557] 5592. The device of item 5517, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[6558] 5593. The device of item 5517, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[6559] 5594. The device of item 5517, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[6560] 5595. The device of item 5517, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[6561] 5596. The device of item 5517, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[6562] 5597. The device of item 5517, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[6563] 5598. The device of item 5517, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[6564] 5599. The device of item 5517, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[6565] 5600. The device of item 5517, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[6566] 5601. The device of item 5517, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[6567] 5602. The device of item 5517, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[6568] 5603. The device of item 5517, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[6569] 5604. The device of item 5517, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[6570] 5605. The device of item 5517, further comprising an
anti-thrombotic agent.
[6571] 5606. The device of item 5517, further comprising a
visualization agent.
[6572] 5607. The device of item 5517, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[6573] 5608. The device of item 5517, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[6574] 5609. The device of item 5517, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[6575] 5610. The device of item 5517, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[6576] 5611. The device of item 5517, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[6577] 5612. The device of item 5517, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[6578] 5613. The device of item 5517, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[6579] 5614. The device of item 5517, further comprising an
echogenic material.
[6580] 5615. The device of item 5517, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[6581] 5616. The device of item 5517 wherein the device is
sterile.
[6582] 5617. The device of item 5517 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[6583] 5618. The device of item 5517 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[6584] 5619. The device of item 5517 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[6585] 5620. The device of item 5517 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[6586] 5621. The device of item 5517 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[6587] 5622. The device of item 5517 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[6588] 5623. The device of item 5517 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[6589] 5624. The device of item 5517 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[6590] 5625. The device of item 5517 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[6591] 5626. The device of item 5517 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[6592] 5627. The device of item 5517 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[6593] 5628. The device of item 5517 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[6594] 5629. The device of item 5517 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[6595] 5630. The device of item 5517 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[6596] 5631. The device of item 5517 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[6597] 5632. The device of item 5517 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[6598] 5633. The device of item 5517 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[6599] 5634. The device of item 5517 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[6600] 5635. The device of item 5517 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[6601] 5636. The device of item 5517 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[6602] 5637. The device of item 5517 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[6603] 5638. The device of item 5517 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[6604] 5639. The device of item 5517 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[6605] 5640. The device of item 5517 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[6606] 5641. A medical device comprising a Vas Deferens implant and
a fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
[6607] 5642. The device of item 5641 wherein the fibrosing agent
promotes regeneration.
[6608] 5643. The device of item 5641 wherein the fibrosing agent
promotes angiogenesis.
[6609] 5644. The device of item 5641 wherein the fibrosing agent
promotes fibroblast migration.
[6610] 5645. The device of item 5641 wherein the fibrosing agent
promotes fibroblast proliferation.
[6611] 5646. The device of item 5641 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[6612] 5647. The device of item 5641 wherein the fibrosing agent
promotes tissue remodeling.
[6613] 5648. The device of item 5641 wherein the fibrosing agent is
an arterial vessel wall irritant.
[6614] 5649. The device of item 5641 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[6615] 5650. The device of item 5641 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[6616] 5651. The device of item 5641 wherein the fibrosing agent is
or comprises silk.
[6617] 5652. The device of item 5641 wherein the fibrosing agent is
or comprises mineral particles.
[6618] 5653. The device of item 5641 wherein the fibrosing agent is
or comprises chitosan.
[6619] 5654. The device of item 5641 wherein the fibrosing agent is
or comprises polylysine.
[6620] 5655. The device of item 5641 wherein the fibrosing agent is
or comprises fibronectin.
[6621] 5656. The device of item 5641 wherein the fibrosing agent is
or comprises bleomycin.
[6622] 5657. The device of item 5641 wherein the fibrosing agent is
or comprises CTGF.
[6623] 5658. The device of item 5641 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[6624] 5659. The device of item 5641 wherein the fibrosing agent is
in the form of a particulate.
[6625] 5660. The device of item 5641 wherein the composition
further comprises an inflammatory cytokine.
[6626] 5661. The device of item 5641 wherein the composition
further comprises an agent that stimulates cell proliferation.
[6627] 5662. The device of item 5641 wherein the composition is in
the form of a gel, paste, or spray.
[6628] 5663. The device of item 5641 wherein the fibrosing agent is
in the form of tufts.
[6629] 5664. The device of item 5641, further comprising a
polymer.
[6630] 5665. The device of item 5641, further comprising a
polymeric carrier.
[6631] 5666. The device of item 5641 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[6632] 5667. The device of item 5641 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[6633] 5668. The device of item 5641, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[6634] 5669. The device of item 5641, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[6635] 5670. The device of item 5641, further comprising a coating,
wherein the coating directly contacts the device.
[6636] 5671. The device of item 5641, further comprising a coating,
wherein the coating indirectly contacts the device.
[6637] 5672. The device of item 5641, further comprising a coating,
wherein the coating partially covers the device.
[6638] 5673. The device of item 5641, further comprising a coating,
wherein the coating completely covers the device.
[6639] 5674. The device of item 5641, further comprising a coating,
wherein the coating is a uniform coating.
[6640] 5675. The device of item 5641, further comprising a coating,
wherein the coating is a non-uniform coating.
[6641] 5676. The device of item 5641, further comprising a coating,
wherein the coating is a discontinuous coating.
[6642] 5677. The device of item 5641, further comprising a coating,
wherein the coating is a patterned coating.
[6643] 5678. The device of item 5641, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[6644] 5679. The device of item 5641, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[6645] 5680. The device of item 5641, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[6646] 5681. The device of item 5641, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[6647] 5682. The device of item 5641, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[6648] 5683. The device of item 5641, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.,
[6649] 5684. The device of item 5641, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[6650] 5685. The device of item 5641, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[6651] 5686. The device of item 5641, further comprising a coating,
wherein the coating further comprises a polymer.
[6652] 5687. The device of item 5641, further comprising a first
coating having a first composition and the second coating having a
second composition.
[6653] 5688. The device of item 5641, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[6654] 5689. The device of item 5641, further comprising a
polymer.
[6655] 5690. The device of item 5641, further comprising a
polymeric carrier.
[6656] 5691. The device of item 5641, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[6657] 5692. The device of item 5641, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[6658] 5693. The device of item 5641, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[6659] 5694. The device of item 5641, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[6660] 5695. The device of item 5641, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[6661] 5696. The device of item 5641, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[6662] 5697. The device of item 5641, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[6663] 5698. The device of item 5641, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[6664] 5699. The device of item 5641, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[6665] 5700. The device of item 5641, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[6666] 5701. The device of item 5641, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[6667] 5702. The device of item 5641, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[6668] 5703. The device of item 5641, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[6669] 5704. The device of item 5641, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[6670] 5705. The device of item 5641, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[6671] 5706. The device of item 5641, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[6672] 5707. The device of item 5641, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[6673] 5708. The device of item 5641, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[6674] 5709. The device of item 5641, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[6675] 5710. The device of item 5641, further comprising a
lubricious coating.
[6676] 5711. The device of item 5641 wherein the fibrosing agent is
located within pores or holes of the device.
[6677] 5712. The device of item 5641 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[6678] 5713. The device of item 5641, further comprising a second
pharmaceutically active agent.
[6679] 5714. The device of item 5641, further comprising an
anti-inflammatory agent.
[6680] 5715. The device of item 5641, further comprising an agent
that inhibits infection.
[6681] 5716. The device of item 5641, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[6682] 5717. The device of item 5641, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[6683] 5718. The device of item 5641, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[6684] 5719. The device of item 5641, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[6685] 5720. The device of item 5641, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[6686] 5721. The device of item 5641, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[6687] 5722. The device of item 5641, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[6688] 5723. The device of item 5641, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[6689] 5724. The device of item 5641, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[6690] 5725. The device of item 5641, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[6691] 5726. The device of item 5641, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[6692] 5727. The device of item 5641, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[6693] 5728. The device of item 5641, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[6694] 5729. The device of item 5641, further comprising an
anti-thrombotic agent.
[6695] 5730. The device of item 5641, further comprising a
visualization agent.
[6696] 5731. The device of item 5641, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[6697] 5732. The device of item 5641, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[6698] 5733. The device of item 5641, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[6699] 5734. The device of item 5641, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[6700] 5735. The device of item 5641, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[6701] 5736. The device of item 5641, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[6702] 5737. The device of item 5641, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[6703] 5738. The device of item 5641, further comprising an
echogenic material.
[6704] 5739. The device of item 5641, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[6705] 5740. The device of item 5641 wherein the device is
sterile.
[6706] 5741. The device of item 5641 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[6707] 5742. The device of item 5641 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[6708] 5743. The device of item 5641 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[6709] 5744. The device of item 5641 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[6710] 5745. The device of item 5641 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[6711] 5746. The device of item 5641 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[6712] 5747. The device of item 5641 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[6713] 5748. The device of item 5641 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[6714] 5749. The device of item 5641 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[6715] 5750. The device of item 5641 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[6716] 5751. The device of item 5641 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[6717] 5752. The device of item 5641 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[6718] 5753. The device of item 5641 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[6719] 5754. The device of item 5641 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[6720] 5755. The device of item 5641 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[6721] 5756. The device of item 5641 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[6722] 5757. The device of item 5641 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[6723] 5758. The device of item 5641 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[6724] 5759. The device of item 5641 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[6725] 5760. The device of item 5641 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[6726] 5761. The device of item 5641 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[6727] 5762. The device of item 5641 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[6728] 5763. The device of item 5641 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[6729] 5764. The device of item 5641 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[6730] 5765. The device of item 5641 wherein the Vas Deferens
implant is injectable.
[6731] 5766. The device of item 5641 wherein the Vas Deferens
implant is a vasectomy suture.
[6732] 5767. The device of item 5641 wherein the Vas Deferens
implant is a vasectomy clip.
[6733] 5768. A medical device comprising a gastric restriction
implant and a fibrosing agent, where the fibrosing agent induces a
fibrotic response between the device and a patient in which the
device is implanted.
[6734] 5769. The device of item 5768 wherein the fibrosing agent
promotes regeneration.
[6735] 5770. The device of item 5768 wherein the fibrosing agent
promotes angiogenesis.
[6736] 5771. The device of item 5768 wherein the fibrosing agent
promotes fibroblast migration.
[6737] 5772. The device of item 5768 wherein the fibrosing agent
promotes fibroblast proliferation.
[6738] 5773. The device of item 5768 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[6739] 5774. The device of item 5768 wherein the fibrosing agent
promotes tissue remodeling.
[6740] 5775. The device of item 5768 wherein the fibrosing agent is
an arterial vessel wall irritant.
[6741] 5776. The device of item 5768 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[6742] 5777. The device of item 5768 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[6743] 5778. The device of item 5768 wherein the fibrosing agent is
or comprises silk.
[6744] 5779. The device of item 5768 wherein the fibrosing agent is
or comprises mineral particles.
[6745] 5780. The device of item 5768 wherein the fibrosing agent is
or comprises chitosan.
[6746] 5781. The device of item 5768 wherein the fibrosing agent is
or comprises polylysine.
[6747] 5782. The device of item 5768 wherein the fibrosing agent is
or comprises fibronectin.
[6748] 5783. The device of item 5768 wherein the fibrosing agent is
or comprises bleomycin.
[6749] 5784. The device of item 5768 wherein the fibrosing agent is
or comprises CTGF.
[6750] 5785. The device of item 5768 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[6751] 5786. The device of item 5768 wherein the fibrosing agent is
in the form of a particulate.
[6752] 5787. The device of item 5768 wherein the composition
further comprises an inflammatory cytokine.
[6753] 5788. The device of item 5768 wherein the composition
further comprises an agent that stimulates cell proliferation.
[6754] 5789. The device of item 5768 wherein the composition is in
the form of a gel, paste, or spray.
[6755] 5790. The device of item 5768 wherein the fibrosing agent is
in the form of tufts.
[6756] 5791. The device of item 5768, further comprising a
polymer.
[6757] 5792. The device of item 5768, further comprising a
polymeric carrier.
[6758] 5793. The device of item 5768 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[6759] 5794. The device of item 5768 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[6760] 5795. The device of item 5768, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[6761] 5796. The device of item 5768, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[6762] 5797. The device of item 5768, further comprising a coating,
wherein the coating directly contacts the device.
[6763] 5798. The device of item 5768, further comprising a coating,
wherein the coating indirectly contacts the device.
[6764] 5799. The device of item 5768, further comprising a coating,
wherein the coating partially covers the device.
[6765] 5800. The device of item 5768, further comprising a coating,
wherein the coating completely covers the device.
[6766] 5801. The device of item 5768, further comprising a coating,
wherein the coating is a uniform coating.
[6767] 5802. The device of item 5768, further comprising a coating,
wherein the coating is a non-uniform coating.
[6768] 5803. The device of item 5768, further comprising a coating,
wherein the coating is a discontinuous coating.
[6769] 5804. The device of item 5768, further comprising a coating,
wherein the coating is a patterned coating.
[6770] 5805. The device of item 5768, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[6771] 5806. The device of item 5768, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[6772] 5807. The device of item 5768, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[6773] 5808. The device of item 5768, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[6774] 5809. The device of item 5768, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[6775] 5810. The device of item 5768, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[6776] 5811. The device of item 5768, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[6777] 5812. The device of item 5768, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[6778] 5813. The device of item 5768, further comprising a coating,
wherein the coating further comprises a polymer.
[6779] 5814. The device of item 5768, further comprising a first
coating having a first composition and the second coating having a
second composition.
[6780] 5815. The device of item 5768, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[6781] 5816. The device of item 5768, further comprising a
polymer.
[6782] 5817. The device of item 5768, further comprising a
polymeric carrier.
[6783] 5818. The device of item 5768, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[6784] 5819. The device of item 5768, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[6785] 5820. The device of item 5768, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[6786] 5821. The device of item 5768, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[6787] 5822. The device of item 5768, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[6788] 5823. The device of item 5768, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[6789] 5824. The device of item 5768, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[6790] 5825. The device of item 5768, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[6791] 5826. The device of item 5768, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[6792] 5827. The device of item 5768, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[6793] 5828. The device of item 5768, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[6794] 5829. The device of item 5768, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[6795] 5830. The device of item 5768, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[6796] 5831. The device of item 5768, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[6797] 5832. The device of item 5768, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[6798] 5833. The device of item 5768, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[6799] 5834. The device of item 5768, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[6800] 5835. The device of item 5768, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[6801] 5836. The device of item 5768, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[6802] 5837. The device of item 5768, further comprising a
lubricious coating.
[6803] 5838. The device of item 5768 wherein the fibrosing agent is
located within pores or holes of the device.
[6804] 5839. The device of item 5768 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[6805] 5840. The device of item 5768, further comprising a second
pharmaceutically active agent.
[6806] 5841. The device of item 5768, further comprising an
anti-inflammatory agent.
[6807] 5842. The device of item 5768, further comprising an agent
that inhibits infection.
[6808] 5843. The device of item 5768, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[6809] 5844. The device of item 5768, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[6810] 5845. The device of item 5768, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[6811] 5846. The device of item 5768, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[6812] 5847. The device of item 5768, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[6813] 5848. The device of item 5768, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[6814] 5849. The device of item 5768, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[6815] 5850. The device of item 5768, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[6816] 5851. The device of item 5768, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[6817] 5852. The device of item 5768, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[6818] 5853. The device of item 5768, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[6819] 5854. The device of item 5768, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[6820] 5855. The device of item 5768, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[6821] 5856. The device of item 5768, further comprising an
anti-thrombotic agent.
[6822] 5857. The device of item 5768, further comprising a
visualization agent.
[6823] 5858. The device of item 5768, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[6824] 5859. The device of item 5768, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[6825] 5860. The device of item 5768, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[6826] 5861. The device of item 5768, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[6827] 5862. The device of item 5768, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[6828] 5863. The device of item 5768, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[6829] 5864. The device of item 5768, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[6830] 5865. The device of item 5768, further comprising an
echogenic material.
[6831] 5866. The device of item 5768, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[6832] 5867. The device of item 5768 wherein the device is
sterile.
[6833] 5868. The device of item 5768 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[6834] 5869. The device of item 5768 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[6835] 5870. The device of item 5768 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[6836] 5871. The device of item 5768 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[6837] 5872. The device of item 5768 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[6838] 5873. The device of item 5768 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[6839] 5874. The device of item 5768 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[6840] 5875. The device of item 5768 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[6841] 5876. The device of item 5768 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[6842] 5877. The device of item 5768 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[6843] 5878. The device of item 5768 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[6844] 5879. The device of item 5768 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[6845] 5880. The device of item 5768 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[6846] 5881. The device of item 5768 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[6847] 5882. The device of item 5768 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[6848] 5883. The device of item 5768 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[6849] 5884. The device of item 5768 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[6850] 5885. The device of item 5768 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[6851] 5886. The device of item 5768 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[6852] 5887. The device of item 5768 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[6853] 5888. The device of item 5768 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[6854] 5889. The device of item 5768 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[6855] 5890. The device of item 5768 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[6856] 5891. The device of item 5768 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[6857] 5892. The device of item 5768 wherein the gastric
restriction implant is an inflatable cuff.
[6858] 5893. The device of item 5768 wherein the gastric
restriction implant is a space occuping device.
[6859] 5894. A medical device comprising a suture-based endoluminal
implant for partitioning the stomach, and a fibrosing agent, where
the fibrosing agent induces a fibrotic response between the device
and a patient in which the device is implanted.
[6860] 5895. The device of item 5894 wherein the fibrosing agent
promotes regeneration.
[6861] 5896. The device of item 5894 wherein the fibrosing agent
promotes angiogenesis.
[6862] 5897. The device of item 5894 wherein the fibrosing agent
promotes fibroblast migration.
[6863] 5898. The device of item 5894 wherein the fibrosing agent
promotes fibroblast proliferation.
[6864] 5899. The device of item 5894 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[6865] 5900. The device of item 5894 wherein the fibrosing agent
promotes tissue remodeling.
[6866] 5901. The device of item 5894 wherein the fibrosing agent is
an arterial vessel wall irritant.
[6867] 5902. The device of item 5894 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[6868] 5903. The device of item 5894 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[6869] 5904. The device of item 5894 wherein the fibrosing agent is
or comprises silk.
[6870] 5905. The device of item 5894 wherein the fibrosing agent is
or comprises mineral particles.
[6871] 5906. The device of item 5894 wherein the fibrosing agent is
or comprises chitosan.
[6872] 5907. The device of item 5894 wherein the fibrosing agent is
or comprises polylysine.
[6873] 5908. The device of item 5894 wherein the fibrosing agent is
or comprises fibronectin.
[6874] 5909. The device of item 5894 wherein the fibrosing agent is
or comprises bleomycin.
[6875] 5910. The device of item 5894 wherein the fibrosing agent is
or comprises CTGF.
[6876] 5911. The device of item 5894 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[6877] 5912. The device of item 5894 wherein the fibrosing agent is
in the form of a particulate.
[6878] 5913. The device of item 5894 wherein the composition
further comprises an inflammatory cytokine.
[6879] 5914. The device of item 5894 wherein the composition
further comprises an agent that stimulates cell proliferation.
[6880] 5915. The device of item 5894 wherein the composition is in
the form of a gel, paste, or spray.
[6881] 5916. The device of item 5894 wherein the fibrosing agent is
in the form of tufts.
[6882] 5917. The device of item 5894, further comprising a
polymer.
[6883] 5918. The device of item 5894, further comprising a
polymeric carrier.
[6884] 5919. The device of item 5894 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[6885] 5920. The device of item 5894 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[6886] 5921. The device of item 5894, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[6887] 5922. The device of item 5894, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[6888] 5923. The device of item 5894, further comprising a coating,
wherein the coating directly contacts the device.
[6889] 5924. The device of item 5894, further comprising a coating,
wherein the coating indirectly contacts the device.
[6890] 5925. The device of item 5894, further comprising a coating,
wherein the coating partially covers the device.
[6891] 5926. The device of item 5894, further comprising a coating,
wherein the coating completely covers the device.
[6892] 5927. The device of item 5894, further comprising a coating,
wherein the coating is a uniform coating.
[6893] 5928. The device of item 5894, further comprising a coating,
wherein the coating is a non-uniform coating.
[6894] 5929. The device of item 5894, further comprising a coating,
wherein the coating is a discontinuous coating.
[6895] 5930. The device of item 5894, further comprising a coating,
wherein the coating is a patterned coating.
[6896] 5931. The device of item 5894, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[6897] 5932. The device of item 5894, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[6898] 5933. The device of item 5894, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[6899] 5934. The device of item 5894, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[6900] 5935. The device of item 5894, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[6901] 5936. The device of item 5894, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[6902] 5937. The device of item 5894, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[6903] 5938. The device of item 5894, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[6904] 5939. The device of item 5894, further comprising a coating,
wherein the coating further comprises a polymer.
[6905] 5940. The device of item 5894, further comprising a first
coating having a first composition and the second coating having a
second composition.
[6906] 5941. The device of item 5894, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[6907] 5942. The device of item 5894, further comprising a
polymer.
[6908] 5943. The device of item 5894, further comprising a
polymeric carrier.
[6909] 5944. The device of item 5894, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[6910] 5945. The device of item 5894, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[6911] 5946. The device of item 5894, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[6912] 5947. The device of item 5894, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[6913] 5948. The device of item 5894, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[6914] 5949. The device of item 5894, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[6915] 5950. The device of item 5894, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[6916] 5951. The device of item 5894, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[6917] 5952. The device of item 5894, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[6918] 5953. The device of item 5894, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[6919] 5954. The device of item 5894, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[6920] 5955. The device of item 5894, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[6921] 5956. The device of item 5894, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[6922] 5957. The device of item 5894, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[6923] 5958. The device of item 5894, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[6924] 5959. The device of item 5894, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[6925] 5960. The device of item 5894, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[6926] 5961. The device of item 5894, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[6927] 5962. The device of item 5894, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[6928] 5963. The device of item 5894, further comprising a
lubricious coating.
[6929] 5964. The device of item 5894 wherein the fibrosing agent is
located within pores or holes of the device.
[6930] 5965. The device of item 5894 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[6931] 5966. The device of item 5894, further comprising a second
pharmaceutically active agent.
[6932] 5967. The device of item 5894, further comprising an
anti-inflammatory agent.
[6933] 5968. The device of item 5894, further comprising an agent
that inhibits infection.
[6934] 5969. The device of item 5894, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[6935] 5970. The device of item 5894, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[6936] 5971. The device of item 5894, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[6937] 5972. The device of item 5894, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[6938] 5973. The device of item 5894, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[6939] 5974. The device of item 5894, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[6940] 5975. The device of item 5894, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[6941] 5976. The device of item 5894, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[6942] 5977. The device of item 5894, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[6943] 5978. The device of item 5894, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[6944] 5979. The device of item 5894, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[6945] 5980. The device of item 5894, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[6946] 5981. The device of item 5894, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[6947] 5982. The device of item 5894, further comprising an
anti-thrombotic agent.
[6948] 5983. The device of item 5894, further comprising a
visualization agent.
[6949] 5984. The device of item 5894, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[6950] 5985. The device of item 5894, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[6951] 5986. The device of item 5894, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[6952] 5987. The device of item 5894, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[6953] 5988. The device of item 5894, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[6954] 5989. The device of item 5894, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[6955] 5990. The device of item 5894, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[6956] 5991. The device of item 5894, further comprising an
echogenic material.
[6957] 5992. The device of item 5894, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[6958] 5993. The device of item 5894 wherein the device is
sterile.
[6959] 5994. The device of item 5894 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[6960] 5995. The device of item 5894 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[6961] 5996. The device of item 5894 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[6962] 5997. The device of item 5894 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[6963] 5998. The device of item 5894 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[6964] 5999. The device of item 5894 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[6965] 6000. The device of item 5894 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[6966] 6001. The device of item 5894 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[6967] 6002. The device of item 5894 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[6968] 6003. The device of item 5894 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[6969] 6004. The device of item 5894 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[6970] 6005. The device of item 5894 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[6971] 6006. The device of item 5894 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[6972] 6007. The device of item 5894 wherein the device comprises
about 0.01 g to about 10 .mu.g of the fibrosing agent.
[6973] 6008. The device of item 5894 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[6974] 6009. The device of item 5894 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[6975] 6010. The device of item 5894 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[6976] 6011. The device of item 5894 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[6977] 6012. The device of item 5894 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[6978] 6013. The device of item 5894 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[6979] 6014. The device of item 5894 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[6980] 6015. The device of item 5894 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[6981] 6016. The device of item 5894 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[6982] 6017. The device of item 5894 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[6983] 6018. A medical device comprising an electrostimulation
implant and a fibrosing agent, where the fibrosing agent induces a
fibrotic response between the device and a patient in which the
device is implanted.
[6984] 6019. The device of item 6018 wherein the fibrosing agent
promotes regeneration.
[6985] 6020. The device of item 6018 wherein the fibrosing agent
promotes angiogenesis.
[6986] 6021. The device of item 6018 wherein the fibrosing agent
promotes fibroblast migration.
[6987] 6022. The device of item 6018 wherein the fibrosing agent
promotes fibroblast proliferation.
[6988] 6023. The device of item 6018 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[6989] 6024. The device of item 6018 wherein the fibrosing agent
promotes tissue remodeling.
[6990] 6025. The device of item 6018 wherein the fibrosing agent is
an arterial vessel wall irritant.
[6991] 6026. The device of item 6018 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[6992] 6027. The device of item 6018 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[6993] 6028. The device of item 6018 wherein the fibrosing agent is
or comprises silk.
[6994] 6029. The device of item 6018 wherein the fibrosing agent is
or comprises mineral particles.
[6995] 6030. The device of item 6018 wherein the fibrosing agent is
or comprises chitosan.
[6996] 6031. The device of item 6018 wherein the fibrosing agent is
or comprises polylysine.
[6997] 6032. The device of item 6018 wherein the fibrosing agent is
or comprises fibronectin.
[6998] 6033. The device of item 6018 wherein the fibrosing agent is
or comprises bleomycin.
[6999] 6034. The device of item 6018 wherein the fibrosing agent is
or comprises CTGF.
[7000] 6035. The device of item 6018 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[7001] 6036. The device of item 6018 wherein the fibrosing agent is
in the form of a particulate.
[7002] 6037. The device of item 6018 wherein the composition
further comprises an inflammatory cytokine.
[7003] 6038. The device of item 6018 wherein the composition
further comprises an agent that stimulates cell proliferation.
[7004] 6039. The device of item 6018 wherein the composition is in
the form of a gel, paste, or spray.
[7005] 6040. The device of item 6018 wherein the fibrosing agent is
in the form of tufts.
[7006] 6041. The device of item 6018, further comprising a
polymer.
[7007] 6042. The device of item 6018, further comprising a
polymeric carrier.
[7008] 6043. The device of item 6018 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[7009] 6044. The device of item 6018 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[7010] 6045. The device of item 6018, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[7011] 6046. The device of item 6018, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[7012] 6047. The device of item 6018, further comprising a coating,
wherein the coating directly contacts the device.
[7013] 6048. The device of item 6018, further comprising a coating,
wherein the coating indirectly contacts the device.
[7014] 6049. The device of item 6018, further comprising a coating,
wherein the coating partially covers the device.
[7015] 6050. The device of item 6018, further comprising a coating,
wherein the coating completely covers the device.
[7016] 6051. The device of item 6018, further comprising a coating,
wherein the coating is a uniform coating.
[7017] 6052. The device of item 6018, further comprising a coating,
wherein the coating is a non-uniform coating.
[7018] 6053. The device of item 6018, further comprising a coating,
wherein the coating is a discontinuous coating.
[7019] 6054. The device of item 6018, further comprising a coating,
wherein the coating is a patterned coating.
[7020] 6055. The device of item 6018, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[7021] 6056. The device of item 6018, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[7022] 6057. The device of item 6018, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[7023] 6058. The device of item 6018, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[7024] 6059. The device of item 6018, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[7025] 6060. The device of item 6018, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[7026] 6061. The device of item 6018, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[7027] 6062. The device of item 6018, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[7028] 6063. The device of item 6018, further comprising a coating,
wherein the coating further comprises a polymer.
[7029] 6064. The device of item 6018, further comprising a first
coating having a first composition and the second coating having a
second composition.
[7030] 6065. The device of item 6018, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[7031] 6066. The device of item 6018, further comprising a
polymer.
[7032] 6067. The device of item 6018, further comprising a
polymeric carrier.
[7033] 6068. The device of item 6018, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[7034] 6069. The device of item 6018, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[7035] 6070. The device of item 6018, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[7036] 6071. The device of item 6018, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[7037] 6072. The device of item 6018, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[7038] 6073. The device of item 6018, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[7039] 6074. The device of item 6018, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[7040] 6075. The device of item 6018, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[7041] 6076. The device of item 6018, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[7042] 6077. The device of item 6018, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[7043] 6078. The device of item 6018, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[7044] 6079. The device of item 6018, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[7045] 6080. The device of item 6018, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[7046] 6081. The device of item 6018, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[7047] 6082. The device of item 6018, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[7048] 6083. The device of item 6018, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[7049] 6084. The device of item 6018, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[7050] 6085. The device of item 6018, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[7051] 6086. The device of item 6018, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[7052] 6087. The device of item 6018, further comprising a
lubricious coating.
[7053] 6088. The device of item 6018 wherein the fibrosing agent is
located within pores or holes of the device.
[7054] 6089. The device of item 6018 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[7055] 6090. The device of item 6018, further comprising a second
pharmaceutically active agent.
[7056] 6091. The device of item 6018, further comprising an
anti-inflammatory agent.
[7057] 6092. The device of item 6018, further comprising an agent
that inhibits infection.
[7058] 6093. The device of item 6018, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[7059] 6094. The device of item 6018, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[7060] 6095. The device of item 6018, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[7061] 6096. The device of item 6018, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[7062] 6097. The device of item 6018, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[7063] 6098. The device of item 6018, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[7064] 6099. The device of item 6018, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[7065] 6100. The device of item 6018, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[7066] 6101. The device of item 6018, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[7067] 6102. The device of item 6018, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[7068] 6103. The device of item 6018, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[7069] 6104. The device of item 6018, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[7070] 6105. The device of item 6018, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[7071] 6106. The device of item 6018, further comprising an
anti-thrombotic agent.
[7072] 6107. The device of item 6018, further comprising a
visualization agent.
[7073] 6108. The device of item 6018, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[7074] 6109. The device of item 6018, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[7075] 6110. The device of item 6018, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[7076] 6111. The device of item 6018, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[7077] 6112. The device of item 6018, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[7078] 6113. The device of item 6018, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[7079] 6114. The device of item 6018, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[7080] 6115. The device of item 6018, further comprising an
echogenic material.
[7081] 6116. The device of item 6018, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[7082] 6117. The device of item 6018 wherein the device is
sterile.
[7083] 6118. The device of item 6018 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[7084] 6119. The device of item 6018 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[7085] 6120. The device of item 6018 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[7086] 6121. The device of item 6018 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[7087] 6122. The device of item 6018 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[7088] 6123. The device of item 6018 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[7089] 6124. The device of item 6018 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[7090] 6125. The device of item 6018 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[7091] 6126. The device of item 6018 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[7092] 6127. The device of item 6018 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[7093] 6128. The device of item 6018 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[7094] 6129. The device of item 6018 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[7095] 6130. The device of item 6018 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[7096] 6131. The device of item 6018 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[7097] 6132. The device of item 6018 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[7098] 6133. The device of item 6018 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[7099] 6134. The device of item 6018 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[7100] 6135. The device of item 6018 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[7101] 6136. The device of item 6018 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[7102] 6137. The device of item 6018 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[7103] 6138. The device of item 6018 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[7104] 6139. The device of item 6018 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[7105] 6140. The device of item 6018 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[7106] 6141. The device of item 6018 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[7107] 6142. The device of item 6018 wherein the electostimulation
implant is a neural electostimulation implant.
[7108] 6143. The device of item 6018 wherein the electostimulation
implant is a non-neural electostimulation implant.
[7109] 6144. A medical device comprising a soft palate implant and
a fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
[7110] 6145. The device of item 6144 wherein the fibrosing agent
promotes regeneration.
[7111] 6146. The device of item 6144 wherein the fibrosing agent
promotes angiogenesis.
[7112] 6147. The device of item 6144 wherein the fibrosing agent
promotes fibroblast migration.
[7113] 6148. The device of item 6144 wherein the fibrosing agent
promotes fibroblast proliferation.
[7114] 6149. The device of item 6144 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[7115] 6150. The device of item 6144 wherein the fibrosing agent
promotes tissue remodeling.
[7116] 6151. The device of item 6144 wherein the fibrosing agent is
an arterial vessel wall irritant.
[7117] 6152. The device of item 6144 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[7118] 6153. The device of item 6144 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[7119] 6154. The device of item 6144 wherein the fibrosing agent is
or comprises silk.
[7120] 6155. The device of item 6144 wherein the fibrosing agent is
or comprises mineral particles.
[7121] 6156. The device of item 6144 wherein the fibrosing agent is
or comprises chitosan.
[7122] 6157. The device of item 6144 wherein the fibrosing agent is
or comprises polylysine.
[7123] 6158. The device of item 6144 wherein the fibrosing agent is
or comprises fibronectin.
[7124] 6159. The device of item 6144 wherein the fibrosing agent is
or comprises bleomycin.
[7125] 6160. The device of item 6144 wherein the fibrosing agent is
or comprises CTGF.
[7126] 6161. The device of item 6144 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[7127] 6162. The device of item 6144 wherein the fibrosing agent is
in the form of a particulate.
[7128] 6163. The device of item 6144 wherein the composition
further comprises an inflammatory cytokine.
[7129] 6164. The device of item 6144 wherein the composition
further comprises an agent that stimulates cell proliferation.
[7130] 6165. The device of item 6144 wherein the composition is in
the form of a gel, paste, or spray.
[7131] 6166. The device of item 6144 wherein the fibrosing agent is
in the form of tufts.
[7132] 6167. The device of item 6144, further comprising a
polymer.
[7133] 6168. The device of item 6144, further comprising a
polymeric carrier.
[7134] 6169. The device of item 6144 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[7135] 6170. The device of item 6144 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[7136] 6171. The device of item 6144, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[7137] 6172. The device of item 6144, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[7138] 6173. The device of item 6144, further comprising a coating,
wherein the coating directly contacts the device.
[7139] 6174. The device of item 6144, further comprising a coating,
wherein the coating indirectly contacts the device.
[7140] 6175. The device of item 6144, further comprising a coating,
wherein the coating partially covers the device.
[7141] 6176. The device of item 6144, further comprising a coating,
wherein the coating completely covers the device.
[7142] 6177. The device of item 6144, further comprising a coating,
wherein the coating is a uniform coating.
[7143] 6178. The device of item 6144, further comprising a coating,
wherein the coating is a non-uniform coating.
[7144] 6179. The device of item 6144, further comprising a coating,
wherein the coating is a discontinuous coating.
[7145] 6180. The device of item 6144, further comprising a coating,
wherein the coating is a patterned coating.
[7146] 6181. The device of item 6144, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[7147] 6182. The device of item 6144, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[7148] 6183. The device of item 6144, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[7149] 6184. The device of item 6144, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[7150] 6185. The device of item 6144, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[7151] 6186. The device of item 6144, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[7152] 6187. The device of item 6144, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[7153] 6188. The device of item 6144, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[7154] 6189. The device of item 6144, further comprising a coating,
wherein the coating further comprises a polymer.
[7155] 6190. The device of item 6144, further comprising a first
coating having a first composition and the second coating having a
second composition.
[7156] 6191. The device of item 6144, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[7157] 6192. The device of item 6144, further comprising a
polymer.
[7158] 6193. The device of item 6144, further comprising a
polymeric carrier.
[7159] 6194. The device of item 6144, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[7160] 6195. The device of item 6144, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[7161] 6196. The device of item 6144, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[7162] 6197. The device of item 6144, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[7163] 6198. The device of item 6144, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[7164] 6199. The device of item 6144, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[7165] 6200. The device of item 6144, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[7166] 6201. The device of item 6144, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[7167] 6202. The device of item 6144, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[7168] 6203. The device of item 6144, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[7169] 6204. The device of item 6144, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[7170] 6205. The device of item 6144, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[7171] 6206. The device of item 6144, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[7172] 6207. The device of item 6144, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[7173] 6208. The device of item 6144, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[7174] 6209. The device of item 6144, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[7175] 6210. The device of item 6144, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[7176] 6211. The device of item 6144, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[7177] 6212. The device of item 6144, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[7178] 6213. The device of item 6144, further comprising a
lubricious coating.
[7179] 6214. The device of item 6144 wherein the fibrosing agent is
located within pores or holes of the device.
[7180] 6215. The device of item 6144 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[7181] 6216. The device of item 6144, further comprising a second
pharmaceutically active agent.
[7182] 6217. The device of item 6144, further comprising an
anti-inflammatory agent.
[7183] 6218. The device of item 6144, further comprising an agent
that inhibits infection.
[7184] 6219. The device of item 6144, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[7185] 6220. The device of item 6144, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[7186] 6221. The device of item 6144, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[7187] 6222. The device of item 6144, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[7188] 6223. The device of item 6144, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[7189] 6224. The device of item 6144, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[7190] 6225. The device of item 6144, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[7191] 6226. The device of item 6144, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[7192] 6227. The device of item 6144, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[7193] 6228. The device of item 6144, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[7194] 6229. The device of item 6144, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[7195] 6230. The device of item 6144, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[7196] 6231. The device of item 6144, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[7197] 6232. The device of item 6144, further comprising an
anti-thrombotic agent.
[7198] 6233. The device of item 6144, further comprising a
visualization agent.
[7199] 6234. The device of item 6144, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[7200] 6235. The device of item 6144, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[7201] 6236. The device of item 6144, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[7202] 6237. The device of item 6144, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[7203] 6238. The device of item 6144, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[7204] 6239. The device of item 6144, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[7205] 6240. The device of item 6144, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[7206] 6241. The device of item 6144, further comprising an
echogenic material.
[7207] 6242. The device of item 6144, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[7208] 6243. The device of item 6144 wherein the device is
sterile.
[7209] 6244. The device of item 6144 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[7210] 6245. The device of item 6144 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[7211] 6246. The device of item 6144 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[7212] 6247. The device of item 6144 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[7213] 6248. The device of item 6144 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[7214] 6249. The device of item 6144 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[7215] 6250. The device of item 6144 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[7216] 6251. The device of item 6144 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[7217] 6252. The device of item 6144 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[7218] 6253. The device of item 6144 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[7219] 6254. The device of item 6144 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[7220] 6255. The device of item 6144 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[7221] 6256. The device of item 6144 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[7222] 6257. The device of item 6144 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[7223] 6258. The device of item 6144 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[7224] 6259. The device of item 6144 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[7225] 6260. The device of item 6144 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[7226] 6261. The device of item 6144 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[7227] 6262. The device of item 6144 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[7228] 6263. The device of item 6144 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[7229] 6264. The device of item 6144 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[7230] 6265. The device of item 6144 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[7231] 6266. The device of item 6144 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[7232] 6267. The device of item 6144 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[7233] 6268. The device of item 6144 wherein the soft palate
implant is injectable.
[7234] 6269. A medical device comprising a vascular coil implant
and a fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
[7235] 6270. The device of item 6269 wherein the fibrosing agent
promotes regeneration.
[7236] 6271. The device of item 6269 wherein the fibrosing agent
promotes angiogenesis.
[7237] 6272. The device of item 6269 wherein the fibrosing agent
promotes fibroblast migration.
[7238] 6273. The device of item 6269 wherein the fibrosing agent
promotes fibroblast proliferation.
[7239] 6274. The device of item 6269 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[7240] 6275. The device of item 6269 wherein the fibrosing agent
promotes tissue remodeling.
[7241] 6276. The device of item 6269 wherein the fibrosing agent is
an arterial vessel wall irritant.
[7242] 6277. The device of item 6269 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[7243] 6278. The device of item 6269 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[7244] 6279. The device of item 6269 wherein the fibrosing agent is
or comprises silk.
[7245] 6280. The device of item 6269 wherein the fibrosing agent is
or comprises mineral particles.
[7246] 6281. The device of item 6269 wherein the fibrosing agent is
or comprises chitosan.
[7247] 6282. The device of item 6269 wherein the fibrosing agent is
or comprises polylysine.
[7248] 6283. The device of item 6269 wherein the fibrosing agent is
or comprises fibronectin.
[7249] 6284. The device of item 6269 wherein the fibrosing agent is
or comprises bleomycin.
[7250] 6285. The device of item 6269 wherein the fibrosing agent is
or comprises CTGF.
[7251] 6286. The device of item 6269 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[7252] 6287. The device of item 6269 wherein the fibrosing agent is
in the form of a particulate.
[7253] 6288. The device of item 6269 wherein the composition
further comprises an inflammatory cytokine.
[7254] 6289. The device of item 6269 wherein the composition
further comprises an agent that stimulates cell proliferation.
[7255] 6290. The device of item 6269 wherein the composition is in
the form of a gel, paste, or spray.
[7256] 6291. The device of item 6269 wherein the fibrosing agent is
in the form of tufts.
[7257] 6292. The device of item 6269, further comprising a
polymer.
[7258] 6293. The device of item 6269, further comprising a
polymeric carrier.
[7259] 6294. The device of item 6269 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[7260] 6295. The device of item 6269 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[7261] 6296. The device of item 6269, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[7262] 6297. The device of item 6269, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[7263] 6298. The device of item 6269, further comprising a coating,
wherein the coating directly contacts the device.
[7264] 6299. The device of item 6269, further comprising a coating,
wherein the coating indirectly contacts the device.
[7265] 6300. The device of item 6269, further comprising a coating,
wherein the coating partially covers the device.
[7266] 6301. The device of item 6269, further comprising a coating,
wherein the coating completely covers the device.
[7267] 6302. The device of item 6269, further comprising a coating,
wherein the coating is a uniform coating.
[7268] 6303. The device of item 6269, further comprising a coating,
wherein the coating is a non-uniform coating.
[7269] 6304. The device of item 6269, further comprising a coating,
wherein the coating is a discontinuous coating.
[7270] 6305. The device of item 6269, further comprising a coating,
wherein the coating is a patterned coating.
[7271] 6306. The device of item 6269, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[7272] 6307. The device of item 6269, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[7273] 6308. The device of item 6269, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[7274] 6309. The device of item 6269, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[7275] 6310. The device of item 6269, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[7276] 6311. The device of item 6269, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[7277] 6312. The device of item 6269, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[7278] 6313. The device of item 6269, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[7279] 6314. The device of item 6269, further comprising a coating,
wherein the coating further comprises a polymer.
[7280] 6315. The device of item 6269, further comprising a first
coating having a first composition and the second coating having a
second composition.
[7281] 6316. The device of item 6269, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[7282] 6317. The device of item 6269, further comprising a
polymer.
[7283] 6318. The device of item 6269, further comprising a
polymeric carrier.
[7284] 6319. The device of item 6269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[7285] 6320. The device of item 6269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[7286] 6321. The device of item 6269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[7287] 6322. The device of item 6269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[7288] 6323. The device of item 6269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[7289] 6324. The device of item 6269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[7290] 6325. The device of item 6269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[7291] 6326. The device of item 6269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[7292] 6327. The device of item 6269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[7293] 6328. The device of item 6269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[7294] 6329. The device of item 6269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[7295] 6330. The device of item 6269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[7296] 6331. The device of item 6269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[7297] 6332. The device of item 6269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[7298] 6333. The device of item 6269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[7299] 6334. The device of item 6269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[7300] 6335. The device of item 6269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[7301] 6336. The device of item 6269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[7302] 6337. The device of item 6269, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[7303] 6338. The device of item 6269, further comprising a
lubricious coating.
[7304] 6339. The device of item 6269 wherein the fibrosing agent is
located within pores or holes of the device.
[7305] 6340. The device of item 6269 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[7306] 6341. The device of item 6269, further comprising a second
pharmaceutically active agent.
[7307] 6342. The device of item 6269, further comprising an
anti-inflammatory agent.
[7308] 6343. The device of item 6269, further comprising an agent
that inhibits infection.
[7309] 6344. The device of item 6269, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[7310] 6345. The device of item 6269, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[7311] 6346. The device of item 6269, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[7312] 6347. The device of item 6269, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[7313] 6348. The device of item 6269, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[7314] 6349. The device of item 6269, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[7315] 6350. The device of item 6269, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[7316] 6351. The device of item 6269, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[7317] 6352. The device of item 6269, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[7318] 6353. The device of item 6269, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[7319] 6354. The device of item 6269, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[7320] 6355. The device of item 6269, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[7321] 6356. The device of item 6269, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[7322] 6357. The device of item 6269, further comprising an
anti-thrombotic agent.
[7323] 6358. The device of item 6269, further comprising a
visualization agent.
[7324] 6359. The device of item 6269, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[7325] 6360. The device of item 6269, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[7326] 6361. The device of item 6269, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[7327] 6362. The device of item 6269, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[7328] 6363. The device of item 6269, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[7329] 6364. The device of item 6269, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[7330] 6365. The device of item 6269, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[7331] 6366. The device of item 6269, further comprising an
echogenic material.
[7332] 6367. The device of item 6269, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[7333] 6368. The device of item 6269 wherein the device is
sterile.
[7334] 6369. The device of item 6269 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[7335] 6370. The device of item 6269 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[7336] 6371. The device of item 6269 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[7337] 6372. The device of item 6269 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[7338] 6373. The device of item 6269 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[7339] 6374. The device of item 6269 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[7340] 6375. The device of item 6269 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[7341] 6376. The device of item 6269 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[7342] 6377. The device of item 6269 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[7343] 6378. The device of item 6269 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[7344] 6379. The device of item 6269 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[7345] 6380. The device of item 6269 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[7346] 6381. The device of item 6269 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[7347] 6382. The device of item 6269 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[7348] 6383. The device of item 6269 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[7349] 6384. The device of item 6269 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[7350] 6385. The device of item 6269 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[7351] 6386. The device of item 6269 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[7352] 6387. The device of item 6269 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[7353] 6388. The device of item 6269 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[7354] 6389. The device of item 6269 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[7355] 6390. The device of item 6269 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[7356] 6391. The device of item 6269 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[7357] 6392. The device of item 6269 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[7358] 6393. The device of item 6269 wherein the vascular coil
implant is composed of a porous, flexible PTFE material.
[7359] 6394. The device of item 6269 wherein the vascular coil
implant is composed of a bioactive component.
[7360] 6395. The device of item 6269 wherein the vascular coil
implant is biologically inert.
[7361] 6396. The device of item 6269 wherein the vascular coil
implant have a first state prior to insertion (primary phase) and a
second state post insertion (secondary phase).
[7362] 6397. A medical device comprising a vaso-occlusive coil
implant and a fibrosing agent, where the fibrosing agent induces a
fibrotic response between the device and a patient in which the
device is implanted.
[7363] 6398. The device of item 6397 wherein the fibrosing agent
promotes regeneration.
[7364] 6399. The device of item 6397 wherein the fibrosing agent
promotes angiogenesis.
[7365] 6400. The device of item 6397 wherein the fibrosing agent
promotes fibroblast migration.
[7366] 6401. The device of item 6397 wherein the fibrosing agent
promotes fibroblast proliferation.
[7367] 6402. The device of item 6397 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[7368] 6403. The device of item 6397 wherein the fibrosing agent
promotes tissue remodeling.
[7369] 6404. The device of item 6397 wherein the fibrosing agent is
an arterial vessel wall irritant.
[7370] 6405. The device of item 6397 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[7371] 6406. The device of item 6397 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[7372] 6407. The device of item 6397 wherein the fibrosing agent is
or comprises silk.
[7373] 6408. The device of item 6397 wherein the fibrosing agent is
or comprises mineral particles.
[7374] 6409. The device of item 6397 wherein the fibrosing agent is
or comprises chitosan.
[7375] 6410. The device of item 6397 wherein the fibrosing agent is
or comprises polylysine.
[7376] 6411. The device of item 6397 wherein the fibrosing agent is
or comprises fibronectin.
[7377] 6412. The device of item 6397 wherein the fibrosing agent is
or comprises bleomycin.
[7378] 6413. The device of item 6397 wherein the fibrosing agent is
or comprises CTGF.
[7379] 6414. The device of item 6397 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[7380] 6415. The device of item 6397 wherein the fibrosing agent is
in the form of a particulate.
[7381] 6416. The device of item 6397 wherein the composition
further comprises an inflammatory cytokine.
[7382] 6417. The device of item 6397 wherein the composition
further comprises an agent that stimulates cell proliferation.
[7383] 6418. The device of item 6397 wherein the composition is in
the form of a gel, paste, or spray.
[7384] 6419. The device of item 6397 wherein the fibrosing agent is
in the form of tufts.
[7385] 6420. The device of item 6397, further comprising a
polymer.
[7386] 6421. The device of item 6397, further comprising a
polymeric carrier.
[7387] 6422. The device of item 6397 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[7388] 6423. The device of item 6397 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[7389] 6424. The device of item 6397, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[7390] 6425. The device of item 6397, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[7391] 6426. The device of item 6397, further comprising a coating,
wherein the coating directly contacts the device.
[7392] 6427. The device of item 6397, further comprising a coating,
wherein the coating indirectly contacts the device.
[7393] 6428. The device of item 6397, further comprising a coating,
wherein the coating partially covers the device.
[7394] 6429. The device of item 6397, further comprising a coating,
wherein the coating completely covers the device.
[7395] 6430. The device of item 6397, further comprising a coating,
wherein the coating is a uniform coating.
[7396] 6431. The device of item 6397, further comprising a coating,
wherein the coating is a non-uniform coating.
[7397] 6432. The device of item 6397, further comprising a coating,
wherein the coating is a discontinuous coating.
[7398] 6433. The device of item 6397, further comprising a coating,
wherein the coating is a patterned coating.
[7399] 6434. The device of item 6397, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[7400] 6435. The device of item 6397, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[7401] 6436. The device of item 6397, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[7402] 6437. The device of item 6397, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[7403] 6438. The device of item 6397, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[7404] 6439. The device of item 6397, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[7405] 6440. The device of item 6397, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[7406] 6441. The device of item 6397, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[7407] 6442. The device of item 6397, further comprising a coating,
wherein the coating further comprises a polymer.
[7408] 6443. The device of item 6397, further comprising a first
coating having a first composition and the second coating having a
second composition.
[7409] 6444. The device of item 6397, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[7410] 6445. The device of item 6397, further comprising a
polymer.
[7411] 6446. The device of item 6397, further comprising a
polymeric carrier.
[7412] 6447. The device of item 6397, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[7413] 6448. The device of item 6397, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[7414] 6449. The device of item 6397, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[7415] 6450. The device of item 6397, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[7416] 6451. The device of item 6397, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[7417] 6452. The device of item 6397, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[7418] 6453. The device of item 6397, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[7419] 6454. The device of item 6397, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[7420] 6455. The device of item 6397, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[7421] 6456. The device of item 6397, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[7422] 6457. The device of item 6397, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[7423] 6458. The device of item 6397, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[7424] 6459. The device of item 6397, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[7425] 6460. The device of item 6397, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[7426] 6461. The device of item 6397, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[7427] 6462. The device of item 6397, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[7428] 6463. The device of item 6397, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[7429] 6464. The device of item 6397, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[7430] 6465. The device of item 6397, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[7431] 6466. The device of item 6397, further comprising a
lubricious coating.
[7432] 6467. The device of item 6397 wherein the fibrosing agent is
located within pores or holes of the device.
[7433] 6468. The device of item 6397 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[7434] 6469. The device of item 6397, further comprising a second
pharmaceutically active agent.
[7435] 6470. The device of item 6397, further comprising an
anti-inflammatory agent.
[7436] 6471. The device of item 6397, further comprising an agent
that inhibits infection.
[7437] 6472. The device of item 6397, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[7438] 6473. The device of item 6397, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[7439] 6474. The device of item 6397, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[7440] 6475. The device of item 6397, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[7441] 6476. The device of item 6397, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[7442] 6477. The device of item 6397, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[7443] 6478. The device of item 6397, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[7444] 6479. The device of item 6397, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[7445] 6480. The device of item 6397, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[7446] 6481. The device of item 6397, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[7447] 6482. The device of item 6397, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[7448] 6483. The device of item 6397, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[7449] 6484. The device of item 6397, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[7450] 6485. The device of item 6397, further comprising an
anti-thrombotic agent.
[7451] 6486. The device of item 6397, further comprising a
visualization agent.
[7452] 6487. The device of item 6397, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[7453] 6488. The device of item 6397, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[7454] 6489. The device of item 6397, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[7455] 6490. The device of item 6397, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[7456] 6491. The device of item 6397, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[7457] 6492. The device of item 6397, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[7458] 6493. The device of item 6397, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[7459] 6494. The device of item 6397, further comprising an
echogenic material.
[7460] 6495. The device of item 6397, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[7461] 6496. The device of item 6397 wherein the device is
sterile.
[7462] 6497. The device of item 6397 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[7463] 6498. The device of item 6397 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[7464] 6499. The device of item 6397 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[7465] 6500. The device of item 6397 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[7466] 6501. The device of item 6397 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[7467] 6502. The device of item 6397 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[7468] 6503. The device of item 6397 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[7469] 6504. The device of item 6397 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[7470] 6505. The device of item 6397 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[7471] 6506. The device of item 6397 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[7472] 6507. The device of item 6397 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[7473] 6508. The device of item 6397 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[7474] 6509. The device of item 6397 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[7475] 6510. The device of item 6397 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[7476] 6511. The device of item 6397 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[7477] 6512. The device of item 6397 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[7478] 6513. The device of item 6397 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[7479] 6514. The device of item 6397 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[7480] 6515. The device of item 6397 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[7481] 6516. The device of item 6397 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[7482] 6517. The device of item 6397 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[7483] 6518. The device of item 6397 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[7484] 6519. The device of item 6397 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[7485] 6520. The device of item 6397 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[7486] 6521. A medical device comprising a vaso-occlusion implant
and a fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
[7487] 6522. The device of item 6521 wherein the fibrosing agent
promotes regeneration.
[7488] 6523. The device of item 6521 wherein the fibrosing agent
promotes angiogenesis.
[7489] 6524. The device of item 6521 wherein the fibrosing agent
promotes fibroblast migration.
[7490] 6525. The device of item 6521 wherein the fibrosing agent
promotes fibroblast proliferation.
[7491] 6526. The device of item 6521 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[7492] 6527. The device of item 6521 wherein the fibrosing agent
promotes tissue remodeling.
[7493] 6528. The device of item 6521 wherein the fibrosing agent is
an arterial vessel wall irritant.
[7494] 6529. The device of item 6521 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[7495] 6530. The device of item 6521 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[7496] 6531. The device of item 6521 wherein the fibrosing agent is
or comprises silk.
[7497] 6532. The device of item 6521 wherein the fibrosing agent is
or comprises mineral particles.
[7498] 6533. The device of item 6521 wherein the fibrosing agent is
or comprises chitosan.
[7499] 6534. The device of item 6521 wherein the fibrosing agent is
or comprises polylysine.
[7500] 6535. The device of item 6521 wherein the fibrosing agent is
or comprises fibronectin.
[7501] 6536. The device of item 6521 wherein the fibrosing agent is
or comprises bleomycin.
[7502] 6537. The device of item 6521 wherein the fibrosing agent is
or comprises CTGF.
[7503] 6538. The device of item 6521 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[7504] 6539. The device of item 6521 wherein the fibrosing agent is
in the form of a particulate.
[7505] 6540. The device of item 6521 wherein the composition
further comprises an inflammatory cytokine.
[7506] 6541. The device of item 6521 wherein the composition
further comprises an agent that stimulates cell proliferation.
[7507] 6542. The device of item 6521 wherein the composition is in
the form of a gel, paste, or spray.
[7508] 6543. The device of item 6521 wherein the fibrosing agent is
in the form of tufts.
[7509] 6544. The device of item 6521, further comprising a
polymer.
[7510] 6545. The device of item 6521, further comprising a
polymeric carrier.
[7511] 6546. The device of item 6521 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[7512] 6547. The device of item 6521 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[7513] 6548. The device of item 6521, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[7514] 6549. The device of item 6521, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[7515] 6550. The device of item 6521, further comprising a coating,
wherein the coating directly contacts the device.
[7516] 6551. The device of item 6521, further comprising a coating,
wherein the coating indirectly contacts the device.
[7517] 6552. The device of item 6521, further comprising a coating,
wherein the coating partially covers the device.
[7518] 6553. The device of item 6521, further comprising a coating,
wherein the coating completely covers the device.
[7519] 6554. The device of item 6521, further comprising a coating,
wherein the coating is a uniform coating.
[7520] 6555. The device of item 6521, further comprising a coating,
wherein the coating is a non-uniform coating.
[7521] 6556. The device of item 6521, further comprising a coating,
wherein the coating is a discontinuous coating.
[7522] 6557. The device of item 6521, further comprising a coating,
wherein the coating is a patterned coating.
[7523] 6558. The device of item 6521, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[7524] 6559. The device of item 6521, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[7525] 6560. The device of item 6521, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[7526] 6561. The device of item 6521, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[7527] 6562. The device of item 6521, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[7528] 6563. The device of item 6521, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[7529] 6564. The device of item 6521, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[7530] 6565. The device of item 6521, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[7531] 6566. The device of item 6521, further comprising a coating,
wherein the coating further comprises a polymer.
[7532] 6567. The device of item 6521, further comprising a first
coating having a first composition and the second coating having a
second composition.
[7533] 6568. The device of item 6521, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[7534] 6569. The device of item 6521, further comprising a
polymer.
[7535] 6570. The device of item 6521, further comprising a
polymeric carrier.
[7536] 6571. The device of item 6521, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[7537] 6572. The device of item 6521, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[7538] 6573. The device of item 6521, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[7539] 6574. The device of item 6521, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[7540] 6575. The device of item 6521, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[7541] 6576. The device of item 6521, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[7542] 6577. The device of item 6521, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[7543] 6578. The device of item 6521, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[7544] 6579. The device of item 6521, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[7545] 6580. The device of item 6521, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[7546] 6581. The device of item 6521, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[7547] 6582. The device of item 6521, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[7548] 6583. The device of item 6521, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[7549] 6584. The device of item 6521, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[7550] 6585. The device of item 6521, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[7551] 6586. The device of item 6521, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[7552] 6587. The device of item 6521, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[7553] 6588. The device of item 6521, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[7554] 6589. The device of item 6521, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[7555] 6590. The device of item 6521, further comprising a
lubricious coating.
[7556] 6591. The device of item 6521 wherein the fibrosing agent is
located within pores or holes of the device.
[7557] 6592. The device of item 6521 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[7558] 6593. The device of item 6521, further comprising a second
pharmaceutically active agent.
[7559] 6594. The device of item 6521, further comprising an
anti-inflammatory agent.
[7560] 6595. The device of item 6521, further comprising an agent
that inhibits infection.
[7561] 6596. The device of item 6521, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[7562] 6597. The device of item 6521, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[7563] 6598. The device of item 6521, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[7564] 6599. The device of item 6521, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[7565] 6600. The device of item 6521, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[7566] 6601. The device of item 6521, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[7567] 6602. The device of item 6521, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[7568] 6603. The device of item 6521, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[7569] 6604. The device of item 6521, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[7570] 6605. The device of item 6521, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[7571] 6606. The device of item 6521, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[7572] 6607. The device of item 6521, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[7573] 6608. The device of item 6521, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[7574] 6609. The device of item 6521, further comprising an
anti-thrombotic agent.
[7575] 6610. The device of item 6521, further comprising a
visualization agent.
[7576] 6611. The device of item 6521, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[7577] 6612. The device of item 6521, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[7578] 6613. The device of item 6521, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[7579] 6614. The device of item 6521, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[7580] 6615. The device of item 6521, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[7581] 6616. The device of item 6521, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[7582] 6617. The device of item 6521, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[7583] 6618. The device of item 6521, further comprising an
echogenic material.
[7584] 6619. The device of item 6521, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[7585] 6620. The device of item 6521 wherein the device is
sterile.
[7586] 6621. The device of item 6521 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[7587] 6622. The device of item 6521 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[7588] 6623. The device of item 6521 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[7589] 6624. The device of item 6521 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[7590] 6625. The device of item 6521 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[7591] 6626. The device of item 6521 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[7592] 6627. The device of item 6521 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[7593] 6628. The device of item 6521 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[7594] 6629. The device of item 6521 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[7595] 6630. The device of item 6521 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[7596] 6631. The device of item 6521 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[7597] 6632. The device of item 6521 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[7598] 6633. The device of item 6521 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[7599] 6634. The device of item 6521 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[7600] 6635. The device of item 6521 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[7601] 6636. The device of item 6521 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[7602] 6637. The device of item 6521 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[7603] 6638. The device of item 6521 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[7604] 6639. The device of item 6521 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[7605] 6640. The device of item 6521 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[7606] 6641. The device of item 6521 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[7607] 6642. The device of item 6521 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[7608] 6643. The device of item 6521 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[7609] 6644. The device of item 6521 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[7610] 6645. A medical device comprising a non-coiled
vaso-occlusive implant and a fibrosing agent, where the fibrosing
agent induces a fibrotic response between the device and a patient
in which the device is implanted.
[7611] 6646. The device of item 6645 wherein the fibrosing agent
promotes regeneration.
[7612] 6647. The device of item 6645 wherein the fibrosing agent
promotes angiogenesis.
[7613] 6648. The device of item 6645 wherein the fibrosing agent
promotes fibroblast migration.
[7614] 6649. The device of item 6645 wherein the fibrosing agent
promotes fibroblast proliferation.
[7615] 6650. The device of item 6645 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[7616] 6651. The device of item 6645 wherein the fibrosing agent
promotes tissue remodeling.
[7617] 6652. The device of item 6645 wherein the fibrosing agent is
an arterial vessel wall irritant.
[7618] 6653. The device of item 6645 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[7619] 6654. The device of item 6645 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[7620] 6655. The device of item 6645 wherein the fibrosing agent is
or comprises silk.
[7621] 6656. The device of item 6645 wherein the fibrosing agent is
or comprises mineral particles.
[7622] 6657. The device of item 6645 wherein the fibrosing agent is
or comprises chitosan.
[7623] 6658. The device of item 6645 wherein the fibrosing agent is
or comprises polylysine.
[7624] 6659. The device of item 6645 wherein the fibrosing agent is
or comprises fibronectin.
[7625] 6660. The device of item 6645 wherein the fibrosing agent is
or comprises bleomycin.
[7626] 6661. The device of item 6645 wherein the fibrosing agent is
or comprises CTGF.
[7627] 6662. The device of item 6645 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[7628] 6663. The device of item 6645 wherein the fibrosing agent is
in the form of a particulate.
[7629] 6664. The device of item 6645 wherein the composition
further comprises an inflammatory cytokine.
[7630] 6665. The device of item 6645 wherein the composition
further comprises an agent that stimulates cell proliferation.
[7631] 6666. The device of item 6645 wherein the composition is in
the form of a gel, paste, or spray.
[7632] 6667. The device of item 6645 wherein the fibrosing agent is
in the form of tufts.
[7633] 6668. The device of item 6645, further comprising a
polymer.
[7634] 6669. The device of item 6645, further comprising a
polymeric carrier.
[7635] 6670. The device of item 6645 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[7636] 6671. The device of item 6645 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[7637] 6672. The device of item 6645, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[7638] 6673. The device of item 6645, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[7639] 6674. The device of item 6645, further comprising a coating,
wherein the coating directly contacts the device.
[7640] 6675. The device of item 6645, further comprising a coating,
wherein the coating indirectly contacts the device.
[7641] 6676. The device of item 6645, further comprising a coating,
wherein the coating partially covers the device.
[7642] 6677. The device of item 6645, further comprising a coating,
wherein the coating completely covers the device.
[7643] 6678. The device of item 6645, further comprising a coating,
wherein the coating is a uniform coating.
[7644] 6679. The device of item 6645, further comprising a coating,
wherein the coating is a non-uniform coating.
[7645] 6680. The device of item 6645, further comprising a coating,
wherein the coating is a discontinuous coating.
[7646] 6681. The device of item 6645, further comprising a coating,
wherein the coating is a patterned coating.
[7647] 6682. The device of item 6645, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[7648] 6683. The device of item 6645, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[7649] 6684. The device of item 6645, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[7650] 6685. The device of item 6645, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[7651] 6686. The device of item 6645, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[7652] 6687. The device of item 6645, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[7653] 6688. The device of item 6645, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[7654] 6689. The device of item 6645, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[7655] 6690. The device of item 6645, further comprising a coating,
wherein the coating further comprises a polymer.
[7656] 6691. The device of item 6645, further comprising a first
coating having a first composition and the second coating having a
second composition.
[7657] 6692. The device of item 6645, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[7658] 6693. The device of item 6645, further comprising a
polymer.
[7659] 6694. The device of item 6645, further comprising a
polymeric carrier.
[7660] 6695. The device of item 6645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[7661] 6696. The device of item 6645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[7662] 6697. The device of item 6645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[7663] 6698. The device of item 6645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[7664] 6699. The device of item 6645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[7665] 6700. The device of item 6645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[7666] 6701. The device of item 6645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[7667] 6702. The device of item 6645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[7668] 6703. The device of item 6645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[7669] 6704. The device of item 6645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[7670] 6705. The device of item 6645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[7671] 6706. The device of item 6645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[7672] 6707. The device of item 6645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[7673] 6708. The device of item 6645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[7674] 6709. The device of item 6645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[7675] 6710. The device of item 6645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[7676] 6711. The device of item 6645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[7677] 6712. The device of item 6645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[7678] 6713. The device of item 6645, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[7679] 6714. The device of item 6645, further comprising a
lubricious coating.
[7680] 6715. The device of item 6645 wherein the fibrosing agent is
located within pores or holes of the device.
[7681] 6716. The device of item 6645 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[7682] 6717. The device of item 6645, further comprising a second
pharmaceutically active agent.
[7683] 6718. The device of item 6645, further comprising an
anti-inflammatory agent.
[7684] 6719. The device of item 6645, further comprising an agent
that inhibits infection.
[7685] 6720. The device of item 6645, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[7686] 6721. The device of item 6645, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[7687] 6722. The device of item 6645, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[7688] 6723. The device of item 6645, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[7689] 6724. The device of item 6645, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[7690] 6725. The device of item 6645, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[7691] 6726. The device of item 6645, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[7692] 6727. The device of item 6645, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[7693] 6728. The device of item 6645, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[7694] 6729. The device of item 6645, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[7695] 6730. The device of item 6645, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[7696] 6731. The device of item 6645, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[7697] 6732. The device of item 6645, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[7698] 6733. The device of item 6645, further comprising an
anti-thrombotic agent.
[7699] 6734. The device of item 6645, further comprising a
visualization agent.
[7700] 6735. The device of item 6645, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[7701] 6736. The device of item 6645, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[7702] 6737. The device of item 6645, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[7703] 6738. The device of item 6645, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[7704] 6739. The device of item 6645, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[7705] 6740. The device of item 6645, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[7706] 6741. The device of item 6645, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[7707] 6742. The device of item 6645, further comprising an
echogenic material.
[7708] 6743. The device of item 6645, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[7709] 6744. The device of item 6645 wherein the device is
sterile.
[7710] 6745. The device of item 6645 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[7711] 6746. The device of item 6645 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[7712] 6747. The device of item 6645 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[7713] 6748. The device of item 6645 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[7714] 6749. The device of item 6645 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[7715] 6750. The device of item 6645 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[7716] 6751. The device of item 6645 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[7717] 6752. The device of item 6645 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[7718] 6753. The device of item 6645 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[7719] 6754. The device of item 6645 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[7720] 6755. The device of item 6645 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[7721] 6756. The device of item 6645 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[7722] 6757. The device of item 6645 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[7723] 6758. The device of item 6645 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[7724] 6759. The device of item 6645 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[7725] 6760. The device of item 6645 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[7726] 6761. The device of item 6645 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[7727] 6762. The device of item 6645 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[7728] 6763. The device of item 6645 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[7729] 6764. The device of item 6645 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[7730] 6765. The device of item 6645 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[7731] 6766. The device of item 6645 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[7732] 6767. The device of item 6645 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[7733] 6768. The device of item 6645 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[7734] 6769. The device of item 6645 wherein the vascular occlusion
implant is expandable.
[7735] 6770. A medical device comprising a hernia mesh implant and
a fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
[7736] 6771. The device of item 6770 wherein the fibrosing agent
promotes regeneration.
[7737] 6772. The device of item 6770 wherein the fibrosing agent
promotes angiogenesis.
[7738] 6773. The device of item 6770 wherein the fibrosing agent
promotes fibroblast migration.
[7739] 6774. The device of item 6770 wherein the fibrosing agent
promotes fibroblast proliferation.
[7740] 6775. The device of item 6770 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[7741] 6776. The device of item 6770 wherein the fibrosing agent
promotes tissue remodeling.
[7742] 6777. The device of item 6770 wherein the fibrosing agent is
an arterial vessel wall irritant.
[7743] 6778. The device of item 6770 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[7744] 6779. The device of item 6770 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[7745] 6780. The device of item 6770 wherein the fibrosing agent is
or comprises silk.
[7746] 6781. The device of item 6770 wherein the fibrosing agent is
or comprises mineral particles.
[7747] 6782. The device of item 6770 wherein the fibrosing agent is
or comprises chitosan.
[7748] 6783. The device of item 6770 wherein the fibrosing agent is
or comprises polylysine.
[7749] 6784. The device of item 6770 wherein the fibrosing agent is
or comprises fibronectin.
[7750] 6785. The device of item 6770 wherein the fibrosing agent is
or comprises bleomycin.
[7751] 6786. The device of item 6770 wherein the fibrosing agent is
or comprises CTGF.
[7752] 6787. The device of item 6770 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[7753] 6788. The device of item 6770 wherein the fibrosing agent is
in the form of a particulate.
[7754] 6789. The device of item 6770 wherein the composition
further comprises an inflammatory cytokine.
[7755] 6790. The device of item 6770 wherein the composition
further comprises an agent that stimulates cell proliferation.
[7756] 6791. The device of item 6770 wherein the composition is in
the form of a gel, paste, or spray.
[7757] 6792. The device of item 6770 wherein the fibrosing agent is
in the form of tufts.
[7758] 6793. The device of item 6770, further comprising a
polymer.
[7759] 6794. The device of item 6770, further comprising a
polymeric carrier.
[7760] 6795. The device of item 6770 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[7761] 6796. The device of item 6770 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[7762] 6797. The device of item 6770, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[7763] 6798. The device of item 6770, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[7764] 6799. The device of item 6770, further comprising a coating,
wherein the coating directly contacts the device.
[7765] 6800. The device of item 6770, further comprising a coating,
wherein the coating indirectly contacts the device.
[7766] 6801. The device of item 6770, further comprising a coating,
wherein the coating partially covers the device.
[7767] 6802. The device of item 6770, further comprising a coating,
wherein the coating completely covers the device.
[7768] 6803. The device of item 6770, further comprising a coating,
wherein the coating is a uniform coating.
[7769] 6804. The device of item 6770, further comprising a coating,
wherein the coating is a non-uniform coating.
[7770] 6805. The device of item 6770, further comprising a coating,
wherein the coating is a discontinuous coating.
[7771] 6806. The device of item 6770, further comprising a coating,
wherein the coating is a patterned coating.
[7772] 6807. The device of item 6770, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[7773] 6808. The device of item 6770, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[7774] 6809. The device of item 6770, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[7775] 6810. The device of item 6770, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[7776] 6811. The device of item 6770, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[7777] 6812. The device of item 6770, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[7778] 6813. The device of item 6770, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[7779] 6814. The device of item 6770, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[7780] 6815. The device of item 6770, further comprising a coating,
wherein the coating further comprises a polymer.
[7781] 6816. The device of item 6770, further comprising a first
coating having a first composition and the second coating having a
second composition.
[7782] 6817. The device of item 6770, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[7783] 6818. The device of item 6770, further comprising a
polymer.
[7784] 6819. The device of item 6770, further comprising a
polymeric carrier.
[7785] 6820. The device of item 6770, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[7786] 6821. The device of item 6770, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[7787] 6822. The device of item 6770, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[7788] 6823. The device of item 6770, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[7789] 6824. The device of item 6770, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[7790] 6825. The device of item 6770, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[7791] 6826. The device of item 6770, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[7792] 6827. The device of item 6770, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[7793] 6828. The device of item 6770, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[7794] 6829. The device of item 6770, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[7795] 6830. The device of item 6770, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[7796] 6831. The device of item 6770, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[7797] 6832. The device of item 6770, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[7798] 6833. The device of item 6770, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[7799] 6834. The device of item 6770, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[7800] 6835. The device of item 6770, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[7801] 6836. The device of item 6770, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[7802] 6837. The device of item 6770, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[7803] 6838. The device of item 6770, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[7804] 6839. The device of item 6770, further comprising a
lubricious coating.
[7805] 6840. The device of item 6770 wherein the fibrosing agent is
located within pores or holes of the device.
[7806] 6841. The device of item 6770 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[7807] 6842. The device of item 6770, further comprising a second
pharmaceutically active agent.
[7808] 6843. The device of item 6770, further comprising an
anti-inflammatory agent.
[7809] 6844. The device of item 6770, further comprising an agent
that inhibits infection.
[7810] 6845. The device of item 6770, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[7811] 6846. The device of item 6770, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[7812] 6847. The device of item 6770, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[7813] 6848. The device of item 6770, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[7814] 6849. The device of item 6770, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[7815] 6850. The device of item 6770, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[7816] 6851. The device of item 6770, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[7817] 6852. The device of item 6770, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[7818] 6853. The device of item 6770, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[7819] 6854. The device of item 6770, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[7820] 6855. The device of item 6770, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[7821] 6856. The device of item 6770, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[7822] 6857. The device of item 6770, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[7823] 6858. The device of item 6770, further comprising an
anti-thrombotic agent.
[7824] 6859. The device of item 6770, further comprising a
visualization agent.
[7825] 6860. The device of item 6770, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[7826] 6861. The device of item 6770, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[7827] 6862. The device of item 6770, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[7828] 6863. The device of item 6770, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[7829] 6864. The device of item 6770, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[7830] 6865. The device of item 6770, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[7831] 6866. The device of item 6770, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[7832] 6867. The device of item 6770, further comprising an
echogenic material.
[7833] 6868. The device of item 6770, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[7834] 6869. The device of item 6770 wherein the device is
sterile.
[7835] 6870. The device of item 6770 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[7836] 6871. The device of item 6770 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[7837] 6872. The device of item 6770 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[7838] 6873. The device of item 6770 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[7839] 6874. The device of item 6770 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[7840] 6875. The device of item 6770 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[7841] 6876. The device of item 6770 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[7842] 6877. The device of item 6770 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[7843] 6878. The device of item 6770 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[7844] 6879. The device of item 6770 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[7845] 6880. The device of item 6770 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[7846] 6881. The device of item 6770 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[7847] 6882. The device of item 6770 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[7848] 6883. The device of item 6770 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[7849] 6884. The device of item 6770 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[7850] 6885. The device of item 6770 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[7851] 6886. The device of item 6770 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[7852] 6887. The device of item 6770 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[7853] 6888. The device of item 6770 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[7854] 6889. The device of item 6770 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[7855] 6890. The device of item 6770 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[7856] 6891. The device of item 6770 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[7857] 6892. The device of item 6770 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[7858] 6893. The device of item 6770 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[7859] 6894. The device of item 6770 wherein the hernia mesh
implant is expandable.
[7860] 6895. A medical device comprising a surgical film implant
and a fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
[7861] 6896. The device of item 6895 wherein the fibrosing agent
promotes regeneration.
[7862] 6897. The device of item 6895 wherein the fibrosing agent
promotes angiogenesis.
[7863] 6898. The device of item 6895 wherein the fibrosing agent
promotes fibroblast migration.
[7864] 6899. The device of item 6895 wherein the fibrosing agent
promotes fibroblast proliferation.
[7865] 6900. The device of item 6895 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[7866] 6901. The device of item 6895 wherein the fibrosing agent
promotes tissue remodeling.
[7867] 6902. The device of item 6895 wherein the fibrosing agent is
an arterial vessel wall irritant.
[7868] 6903. The device of item 6895 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[7869] 6904. The device of item 6895 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[7870] 6905. The device of item 6895 wherein the fibrosing agent is
or comprises silk.
[7871] 6906. The device of item 6895 wherein the fibrosing agent is
or comprises mineral particles.
[7872] 6907. The device of item 6895 wherein the fibrosing agent is
or comprises chitosan.
[7873] 6908. The device of item 6895 wherein the fibrosing agent is
or comprises polylysine.
[7874] 6909. The device of item 6895 wherein the fibrosing agent is
or comprises fibronectin.
[7875] 6910. The device of item 6895 wherein the fibrosing agent is
or comprises bleomycin.
[7876] 6911. The device of item 6895 wherein the fibrosing agent is
or comprises CTGF.
[7877] 6912. The device of item 6895 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[7878] 6913. The device of item 6895 wherein the fibrosing agent is
in the form of a particulate.
[7879] 6914. The device of item 6895 wherein the composition
further comprises an inflammatory cytokine.
[7880] 6915. The device of item 6895 wherein the composition
further comprises an agent that stimulates cell proliferation.
[7881] 6916. The device of item 6895 wherein the composition is in
the form of a gel, paste, or spray.
[7882] 6917. The device of item 6895 wherein the fibrosing agent is
in the form of tufts.
[7883] 6918. The device of item 6895, further comprising a
polymer.
[7884] 6919. The device of item 6895, further comprising a
polymeric carrier.
[7885] 6920. The device of item 6895 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[7886] 6921. The device of item 6895 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[7887] 6922. The device of item 6895, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[7888] 6923. The device of item 6895, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[7889] 6924. The device of item 6895, further comprising a coating,
wherein the coating directly contacts the device.
[7890] 6925. The device of item 6895, further comprising a coating,
wherein the coating indirectly contacts the device.
[7891] 6926. The device of item 6895, further comprising a coating,
wherein the coating partially covers the device.
[7892] 6927. The device of item 6895, further comprising a coating,
wherein the coating completely covers the device.
[7893] 6928. The device of item 6895, further comprising a coating,
wherein the coating is a uniform coating.
[7894] 6929. The device of item 6895, further comprising a coating,
wherein the coating is a non-uniform coating.
[7895] 6930. The device of item 6895, further comprising a coating,
wherein the coating is a discontinuous coating.
[7896] 6931. The device of item 6895, further comprising a coating,
wherein the coating is a patterned coating.
[7897] 6932. The device of item 6895, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[7898] 6933. The device of item 6895, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[7899] 6934. The device of item 6895, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[7900] 6935. The device of item 6895, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[7901] 6936. The device of item 6895, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[7902] 6937. The device of item 6895, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[7903] 6938. The device of item 6895, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[7904] 6939. The device of item 6895, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[7905] 6940. The device of item 6895, further comprising a coating,
wherein the coating further comprises a polymer.
[7906] 6941. The device of item 6895, further comprising a first
coating having a first composition and the second coating having a
second composition.
[7907] 6942. The device of item 6895, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[7908] 6943. The device of item 6895, further comprising a
polymer.
[7909] 6944. The device of item 6895, further comprising a
polymeric carrier.
[7910] 6945. The device of item 6895, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[7911] 6946. The device of item 6895, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[7912] 6947. The device of item 6895, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[7913] 6948. The device of item 6895, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[7914] 6949. The device of item 6895, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[7915] 6950. The device of item 6895, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[7916] 6951. The device of item 6895, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[7917] 6952. The device of item 6895, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[7918] 6953. The device of item 6895, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[7919] 6954. The device of item 6895, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[7920] 6955. The device of item 6895, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[7921] 6956. The device of item 6895, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[7922] 6957. The device of item 6895, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[7923] 6958. The device of item 6895, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[7924] 6959. The device of item 6895, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[7925] 6960. The device of item 6895, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[7926] 6961. The device of item 6895, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[7927] 6962. The device of item 6895, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[7928] 6963. The device of item 6895, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[7929] 6964. The device of item 6895, further comprising a
lubricious coating.
[7930] 6965. The device of item 6895 wherein the fibrosing agent is
located within pores or holes of the device.
[7931] 6966. The device of item 6895 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[7932] 6967. The device of item 6895, further comprising a second
pharmaceutically active agent.
[7933] 6968. The device of item 6895, further comprising an
anti-inflammatory agent.
[7934] 6969. The device of item 6895, further comprising an agent
that inhibits infection.
[7935] 6970. The device of item 6895, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[7936] 6971. The device of item 6895, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[7937] 6972. The device of item 6895, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[7938] 6973. The device of item 6895, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[7939] 6974. The device of item 6895, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[7940] 6975. The device of item 6895, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[7941] 6976. The device of item 6895, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[7942] 6977. The device of item 6895, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[7943] 6978. The device of item 6895, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[7944] 6979. The device of item 6895, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[7945] 6980. The device of item 6895, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[7946] 6981. The device of item 6895, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[7947] 6982. The device of item 6895, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[7948] 6983. The device of item 6895, further comprising an
anti-thrombotic agent.
[7949] 6984. The device of item 6895, further comprising a
visualization agent.
[7950] 6985. The device of item 6895, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[7951] 6986. The device of item 6895, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[7952] 6987. The device of item 6895, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[7953] 6988. The device of item 6895, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[7954] 6989. The device of item 6895, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[7955] 6990. The device of item 6895, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[7956] 6991. The device of item 6895, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[7957] 6992. The device of item 6895, further comprising an
echogenic material.
[7958] 6993. The device of item 6895, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[7959] 6994. The device of item 6895 wherein the device is
sterile.
[7960] 6995. The device of item 6895 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[7961] 6996. The device of item 6895 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[7962] 6997. The device of item 6895 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[7963] 6998. The device of item 6895 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[7964] 6999. The device of item 6895 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[7965] 7000. The device of item 6895 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[7966] 7001. The device of item 6895 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[7967] 7002. The device of item 6895 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[7968] 7003. The device of item 6895 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[7969] 7004. The device of item 6895 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[7970] 7005. The device of item 6895 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[7971] 7006. The device of item 6895 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[7972] 7007. The device of item 6895 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[7973] 7008. The device of item 6895 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[7974] 7009. The device of item 6895 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[7975] 7010. The device of item 6895 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[7976] 7011. The device of item 6895 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[7977] 7012. The device of item 6895 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[7978] 7013. The device of item 6895 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[7979] 7014. The device of item 6895 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[7980] 7015. The device of item 6895 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[7981] 7016. The device of item 6895 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[7982] 7017. The device of item 6895 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[7983] 7018. The device of item 6895 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[7984] 7019. A medical device comprising a spinal fusion device and
a fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
[7985] 7020. The device of item 7019 wherein the fibrosing agent
promotes regeneration.
[7986] 7021. The device of item 7019 wherein the fibrosing agent
promotes angiogenesis.
[7987] 7022. The device of item 7019 wherein the fibrosing agent
promotes fibroblast migration.
[7988] 7023. The device of item 7019 wherein the fibrosing agent
promotes fibroblast proliferation.
[7989] 7024. The device of item 7019 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[7990] 7025. The device of item 7019 wherein the fibrosing agent
promotes tissue remodeling.
[7991] 7026. The device of item 7019 wherein the fibrosing agent is
an arterial vessel wall irritant.
[7992] 7027. The device of item 7019 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[7993] 7028. The device of item 7019 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[7994] 7029. The device of item 7019 wherein the fibrosing agent is
or comprises silk.
[7995] 7030. The device of item 7019 wherein the fibrosing agent is
or comprises mineral particles.
[7996] 7031. The device of item 7019 wherein the fibrosing agent is
or comprises chitosan.
[7997] 7032. The device of item 7019 wherein the fibrosing agent is
or comprises polylysine.
[7998] 7033. The device of item 7019 wherein the fibrosing agent is
or comprises fibronectin.
[7999] 7034. The device of item 7019 wherein the fibrosing agent is
or comprises bleomycin.
[8000] 7035. The device of item 7019 wherein the fibrosing agent is
or comprises CTGF.
[8001] 7036. The device of item 7019 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[8002] 7037. The device of item 7019 wherein the fibrosing agent is
in the form of a particulate.
[8003] 7038. The device of item 7019 wherein the composition
further comprises an inflammatory cytokine.
[8004] 7039. The device of item 7019 wherein the composition
further comprises an agent that stimulates cell proliferation.
[8005] 7040. The device of item 7019 wherein the composition is in
the form of a gel, paste, or spray.
[8006] 7041. The device of item 7019 wherein the fibrosing agent is
in the form of tufts.
[8007] 7042. The device of item 7019, further comprising a
polymer.
[8008] 7043. The device of item 7019, further comprising a
polymeric carrier.
[8009] 7044. The device of item 7019 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[8010] 7045. The device of item 7019 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[8011] 7046. The device of item 7019, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[8012] 7047. The device of item 7019, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[8013] 7048. The device of item 7019, further comprising a coating,
wherein the coating directly contacts the device.
[8014] 7049. The device of item 7019, further comprising a coating,
wherein the coating indirectly contacts the device.
[8015] 7050. The device of item 7019, further comprising a coating,
wherein the coating partially covers the device.
[8016] 7051. The device of item 7019, further comprising a coating,
wherein the coating completely covers the device.
[8017] 7052. The device of item 7019, further comprising a coating,
wherein the coating is a uniform coating.
[8018] 7053. The device of item 7019, further comprising a coating,
wherein the coating is a non-uniform coating.
[8019] 7054. The device of item 7019, further comprising a coating,
wherein the coating is a discontinuous coating.
[8020] 7055. The device of item 7019, further comprising a coating,
wherein the coating is a patterned coating.
[8021] 7056. The device of item 7019, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[8022] 7057. The device of item 7019, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[8023] 7058. The device of item 7019, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[8024] 7059. The device of item 7019, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[8025] 7060. The device of item 7019, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[8026] 7061. The device of item 7019, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[8027] 7062. The device of item 7019, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[8028] 7063. The device of item 7019, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[8029] 7064. The device of item 7019, further comprising a coating,
wherein the coating further comprises a polymer.
[8030] 7065. The device of item 7019, further comprising a first
coating having a first composition and the second coating having a
second composition.
[8031] 7066. The device of item 7019, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[8032] 7067. The device of item 7019, further comprising a
polymer.
[8033] 7068. The device of item 7019, further comprising a
polymeric carrier.
[8034] 7069. The device of item 7019, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[8035] 7070. The device of item 7019, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[8036] 7071. The device of item 7019, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[8037] 7072. The device of item 7019, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[8038] 7073. The device of item 7019, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[8039] 7074. The device of item 7019, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[8040] 7075. The device of item 7019, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[8041] 7076. The device of item 7019, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[8042] 7077. The device of item 7019, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[8043] 7078. The device of item 7019, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[8044] 7079. The device of item 7019, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[8045] 7080. The device of item 7019, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[8046] 7081. The device of item 7019, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[8047] 7082. The device of item 7019, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[8048] 7083. The device of item 7019, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[8049] 7084. The device of item 7019, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[8050] 7085. The device of item 7019, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[8051] 7086. The device of item 7019, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[8052] 7087. The device of item 7019, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[8053] 7088. The device of item 7019, further comprising a
lubricious coating.
[8054] 7089. The device of item 7019 wherein the fibrosing agent is
located within pores or holes of the device.
[8055] 7090. The device of item 7019 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[8056] 7091. The device of item 7019, further comprising a second
pharmaceutically active agent.
[8057] 7092. The device of item 7019, further comprising an
anti-inflammatory agent.
[8058] 7093. The device of item 7019, further comprising an agent
that inhibits infection.
[8059] 7094. The device of item 7019, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[8060] 7095. The device of item 7019, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[8061] 7096. The device of item 7019, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[8062] 7097. The device of item 7019, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[8063] 7098. The device of item 7019, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[8064] 7099. The device of item 7019, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[8065] 7100. The device of item 7019, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[8066] 7101. The device of item 7019, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[8067] 7102. The device of item 7019, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[8068] 7103. The device of item 7019, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[8069] 7104. The device of item 7019, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[8070] 7105. The device of item 7019, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[8071] 7106. The device of item 7019, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[8072] 7107. The device of item 7019, further comprising an
anti-thrombotic agent.
[8073] 7108. The device of item 7019, further comprising a
visualization agent.
[8074] 7109. The device of item 7019, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[8075] 7110. The device of item 7019, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[8076] 7111. The device of item 7019, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[8077] 7112. The device of item 7019, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[8078] 7113. The device of item 7019, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[8079] 7114. The device of item 7019, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[8080] 7115. The device of item 7019, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[8081] 7116. The device of item 7019, further comprising an
echogenic material.
[8082] 7117. The device of item 7019, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[8083] 7118. The device of item 7019 wherein the device is
sterile.
[8084] 7119. The device of item 7019 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[8085] 7120. The device of item 7019 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[8086] 7121. The device of item 7019 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[8087] 7122. The device of item 7019 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[8088] 7123. The device of item 7019 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[8089] 7124. The device of item 7019 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[8090] 7125. The device of item 7019 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[8091] 7126. The device of item 7019 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[8092] 7127. The device of item 7019 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[8093] 7128. The device of item 7019 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[8094] 7129. The device of item 7019 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[8095] 7130. The device of item 7019 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[8096] 7131. The device of item 7019 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[8097] 7132. The device of item 7019 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[8098] 7133. The device of item 7019 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[8099] 7134. The device of item 7019 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[8100] 7135. The device of item 7019 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[8101] 7136. The device of item 7019 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[8102] 7137. The device of item 7019 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[8103] 7138. The device of item 7019 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[8104] 7139. The device of item 7019 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[8105] 7140. The device of item 7019 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[8106] 7141. The device of item 7019 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[8107] 7142. The device of item 7019 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[8108] 7143. The device of item 7019 wherein the spinal fusion
device is a fusion basket.
[8109] 7144. The device of item 7019 wherein the spinal fusion
device is a fusion casge apparatus.
[8110] 7145. The device of item 7019 wherein the spinal fusion
device is an interbody case.
[8111] 7146. The device of item 7019 wherein the spinal fusion
device is an interbody implant.
[8112] 7147. The device of item 7019 wherein the spinal fusion
device is a fusion cage anchoring device.
[8113] 7148. The device of item 7019 wherein the spinal fusion
device is a fusion stabilization chamber.
[8114] 7149. The device of item 7019 wherein the spinal fusion
device is a fusion cage anchoring plate.
[8115] 7150. The device of item 7019 wherein the spinal fusion
device is a bone fixation device.
[8116] 7151. The device of item 7019 wherein the spinal fusion
device is an anchoring bone plate.
[8117] 7152. The device of item 7019 wherein the spinal fusion
device is an anchoring bone screw.
[8118] 7153. The device of item 7019 wherein the spinal fusion
device is a tissue filler.
[8119] 7154. The device of item 7019 wherein the spinal fusion
device is a bone cement.
[8120] 7155. The device of item 7019 wherein the spinal fusion
device is an allograft material.
[8121] 7156. The device of item 7019 wherein the spinal fusion
device is an autograft material.
[8122] 7157. The device of item 7019 wherein the spinal fusion
device is a collagen implant.
[8123] 7158. The device of item 7019 wherein the spinal fusion
device is injectable.
[8124] 7159. A medical device comprising a septal occlusion patch
and a fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
[8125] 7160. The device of item 7159 wherein the fibrosing agent
promotes regeneration.
[8126] 7161. The device of item 7159 wherein the fibrosing agent
promotes angiogenesis.
[8127] 7162. The device of item 7159 wherein the fibrosing agent
promotes fibroblast migration.
[8128] 7163. The device of item 7159 wherein the fibrosing agent
promotes fibroblast proliferation.
[8129] 7164. The device of item 7159 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[8130] 7165. The device of item 7159 wherein the fibrosing agent
promotes tissue remodeling.
[8131] 7166. The device of item 7159 wherein the fibrosing agent is
an arterial vessel wall irritant.
[8132] 7167. The device of item 7159 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[8133] 7168. The device of item 7159 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[8134] 7169. The device of item 7159 wherein the fibrosing agent is
or comprises silk.
[8135] 7170. The device of item 7159 wherein the fibrosing agent is
or comprises mineral particles.
[8136] 7171. The device of item 7159 wherein the fibrosing agent is
or comprises chitosan.
[8137] 7172. The device of item 7159 wherein the fibrosing agent is
or comprises polylysine.
[8138] 7173. The device of item 7159 wherein the fibrosing agent is
or comprises fibronectin.
[8139] 7174. The device of item 7159 wherein the fibrosing agent is
or comprises bleomycin.
[8140] 7175. The device of item 7159 wherein the fibrosing agent is
or comprises CTGF.
[8141] 7176. The device of item 7159 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[8142] 7177. The device of item 7159 wherein the fibrosing agent is
in the form of a particulate.
[8143] 7178. The device of item 7159 wherein the composition
further comprises an inflammatory cytokine.
[8144] 7179. The device of item 7159 wherein the composition
further comprises an agent that stimulates cell proliferation.
[8145] 7180. The device of item 7159 wherein the composition is in
the form of a gel, paste, or spray.
[8146] 7181. The device of item 7159 wherein the fibrosing agent is
in the form of tufts.
[8147] 7182. The device of item 7159, further comprising a
polymer.
[8148] 7183. The device of item 7159, further comprising a
polymeric carrier.
[8149] 7184. The device of item 7159 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[8150] 7185. The device of item 7159 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[8151] 7186. The device of item 7159, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[8152] 7187. The device of item 7159, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[8153] 7188. The device of item 7159, further comprising a coating,
wherein the coating directly contacts the device.
[8154] 7189. The device of item 7159, further comprising a coating,
wherein the coating indirectly contacts the device.
[8155] 7190. The device of item 7159, further comprising a coating,
wherein the coating partially covers the device.
[8156] 7191. The device of item 7159, further comprising a coating,
wherein the coating completely covers the device.
[8157] 7192. The device of item 7159, further comprising a coating,
wherein the coating is a uniform coating.
[8158] 7193. The device of item 7159, further comprising a coating,
wherein the coating is a non-uniform coating.
[8159] 7194. The device of item 7159, further comprising a coating,
wherein the coating is a discontinuous coating.
[8160] 7195. The device of item 7159, further comprising a coating,
wherein the coating is a patterned coating.
[8161] 7196. The device of item 7159, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[8162] 7197. The device of item 7159, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[8163] 7198. The device of item 7159, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[8164] 7199. The device of item 7159, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[8165] 7200. The device of item 7159, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[8166] 7201. The device of item 7159, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[8167] 7202. The device of item 7159, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[8168] 7203. The device of item 7159, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[8169] 7204. The device of item 7159, further comprising a coating,
wherein the coating further comprises a polymer.
[8170] 7205. The device of item 7159, further comprising a first
coating having a first composition and the second coating having a
second composition.
[8171] 7206. The device of item 7159, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[8172] 7207. The device of item 7159, further comprising a
polymer.
[8173] 7208. The device of item 7159, further comprising a
polymeric carrier.
[8174] 7209. The device of item 7159, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[8175] 7210. The device of item 7159, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[8176] 7211. The device of item 7159, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[8177] 7212. The device of item 7159, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[8178] 7213. The device of item 7159, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[8179] 7214. The device of item 7159, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[8180] 7215. The device of item 7159, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[8181] 7216. The device of item 7159, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[8182] 7217. The device of item 7159, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[8183] 7218. The device of item 7159, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[8184] 7219. The device of item 7159, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[8185] 7220. The device of item 7159, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[8186] 7221. The device of item 7159, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[8187] 7222. The device of item 7159, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[8188] 7223. The device of item 7159, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[8189] 7224. The device of item 7159, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[8190] 7225. The device of item 7159, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[8191] 7226. The device of item 7159, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[8192] 7227. The device of item 7159, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[8193] 7228. The device of item 7159, further comprising a
lubricious coating.
[8194] 7229. The device of item 7159 wherein the fibrosing agent is
located within pores or holes of the device.
[8195] 7230. The device of item 7159 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[8196] 7231. The device of item 7159, further comprising a second
pharmaceutically active agent.
[8197] 7232. The device of item 7159, further comprising an
anti-inflammatory agent.
[8198] 7233. The device of item 7159, further comprising an agent
that inhibits infection.
[8199] 7234. The device of item 7159, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[8200] 7235. The device of item 7159, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[8201] 7236. The device of item 7159, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[8202] 7237. The device of item 7159, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[8203] 7238. The device of item 7159, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[8204] 7239. The device of item 7159, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[8205] 7240. The device of item 7159, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[8206] 7241. The device of item 7159, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[8207] 7242. The device of item 7159, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[8208] 7243. The device of item 7159, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[8209] 7244. The device of item 7159, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[8210] 7245. The device of item 7159, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[8211] 7246. The device of item 7159, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[8212] 7247. The device of item 7159, further comprising an
anti-thrombotic agent.
[8213] 7248. The device of item 7159, further comprising a
visualization agent.
[8214] 7249. The device of item 7159, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[8215] 7250. The device of item 7159, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[8216] 7251. The device of item 7159, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[8217] 7252. The device of item 7159, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[8218] 7253. The device of item 7159, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[8219] 7254. The device of item 7159, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[8220] 7255. The device of item 7159, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[8221] 7256. The device of item 7159, further comprising an
echogenic material.
[8222] 7257. The device of item 7159, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[8223] 7258. The device of item 7159 wherein the device is
sterile.
[8224] 7259. The device of item 7159 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[8225] 7260. The device of item 7159 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[8226] 7261. The device of item 7159 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[8227] 7262. The device of item 7159 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[8228] 7263. The device of item 7159 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[8229] 7264. The device of item 7159 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[8230] 7265. The device of item 7159 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[8231] 7266. The device of item 7159 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[8232] 7267. The device of item 7159 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[8233] 7268. The device of item 7159 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[8234] 7269. The device of item 7159 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[8235] 7270. The device of item 7159 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[8236] 7271. The device of item 7159 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[8237] 7272. The device of item 7159 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[8238] 7273. The device of item 7159 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[8239] 7274. The device of item 7159 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[8240] 7275. The device of item 7159 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[8241] 7276. The device of item 7159 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[8242] 7277. The device of item 7159 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[8243] 7278. The device of item 7159 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[8244] 7279. The device of item 7159 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[8245] 7280. The device of item 7159 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[8246] 7281. The device of item 7159 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[8247] 7282. The device of item 7159 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[8248] 7283. The device of item 7159 wherein the septal occlusion
patch is a septal closure device.
[8249] 7284. The device of item 7159 wherein the septal occlusion
patch is a shunt closure device.
[8250] 7285. The device of item 7159 wherein the septal occlusion
patch is an intracardic occluder.
[8251] 7286. The device of item 7159 wherein the septal occlusion
patch is an occluding disk.
[8252] 7287. The device of item 7159 wherein the septal occlusion
patch is a defect occluding system.
[8253] 7288. The device of item 7159 wherein the septal occlusion
patch is an intravascular shunt device.
[8254] 7289. A medical device comprising an endoluminal fasterner
and a fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
[8255] 7290. The device of item 7289 wherein the fibrosing agent
promotes regeneration.
[8256] 7291. The device of item 7289 wherein the fibrosing agent
promotes angiogenesis.
[8257] 7292. The device of item 7289 wherein the fibrosing agent
promotes fibroblast migration.
[8258] 7293. The device of item 7289 wherein the fibrosing agent
promotes fibroblast proliferation.
[8259] 7294. The device of item 7289 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[8260] 7295. The device of item 7289 wherein the fibrosing agent
promotes tissue remodeling.
[8261] 7296. The device of item 7289 wherein the fibrosing agent is
an arterial vessel wall irritant.
[8262] 7297. The device of item 7289 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[8263] 7298. The device of item 7289 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[8264] 7299. The device of item 7289 wherein the fibrosing agent is
or comprises silk.
[8265] 7300. The device of item 7289 wherein the fibrosing agent is
or comprises mineral particles.
[8266] 7301. The device of item 7289 wherein the fibrosing agent is
or comprises chitosan.
[8267] 7302. The device of item 7289 wherein the fibrosing agent is
or comprises polylysine.
[8268] 7303. The device of item 7289 wherein the fibrosing agent is
or comprises fibronectin.
[8269] 7304. The device of item 7289 wherein the fibrosing agent is
or comprises bleomycin.
[8270] 7305. The device of item 7289 wherein the fibrosing agent is
or comprises CTGF.
[8271] 7306. The device of item 7289 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[8272] 7307. The device of item 7289 wherein the fibrosing agent is
in the form of a particulate.
[8273] 7308. The device of item 7289 wherein the composition
further comprises an inflammatory cytokine.
[8274] 7309. The device of item 7289 wherein the composition
further comprises an agent that stimulates cell proliferation.
[8275] 7310. The device of item 7289 wherein the composition is in
the form of a gel, paste, or spray.
[8276] 7311. The device of item 7289 wherein the fibrosing agent is
in the form of tufts.
[8277] 7312. The device of item 7289, further comprising a
polymer.
[8278] 7313. The device of item 7289, further comprising a
polymeric carrier.
[8279] 7314. The device of item 7289 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[8280] 7315. The device of item 7289 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[8281] 7316. The device of item 7289, further comprising a coating,
wherein the coating comprises the fibrosing agent.
[8282] 7317. The device of item 7289, further comprising a coating,
wherein the coating is disposed on a surface of the device.
[8283] 7318. The device of item 7289, further comprising a coating,
wherein the coating directly contacts the device.
[8284] 7319. The device of item 7289, further comprising a coating,
wherein the coating indirectly contacts the device.
[8285] 7320. The device of item 7289, further comprising a coating,
wherein the coating partially covers the device.
[8286] 7321. The device of item 7289, further comprising a coating,
wherein the coating completely covers the device.
[8287] 7322. The device of item 7289, further comprising a coating,
wherein the coating is a uniform coating.
[8288] 7323. The device of item 7289, further comprising a coating,
wherein the coating is a non-uniform coating.
[8289] 7324. The device of item 7289, further comprising a coating,
wherein the coating is a discontinuous coating.
[8290] 7325. The device of item 7289, further comprising a coating,
wherein the coating is a patterned coating.
[8291] 7326. The device of item 7289, further comprising a coating,
wherein the coating has a thickness of 100 .mu.m or less.
[8292] 7327. The device of item 7289, further comprising a coating,
wherein the coating has a thickness of 10 .mu.m or less.
[8293] 7328. The device of item 7289, further comprising a coating,
wherein the coating adheres to the surface of the device upon
deployment of the device.
[8294] 7329. The device of item 7289, further comprising a coating,
wherein the coating is stable at room temperature for a period of 1
year.
[8295] 7330. The device of item 7289, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 0.0001% to about 1% by weight.
[8296] 7331. The device of item 7289, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 1% to about 10% by weight.
[8297] 7332. The device of item 7289, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 10% to about 25% by weight.
[8298] 7333. The device of item 7289, further comprising a coating,
wherein the fibrosing agent is present in the coating in an amount
ranging between about 25% to about 70% by weight.
[8299] 7334. The device of item 7289, further comprising a coating,
wherein the coating further comprises a polymer.
[8300] 7335. The device of item 7289, further comprising a first
coating having a first composition and the second coating having a
second composition.
[8301] 7336. The device of item 7289, further comprising a first
coating having a first composition and the second coating having a
second composition, wherein the first composition and the second
composition are different.
[8302] 7337. The device of item 7289, further comprising a
polymer.
[8303] 7338. The device of item 7289, further comprising a
polymeric carrier.
[8304] 7339. The device of item 7289, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
copolymer.
[8305] 7340. The device of item 7289, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a block
copolymer.
[8306] 7341. The device of item 7289, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a random
copolymer.
[8307] 7342. The device of item 7289, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
biodegradable polymer.
[8308] 7343. The device of item 7289, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-biodegradable polymer.
[8309] 7344. The device of item 7289, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophilic polymer.
[8310] 7345. The device of item 7289, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrophobic polymer.
[8311] 7346. The device of item 7289, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophilic domains.
[8312] 7347. The device of item 7289, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
polymer having hydrophobic domains.
[8313] 7348. The device of item 7289, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
non-conductive polymer.
[8314] 7349. The device of item 7289, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
elastomer.
[8315] 7350. The device of item 7289, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrogel.
[8316] 7351. The device of item 7289, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
silicone polymer.
[8317] 7352. The device of item 7289, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
hydrocarbon polymer.
[8318] 7353. The device of item 7289, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
styrene-derived polymer.
[8319] 7354. The device of item 7289, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
butadiene polymer.
[8320] 7355. The device of item 7289, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
macromer.
[8321] 7356. The device of item 7289, further comprising a
polymeric carrier, wherein the polymeric carrier comprises a
poly(ethylene glycol) polymer.
[8322] 7357. The device of item 7289, further comprising a
polymeric carrier, wherein the polymeric carrier comprises an
amorphous polymer.
[8323] 7358. The device of item 7289, further comprising a
lubricious coating.
[8324] 7359. The device of item 7289 wherein the fibrosing agent is
located within pores or holes of the device.
[8325] 7360. The device of item 7289 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[8326] 7361. The device of item 7289, further comprising a second
pharmaceutically active agent.
[8327] 7362. The device of item 7289, further comprising an
anti-inflammatory agent.
[8328] 7363. The device of item 7289, further comprising an agent
that inhibits infection.
[8329] 7364. The device of item 7289, further comprising an agent
that inhibits infection, wherein the agent is an anthracycline.
[8330] 7365. The device of item 7289, further comprising an agent
that inhibits infection, wherein the agent is doxorubicin.
[8331] 7366. The device of item 7289, further comprising an agent
that inhibits infection, wherein the agent is mitoxantrone.
[8332] 7367. The device of item 7289, further comprising an agent
that inhibits infection, wherein the agent is a
fluoropyrimidine.
[8333] 7368. The device of item 7289, further comprising an agent
that inhibits infection, wherein the agent is 5-fluorouracil
(5-FU).
[8334] 7369. The device of item 7289, further comprising an agent
that inhibits infection, wherein the agent is a folic acid
antagonist.
[8335] 7370. The device of item 7289, further comprising an agent
that inhibits infection, wherein the agent is methotrexate.
[8336] 7371. The device of item 7289, further comprising an agent
that inhibits infection, wherein the agent is a podophylotoxin.
[8337] 7372. The device of item 7289, further comprising an agent
that inhibits infection, wherein the agent is etoposide.
[8338] 7373. The device of item 7289, further comprising an agent
that inhibits infection, wherein the agent is a camptothecin.
[8339] 7374. The device of item 7289, further comprising an agent
that inhibits infection, wherein the agent is a hydroxyurea.
[8340] 7375. The device of item 7289, further comprising an agent
that inhibits infection, wherein the agent is a platinum
complex.
[8341] 7376. The device of item 7289, further comprising an agent
that inhibits infection, wherein the agent is cisplatin.
[8342] 7377. The device of item 7289, further comprising an
anti-thrombotic agent.
[8343] 7378. The device of item 7289, further comprising a
visualization agent.
[8344] 7379. The device of item 7289, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises a
metal, a halogenated compound, or a barium containing compound.
[8345] 7380. The device of item 7289, further comprising a
visualization agent, wherein the visualization agent is a
radiopaque material, wherein the radiopaque material comprises
barium, tantalum, or technetium.
[8346] 7381. The device of item 7289, further comprising a
visualization agent, wherein the visualization agent is a MRI
responsive material.
[8347] 7382. The device of item 7289, further comprising a
visualization agent, wherein the visualization agent comprises a
gadolinium chelate.
[8348] 7383. The device of item 7289, further comprising a
visualization agent, wherein the visualization agent comprises
iron, magnesium, manganese, copper, or chromium.
[8349] 7384. The device of item 7289, further comprising a
visualization agent, wherein the visualization agent comprises an
iron oxide compound.
[8350] 7385. The device of item 7289, further comprising a
visualization agent, wherein the visualization agent comprises a
dye, pigment, or colorant.
[8351] 7386. The device of item 7289, further comprising an
echogenic material.
[8352] 7387. The device of item 7289, further comprising an
echogenic material, wherein the echogenic material is in the form
of a coating.
[8353] 7388. The device of item 7289 wherein the device is
sterile.
[8354] 7389. The device of item 7289 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[8355] 7390. The device of item 7289 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[8356] 7391. The device of item 7289 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[8357] 7392. The device of item 7289 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[8358] 7393. The device of item 7289 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[8359] 7394. The device of item 7289 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[8360] 7395. The device of item 7289 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[8361] 7396. The device of item 7289 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[8362] 7397. The device of item 7289 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[8363] 7398. The device of item 7289 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[8364] 7399. The device of item 7289 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[8365] 7400. The device of item 7289 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[8366] 7401. The device of item 7289 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[8367] 7402. The device of item 7289 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[8368] 7403. The device of item 7289 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[8369] 7404. The device of item 7289 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[8370] 7405. The device of item 7289 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[8371] 7406. The device of item 7289 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[8372] 7407. The device of item 7289 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[8373] 7408. The device of item 7289 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[8374] 7409. The device of item 7289 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[8375] 7410. The device of item 7289 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[8376] 7411. The device of item 7289 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[8377] 7412. The device of item 7289 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[8378] 7413. A method of making an injectable composition
comprising combining a fibrosing agent and a bulking agent.
[8379] 7414. The method of item 7413 wherein the fibrosing agent
promotes fibrosis and promotes regeneration.
[8380] 7415. The method of item 7413 wherein the fibrosing agent
promotes angiogenesis.
[8381] 7416. The method of item 7413 wherein the fibrosing agent
promotes fibroblast migration.
[8382] 7417. The method of item 7413 wherein the fibrosing agent
promotes fibroblast proliferation.
[8383] 7418. The method of item 7413 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[8384] 7419. The method of item 7413 wherein the fibrosing agent
promotes tissue remodeling.
[8385] 7420. The method of item 7413 wherein the fibrosing agent is
or comprises an arterial vessel wall irritant.
[8386] 7421. The method of item 7413 wherein the fibrosing agent is
or comprises silk.
[8387] 7422. The method of item 7413 wherein the fibrosing agent is
or comprises silkworm silk.
[8388] 7423. The method of item 7413 wherein the fibrosing agent is
or comprises spider silk.
[8389] 7424. The method of item 7413 wherein the fibrosing agent is
or comprises recombinant silk.
[8390] 7425. The method of item 7413 wherein the fibrosing agent is
or comprises raw silk.
[8391] 7426. The method of item 7413 wherein the fibrosing agent is
or comprises hydrolyzed silk.
[8392] 7427. The method of item 7413 wherein the fibrosing agent is
or comprises acid-treated silk.
[8393] 7428. The method of item 7413 wherein the fibrosing agent is
or comprises acylated silk.
[8394] 7429. The method of item 7413 wherein the fibrosing agent is
in the form of strands.
[8395] 7430. The method of item 7413 wherein the fibrosing agent is
in the form of tufts.
[8396] 7431. The method of item 7413 wherein the fibrosing agent is
in the form of microparticulates.
[8397] 7432. The method of item 7413 wherein the fibrosing agent is
or comprises mineral particles.
[8398] 7433. The method of item 7413 wherein the fibrosing agent is
or comprises talc.
[8399] 7434. The method of item 7413 wherein the fibrosing agent is
or comprises chitosan.
[8400] 7435. The method of item 7413 wherein the fibrosing agent is
or comprises polylysine.
[8401] 7436. The method of item 7413 wherein the fibrosing agent is
or comprises fibronectin.
[8402] 7437. The method of item 7413 wherein the fibrosing agent is
or comprises bleomycin.
[8403] 7438. The method of item 7413 wherein the fibrosing agent is
or comprises CTGF.
[8404] 7439. The method of item 7413 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[8405] 7440. The method of item 7439 wherein the thread is
biodegradable.
[8406] 7441. The method of item 7440 wherein the biodegradable
thread comprises a material selected from the group consisting of
polyester, polyanhydride, poly(anhydride ester), poly(ester-amide),
poly(ester-urea), polyorthoester, polyphosphoester,
polyphosphazine, polycyanoacrylate, collagen, chitosan, hyaluronic
acid, chromic cat gut, alginate, starch, cellulose and cellulose
ester.
[8407] 7442. The method of item 7439 wherein the thread is
non-biodegradable.
[8408] 7443. The method of item 7442 wherein the
non-non-bioderadable thread comprises a material selected from the
group consisting of polyester, polyurethane, silicone,
polyethylene, polypropylene, polystyrene, polyacrylate,
polymethacrylate, and silk.
[8409] 7444. The method of item 7439 wherein the thread is coated
with a polymer.
[8410] 7445. The method of item 7439 wherein the thread is coated
with a pharmaceutical agent that induces a fibrotic response in the
patient.
[8411] 7446. The method of item 7439 wherein the thread is coated
with a pharmaceutical agent that induces an osteogenic response in
the patient.
[8412] 7447. The method of item 7413 wherein the fibrosing agent is
in the form of a particulate.
[8413] 7448. The method of item 7447 wherein the particulate is a
biodegradable particulate.
[8414] 7449. The method of item 7448 wherein the biodegradable
particulate comprises a material selected from the group consisting
of polyester, polyanhydride, poly(anhydride ester),
poly(ester-amide), poly(ester-urea), polyorthoester,
polyphosphoester, polyphosphazine, polycyanoacrylate, collagen,
chitosan, hyaluronic acid, chromic cat gut, alginate, starch,
cellulose and cellulose ester.
[8415] 7450. The method of item 7447 wherein the particulate is
non-biodegradable.
[8416] 7451. The method of item 7450 wherein the non-biodegradable
particulate comprises a material selected from the group consisting
of polyester, polyurethane, silicone, polyethylene, polypropylene,
polystyrene, polyacrylate, polymethacrylate, and silk.
[8417] 7452. The method of item 7447 wherein the particulate is a
particulate form of a member selected from the group consisting of
silk, talc, starch, glass, silicate, silica, calcium phosphate,
calcium sulfate, calcium carbonate, hydroxyapatite, synthetic
mineral, polymethylmethacrylate, silver nitrate, ceramic and other
inorganic particles.
[8418] 7453. The method of item 7447 wherein the particulate is
coated with a polymer.
[8419] 7454. The method of item 7447 wherein the particulate is
coated with a pharmaceutical agent that induces a fibrotic response
in the patient.
[8420] 7455. The method of item 7447 wherein the particulate is
coated with a member selected from the group consisting of silk,
talc, starch, glass, silicate, silica, calcium phosphate, calcium
sulfate, calcium carbonate, hydroxyapatite, synthetic mineral,
polymethylmethacrylate, silver nitrate, ceramic and other inorganic
particles.
[8421] 7456. The method of item 7447 wherein the particulate is
coated with a pharmaceutical agent that induces an osteogenic
response in the patient.
[8422] 7457. The method of item 7413 wherein the composition
further comprises an agent that promotes bone growth.
[8423] 7458. The method of item 7457 wherein the agent that
promotes bone growth is a bone morphogenic protein.
[8424] 7459. The method of item 7457 wherein the agent that
promotes bone growth is an osteogenic growth factor.
[8425] 7460. The method of item 7459 wherein the osteogenic growth
factor is selected from transforming growth factor,
platelet-derived growth factor, and fibroblast growth factor.
[8426] 7461. The method of item 7413 wherein the bulking agent
comprises collagen or crosslinked collagen.
[8427] 7462. The method of item 7413 wherein the bulking agent
comprises hydroxya patite.
[8428] 7463. The method of item 7413 wherein the bulking agent
comprises micronized alloderm acellular matrix.
[8429] 7464. The method of item 7413 wherein the bulking agent
comprises hyaluronic acid.
[8430] 7465. The method of item 7413 wherein the bulking agent is a
hydrogel.
[8431] 7466. The method of item 7413 wherein the bulking agent
comprises beta-glucan.
[8432] 7467. The method of item 7413 wherein the bulking agent
comprises collagen fibrils.
[8433] 7468. The method of item 7413 wherein the bulking agent
comprises hylan polymer.
[8434] 7469. The method of item 7413 wherein the bulking agent
comprises microspheres.
[8435] 7470. The method of item 7413 wherein the bulking agent
comprises polyacrylic acid or polyacrylate.
[8436] 7471. The method of item 7413 wherein the bulking agent
comprises silicon or crosslinked silicon.
[8437] 7472. The method of item 7413 wherein a visualization agent
is combined with the fibrosing agent and/or the bulking agent.
[8438] 7473. The method of item 7413 wherein a coloring agent is
combined with the fibrosing agent and/or the bulking agent.
[8439] 7474. The method of item 7413 wherein the composition is
treated to provide a sterile composition.
[8440] 7475. The method of item 7413 wherein the composition is
formulated to be an urethral bulking agent.
[8441] 7476. The method of item 7413 wherein the composition is
formulated to be an esophageal bulking agent.
[8442] 7477. The method of item 7413 wherein the composition is
formulated to be an anal bulking agent.
[8443] 7478. The method of item 7413 wherein the fibrosing agent is
present in the composition at a concentration within the range of
about 0.005 .mu.g-10 .mu.g per mm.sup.3.
[8444] 7479. A method of making a medical device comprising
combining i) an orthopedic implant and ii) a fibrosing agent or a
composition comprising a fibrosing agent, where the fibrosing agent
induces a fibrotic response between the device and a patient in
which the device is implanted.
[8445] 7480. The method of item 7479 wherein the fibrosing agent
promotes regeneration.
[8446] 7481. The method of item 7479 wherein the fibrosing agent
promotes angiogenesis.
[8447] 7482. The method of item 7479 wherein the fibrosing agent
promotes fibroblast migration.
[8448] 7483. The method of item 7479 wherein the fibrosing agent
promotes fibroblast proliferation.
[8449] 7484. The method of item 7479 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[8450] 7485. The method of item 7479 wherein the fibrosing agent
promotes tissue remodeling.
[8451] 7486. The method of item 7479 wherein the fibrosing agent is
an arterial vessel wall irritant.
[8452] 7487. The method of item 7479 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[8453] 7488. The method of item 7479 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[8454] 7489. The method of item 7479 wherein the fibrosing agent is
or comprises silk.
[8455] 7490. The method of item 7479 wherein the fibrosing agent is
or comprises mineral particles.
[8456] 7491. The method of item 7479 wherein the fibrosing agent is
or comprises chitosan.
[8457] 7492. The method of item 7479 wherein the fibrosing agent is
or comprises polylysine.
[8458] 7493. The method of item 7479 wherein the fibrosing agent is
or comprises fibronectin.
[8459] 7494. The method of item 7479 wherein the fibrosing agent is
or comprises bleomycin.
[8460] 7495. The method of item 7479 wherein the fibrosing agent is
or comprises CTGF.
[8461] 7496. The method of item 7479 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[8462] 7497. The method of item 7479 wherein the fibrosing agent is
in the form of a particulate.
[8463] 7498. The method of item 7479 wherein the composition
further comprises an inflammatory cytokine.
[8464] 7499. The method of item 7479 wherein the composition
further comprises an agent that stimulates cell proliferation.
[8465] 7500. The method of item 7479 wherein the composition is in
the form of a gel or paste.
[8466] 7501. The method of item 7479 wherein the fibrosing agent is
in the form of tufts.
[8467] 7502. The method of item 7479 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[8468] 7503. The method of item 7479 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[8469] 7504. The method of item 7479, wherein the implant is
combined with a coating, and the coating comprises the fibrosing
agent.
[8470] 7505. The method of item 7479, wherein the implant is
combined with a coating, and the coating is disposed on a surface
of the device.
[8471] 7506. The method of item 7479, wherein the implant is
combined with a coating, and the coating directly contacts the
device.
[8472] 7507. The method of item 7479, wherein the implant is
combined with a coating, and the coating indirectly contacts the
device.
[8473] 7508. The method of item 7479, wherein the implant is
combined with a coating, and the coating partially covers the
device.
[8474] 7509. The method of item 7479, wherein the implant is
combined with a coating, and the coating completely covers the
device.
[8475] 7510. The method of item 7479, wherein the implant is
combined with a coating, and the coating is a uniform coating.
[8476] 7511. The method of item 7479, wherein the implant is
combined with a coating, and the coating is a non-uniform
coating.
[8477] 7512. The method of item 7479, wherein the implant is
combined with a coating, and the coating is a discontinuous
coating.
[8478] 7513. The method of item 7479 wherein the implant is
combined with a coating, and the coating is a patterned
coating.
[8479] 7514. The method of item 7479, wherein the implant is
combined with a coating, and the coating has a thickness of 100
.mu.m or less.
[8480] 7515. The method of item 7479, wherein the implant is
combined with a coating, and the coating has a thickness of 10
.mu.m or less.
[8481] 7516. The method of item 7479, wherein the implant is
combined with a coating, and the coating adheres to the surface of
the device upon deployment of the device.
[8482] 7517. The method of item 7479, wherein the implant is
combined with a coating, and the coating is stable at room
temperature for a period of at least 1 year.
[8483] 7518. The method of item 7479, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 0.0001% to about 1% by
weight.
[8484] 7519. The method of item 7479, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 1% to about 10% by
weight.
[8485] 7520. The method of item 7479, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 10% to about 25% by
weight.
[8486] 7521. The method of item 7479, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 25% to about 70% by
weight.
[8487] 7522. The method of item 7479, wherein the implant is
combined with a coating, and the coating further comprises a
polymer.
[8488] 7523. The method of item 7479, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition.
[8489] 7524. The method of item 7479, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition, where the first composition and the
second composition are different.
[8490] 7525. The method of item 7479, wherein the device comprises
a polymer.
[8491] 7526. The method of item 7479, wherein the device comprises
a polymer, and the polymer is a component of the composition.
[8492] 7527. The method of item 7479, wherein the implant is
combined with a polymer, and the polymer is a copolymer.
[8493] 7528. The method of item 7479, wherein the implant is
combined with a polymer, and the polymer is a block copolymer.
[8494] 7529. The method of item 7479, wherein the implant is
combined with a polymer, and the polymer is a random copolymer.
[8495] 7530. The method of item 7479, wherein the implant is
combined with a polymer, and the polymer is a biodegradable
polymer.
[8496] 7531. The method of item 7479, wherein the implant is
combined with a polymer, and the polymer is a non-biodegradable
polymer.
[8497] 7532. The method of item 7479, wherein the implant is
combined with a polymer, and the polymer is a hydrophilic
polymer.
[8498] 7533. The method of item 7479, wherein the implant is
combined with a polymer, and the polymer is a hydrophobic
polymer.
[8499] 7534. The method of item 7479, wherein the implant is
combined with a polymer, and the polymer has hydrophilic
domains.
[8500] 7535. The method of item 7479, wherein the implant is
combined with a polymer, and the polymer has hydrophobic
domains.
[8501] 7536. The method of item 7479, wherein the implant is
combined with a polymer, and the polymer is a non-conductive
polymer.
[8502] 7537. The method of item 7479, wherein the implant is
combined with a polymer, and the polymer is an elastomer.
[8503] 7538. The method of item 7479, wherein the implant is
combined with a polymer, and the polymer is a hydrogel.
[8504] 7539. The method of item 7479, wherein the implant is
combined with a polymer, and the polymer is a silicone polymer.
[8505] 7540. The method of item 7479, wherein the implant is
combined with a polymer, and the polymer is a hydrocarbon
polymer.
[8506] 7541. The method of item 7479, wherein the implant is
combined with a polymer, and the polymer is a styrene-derived
polymer.
[8507] 7542. The method of item 7479, wherein the implant is
combined with a polymer, and the polymer is a butadiene
polymer.
[8508] 7543. The method of item 7479, wherein the implant is
combined with a polymer, and the polymer is a macromer.
[8509] 7544. The method of item 7479, wherein the implant is
combined with a polymer, and the polymer is a poly(ethylene glycol)
polymer.
[8510] 7545. The method of item 7479, wherein the implant is
combined with a polymer, and the polymer is an amorphous
polymer.
[8511] 7546. The method of item 7479, wherein the implant is
combined with a polymer, and the polymer is a lubricious
coating.
[8512] 7547. The method of item 7479 wherein the fibrosing agent is
located within pores or holes of the device.
[8513] 7548. The method of item 7479 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[8514] 7549. The method of item 7479, wherein the implant is
further combined with a second pharmaceutically active agent.
[8515] 7550. The method of item 7479, wherein the implant is
further combined with an anti-inflammatory agent.
[8516] 7551. The method of item 7479 wherein the implant is further
combined with an agent that inhibits infection.
[8517] 7552. The method of item 7479, wherein the implant is
further combined with an anthracycline.
[8518] 7553. The method of item 7479, wherein the implant is
further combined with doxorubicin.
[8519] 7554. The method of item 7479, wherein the implant is
further combined with mitoxantrone.
[8520] 7555. The method of item 7479, wherein the implant is
further combined with a fluoropyrimidine.
[8521] 7556. The method of item 7479, wherein the implant is
further combined with 5-fluorouracil (5-FU).
[8522] 7557. The method of item 7479, wherein the implant is
further combined with a folic acid antagonist.
[8523] 7558. The method of item 7479, wherein the implant is
further combined with methotrexate.
[8524] 7559. The method of item 7479, wherein the implant is
further combined with a podophylotoxin.
[8525] 7560. The method of item 7479, wherein the implant is
further combined with etoposide.
[8526] 7561. The method of item 7479 wherein the implant is further
combined with a camptothecin.
[8527] 7562. The method of item 7479, wherein the implant is
further combined with a hydroxyurea.
[8528] 7563. The method of item 7479, wherein the implant is
further combined with a platinum complex.
[8529] 7564. The method of item 7479, wherein the implant is
further combined with cisplatin.
[8530] 7565. The method of item 7479, wherein the implant is
further combined with an anti-thrombotic agent.
[8531] 7566. The method of item 7479, wherein the implant is
further combined with a visualization agent.
[8532] 7567. The method of item 7479, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises a metal, a halogenated compound, or a
barium containing compound.
[8533] 7568. The method of item 7479, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises barium, tantalum, or technetium.
[8534] 7569. The method of item 7479, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a MRI responsive material.
[8535] 7570. The method of item 7479, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a gadolinium chelate.
[8536] 7571. The method of item 7479, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises iron, magnesium, manganese, copper,
or chromium.
[8537] 7572. The method of item 7479, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises an iron oxide compound.
[8538] 7573. The method of item 7479, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a dye, pigment, or colorant.
[8539] 7574. The method of item 7479, wherein the implant is
further combined with an echogenic material.
[8540] 7575. The method of item 7479, wherein the implant is
further combined with an echogenic material, and the echogenic
material is in the form of a coating.
[8541] 7576. The method of item 7479 wherein the device is
sterilized.
[8542] 7577. The method of item 7479 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[8543] 7578. The method of item 7479 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[8544] 7579. The method of item 7479 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[8545] 7580. The method of item 7479 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[8546] 7581. The method of item 7479 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[8547] 7582. The method of item 7479 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[8548] 7583. The method of item 7479 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[8549] 7584. The method of item 7479 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[8550] 7585. The method of item 7479 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[8551] 7586. The method of item 7479 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[8552] 7587. The method of item 7479 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[8553] 7588. The method of item 7479 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[8554] 7589. The method of item 7479 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[8555] 7590. The method of item 7479 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[8556] 7591. The method of item 7479 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[8557] 7592. The method of item 7479 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[8558] 7593. The method of item 7479 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[8559] 7594. The method of item 7479 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[8560] 7595. The method of item 7479 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[8561] 7596. The method of item 7479 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[8562] 7597. The method of item 7479 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[8563] 7598. The method of item 7479 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[8564] 7599. The method of item 7479 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[8565] 7600. The method of item 7479 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[8566] 7601. The method of item 7479 wherein the orthopedic implant
is used as a substitute for a bone graft.
[8567] 7602. The method of item 7479 wherein the orthopedic implant
is an orthopedic pin implant.
[8568] 7603. The method of item 7479 wherein the orthopedic implant
is an orthopedic nail implant.
[8569] 7604. A method of making a medical device comprising
combining i) an orthopedic prosthesis and ii) a fibrosing agent or
a composition comprising a fibrosing agent, where the fibrosing
agent induces a fibrotic response between the device and a patient
in which the device is implanted.
[8570] 7605. The method of item 7604 wherein the fibrosing agent
promotes regeneration.
[8571] 7606. The method of item 7604 wherein the fibrosing agent
promotes angiogenesis.
[8572] 7607. The method of item 7604 wherein the fibrosing agent
promotes fibroblast migration.
[8573] 7608. The method of item 7604 wherein the fibrosing agent
promotes fibroblast proliferation.
[8574] 7609. The method of item 7604 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[8575] 7610. The method of item 7604 wherein the fibrosing agent
promotes tissue remodeling.
[8576] 7611. The method of item 7604 wherein the fibrosing agent is
an arterial vessel wall irritant.
[8577] 7612. The method of item 7604 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[8578] 7613. The method of item 7604 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[8579] 7614. The method of item 7604 wherein the fibrosing agent is
or comprises silk.
[8580] 7615. The method of item 7604 wherein the fibrosing agent is
or comprises mineral particles.
[8581] 7616. The method of item 7604 wherein the fibrosing agent is
or comprises chitosan.
[8582] 7617. The method of item 7604 wherein the fibrosing agent is
or comprises polylysine.
[8583] 7618. The method of item 7604 wherein the fibrosing agent is
or comprises fibronectin.
[8584] 7619. The method of item 7604 wherein the fibrosing agent is
or comprises bleomycin.
[8585] 7620. The method of item 7604 wherein the fibrosing agent is
or comprises CTGF.
[8586] 7621. The method of item 7604 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[8587] 7622. The method of item 7604 wherein the fibrosing agent is
in the form of a particulate.
[8588] 7623. The method of item 7604 wherein the composition
further comprises an inflammatory cytokine.
[8589] 7624. The method of item 7604 wherein the composition
further comprises an agent that stimulates cell proliferation.
[8590] 7625. The method of item 7604 wherein the composition is in
the form of a gel or paste.
[8591] 7626. The method of item 7604 wherein the fibrosing agent is
in the form of tufts.
[8592] 7627. The method of item 7604 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[8593] 7628. The method of item 7604 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[8594] 7629. The method of item 7604, wherein the prosthesis is
combined with a coating, and the coating comprises the fibrosing
agent.
[8595] 7630. The method of item 7604, wherein the prosthesis is
combined with a coating, and the coating is disposed on a surface
of the device.
[8596] 7631. The method of item 7604, wherein the prosthesis is
combined with a coating, and the coating directly contacts the
device.
[8597] 7632. The method of item 7604, wherein the prosthesis is
combined with a coating, and the coating indirectly contacts the
device.
[8598] 7633. The method of item 7604, wherein the prosthesis is
combined with a coating, and the coating partially covers the
device.
[8599] 7634. The method of item 7604, wherein the prosthesis is
combined with a coating, and the coating completely covers the
device.
[8600] 7635. The method of item 7604, wherein the prosthesis is
combined with a coating, and the coating is a uniform coating.
[8601] 7636. The method of item 7604, wherein the prosthesis is
combined with a coating, and the coating is a non-uniform
coating.
[8602] 7637. The method of item 7604, wherein the prosthesis is
combined with a coating, and the coating is a discontinuous
coating.
[8603] 7638. The method of item 7604 wherein the prosthesis is
combined with a coating, and the coating is a patterned
coating.
[8604] 7639. The method of item 7604, wherein the prosthesis is
combined with a coating, and the coating has a thickness of 100
.mu.m or less.
[8605] 7640. The method of item 7604, wherein the prosthesis is
combined with a coating, and the coating has a thickness of 10
.mu.m or less.
[8606] 7641. The method of item 7604, wherein the prosthesis is
combined with a coating, and the coating adheres to the surface of
the device upon deployment of the device.
[8607] 7642. The method of item 7604, wherein the prosthesis is
combined with a coating, and the coating is stable at room
temperature for a period of at least 1 year.
[8608] 7643. The method of item 7604, wherein the prosthesis is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 0.0001% to about 1% by
weight.
[8609] 7644. The method of item 7604, wherein the prosthesis is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 1% to about 10% by
weight.
[8610] 7645. The method of item 7604, wherein the prosthesis is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 10% to about 25% by
weight.
[8611] 7646. The method of item 7604, wherein the prosthesis is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 25% to about 70% by
weight.
[8612] 7647. The method of item 7604, wherein the prosthesis is
combined with a coating, and the coating further comprises a
polymer.
[8613] 7648. The method of item 7604, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition.
[8614] 7649. The method of item 7604, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition, where the first composition and the
second composition are different.
[8615] 7650. The method of item 7604, wherein the device comprises
a polymer.
[8616] 7651. The method of item 7604, wherein the device comprises
a polymer, and the polymer is a component of the composition.
[8617] 7652. The method of item 7604, wherein the prosthesis is
combined with a polymer, and the polymer is a copolymer.
[8618] 7653. The method of item 7604, wherein the prosthesis is
combined with a polymer, and the polymer is a block copolymer.
[8619] 7654. The method of item 7604, wherein the prosthesis is
combined with a polymer, and the polymer is a random copolymer.
[8620] 7655. The method of item 7604, wherein the prosthesis is
combined with a polymer, and the polymer is a biodegradable
polymer.
[8621] 7656. The method of item 7604, wherein the prosthesis is
combined with a polymer, and the polymer is a non-biodegradable
polymer.
[8622] 7657. The method of item 7604, wherein the prosthesis is
combined with a polymer, and the polymer is a hydrophilic
polymer.
[8623] 7658. The method of item 7604, wherein the prosthesis is
combined with a polymer, and the polymer is a hydrophobic
polymer.
[8624] 7659. The method of item 7604, wherein the prosthesis is
combined with a polymer, and the polymer has hydrophilic
domains.
[8625] 7660. The method of item 7604, wherein the prosthesis is
combined with a polymer, and the polymer has hydrophobic
domains.
[8626] 7661. The method of item 7604, wherein the prosthesis is
combined with a polymer, and the polymer is a non-conductive
polymer.
[8627] 7662. The method of item 7604, wherein the prosthesis is
combined with a polymer, and the polymer is an elastomer.
[8628] 7663. The method of item 7604, wherein the prosthesis is
combined with a polymer, and the polymer is a hydrogel.
[8629] 7664. The method of item 7604, wherein the prosthesis is
combined with a polymer, and the polymer is a silicone polymer.
[8630] 7665. The method of item 7604, wherein the prosthesis is
combined with a polymer, and the polymer is a hydrocarbon
polymer.
[8631] 7666. The method of item 7604, wherein the prosthesis is
combined with a polymer, and the polymer is a styrene-derived
polymer.
[8632] 7667. The method of item 7604, wherein the prosthesis is
combined with a polymer, and the polymer is a butadiene
polymer.
[8633] 7668. The method of item 7604, wherein the prosthesis is
combined with a polymer, and the polymer is a macromer.
[8634] 7669. The method of item 7604, wherein the prosthesis is
combined with a polymer, and the polymer is a poly(ethylene glycol)
polymer.
[8635] 7670. The method of item 7604, wherein the prosthesis is
combined with a polymer, and the polymer is an amorphous
polymer.
[8636] 7671. The method of item 7604, wherein the prosthesis is
combined with a polymer, and the polymer is a lubricious
coating.
[8637] 7672. The method of item 7604 wherein the fibrosing agent is
located within pores or holes of the device.
[8638] 7673. The method of item 7604 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[8639] 7674. The method of item 7604, wherein the prosthesis is
further combined with a second pharmaceutically active agent.
[8640] 7675. The method of item 7604, wherein the prosthesis is
further combined with an anti-inflammatory agent.
[8641] 7676. The method of item 7604 wherein the prosthesis is
further combined with an agent that inhibits infection.
[8642] 7677. The method of item 7604, wherein the prosthesis is
further combined with an anthracycline.
[8643] 7678. The method of item 7604, wherein the prosthesis is
further combined with doxorubicin.
[8644] 7679. The method of item 7604, wherein the prosthesis is
further combined with mitoxantrone.
[8645] 7680. The method of item 7604, wherein the prosthesis is
further combined with a fluoropyrimidine.
[8646] 7681. The method of item 7604, wherein the prosthesis is
further combined with 5-fluorouracil (5-FU).
[8647] 7682. The method of item 7604, wherein the prosthesis is
further combined with a folic acid antagonist.
[8648] 7683. The method of item 7604, wherein the prosthesis is
further combined with methotrexate.
[8649] 7684. The method of item 7604, wherein the prosthesis is
further combined with a podophylotoxin.
[8650] 7685. The method of item 7604, wherein the prosthesis is
further combined with etoposide.
[8651] 7686. The method of item 7604 wherein the prosthesis is
further combined with a camptothecin.
[8652] 7687. The method of item 7604, wherein the prosthesis is
further combined with a hydroxyurea.
[8653] 7688. The method of item 7604, wherein the prosthesis is
further combined with a platinum complex.
[8654] 7689. The method of item 7604, wherein the prosthesis is
further combined with cisplatin.
[8655] 7690. The method of item 7604, wherein the prosthesis is
further combined with an anti-thrombotic agent.
[8656] 7691. The method of item 7604, wherein the prosthesis is
further combined with a visualization agent.
[8657] 7692. The method of item 7604, wherein the prosthesis is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises a metal, a halogenated compound, or a
barium containing compound.
[8658] 7693. The method of item 7604, wherein the prosthesis is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises barium, tantalum, or technetium.
[8659] 7694. The method of item 7604, wherein the prosthesis is
further combined with a visualization agent, wherein the
visualization agent is a MRI responsive material.
[8660] 7695. The method of item 7604, wherein the prosthesis is
further combined with a visualization agent, wherein the
visualization agent comprises a gadolinium chelate.
[8661] 7696. The method of item 7604, wherein the prosthesis is
further combined with a visualization agent, wherein the
visualization agent comprises iron, magnesium, manganese, copper,
or chromium.
[8662] 7697. The method of item 7604, wherein the prosthesis is
further combined with a visualization agent, wherein the
visualization agent comprises an iron oxide compound.
[8663] 7698. The method of item 7604, wherein the prosthesis is
further combined with a visualization agent, wherein the
visualization agent comprises a dye, pigment, or colorant.
[8664] 7699. The method of item 7604, wherein the prosthesis is
further combined with an echogenic material.
[8665] 7700. The method of item 7604, wherein the prosthesis is
further combined with an echogenic material, and the echogenic
material is in the form of a coating.
[8666] 7701. The method of item 7604 wherein the device is
sterilized.
[8667] 7702. The method of item 7604 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[8668] 7703. The method of item 7604 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[8669] 7704. The method of item 7604 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[8670] 7705. The method of item 7604 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[8671] 7706. The method of item 7604 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[8672] 7707. The method of item 7604 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[8673] 7708. The method of item 7604 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[8674] 7709. The method of item 7604 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[8675] 7710. The method of item 7604 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[8676] 7711. The method of item 7604 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[8677] 7712. The method of item 7604 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[8678] 7713. The method of item 7604 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[8679] 7714. The method of item 7604 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[8680] 7715. The method of item 7604 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[8681] 7716. The method of item 7604 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[8682] 7717. The method of item 7604 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[8683] 7718. The method of item 7604 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[8684] 7719. The method of item 7604 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[8685] 7720. The method of item 7604 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[8686] 7721. The method of item 7604 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[8687] 7722. The method of item 7604 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[8688] 7723. The method of item 7604 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[8689] 7724. The method of item 7604 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[8690] 7725. The method of item 7604 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[8691] 7726. The method of item 7604 wherein the orthopedic implant
is a knee implant.
[8692] 7727. The method of item 7604 wherein the orthopedic implant
is hip implant.
[8693] 7728. The method of item 7604 wherein the orthopedic implant
is a shoulder implant.
[8694] 7729. The method of item 7604 wherein the orthopedic implant
is a digit implant.
[8695] 7730. A method of making a medical device comprising
combining i) a dental implant and ii) a fibrosing agent or a
composition comprising a fibrosing agent, where the fibrosing agent
induces a fibrotic response between the device and a patient in
which the device is implanted.
[8696] 7731. The method of item 7730 wherein the fibrosing agent
promotes regeneration.
[8697] 7732. The method of item 7730 wherein the fibrosing agent
promotes angiogenesis.
[8698] 7733. The method of item 7730 wherein the fibrosing agent
promotes fibroblast migration.
[8699] 7734. The method of item 7730 wherein the fibrosing agent
promotes fibroblast proliferation.
[8700] 7735. The method of item 7730 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[8701] 7736. The method of item 7730 wherein the fibrosing agent
promotes tissue remodeling.
[8702] 7737. The method of item 7730 wherein the fibrosing agent is
an arterial vessel wall irritant.
[8703] 7738. The method of item 7730 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[8704] 7739. The method of item 7730 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[8705] 7740. The method of item 7730 wherein the fibrosing agent is
or comprises silk.
[8706] 7741. The method of item 7730 wherein the fibrosing agent is
or comprises mineral particles.
[8707] 7742. The method of item 7730 wherein the fibrosing agent is
or comprises chitosan.
[8708] 7743. The method of item 7730 wherein the fibrosing agent is
or comprises polylysine.
[8709] 7744. The method of item 7730 wherein the fibrosing agent is
or comprises fibronectin.
[8710] 7745. The method of item 7730 wherein the fibrosing agent is
or comprises bleomycin.
[8711] 7746. The method of item 7730 wherein the fibrosing agent is
or comprises CTGF.
[8712] 7747. The method of item 7730 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[8713] 7748. The method of item 7730 wherein the fibrosing agent is
in the form of a particulate.
[8714] 7749. The method of item 7730 wherein the composition
further comprises an inflammatory cytokine.
[8715] 7750. The method of item 7730 wherein the composition
further comprises an agent that stimulates cell proliferation.
[8716] 7751. The method of item 7730 wherein the composition is in
the form of a gel or paste.
[8717] 7752. The method of item 7730 wherein the fibrosing agent is
in the form of tufts.
[8718] 7753. The method of item 7730 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[8719] 7754. The method of item 7730 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[8720] 7755. The method of item 7730, wherein the implant is
combined with a coating, and the coating comprises the fibrosing
agent.
[8721] 7756. The method of item 7730, wherein the implant is
combined with a coating, and the coating is disposed on a surface
of the device.
[8722] 7757. The method of item 7730, wherein the implant is
combined with a coating, and the coating directly contacts the
device.
[8723] 7758. The method of item 7730, wherein the implant is
combined with a coating, and the coating indirectly contacts the
device.
[8724] 7759. The method of item 7730, wherein the implant is
combined with a coating, and the coating partially covers the
device.
[8725] 7760. The method of item 7730, wherein the implant is
combined with a coating, and the coating completely covers the
device.
[8726] 7761. The method of item 7730, wherein the implant is
combined with a coating, and the coating is a uniform coating.
[8727] 7762. The method of item 7730, wherein the implant is
combined with a coating, and the coating is a non-uniform
coating.
[8728] 7763. The method of item 7730, wherein the implant is
combined with a coating, and the coating is a discontinuous
coating.
[8729] 7764. The method of item 7730 wherein the implant is
combined with a coating, and the coating is a patterned
coating.
[8730] 7765. The method of item 7730, wherein the implant is
combined with a coating, and the coating has a thickness of 100
.mu.m or less.
[8731] 7766. The method of item 7730, wherein the implant is
combined with a coating, and the coating has a thickness of 10
.mu.m or less.
[8732] 7767. The method of item 7730, wherein the implant is
combined with a coating, and the coating adheres to the surface of
the device upon deployment of the device.
[8733] 7768. The method of item 7730, wherein the implant is
combined with a coating, and the coating is stable at room
temperature for a period of at least 1 year.
[8734] 7769. The method of item 7730, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 0.0001% to about 1% by
weight.
[8735] 7770. The method of item 7730, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 1% to about 10% by
weight.
[8736] 7771. The method of item 7730, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 10% to about 25% by
weight.
[8737] 7772. The method of item 7730, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 25% to about 70% by
weight.
[8738] 7773. The method of item 7730, wherein the implant is
combined with a coating, and the coating further comprises a
polymer.
[8739] 7774. The method of item 7730, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition.
[8740] 7775. The method of item 7730, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition, where the first composition and the
second composition are different.
[8741] 7776. The method of item 7730, wherein the device comprises
a polymer.
[8742] 7777. The method of item 7730, wherein the device comprises
a polymer, and the polymer is a component of the composition.
[8743] 7778. The method of item 7730, wherein the implant is
combined with a polymer, and the polymer is a copolymer.
[8744] 7779. The method of item 7730, wherein the implant is
combined with a polymer, and the polymer is a block copolymer.
[8745] 7780. The method of item 7730, wherein the implant is
combined with a polymer, and the polymer is a random copolymer.
[8746] 7781. The method of item 7730, wherein the implant is
combined with a polymer, and the polymer is a biodegradable
polymer.
[8747] 7782. The method of item 7730, wherein the implant is
combined with a polymer, and the polymer is a non-biodegradable
polymer.
[8748] 7783. The method of item 7730, wherein the implant is
combined with a polymer, and the polymer is a hydrophilic
polymer.
[8749] 7784. The method of item 7730, wherein the implant is
combined with a polymer, and the polymer is a hydrophobic
polymer.
[8750] 7785. The method of item 7730, wherein the implant is
combined with a polymer, and the polymer has hydrophilic
domains.
[8751] 7786. The method of item 7730, wherein the implant is
combined with a polymer, and the polymer has hydrophobic
domains.
[8752] 7787. The method of item 7730, wherein the implant is
combined with a polymer, and the polymer is a non-conductive
polymer.
[8753] 7788. The method of item 7730, wherein the implant is
combined with a polymer, and the polymer is an elastomer.
[8754] 7789. The method of item 7730, wherein the implant is
combined with a polymer, and the polymer is a hydrogel.
[8755] 7790. The method of item 7730, wherein the implant is
combined with a polymer, and the polymer is a silicone polymer.
[8756] 7791. The method of item 7730, wherein the implant is
combined with a polymer, and the polymer is a hydrocarbon
polymer.
[8757] 7792. The method of item 7730, wherein the implant is
combined with a polymer, and the polymer is a styrene-derived
polymer.
[8758] 7793. The method of item 7730, wherein the implant is
combined with a polymer, and the polymer is a butadiene
polymer.
[8759] 7794. The method of item 7730, wherein the implant is
combined with a polymer, and the polymer is a macromer.
[8760] 7795. The method of item 7730, wherein the implant is
combined with a polymer, and the polymer is a poly(ethylene glycol)
polymer.
[8761] 7796. The method of item 7730, wherein the implant is
combined with a polymer, and the polymer is an amorphous
polymer.
[8762] 7797. The method of item 7730, wherein the implant is
combined with a polymer, and the polymer is a lubricious
coating.
[8763] 7798. The method of item 7730 wherein the fibrosing agent is
located within pores or holes of the device.
[8764] 7799. The method of item 7730 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[8765] 7800. The method of item 7730, wherein the implant is
further combined with a second pharmaceutically active agent.
[8766] 7801. The method of item 7730, wherein the implant is
further combined with an anti-inflammatory agent.
[8767] 7802. The method of item 7730 wherein the implant is further
combined with an agent that inhibits infection.
[8768] 7803. The method of item 7730, wherein the implant is
further combined with an anthracycline.
[8769] 7804. The method of item 7730, wherein the implant is
further combined with doxorubicin.
[8770] 7805. The method of item 7730, wherein the implant is
further combined with mitoxantrone.
[8771] 7806. The method of item 7730, wherein the implant is
further combined with a fluoropyrimidine.
[8772] 7807. The method of item 7730, wherein the implant is
further combined with 5-fluorouracil (5-FU).
[8773] 7808. The method of item 7730, wherein the implant is
further combined with a folic acid antagonist.
[8774] 7809. The method of item 7730, wherein the implant is
further combined with methotrexate.
[8775] 7810. The method of item 7730, wherein the implant is
further combined with a podophylotoxin.
[8776] 7811. The method of item 7730, wherein the implant is
further combined with etoposide.
[8777] 7812. The method of item 7730 wherein the implant is further
combined with a camptothecin.
[8778] 7813. The method of item 7730, wherein the implant is
further combined with a hydroxyurea.
[8779] 7814. The method of item 7730, wherein the implant is
further combined with a platinum complex.
[8780] 7815. The method of item 7730, wherein the implant is
further combined with cisplatin.
[8781] 7816. The method of item 7730, wherein the implant is
further combined with an anti-thrombotic agent.
[8782] 7817. The method of item 7730, wherein the implant is
further combined with a visualization agent.
[8783] 7818. The method of item 7730, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises a metal, a halogenated compound, or a
barium containing compound.
[8784] 7819. The method of item 7730, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises barium, tantalum, or technetium.
[8785] 7820. The method of item 7730, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a MRI responsive material.
[8786] 7821. The method of item 7730, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a gadolinium chelate.
[8787] 7822. The method of item 7730, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises iron, magnesium, manganese, copper,
or chromium.
[8788] 7823. The method of item 7730, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises an iron oxide compound.
[8789] 7824. The method of item 7730, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a dye, pigment, or colorant.
[8790] 7825. The method of item 7730, wherein the implant is
further combined with an echogenic material.
[8791] 7826. The method of item 7730, wherein the implant is
further combined with an echogenic material, and the echogenic
material is in the form of a coating.
[8792] 7827. The method of item 7730 wherein the device is
sterilized.
[8793] 7828. The method of item 7730 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[8794] 7829. The method of item 7730 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[8795] 7830. The method of item 7730 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[8796] 7831. The method of item 7730 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[8797] 7832. The method of item 7730 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[8798] 7833. The method of item 7730 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[8799] 7834. The method of item 7730 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[8800] 7835. The method of item 7730 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[8801] 7836. The method of item 7730 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[8802] 7837. The method of item 7730 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[8803] 7838. The method of item 7730 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[8804] 7839. The method of item 7730 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[8805] 7840. The method of item 7730 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[8806] 7841. The method of item 7730 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[8807] 7842. The method of item 7730 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[8808] 7843. The method of item 7730 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[8809] 7844. The method of item 7730 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[8810] 7845. The method of item 7730 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[8811] 7846. The method of item 7730 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[8812] 7847. The method of item 7730 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[8813] 7848. The method of item 7730 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[8814] 7849. The method of item 7730 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[8815] 7850. The method of item 7730 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[8816] 7851. The method of item 7730 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[8817] 7852. The method of item 7730 wherein the implant is a
titanium fixture for replacement of the root portion of a missing
natural tooth.
[8818] 7853. The method of item 7730 wherein the implant is an
endosteal implant.
[8819] 7854. The method of item 7730 wherein the implant is an
subperiosteal implant.
[8820] 7855. The method of item 7730 wherein the implant is a
guided bone regeneration (GBR) implant.
[8821] 7856. The method of item 7730 wherein the implant is a
dental implant that controls the healing process subsequent to
periodontal disease.
[8822] 7857. A method of making a medical device comprising
combining i) an internal fixation implant and ii) a fibrosing agent
or a composition comprising a fibrosing agent, where the fibrosing
agent induces a fibrotic response between the device and a patient
in which the device is implanted.
[8823] 7858. The method of item 7857 wherein the fibrosing agent
promotes regeneration.
[8824] 7859. The method of item 7857 wherein the fibrosing agent
promotes angiogenesis.
[8825] 7860. The method of item 7857 wherein the fibrosing agent
promotes fibroblast migration.
[8826] 7861. The method of item 7857 wherein the fibrosing agent
promotes fibroblast proliferation.
[8827] 7862. The method of item 7857 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[8828] 7863. The method of item 7857 wherein the fibrosing agent
promotes tissue remodeling.
[8829] 7864. The method of item 7857 wherein the fibrosing agent is
an arterial vessel wall irritant.
[8830] 7865. The method of item 7857 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[8831] 7866. The method of item 7857 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[8832] 7867. The method of item 7857 wherein the fibrosing agent is
or comprises silk.
[8833] 7868. The method of item 7857 wherein the fibrosing agent is
or comprises mineral particles.
[8834] 7869. The method of item 7857 wherein the fibrosing agent is
or comprises chitosan.
[8835] 7870. The method of item 7857 wherein the fibrosing agent is
or comprises polylysine.
[8836] 7871. The method of item 7857 wherein the fibrosing agent is
or comprises fibronectin.
[8837] 7872. The method of item 7857 wherein the fibrosing agent is
or comprises bleomycin.
[8838] 7873. The method of item 7857 wherein the fibrosing agent is
or comprises CTGF.
[8839] 7874. The method of item 7857 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[8840] 7875. The method of item 7857 wherein the fibrosing agent is
in the form of a particulate.
[8841] 7876. The method of item 7857 wherein the composition
further comprises an inflammatory cytokine.
[8842] 7877. The method of item 7857 wherein the composition
further comprises an agent that stimulates cell proliferation.
[8843] 7878. The method of item 7857 wherein the composition is in
the form of a gel or paste.
[8844] 7879. The method of item 7857 wherein the fibrosing agent is
in the form of tufts.
[8845] 7880. The method of item 7857 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[8846] 7881. The method of item 7857 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[8847] 7882. The method of item 7857, wherein the implant is
combined with a coating, and the coating comprises the fibrosing
agent.
[8848] 7883. The method of item 7857, wherein the implant is
combined with a coating, and the coating is disposed on a surface
of the device.
[8849] 7884. The method of item 7857, wherein the implant is
combined with a coating, and the coating directly contacts the
device.
[8850] 7885. The method of item 7857, wherein the implant is
combined with a coating, and the coating indirectly contacts the
device.
[8851] 7886. The method of item 7857, wherein the implant is
combined with a coating, and the coating partially covers the
device.
[8852] 7887. The method of item 7857, wherein the implant is
combined with a coating, and the coating completely covers the
device.
[8853] 7888. The method of item 7857, wherein the implant is
combined with a coating, and the coating is a uniform coating.
[8854] 7889. The method of item 7857, wherein the implant is
combined with a coating, and the coating is a non-uniform
coating.
[8855] 7890. The method of item 7857, wherein the implant is
combined with a coating, and the coating is a discontinuous
coating.
[8856] 7891. The method of item 7857 wherein the implant is
combined with a coating, and the coating is a patterned
coating.
[8857] 7892. The method of item 7857, wherein the implant is
combined with a coating, and the coating has a thickness of 100
.mu.m or less.
[8858] 7893. The method of item 7857, wherein the implant is
combined with a coating, and the coating has a thickness of 10
.mu.m or less.
[8859] 7894. The method of item 7857, wherein the implant is
combined with a coating, and the coating adheres to the surface of
the device upon deployment of the device.
[8860] 7895. The method of item 7857, wherein the implant is
combined with a coating, and the coating is stable at room
temperature for a period of at least 1 year.
[8861] 7896. The method of item 7857, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 0.0001% to about 1% by
weight.
[8862] 7897. The method of item 7857, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 1% to about 10% by
weight.
[8863] 7898. The method of item 7857, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 10% to about 25% by
weight.
[8864] 7899. The method of item 7857, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 25% to about 70% by
weight.
[8865] 7900. The method of item 7857, wherein the implant is
combined with a coating, and the coating further comprises a
polymer.
[8866] 7901. The method of item 7857, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition.
[8867] 7902. The method of item 7857, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition, where the first composition and the
second composition are different.
[8868] 7903. The method of item 7857, wherein the device comprises
a polymer.
[8869] 7904. The method of item 7857, wherein the device comprises
a polymer, and the polymer is a component of the composition.
[8870] 7905. The method of item 7857, wherein the implant is
combined with a polymer, and the polymer is a copolymer.
[8871] 7906. The method of item 7857, wherein the implant is
combined with a polymer, and the polymer is a block copolymer.
[8872] 7907. The method of item 7857, wherein the implant is
combined with a polymer, and the polymer is a random copolymer.
[8873] 7908. The method of item 7857, wherein the implant is
combined with a polymer, and the polymer is a biodegradable
polymer.
[8874] 7909. The method of item 7857, wherein the implant is
combined with a polymer, and the polymer is a non-biodegradable
polymer.
[8875] 7910. The method of item 7857, wherein the implant is
combined with a polymer, and the polymer is a hydrophilic
polymer.
[8876] 7911. The method of item 7857, wherein the implant is
combined with a polymer, and the polymer is a hydrophobic
polymer.
[8877] 7912. The method of item 7857, wherein the implant is
combined with a polymer, and the polymer has hydrophilic
domains.
[8878] 7913. The method of item 7857, wherein the implant is
combined with a polymer, and the polymer has hydrophobic
domains.
[8879] 7914. The method of item 7857, wherein the implant is
combined with a polymer, and the polymer is a non-conductive
polymer.
[8880] 7915. The method of item 7857, wherein the implant is
combined with a polymer, and the polymer is an elastomer.
[8881] 7916. The method of item 7857, wherein the implant is
combined with a polymer, and the polymer is a hydrogel.
[8882] 7917. The method of item 7857, wherein the implant is
combined with a polymer, and the polymer is a silicone polymer.
[8883] 7918. The method of item 7857, wherein the implant is
combined with a polymer, and the polymer is a hydrocarbon
polymer.
[8884] 7919. The method of item 7857, wherein the implant is
combined with a polymer, and the polymer is a styrene-derived
polymer.
[8885] 7920. The method of item 7857, wherein the implant is
combined with a polymer, and the polymer is a butadiene
polymer.
[8886] 7921. The method of item 7857, wherein the implant is
combined with a polymer, and the polymer is a macromer.
[8887] 7922. The method of item 7857, wherein the implant is
combined with a polymer, and the polymer is a poly(ethylene glycol)
polymer.
[8888] 7923. The method of item 7857, wherein the implant is
combined with a polymer, and the polymer is an amorphous
polymer.
[8889] 7924. The method of item 7857, wherein the implant is
combined with a polymer, and the polymer is a lubricious
coating.
[8890] 7925. The method of item 7857 wherein the fibrosing agent is
located within pores or holes of the device.
[8891] 7926. The method of item 7857 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[8892] 7927. The method of item 7857, wherein the implant is
further combined with a second pharmaceutically active agent.
[8893] 7928. The method of item 7857, wherein the implant is
further combined with an anti-inflammatory agent.
[8894] 7929. The method of item 7857 wherein the implant is further
combined with an agent that inhibits infection.
[8895] 7930. The method of item 7857, wherein the implant is
further combined with an anthracycline.
[8896] 7931. The method of item 7857, wherein the implant is
further combined with doxorubicin.
[8897] 7932. The method of item 7857, wherein the implant is
further combined with mitoxantrone.
[8898] 7933. The method of item 7857, wherein the implant is
further combined with a fluoropyrimidine.
[8899] 7934. The method of item 7857, wherein the implant is
further combined with 5-fluorouracil (5-FU).
[8900] 7935. The method of item 7857, wherein the implant is
further combined with a folic acid antagonist.
[8901] 7936. The method of item 7857, wherein the implant is
further combined with methotrexate.
[8902] 7937. The method of item 7857, wherein the implant is
further combined with a podophylotoxin.
[8903] 7938. The method of item 7857, wherein the implant is
further combined with etoposide.
[8904] 7939. The method of item 7857 wherein the implant is further
combined with a camptothecin.
[8905] 7940. The method of item 7857, wherein the implant is
further combined with a hydroxyurea.
[8906] 7941. The method of item 7857, wherein the implant is
further combined with a platinum complex.
[8907] 7942. The method of item 7857, wherein the implant is
further combined with cisplatin.
[8908] 7943. The method of item 7857, wherein the implant is
further combined with an anti-thrombotic agent.
[8909] 7944. The method of item 7857, wherein the implant is
further combined with a visualization agent.
[8910] 7945. The method of item 7857, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises a metal, a halogenated compound, or a
barium containing compound.
[8911] 7946. The method of item 7857, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises barium, tantalum, or technetium.
[8912] 7947. The method of item 7857, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a MRI responsive material.
[8913] 7948. The method of item 7857, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a gadolinium chelate.
[8914] 7949. The method of item 7857, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises iron, magnesium, manganese, copper,
or chromium.
[8915] 7950. The method of item 7857, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises an iron oxide compound.
[8916] 7951. The method of item 7857, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a dye, pigment, or colorant.
[8917] 7952. The method of item 7857, wherein the implant is
further combined with an echogenic material.
[8918] 7953. The method of item 7857, wherein the implant is
further combined with an echogenic material, and the echogenic
material is in the form of a coating.
[8919] 7954. The method of item 7857 wherein the device is
sterilized.
[8920] 7955. The method of item 7857 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[8921] 7956. The method of item 7857 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[8922] 7957. The method of item 7857 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[8923] 7958. The method of item 7857 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[8924] 7959. The method of item 7857 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[8925] 7960. The method of item 7857 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[8926] 7961. The method of item 7857 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[8927] 7962. The method of item 7857 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[8928] 7963. The method of item 7857 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[8929] 7964. The method of item 7857 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[8930] 7965. The method of item 7857 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[8931] 7966. The method of item 7857 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[8932] 7967. The method of item 7857 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[8933] 7968. The method of item 7857 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[8934] 7969. The method of item 7857 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[8935] 7970. The method of item 7857 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[8936] 7971. The method of item 7857 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[8937] 7972. The method of item 7857 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[8938] 7973. The method of item 7857 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[8939] 7974. The method of item 7857 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[8940] 7975. The method of item 7857 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[8941] 7976. The method of item 7857 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[8942] 7977. The method of item 7857 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[8943] 7978. The method of item 7857 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[8944] 7979. The method of item 7857 wherein the implant comprises
a screw.
[8945] 7980. The method of item 7857 wherein the implant is, or
comprises, a fixation screw.
[8946] 7981. The method of item 7857 wherein the implant is, or
comprises, an interferential screw.
[8947] 7982. The method of item 7857 wherein the implant is, or
comprises, a trochanteric screw.
[8948] 7983. The method of item 7857 wherein the implant comprises
a pin.
[8949] 7984. The method of item 7857 wherein the implant comprises
a side plate.
[8950] 7985. The method of item 7857 wherein the implant is an
intramedullary nail.
[8951] 7986. The method of item 7857 wherein the implant is an
intramedullary pin.
[8952] 7987. The method of item 7857 wherein the implant is a bone
plate.
[8953] 7988. The method of item 7857 wherein the implant is bone
screw.
[8954] 7989. The method of item 7857 wherein the implant is a
smooth pin.
[8955] 7990. The method of item 7857 wherein the implant is a
threaded pin.
[8956] 7991. The method of item 7857 wherein the implant is a
wire.
[8957] 7992. The method of item 7857 wherein the implant is a
plate.
[8958] 7993. A method of making a medical device comprising
combining i) an external fixation implant and ii) a fibrosing agent
or a composition comprising a fibrosing agent, where the fibrosing
agent induces a fibrotic response between the device and a patient
in which the device is implanted.
[8959] 7994. The method of item 7993 wherein the fibrosing agent
promotes regeneration.
[8960] 7995. The method of item 7993 wherein the fibrosing agent
promotes angiogenesis.
[8961] 7996. The method of item 7993 wherein the fibrosing agent
promotes fibroblast migration.
[8962] 7997. The method of item 7993 wherein the fibrosing agent
promotes fibroblast proliferation.
[8963] 7998. The method of item 7993 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[8964] 7999. The method of item 7993 wherein the fibrosing agent
promotes tissue remodeling.
[8965] 8000. The method of item 7993 wherein the fibrosing agent is
an arterial vessel wall irritant.
[8966] 8001. The method of item 7993 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[8967] 8002. The method of item 7993 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[8968] 8003. The method of item 7993 wherein the fibrosing agent is
or comprises silk.
[8969] 8004. The method of item 7993 wherein the fibrosing agent is
or comprises mineral particles.
[8970] 8005. The method of item 7993 wherein the fibrosing agent is
or comprises chitosan.
[8971] 8006. The method of item 7993 wherein the fibrosing agent is
or comprises polylysine.
[8972] 8007. The method of item 7993 wherein the fibrosing agent is
or comprises fibronectin.
[8973] 8008. The method of item 7993 wherein the fibrosing agent is
or comprises bleomycin.
[8974] 8009. The method of item 7993 wherein the fibrosing agent is
or comprises CTGF.
[8975] 8010. The method of item 7993 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[8976] 8011. The method of item 7993 wherein the fibrosing agent is
in the form of a particulate.
[8977] 8012. The method of item 7993 wherein the composition
further comprises an inflammatory cytokine.
[8978] 8013. The method of item 7993 wherein the composition
further comprises an agent that stimulates cell proliferation.
[8979] 8014. The method of item 7993 wherein the composition is in
the form of a gel or paste.
[8980] 8015. The method of item 7993 wherein the fibrosing agent is
in the form of tufts.
[8981] 8016. The method of item 7993 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[8982] 8017. The method of item 7993 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[8983] 8018. The method of item 7993, wherein the implant is
combined with a coating, and the coating comprises the fibrosing
agent.
[8984] 8019. The method of item 7993, wherein the implant is
combined with a coating, and the coating is disposed on a surface
of the device.
[8985] 8020. The method of item 7993, wherein the implant is
combined with a coating, and the coating directly contacts the
device.
[8986] 8021. The method of item 7993, wherein the implant is
combined with a coating, and the coating indirectly contacts the
device.
[8987] 8022. The method of item 7993, wherein the implant is
combined with a coating, and the coating partially covers the
device.
[8988] 8023. The method of item 7993, wherein the implant is
combined with a coating, and the coating completely covers the
device.
[8989] 8024. The method of item 7993, wherein the implant is
combined with a coating, and the coating is a uniform coating.
[8990] 8025. The method of item 7993, wherein the implant is
combined with a coating, and the coating is a non-uniform
coating.
[8991] 8026. The method of item 7993, wherein the implant is
combined with a coating, and the coating is a discontinuous
coating.
[8992] 8027. The method of item 7993 wherein the implant is
combined with a coating, and the coating is a patterned
coating.
[8993] 8028. The method of item 7993, wherein the implant is
combined with a coating, and the coating has a thickness of 100
.mu.m or less.
[8994] 8029. The method of item 7993, wherein the implant is
combined with a coating, and the coating has a thickness of 10
.mu.m or less.
[8995] 8030. The method of item 7993, wherein the implant is
combined with a coating, and the coating adheres to the surface of
the device upon deployment of the device.
[8996] 8031. The method of item 7993, wherein the implant is
combined with a coating, and the coating is stable at room
temperature for a period of at least 1 year.
[8997] 8032. The method of item 7993, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 0.0001% to about 1% by
weight.
[8998] 8033. The method of item 7993, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 1% to about 10% by
weight.
[8999] 8034. The method of item 7993, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 10% to about 25% by
weight.
[9000] 8035. The method of item 7993, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 25% to about 70% by
weight.
[9001] 8036. The method of item 7993, wherein the implant is
combined with a coating, and the coating further comprises a
polymer.
[9002] 8037. The method of item 7993, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition.
[9003] 8038. The method of item 7993, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition, where the first composition and the
second composition are different.
[9004] 8039. The method of item 7993, wherein the device comprises
a polymer.
[9005] 8040. The method of item 7993, wherein the device comprises
a polymer, and the polymer is a component of the composition.
[9006] 8041. The method of item 7993, wherein the implant is
combined with a polymer, and the polymer is a copolymer.
[9007] 8042. The method of item 7993, wherein the implant is
combined with a polymer, and the polymer is a block copolymer.
[9008] 8043. The method of item 7993, wherein the implant is
combined with a polymer, and the polymer is a random copolymer.
[9009] 8044. The method of item 7993, wherein the implant is
combined with a polymer, and the polymer is a biodegradable
polymer.
[9010] 8045. The method of item 7993, wherein the implant is
combined with a polymer, and the polymer is a non-biodegradable
polymer.
[9011] 8046. The method of item 7993, wherein the implant is
combined with a polymer, and the polymer is a hydrophilic
polymer.
[9012] 8047. The method of item 7993, wherein the implant is
combined with a polymer, and the polymer is a hydrophobic
polymer.
[9013] 8048. The method of item 7993, wherein the implant is
combined with a polymer, and the polymer has hydrophilic
domains.
[9014] 8049. The method of item 7993, wherein the implant is
combined with a polymer, and the polymer has hydrophobic
domains.
[9015] 8050. The method of item 7993, wherein the implant is
combined with a polymer, and the polymer is a non-conductive
polymer.
[9016] 8051. The method of item 7993, wherein the implant is
combined with a polymer, and the polymer is an elastomer.
[9017] 8052. The method of item 7993, wherein the implant is
combined with a polymer, and the polymer is a hydrogel.
[9018] 8053. The method of item 7993, wherein the implant is
combined with a polymer, and the polymer is a silicone polymer.
[9019] 8054. The method of item 7993, wherein the implant is
combined with a polymer, and the polymer is a hydrocarbon
polymer.
[9020] 8055. The method of item 7993, wherein the implant is
combined with a polymer, and the polymer is a styrene-derived
polymer.
[9021] 8056. The method of item 7993, wherein the implant is
combined with a polymer, and the polymer is a butadiene
polymer.
[9022] 8057. The method of item 7993, wherein the implant is
combined with a polymer, and the polymer is a macromer.
[9023] 8058. The method of item 7993, wherein the implant is
combined with a polymer, and the polymer is a poly(ethylene glycol)
polymer.
[9024] 8059. The method of item 7993, wherein the implant is
combined with a polymer, and the polymer is an amorphous
polymer.
[9025] 8060. The method of item 7993, wherein the implant is
combined with a polymer, and the polymer is a lubricious
coating.
[9026] 8061. The method of item 7993 wherein the fibrosing agent is
located within pores or holes of the device.
[9027] 8062. The method of item 7993 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[9028] 8063. The method of item 7993, wherein the implant is
further combined with a second pharmaceutically active agent.
[9029] 8064. The method of item 7993, wherein the implant is
further combined with an anti-inflammatory agent.
[9030] 8065. The method of item 7993 wherein the implant is further
combined with an agent that inhibits infection.
[9031] 8066. The method of item 7993, wherein the implant is
further combined with an anthracycline.
[9032] 8067. The method of item 7993, wherein the implant is
further combined with doxorubicin.
[9033] 8068. The method of item 7993, wherein the implant is
further combined with mitoxantrone.
[9034] 8069. The method of item 7993, wherein the implant is
further combined with a fluoropyrimidine.
[9035] 8070. The method of item 7993, wherein the implant is
further combined with 5-fluorouracil (5-FU).
[9036] 8071. The method of item 7993, wherein the implant is
further combined with a folic acid antagonist.
[9037] 8072. The method of item 7993, wherein the implant is
further combined with methotrexate.
[9038] 8073. The method of item 7993, wherein the implant is
further combined with a podophylotoxin.
[9039] 8074. The method of item 7993, wherein the implant is
further combined with etoposide.
[9040] 8075. The method of item 7993 wherein the implant is further
combined with a camptothecin.
[9041] 8076. The method of item 7993, wherein the implant is
further combined with a hydroxyurea.
[9042] 8077. The method of item 7993, wherein the implant is
further combined with a platinum complex.
[9043] 8078. The method of item 7993, wherein the implant is
further combined with cisplatin.
[9044] 8079. The method of item 7993, wherein the implant is
further combined with an anti-thrombotic agent.
[9045] 8080. The method of item 7993, wherein the implant is
further combined with a visualization agent.
[9046] 8081. The method of item 7993, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises a metal, a halogenated compound, or a
barium containing compound.
[9047] 8082. The method of item 7993, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises barium, tantalum, or technetium.
[9048] 8083. The method of item 7993, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a MRI responsive material.
[9049] 8084. The method of item 7993, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a gadolinium chelate.
[9050] 8085. The method of item 7993, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises iron, magnesium, manganese, copper,
or chromium.
[9051] 8086. The method of item 7993, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises an iron oxide compound.
[9052] 8087. The method of item 7993, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a dye, pigment, or colorant.
[9053] 8088. The method of item 7993, wherein the implant is
further combined with an echogenic material.
[9054] 8089. The method of item 7993, wherein the implant is
further combined with an echogenic material, and the echogenic
material is in the form of a coating.
[9055] 8090. The method of item 7993 wherein the device is
sterilized.
[9056] 8091. The method of item 7993 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[9057] 8092. The method of item 7993 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[9058] 8093. The method of item 7993 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[9059] 8094. The method of item 7993 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[9060] 8095. The method of item 7993 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[9061] 8096. The method of item 7993 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[9062] 8097. The method of item 7993 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[9063] 8098. The method of item 7993 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[9064] 8099. The method of item 7993 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[9065] 8100. The method of item 7993 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[9066] 8101. The method of item 7993 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[9067] 8102. The method of item 7993 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[9068] 8103. The method of item 7993 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[9069] 8104. The method of item 7993 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[9070] 8105. The method of item 7993 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[9071] 8106. The method of item 7993 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[9072] 8107. The method of item 7993 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[9073] 8108. The method of item 7993 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[9074] 8109. The method of item 7993 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[9075] 8110. The method of item 7993 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[9076] 8111. The method of item 7993 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[9077] 8112. The method of item 7993 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[9078] 8113. The method of item 7993 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[9079] 8114. The method of item 7993 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[9080] 8115. The method of item 7993 wherein the implant is in the
form of a pin.
[9081] 8116. The method of item 7993 wherein the implant is used to
stabilize transverse fractures.
[9082] 8117. The method of item 7993 wherein the implant comprises
steel.
[9083] 8118. A method of making a medical device comprising
combining i) a collagen implant and ii) a fibrosing agent or a
composition comprising a fibrosing agent, where the fibrosing agent
induces a fibrotic response between the device and a patient in
which the device is implanted.
[9084] 8119. The method of item 8118 wherein the fibrosing agent
promotes regeneration.
[9085] 8120. The method of item 8118 wherein the fibrosing agent
promotes angiogenesis.
[9086] 8121. The method of item 8118 wherein the fibrosing agent
promotes fibroblast migration.
[9087] 8122. The method of item 8118 wherein the fibrosing agent
promotes fibroblast proliferation.
[9088] 8123. The method of item 8118 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[9089] 8124. The method of item 8118 wherein the fibrosing agent
promotes tissue remodeling.
[9090] 8125. The method of item 8118 wherein the fibrosing agent is
an arterial vessel wall irritant.
[9091] 8126. The method of item 8118 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[9092] 8127. The method of item 8118 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[9093] 8128. The method of item 8118 wherein the fibrosing agent is
or comprises silk.
[9094] 8129. The method of item 8118 wherein the fibrosing agent is
or comprises mineral particles.
[9095] 8130. The method of item 8118 wherein the fibrosing agent is
or comprises chitosan.
[9096] 8131. The method of item 8118 wherein the fibrosing agent is
or comprises polylysine.
[9097] 8132. The method of item 8118 wherein the fibrosing agent is
or comprises fibronectin.
[9098] 8133. The method of item 8118 wherein the fibrosing agent is
or comprises bleomycin.
[9099] 8134. The method of item 8118 wherein the fibrosing agent is
or comprises CTGF.
[9100] 8135. The method of item 8118 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[9101] 8136. The method of item 8118 wherein the fibrosing agent is
in the form of a particulate.
[9102] 8137. The method of item 8118 wherein the composition
further comprises an inflammatory cytokine.
[9103] 8138. The method of item 8118 wherein the composition
further comprises an agent that stimulates cell proliferation.
[9104] 8139. The method of item 8118 wherein the composition is in
the form of a gel or paste.
[9105] 8140. The method of item 8118 wherein the fibrosing agent is
in the form of tufts.
[9106] 8141. The method of item 8118 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[9107] 8142. The method of item 8118 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[9108] 8143. The method of item 8118, wherein the implant is
combined with a coating, and the coating comprises the fibrosing
agent.
[9109] 8144. The method of item 8118, wherein the implant is
combined with a coating, and the coating is disposed on a surface
of the device.
[9110] 8145. The method of item 8118, wherein the implant is
combined with a coating, and the coating directly contacts the
device.
[9111] 8146. The method of item 8118, wherein the implant is
combined with a coating, and the coating indirectly contacts the
device.
[9112] 8147. The method of item 8118, wherein the implant is
combined with a coating, and the coating partially covers the
device.
[9113] 8148. The method of item 8118, wherein the implant is
combined with a coating, and the coating completely covers the
device.
[9114] 8149. The method of item 8118, wherein the implant is
combined with a coating, and the coating is a uniform coating.
[9115] 8150. The method of item 8118, wherein the implant is
combined with a coating, and the coating is a non-uniform
coating.
[9116] 8151. The method of item 8118, wherein the implant is
combined with a coating, and the coating is a discontinuous
coating.
[9117] 8152. The method of item 8118 wherein the implant is
combined with a coating, and the coating is a patterned
coating.
[9118] 8153. The method of item 8118, wherein the implant is
combined with a coating, and the coating has a thickness of 100
.mu.m or less.
[9119] 8154. The method of item 8118, wherein the implant is
combined with a coating, and the coating has a thickness of 10
.mu.m or less.
[9120] 8155. The method of item 8118, wherein the implant is
combined with a coating, and the coating adheres to the surface of
the device upon deployment of the device.
[9121] 8156. The method of item 8118, wherein the implant is
combined with a coating, and the coating is stable at room
temperature for a period of at least 1 year.
[9122] 8157. The method of item 8118, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 0.0001% to about 1% by
weight.
[9123] 8158. The method of item 8118, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 1% to about 10% by
weight.
[9124] 8159. The method of item 8118, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 10% to about 25% by
weight.
[9125] 8160. The method of item 8118, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 25% to about 70% by
weight.
[9126] 8161. The method of item 8118, wherein the implant is
combined with a coating, and the coating further comprises a
polymer.
[9127] 8162. The method of item 8118, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition.
[9128] 8163. The method of item 8118, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition, where the first composition and the
second composition are different.
[9129] 8164. The method of item 8118, wherein the device comprises
a polymer.
[9130] 8165. The method of item 8118, wherein the device comprises
a polymer, and the polymer is a component of the composition.
[9131] 8166. The method of item 8118, wherein the implant is
combined with a polymer, and the polymer is a copolymer.
[9132] 8167. The method of item 8118, wherein the implant is
combined with a polymer, and the polymer is a block copolymer.
[9133] 8168. The method of item 8118, wherein the implant is
combined with a polymer, and the polymer is a random copolymer.
[9134] 8169. The method of item 8118, wherein the implant is
combined with a polymer, and the polymer is a biodegradable
polymer.
[9135] 8170. The method of item 8118, wherein the implant is
combined with a polymer, and the polymer is a non-biodegradable
polymer.
[9136] 8171. The method of item 8118, wherein the implant is
combined with a polymer, and the polymer is a hydrophilic
polymer.
[9137] 8172. The method of item 8118, wherein the implant is
combined with a polymer, and the polymer is a hydrophobic
polymer.
[9138] 8173. The method of item 8118, wherein the implant is
combined with a polymer, and the polymer has hydrophilic
domains.
[9139] 8174. The method of item 8118, wherein the implant is
combined with a polymer, and the polymer has hydrophobic
domains.
[9140] 8175. The method of item 8118, wherein the implant is
combined with a polymer, and the polymer is a non-conductive
polymer.
[9141] 8176. The method of item 8118, wherein the implant is
combined with a polymer, and the polymer is an elastomer.
[9142] 8177. The method of item 8118, wherein the implant is
combined with a polymer, and the polymer is a hydrogel.
[9143] 8178. The method of item 8118, wherein the implant is
combined with a polymer, and the polymer is a silicone polymer.
[9144] 8179. The method of item 8118, wherein the implant is
combined with a polymer, and the polymer is a hydrocarbon
polymer.
[9145] 8180. The method of item 8118, wherein the implant is
combined with a polymer, and the polymer is a styrene-derived
polymer.
[9146] 8181. The method of item 8118, wherein the implant is
combined with a polymer, and the polymer is a butadiene
polymer.
[9147] 8182. The method of item 8118, wherein the implant is
combined with a polymer, and the polymer is a macromer.
[9148] 8183. The method of item 8118, wherein the implant is
combined with a polymer, and the polymer is a poly(ethylene glycol)
polymer.
[9149] 8184. The method of item 8118, wherein the implant is
combined with a polymer, and the polymer is an amorphous
polymer.
[9150] 8185. The method of item 8118, wherein the implant is
combined with a polymer, and the polymer is a lubricious
coating.
[9151] 8186. The method of item 8118 wherein the fibrosing agent is
located within pores or holes of the device.
[9152] 8187. The method of item 8118 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[9153] 8188. The method of item 8118, wherein the implant is
further combined with a second pharmaceutically active agent.
[9154] 8189. The method of item 8118, wherein the implant is
further combined with an anti-inflammatory agent.
[9155] 8190. The method of item 8118 wherein the implant is further
combined with an agent that inhibits infection.
[9156] 8191. The method of item 8118, wherein the implant is
further combined with an anthracycline.
[9157] 8192. The method of item 8118, wherein the implant is
further combined with doxorubicin.
[9158] 8193. The method of item 8118, wherein the implant is
further combined with mitoxantrone.
[9159] 8194. The method of item 8118, wherein the implant is
further combined with a fluoropyrimidine.
[9160] 8195. The method of item 8118, wherein the implant is
further combined with 5-fluorouracil (5-FU).
[9161] 8196. The method of item 8118, wherein the implant is
further combined with a folic acid antagonist.
[9162] 8197. The method of item 8118, wherein the implant is
further combined with methotrexate.
[9163] 8198. The method of item 8118, wherein the implant is
further combined with a podophylotoxin.
[9164] 8199. The method of item 8118, wherein the implant is
further combined with etoposide.
[9165] 8200. The method of item 8118 wherein the implant is further
combined with a camptothecin.
[9166] 8201. The method of item 8118, wherein the implant is
further combined with a hydroxyurea.
[9167] 8202. The method of item 8118, wherein the implant is
further combined with a platinum complex.
[9168] 8203. The method of item 8118, wherein the implant is
further combined with cisplatin.
[9169] 8204. The method of item 8118, wherein the implant is
further combined with an anti-thrombotic agent.
[9170] 8205. The method of item 8118, wherein the implant is
further combined with a visualization agent.
[9171] 8206. The method of item 8118, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises a metal, a halogenated compound, or a
barium containing compound.
[9172] 8207. The method of item 8118, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises barium, tantalum, or technetium.
[9173] 8208. The method of item 8118, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a MRI responsive material.
[9174] 8209. The method of item 8118, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a gadolinium chelate.
[9175] 8210. The method of item 8118, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises iron, magnesium, manganese, copper,
or chromium.
[9176] 8211. The method of item 8118, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises an iron oxide compound.
[9177] 8212. The method of item 8118, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a dye, pigment, or colorant.
[9178] 8213. The method of item 8118, wherein the implant is
further combined with an echogenic material.
[9179] 8214. The method of item 8118, wherein the implant is
further combined with an echogenic material, and the echogenic
material is in the form of a coating.
[9180] 8215. The method of item 8118 wherein the device is
sterilized.
[9181] 8216. The method of item 8118 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[9182] 8217. The method of item 8118 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[9183] 8218. The method of item 8118 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[9184] 8219. The method of item 8118 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[9185] 8220. The method of item 8118 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[9186] 8221. The method of item 8118 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[9187] 8222. The method of item 8118 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[9188] 8223. The method of item 8118 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[9189] 8224. The method of item 8118 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[9190] 8225. The method of item 8118 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[9191] 8226. The method of item 8118 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[9192] 8227. The method of item 8118 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[9193] 8228. The method of item 8118 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[9194] 8229. The method of item 8118 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[9195] 8230. The method of item 8118 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[9196] 8231. The method of item 8118 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[9197] 8232. The method of item 8118 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[9198] 8233. The method of item 8118 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[9199] 8234. The method of item 8118 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[9200] 8235. The method of item 8118 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[9201] 8236. The method of item 8118 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[9202] 8237. The method of item 8118 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[9203] 8238. The method of item 8118 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[9204] 8239. The method of item 8118 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[9205] 8240. The method of item 8118 wherein the implant is a
dental implant.
[9206] 8241. The method of item 8118 wherein the implant is an
orthopedic implant.
[9207] 8242. The method of item 8118 wherein the implant is a
surgical mesh.
[9208] 8243. The method of item 8118 wherein the implant is made,
in whole or part, from crosslinked collagen.
[9209] 8244. A method of making a medical device comprising
combining i) a Fallopian tube implant and ii) a fibrosing agent or
a composition comprising a fibrosing agent, where the fibrosing
agent induces a fibrotic response between the device and a patient
in which the device is implanted.
[9210] 8245. The method of item 8244 wherein the fibrosing agent
promotes regeneration.
[9211] 8246. The method of item 8244 wherein the fibrosing agent
promotes angiogenesis.
[9212] 8247. The method of item 8244 wherein the fibrosing agent
promotes fibroblast migration.
[9213] 8248. The method of item 8244 wherein the fibrosing agent
promotes fibroblast proliferation.
[9214] 8249. The method of item 8244 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[9215] 8250. The method of item 8244 wherein the fibrosing agent
promotes tissue remodeling.
[9216] 8251. The method of item 8244 wherein the fibrosing agent is
an arterial vessel wall irritant.
[9217] 8252. The method of item 8244 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[9218] 8253. The method of item 8244 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[9219] 8254. The method of item 8244 wherein the fibrosing agent is
or comprises silk.
[9220] 8255. The method of item 8244 wherein the fibrosing agent is
or comprises mineral particles.
[9221] 8256. The method of item 8244 wherein the fibrosing agent is
or comprises chitosan.
[9222] 8257. The method of item 8244 wherein the fibrosing agent is
or comprises polylysine.
[9223] 8258. The method of item 8244 wherein the fibrosing agent is
or comprises fibronectin.
[9224] 8259. The method of item 8244 wherein the fibrosing agent is
or comprises bleomycin.
[9225] 8260. The method of item 8244 wherein the fibrosing agent is
or comprises CTGF.
[9226] 8261. The method of item 8244 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[9227] 8262. The method of item 8244 wherein the fibrosing agent is
in the form of a particulate.
[9228] 8263. The method of item 8244 wherein the composition
further comprises an inflammatory cytokine.
[9229] 8264. The method of item 8244 wherein the composition
further comprises an agent that stimulates cell proliferation.
[9230] 8265. The method of item 8244 wherein the composition is in
the form of a gel or paste.
[9231] 8266. The method of item 8244 wherein the fibrosing agent is
in the form of tufts.
[9232] 8267. The method of item 8244 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[9233] 8268. The method of item 8244 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[9234] 8269. The method of item 8244, wherein the implant is
combined with a coating, and the coating comprises the fibrosing
agent.
[9235] 8270. The method of item 8244, wherein the implant is
combined with a coating, and the coating is disposed on a surface
of the device.
[9236] 8271. The method of item 8244, wherein the implant is
combined with a coating, and the coating directly contacts the
device.
[9237] 8272. The method of item 8244, wherein the implant is
combined with a coating, and the coating indirectly contacts the
device.
[9238] 8273. The method of item 8244, wherein the implant is
combined with a coating, and the coating partially covers the
device.
[9239] 8274. The method of item 8244, wherein the implant is
combined with a coating, and the coating completely covers the
device.
[9240] 8275. The method of item 8244, wherein the implant is
combined with a coating, and the coating is a uniform coating.
[9241] 8276. The method of item 8244, wherein the implant is
combined with a coating, and the coating is a non-uniform
coating.
[9242] 8277. The method of item 8244, wherein the implant is
combined with a coating, and the coating is a discontinuous
coating.
[9243] 8278. The method of item 8244 wherein the implant is
combined with a coating, and the coating is a patterned
coating.
[9244] 8279. The method of item 8244, wherein the implant is
combined with a coating, and the coating has a thickness of 100
.mu.m or less.
[9245] 8280. The method of item 8244, wherein the implant is
combined with a coating, and the coating has a thickness of 10
.mu.m or less.
[9246] 8281. The method of item 8244, wherein the implant is
combined with a coating, and the coating adheres to the surface of
the device upon deployment of the device.
[9247] 8282. The method of item 8244, wherein the implant is
combined with a coating, and the coating is stable at room
temperature for a period of at least 1 year.
[9248] 8283. The method of item 8244, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 0.0001% to about 1% by
weight.
[9249] 8284. The method of item 8244, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 1% to about 10% by
weight.
[9250] 8285. The method of item 8244, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 10% to about 25% by
weight.
[9251] 8286. The method of item 8244, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 25% to about 70% by
weight.
[9252] 8287. The method of item 8244, wherein the implant is
combined with a coating, and the coating further comprises a
polymer.
[9253] 8288. The method of item 8244, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition.
[9254] 8289. The method of item 8244, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition, where the first composition and the
second composition are different.
[9255] 8290. The method of item 8244, wherein the device comprises
a polymer.
[9256] 8291. The method of item 8244, wherein the device comprises
a polymer, and the polymer is a component of the composition.
[9257] 8292. The method of item 8244, wherein the implant is
combined with a polymer, and the polymer is a copolymer.
[9258] 8293. The method of item 8244, wherein the implant is
combined with a polymer, and the polymer is a block copolymer.
[9259] 8294. The method of item 8244, wherein the implant is
combined with a polymer, and the polymer is a random copolymer.
[9260] 8295. The method of item 8244, wherein the implant is
combined with a polymer, and the polymer is a biodegradable
polymer.
[9261] 8296. The method of item 8244, wherein the implant is
combined with a polymer, and the polymer is a non-biodegradable
polymer.
[9262] 8297. The method of item 8244, wherein the implant is
combined with a polymer, and the polymer is a hydrophilic
polymer.
[9263] 8298. The method of item 8244, wherein the implant is
combined with a polymer, and the polymer is a hydrophobic
polymer.
[9264] 8299. The method of item 8244, wherein the implant is
combined with a polymer, and the polymer has hydrophilic
domains.
[9265] 8300. The method of item 8244, wherein the implant is
combined with a polymer, and the polymer has hydrophobic
domains.
[9266] 8301. The method of item 8244, wherein the implant is
combined with a polymer, and the polymer is a non-conductive
polymer.
[9267] 8302. The method of item 8244, wherein the implant is
combined with a polymer, and the polymer is an elastomer.
[9268] 8303. The method of item 8244, wherein the implant is
combined with a polymer, and the polymer is a hydrogel.
[9269] 8304. The method of item 8244, wherein the implant is
combined with a polymer, and the polymer is a silicone polymer.
[9270] 8305. The method of item 8244, wherein the implant is
combined with a polymer, and the polymer is a hydrocarbon
polymer.
[9271] 8306. The method of item 8244, wherein the implant is
combined with a polymer, and the polymer is a styrene-derived
polymer.
[9272] 8307. The method of item 8244, wherein the implant is
combined with a polymer, and the polymer is a butadiene
polymer.
[9273] 8308. The method of item 8244, wherein the implant is
combined with a polymer, and the polymer is a macromer.
[9274] 8309. The method of item 8244, wherein the implant is
combined with a polymer, and the polymer is a poly(ethylene glycol)
polymer.
[9275] 8310. The method of item 8244, wherein the implant is
combined with a polymer, and the polymer is an amorphous
polymer.
[9276] 8311. The method of item 8244, wherein the implant is
combined with a polymer, and the polymer is a lubricious
coating.
[9277] 8312. The method of item 8244 wherein the fibrosing agent is
located within pores or holes of the device.
[9278] 8313. The method of item 8244 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[9279] 8314. The method of item 8244, wherein the implant is
further combined with a second pharmaceutically active agent.
[9280] 8315. The method of item 8244, wherein the implant is
further combined with an anti-inflammatory agent.
[9281] 8316. The method of item 8244 wherein the implant is further
combined with an agent that inhibits infection.
[9282] 8317. The method of item 8244, wherein the implant is
further combined with an anthracycline.
[9283] 8318. The method of item 8244, wherein the implant is
further combined with doxorubicin.
[9284] 8319. The method of item 8244, wherein the implant is
further combined with mitoxantrone.
[9285] 8320. The method of item 8244, wherein the implant is
further combined with a fluoropyrimidine.
[9286] 8321. The method of item 8244, wherein the implant is
further combined with 5-fluorouracil (5-FU).
[9287] 8322. The method of item 8244, wherein the implant is
further combined with a folic acid antagonist.
[9288] 8323. The method of item 8244, wherein the implant is
further combined with methotrexate.
[9289] 8324. The method of item 8244, wherein the implant is
further combined with a podophylotoxin.
[9290] 8325. The method of item 8244, wherein the implant is
further combined with etoposide.
[9291] 8326. The method of item 8244 wherein the implant is further
combined with a camptothecin.
[9292] 8327. The method of item 8244, wherein the implant is
further combined with a hydroxyurea.
[9293] 8328. The method of item 8244, wherein the implant is
further combined with a platinum complex.
[9294] 8329. The method of item 8244, wherein the implant is
further combined with cisplatin.
[9295] 8330. The method of item 8244, wherein the implant is
further combined with an anti-thrombotic agent.
[9296] 8331. The method of item 8244, wherein the implant is
further combined with a visualization agent.
[9297] 8332. The method of item 8244, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises a metal, a halogenated compound, or a
barium containing compound.
[9298] 8333. The method of item 8244, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises barium, tantalum, or technetium.
[9299] 8334. The method of item 8244, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a MRI responsive material.
[9300] 8335. The method of item 8244, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a gadolinium chelate.
[9301] 8336. The method of item 8244, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises iron, magnesium, manganese, copper,
or chromium.
[9302] 8337. The method of item 8244, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises an iron oxide compound.
[9303] 8338. The method of item 8244, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a dye, pigment, or colorant.
[9304] 8339. The method of item 8244, wherein the implant is
further combined with an echogenic material.
[9305] 8340. The method of item 8244, wherein the implant is
further combined with an echogenic material, and the echogenic
material is in the form of a coating.
[9306] 8341. The method of item 8244 wherein the device is
sterilized.
[9307] 8342. The method of item 8244 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[9308] 8343. The method of item 8244 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[9309] 8344. The method of item 8244 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[9310] 8345. The method of item 8244 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[9311] 8346. The method of item 8244 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[9312] 8347. The method of item 8244 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[9313] 8348. The method of item 8244 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[9314] 8349. The method of item 8244 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[9315] 8350. The method of item 8244 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[9316] 8351. The method of item 8244 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[9317] 8352. The method of item 8244 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[9318] 8353. The method of item 8244 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[9319] 8354. The method of item 8244 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[9320] 8355. The method of item 8244 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[9321] 8356. The method of item 8244 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[9322] 8357. The method of item 8244 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[9323] 8358. The method of item 8244 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[9324] 8359. The method of item 8244 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[9325] 8360. The method of item 8244 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[9326] 8361. The method of item 8244 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[9327] 8362. The method of item 8244 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[9328] 8363. The method of item 8244 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[9329] 8364. The method of item 8244 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[9330] 8365. The method of item 8244 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[9331] 8366. The method of item 8244 wherein the implant is a duct
clamp.
[9332] 8367. The method of item 8244 wherein the implant is a
valved sterilization device.
[9333] 8368. The method of item 8244 wherein the implant is an
implantable, intrafallopian, female sterilization device.
[9334] 8369. The method of item 8244 wherein the implant is an
occlusive wire or coil fallopian tube implant.
[9335] 8370. The method of item 8244 wherein the implant is a
transcatheter occluding implant.
[9336] 8371. The method of item 8244 wherein the implant is a
fallopian tube stent.
[9337] 8372. The method of item 8244 wherein the implant is a
contraceptive uterine implant.
[9338] 8373. A method of making a medical device comprising
combining i) a prosthetic anal sphincter and ii) a fibrosing agent
or a composition comprising a fibrosing agent, where the fibrosing
agent induces a fibrotic response between the device and a patient
in which the device is implanted.
[9339] 8374. The method of item 8373 wherein the fibrosing agent
promotes regeneration.
[9340] 8375. The method of item 8373 wherein the fibrosing agent
promotes angiogenesis.
[9341] 8376. The method of item 8373 wherein the fibrosing agent
promotes fibroblast migration.
[9342] 8377. The method of item 8373 wherein the fibrosing agent
promotes fibroblast proliferation.
[9343] 8378. The method of item 8373 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[9344] 8379. The method of item 8373 wherein the fibrosing agent
promotes tissue remodeling.
[9345] 8380. The method of item 8373 wherein the fibrosing agent is
an arterial vessel wall irritant.
[9346] 8381. The method of item 8373 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[9347] 8382. The method of item 8373 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[9348] 8383. The method of item 8373 wherein the fibrosing agent is
or comprises silk.
[9349] 8384. The method of item 8373 wherein the fibrosing agent is
or comprises mineral particles.
[9350] 8385. The method of item 8373 wherein the fibrosing agent is
or comprises chitosan.
[9351] 8386. The method of item 8373 wherein the fibrosing agent is
or comprises polylysine.
[9352] 8387. The method of item 8373 wherein the fibrosing agent is
or comprises fibronectin.
[9353] 8388. The method of item 8373 wherein the fibrosing agent is
or comprises bleomycin.
[9354] 8389. The method of item 8373 wherein the fibrosing agent is
or comprises CTGF.
[9355] 8390. The method of item 8373 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[9356] 8391. The method of item 8373 wherein the fibrosing agent is
in the form of a particulate.
[9357] 8392. The method of item 8373 wherein the composition
further comprises an inflammatory cytokine.
[9358] 8393. The method of item 8373 wherein the composition
further comprises an agent that stimulates cell proliferation.
[9359] 8394. The method of item 8373 wherein the composition is in
the form of a gel or paste.
[9360] 8395. The method of item 8373 wherein the fibrosing agent is
in the form of tufts.
[9361] 8396. The method of item 8373 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[9362] 8397. The method of item 8373 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[9363] 8398. The method of item 8373, wherein the implant is
combined with a coating, and the coating comprises the fibrosing
agent.
[9364] 8399. The method of item 8373, wherein the implant is
combined with a coating, and the coating is disposed on a surface
of the device.
[9365] 8400. The method of item 8373, wherein the implant is
combined with a coating, and the coating directly contacts the
device.
[9366] 8401. The method of item 8373, wherein the implant is
combined with a coating, and the coating indirectly contacts the
device.
[9367] 8402. The method of item 8373, wherein the implant is
combined with a coating, and the coating partially covers the
device.
[9368] 8403. The method of item 8373, wherein the implant is
combined with a coating, and the coating completely covers the
device.
[9369] 8404. The method of item 8373, wherein the implant is
combined with a coating, and the coating is a uniform coating.
[9370] 8405. The method of item 8373, wherein the implant is
combined with a coating, and the coating is a non-uniform
coating.
[9371] 8406. The method of item 8373, wherein the implant is
combined with a coating, and the coating is a discontinuous
coating.
[9372] 8407. The method of item 8373 wherein the implant is
combined with a coating, and the coating is a patterned
coating.
[9373] 8408. The method of item 8373, wherein the implant is
combined with a coating, and the coating has a thickness of 100
.mu.m or less.
[9374] 8409. The method of item 8373, wherein the implant is
combined with a coating, and the coating has a thickness of 10
.mu.m or less.
[9375] 8410. The method of item 8373, wherein the implant is
combined with a coating, and the coating adheres to the surface of
the device upon deployment of the device.
[9376] 8411. The method of item 8373, wherein the implant is
combined with a coating, and the coating is stable at room
temperature for a period of at least 1 year.
[9377] 8412. The method of item 8373, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 0.0001% to about 1% by
weight.
[9378] 8413. The method of item 8373, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 1% to about 10% by
weight.
[9379] 8414. The method of item 8373, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 10% to about 25% by
weight.
[9380] 8415. The method of item 8373, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 25% to about 70% by
weight.
[9381] 8416. The method of item 8373, wherein the implant is
combined with a coating, and the coating further comprises a
polymer.
[9382] 8417. The method of item 8373, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition.
[9383] 8418. The method of item 8373, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition, where the first composition and the
second composition are different.
[9384] 8419. The method of item 8373, wherein the device comprises
a polymer.
[9385] 8420. The method of item 8373, wherein the device comprises
a polymer, and the polymer is a component of the composition.
[9386] 8421. The method of item 8373, wherein the implant is
combined with a polymer, and the polymer is a copolymer.
[9387] 8422. The method of item 8373, wherein the implant is
combined with a polymer, and the polymer is a block copolymer.
[9388] 8423. The method of item 8373, wherein the implant is
combined with a polymer, and the polymer is a random copolymer.
[9389] 8424. The method of item 8373, wherein the implant is
combined with a polymer, and the polymer is a biodegradable
polymer.
[9390] 8425. The method of item 8373, wherein the implant is
combined with a polymer, and the polymer is a non-biodegradable
polymer.
[9391] 8426. The method of item 8373, wherein the implant is
combined with a polymer, and the polymer is a hydrophilic
polymer.
[9392] 8427. The method of item 8373, wherein the implant is
combined with a polymer, and the polymer is a hydrophobic
polymer.
[9393] 8428. The method of item 8373, wherein the implant is
combined with a polymer, and the polymer has hydrophilic
domains.
[9394] 8429. The method of item 8373, wherein the implant is
combined with a polymer, and the polymer has hydrophobic
domains.
[9395] 8430. The method of item 8373, wherein the implant is
combined with a polymer, and the polymer is a non-conductive
polymer.
[9396] 8431. The method of item 8373, wherein the implant is
combined with a polymer, and the polymer is an elastomer.
[9397] 8432. The method of item 8373, wherein the implant is
combined with a polymer, and the polymer is a hydrogel.
[9398] 8433. The method of item 8373, wherein the implant is
combined with a polymer, and the polymer is a silicone polymer.
[9399] 8434. The method of item 8373, wherein the implant is
combined with a polymer, and the polymer is a hydrocarbon
polymer.
[9400] 8435. The method of item 8373, wherein the implant is
combined with a polymer, and the polymer is a styrene-derived
polymer.
[9401] 8436. The method of item 8373, wherein the implant is
combined with a polymer, and the polymer is a butadiene
polymer.
[9402] 8437. The method of item 8373, wherein the implant is
combined with a polymer, and the polymer is a macromer.
[9403] 8438. The method of item 8373, wherein the implant is
combined with a polymer, and the polymer is a poly(ethylene glycol)
polymer.
[9404] 8439. The method of item 8373, wherein the implant is
combined with a polymer, and the polymer is an amorphous
polymer.
[9405] 8440. The method of item 8373, wherein the implant is
combined with a polymer, and the polymer is a lubricious
coating.
[9406] 8441. The method of item 8373 wherein the fibrosing agent is
located within pores or holes of the device.
[9407] 8442. The method of item 8373 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[9408] 8443. The method of item 8373, wherein the implant is
further combined with a second pharmaceutically active agent.
[9409] 8444. The method of item 8373, wherein the implant is
further combined with an anti-inflammatory agent.
[9410] 8445. The method of item 8373 wherein the implant is further
combined with an agent that inhibits infection.
[9411] 8446. The method of item 8373, wherein the implant is
further combined with an anthracycline.
[9412] 8447. The method of item 8373, wherein the implant is
further combined with doxorubicin.
[9413] 8448. The method of item 8373, wherein the implant is
further combined with mitoxantrone.
[9414] 8449. The method of item 8373, wherein the implant is
further combined with a fluoropyrimidine.
[9415] 8450. The method of item 8373, wherein the implant is
further combined with 5-fluorouracil (5-FU).
[9416] 8451. The method of item 8373, wherein the implant is
further combined with a folic acid antagonist.
[9417] 8452. The method of item 8373, wherein the implant is
further combined with methotrexate.
[9418] 8453. The method of item 8373, wherein the implant is
further combined with a podophylotoxin.
[9419] 8454. The method of item 8373, wherein the implant is
further combined with etoposide.
[9420] 8455. The method of item 8373 wherein the implant is further
combined with a camptothecin.
[9421] 8456. The method of item 8373, wherein the implant is
further combined with a hydroxyurea.
[9422] 8457. The method of item 8373, wherein the implant is
further combined with a platinum complex.
[9423] 8458. The method of item 8373, wherein the implant is
further combined with cisplatin.
[9424] 8459. The method of item 8373, wherein the implant is
further combined with an anti-thrombotic agent.
[9425] 8460. The method of item 8373, wherein the implant is
further combined with a visualization agent.
[9426] 8461. The method of item 8373, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises a metal, a halogenated compound, or a
barium containing compound.
[9427] 8462. The method of item 8373, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises barium, tantalum, or technetium.
[9428] 8463. The method of item 8373, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a MRI responsive material.
[9429] 8464. The method of item 8373, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a gadolinium chelate.
[9430] 8465. The method of item 8373, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises iron, magnesium, manganese, copper,
or chromium.
[9431] 8466. The method of item 8373, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises an iron oxide compound.
[9432] 8467. The method of item 8373, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a dye, pigment, or colorant.
[9433] 8468. The method of item 8373, wherein the implant is
further combined with an echogenic material.
[9434] 8469. The method of item 8373, wherein the implant is
further combined with an echogenic material, and the echogenic
material is in the form of a coating.
[9435] 8470. The method of item 8373 wherein the device is
sterilized.
[9436] 8471. The method of item 8373 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[9437] 8472. The method of item 8373 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[9438] 8473. The method of item 8373 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[9439] 8474. The method of item 8373 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[9440] 8475. The method of item 8373 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[9441] 8476. The method of item 8373 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[9442] 8477. The method of item 8373 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[9443] 8478. The method of item 8373 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[9444] 8479. The method of item 8373 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[9445] 8480. The method of item 8373 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[9446] 8481. The method of item 8373 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[9447] 8482. The method of item 8373 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[9448] 8483. The method of item 8373 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[9449] 8484. The method of item 8373 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[9450] 8485. The method of item 8373 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[9451] 8486. The method of item 8373 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[9452] 8487. The method of item 8373 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[9453] 8488. The method of item 8373 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[9454] 8489. The method of item 8373 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[9455] 8490. The method of item 8373 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[9456] 8491. The method of item 8373 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[9457] 8492. The method of item 8373 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[9458] 8493. The method of item 8373 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[9459] 8494. The method of item 8373 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[9460] 8495. The method of item 8373 wherein the implant is, or
comprises, an ablation device.
[9461] 8496. The method of item 8373 wherein the implant is, or
comprises, a nerve stimulator.
[9462] 8497. The method of item 8373 wherein the implant is, or
comprises, a pump.
[9463] 8498. The method of item 8373 wherein the implant is, or
comprises, a stapling device.
[9464] 8499. A method of making a medical device comprising
combining i) an implantable male contraceptive device and ii) a
fibrosing agent or a composition comprising a fibrosing agent,
where the fibrosing agent induces a fibrotic response between the
device and a patient in which the device is implanted.
[9465] 8500. The method of item 8499 wherein the fibrosing agent
promotes regeneration.
[9466] 8501. The method of item 8499 wherein the fibrosing agent
promotes angiogenesis.
[9467] 8502. The method of item 8499 wherein the fibrosing agent
promotes fibroblast migration.
[9468] 8503. The method of item 8499 wherein the fibrosing agent
promotes fibroblast proliferation.
[9469] 8504. The method of item 8499 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[9470] 8505. The method of item 8499 wherein the fibrosing agent
promotes tissue remodeling.
[9471] 8506. The method of item 8499 wherein the fibrosing agent is
an arterial vessel wall irritant.
[9472] 8507. The method of item 8499 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[9473] 8508. The method of item 8499 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[9474] 8509. The method of item 8499 wherein the fibrosing agent is
or comprises silk.
[9475] 8510. The method of item 8499 wherein the fibrosing agent is
or comprises mineral particles.
[9476] 8511. The method of item 8499 wherein the fibrosing agent is
or comprises chitosan.
[9477] 8512. The method of item 8499 wherein the fibrosing agent is
or comprises polylysine.
[9478] 8513. The method of item 8499 wherein the fibrosing agent is
or comprises fibronectin.
[9479] 8514. The method of item 8499 wherein the fibrosing agent is
or comprises bleomycin.
[9480] 8515. The method of item 8499 wherein the fibrosing agent is
or comprises CTGF.
[9481] 8516. The method of item 8499 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[9482] 8517. The method of item 8499 wherein the fibrosing agent is
in the form of a particulate.
[9483] 8518. The method of item 8499 wherein the composition
further comprises an inflammatory cytokine.
[9484] 8519. The method of item 8499 wherein the composition
further comprises an agent that stimulates cell proliferation.
[9485] 8520. The method of item 8499 wherein the composition is in
the form of a gel or paste.
[9486] 8521. The method of item 8499 wherein the fibrosing agent is
in the form of tufts.
[9487] 8522. The method of item 8499 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[9488] 8523. The method of item 8499 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[9489] 8524. The method of item 8499, wherein the implant is
combined with a coating, and the coating comprises the fibrosing
agent.
[9490] 8525. The method of item 8499, wherein the implant is
combined with a coating, and the coating is disposed on a surface
of the device.
[9491] 8526. The method of item 8499, wherein the implant is
combined with a coating, and the coating directly contacts the
device.
[9492] 8527. The method of item 8499, wherein the implant is
combined with a coating, and the coating indirectly contacts the
device.
[9493] 8528. The method of item 8499, wherein the implant is
combined with a coating, and the coating partially covers the
device.
[9494] 8529. The method of item 8499, wherein the implant is
combined with a coating, and the coating completely covers the
device.
[9495] 8530. The method of item 8499, wherein the implant is
combined with a coating, and the coating is a uniform coating.
[9496] 8531. The method of item 8499, wherein the implant is
combined with a coating, and the coating is a non-uniform
coating.
[9497] 8532. The method of item 8499, wherein the implant is
combined with a coating, and the coating is a discontinuous
coating.
[9498] 8533. The method of item 8499 wherein the implant is
combined with a coating, and the coating is a patterned
coating.
[9499] 8534. The method of item 8499, wherein the implant is
combined with a coating, and the coating has a thickness of 100
.mu.m or less.
[9500] 8535. The method of item 8499, wherein the implant is
combined with a coating, and the coating has a thickness of 10
.mu.m or less.
[9501] 8536. The method of item 8499, wherein the implant is
combined with a coating, and the coating adheres to the surface of
the device upon deployment of the device.
[9502] 8537. The method of item 8499, wherein the implant is
combined with a coating, and the coating is stable at room
temperature for a period of at least 1 year.
[9503] 8538. The method of item 8499, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 0.0001% to about 1% by
weight.
[9504] 8539. The method of item 8499, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 1% to about 10% by
weight.
[9505] 8540. The method of item 8499, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 10% to about 25% by
weight.
[9506] 8541. The method of item 8499, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 25% to about 70% by
weight.
[9507] 8542. The method of item 8499, wherein the implant is
combined with a coating, and the coating further comprises a
polymer.
[9508] 8543. The method of item 8499, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition.
[9509] 8544. The method of item 8499, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition, where the first composition and the
second composition are different.
[9510] 8545. The method of item 8499, wherein the device comprises
a polymer.
[9511] 8546. The method of item 8499, wherein the device comprises
a polymer, and the polymer is a component of the composition.
[9512] 8547. The method of item 8499, wherein the implant is
combined with a polymer, and the polymer is a copolymer.
[9513] 8548. The method of item 8499, wherein the implant is
combined with a polymer, and the polymer is a block copolymer.
[9514] 8549. The method of item 8499, wherein the implant is
combined with a polymer, and the polymer is a random copolymer.
[9515] 8550. The method of item 8499, wherein the implant is
combined with a polymer, and the polymer is a biodegradable
polymer.
[9516] 8551. The method of item 8499, wherein the implant is
combined with a polymer, and the polymer is a non-biodegradable
polymer.
[9517] 8552. The method of item 8499, wherein the implant is
combined with a polymer, and the polymer is a hydrophilic
polymer.
[9518] 8553. The method of item 8499, wherein the implant is
combined with a polymer, and the polymer is a hydrophobic
polymer.
[9519] 8554. The method of item 8499, wherein the implant is
combined with a polymer, and the polymer has hydrophilic
domains.
[9520] 8555. The method of item 8499, wherein the implant is
combined with a polymer, and the polymer has hydrophobic
domains.
[9521] 8556. The method of item 8499, wherein the implant is
combined with a polymer, and the polymer is a non-conductive
polymer.
[9522] 8557. The method of item 8499, wherein the implant is
combined with a polymer, and the polymer is an elastomer.
[9523] 8558. The method of item 8499, wherein the implant is
combined with a polymer, and the polymer is a hydrogel.
[9524] 8559. The method of item 8499, wherein the implant is
combined with a polymer, and the polymer is a silicone polymer.
[9525] 8560. The method of item 8499, wherein the implant is
combined with a polymer, and the polymer is a hydrocarbon
polymer.
[9526] 8561. The method of item 8499, wherein the implant is
combined with a polymer, and the polymer is a styrene-derived
polymer.
[9527] 8562. The method of item 8499, wherein the implant is
combined with a polymer, and the polymer is a butadiene
polymer.
[9528] 8563. The method of item 8499, wherein the implant is
combined with a polymer, and the polymer is a macromer.
[9529] 8564. The method of item 8499, wherein the implant is
combined with a polymer, and the polymer is a poly(ethylene glycol)
polymer.
[9530] 8565. The method of item 8499, wherein the implant is
combined with a polymer, and the polymer is an amorphous
polymer.
[9531] 8566. The method of item 8499, wherein the implant is
combined with a polymer, and the polymer is a lubricious
coating.
[9532] 8567. The method of item 8499 wherein the fibrosing agent is
located within pores or holes of the device.
[9533] 8568. The method of item 8499 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[9534] 8569. The method of item 8499, wherein the implant is
further combined with a second pharmaceutically active agent.
[9535] 8570. The method of item 8499, wherein the implant is
further combined with an anti-inflammatory agent.
[9536] 8571. The method of item 8499 wherein the implant is further
combined with an agent that inhibits infection.
[9537] 8572. The method of item 8499, wherein the implant is
further combined with an anthracycline.
[9538] 8573. The method of item 8499, wherein the implant is
further combined with doxorubicin.
[9539] 8574. The method of item 8499, wherein the implant is
further combined with mitoxantrone.
[9540] 8575. The method of item 8499, wherein the implant is
further combined with a fluoropyrimidine.
[9541] 8576. The method of item 8499, wherein the implant is
further combined with 5-fluorouracil (5-FU).
[9542] 8577. The method of item 8499, wherein the implant is
further combined with a folic acid antagonist.
[9543] 8578. The method of item 8499, wherein the implant is
further combined with methotrexate.
[9544] 8579. The method of item 8499, wherein the implant is
further combined with a podophylotoxin.
[9545] 8580. The method of item 8499, wherein the implant is
further combined with etoposide.
[9546] 8581. The method of item 8499 wherein the implant is further
combined with a camptothecin.
[9547] 8582. The method of item 8499, wherein the implant is
further combined with a hydroxyurea.
[9548] 8583. The method of item 8499, wherein the implant is
further combined with a platinum complex.
[9549] 8584. The method of item 8499, wherein the implant is
further combined with cisplatin.
[9550] 8585. The method of item 8499, wherein the implant is
further combined with an anti-thrombotic agent.
[9551] 8586. The method of item 8499, wherein the implant is
further combined with a visualization agent.
[9552] 8587. The method of item 8499, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises a metal, a halogenated compound, or a
barium containing compound.
[9553] 8588. The method of item 8499, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises barium, tantalum, or technetium.
[9554] 8589. The method of item 8499, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a MRI responsive material.
[9555] 8590. The method of item 8499, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a gadolinium chelate.
[9556] 8591. The method of item 8499, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises iron, magnesium, manganese, copper,
or chromium.
[9557] 8592. The method of item 8499, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises an iron oxide compound.
[9558] 8593. The method of item 8499, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a dye, pigment, or colorant.
[9559] 8594. The method of item 8499, wherein the implant is
further combined with an echogenic material.
[9560] 8595. The method of item 8499, wherein the implant is
further combined with an echogenic material, and the echogenic
material is in the form of a coating.
[9561] 8596. The method of item 8499 wherein the device is
sterilized.
[9562] 8597. The method of item 8499 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[9563] 8598. The method of item 8499 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[9564] 8599. The method of item 8499 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[9565] 8600. The method of item 8499 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[9566] 8601. The method of item 8499 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[9567] 8602. The method of item 8499 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[9568] 8603. The method of item 8499 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[9569] 8604. The method of item 8499 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[9570] 8605. The method of item 8499 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[9571] 8606. The method of item 8499 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[9572] 8607. The method of item 8499 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[9573] 8608. The method of item 8499 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[9574] 8609. The method of item 8499 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[9575] 8610. The method of item 8499 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[9576] 8611. The method of item 8499 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[9577] 8612. The method of item 8499 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[9578] 8613. The method of item 8499 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[9579] 8614. The method of item 8499 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[9580] 8615. The method of item 8499 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[9581] 8616. The method of item 8499 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[9582] 8617. The method of item 8499 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[9583] 8618. The method of item 8499 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[9584] 8619. The method of item 8499 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[9585] 8620. The method of item 8499 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[9586] 8621. The method of item 8499 wherein the implant is, or
comprises, a valved sterilization device for surgical insertion
into the Vas Deferens.
[9587] 8622. The method of item 8499 wherein the implant is, or
comprises, a reversible male sterilization device.
[9588] 8623. The method of item 8499 wherein the implant is, or
comprises, a vasectomy clip.
[9589] 8624. The method of item 8499 wherein the implant is, or
comprises, a vasectomy suture.
[9590] 8625. The method of item 8499 wherein the implant is
implanted in the Vas Deferens.
[9591] 8626. A method of making a medical device comprising
combining i) gastric restriction implant and ii) a fibrosing agent
or a composition comprising a fibrosing agent, where the fibrosing
agent induces a fibrotic response between the device and a patient
in which the device is implanted.
[9592] 8627. The method of item 8626 wherein the fibrosing agent
promotes regeneration.
[9593] 8628. The method of item 8626 wherein the fibrosing agent
promotes angiogenesis.
[9594] 8629. The method of item 8626 wherein the fibrosing agent
promotes fibroblast migration.
[9595] 8630. The method of item 8626 wherein the fibrosing agent
promotes fibroblast proliferation.
[9596] 8631. The method of item 8626 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[9597] 8632. The method of item 8626 wherein the fibrosing agent
promotes tissue remodeling.
[9598] 8633. The method of item 8626 wherein the fibrosing agent is
an arterial vessel wall irritant.
[9599] 8634. The method of item 8626 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[9600] 8635. The method of item 8626 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[9601] 8636. The method of item 8626 wherein the fibrosing agent is
or comprises silk.
[9602] 8637. The method of item 8626 wherein the fibrosing agent is
or comprises mineral particles.
[9603] 8638. The method of item 8626 wherein the fibrosing agent is
or comprises chitosan.
[9604] 8639. The method of item 8626 wherein the fibrosing agent is
or comprises polylysine.
[9605] 8640. The method of item 8626 wherein the fibrosing agent is
or comprises fibronectin.
[9606] 8641. The method of item 8626 wherein the fibrosing agent is
or comprises bleomycin.
[9607] 8642. The method of item 8626 wherein the fibrosing agent is
or comprises CTGF.
[9608] 8643. The method of item 8626 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[9609] 8644. The method of item 8626 wherein the fibrosing agent is
in the form of a particulate.
[9610] 8645. The method of item 8626 wherein the composition
further comprises an inflammatory cytokine.
[9611] 8646. The method of item 8626 wherein the composition
further comprises an agent that stimulates cell proliferation.
[9612] 8647. The method of item 8626 wherein the composition is in
the form of a gel or paste.
[9613] 8648. The method of item 8626 wherein the fibrosing agent is
in the form of tufts.
[9614] 8649. The method of item 8626 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[9615] 8650. The method of item 8626 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[9616] 8651. The method of item 8626, wherein the implant is
combined with a coating, and the coating comprises the fibrosing
agent.
[9617] 8652. The method of item 8626, wherein the implant is
combined with a coating, and the coating is disposed on a surface
of the device.
[9618] 8653. The method of item 8626, wherein the implant is
combined with a coating, and the coating directly contacts the
device.
[9619] 8654. The method of item 8626, wherein the implant is
combined with a coating, and the coating indirectly contacts the
device.
[9620] 8655. The method of item 8626, wherein the implant is
combined with a coating, and the coating partially covers the
device.
[9621] 8656. The method of item 8626, wherein the implant is
combined with a coating, and the coating completely covers the
device.
[9622] 8657. The method of item 8626, wherein the implant is
combined with a coating, and the coating is a uniform coating.
[9623] 8658. The method of item 8626, wherein the implant is
combined with a coating, and the coating is a non-uniform
coating.
[9624] 8659. The method of item 8626, wherein the implant is
combined with a coating, and the coating is a discontinuous
coating.
[9625] 8660. The method of item 8626 wherein the implant is
combined with a coating, and the coating is a patterned
coating.
[9626] 8661. The method of item 8626, wherein the implant is
combined with a coating, and the coating has a thickness of 100
.mu.m or less.
[9627] 8662. The method of item 8626, wherein the implant is
combined with a coating, and the coating has a thickness of 10
.mu.m or less.
[9628] 8663. The method of item 8626, wherein the implant is
combined with a coating, and the coating adheres to the surface of
the device upon deployment of the device.
[9629] 8664. The method of item 8626, wherein the implant is
combined with a coating, and the coating is stable at room
temperature for a period of at least 1 year.
[9630] 8665. The method of item 8626, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 0.0001% to about 1% by
weight.
[9631] 8666. The method of item 8626, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 1% to about 10% by
weight.
[9632] 8667. The method of item 8626, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 10% to about 25% by
weight.
[9633] 8668. The method of item 8626, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 25% to about 70% by
weight.
[9634] 8669. The method of item 8626, wherein the implant is
combined with a coating, and the coating further comprises a
polymer.
[9635] 8670. The method of item 8626, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition.
[9636] 8671. The method of item 8626, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition, where the first composition and the
second composition are different.
[9637] 8672. The method of item 8626, wherein the device comprises
a polymer.
[9638] 8673. The method of item 8626, wherein the device comprises
a polymer, and the polymer is a component of the composition.
[9639] 8674. The method of item 8626, wherein the implant is
combined with a polymer, and the polymer is a copolymer.
[9640] 8675. The method of item 8626, wherein the implant is
combined with a polymer, and the polymer is a block copolymer.
[9641] 8676. The method of item 8626, wherein the implant is
combined with a polymer, and the polymer is a random copolymer.
[9642] 8677. The method of item 8626, wherein the implant is
combined with a polymer, and the polymer is a biodegradable
polymer.
[9643] 8678. The method of item 8626, wherein the implant is
combined with a polymer, and the polymer is a non-biodegradable
polymer.
[9644] 8679. The method of item 8626, wherein the implant is
combined with a polymer, and the polymer is a hydrophilic
polymer.
[9645] 8680. The method of item 8626, wherein the implant is
combined with a polymer, and the polymer is a hydrophobic
polymer.
[9646] 8681. The method of item 8626, wherein the implant is
combined with a polymer, and the polymer has hydrophilic
domains.
[9647] 8682. The method of item 8626, wherein the implant is
combined with a polymer, and the polymer has hydrophobic
domains.
[9648] 8683. The method of item 8626, wherein the implant is
combined with a polymer, and the polymer is a non-conductive
polymer.
[9649] 8684. The method of item 8626, wherein the implant is
combined with a polymer, and the polymer is an elastomer.
[9650] 8685. The method of item 8626, wherein the implant is
combined with a polymer, and the polymer is a hydrogel.
[9651] 8686. The method of item 8626, wherein the implant is
combined with a polymer, and the polymer is a silicone polymer.
[9652] 8687. The method of item 8626, wherein the implant is
combined with a polymer, and the polymer is a hydrocarbon
polymer.
[9653] 8688. The method of item 8626, wherein the implant is
combined with a polymer, and the polymer is a styrene-derived
polymer.
[9654] 8689. The method of item 8626, wherein the implant is
combined with a polymer, and the polymer is a butadiene
polymer.
[9655] 8690. The method of item 8626, wherein the implant is
combined with a polymer, and the polymer is a macromer.
[9656] 8691. The method of item 8626, wherein the implant is
combined with a polymer, and the polymer is a poly(ethylene glycol)
polymer.
[9657] 8692. The method of item 8626, wherein the implant is
combined with a polymer, and the polymer is an amorphous
polymer.
[9658] 8693. The method of item 8626, wherein the implant is
combined with a polymer, and the polymer is a lubricious
coating.
[9659] 8694. The method of item 8626 wherein the fibrosing agent is
located within pores or holes of the device.
[9660] 8695. The method of item 8626 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[9661] 8696. The method of item 8626, wherein the implant is
further combined with a second pharmaceutically active agent.
[9662] 8697. The method of item 8626, wherein the implant is
further combined with an anti-inflammatory agent.
[9663] 8698. The method of item 8626 wherein the implant is further
combined with an agent that inhibits infection.
[9664] 8699. The method of item 8626, wherein the implant is
further combined with an anthracycline.
[9665] 8700. The method of item 8626, wherein the implant is
further combined with doxorubicin.
[9666] 8701. The method of item 8626, wherein the implant is
further combined with mitoxantrone.
[9667] 8702. The method of item 8626, wherein the implant is
further combined with a fluoropyrimidine.
[9668] 8703. The method of item 8626, wherein the implant is
further combined with 5-fluorouracil (5-FU).
[9669] 8704. The method of item 8626, wherein the implant is
further combined with a folic acid antagonist.
[9670] 8705. The method of item 8626, wherein the implant is
further combined with methotrexate.
[9671] 8706. The method of item 8626, wherein the implant is
further combined with a podophylotoxin.
[9672] 8707. The method of item 8626, wherein the implant is
further combined with etoposide.
[9673] 8708. The method of item 8626 wherein the implant is further
combined with a camptothecin.
[9674] 8709. The method of item 8626, wherein the implant is
further combined with a hydroxyurea.
[9675] 8710. The method of item 8626, wherein the implant is
further combined with a platinum complex.
[9676] 8711. The method of item 8626, wherein the implant is
further combined with cisplatin.
[9677] 8712. The method of item 8626, wherein the implant is
further combined with an anti-thrombotic agent.
[9678] 8713. The method of item 8626, wherein the implant is
further combined with a visualization agent.
[9679] 8714. The method of item 8626, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises a metal, a halogenated compound, or a
barium containing compound.
[9680] 8715. The method of item 8626, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises barium, tantalum, or technetium.
[9681] 8716. The method of item 8626, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a MRI responsive material.
[9682] 8717. The method of item 8626, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a gadolinium chelate.
[9683] 8718. The method of item 8626, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises iron, magnesium, manganese, copper,
or chromium.
[9684] 8719. The method of item 8626, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises an iron oxide compound.
[9685] 8720. The method of item 8626, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a dye, pigment, or colorant.
[9686] 8721. The method of item 8626, wherein the implant is
further combined with an echogenic material.
[9687] 8722. The method of item 8626, wherein the implant is
further combined with an echogenic material, and the echogenic
material is in the form of a coating.
[9688] 8723. The method of item 8626 wherein the device is
sterilized.
[9689] 8724. The method of item 8626 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[9690] 8725. The method of item 8626 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[9691] 8726. The method of item 8626 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[9692] 8727. The method of item 8626 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[9693] 8728. The method of item 8626 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[9694] 8729. The method of item 8626 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[9695] 8730. The method of item 8626 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[9696] 8731. The method of item 8626 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[9697] 8732. The method of item 8626 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[9698] 8733. The method of item 8626 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[9699] 8734. The method of item 8626 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[9700] 8735. The method of item 8626 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[9701] 8736. The method of item 8626 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[9702] 8737. The method of item 8626 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[9703] 8738. The method of item 8626 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[9704] 8739. The method of item 8626 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[9705] 8740. The method of item 8626 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[9706] 8741. The method of item 8626 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[9707] 8742. The method of item 8626 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[9708] 8743. The method of item 8626 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[9709] 8744. The method of item 8626 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[9710] 8745. The method of item 8626 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[9711] 8746. The method of item 8626 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[9712] 8747. The method of item 8626 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[9713] 8748. The method of item 8626 wherein the implant is, or
comprises, an inflatable cuff.
[9714] 8749. The method of item 8626 wherein the implant is, or
comprises, a space-occupying device.
[9715] 8750. A method of making a medical device comprising
combining i) a suture-based endoluminal implant for partitioning a
stomach, with ii) a fibrosing agent or a composition comprising a
fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
[9716] 8751. The method of item 8750 wherein the fibrosing agent
promotes regeneration.
[9717] 8752. The method of item 8750 wherein the fibrosing agent
promotes angiogenesis.
[9718] 8753. The method of item 8750 wherein the fibrosing agent
promotes fibroblast migration.
[9719] 8754. The method of item 8750 wherein the fibrosing agent
promotes fibroblast proliferation.
[9720] 8755. The method of item 8750 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[9721] 8756. The method of item 8750 wherein the fibrosing agent
promotes tissue remodeling.
[9722] 8757. The method of item 8750 wherein the fibrosing agent is
an arterial vessel wall irritant.
[9723] 8758. The method of item 8750 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[9724] 8759. The method of item 8750 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[9725] 8760. The method of item 8750 wherein the fibrosing agent is
or comprises silk.
[9726] 8761. The method of item 8750 wherein the fibrosing agent is
or comprises mineral particles.
[9727] 8762. The method of item 8750 wherein the fibrosing agent is
or comprises chitosan.
[9728] 8763. The method of item 8750 wherein the fibrosing agent is
or comprises polylysine.
[9729] 8764. The method of item 8750 wherein the fibrosing agent is
or comprises fibronectin.
[9730] 8765. The method of item 8750 wherein the fibrosing agent is
or comprises bleomycin.
[9731] 8766. The method of item 8750 wherein the fibrosing agent is
or comprises CTGF.
[9732] 8767. The method of item 8750 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[9733] 8768. The method of item 8750 wherein the fibrosing agent is
in the form of a particulate.
[9734] 8769. The method of item 8750 wherein the composition
further comprises an inflammatory cytokine.
[9735] 8770. The method of item 8750 wherein the composition
further comprises an agent that stimulates cell proliferation.
[9736] 8771. The method of item 8750 wherein the composition is in
the form of a gel or paste.
[9737] 8772. The method of item 8750 wherein the fibrosing agent is
in the form of tufts.
[9738] 8773. The method of item 8750 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[9739] 8774. The method of item 8750 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[9740] 8775. The method of item 8750, wherein the implant is
combined with a coating, and the coating comprises the fibrosing
agent.
[9741] 8776. The method of item 8750, wherein the implant is
combined with a coating, and the coating is disposed on a surface
of the device.
[9742] 8777. The method of item 8750, wherein the implant is
combined with a coating, and the coating directly contacts the
device.
[9743] 8778. The method of item 8750, wherein the implant is
combined with a coating, and the coating indirectly contacts the
device.
[9744] 8779. The method of item 8750, wherein the implant is
combined with a coating, and the coating partially covers the
device.
[9745] 8780. The method of item 8750, wherein the implant is
combined with a coating, and the coating completely covers the
device.
[9746] 8781. The method of item 8750, wherein the implant is
combined with a coating, and the coating is a uniform coating.
[9747] 8782. The method of item 8750, wherein the implant is
combined with a coating, and the coating is a non-uniform
coating.
[9748] 8783. The method of item 8750, wherein the implant is
combined with a coating, and the coating is a discontinuous
coating.
[9749] 8784. The method of item 8750 wherein the implant is
combined with a coating, and the coating is a patterned
coating.
[9750] 8785. The method of item 8750, wherein the implant is
combined with a coating, and the coating has a thickness of 100
.mu.m or less.
[9751] 8786. The method of item 8750, wherein the implant is
combined with a coating, and the coating has a thickness of 10
.mu.m or less.
[9752] 8787. The method of item 8750, wherein the implant is
combined with a coating, and the coating adheres to the surface of
the device upon deployment of the device.
[9753] 8788. The method of item 8750, wherein the implant is
combined with a coating, and the coating is stable at room
temperature for a period of at least 1 year.
[9754] 8789. The method of item 8750, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 0.0001% to about 1% by
weight.
[9755] 8790. The method of item 8750, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 1% to about 10% by
weight.
[9756] 8791. The method of item 8750, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 10% to about 25% by
weight.
[9757] 8792. The method of item 8750, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 25% to about 70% by
weight.
[9758] 8793. The method of item 8750, wherein the implant is
combined with a coating, and the coating further comprises a
polymer.
[9759] 8794. The method of item 8750, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition.
[9760] 8795. The method of item 8750, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition, where the first composition and the
second composition are different.
[9761] 8796. The method of item 8750, wherein the device comprises
a polymer.
[9762] 8797. The method of item 8750, wherein the device comprises
a polymer, and the polymer is a component of the composition.
[9763] 8798. The method of item 8750, wherein the implant is
combined with a polymer, and the polymer is a copolymer.
[9764] 8799. The method of item 8750, wherein the implant is
combined with a polymer, and the polymer is a block copolymer.
[9765] 8800. The method of item 8750, wherein the implant is
combined with a polymer, and the polymer is a random copolymer.
[9766] 8801. The method of item 8750, wherein the implant is
combined with a polymer, and the polymer is a biodegradable
polymer.
[9767] 8802. The method of item 8750, wherein the implant is
combined with a polymer, and the polymer is a non-biodegradable
polymer.
[9768] 8803. The method of item 8750, wherein the implant is
combined with a polymer, and the polymer is a hydrophilic
polymer.
[9769] 8804. The method of item 8750, wherein the implant is
combined with a polymer, and the polymer is a hydrophobic
polymer.
[9770] 8805. The method of item 8750, wherein the implant is
combined with a polymer, and the polymer has hydrophilic
domains.
[9771] 8806. The method of item 8750, wherein the implant is
combined with a polymer, and the polymer has hydrophobic
domains.
[9772] 8807. The method of item 8750, wherein the implant is
combined with a polymer, and the polymer is a non-conductive
polymer.
[9773] 8808. The method of item 8750, wherein the implant is
combined with a polymer, and the polymer is an elastomer.
[9774] 8809. The method of item 8750, wherein the implant is
combined with a polymer, and the polymer is a hydrogel.
[9775] 8810. The method of item 8750, wherein the implant is
combined with a polymer, and the polymer is a silicone polymer.
[9776] 8811. The method of item 8750, wherein the implant is
combined with a polymer, and the polymer is a hydrocarbon
polymer.
[9777] 8812. The method of item 8750, wherein the implant is
combined with a polymer, and the polymer is a styrene-derived
polymer.
[9778] 8813. The method of item 8750, wherein the implant is
combined with a polymer, and the polymer is a butadiene
polymer.
[9779] 8814. The method of item 8750, wherein the implant is
combined with a polymer, and the polymer is a macromer.
[9780] 8815. The method of item 8750, wherein the implant is
combined with a polymer, and the polymer is a poly(ethylene glycol)
polymer.
[9781] 8816. The method of item 8750, wherein the implant is
combined with a polymer, and the polymer is an amorphous
polymer.
[9782] 8817. The method of item 8750, wherein the implant is
combined with a polymer, and the polymer is a lubricious
coating.
[9783] 8818. The method of item 8750 wherein the fibrosing agent is
located within pores or holes of the device.
[9784] 8819. The method of item 8750 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[9785] 8820. The method of item 8750, wherein the implant is
further combined with a second pharmaceutically active agent.
[9786] 8821. The method of item 8750, wherein the implant is
further combined with an anti-inflammatory agent.
[9787] 8822. The method of item 8750 wherein the implant is further
combined with an agent that inhibits infection.
[9788] 8823. The method of item 8750, wherein the implant is
further combined with an anthracycline.
[9789] 8824. The method of item 8750, wherein the implant is
further combined with doxorubicin.
[9790] 8825. The method of item 8750, wherein the implant is
further combined with mitoxantrone.
[9791] 8826. The method of item 8750, wherein the implant is
further combined with a fluoropyrimidine.
[9792] 8827. The method of item 8750, wherein the implant is
further combined with 5-fluorouracil (5-FU).
[9793] 8828. The method of item 8750, wherein the implant is
further combined with a folic acid antagonist.
[9794] 8829. The method of item 8750, wherein the implant is
further combined with methotrexate.
[9795] 8830. The method of item 8750, wherein the implant is
further combined with a podophylotoxin.
[9796] 8831. The method of item 8750, wherein the implant is
further combined with etoposide.
[9797] 8832. The method of item 8750 wherein the implant is further
combined with a camptothecin.
[9798] 8833. The method of item 8750, wherein the implant is
further combined with a hydroxyurea.
[9799] 8834. The method of item 8750, wherein the implant is
further combined with a platinum complex.
[9800] 8835. The method of item 8750, wherein the implant is
further combined with cisplatin.
[9801] 8836. The method of item 8750, wherein the implant is
further combined with an anti-thrombotic agent.
[9802] 8837. The method of item 8750, wherein the implant is
further combined with a visualization agent.
[9803] 8838. The method of item 8750, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises a metal, a halogenated compound, or a
barium containing compound.
[9804] 8839. The method of item 8750, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises barium, tantalum, or technetium.
[9805] 8840. The method of item 8750, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a MRI responsive material.
[9806] 8841. The method of item 8750, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a gadolinium chelate.
[9807] 8842. The method of item 8750, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises iron, magnesium, manganese, copper,
or chromium.
[9808] 8843. The method of item 8750, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises an iron oxide compound.
[9809] 8844. The method of item 8750, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a dye, pigment, or colorant.
[9810] 8845. The method of item 8750, wherein the implant is
further combined with an echogenic material.
[9811] 8846. The method of item 8750, wherein the implant is
further combined with an echogenic material, and the echogenic
material is in the form of a coating.
[9812] 8847. The method of item 8750 wherein the device is
sterilized.
[9813] 8848. The method of item 8750 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[9814] 8849. The method of item 8750 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[9815] 8850. The method of item 8750 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[9816] 8851. The method of item 8750 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[9817] 8852. The method of item 8750 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[9818] 8853. The method of item 8750 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[9819] 8854. The method of item 8750 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[9820] 8855. The method of item 8750 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[9821] 8856. The method of item 8750 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[9822] 8857. The method of item 8750 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[9823] 8858. The method of item 8750 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[9824] 8859. The method of item 8750 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[9825] 8860. The method of item 8750 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[9826] 8861. The method of item 8750 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[9827] 8862. The method of item 8750 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[9828] 8863. The method of item 8750 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[9829] 8864. The method of item 8750 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[9830] 8865. The method of item 8750 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[9831] 8866. The method of item 8750 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[9832] 8867. The method of item 8750 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[9833] 8868. The method of item 8750 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[9834] 8869. The method of item 8750 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[9835] 8870. The method of item 8750 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[9836] 8871. The method of item 8750 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[9837] 8872. A method of making a medical device comprising
combining i) an electrostimulation implant for partitioning a
stomach, with ii) a fibrosing agent or a composition comprising a
fibrosing agent, where the fibrosing agent induces a fibrotic
response between the device and a patient in which the device is
implanted.
[9838] 8873. The method of item 8872 wherein the fibrosing agent
promotes regeneration.
[9839] 8874. The method of item 8872 wherein the fibrosing agent
promotes angiogenesis.
[9840] 8875. The method of item 8872 wherein the fibrosing agent
promotes fibroblast migration.
[9841] 8876. The method of item 8872 wherein the fibrosing agent
promotes fibroblast proliferation.
[9842] 8877. The method of item 8872 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[9843] 8878. The method of item 8872 wherein the fibrosing agent
promotes tissue remodeling.
[9844] 8879. The method of item 8872 wherein the fibrosing agent is
an arterial vessel wall irritant.
[9845] 8880. The method of item 8872 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[9846] 8881. The method of item 8872 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[9847] 8882. The method of item 8872 wherein the fibrosing agent is
or comprises silk.
[9848] 8883. The method of item 8872 wherein the fibrosing agent is
or comprises mineral particles.
[9849] 8884. The method of item 8872 wherein the fibrosing agent is
or comprises chitosan.
[9850] 8885. The method of item 8872 wherein the fibrosing agent is
or comprises polylysine.
[9851] 8886. The method of item 8872 wherein the fibrosing agent is
or comprises fibronectin.
[9852] 8887. The method of item 8872 wherein the fibrosing agent is
or comprises bleomycin.
[9853] 8888. The method of item 8872 wherein the fibrosing agent is
or comprises CTGF.
[9854] 8889. The method of item 8872 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[9855] 8890. The method of item 8872 wherein the fibrosing agent is
in the form of a particulate.
[9856] 8891. The method of item 8872 wherein the composition
further comprises an inflammatory cytokine.
[9857] 8892. The method of item 8872 wherein the composition
further comprises an agent that stimulates cell proliferation.
[9858] 8893. The method of item 8872 wherein the composition is in
the form of a gel or paste.
[9859] 8894. The method of item 8872 wherein the fibrosing agent is
in the form of tufts.
[9860] 8895. The method of item 8872 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[9861] 8896. The method of item 8872 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[9862] 8897. The method of item 8872, wherein the implant is
combined with a coating, and the coating comprises the fibrosing
agent.
[9863] 8898. The method of item 8872, wherein the implant is
combined with a coating, and the coating is disposed on a surface
of the device.
[9864] 8899. The method of item 8872, wherein the implant is
combined with a coating, and the coating directly contacts the
device.
[9865] 8900. The method of item 8872, wherein the implant is
combined with a coating, and the coating indirectly contacts the
device.
[9866] 8901. The method of item 8872, wherein the implant is
combined with a coating, and the coating partially covers the
device.
[9867] 8902. The method of item 8872, wherein the implant is
combined with a coating, and the coating completely covers the
device.
[9868] 8903. The method of item 8872, wherein the implant is
combined with a coating, and the coating is a uniform coating.
[9869] 8904. The method of item 8872, wherein the implant is
combined with a coating, and the coating is a non-uniform
coating.
[9870] 8905. The method of item 8872, wherein the implant is
combined with a coating, and the coating is a discontinuous
coating.
[9871] 8906. The method of item 8872 wherein the implant is
combined with a coating, and the coating is a patterned
coating.
[9872] 8907. The method of item 8872, wherein the implant is
combined with a coating, and the coating has a thickness of 100
.mu.m or less.
[9873] 8908. The method of item 8872, wherein the implant is
combined with a coating, and the coating has a thickness of 10
.mu.m or less.
[9874] 8909. The method of item 8872, wherein the implant is
combined with a coating, and the coating adheres to the surface of
the device upon deployment of the device.
[9875] 8910. The method of item 8872, wherein the implant is
combined with a coating, and the coating is stable at room
temperature for a period of at least 1 year.
[9876] 8911. The method of item 8872, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 0.0001% to about 1% by
weight.
[9877] 8912. The method of item 8872, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 1% to about 10% by
weight.
[9878] 8913. The method of item 8872, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 10% to about 25% by
weight.
[9879] 8914. The method of item 8872, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 25% to about 70% by
weight.
[9880] 8915. The method of item 8872, wherein the implant is
combined with a coating, and the coating further comprises a
polymer.
[9881] 8916. The method of item 8872, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition.
[9882] 8917. The method of item 8872, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition, where the first composition and the
second composition are different.
[9883] 8918. The method of item 8872, wherein the device comprises
a polymer.
[9884] 8919. The method of item 8872, wherein the device comprises
a polymer, and the polymer is a component of the composition.
[9885] 8920. The method of item 8872, wherein the implant is
combined with a polymer, and the polymer is a copolymer.
[9886] 8921. The method of item 8872, wherein the implant is
combined with a polymer, and the polymer is a block copolymer.
[9887] 8922. The method of item 8872, wherein the implant is
combined with a polymer, and the polymer is a random copolymer.
[9888] 8923. The method of item 8872, wherein the implant is
combined with a polymer, and the polymer is a biodegradable
polymer.
[9889] 8924. The method of item 8872, wherein the implant is
combined with a polymer, and the polymer is a non-biodegradable
polymer.
[9890] 8925. The method of item 8872, wherein the implant is
combined with a polymer, and the polymer is a hydrophilic
polymer.
[9891] 8926. The method of item 8872, wherein the implant is
combined with a polymer, and the polymer is a hydrophobic
polymer.
[9892] 8927. The method of item 8872, wherein the implant is
combined with a polymer, and the polymer has hydrophilic
domains.
[9893] 8928. The method of item 8872, wherein the implant is
combined with a polymer, and the polymer has hydrophobic
domains.
[9894] 8929. The method of item 8872, wherein the implant is
combined with a polymer, and the polymer is a non-conductive
polymer.
[9895] 8930. The method of item 8872, wherein the implant is
combined with a polymer, and the polymer is an elastomer.
[9896] 8931. The method of item 8872, wherein the implant is
combined with a polymer, and the polymer is a hydrogel.
[9897] 8932. The method of item 8872, wherein the implant is
combined with a polymer, and the polymer is a silicone polymer.
[9898] 8933. The method of item 8872, wherein the implant is
combined with a polymer, and the polymer is a hydrocarbon
polymer.
[9899] 8934. The method of item 8872, wherein the implant is
combined with a polymer, and the polymer is a styrene-derived
polymer.
[9900] 8935. The method of item 8872, wherein the implant is
combined with a polymer, and the polymer is a butadiene
polymer.
[9901] 8936. The method of item 8872, wherein the implant is
combined with a polymer, and the polymer is a macromer.
[9902] 8937. The method of item 8872, wherein the implant is
combined with a polymer, and the polymer is a poly(ethylene glycol)
polymer.
[9903] 8938. The method of item 8872, wherein the implant is
combined with a polymer, and the polymer is an amorphous
polymer.
[9904] 8939. The method of item 8872, wherein the implant is
combined with a polymer, and the polymer is a lubricious
coating.
[9905] 8940. The method of item 8872 wherein the fibrosing agent is
located within pores or holes of the device.
[9906] 8941. The method of item 8872 wherein the fibrosing agent is
located within a channel, lumen, or divet of the device.
[9907] 8942. The method of item 8872, wherein the implant is
further combined with a second pharmaceutically active agent.
[9908] 8943. The method of item 8872, wherein the implant is
further combined with an anti-inflammatory agent.
[9909] 8944. The method of item 8872 wherein the implant is further
combined with an agent that inhibits infection.
[9910] 8945. The method of item 8872, wherein the implant is
further combined with an anthracycline.
[9911] 8946. The method of item 8872, wherein the implant is
further combined with doxorubicin.
[9912] 8947. The method of item 8872, wherein the implant is
further combined with mitoxantrone.
[9913] 8948. The method of item 8872, wherein the implant is
further combined with a fluoropyrimidine.
[9914] 8949. The method of item 8872, wherein the implant is
further combined with 5-fluorouracil (5-FU).
[9915] 8950. The method of item 8872, wherein the implant is
further combined with a folic acid antagonist.
[9916] 8951. The method of item 8872, wherein the implant is
further combined with methotrexate.
[9917] 8952. The method of item 8872, wherein the implant is
further combined with a podophylotoxin.
[9918] 8953. The method of item 8872, wherein the implant is
further combined with etoposide.
[9919] 8954. The method of item 8872 wherein the implant is further
combined with a camptothecin.
[9920] 8955. The method of item 8872, wherein the implant is
further combined with a hydroxyurea.
[9921] 8956. The method of item 8872, wherein the implant is
further combined with a platinum complex.
[9922] 8957. The method of item 8872, wherein the implant is
further combined with cisplatin.
[9923] 8958. The method of item 8872, wherein the implant is
further combined with an anti-thrombotic agent.
[9924] 8959. The method of item 8872, wherein the implant is
further combined with a visualization agent.
[9925] 8960. The method of item 8872, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises a metal, a halogenated compound, or a
barium containing compound.
[9926] 8961. The method of item 8872, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises barium, tantalum, or technetium.
[9927] 8962. The method of item 8872, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a MRI responsive material.
[9928] 8963. The method of item 8872, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a gadolinium chelate.
[9929] 8964. The method of item 8872, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises iron, magnesium, manganese, copper,
or chromium.
[9930] 8965. The method of item 8872, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises an iron oxide compound.
[9931] 8966. The method of item 8872, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a dye, pigment, or colorant.
[9932] 8967. The method of item 8872, wherein the implant is
further combined with an echogenic material.
[9933] 8968. The method of item 8872, wherein the implant is
further combined with an echogenic material, and the echogenic
material is in the form of a coating.
[9934] 8969. The method of item 8872 wherein the device is
sterilized.
[9935] 8970. The method of item 8872 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device.
[9936] 8971. The method of item 8872 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is connective tissue.
[9937] 8972. The method of item 8872 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is muscle tissue.
[9938] 8973. The method of item 8872 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is nerve tissue.
[9939] 8974. The method of item 8872 wherein the fibrosing agent is
released into tissue in the vicinity of the device after deployment
of the device, wherein the tissue is epithelium tissue.
[9940] 8975. The method of item 8872 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from the time of deployment of the device to about 1
year.
[9941] 8976. The method of item 8872 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1 month to 6 months.
[9942] 8977. The method of item 8872 wherein the fibrosing agent is
released in effective concentrations from the device over a period
ranging from about 1-90 days.
[9943] 8978. The method of item 8872 wherein the fibrosing agent is
released in effective concentrations from the device at a constant
rate.
[9944] 8979. The method of item 8872 wherein the fibrosing agent is
released in effective concentrations from the device at an
increasing rate.
[9945] 8980. The method of item 8872 wherein the fibrosing agent is
released in effective concentrations from the device at a
decreasing rate.
[9946] 8981. The method of item 8872 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[9947] 8982. The method of item 8872 wherein the fibrosing agent is
released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[9948] 8983. The method of item 8872 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[9949] 8984. The method of item 8872 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[9950] 8985. The method of item 8872 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[9951] 8986. The method of item 8872 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[9952] 8987. The method of item 8872 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[9953] 8988. The method of item 8872 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[9954] 8989. The method of item 8872 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[9955] 8990. The method of item 8872 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[9956] 8991. The method of item 8872 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[9957] 8992. The method of item 8872 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[9958] 8993. The method of item 8872 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[9959] 8994. The method of item 8872 wherein the implant is a
neural electrostimulation implant.
[9960] 8995. The method of item 8872 wherein the implant is a
non-neural electrostimulation implant.
[9961] 8996. A method of making a medical device comprising
combining i) a soft palate implant, with ii) a fibrosing agent or a
composition comprising a fibrosing agent, where the fibrosing agent
induces a fibrotic response between the device and a patient in
which the device is implanted.
[9962] 8997. The method of item 8996 wherein the fibrosing agent
promotes regeneration.
[9963] 8998. The method of item 8996 wherein the fibrosing agent
promotes angiogenesis.
[9964] 8999. The method of item 8996 wherein the fibrosing agent
promotes fibroblast migration.
[9965] 9000. The method of item 8996 wherein the fibrosing agent
promotes fibroblast proliferation.
[9966] 9001. The method of item 8996 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[9967] 9002. The method of item 8996 wherein the fibrosing agent
promotes tissue remodeling.
[9968] 9003. The method of item 8996 wherein the fibrosing agent is
an arterial vessel wall irritant.
[9969] 9004. The method of item 8996 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[9970] 9005. The method of item 8996 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[9971] 9006. The method of item 8996 wherein the fibrosing agent is
or comprises silk.
[9972] 9007. The method of item 8996 wherein the fibrosing agent is
or comprises mineral particles.
[9973] 9008. The method of item 8996 wherein the fibrosing agent is
or comprises chitosan.
[9974] 9009. The method of item 8996 wherein the fibrosing agent is
or comprises polylysine.
[9975] 9010. The method of item 8996 wherein the fibrosing agent is
or comprises fibronectin.
[9976] 9011. The method of item 8996 wherein the fibrosing agent is
or comprises bleomycin.
[9977] 9012. The method of item 8996 wherein the fibrosing agent is
or comprises CTGF.
[9978] 9013. The method of item 8996 wherein the fibrosing agent is
in the form of a thread, or is in contact with a thread.
[9979] 9014. The method of item 8996 wherein the fibrosing agent is
in the form of a particulate.
[9980] 9015. The method of item 8996 wherein the composition
further comprises an inflammatory cytokine.
[9981] 9016. The method of item 8996 wherein the composition
further comprises an agent that stimulates cell proliferation.
[9982] 9017. The method of item 8996 wherein the composition is in
the form of a gel or paste.
[9983] 9018. The method of item 8996 wherein the fibrosing agent is
in the form of tufts.
[9984] 9019. The method of item 8996 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[9985] 9020. The method of item 8996 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[9986] 9021. The method of item 8996, wherein the implant is
combined with a coating, and the coating comprises the fibrosing
agent.
[9987] 9022. The method of item 8996, wherein the implant is
combined with a coating, and the coating is disposed on a surface
of the device.
[9988] 9023. The method of item 8996, wherein the implant is
combined with a coating, and the coating directly contacts the
device.
[9989] 9024. The method of item 8996, wherein the implant is
combined with a coating, and the coating indirectly contacts the
device.
[9990] 9025. The method of item 8996, wherein the implant is
combined with a coating, and the coating partially covers the
device.
[9991] 9026. The method of item 8996, wherein the implant is
combined with a coating, and the coating completely covers the
device.
[9992] 9027. The method of item 8996, wherein the implant is
combined with a coating, and the coating is a uniform coating.
[9993] 9028. The method of item 8996, wherein the implant is
combined with a coating, and the coating is a non-uniform
coating.
[9994] 9029. The method of item 8996, wherein the implant is
combined with a coating, and the coating is a discontinuous
coating.
[9995] 9030. The method of item 8996 wherein the implant is
combined with a coating, and the coating is a patterned
coating.
[9996] 9031. The method of item 8996, wherein the implant is
combined with a coating, and the coating has a thickness of 100
.mu.m or less.
[9997] 9032. The method of item 8996, wherein the implant is
combined with a coating, and the coating has a thickness of 10
.mu.m or less.
[9998] 9033. The method of item 8996, wherein the implant is
combined with a coating, and the coating adheres to the surface of
the device upon deployment of the device.
[9999] 9034. The method of item 8996, wherein the implant is
combined with a coating, and the coating is stable at room
temperature for a period of at least 1 year.
[10000] 9035. The method of item 8996, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 0.0001% to about 1% by
weight.
[10001] 9036. The method of item 8996, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 1% to about 10% by
weight.
[10002] 9037. The method of item 8996, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 10% to about 25% by
weight.
[10003] 9038. The method of item 8996, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 25% to about 70% by
weight.
[10004] 9039. The method of item 8996, wherein the implant is
combined with a coating, and the coating further comprises a
polymer.
[10005] 9040. The method of item 8996, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition.
[10006] 9041. The method of item 8996, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition, where the first composition and the
second composition are different.
[10007] 9042. The method of item 8996, wherein the device comprises
a polymer.
[10008] 9043. The method of item 8996, wherein the device comprises
a polymer, and the polymer is a component of the composition.
[10009] 9044. The method of item 8996, wherein the implant is
combined with a polymer, and the polymer is a copolymer.
[10010] 9045. The method of item 8996, wherein the implant is
combined with a polymer, and the polymer is a block copolymer.
[10011] 9046. The method of item 8996, wherein the implant is
combined with a polymer, and the polymer is a random copolymer.
[10012] 9047. The method of item 8996, wherein the implant is
combined with a polymer, and the polymer is a biodegradable
polymer.
[10013] 9048. The method of item 8996, wherein the implant is
combined with a polymer, and the polymer is a non-biodegradable
polymer.
[10014] 9049. The method of item 8996, wherein the implant is
combined with a polymer, and the polymer is a hydrophilic
polymer.
[10015] 9050. The method of item 8996, wherein the implant is
combined with a polymer, and the polymer is a hydrophobic
polymer.
[10016] 9051. The method of item 8996, wherein the implant is
combined with a polymer, and the polymer has hydrophilic
domains.
[10017] 9052. The method of item 8996, wherein the implant is
combined with a polymer, and the polymer has hydrophobic
domains.
[10018] 9053. The method of item 8996, wherein the implant is
combined with a polymer, and the polymer is a non-conductive
polymer.
[10019] 9054. The method of item 8996, wherein the implant is
combined with a polymer, and the polymer is an elastomer.
[10020] 9055. The method of item 8996, wherein the implant is
combined with a polymer, and the polymer is a hydrogel.
[10021] 9056. The method of item 8996, wherein the implant is
combined with a polymer, and the polymer is a silicone polymer.
[10022] 9057. The method of item 8996, wherein the implant is
combined with a polymer, and the polymer is a hydrocarbon
polymer.
[10023] 9058. The method of item 8996, wherein the implant is
combined with a polymer, and the polymer is a styrene-derived
polymer.
[10024] 9059. The method of item 8996, wherein the implant is
combined with a polymer, and the polymer is a butadiene
polymer.
[10025] 9060. The method of item 8996, wherein the implant is
combined with a polymer, and the polymer is a macromer.
[10026] 9061. The method of item 8996, wherein the implant is
combined with a polymer, and the polymer is a poly(ethylene glycol)
polymer.
[10027] 9062. The method of item 8996, wherein the implant is
combined with a polymer, and the polymer is an amorphous
polymer.
[10028] 9063. The method of item 8996, wherein the implant is
combined with a polymer, and the polymer is a lubricious
coating.
[10029] 9064. The method of item 8996 wherein the fibrosing agent
is located within pores or holes of the device.
[10030] 9065. The method of item 8996 wherein the fibrosing agent
is located within a channel, lumen, or divet of the device.
[10031] 9066. The method of item 8996, wherein the implant is
further combined with a second pharmaceutically active agent.
[10032] 9067. The method of item 8996, wherein the implant is
further combined with an anti-inflammatory agent.
[10033] 9068. The method of item 8996 wherein the implant is
further combined with an agent that inhibits infection.
[10034] 9069. The method of item 8996, wherein the implant is
further combined with an anthracycline.
[10035] 9070. The method of item 8996, wherein the implant is
further combined with doxorubicin.
[10036] 9071. The method of item 8996, wherein the implant is
further combined with mitoxantrone.
[10037] 9072. The method of item 8996, wherein the implant is
further combined with a fluoropyrimidine.
[10038] 9073. The method of item 8996, wherein the implant is
further combined with 5-fluorouracil (5-FU).
[10039] 9074. The method of item 8996, wherein the implant is
further combined with a folic acid antagonist.
[10040] 9075. The method of item 8996, wherein the implant is
further combined with methotrexate.
[10041] 9076. The method of item 8996, wherein the implant is
further combined with a podophylotoxin.
[10042] 9077. The method of item 8996, wherein the implant is
further combined with etoposide.
[10043] 9078. The method of item 8996 wherein the implant is
further combined with a camptothecin.
[10044] 9079. The method of item 8996, wherein the implant is
further combined with a hydroxyurea.
[10045] 9080. The method of item 8996, wherein the implant is
further combined with a platinum complex.
[10046] 9081. The method of item 8996, wherein the implant is
further combined with cisplatin.
[10047] 9082. The method of item 8996, wherein the implant is
further combined with an anti-thrombotic agent.
[10048] 9083. The method of item 8996, wherein the implant is
further combined with a visualization agent.
[10049] 9084. The method of item 8996, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises a metal, a halogenated compound, or a
barium containing compound.
[10050] 9085. The method of item 8996, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises barium, tantalum, or technetium.
[10051] 9086. The method of item 8996, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a MRI responsive material.
[10052] 9087. The method of item 8996, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a gadolinium chelate.
[10053] 9088. The method of item 8996, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises iron, magnesium, manganese, copper,
or chromium.
[10054] 9089. The method of item 8996, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises an iron oxide compound.
[10055] 9090. The method of item 8996, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a dye, pigment, or colorant.
[10056] 9091. The method of item 8996, wherein the implant is
further combined with an echogenic material.
[10057] 9092. The method of item 8996, wherein the implant is
further combined with an echogenic material, and the echogenic
material is in the form of a coating.
[10058] 9093. The method of item 8996 wherein the device is
sterilized.
[10059] 9094. The method of item 8996 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device.
[10060] 9095. The method of item 8996 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is connective
tissue.
[10061] 9096. The method of item 8996 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is muscle tissue.
[10062] 9097. The method of item 8996 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is nerve tissue.
[10063] 9098. The method of item 8996 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is epithelium
tissue.
[10064] 9099. The method of item 8996 wherein the fibrosing agent
is released in effective concentrations from the device over a
period ranging from the time of deployment of the device to about 1
year.
[10065] 9100. The method of item 8996 wherein the fibrosing agent
is released in effective concentrations from the device over a
period ranging from about 1 month to 6 months.
[10066] 9101. The method of item 8996 wherein the fibrosing agent
is released in effective concentrations from the device over a
period ranging from about 1-90 days.
[10067] 9102. The method of item 8996 wherein the fibrosing agent
is released in effective concentrations from the device at a
constant rate.
[10068] 9103. The method of item 8996 wherein the fibrosing agent
is released in effective concentrations from the device at an
increasing rate.
[10069] 9104. The method of item 8996 wherein the fibrosing agent
is released in effective concentrations from the device at a
decreasing rate.
[10070] 9105. The method of item 8996 wherein the fibrosing agent
is released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[10071] 9106. The method of item 8996 wherein the fibrosing agent
is released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[10072] 9107. The method of item 8996 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[10073] 9108. The method of item 8996 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[10074] 9109. The method of item 8996 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[10075] 9110. The method of item 8996 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[10076] 9111. The method of item 8996 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[10077] 9112. The method of item 8996 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[10078] 9113. The method of item 8996 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[10079] 9114. The method of item 8996 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[10080] 9115. The method of item 8996 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[10081] 9116. The method of item 8996 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[10082] 9117. The method of item 8996 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[10083] 9118. A method of making a medical device comprising
combining i) a vascular coil implant, with ii) a fibrosing agent or
a composition comprising a fibrosing agent, where the fibrosing
agent induces a fibrotic response between the device and a patient
in which the device is implanted.
[10084] 9119. The method of item 9118 wherein the fibrosing agent
promotes regeneration.
[10085] 9120. The method of item 9118 wherein the fibrosing agent
promotes angiogenesis.
[10086] 9121. The method of item 9118 wherein the fibrosing agent
promotes fibroblast migration.
[10087] 9122. The method of item 9118 wherein the fibrosing agent
promotes fibroblast proliferation.
[10088] 9123. The method of item 9118 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[10089] 9124. The method of item 9118 wherein the fibrosing agent
promotes tissue remodeling.
[10090] 9125. The method of item 9118 wherein the fibrosing agent
is an arterial vessel wall irritant.
[10091] 9126. The method of item 9118 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[10092] 9127. The method of item 9118 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[10093] 9128. The method of item 9118 wherein the fibrosing agent
is or comprises silk.
[10094] 9129. The method of item 9118 wherein the fibrosing agent
is or comprises mineral particles.
[10095] 9130. The method of item 9118 wherein the fibrosing agent
is or comprises chitosan.
[10096] 9131. The method of item 9118 wherein the fibrosing agent
is or comprises polylysine.
[10097] 9132. The method of item 9118 wherein the fibrosing agent
is or comprises fibronectin.
[10098] 9133. The method of item 9118 wherein the fibrosing agent
is or comprises bleomycin.
[10099] 9134. The method of item 9118 wherein the fibrosing agent
is or comprises CTGF.
[10100] 9135. The method of item 9118 wherein the fibrosing agent
is in the form of a thread, or is in contact with a thread.
[10101] 9136. The method of item 9118 wherein the fibrosing agent
is in the form of a particulate.
[10102] 9137. The method of item 9118 wherein the composition
further comprises an inflammatory cytokine.
[10103] 9138. The method of item 9118 wherein the composition
further comprises an agent that stimulates cell proliferation.
[10104] 9139. The method of item 9118 wherein the composition is in
the form of a gel or paste.
[10105] 9140. The method of item 9118 wherein the fibrosing agent
is in the form of tufts.
[10106] 9141. The method of item 9118 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[10107] 9142. The method of item 9118 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[10108] 9143. The method of item 9118, wherein the implant is
combined with a coating, and the coating comprises the fibrosing
agent.
[10109] 9144. The method of item 9118, wherein the implant is
combined with a coating, and the coating is disposed on a surface
of the device.
[10110] 9145. The method of item 9118, wherein the implant is
combined with a coating, and the coating directly contacts the
device.
[10111] 9146. The method of item 9118, wherein the implant is
combined with a coating, and the coating indirectly contacts the
device.
[10112] 9147. The method of item 9118, wherein the implant is
combined with a coating, and the coating partially covers the
device.
[10113] 9148. The method of item 9118, wherein the implant is
combined with a coating, and the coating completely covers the
device.
[10114] 9149. The method of item 9118, wherein the implant is
combined with a coating, and the coating is a uniform coating.
[10115] 9150. The method of item 9118, wherein the implant is
combined with a coating, and the coating is a non-uniform
coating.
[10116] 9151. The method of item 9118, wherein the implant is
combined with a coating, and the coating is a discontinuous
coating.
[10117] 9152. The method of item 9118 wherein the implant is
combined with a coating, and the coating is a patterned
coating.
[10118] 9153. The method of item 9118, wherein the implant is
combined with a coating, and the coating has a thickness of 100
.mu.m or less.
[10119] 9154. The method of item 9118, wherein the implant is
combined with a coating, and the coating has a thickness of 10
.mu.m or less.
[10120] 9155. The method of item 9118, wherein the implant is
combined with a coating, and the coating adheres to the surface of
the device upon deployment of the device.
[10121] 9156. The method of item 9118, wherein the implant is
combined with a coating, and the coating is stable at room
temperature for a period of at least 1 year.
[10122] 9157. The method of item 9118, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 0.0001% to about 1% by
weight.
[10123] 9158. The method of item 9118, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 1% to about 10% by
weight.
[10124] 9159. The method of item 9118, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 10% to about 25% by
weight.
[10125] 9160. The method of item 9118, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 25% to about 70% by
weight.
[10126] 9161. The method of item 9118, wherein the implant is
combined with a coating, and the coating further comprises a
polymer.
[10127] 9162. The method of item 9118, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition.
[10128] 9163. The method of item 9118, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition, where the first composition and the
second composition are different.
[10129] 9164. The method of item 9118, wherein the device comprises
a polymer.
[10130] 9165. The method of item 9118, wherein the device comprises
a polymer, and the polymer is a component of the composition.
[10131] 9166. The method of item 9118, wherein the implant is
combined with a polymer, and the polymer is a copolymer.
[10132] 9167. The method of item 9118, wherein the implant is
combined with a polymer, and the polymer is a block copolymer.
[10133] 9168. The method of item 9118, wherein the implant is
combined with a polymer, and the polymer is a random copolymer.
[10134] 9169. The method of item 9118, wherein the implant is
combined with a polymer, and the polymer is a biodegradable
polymer.
[10135] 9170. The method of item 9118, wherein the implant is
combined with a polymer, and the polymer is a non-biodegradable
polymer.
[10136] 9171. The method of item 9118, wherein the implant is
combined with a polymer, and the polymer is a hydrophilic
polymer.
[10137] 9172. The method of item 9118, wherein the implant is
combined with a polymer, and the polymer is a hydrophobic
polymer.
[10138] 9173. The method of item 9118, wherein the implant is
combined with a polymer, and the polymer has hydrophilic
domains.
[10139] 9174. The method of item 9118, wherein the implant is
combined with a polymer, and the polymer has hydrophobic
domains.
[10140] 9175. The method of item 9118, wherein the implant is
combined with a polymer, and the polymer is a non-conductive
polymer.
[10141] 9176. The method of item 9118, wherein the implant is
combined with a polymer, and the polymer is an elastomer.
[10142] 9177. The method of item 9118, wherein the implant is
combined with a polymer, and the polymer is a hydrogel.
[10143] 9178. The method of item 9118, wherein the implant is
combined with a polymer, and the polymer is a silicone polymer.
[10144] 9179. The method of item 9118, wherein the implant is
combined with a polymer, and the polymer is a hydrocarbon
polymer.
[10145] 9180. The method of item 9118, wherein the implant is
combined with a polymer, and the polymer is a styrene-derived
polymer.
[10146] 9181. The method of item 9118, wherein the implant is
combined with a polymer, and the polymer is a butadiene
polymer.
[10147] 9182. The method of item 9118, wherein the implant is
combined with a polymer, and the polymer is a macromer.
[10148] 9183. The method of item 9118, wherein the implant is
combined with a polymer, and the polymer is a poly(ethylene glycol)
polymer.
[10149] 9184. The method of item 9118, wherein the implant is
combined with a polymer, and the polymer is an amorphous
polymer.
[10150] 9185. The method of item 9118, wherein the implant is
combined with a polymer, and the polymer is a lubricious
coating.
[10151] 9186. The method of item 9118 wherein the fibrosing agent
is located within pores or holes of the device.
[10152] 9187. The method of item 9118 wherein the fibrosing agent
is located within a channel, lumen, or divet of the device.
[10153] 9188. The method of item 9118, wherein the implant is
further combined with a second pharmaceutically active agent.
[10154] 9189. The method of item 9118, wherein the implant is
further combined with an anti-inflammatory agent.
[10155] 9190. The method of item 9118 wherein the implant is
further combined with an agent that inhibits infection.
[10156] 9191. The method of item 9118, wherein the implant is
further combined with an anthracycline.
[10157] 9192. The method of item 9118, wherein the implant is
further combined with doxorubicin.
[10158] 9193. The method of item 9118, wherein the implant is
further combined with mitoxantrone.
[10159] 9194. The method of item 9118, wherein the implant is
further combined with a fluoropyrimidine.
[10160] 9195. The method of item 9118, wherein the implant is
further combined with 5-fluorouracil (5-FU).
[10161] 9196. The method of item 9118, wherein the implant is
further combined with a folic acid antagonist.
[10162] 9197. The method of item 9118, wherein the implant is
further combined with methotrexate.
[10163] 9198. The method of item 9118, wherein the implant is
further combined with a podophylotoxin.
[10164] 9199. The method of item 9118, wherein the implant is
further combined with etoposide.
[10165] 9200. The method of item 9118 wherein the implant is
further combined with a camptothecin.
[10166] 9201. The method of item 9118, wherein the implant is
further combined with a hydroxyurea.
[10167] 9202. The method of item 9118, wherein the implant is
further combined with a platinum complex.
[10168] 9203. The method of item 9118, wherein the implant is
further combined with cisplatin.
[10169] 9204. The method of item 9118, wherein the implant is
further combined with an anti-thrombotic agent.
[10170] 9205. The method of item 9118, wherein the implant is
further combined with a visualization agent.
[10171] 9206. The method of item 9118, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises a metal, a halogenated compound, or a
barium containing compound.
[10172] 9207. The method of item 9118, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises barium, tantalum, or technetium.
[10173] 9208. The method of item 9118, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a MRI responsive material.
[10174] 9209. The method of item 9118, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a gadolinium chelate.
[10175] 9210. The method of item 9118, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises iron, magnesium, manganese, copper,
or chromium.
[10176] 9211. The method of item 9118, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises an iron oxide compound.
[10177] 9212. The method of item 9118, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a dye, pigment, or colorant.
[10178] 9213. The method of item 9118, wherein the implant is
further combined with an echogenic material.
[10179] 9214. The method of item 9118, wherein the implant is
further combined with an echogenic material, and the echogenic
material is in the form of a coating.
[10180] 9215. The method of item 9118 wherein the device is
sterilized.
[10181] 9216. The method of item 9118 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device.
[10182] 9217. The method of item 9118 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is connective
tissue.
[10183] 9218. The method of item 9118 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is muscle tissue.
[10184] 9219. The method of item 9118 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is nerve tissue.
[10185] 9220. The method of item 9118 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is epithelium
tissue.
[10186] 9221. The method of item 9118 wherein the fibrosing agent
is released in effective concentrations from the device over a
period ranging from the time of deployment of the device to about 1
year.
[10187] 9222. The method of item 9118 wherein the fibrosing agent
is released in effective concentrations from the device over a
period ranging from about 1 month to 6 months.
[10188] 9223. The method of item 9118 wherein the fibrosing agent
is released in effective concentrations from the device over a
period ranging from about 1-90 days.
[10189] 9224. The method of item 9118 wherein the fibrosing agent
is released in effective concentrations from the device at a
constant rate.
[10190] 9225. The method of item 9118 wherein the fibrosing agent
is released in effective concentrations from the device at an
increasing rate.
[10191] 9226. The method of item 9118 wherein the fibrosing agent
is released in effective concentrations from the device at a
decreasing rate.
[10192] 9227. The method of item 9118 wherein the fibrosing agent
is released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[10193] 9228. The method of item 9118 wherein the fibrosing agent
is released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[10194] 9229. The method of item 9118 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[10195] 9230. The method of item 9118 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[10196] 9231. The method of item 9118 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[10197] 9232. The method of item 9118 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[10198] 9233. The method of item 9118 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[10199] 9234. The method of item 9118 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[10200] 9235. The method of item 9118 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[10201] 9236. The method of item 9118 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[10202] 9237. The method of item 9118 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[10203] 9238. The method of item 9118 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[10204] 9239. The method of item 9118 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[10205] 9240. The method of item 9118 wherein the vascular coil
implant comprises fluorinated polymer.
[10206] 9241. The method of item 9118 wherein the vascular coil
implant is porous.
[10207] 9242. The method of item 9118 wherein the vascular coil
implant comprises a bioactive material.
[10208] 9243. The method of item 9118 wherein the vascular coil
implant is biologically inert.
[10209] 9244. The method of item 9118 wherein the vascular coil
implant has a first state prior to insertion and a second state
post insertion.
[10210] 9245. A method of making a medical device comprising
combining i) a vaso-occlusive coil implant, with ii) a fibrosing
agent or a composition comprising a fibrosing agent, where the
fibrosing agent induces a fibrotic response between the device and
a patient in which the device is implanted.
[10211] 9246. The method of item 9245 wherein the fibrosing agent
promotes regeneration.
[10212] 9247. The method of item 9245 wherein the fibrosing agent
promotes angiogenesis.
[10213] 9248. The method of item 9245 wherein the fibrosing agent
promotes fibroblast migration.
[10214] 9249. The method of item 9245 wherein the fibrosing agent
promotes fibroblast proliferation.
[10215] 9250. The method of item 9245 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[10216] 9251. The method of item 9245 wherein the fibrosing agent
promotes tissue remodeling.
[10217] 9252. The method of item 9245 wherein the fibrosing agent
is an arterial vessel wall irritant.
[10218] 9253. The method of item 9245 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[10219] 9254. The method of item 9245 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[10220] 9255. The method of item 9245 wherein the fibrosing agent
is or comprises silk.
[10221] 9256. The method of item 9245 wherein the fibrosing agent
is or comprises mineral particles.
[10222] 9257. The method of item 9245 wherein the fibrosing agent
is or comprises chitosan.
[10223] 9258. The method of item 9245 wherein the fibrosing agent
is or comprises polylysine.
[10224] 9259. The method of item 9245 wherein the fibrosing agent
is or comprises fibronectin.
[10225] 9260. The method of item 9245 wherein the fibrosing agent
is or comprises bleomycin.
[10226] 9261. The method of item 9245 wherein the fibrosing agent
is or comprises CTGF.
[10227] 9262. The method of item 9245 wherein the fibrosing agent
is in the form of a thread, or is in contact with a thread.
[10228] 9263. The method of item 9245 wherein the fibrosing agent
is in the form of a particulate.
[10229] 9264. The method of item 9245 wherein the composition
further comprises an inflammatory cytokine.
[10230] 9265. The method of item 9245 wherein the composition
further comprises an agent that stimulates cell proliferation.
[10231] 9266. The method of item 9245 wherein the composition is in
the form of a gel or paste.
[10232] 9267. The method of item 9245 wherein the fibrosing agent
is in the form of tufts.
[10233] 9268. The method of item 9245 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[10234] 9269. The method of item 9245 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[10235] 9270. The method of item 9245, wherein the implant is
combined with a coating, and the coating comprises the fibrosing
agent.
[10236] 9271. The method of item 9245, wherein the implant is
combined with a coating, and the coating is disposed on a surface
of the device.
[10237] 9272. The method of item 9245, wherein the implant is
combined with a coating, and the coating directly contacts the
device.
[10238] 9273. The method of item 9245, wherein the implant is
combined with a coating, and the coating indirectly contacts the
device.
[10239] 9274. The method of item 9245, wherein the implant is
combined with a coating, and the coating partially covers the
device.
[10240] 9275. The method of item 9245, wherein the implant is
combined with a coating, and the coating completely covers the
device.
[10241] 9276. The method of item 9245, wherein the implant is
combined with a coating, and the coating is a uniform coating.
[10242] 9277. The method of item 9245, wherein the implant is
combined with a coating, and the coating is a non-uniform
coating.
[10243] 9278. The method of item 9245, wherein the implant is
combined with a coating, and the coating is a discontinuous
coating.
[10244] 9279. The method of item 9245 wherein the implant is
combined with a coating, and the coating is a patterned
coating.
[10245] 9280. The method of item 9245, wherein the implant is
combined with a coating, and the coating has a thickness of 100
.mu.m or less.
[10246] 9281. The method of item 9245, wherein the implant is
combined with a coating, and the coating has a thickness of 10
.mu.m or less.
[10247] 9282. The method of item 9245, wherein the implant is
combined with a coating, and the coating adheres to the surface of
the device upon deployment of the device.
[10248] 9283. The method of item 9245, wherein the implant is
combined with a coating, and the coating is stable at room
temperature for a period of at least 1 year.
[10249] 9284. The method of item 9245, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 0.0001% to about 1% by
weight.
[10250] 9285. The method of item 9245, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 1% to about 10% by
weight.
[10251] 9286. The method of item 9245, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 10% to about 25% by
weight.
[10252] 9287. The method of item 9245, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 25% to about 70% by
weight.
[10253] 9288. The method of item 9245, wherein the implant is
combined with a coating, and the coating further comprises a
polymer.
[10254] 9289. The method of item 9245, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition.
[10255] 9290. The method of item 9245, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition, where the first composition and the
second composition are different.
[10256] 9291. The method of item 9245, wherein the device comprises
a polymer.
[10257] 9292. The method of item 9245, wherein the device comprises
a polymer, and the polymer is a component of the composition.
[10258] 9293. The method of item 9245, wherein the implant is
combined with a polymer, and the polymer is a copolymer.
[10259] 9294. The method of item 9245, wherein the implant is
combined with a polymer, and the polymer is a block copolymer.
[10260] 9295. The method of item 9245, wherein the implant is
combined with a polymer, and the polymer is a random copolymer.
[10261] 9296. The method of item 9245, wherein the implant is
combined with a polymer, and the polymer is a biodegradable
polymer.
[10262] 9297. The method of item 9245, wherein the implant is
combined with a polymer, and the polymer is a non-biodegradable
polymer.
[10263] 9298. The method of item 9245, wherein the implant is
combined with a polymer, and the polymer is a hydrophilic
polymer.
[10264] 9299. The method of item 9245, wherein the implant is
combined with a polymer, and the polymer is a hydrophobic
polymer.
[10265] 9300. The method of item 9245, wherein the implant is
combined with a polymer, and the polymer has hydrophilic
domains.
[10266] 9301. The method of item 9245, wherein the implant is
combined with a polymer, and the polymer has hydrophobic
domains.
[10267] 9302. The method of item 9245, wherein the implant is
combined with a polymer, and the polymer is a non-conductive
polymer.
[10268] 9303. The method of item 9245, wherein the implant is
combined with a polymer, and the polymer is an elastomer.
[10269] 9304. The method of item 9245, wherein the implant is
combined with a polymer, and the polymer is a hydrogel.
[10270] 9305. The method of item 9245, wherein the implant is
combined with a polymer, and the polymer is a silicone polymer.
[10271] 9306. The method of item 9245, wherein the implant is
combined with a polymer, and the polymer is a hydrocarbon
polymer.
[10272] 9307. The method of item 9245, wherein the implant is
combined with a polymer, and the polymer is a styrene-derived
polymer.
[10273] 9308. The method of item 9245, wherein the implant is
combined with a polymer, and the polymer is a butadiene
polymer.
[10274] 9309. The method of item 9245, wherein the implant is
combined with a polymer, and the polymer is a macromer.
[10275] 9310. The method of item 9245, wherein the implant is
combined with a polymer, and the polymer is a poly(ethylene glycol)
polymer.
[10276] 9311. The method of item 9245, wherein the implant is
combined with a polymer, and the polymer is an amorphous
polymer.
[10277] 9312. The method of item 9245, wherein the implant is
combined with a polymer, and the polymer is a lubricious
coating.
[10278] 9313. The method of item 9245 wherein the fibrosing agent
is located within pores or holes of the device.
[10279] 9314. The method of item 9245 wherein the fibrosing agent
is located within a channel, lumen, or divet of the device.
[10280] 9315. The method of item 9245, wherein the implant is
further combined with a second pharmaceutically active agent.
[10281] 9316. The method of item 9245, wherein the implant is
further combined with an anti-inflammatory agent.
[10282] 9317. The method of item 9245 wherein the implant is
further combined with an agent that inhibits infection.
[10283] 9318. The method of item 9245, wherein the implant is
further combined with an anthracycline.
[10284] 9319. The method of item 9245, wherein the implant is
further combined with doxorubicin.
[10285] 9320. The method of item 9245, wherein the implant is
further combined with mitoxantrone.
[10286] 9321. The method of item 9245, wherein the implant is
further combined with a fluoropyrimidine.
[10287] 9322. The method of item 9245, wherein the implant is
further combined with 5-fluorouracil (5-FU).
[10288] 9323. The method of item 9245, wherein the implant is
further combined with a folic acid antagonist.
[10289] 9324. The method of item 9245, wherein the implant is
further combined with methotrexate.
[10290] 9325. The method of item 9245, wherein the implant is
further combined with a podophylotoxin.
[10291] 9326. The method of item 9245, wherein the implant is
further combined with etoposide.
[10292] 9327. The method of item 9245 wherein the implant is
further combined with a camptothecin.
[10293] 9328. The method of item 9245, wherein the implant is
further combined with a hydroxyurea.
[10294] 9329. The method of item 9245, wherein the implant is
further combined with a platinum complex.
[10295] 9330. The method of item 9245, wherein the implant is
further combined with cisplatin.
[10296] 9331. The method of item 9245, wherein the implant is
further combined with an anti-thrombotic agent.
[10297] 9332. The method of item 9245, wherein the implant is
further combined with a visualization agent.
[10298] 9333. The method of item 9245, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises a metal, a halogenated compound, or a
barium containing compound.
[10299] 9334. The method of item 9245, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises barium, tantalum, or technetium.
[10300] 9335. The method of item 9245, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a MRI responsive material.
[10301] 9336. The method of item 9245, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a gadolinium chelate.
[10302] 9337. The method of item 9245, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises iron, magnesium, manganese, copper,
or chromium.
[10303] 9338. The method of item 9245, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises an iron oxide compound.
[10304] 9339. The method of item 9245, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a dye, pigment, or colorant.
[10305] 9340. The method of item 9245, wherein the implant is
further combined with an echogenic material.
[10306] 9341. The method of item 9245, wherein the implant is
further combined with an echogenic material, and the echogenic
material is in the form of a coating.
[10307] 9342. The method of item 9245 wherein the device is
sterilized.
[10308] 9343. The method of item 9245 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device.
[10309] 9344. The method of item 9245 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is connective
tissue.
[10310] 9345. The method of item 9245 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is muscle tissue.
[10311] 9346. The method of item 9245 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is nerve tissue.
[10312] 9347. The method of item 9245 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is epithelium
tissue.
[10313] 9348. The method of item 9245 wherein the fibrosing agent
is released in effective concentrations from the device over a
period ranging from the time of deployment of the device to about 1
year.
[10314] 9349. The method of item 9245 wherein the fibrosing agent
is released in effective concentrations from the device over a
period ranging from about 1 month to 6 months.
[10315] 9350. The method of item 9245 wherein the fibrosing agent
is released in effective concentrations from the device over a
period ranging from about 1-90 days.
[10316] 9351. The method of item 9245 wherein the fibrosing agent
is released in effective concentrations from the device at a
constant rate.
[10317] 9352. The method of item 9245 wherein the fibrosing agent
is released in effective concentrations from the device at an
increasing rate.
[10318] 9353. The method of item 9245 wherein the fibrosing agent
is released in effective concentrations from the device at a
decreasing rate.
[10319] 9354. The method of item 9245 wherein the fibrosing agent
is released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[10320] 9355. The method of item 9245 wherein the fibrosing agent
is released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[10321] 9356. The method of item 9245 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[10322] 9357. The method of item 9245 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[10323] 9358. The method of item 9245 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[10324] 9359. The method of item 9245 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[10325] 9360. The method of item 9245 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[10326] 9361. The method of item 9245 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[10327] 9362. The method of item 9245 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[10328] 9363. The method of item 9245 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[10329] 9364. The method of item 9245 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[10330] 9365. The method of item 9245 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[10331] 9366. The method of item 9245 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[10332] 9367. A method of making a medical device comprising
combining i) a vaso-occlusion implant, with ii) a fibrosing agent
or a composition comprising a fibrosing agent, where the fibrosing
agent induces a fibrotic response between the device and a patient
in which the device is implanted.
[10333] 9368. The method of item 9367 wherein the fibrosing agent
promotes regeneration.
[10334] 9369. The method of item 9367 wherein the fibrosing agent
promotes angiogenesis.
[10335] 9370. The method of item 9367 wherein the fibrosing agent
promotes fibroblast migration.
[10336] 9371. The method of item 9367 wherein the fibrosing agent
promotes fibroblast proliferation.
[10337] 9372. The method of item 9367 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[10338] 9373. The method of item 9367 wherein the fibrosing agent
promotes tissue remodeling.
[10339] 9374. The method of item 9367 wherein the fibrosing agent
is an arterial vessel wall irritant.
[10340] 9375. The method of item 9367 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[10341] 9376. The method of item 9367 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[10342] 9377. The method of item 9367 wherein the fibrosing agent
is or comprises silk.
[10343] 9378. The method of item 9367 wherein the fibrosing agent
is or comprises mineral particles.
[10344] 9379. The method of item 9367 wherein the fibrosing agent
is or comprises chitosan.
[10345] 9380. The method of item 9367 wherein the fibrosing agent
is or comprises polylysine.
[10346] 9381. The method of item 9367 wherein the fibrosing agent
is or comprises fibronectin.
[10347] 9382. The method of item 9367 wherein the fibrosing agent
is or comprises bleomycin.
[10348] 9383. The method of item 9367 wherein the fibrosing agent
is or comprises CTGF.
[10349] 9384. The method of item 9367 wherein the fibrosing agent
is in the form of a thread, or is in contact with a thread.
[10350] 9385. The method of item 9367 wherein the fibrosing agent
is in the form of a particulate.
[10351] 9386. The method of item 9367 wherein the composition
further comprises an inflammatory cytokine.
[10352] 9387. The method of item 9367 wherein the composition
further comprises an agent that stimulates cell proliferation.
[10353] 9388. The method of item 9367 wherein the composition is in
the form of a gel or paste.
[10354] 9389. The method of item 9367 wherein the fibrosing agent
is in the form of tufts.
[10355] 9390. The method of item 9367 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[10356] 9391. The method of item 9367 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[10357] 9392. The method of item 9367, wherein the implant is
combined with a coating, and the coating comprises the fibrosing
agent.
[10358] 9393. The method of item 9367, wherein the implant is
combined with a coating, and the coating is disposed on a surface
of the device.
[10359] 9394. The method of item 9367, wherein the implant is
combined with a coating, and the coating directly contacts the
device.
[10360] 9395. The method of item 9367, wherein the implant is
combined with a coating, and the coating indirectly contacts the
device.
[10361] 9396. The method of item 9367, wherein the implant is
combined with a coating, and the coating partially covers the
device.
[10362] 9397. The method of item 9367, wherein the implant is
combined with a coating, and the coating completely covers the
device.
[10363] 9398. The method of item 9367, wherein the implant is
combined with a coating, and the coating is a uniform coating.
[10364] 9399. The method of item 9367, wherein the implant is
combined with a coating, and the coating is a non-uniform
coating.
[10365] 9400. The method of item 9367, wherein the implant is
combined with a coating, and the coating is a discontinuous
coating.
[10366] 9401. The method of item 9367 wherein the implant is
combined with a coating, and the coating is a patterned
coating.
[10367] 9402. The method of item 9367, wherein the implant is
combined with a coating, and the coating has a thickness of 100
.mu.m or less.
[10368] 9403. The method of item 9367, wherein the implant is
combined with a coating, and the coating has a thickness of 10
.mu.m or less.
[10369] 9404. The method of item 9367, wherein the implant is
combined with a coating, and the coating adheres to the surface of
the device upon deployment of the device.
[10370] 9405. The method of item 9367, wherein the implant is
combined with a coating, and the coating is stable at room
temperature for a period of at least 1 year.
[10371] 9406. The method of item 9367, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 0.0001% to about 1% by
weight.
[10372] 9407. The method of item 9367, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 1% to about 10% by
weight.
[10373] 9408. The method of item 9367, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 10% to about 25% by
weight.
[10374] 9409. The method of item 9367, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 25% to about 70% by
weight.
[10375] 9410. The method of item 9367, wherein the implant is
combined with a coating, and the coating further comprises a
polymer.
[10376] 9411. The method of item 9367, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition.
[10377] 9412. The method of item 9367, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition, where the first composition and the
second composition are different.
[10378] 9413. The method of item 9367, wherein the device comprises
a polymer.
[10379] 9414. The method of item 9367, wherein the device comprises
a polymer, and the polymer is a component of the composition.
[10380] 9415. The method of item 9367, wherein the implant is
combined with a polymer, and the polymer is a copolymer.
[10381] 9416. The method of item 9367, wherein the implant is
combined with a polymer, and the polymer is a block copolymer.
[10382] 9417. The method of item 9367, wherein the implant is
combined with a polymer, and the polymer is a random copolymer.
[10383] 9418. The method of item 9367, wherein the implant is
combined with a polymer, and the polymer is a biodegradable
polymer.
[10384] 9419. The method of item 9367, wherein the implant is
combined with a polymer, and the polymer is a non-biodegradable
polymer.
[10385] 9420. The method of item 9367, wherein the implant is
combined with a polymer, and the polymer is a hydrophilic
polymer.
[10386] 9421. The method of item 9367, wherein the implant is
combined with a polymer, and the polymer is a hydrophobic
polymer.
[10387] 9422. The method of item 9367, wherein the implant is
combined with a polymer, and the polymer has hydrophilic
domains.
[10388] 9423. The method of item 9367, wherein the implant is
combined with a polymer, and the polymer has hydrophobic
domains.
[10389] 9424. The method of item 9367, wherein the implant is
combined with a polymer, and the polymer is a non-conductive
polymer.
[10390] 9425. The method of item 9367, wherein the implant is
combined with a polymer, and the polymer is an elastomer.
[10391] 9426. The method of item 9367, wherein the implant is
combined with a polymer, and the polymer is a hydrogel.
[10392] 9427. The method of item 9367, wherein the implant is
combined with a polymer, and the polymer is a silicone polymer.
[10393] 9428. The method of item 9367, wherein the implant is
combined with a polymer, and the polymer is a hydrocarbon
polymer.
[10394] 9429. The method of item 9367, wherein the implant is
combined with a polymer, and the polymer is a styrene-derived
polymer.
[10395] 9430. The method of item 9367, wherein the implant is
combined with a polymer, and the polymer is a butadiene
polymer.
[10396] 9431. The method of item 9367, wherein the implant is
combined with a polymer, and the polymer is a macromer.
[10397] 9432. The method of item 9367, wherein the implant is
combined with a polymer, and the polymer is a poly(ethylene glycol)
polymer.
[10398] 9433. The method of item 9367, wherein the implant is
combined with a polymer, and the polymer is an amorphous
polymer.
[10399] 9434. The method of item 9367, wherein the implant is
combined with a polymer, and the polymer is a lubricious
coating.
[10400] 9435. The method of item 9367 wherein the fibrosing agent
is located within pores or holes of the device.
[10401] 9436. The method of item 9367 wherein the fibrosing agent
is located within a channel, lumen, or divet of the device.
[10402] 9437. The method of item 9367, wherein the implant is
further combined with a second pharmaceutically active agent.
[10403] 9438. The method of item 9367, wherein the implant is
further combined with an anti-inflammatory agent.
[10404] 9439. The method of item 9367 wherein the implant is
further combined with an agent that inhibits infection.
[10405] 9440. The method of item 9367, wherein the implant is
further combined with an anthracycline.
[10406] 9441. The method of item 9367, wherein the implant is
further combined with doxorubicin.
[10407] 9442. The method of item 9367, wherein the implant is
further combined with mitoxantrone.
[10408] 9443. The method of item 9367, wherein the implant is
further combined with a fluoropyrimidine.
[10409] 9444. The method of item 9367, wherein the implant is
further combined with 5-fluorouracil (5-FU).
[10410] 9445. The method of item 9367, wherein the implant is
further combined with a folic acid antagonist.
[10411] 9446. The method of item 9367, wherein the implant is
further combined with methotrexate.
[10412] 9447. The method of item 9367, wherein the implant is
further combined with a podophylotoxin.
[10413] 9448. The method of item 9367, wherein the implant is
further combined with etoposide.
[10414] 9449. The method of item 9367 wherein the implant is
further combined with a camptothecin.
[10415] 9450. The method of item 9367, wherein the implant is
further combined with a hydroxyurea.
[10416] 9451. The method of item 9367, wherein the implant is
further combined with a platinum complex.
[10417] 9452. The method of item 9367, wherein the implant is
further combined with cisplatin.
[10418] 9453. The method of item 9367, wherein the implant is
further combined with an anti-thrombotic agent.
[10419] 9454. The method of item 9367, wherein the implant is
further combined with a visualization agent.
[10420] 9455. The method of item 9367, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises a metal, a halogenated compound, or a
barium containing compound.
[10421] 9456. The method of item 9367, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises barium, tantalum, or technetium.
[10422] 9457. The method of item 9367, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a MRI responsive material.
[10423] 9458. The method of item 9367, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a gadolinium chelate.
[10424] 9459. The method of item 9367, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises iron, magnesium, manganese, copper,
or chromium.
[10425] 9460. The method of item 9367, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises an iron oxide compound.
[10426] 9461. The method of item 9367, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a dye, pigment, or colorant.
[10427] 9462. The method of item 9367, wherein the implant is
further combined with an echogenic material.
[10428] 9463. The method of item 9367, wherein the implant is
further combined with an echogenic material, and the echogenic
material is in the form of a coating.
[10429] 9464. The method of item 9367 wherein the device is
sterilized.
[10430] 9465. The method of item 9367 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device.
[10431] 9466. The method of item 9367 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is connective
tissue.
[10432] 9467. The method of item 9367 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is muscle tissue.
[10433] 9468. The method of item 9367 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is nerve tissue.
[10434] 9469. The method of item 9367 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is epithelium
tissue.
[10435] 9470. The method of item 9367 wherein the fibrosing agent
is released in effective concentrations from the device over a
period ranging from the time of deployment of the device to about 1
year.
[10436] 9471. The method of item 9367 wherein the fibrosing agent
is released in effective concentrations from the device over a
period ranging from about 1 month to 6 months.
[10437] 9472. The method of item 9367 wherein the fibrosing agent
is released in effective concentrations from the device over a
period ranging from about 1-90 days.
[10438] 9473. The method of item 9367 wherein the fibrosing agent
is released in effective concentrations from the device at a
constant rate.
[10439] 9474. The method of item 9367 wherein the fibrosing agent
is released in effective concentrations from the device at an
increasing rate.
[10440] 9475. The method of item 9367 wherein the fibrosing agent
is released in effective concentrations from the device at a
decreasing rate.
[10441] 9476. The method of item 9367 wherein the fibrosing agent
is released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[10442] 9477. The method of item 9367 wherein the fibrosing agent
is released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[10443] 9478. The method of item 9367 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[10444] 9479. The method of item 9367 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[10445] 9480. The method of item 9367 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[10446] 9481. The method of item 9367 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[10447] 9482. The method of item 9367 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[10448] 9483. The method of item 9367 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[10449] 9484. The method of item 9367 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[10450] 9485. The method of item 9367 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[10451] 9486. The method of item 9367 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[10452] 9487. The method of item 9367 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[10453] 9488. The method of item 9367 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[10454] 9489. A method of making a medical device comprising
combining i) a non-coiled vaso-occlusive implant, with ii) a
fibrosing agent or a composition comprising a fibrosing agent,
where the fibrosing agent induces a fibrotic response between the
device and a patient in which the device is implanted.
[10455] 9490. The method of item 9489 wherein the fibrosing agent
promotes regeneration.
[10456] 9491. The method of item 9489 wherein the fibrosing agent
promotes angiogenesis.
[10457] 9492. The method of item 9489 wherein the fibrosing agent
promotes fibroblast migration.
[10458] 9493. The method of item 9489 wherein the fibrosing agent
promotes fibroblast proliferation.
[10459] 9494. The method of item 9489 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[10460] 9495. The method of item 9489 wherein the fibrosing agent
promotes tissue remodeling.
[10461] 9496. The method of item 9489 wherein the fibrosing agent
is an arterial vessel wall irritant.
[10462] 9497. The method of item 9489 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[10463] 9498. The method of item 9489 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[10464] 9499. The method of item 9489 wherein the fibrosing agent
is or comprises silk.
[10465] 9500. The method of item 9489 wherein the fibrosing agent
is or comprises mineral particles.
[10466] 9501. The method of item 9489 wherein the fibrosing agent
is or comprises chitosan.
[10467] 9502. The method of item 9489 wherein the fibrosing agent
is or comprises polylysine.
[10468] 9503. The method of item 9489 wherein the fibrosing agent
is or comprises fibronectin.
[10469] 9504. The method of item 9489 wherein the fibrosing agent
is or comprises bleomycin.
[10470] 9505. The method of item 9489 wherein the fibrosing agent
is or comprises CTGF.
[10471] 9506. The method of item 9489 wherein the fibrosing agent
is in the form of a thread, or is in contact with a thread.
[10472] 9507. The method of item 9489 wherein the fibrosing agent
is in the form of a particulate.
[10473] 9508. The method of item 9489 wherein the composition
further comprises an inflammatory cytokine.
[10474] 9509. The method of item 9489 wherein the composition
further comprises an agent that stimulates cell proliferation.
[10475] 9510. The method of item 9489 wherein the composition is in
the form of a gel or paste.
[10476] 9511. The method of item 9489 wherein the fibrosing agent
is in the form of tufts.
[10477] 9512. The method of item 9489 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[10478] 9513. The method of item 9489 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[10479] 9514. The method of item 9489, wherein the implant is
combined with a coating, and the coating comprises the fibrosing
agent.
[10480] 9515. The method of item 9489, wherein the implant is
combined with a coating, and the coating is disposed on a surface
of the device.
[10481] 9516. The method of item 9489, wherein the implant is
combined with a coating, and the coating directly contacts the
device.
[10482] 9517. The method of item 9489, wherein the implant is
combined with a coating, and the coating indirectly contacts the
device.
[10483] 9518. The method of item 9489, wherein the implant is
combined with a coating, and the coating partially covers the
device.
[10484] 9519. The method of item 9489, wherein the implant is
combined with a coating, and the coating completely covers the
device.
[10485] 9520. The method of item 9489, wherein the implant is
combined with a coating, and the coating is a uniform coating.
[10486] 9521. The method of item 9489, wherein the implant is
combined with a coating, and the coating is a non-uniform
coating.
[10487] 9522. The method of item 9489, wherein the implant is
combined with a coating, and the coating is a discontinuous
coating.
[10488] 9523. The method of item 9489 wherein the implant is
combined with a coating, and the coating is a patterned
coating.
[10489] 9524. The method of item 9489, wherein the implant is
combined with a coating, and the coating has a thickness of 100
.mu.m or less.
[10490] 9525. The method of item 9489, wherein the implant is
combined with a coating, and the coating has a thickness of 10
.mu.m or less.
[10491] 9526. The method of item 9489, wherein the implant is
combined with a coating, and the coating adheres to the surface of
the device upon deployment of the device.
[10492] 9527. The method of item 9489, wherein the implant is
combined with a coating, and the coating is stable at room
temperature for a period of at least 1 year.
[10493] 9528. The method of item 9489, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 0.0001% to about 1% by
weight.
[10494] 9529. The method of item 9489, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 1% to about 10% by
weight.
[10495] 9530. The method of item 9489, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 10% to about 25% by
weight.
[10496] 9531. The method of item 9489, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 25% to about 70% by
weight.
[10497] 9532. The method of item 9489, wherein the implant is
combined with a coating, and the coating further comprises a
polymer.
[10498] 9533. The method of item 9489, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition.
[10499] 9534. The method of item 9489, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition, where the first composition and the
second composition are different.
[10500] 9535. The method of item 9489, wherein the device comprises
a polymer.
[10501] 9536. The method of item 9489, wherein the device comprises
a polymer, and the polymer is a component of the composition.
[10502] 9537. The method of item 9489, wherein the implant is
combined with a polymer, and the polymer is a copolymer.
[10503] 9538. The method of item 9489, wherein the implant is
combined with a polymer, and the polymer is a block copolymer.
[10504] 9539. The method of item 9489, wherein the implant is
combined with a polymer, and the polymer is a random copolymer.
[10505] 9540. The method of item 9489, wherein the implant is
combined with a polymer, and the polymer is a biodegradable
polymer.
[10506] 9541. The method of item 9489, wherein the implant is
combined with a polymer, and the polymer is a non-biodegradable
polymer.
[10507] 9542. The method of item 9489, wherein the implant is
combined with a polymer, and the polymer is a hydrophilic
polymer.
[10508] 9543. The method of item 9489, wherein the implant is
combined with a polymer, and the polymer is a hydrophobic
polymer.
[10509] 9544. The method of item 9489, wherein the implant is
combined with a polymer, and the polymer has hydrophilic
domains.
[10510] 9545. The method of item 9489, wherein the implant is
combined with a polymer, and the polymer has hydrophobic
domains.
[10511] 9546. The method of item 9489, wherein the implant is
combined with a polymer, and the polymer is a non-conductive
polymer.
[10512] 9547. The method of item 9489, wherein the implant is
combined with a polymer, and the polymer is an elastomer.
[10513] 9548. The method of item 9489, wherein the implant is
combined with a polymer, and the polymer is a hydrogel.
[10514] 9549. The method of item 9489, wherein the implant is
combined with a polymer, and the polymer is a silicone polymer.
[10515] 9550. The method of item 9489, wherein the implant is
combined with a polymer, and the polymer is a hydrocarbon
polymer.
[10516] 9551. The method of item 9489, wherein the implant is
combined with a polymer, and the polymer is a styrene-derived
polymer.
[10517] 9552. The method of item 9489, wherein the implant is
combined with a polymer, and the polymer is a butadiene
polymer.
[10518] 9553. The method of item 9489, wherein the implant is
combined with a polymer, and the polymer is a macromer.
[10519] 9554. The method of item 9489, wherein the implant is
combined with a polymer, and the polymer is a poly(ethylene glycol)
polymer.
[10520] 9555. The method of item 9489, wherein the implant is
combined with a polymer, and the polymer is an amorphous
polymer.
[10521] 9556. The method of item 9489, wherein the implant is
combined with a polymer, and the polymer is a lubricious
coating.
[10522] 9557. The method of item 9489 wherein the fibrosing agent
is located within pores or holes of the device.
[10523] 9558. The method of item 9489 wherein the fibrosing agent
is located within a channel, lumen, or divet of the device.
[10524] 9559. The method of item 9489, wherein the implant is
further combined with a second pharmaceutically active agent.
[10525] 9560. The method of item 9489, wherein the implant is
further combined with an anti-inflammatory agent.
[10526] 9561. The method of item 9489 wherein the implant is
further combined with an agent that inhibits infection.
[10527] 9562. The method of item 9489, wherein the implant is
further combined with an anthracycline.
[10528] 9563. The method of item 9489, wherein the implant is
further combined with doxorubicin.
[10529] 9564. The method of item 9489, wherein the implant is
further combined with mitoxantrone.
[10530] 9565. The method of item 9489, wherein the implant is
further combined with a fluoropyrimidine.
[10531] 9566. The method of item 9489, wherein the implant is
further combined with 5-fluorouracil (5-FU).
[10532] 9567. The method of item 9489, wherein the implant is
further combined with a folic acid antagonist.
[10533] 9568. The method of item 9489, wherein the implant is
further combined with methotrexate.
[10534] 9569. The method of item 9489, wherein the implant is
further combined with a podophylotoxin.
[10535] 9570. The method of item 9489, wherein the implant is
further combined with etoposide.
[10536] 9571. The method of item 9489 wherein the implant is
further combined with a camptothecin.
[10537] 9572. The method of item 9489, wherein the implant is
further combined with a hydroxyurea.
[10538] 9573. The method of item 9489, wherein the implant is
further combined with a platinum complex.
[10539] 9574. The method of item 9489, wherein the implant is
further combined with cisplatin.
[10540] 9575. The method of item 9489, wherein the implant is
further combined with an anti-thrombotic agent.
[10541] 9576. The method of item 9489, wherein the implant is
further combined with a visualization agent.
[10542] 9577. The method of item 9489, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises a metal, a halogenated compound, or a
barium containing compound.
[10543] 9578. The method of item 9489, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises barium, tantalum, or technetium.
[10544] 9579. The method of item 9489, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a MRI responsive material.
[10545] 9580. The method of item 9489, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a gadolinium chelate.
[10546] 9581. The method of item 9489, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises iron, magnesium, manganese, copper,
or chromium.
[10547] 9582. The method of item 9489, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises an iron oxide compound.
[10548] 9583. The method of item 9489, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a dye, pigment, or colorant.
[10549] 9584. The method of item 9489, wherein the implant is
further combined with an echogenic material.
[10550] 9585. The method of item 9489, wherein the implant is
further combined with an echogenic material, and the echogenic
material is in the form of a coating.
[10551] 9586. The method of item 9489 wherein the device is
sterilized.
[10552] 9587. The method of item 9489 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device.
[10553] 9588. The method of item 9489 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is connective
tissue.
[10554] 9589. The method of item 9489 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is muscle tissue.
[10555] 9590. The method of item 9489 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is nerve tissue.
[10556] 9591. The method of item 9489 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is epithelium
tissue.
[10557] 9592. The method of item 9489 wherein the fibrosing agent
is released in effective concentrations from the device over a
period ranging from the time of deployment of the device to about 1
year.
[10558] 9593. The method of item 9489 wherein the fibrosing agent
is released in effective concentrations from the device over a
period ranging from about 1 month to 6 months.
[10559] 9594. The method of item 9489 wherein the fibrosing agent
is released in effective concentrations from the device over a
period ranging from about 1-90 days.
[10560] 9595. The method of item 9489 wherein the fibrosing agent
is released in effective concentrations from the device at a
constant rate.
[10561] 9596. The method of item 9489 wherein the fibrosing agent
is released in effective concentrations from the device at an
increasing rate.
[10562] 9597. The method of item 9489 wherein the fibrosing agent
is released in effective concentrations from the device at a
decreasing rate.
[10563] 9598. The method of item 9489 wherein the fibrosing agent
is released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[10564] 9599. The method of item 9489 wherein the fibrosing agent
is released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[10565] 9600. The method of item 9489 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[10566] 9601. The method of item 9489 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[10567] 9602. The method of item 9489 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[10568] 9603. The method of item 9489 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[10569] 9604. The method of item 9489 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[10570] 9605. The method of item 9489 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[10571] 9606. The method of item 9489 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[10572] 9607. The method of item 9489 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[10573] 9608. The method of item 9489 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[10574] 9609. The method of item 9489 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[10575] 9610. The method of item 9489 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[10576] 9611. The method of item 9489 wherein the implant is
expandable.
[10577] 9612. A method of making a medical device comprising
combining i) a hernia mesh implant, with ii) a fibrosing agent or a
composition comprising a fibrosing agent, where the fibrosing agent
induces a fibrotic response between the device and a patient in
which the device is implanted.
[10578] 9613. The method of item 9612 wherein the fibrosing agent
promotes regeneration.
[10579] 9614. The method of item 9612 wherein the fibrosing agent
promotes angiogenesis.
[10580] 9615. The method of item 9612 wherein the fibrosing agent
promotes fibroblast migration.
[10581] 9616. The method of item 9612 wherein the fibrosing agent
promotes fibroblast proliferation.
[10582] 9617. The method of item 9612 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[10583] 9618. The method of item 9612 wherein the fibrosing agent
promotes tissue remodeling.
[10584] 9619. The method of item 9612 wherein the fibrosing agent
is an arterial vessel wall irritant.
[10585] 9620. The method of item 9612 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[10586] 9621. The method of item 9612 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[10587] 9622. The method of item 9612 wherein the fibrosing agent
is or comprises silk.
[10588] 9623. The method of item 9612 wherein the fibrosing agent
is or comprises mineral particles.
[10589] 9624. The method of item 9612 wherein the fibrosing agent
is or comprises chitosan.
[10590] 9625. The method of item 9612 wherein the fibrosing agent
is or comprises polylysine.
[10591] 9626. The method of item 9612 wherein the fibrosing agent
is or comprises fibronectin.
[10592] 9627. The method of item 9612 wherein the fibrosing agent
is or comprises bleomycin.
[10593] 9628. The method of item 9612 wherein the fibrosing agent
is or comprises CTGF.
[10594] 9629. The method of item 9612 wherein the fibrosing agent
is in the form of a thread, or is in contact with a thread.
[10595] 9630. The method of item 9612 wherein the fibrosing agent
is in the form of a particulate.
[10596] 9631. The method of item 9612 wherein the composition
further comprises an inflammatory cytokine.
[10597] 9632. The method of item 9612 wherein the composition
further comprises an agent that stimulates cell proliferation.
[10598] 9633. The method of item 9612 wherein the composition is in
the form of a gel or paste.
[10599] 9634. The method of item 9612 wherein the fibrosing agent
is in the form of tufts.
[10600] 9635. The method of item 9612 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[10601] 9636. The method of item 9612 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[10602] 9637. The method of item 9612, wherein the implant is
combined with a coating, and the coating comprises the fibrosing
agent.
[10603] 9638. The method of item 9612, wherein the implant is
combined with a coating, and the coating is disposed on a surface
of the device.
[10604] 9639. The method of item 9612, wherein the implant is
combined with a coating, and the coating directly contacts the
device.
[10605] 9640. The method of item 9612, wherein the implant is
combined with a coating, and the coating indirectly contacts the
device.
[10606] 9641. The method of item 9612, wherein the implant is
combined with a coating, and the coating partially covers the
device.
[10607] 9642. The method of item 9612, wherein the implant is
combined with a coating, and the coating completely covers the
device.
[10608] 9643. The method of item 9612, wherein the implant is
combined with a coating, and the coating is a uniform coating.
[10609] 9644. The method of item 9612, wherein the implant is
combined with a coating, and the coating is a non-uniform
coating.
[10610] 9645. The method of item 9612, wherein the implant is
combined with a coating, and the coating is a discontinuous
coating.
[10611] 9646. The method of item 9612 wherein the implant is
combined with a coating, and the coating is a patterned
coating.
[10612] 9647. The method of item 9612, wherein the implant is
combined with a coating, and the coating has a thickness of 100
.mu.m or less.
[10613] 9648. The method of item 9612, wherein the implant is
combined with a coating, and the coating has a thickness of 10
.mu.m or less.
[10614] 9649. The method of item 9612, wherein the implant is
combined with a coating, and the coating adheres to the surface of
the device upon deployment of the device.
[10615] 9650. The method of item 9612, wherein the implant is
combined with a coating, and the coating is stable at room
temperature for a period of at least 1 year.
[10616] 9651. The method of item 9612, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 0.0001% to about 1% by
weight.
[10617] 9652. The method of item 9612, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 1% to about 10% by
weight.
[10618] 9653. The method of item 9612, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 10% to about 25% by
weight.
[10619] 9654. The method of item 9612, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 25% to about 70% by
weight.
[10620] 9655. The method of item 9612, wherein the implant is
combined with a coating, and the coating further comprises a
polymer.
[10621] 9656. The method of item 9612, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition.
[10622] 9657. The method of item 9612, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition, where the first composition and the
second composition are different.
[10623] 9658. The method of item 9612, wherein the device comprises
a polymer.
[10624] 9659. The method of item 9612, wherein the device comprises
a polymer, and the polymer is a component of the composition.
[10625] 9660. The method of item 9612, wherein the implant is
combined with a polymer, and the polymer is a copolymer.
[10626] 9661. The method of item 9612, wherein the implant is
combined with a polymer, and the polymer is a block copolymer.
[10627] 9662. The method of item 9612, wherein the implant is
combined with a polymer, and the polymer is a random copolymer.
[10628] 9663. The method of item 9612, wherein the implant is
combined with a polymer, and the polymer is a biodegradable
polymer.
[10629] 9664. The method of item 9612, wherein the implant is
combined with a polymer, and the polymer is a non-biodegradable
polymer.
[10630] 9665. The method of item 9612, wherein the implant is
combined with a polymer, and the polymer is a hydrophilic
polymer.
[10631] 9666. The method of item 9612, wherein the implant is
combined with a polymer, and the polymer is a hydrophobic
polymer.
[10632] 9667. The method of item 9612, wherein the implant is
combined with a polymer, and the polymer has hydrophilic
domains.
[10633] 9668. The method of item 9612, wherein the implant is
combined with a polymer, and the polymer has hydrophobic
domains.
[10634] 9669. The method of item 9612, wherein the implant is
combined with a polymer, and the polymer is a non-conductive
polymer.
[10635] 9670. The method of item 9612, wherein the implant is
combined with a polymer, and the polymer is an elastomer.
[10636] 9671. The method of item 9612, wherein the implant is
combined with a polymer, and the polymer is a hydrogel.
[10637] 9672. The method of item 9612, wherein the implant is
combined with a polymer, and the polymer is a silicone polymer.
[10638] 9673. The method of item 9612, wherein the implant is
combined with a polymer, and the polymer is a hydrocarbon
polymer.
[10639] 9674. The method of item 9612, wherein the implant is
combined with a polymer, and the polymer is a styrene-derived
polymer.
[10640] 9675. The method of item 9612, wherein the implant is
combined with a polymer, and the polymer is a butadiene
polymer.
[10641] 9676. The method of item 9612, wherein the implant is
combined with a polymer, and the polymer is a macromer.
[10642] 9677. The method of item 9612, wherein the implant is
combined with a polymer, and the polymer is a poly(ethylene glycol)
polymer.
[10643] 9678. The method of item 9612, wherein the implant is
combined with a polymer, and the polymer is an amorphous
polymer.
[10644] 9679. The method of item 9612, wherein the implant is
combined with a polymer, and the polymer is a lubricious
coating.
[10645] 9680. The method of item 9612 wherein the fibrosing agent
is located within pores or holes of the device.
[10646] 9681. The method of item 9612 wherein the fibrosing agent
is located within a channel, lumen, or divet of the device.
[10647] 9682. The method of item 9612, wherein the implant is
further combined with a second pharmaceutically active agent.
[10648] 9683. The method of item 9612, wherein the implant is
further combined with an anti-inflammatory agent.
[10649] 9684. The method of item 9612 wherein the implant is
further combined with an agent that inhibits infection.
[10650] 9685. The method of item 9612, wherein the implant is
further combined with an anthracycline.
[10651] 9686. The method of item 9612, wherein the implant is
further combined with doxorubicin.
[10652] 9687. The method of item 9612, wherein the implant is
further combined with mitoxantrone.
[10653] 9688. The method of item 9612, wherein the implant is
further combined with a fluoropyrimidine.
[10654] 9689. The method of item 9612, wherein the implant is
further combined with 5-fluorouracil (5-FU).
[10655] 9690. The method of item 9612, wherein the implant is
further combined with a folic acid antagonist.
[10656] 9691. The method of item 9612, wherein the implant is
further combined with methotrexate.
[10657] 9692. The method of item 9612, wherein the implant is
further combined with a podophylotoxin.
[10658] 9693. The method of item 9612, wherein the implant is
further combined with etoposide.
[10659] 9694. The method of item 9612 wherein the implant is
further combined with a camptothecin.
[10660] 9695. The method of item 9612, wherein the implant is
further combined with a hydroxyurea.
[10661] 9696. The method of item 9612, wherein the implant is
further combined with a platinum complex.
[10662] 9697. The method of item 9612, wherein the implant is
further combined with cisplatin.
[10663] 9698. The method of item 9612, wherein the implant is
further combined with an anti-thrombotic agent.
[10664] 9699. The method of item 9612, wherein the implant is
further combined with a visualization agent.
[10665] 9700. The method of item 9612, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises a metal, a halogenated compound, or a
barium containing compound.
[10666] 9701. The method of item 9612, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises barium, tantalum, or technetium.
[10667] 9702. The method of item 9612, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a MRI responsive material.
[10668] 9703. The method of item 9612, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a gadolinium chelate.
[10669] 9704. The method of item 9612, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises iron, magnesium, manganese, copper,
or chromium.
[10670] 9705. The method of item 9612, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises an iron oxide compound.
[10671] 9706. The method of item 9612, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a dye, pigment, or colorant.
[10672] 9707. The method of item 9612, wherein the implant is
further combined with an echogenic material.
[10673] 9708. The method of item 9612, wherein the implant is
further combined with an echogenic material, and the echogenic
material is in the form of a coating.
[10674] 9709. The method of item 9612 wherein the device is
sterilized.
[10675] 9710. The method of item 9612 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device.
[10676] 9711. The method of item 9612 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is connective
tissue.
[10677] 9712. The method of item 9612 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is muscle tissue.
[10678] 9713. The method of item 9612 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is nerve tissue.
[10679] 9714. The method of item 9612 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is epithelium
tissue.
[10680] 9715. The method of item 9612 wherein the fibrosing agent
is released in effective concentrations from the device over a
period ranging from the time of deployment of the device to about 1
year.
[10681] 9716. The method of item 9612 wherein the fibrosing agent
is released in effective concentrations from the device over a
period ranging from about 1 month to 6 months.
[10682] 9717. The method of item 9612 wherein the fibrosing agent
is released in effective concentrations from the device over a
period ranging from about 1-90 days.
[10683] 9718. The method of item 9612 wherein the fibrosing agent
is released in effective concentrations from the device at a
constant rate.
[10684] 9719. The method of item 9612 wherein the fibrosing agent
is released in effective concentrations from the device at an
increasing rate.
[10685] 9720. The method of item 9612 wherein the fibrosing agent
is released in effective concentrations from the device at a
decreasing rate.
[10686] 9721. The method of item 9612 wherein the fibrosing agent
is released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[10687] 9722. The method of item 9612 wherein the fibrosing agent
is released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[10688] 9723. The method of item 9612 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[10689] 9724. The method of item 9612 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[10690] 9725. The method of item 9612 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[10691] 9726. The method of item 9612 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[10692] 9727. The method of item 9612 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[10693] 9728. The method of item 9612 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[10694] 9729. The method of item 9612 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[10695] 9730. The method of item 9612 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[10696] 9731. The method of item 9612 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[10697] 9732. The method of item 9612 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[10698] 9733. The method of item 9612 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[10699] 9734. The method of item 9612 wherein the hernia mesh is
made, in whole or part, from synthetic fiber.
[10700] 9735. The method of item 9612 wherein the hernia mesh
comprises polypropylene.
[10701] 9736. A method of making a medical device comprising
combining i) a surgical film implant, with ii) a fibrosing agent or
a composition comprising a fibrosing agent, where the fibrosing
agent induces a fibrotic response between the device and a patient
in which the device is implanted.
[10702] 9737. The method of item 9736 wherein the fibrosing agent
promotes regeneration.
[10703] 9738. The method of item 9736 wherein the fibrosing agent
promotes angiogenesis.
[10704] 9739. The method of item 9736 wherein the fibrosing agent
promotes fibroblast migration.
[10705] 9740. The method of item 9736 wherein the fibrosing agent
promotes fibroblast proliferation.
[10706] 9741. The method of item 9736 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[10707] 9742. The method of item 9736 wherein the fibrosing agent
promotes tissue remodeling.
[10708] 9743. The method of item 9736 wherein the fibrosing agent
is an arterial vessel wall irritant.
[10709] 9744. The method of item 9736 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[10710] 9745. The method of item 9736 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[10711] 9746. The method of item 9736 wherein the fibrosing agent
is or comprises silk.
[10712] 9747. The method of item 9736 wherein the fibrosing agent
is or comprises mineral particles.
[10713] 9748. The method of item 9736 wherein the fibrosing agent
is or comprises chitosan.
[10714] 9749. The method of item 9736 wherein the fibrosing agent
is or comprises polylysine.
[10715] 9750. The method of item 9736 wherein the fibrosing agent
is or comprises fibronectin.
[10716] 9751. The method of item 9736 wherein the fibrosing agent
is or comprises bleomycin.
[10717] 9752. The method of item 9736 wherein the fibrosing agent
is or comprises CTGF.
[10718] 9753. The method of item 9736 wherein the fibrosing agent
is in the form of a thread, or is in contact with a thread.
[10719] 9754. The method of item 9736 wherein the fibrosing agent
is in the form of a particulate.
[10720] 9755. The method of item 9736 wherein the composition
further comprises an inflammatory cytokine.
[10721] 9756. The method of item 9736 wherein the composition
further comprises an agent that stimulates cell proliferation.
[10722] 9757. The method of item 9736 wherein the composition is in
the form of a gel or paste.
[10723] 9758. The method of item 9736 wherein the fibrosing agent
is in the form of tufts.
[10724] 9759. The method of item 9736 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[10725] 9760. The method of item 9736 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[10726] 9761. The method of item 9736, wherein the implant is
combined with a coating, and the coating comprises the fibrosing
agent.
[10727] 9762. The method of item 9736, wherein the implant is
combined with a coating, and the coating is disposed on a surface
of the device.
[10728] 9763. The method of item 9736, wherein the implant is
combined with a coating, and the coating directly contacts the
device.
[10729] 9764. The method of item 9736, wherein the implant is
combined with a coating, and the coating indirectly contacts the
device.
[10730] 9765. The method of item 9736, wherein the implant is
combined with a coating, and the coating partially covers the
device.
[10731] 9766. The method of item 9736, wherein the implant is
combined with a coating, and the coating completely covers the
device.
[10732] 9767. The method of item 9736, wherein the implant is
combined with a coating, and the coating is a uniform coating.
[10733] 9768. The method of item 9736, wherein the implant is
combined with a coating, and the coating is a non-uniform
coating.
[10734] 9769. The method of item 9736, wherein the implant is
combined with a coating, and the coating is a discontinuous
coating.
[10735] 9770. The method of item 9736 wherein the implant is
combined with a coating, and the coating is a patterned
coating.
[10736] 9771. The method of item 9736, wherein the implant is
combined with a coating, and the coating has a thickness of 100
.mu.m or less.
[10737] 9772. The method of item 9736, wherein the implant is
combined with a coating, and the coating has a thickness of 10
.mu.m or less.
[10738] 9773. The method of item 9736, wherein the implant is
combined with a coating, and the coating adheres to the surface of
the device upon deployment of the device.
[10739] 9774. The method of item 9736, wherein the implant is
combined with a coating, and the coating is stable at room
temperature for a period of at least 1 year.
[10740] 9775. The method of item 9736, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 0.0001% to about 1% by
weight.
[10741] 9776. The method of item 9736, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 1% to about 10% by
weight.
[10742] 9777. The method of item 9736, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 10% to about 25% by
weight.
[10743] 9778. The method of item 9736, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 25% to about 70% by
weight.
[10744] 9779. The method of item 9736, wherein the implant is
combined with a coating, and the coating further comprises a
polymer.
[10745] 9780. The method of item 9736, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition.
[10746] 9781. The method of item 9736, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition, where the first composition and the
second composition are different.
[10747] 9782. The method of item 9736, wherein the device comprises
a polymer.
[10748] 9783. The method of item 9736, wherein the device comprises
a polymer, and the polymer is a component of the composition.
[10749] 9784. The method of item 9736, wherein the implant is
combined with a polymer, and the polymer is a copolymer.
[10750] 9785. The method of item 9736, wherein the implant is
combined with a polymer, and the polymer is a block copolymer.
[10751] 9786. The method of item 9736, wherein the implant is
combined with a polymer, and the polymer is a random copolymer.
[10752] 9787. The method of item 9736, wherein the implant is
combined with a polymer, and the polymer is a biodegradable
polymer.
[10753] 9788. The method of item 9736, wherein the implant is
combined with a polymer, and the polymer is a non-biodegradable
polymer.
[10754] 9789. The method of item 9736, wherein the implant is
combined with a polymer, and the polymer is a hydrophilic
polymer.
[10755] 9790. The method of item 9736, wherein the implant is
combined with a polymer, and the polymer is a hydrophobic
polymer.
[10756] 9791. The method of item 9736, wherein the implant is
combined with a polymer, and the polymer has hydrophilic
domains.
[10757] 9792. The method of item 9736, wherein the implant is
combined with a polymer, and the polymer has hydrophobic
domains.
[10758] 9793. The method of item 9736, wherein the implant is
combined with a polymer, and the polymer is a non-conductive
polymer.
[10759] 9794. The method of item 9736, wherein the implant is
combined with a polymer, and the polymer is an elastomer.
[10760] 9795. The method of item 9736, wherein the implant is
combined with a polymer, and the polymer is a hydrogel.
[10761] 9796. The method of item 9736, wherein the implant is
combined with a polymer, and the polymer is a silicone polymer.
[10762] 9797. The method of item 9736, wherein the implant is
combined with a polymer, and the polymer is a hydrocarbon
polymer.
[10763] 9798. The method of item 9736, wherein the implant is
combined with a polymer, and the polymer is a styrene-derived
polymer.
[10764] 9799. The method of item 9736, wherein the implant is
combined with a polymer, and the polymer is a butadiene
polymer.
[10765] 9800. The method of item 9736, wherein the implant is
combined with a polymer, and the polymer is a macromer.
[10766] 9801. The method of item 9736, wherein the implant is
combined with a polymer, and the polymer is a poly(ethylene glycol)
polymer.
[10767] 9802. The method of item 9736, wherein the implant is
combined with a polymer, and the polymer is an amorphous
polymer.
[10768] 9803. The method of item 9736, wherein the implant is
combined with a polymer, and the polymer is a lubricious
coating.
[10769] 9804. The method of item 9736 wherein the fibrosing agent
is located within pores or holes of the device.
[10770] 9805. The method of item 9736 wherein the fibrosing agent
is located within a channel, lumen, or divet of the device.
[10771] 9806. The method of item 9736, wherein the implant is
further combined with a second pharmaceutically active agent.
[10772] 9807. The method of item 9736, wherein the implant is
further combined with an anti-inflammatory agent.
[10773] 9808. The method of item 9736 wherein the implant is
further combined with an agent that inhibits infection.
[10774] 9809. The method of item 9736, wherein the implant is
further combined with an anthracycline.
[10775] 9810. The method of item 9736, wherein the implant is
further combined with doxorubicin.
[10776] 9811. The method of item 9736, wherein the implant is
further combined with mitoxantrone.
[10777] 9812. The method of item 9736, wherein the implant is
further combined with a fluoropyrimidine.
[10778] 9813. The method of item 9736, wherein the implant is
further combined with 5-fluorouracil (5-FU).
[10779] 9814. The method of item 9736, wherein the implant is
further combined with a folic acid antagonist.
[10780] 9815. The method of item 9736, wherein the implant is
further combined with methotrexate.
[10781] 9816. The method of item 9736, wherein the implant is
further combined with a podophylotoxin.
[10782] 9817. The method of item 9736, wherein the implant is
further combined with etoposide.
[10783] 9818. The method of item 9736 wherein the implant is
further combined with a camptothecin.
[10784] 9819. The method of item 9736, wherein the implant is
further combined with a hydroxyurea.
[10785] 9820. The method of item 9736, wherein the implant is
further combined with a platinum complex.
[10786] 9821. The method of item 9736, wherein the implant is
further combined with cisplatin.
[10787] 9822. The method of item 9736, wherein the implant is
further combined with an anti-thrombotic agent.
[10788] 9823. The method of item 9736, wherein the implant is
further combined with a visualization agent.
[10789] 9824. The method of item 9736, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises a metal, a halogenated compound, or a
barium containing compound.
[10790] 9825. The method of item 9736, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises barium, tantalum, or technetium.
[10791] 9826. The method of item 9736, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a MRI responsive material.
[10792] 9827. The method of item 9736, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a gadolinium chelate.
[10793] 9828. The method of item 9736, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises iron, magnesium, manganese, copper,
or chromium.
[10794] 9829. The method of item 9736, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises an iron oxide compound.
[10795] 9830. The method of item 9736, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a dye, pigment, or colorant.
[10796] 9831. The method of item 9736, wherein the implant is
further combined with an echogenic material.
[10797] 9832. The method of item 9736, wherein the implant is
further combined with an echogenic material, and the echogenic
material is in the form of a coating.
[10798] 9833. The method of item 9736 wherein the device is
sterilized.
[10799] 9834. The method of item 9736 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device.
[10800] 9835. The method of item 9736 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is connective
tissue.
[10801] 9836. The method of item 9736 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is muscle tissue.
[10802] 9837. The method of item 9736 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is nerve tissue.
[10803] 9838. The method of item 9736 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is epithelium
tissue.
[10804] 9839. The method of item 9736 wherein the fibrosing agent
is released in effective concentrations from the device over a
period ranging from the time of deployment of the device to about 1
year.
[10805] 9840. The method of item 9736 wherein the fibrosing agent
is released in effective concentrations from the device over a
period ranging from about 1 month to 6 months.
[10806] 9841. The method of item 9736 wherein the fibrosing agent
is released in effective concentrations from the device over a
period ranging from about 1-90 days.
[10807] 9842. The method of item 9736 wherein the fibrosing agent
is released in effective concentrations from the device at a
constant rate.
[10808] 9843. The method of item 9736 wherein the fibrosing agent
is released in effective concentrations from the device at an
increasing rate.
[10809] 9844. The method of item 9736 wherein the fibrosing agent
is released in effective concentrations from the device at a
decreasing rate.
[10810] 9845. The method of item 9736 wherein the fibrosing agent
is released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[10811] 9846. The method of item 9736 wherein the fibrosing agent
is released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[10812] 9847. The method of item 9736 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[10813] 9848. The method of item 9736 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[10814] 9849. The method of item 9736 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[10815] 9850. The method of item 9736 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[10816] 9851. The method of item 9736 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[10817] 9852. The method of item 9736 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[10818] 9853. The method of item 9736 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[10819] 9854. The method of item 9736 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[10820] 9855. The method of item 9736 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[10821] 9856. The method of item 9736 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[10822] 9857. The method of item 9736 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[10823] 9858. The method of item 9736 wherein the surgical film
implant comprises cellulose or a cellulose derivative.
[10824] 9859. The method of item 9736 wherein the surgical film
implant is porous.
[10825] 9860. The method of item 9736 wherein the surgical film
implant is biodegradable.
[10826] 9861. A method of making a medical device comprising
combining i) a spinal fusion implant, with ii) a fibrosing agent or
a composition comprising a fibrosing agent, where the fibrosing
agent induces a fibrotic response between the device and a patient
in which the device is implanted.
[10827] 9862. The method of item 9861 wherein the fibrosing agent
promotes regeneration.
[10828] 9863. The method of item 9861 wherein the fibrosing agent
promotes angiogenesis.
[10829] 9864. The method of item 9861 wherein the fibrosing agent
promotes fibroblast migration.
[10830] 9865. The method of item 9861 wherein the fibrosing agent
promotes fibroblast proliferation.
[10831] 9866. The method of item 9861 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[10832] 9867. The method of item 9861 wherein the fibrosing agent
promotes tissue remodeling.
[10833] 9868. The method of item 9861 wherein the fibrosing agent
is an arterial vessel wall irritant.
[10834] 9869. The method of item 9861 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[10835] 9870. The method of item 9861 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[10836] 9871. The method of item 9861 wherein the fibrosing agent
is or comprises silk.
[10837] 9872. The method of item 9861 wherein the fibrosing agent
is or comprises mineral particles.
[10838] 9873. The method of item 9861 wherein the fibrosing agent
is or comprises chitosan.
[10839] 9874. The method of item 9861 wherein the fibrosing agent
is or comprises polylysine.
[10840] 9875. The method of item 9861 wherein the fibrosing agent
is or comprises fibronectin.
[10841] 9876. The method of item 9861 wherein the fibrosing agent
is or comprises bleomycin.
[10842] 9877. The method of item 9861 wherein the fibrosing agent
is or comprises CTGF.
[10843] 9878. The method of item 9861 wherein the fibrosing agent
is in the form of a thread, or is in contact with a thread.
[10844] 9879. The method of item 9861 wherein the fibrosing agent
is in the form of a particulate.
[10845] 9880. The method of item 9861 wherein the composition
further comprises an inflammatory cytokine.
[10846] 9881. The method of item 9861 wherein the composition
further comprises an agent that stimulates cell proliferation.
[10847] 9882. The method of item 9861 wherein the composition is in
the form of a gel or paste.
[10848] 9883. The method of item 9861 wherein the fibrosing agent
is in the form of tufts.
[10849] 9884. The method of item 9861 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[10850] 9885. The method of item 9861 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[10851] 9886. The method of item 9861, wherein the implant is
combined with a coating, and the coating comprises the fibrosing
agent.
[10852] 9887. The method of item 9861, wherein the implant is
combined with a coating, and the coating is disposed on a surface
of the device.
[10853] 9888. The method of item 9861, wherein the implant is
combined with a coating, and the coating directly contacts the
device.
[10854] 9889. The method of item 9861, wherein the implant is
combined with a coating, and the coating indirectly contacts the
device.
[10855] 9890. The method of item 9861, wherein the implant is
combined with a coating, and the coating partially covers the
device.
[10856] 9891. The method of item 9861, wherein the implant is
combined with a coating, and the coating completely covers the
device.
[10857] 9892. The method of item 9861, wherein the implant is
combined with a coating, and the coating is a uniform coating.
[10858] 9893. The method of item 9861, wherein the implant is
combined with a coating, and the coating is a non-uniform
coating.
[10859] 9894. The method of item 9861, wherein the implant is
combined with a coating, and the coating is a discontinuous
coating.
[10860] 9895. The method of item 9861 wherein the implant is
combined with a coating, and the coating is a patterned
coating.
[10861] 9896. The method of item 9861, wherein the implant is
combined with a coating, and the coating has a thickness of 100
.mu.m or less.
[10862] 9897. The method of item 9861, wherein the implant is
combined with a coating, and the coating has a thickness of 10
.mu.m or less.
[10863] 9898. The method of item 9861, wherein the implant is
combined with a coating, and the coating adheres to the surface of
the device upon deployment of the device.
[10864] 9899. The method of item 9861, wherein the implant is
combined with a coating, and the coating is stable at room
temperature for a period of at least 1 year.
[10865] 9900. The method of item 9861, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 0.0001% to about 1% by
weight.
[10866] 9901. The method of item 9861, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 1% to about 10% by
weight.
[10867] 9902. The method of item 9861, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 10% to about 25% by
weight.
[10868] 9903. The method of item 9861, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 25% to about 70% by
weight.
[10869] 9904. The method of item 9861, wherein the implant is
combined with a coating, and the coating further comprises a
polymer.
[10870] 9905. The method of item 9861, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition.
[10871] 9906. The method of item 9861, wherein the device comprises
a first coating having a first composition and a second coating
having a second composition, where the first composition and the
second composition are different.
[10872] 9907. The method of item 9861, wherein the device comprises
a polymer.
[10873] 9908. The method of item 9861, wherein the device comprises
a polymer, and the polymer is a component of the composition.
[10874] 9909. The method of item 9861, wherein the implant is
combined with a polymer, and the polymer is a copolymer.
[10875] 9910. The method of item 9861, wherein the implant is
combined with a polymer, and the polymer is a block copolymer.
[10876] 9911. The method of item 9861, wherein the implant is
combined with a polymer, and the polymer is a random copolymer.
[10877] 9912. The method of item 9861, wherein the implant is
combined with a polymer, and the polymer is a biodegradable
polymer.
[10878] 9913. The method of item 9861, wherein the implant is
combined with a polymer, and the polymer is a non-biodegradable
polymer.
[10879] 9914. The method of item 9861, wherein the implant is
combined with a polymer, and the polymer is a hydrophilic
polymer.
[10880] 9915. The method of item 9861, wherein the implant is
combined with a polymer, and the polymer is a hydrophobic
polymer.
[10881] 9916. The method of item 9861, wherein the implant is
combined with a polymer, and the polymer has hydrophilic
domains.
[10882] 9917. The method of item 9861, wherein the implant is
combined with a polymer, and the polymer has hydrophobic
domains.
[10883] 9918. The method of item 9861, wherein the implant is
combined with a polymer, and the polymer is a non-conductive
polymer.
[10884] 9919. The method of item 9861, wherein the implant is
combined with a polymer, and the polymer is an elastomer.
[10885] 9920. The method of item 9861, wherein the implant is
combined with a polymer, and the polymer is a hydrogel.
[10886] 9921. The method of item 9861, wherein the implant is
combined with a polymer, and the polymer is a silicone polymer.
[10887] 9922. The method of item 9861, wherein the implant is
combined with a polymer, and the polymer is a hydrocarbon
polymer.
[10888] 9923. The method of item 9861, wherein the implant is
combined with a polymer, and the polymer is a styrene-derived
polymer.
[10889] 9924. The method of item 9861, wherein the implant is
combined with a polymer, and the polymer is a butadiene
polymer.
[10890] 9925. The method of item 9861, wherein the implant is
combined with a polymer, and the polymer is a macromer.
[10891] 9926. The method of item 9861, wherein the implant is
combined with a polymer, and the polymer is a poly(ethylene glycol)
polymer.
[10892] 9927. The method of item 9861, wherein the implant is
combined with a polymer, and the polymer is an amorphous
polymer.
[10893] 9928. The method of item 9861, wherein the implant is
combined with a polymer, and the polymer is a lubricious
coating.
[10894] 9929. The method of item 9861 wherein the fibrosing agent
is located within pores or holes of the device.
[10895] 9930. The method of item 9861 wherein the fibrosing agent
is located within a channel, lumen, or divet of the device.
[10896] 9931. The method of item 9861, wherein the implant is
further combined with a second pharmaceutically active agent.
[10897] 9932. The method of item 9861, wherein the implant is
further combined with an anti-inflammatory agent.
[10898] 9933. The method of item 9861 wherein the implant is
further combined with an agent that inhibits infection.
[10899] 9934. The method of item 9861, wherein the implant is
further combined with an anthracycline.
[10900] 9935. The method of item 9861, wherein the implant is
further combined with doxorubicin.
[10901] 9936. The method of item 9861, wherein the implant is
further combined with mitoxantrone.
[10902] 9937. The method of item 9861, wherein the implant is
further combined with a fluoropyrimidine.
[10903] 9938. The method of item 9861, wherein the implant is
further combined with 5-fluorouracil (5-FU).
[10904] 9939. The method of item 9861, wherein the implant is
further combined with a folic acid antagonist.
[10905] 9940. The method of item 9861, wherein the implant is
further combined with methotrexate.
[10906] 9941. The method of item 9861, wherein the implant is
further combined with a podophylotoxin.
[10907] 9942. The method of item 9861, wherein the implant is
further combined with etoposide.
[10908] 9943. The method of item 9861 wherein the implant is
further combined with a camptothecin.
[10909] 9944. The method of item 9861, wherein the implant is
further combined with a hydroxyurea.
[10910] 9945. The method of item 9861, wherein the implant is
further combined with a platinum complex.
[10911] 9946. The method of item 9861, wherein the implant is
further combined with cisplatin.
[10912] 9947. The method of item 9861, wherein the implant is
further combined with an anti-thrombotic agent.
[10913] 9948. The method of item 9861, wherein the implant is
further combined with a visualization agent.
[10914] 9949. The method of item 9861, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises a metal, a halogenated compound, or a
barium containing compound.
[10915] 9950. The method of item 9861, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises barium, tantalum, or technetium.
[10916] 9951. The method of item 9861, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a MRI responsive material.
[10917] 9952. The method of item 9861, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a gadolinium chelate.
[10918] 9953. The method of item 9861, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises iron, magnesium, manganese, copper,
or chromium.
[10919] 9954. The method of item 9861, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises an iron oxide compound.
[10920] 9955. The method of item 9861, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a dye, pigment, or colorant.
[10921] 9956. The method of item 9861, wherein the implant is
further combined with an echogenic material.
[10922] 9957. The method of item 986.1, wherein the implant is
further combined with an echogenic material, and the echogenic
material is in the form of a coating.
[10923] 9958. The method of item 9861 wherein the device is
sterilized.
[10924] 9959. The method of item 9861 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device.
[10925] 9960. The method of item 9861 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is connective
tissue.
[10926] 9961. The method of item 9861 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is muscle tissue.
[10927] 9962. The method of item 9861 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is nerve tissue.
[10928] 9963. The method of item 9861 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is epithelium
tissue.
[10929] 9964. The method of item 9861 wherein the fibrosing agent
is released in effective concentrations from the device over a
period ranging from the time of deployment of the device to about 1
year.
[10930] 9965. The method of item 9861 wherein the fibrosing agent
is released in effective concentrations from the device over a
period ranging from about 1 month to 6 months.
[10931] 9966. The method of item 9861 wherein the fibrosing agent
is released in effective concentrations from the device over a
period ranging from about 1-90 days.
[10932] 9967. The method of item 9861 wherein the fibrosing agent
is released in effective concentrations from the device at a
constant rate.
[10933] 9968. The method of item 9861 wherein the fibrosing agent
is released in effective concentrations from the device at an
increasing rate.
[10934] 9969. The method of item 9861 wherein the fibrosing agent
is released in effective concentrations from the device at a
decreasing rate.
[10935] 9970. The method of item 9861 wherein the fibrosing agent
is released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[10936] 9971. The method of item 9861 wherein the fibrosing agent
is released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[10937] 9972. The method of item 9861 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[10938] 9973. The method of item 9861 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[10939] 9974. The method of item 9861 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[10940] 9975. The method of item 9861 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[10941] 9976. The method of item 9861 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[10942] 9977. The method of item 9861 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[10943] 9978. The method of item 9861 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[10944] 9979. The method of item 9861 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[10945] 9980. The method of item 9861 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[10946] 9981. The method of item 9861 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[10947] 9982. The method of item 9861 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[10948] 9983. The method of item 9861 wherein the spinal fusion
device is a fusion basket.
[10949] 9984. The method of item 9861 wherein the spinal fusion
device is a fusion cage apparatus.
[10950] 9985. The method of item 9861 wherein the spinal fusion
device is an interbody case.
[10951] 9986. The method of item 9861 wherein the spinal fusion
device is an interbody implant.
[10952] 9987. The method of item 9861 wherein the spinal fusion
device is a fusion cage anchoring device.
[10953] 9988. The method of item 9861 wherein the spinal fusion
device is a fusion stabilization chamber.
[10954] 9989. The method of item 9861 wherein the spinal fusion
device is a fusion cage anchoring plate.
[10955] 9990. The method of item 9861 wherein the spinal fusion
device is a bone fixation device.
[10956] 9991. The method of item 9861 wherein the spinal fusion
device is an anchoring bone plate.
[10957] 9992. The method of item 9861 wherein the spinal fusion
device is an anchoring bone screw.
[10958] 9993. The method of item 9861 wherein the spinal fusion
device is a tissue filler.
[10959] 9994. The method of item 9861 wherein the spinal fusion
device is a bone cement.
[10960] 9995. The method of item 9861 wherein the spinal fusion
device is an allograft material.
[10961] 9996. The method of item 9861 wherein the spinal fusion
device is an autograft material.
[10962] 9997. The method of item 9861 wherein the spinal fusion
device is a collagen implant.
[10963] 9998. The method of item 9861 wherein the spinal fusion
device is injectable.
[10964] 9999. A method of making a medical device comprising
combining i) a septal occlusion patch implant, with ii) a fibrosing
agent or a composition comprising a fibrosing agent, where the
fibrosing agent induces a fibrotic response between the device and
a patient in which the device is implanted.
[10965] 10000. The method of item 9999 wherein the fibrosing agent
promotes regeneration.
[10966] 10001. The method of item 9999 wherein the fibrosing agent
promotes angiogenesis.
[10967] 10002. The method of item 9999 wherein the fibrosing agent
promotes fibroblast migration.
[10968] 10003. The method of item 9999 wherein the fibrosing agent
promotes fibroblast proliferation.
[10969] 10004. The method of item 9999 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[10970] 10005. The method of item 9999 wherein the fibrosing agent
promotes tissue remodeling.
[10971] 10006. The method of item 9999 wherein the fibrosing agent
is an arterial vessel wall irritant.
[10972] 10007. The method of item 9999 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[10973] 10008. The method of item 9999 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[10974] 10009. The method of item 9999 wherein the fibrosing agent
is or comprises silk.
[10975] 10010. The method of item 9999 wherein the fibrosing agent
is or comprises mineral particles.
[10976] 10011. The method of item 9999 wherein the fibrosing agent
is or comprises chitosan.
[10977] 10012. The method of item 9999 wherein the fibrosing agent
is or comprises polylysine.
[10978] 10013. The method of item 9999 wherein the fibrosing agent
is or comprises fibronectin.
[10979] 10014. The method of item 9999 wherein the fibrosing agent
is or comprises bleomycin.
[10980] 10015. The method of item 9999 wherein the fibrosing agent
is or comprises CTGF.
[10981] 10016. The method of item 9999 wherein the fibrosing agent
is in the form of a thread, or is in contact with a thread.
[10982] 10017. The method of item 9999 wherein the fibrosing agent
is in the form of a particulate.
[10983] 10018. The method of item 9999 wherein the composition
further comprises an inflammatory cytokine.
[10984] 10019. The method of item 9999 wherein the composition
further comprises an agent that stimulates cell proliferation.
[10985] 10020. The method of item 9999 wherein the composition is
in the form of a gel or paste.
[10986] 10021. The method of item 9999 wherein the fibrosing agent
is in the form of tufts.
[10987] 10022. The method of item 9999 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[10988] 10023. The method of item 9999 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[10989] 10024. The method of item 9999, wherein the implant is
combined with a coating, and the coating comprises the fibrosing
agent.
[10990] 10025. The method of item 9999, wherein the implant is
combined with a coating, and the coating is disposed on a surface
of the device.
[10991] 10026. The method of item 9999, wherein the implant is
combined with a coating, and the coating directly contacts the
device.
[10992] 10027. The method of item 9999, wherein the implant is
combined with a coating, and the coating indirectly contacts the
device.
[10993] 10028. The method of item 9999, wherein the implant is
combined with a coating, and the coating partially covers the
device.
[10994] 10029. The method of item 9999, wherein the implant is
combined with a coating, and the coating completely covers the
device.
[10995] 10030. The method of item 9999, wherein the implant is
combined with a coating, and the coating is a uniform coating.
[10996] 10031. The method of item 9999, wherein the implant is
combined with a coating, and the coating is a non-uniform
coating.
[10997] 10032. The method of item 9999, wherein the implant is
combined with a coating, and the coating is a discontinuous
coating.
[10998] 10033. The method of item 9999 wherein the implant is
combined with a coating, and the coating is a patterned
coating.
[10999] 10034. The method of item 9999, wherein the implant is
combined with a coating, and the coating has a thickness of 100
.mu.m or less.
[11000] 10035. The method of item 9999, wherein the implant is
combined with a coating, and the coating has a thickness of 10
.mu.m or less.
[11001] 10036. The method of item 9999, wherein the implant is
combined with a coating, and the coating adheres to the surface of
the device upon deployment of the device.
[11002] 10037. The method of item 9999, wherein the implant is
combined with a coating, and the coating is stable at room
temperature for a period of at least 1 year.
[11003] 10038. The method of item 9999, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 0.0001% to about 1% by
weight.
[11004] 10039. The method of item 9999, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 1% to about 10% by
weight.
[11005] 10040. The method of item 9999, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 10% to about 25% by
weight.
[11006] 10041. The method of item 9999, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 25% to about 70% by
weight.
[11007] 10042. The method of item 9999, wherein the implant is
combined with a coating, and the coating further comprises a
polymer.
[11008] 10043. The method of item 9999, wherein the device
comprises a first coating having a first composition and a second
coating having a second composition.
[11009] 10044. The method of item 9999, wherein the device
comprises a first coating having a first composition and a second
coating having a second composition, where the first composition
and the second composition are different.
[11010] 10045. The method of item 9999, wherein the device
comprises a polymer.
[11011] 10046. The method of item 9999, wherein the device
comprises a polymer, and the polymer is a component of the
composition.
[11012] 10047. The method of item 9999, wherein the implant is
combined with a polymer, and the polymer is a copolymer.
[11013] 10048. The method of item 9999, wherein the implant is
combined with a polymer, and the polymer is a block copolymer.
[11014] 10049. The method of item 9999, wherein the implant is
combined with a polymer, and the polymer is a random copolymer.
[11015] 10050. The method of item 9999, wherein the implant is
combined with a polymer, and the polymer is a biodegradable
polymer.
[11016] 10051. The method of item 9999, wherein the implant is
combined with a polymer, and the polymer is a non-biodegradable
polymer.
[11017] 10052. The method of item 9999, wherein the implant is
combined with a polymer, and the polymer is a hydrophilic
polymer.
[11018] 10053. The method of item 9999, wherein the implant is
combined with a polymer, and the polymer is a hydrophobic
polymer.
[11019] 10054. The method of item 9999, wherein the implant is
combined with a polymer, and the polymer has hydrophilic
domains.
[11020] 10055. The method of item 9999, wherein the implant is
combined with a polymer, and the polymer has hydrophobic
domains.
[11021] 10056. The method of item 9999, wherein the implant is
combined with a polymer, and the polymer is a non-conductive
polymer.
[11022] 10057. The method of item 9999, wherein the implant is
combined with a polymer, and the polymer is an elastomer.
[11023] 10058. The method of item 9999, wherein the implant is
combined with a polymer, and the polymer is a hydrogel.
[11024] 10059. The method of item 9999, wherein the implant is
combined with a polymer, and the polymer is a silicone polymer.
[11025] 10060. The method of item 9999, wherein the implant is
combined with a polymer, and the polymer is a hydrocarbon
polymer.
[11026] 10061. The method of item 9999, wherein the implant is
combined with a polymer, and the polymer is a styrene-derived
polymer.
[11027] 10062. The method of item 9999, wherein the implant is
combined with a polymer, and the polymer is a butadiene
polymer.
[11028] 10063. The method of item 9999, wherein the implant is
combined with a polymer, and the polymer is a macromer.
[11029] 10064. The method of item 9999, wherein the implant is
combined with a polymer, and the polymer is a poly(ethylene glycol)
polymer.
[11030] 10065. The method of item 9999, wherein the implant is
combined with a polymer, and the polymer is an amorphous
polymer.
[11031] 10066. The method of item 9999, wherein the implant is
combined with a polymer, and the polymer is a lubricious
coating.
[11032] 10067. The method of item 9999 wherein the fibrosing agent
is located within pores or holes of the device.
[11033] 10068. The method of item 9999 wherein the fibrosing agent
is located within a channel, lumen, or divet of the device.
[11034] 10069. The method of item 9999, wherein the implant is
further combined with a second pharmaceutically active agent.
[11035] 10070. The method of item 9999, wherein the implant is
further combined with an anti-inflammatory agent.
[11036] 10071. The method of item 9999 wherein the implant is
further combined with an agent that inhibits infection.
[11037] 10072. The method of item 9999, wherein the implant is
further combined with an anthracycline.
[11038] 10073. The method of item 9999, wherein the implant is
further combined with doxorubicin.
[11039] 10074. The method of item 9999, wherein the implant is
further combined with mitoxantrone.
[11040] 10075. The method of item 9999, wherein the implant is
further combined with a fluoropyrimidine.
[11041] 10076. The method of item 9999, wherein the implant is
further combined with 5-fluorouracil (5-FU).
[11042] 10077. The method of item 9999, wherein the implant is
further combined with a folic acid antagonist.
[11043] 10078. The method of item 9999, wherein the implant is
further combined with methotrexate.
[11044] 10079. The method of item 9999, wherein the implant is
further combined with a podophylotoxin.
[11045] 10080. The method of item 9999, wherein the implant is
further combined with etoposide.
[11046] 10081. The method of item 9999 wherein the implant is
further combined with a camptothecin.
[11047] 10082. The method of item 9999, wherein the implant is
further combined with a hydroxyurea.
[11048] 10083. The method of item 9999, wherein the implant is
further combined with a platinum complex.
[11049] 10084. The method of item 9999, wherein the implant is
further combined with cisplatin.
[11050] 10085. The method of item 9999, wherein the implant is
further combined with an anti-thrombotic agent.
[11051] 10086. The method of item 9999, wherein the implant is
further combined with a visualization agent.
[11052] 10087. The method of item 9999, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises a metal, a halogenated compound, or a
barium containing compound.
[11053] 10088. The method of item 9999, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises barium, tantalum, or technetium.
[11054] 10089. The method of item 9999, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a MRI responsive material.
[11055] 10090. The method of item 9999, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a gadolinium chelate.
[11056] 10091. The method of item 9999, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises iron, magnesium, manganese, copper,
or chromium.
[11057] 10092. The method of item 9999, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises an iron oxide compound.
[11058] 10093. The method of item 9999, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a dye, pigment, or colorant.
[11059] 10094. The method of item 9999, wherein the implant is
further combined with an echogenic material.
[11060] 10095. The method of item 9999, wherein the implant is
further combined with an echogenic material, and the echogenic
material is in the form of a coating.
[11061] 10096. The method of item 9999 wherein the device is
sterilized.
[11062] 10097. The method of item 9999 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device.
[11063] 10098. The method of item 9999 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein
[11064] the tissue is connective tissue.
[11065] 10099. The method of item 9999 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is muscle tissue.
[11066] 10100. The method of item 9999 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is nerve tissue.
[11067] 10101. The method of item 9999 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is epithelium
tissue.
[11068] 10102. The method of item 9999 wherein the fibrosing agent
is released in effective concentrations from the device over a
period ranging from the time of deployment of the device to about 1
year.
[11069] 10103. The method of item 9999 wherein the fibrosing agent
is released in effective concentrations from the device over a
period ranging from about 1 month to 6 months.
[11070] 10104. The method of item 9999 wherein the fibrosing agent
is released in effective concentrations from the device over a
period ranging from about 1-90 days.
[11071] 10105. The method of item 9999 wherein the fibrosing agent
is released in effective concentrations from the device at a
constant rate.
[11072] 10106. The method of item 9999 wherein the fibrosing agent
is released in effective concentrations from the device at an
increasing rate.
[11073] 10107. The method of item 9999 wherein the fibrosing agent
is released in effective concentrations from the device at a
decreasing rate.
[11074] 10108. The method of item 9999 wherein the fibrosing agent
is released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[11075] 10109. The method of item 9999 wherein the fibrosing agent
is released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[11076] 10110. The method of item 9999 wherein the device comprises
about 0.01 .mu.g to about 10 .mu.g of the fibrosing agent.
[11077] 10111. The method of item 9999 wherein the device comprises
about 10 .mu.g to about 10 mg of the fibrosing agent.
[11078] 10112. The method of item 9999 wherein the device comprises
about 10 mg to about 250 mg of the fibrosing agent.
[11079] 10113. The method of item 9999 wherein the device comprises
about 250 mg to about 1000 mg of the fibrosing agent.
[11080] 10114. The method of item 9999 wherein the device comprises
about 1000 mg to about 2500 mg of the fibrosing agent.
[11081] 10115. The method of item 9999 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[11082] 10116. The method of item 9999 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[11083] 10117. The method of item 9999 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[11084] 10118. The method of item 9999 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[11085] 10119. The method of item 9999 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[11086] 10120. The method of item 9999 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[11087] 10121. The method of item 9999 wherein the septal occlusion
patch is a septal closure device.
[11088] 10122. The method of item 9999 wherein the septal occlusion
patch is a shunt closure device.
[11089] 10123. The method of item 9999 wherein the septal occlusion
patch is an intracardiac occluder.
[11090] 10124. The method of item 9999 wherein the septal occlusion
patch is a defect occluding system.
[11091] 10125. The method of item 9999 wherein the septal occlusion
patch is an intravascular shunt device.
[11092] 10126. A method of making a medical device comprising
combining i) an endoluminal fastener implant with ii) a fibrosing
agent or a composition comprising a fibrosing agent, where the
fibrosing agent induces a fibrotic response between the device and
a patient in which the device is implanted.
[11093] 10127. The method of item 10126 wherein the fibrosing agent
promotes regeneration.
[11094] 10128. The method of item 10126 wherein the fibrosing agent
promotes angiogenesis.
[11095] 10129. The method of item 10126 wherein the fibrosing agent
promotes fibroblast migration.
[11096] 10130. The method of item 10126 wherein the fibrosing agent
promotes fibroblast proliferation.
[11097] 10131. The method of item 10126 wherein the fibrosing agent
promotes deposition of extracellular matrix (ECM).
[11098] 10132. The method of item 10126 wherein the fibrosing agent
promotes tissue remodeling.
[11099] 10133. The method of item 10126 wherein the fibrosing agent
is an arterial vessel wall irritant.
[11100] 10134. The method of item 10126 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[11101] 10135. The method of item 10126 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[11102] 10136. The method of item 10126 wherein the fibrosing agent
is or comprises silk.
[11103] 10137. The method of item 10126 wherein the fibrosing agent
is or comprises mineral particles.
[11104] 10138. The method of item 10126 wherein the fibrosing agent
is or comprises chitosan.
[11105] 10139. The method of item 10126 wherein the fibrosing agent
is or comprises polylysine.
[11106] 10140. The method of item 10126 wherein the fibrosing agent
is or comprises fibronectin.
[11107] 10141. The method of item 10126 wherein the fibrosing agent
is or comprises bleomycin.
[11108] 10142. The method of item 10126 wherein the fibrosing agent
is or comprises CTGF.
[11109] 10143. The method of item 10126 wherein the fibrosing agent
is in the form of a thread, or is in contact with a thread.
[11110] 10144. The method of item 10126 wherein the fibrosing agent
is in the form of a particulate.
[11111] 10145. The method of item 10126 wherein the composition
further comprises an inflammatory cytokine.
[11112] 10146. The method of item 10126 wherein the composition
further comprises an agent that stimulates cell proliferation.
[11113] 10147. The method of item 10126 wherein the composition is
in the form of a gel or paste.
[11114] 10148. The method of item 10126 wherein the fibrosing agent
is in the form of tufts.
[11115] 10149. The method of item 10126 wherein the fibrosing agent
promotes adhesion between the device and a host into which the
device is implanted.
[11116] 10150. The method of item 10126 wherein the device delivers
the fibrosing agent locally to tissue proximate to the device.
[11117] 10151. The method of item 10126, wherein the implant is
combined with a coating, and the coating comprises the fibrosing
agent.
[11118] 10152. The method of item 10126, wherein the implant is
combined with a coating, and the coating is disposed on a surface
of the device.
[11119] 10153. The method of item 10126, wherein the implant is
combined with a coating, and the coating directly contacts the
device.
[11120] 10154. The method of item 10126, wherein the implant is
combined with a coating, and the coating indirectly contacts the
device.
[11121] 10155. The method of item 10126, wherein the implant is
combined with a coating, and the coating partially covers the
device.
[11122] 10156. The method of item 10126, wherein the implant is
combined with a coating, and the coating completely covers the
device.
[11123] 10157. The method of item 10126, wherein the implant is
combined with a coating, and the coating is a uniform coating.
[11124] 10158. The method of item 10126, wherein the implant is
combined with a coating, and the coating is a non-uniform
coating.
[11125] 10159. The method of item 10126, wherein the implant is
combined with a coating, and the coating is a discontinuous
coating.
[11126] 10160. The method of item 10126 wherein the implant is
combined with a coating, and the coating is a patterned
coating.
[11127] 10161. The method of item 10126, wherein the implant is
combined with a coating, and the coating has a thickness of 100
.mu.m or less.
[11128] 10162. The method of item 10126, wherein the implant is
combined with a coating, and the coating has a thickness of 10
.mu.m or less.
[11129] 10163. The method of item 10126, wherein the implant is
combined with a coating, and the coating adheres to the surface of
the device upon deployment of the device.
[11130] 10164. The method of item 10126, wherein the implant is
combined with a coating, and the coating is stable at room
temperature for a period of at least 1 year.
[11131] 10165. The method of item 10126, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 0.0001% to about 1% by
weight.
[11132] 10166. The method of item 10126, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 1% to about 10% by
weight.
[11133] 10167. The method of item 10126, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 10% to about 25% by
weight.
[11134] 10168. The method of item 10126, wherein the implant is
combined with a coating, and the fibrosing agent is present in the
coating in an amount ranging between about 25% to about 70% by
weight.
[11135] 10169. The method of item 10126, wherein the implant is
combined with a coating, and the coating further comprises a
polymer.
[11136] 10170. The method of item 10126, wherein the device
comprises a first coating having a first composition and a second
coating having a second composition.
[11137] 10171. The method of item 10126, wherein the device
comprises a first coating having a first composition and a second
coating having a second composition, where the first composition
and the second composition are different.
[11138] 10172. The method of item 10126, wherein the device
comprises a polymer.
[11139] 10173. The method of item 10126, wherein the device
comprises a polymer, and the polymer is a component of the
composition.
[11140] 10174. The method of item 10126, wherein the implant is
combined with a polymer, and the polymer is a copolymer.
[11141] 10175. The method of item 10126, wherein the implant is
combined with a polymer, and the polymer is a block copolymer.
[11142] 10176. The method of item 10126, wherein the implant is
combined with a polymer, and the polymer is a random copolymer.
[11143] 10177. The method of item 10126, wherein the implant is
combined with a polymer, and the polymer is a biodegradable
polymer.
[11144] 10178. The method of item 10126, wherein the implant is
combined with a polymer, and the polymer is a non-biodegradable
polymer.
[11145] 10179. The method of item 10126, wherein the implant is
combined with a polymer, and the polymer is a hydrophilic
polymer.
[11146] 10180. The method of item 10126, wherein the implant is
combined with a polymer, and the polymer is a hydrophobic
polymer.
[11147] 10181. The method of item 10126, wherein the implant is
combined with a polymer, and the polymer has hydrophilic
domains.
[11148] 10182. The method of item 10126, wherein the implant is
combined with a polymer, and the polymer has hydrophobic
domains.
[11149] 10183. The method of item 10126, wherein the implant is
combined with a polymer, and the polymer is a non-conductive
polymer.
[11150] 10184. The method of item 10126, wherein the implant is
combined with a polymer, and the polymer is an elastomer.
[11151] 10185. The method of item 10126, wherein the implant is
combined with a polymer, and the polymer is a hydrogel.
[11152] 10186. The method of item 10126, wherein the implant is
combined with a polymer, and the polymer is a silicone polymer.
[11153] 10187. The method of item 10126, wherein the implant is
combined with a polymer, and the polymer is a hydrocarbon
polymer.
[11154] 10188. The method of item 10126, wherein the implant is
combined with a polymer, and the polymer is a styrene-derived
polymer.
[11155] 10189. The method of item 10126, wherein the implant is
combined with a polymer, and the polymer is a butadiene
polymer.
[11156] 10190. The method of item 10126, wherein the implant is
combined with a polymer, and the polymer is a macromer.
[11157] 10191. The method of item 10126, wherein the implant is
combined with a polymer, and the polymer is a poly(ethylene glycol)
polymer.
[11158] 10192. The method of item 10126, wherein the implant is
combined with a polymer, and the polymer is an amorphous
polymer.
[11159] 10193. The method of item 10126, wherein the implant is
combined with a polymer, and the polymer is a lubricious
coating.
[11160] 10194. The method of item 10126 wherein the fibrosing agent
is located within pores or holes of the device.
[11161] 10195. The method of item 10126 wherein the fibrosing agent
is located within a channel, lumen, or divet of the device.
[11162] 10196. The method of item 10126, wherein the implant is
further combined with a second pharmaceutically active agent.
[11163] 10197. The method of item 10126, wherein the implant is
further combined with an anti-inflammatory agent.
[11164] 10198. The method of item 10126 wherein the implant is
further combined with an agent that inhibits infection.
[11165] 10199. The method of item 10126, wherein the implant is
further combined with an anthracycline.
[11166] 10200. The method of item 10126, wherein the implant is
further combined with doxorubicin.
[11167] 10201. The method of item 10126, wherein the implant is
further combined with mitoxantrone.
[11168] 10202. The method of item 10126, wherein the implant is
further combined with a fluoropyrimidine.
[11169] 10203. The method of item 10126, wherein the implant is
further combined with 5-fluorouracil (5-FU).
[11170] 10204. The method of item 10126, wherein the implant is
further combined with a folic acid antagonist.
[11171] 10205. The method of item 10126, wherein the implant is
further combined with methotrexate.
[11172] 10206. The method of item 10126, wherein the implant is
further combined with a podophylotoxin.
[11173] 10207. The method of item 10126, wherein the implant is
further combined with etoposide.
[11174] 10208. The method of item 10126 wherein the implant is
further combined with a camptothecin.
[11175] 10209. The method of item 10126, wherein the implant is
further combined with a hydroxyurea.
[11176] 10210. The method of item 10126, wherein the implant is
further combined with a platinum complex.
[11177] 10211. The method of item 10126, wherein the implant is
further combined with cisplatin.
[11178] 10212. The method of item 10126, wherein the implant is
further combined with an anti-thrombotic agent.
[11179] 10213. The method of item 10126, wherein the implant is
further combined with a visualization agent.
[11180] 10214. The method of item 10126, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises a metal, a halogenated compound, or a
barium containing compound.
[11181] 10215. The method of item 10126, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a radiopaque material, wherein the
radiopaque material comprises barium, tantalum, or technetium.
[11182] 10216. The method of item 10126, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent is a MRI responsive material.
[11183] 10217. The method of item 10126, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a gadolinium chelate.
[11184] 10218. The method of item 10126, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises iron, magnesium, manganese, copper,
or chromium.
[11185] 10219. The method of item 10126, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises an iron oxide compound.
[11186] 10220. The method of item 10126, wherein the implant is
further combined with a visualization agent, wherein the
visualization agent comprises a dye, pigment, or colorant.
[11187] 10221. The method of item 10126, wherein the implant is
further combined with an echogenic material.
[11188] 10222. The method of item 10126, wherein the implant is
further combined with an echogenic material, and the echogenic
material is in the form of a coating.
[11189] 10223. The method of item 10126 wherein the device is
sterilized.
[11190] 10224. The method of item 10126 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device.
[11191] 10225. The method of item 10126 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is connective
tissue.
[11192] 10226. The method of item 10126 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is muscle tissue.
[11193] 10227. The method of item 10126 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is nerve tissue.
[11194] 10228. The method of item 10126 wherein the fibrosing agent
is released into tissue in the vicinity of the device after
deployment of the device, wherein the tissue is epithelium
tissue.
[11195] 10229. The method of item 10126 wherein the fibrosing agent
is released in effective concentrations from the device over a
period ranging from the time of deployment of the device to about 1
year.
[11196] 10230. The method of item 10126 wherein the fibrosing agent
is released in effective concentrations from the device over a
period ranging from about 1 month to 6 months.
[11197] 10231. The method of item 10126 wherein the fibrosing agent
is released in effective concentrations from the device over a
period ranging from about 1-90 days.
[11198] 10232. The method of item 10126 wherein the fibrosing agent
is released in effective concentrations from the device at a
constant rate.
[11199] 10233. The method of item 10126 wherein the fibrosing agent
is released in effective concentrations from the device at an
increasing rate.
[11200] 10234. The method of item 10126 wherein the fibrosing agent
is released in effective concentrations from the device at a
decreasing rate.
[11201] 10235. The method of item 10126 wherein the fibrosing agent
is released in effective concentrations from the composition
comprising the fibrosing agent by diffusion over a period ranging
from the time of deployment of the device to about 90 days.
[11202] 10236. The method of item 10126 wherein the fibrosing agent
is released in effective concentrations from the composition
comprising the fibrosing agent by erosion of the composition over a
period ranging from the time of deployment of the device to about
90 days.
[11203] 10237. The method of item 10126 wherein the device
comprises about 0.01 .mu.g to about 10 .mu.g of the fibrosing
agent.
[11204] 10238. The method of item 10126 wherein the device
comprises about 10 .mu.g to about 10 mg of the fibrosing agent.
[11205] 10239. The method of item 10126 wherein the device
comprises about 10 mg to about 250 mg of the fibrosing agent.
[11206] 10240. The method of item 10126 wherein the device
comprises about 250 mg to about 1000 mg of the fibrosing agent.
[11207] 10241. The method of item 10126 wherein the device
comprises about 1000 mg to about 2500 mg of the fibrosing
agent.
[11208] 10242. The method of item 10126 wherein a surface of the
device comprises less than 0.01 .mu.g of the fibrosing agent per
mm.sup.2 of device surface to which the fibrosing agent is
applied.
[11209] 10243. The method of item 10126 wherein a surface of the
device comprises about 0.01 .mu.g to about 1 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[11210] 10244. The method of item 10126 wherein a surface of the
device comprises about 1 .mu.g to about 10 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[11211] 10245. The method of item 10126 wherein a surface of the
device comprises about 10 .mu.g to about 250 .mu.g of the fibrosing
agent per mm.sup.2 of device surface to which the fibrosing agent
is applied.
[11212] 10246. The method of item 10126 wherein a surface of the
device comprises about 250 .mu.g to about 1000 .mu.g of the
fibrosing agent of fibrosing agent per mm.sup.2 of device surface
to which the fibrosing agent is applied.
[11213] 10247. The method of item 10126 wherein a surface of the
device comprises about 1000 .mu.g to about 2500 .mu.g of the
fibrosing agent per mm.sup.2 of device surface to which the
fibrosing agent is applied.
[11214] The following examples are offered by way of illustration,
and not by way of limitation.
EXAMPLES
Example 1
Coating of Medical Implants with Fibronectin
[11215] The coating apparatus consisted of an overhead stirrer
(Fisher Scientific) orientated horizontally. A conical stainless
steel head is attached to the revolving chuck of the stirrer. One
end of an aneurysm coil is pulled up onto the conical head until
held firmly. The other end is attached to a clip-swivel device that
holds the medical implant in a horizontal position, but allowed the
medical implant to rotate along its axis. The stirrer is then set
to rotate at 30 rpm so that the whole medical implant rotates along
the horizontal axis at this speed. A 1% (w/w) fibronectin
(Calbiochem, San Diego, Calif.) solution in sterile water is
prepared. Two hundred microliters of this solution is slowly
pipetted as a 3 mm wide ring located 5 mm from the end of the
medical implant fixed in the conical steel head over a period of 2
minutes as the medical implant rotates. The fibronectin is then
dried under a stream of nitrogen as the medical implant continues
to rotate. When dry, the medical implant is removed, turned around
and the other end of the medical implant coated in the same manner.
Using this method a flexible ring of fibronectin is deposited on
both ends of the medical implant without compromise of the physical
characteristics of the medical implant. Other examples of medical
implants that may be coated in a similar fashion include vascular
(vaso-) occlusive coils and vascular (vaso-) occlusion
implants.
Example 2
Coating of Medical Implants with Poly-L-Lysine
[11216] A medical implant is coated using the procedure described
in Example 1. A 1% (w/w) poly-L-lysine (Sigma, St. Louis, Mo.)
solution in sterile water is prepared. Two hundred microliters of
this solution is slowly pipetted as a 3 mm wide ring located 5 mm
from the end of the medical implant fixed in the conical steel head
over a period of 2 minutes as the medical implant rotates. The
poly-L-lysine is then dried under a stream of nitrogen as the
medical implant continues to rotate. When dry, the medical implant
is removed, turned around and the other end of the medical implant
coated in the same manner. Using this method a flexible ring of
poly-L-Lysine is deposited on both ends of the medical implant
without compromise of the physical characteristics of the medical
implant.
Example 3
Coating of Medical Implants with N-Carboxybutyl Chitosan
[11217] A medical implant is coated using the procedure described
in Example 1. A 1% (w/w) n-carboxybutyl chitosan (Carbomer,
Westborough, Mass.) solution in sterile water is prepared. Two
hundred microliters of this solution is slowly pipetted as a 3 mm
wide ring located 5 mm from the end of the medical implant fixed in
the conical steel head over a period of 2 minutes as the medical
implant rotates. The n-carboxybutyl chitosan is dried under a
stream of nitrogen as the medical implant continues to rotate. When
dry, the medical implant is removed, turned around and the other
end coated in the same manner. Using this method a flexible ring of
n-carboxybutyl chitosan is deposited on both ends of the medical
implant without compromise of the physical characteristics of the
medical implant.
Example 4
Coating of Medical Implants with Bromocriptine In Poly(Ethylene
Vinyl Acetate)
[11218] A medical implant is coated using the procedure described
in Example 1. A 4.5% w/w solution of EVA (60/40 ratio ethylene to
vinyl acetate) (Polysciences USA) is prepared in dichloromethane.
Bromocriptine mesylate (Sigma, St. Louis, Mo.) is
dissolved/suspended in this solution at 5 mg/ml. Two hundred
microliters of this solution is slowly pipetted as a 3 mm wide ring
located 5 mm from the end of the medical implant fixed in the
conical steel head over a period of 2 minutes as the medical
implant rotates. The EVA/bromocriptine is dried under a stream of
nitrogen as the medical implant continues to rotate. When dry, the
medical implant is removed, turned around and the other end of the
medical implant coated in the same manner. Using this method a
flexible ring of EVA/bromocriptine is deposited on both ends of the
medical implant without compromise of the physical characteristics
of the medical implant.
Example 5
Preparation of Inflammatory Microcrystals (Monosodium Urate
Monohydrate and Calcium Pyrophosphate Dihydrate)
[11219] Monosodium urate monohydrate (MSUM) microcrystals were
grown. A solution of uric acid and sodium hydroxide at 55.degree.
C. and pH 8.9 was left to stand overnight at room temperature. The
crystals were rinsed several times with cold (4.degree. C.)
distilled water and dried at 60.degree. C. for 12 hours in a
circulating hot-air oven (Fisher, Isotemp).
[11220] Triclinic calcium pyrophosphate dihydrate (CPPD) crystals
were prepared as follows. A 250 ml beaker containing 103 ml
distilled water was heated in a water bath to 60.degree. C., and
stirred constantly with a TEFLON-coated stir bar. The stirring was
slowed and 0.71 ml of concentrated hydrochloric acid and 0.32 ml of
glacial acetic acid were added, followed by 0.6 g of calcium
acetate. A 150 ml beaker containing 20 ml distilled water was
heated to 60.degree. C. in the water bath, and 0.6 g calcium
acetate added. The rate of stir was increased in the 250 ml beaker,
and 2 g of calcium acid pyrophosphate added rapidly. When the
CaH.sub.2P.sub.2O.sub.7 had nearly all dissolved, the rate of
stirring was reduced for 5 minutes, then over a period of 15
seconds, the contents of the small beaker were poured into the
large beaker with vigorous stirring. In the preparation of
subsequent batches, a minute amount of triclinic CPPD crystals was
added to the large beaker as seed material. Stirring was
discontinued, leaving a white gel. This was allowed to remain
undisturbed in the cooling water bath. The pH of the supernatant
was always less than 3.0. The gel collapsed as CPPD crystals formed
in 24 hours. The crystals were washed in distilled water 3 times,
washed in ethanol then acetone, and air dried.
Example 6
Coating of Medical Implants with Inflammatory Microcrystals
(Monosodium Urate Monohydrate or Calcium Pyrophosphate
Dihydrate)
[11221] A medical implant is coated according to the procedure
described in Example 1. A 4.5% w/w solution of EVA (60/40 ratio
ethylene to vinyl acetate) (Polysciences) is prepared in
dichloromethane. Inflammatory microcrystals (MSUM or CPPD) are
ground in a pestle and mortar to a particle size of 10 to 50
micrometers and suspended in the solution at 5 mg/ml. Two hundred
microliters of this suspension is slowly pipetted as a 3 mm wide
ring located 5 mm from the end of the medical implant fixed in the
conical steel head over a period of 2 minutes as the medical
implant rotates. The EVA/microcrystal coating is then dried under a
stream of nitrogen as the medical implant continues to rotate. When
dry, the medical implant is removed, turned around and the other
end of the medical implant coated in the same manner. Using this
method a flexible ring of EVA/microcrystals is deposited on both
ends of the medical implant without compromise of the physical
characteristics of the medical implant.
Example 7
Coating of Medical Implants with Inflammatory Microcrystals
(Monosodium Urate Monohydrate or Calcium Pyrophosphate
Dihydrate)
[11222] A 1% w/w solution of medical grade polyurethane (PU)
(Thermomedics, Woburn, Mass.) is prepared in dichloromethane.
Inflammatory microcrystals (CPPD or MSUM) are ground in a pestle
and mortar to a particle size of 10 to 50 micrometers and suspended
in the solution at 2 mg/ml. Immediately prior to surgical insertion
each end of a medical implant (e.g., aneurysm coil or hernia mesh)
is inserted into the shaken suspension to a depth of approximately
5 mm for 2 seconds. The medical implant is air-dried (gently
rotated by hand for 3 minutes). Using this method a flexible ring
of coating of EVA/microcrystals is deposited on both ends of the
medical implant without compromise of the physical characteristics
of the medical implant.
Example 8
Coating of Medical Implants with Bromocriptine in Polyurethane
[11223] A 1% w/w solution of medical grade polyurethane (PU)
(Thermomedics) is prepared in dichloromethane. Bromocriptine
mesylate (Sigma) at 5% w/w to PU is dissolved/suspended in this
solution. The solution is placed in a 5 ml Fisher TLC atomizer
(Fisher Scientific). Prior to surgery the medical implant is
suspended vertically in a fume hood and 1 ml of the solution
sprayed (using nitrogen propellant) onto the bottom 1 cm of the
medical implant by revolving the medical implant through 360
degrees. The medical implant is dried for 2 minutes and then the
other end of the medical implant is sprayed in a similar manner.
The medical implant is then further air dried (gently rotated by
hand for 3 minutes). Using this method a flexible ring of
bromocriptine/PU is deposited on both ends of the medical implant
without compromise of the physical characteristics of the medical
implant. It is envisaged that ultimately a bromocriptine/PU
solution in DCM may be available to the surgeon in the form of a
small aerosol can for the above procedure.
Example 9
Coating of Medical Implants with Inflammatory Microcrystals
(Monosodium Urate Monohydrate or Calcium Pyrophosphate
Dihydrate)
[11224] A medical implant is coated according to the procedure
described in Example 1. A 4.5% w/w solution of poly(lactide
co-glycolide) (85:15) (IV 0.61) (Birmingham Polymers, Birmingham,
Ala.) blended with methoxypolyethylene glycol 350 (MePEG 350)
(Union Carbide, Danbury, Conn.) in a ratio of 80:20 w/w
(PLGA:MePEG) is prepared in dichloromethane. Inflammatory
microcrystals are suspended in the solution at 5 mg/ml. Two hundred
microliters of this suspension is slowly pipetted as a 3 mm wide
ring located 5 mm from the end of the medical implant fixed in the
conical steel head over a period of 2 minutes as the medical
implant rotates. The PLGA/MePEG/inflammatory crystals are then
dried under a stream of nitrogen as the medical implant continues
to rotate. When dry, the medical implant is removed, turned around
and the other end of the medical implant coated in the same manner.
Using this method a flexible ring of PLGA/MePEG/microcrystals is
deposited on both ends of the medical implant without compromise of
the physical characteristics of the medical implant.
Example 10
Coating of Medical Implants with Angiotensin 2 Encapsulated in
Polyethylene Glycol (PEG)
[11225] 1.8 grams of polyethylene glycol (PEG 1475) (Union Carbide)
is placed in a flat-bottomed 20 ml glass scintillation vial and
warmed to 50.degree. C. to melt the PEG in a water bath, 200 mg of
glycerol (Fisher Scientific) is added. 2 mg of angiotensin 2
(Sigma) is weighed into the vial and blended/dissolved into the
melted PEG at 50.degree. C. The vial is angled at 10 degrees in a
water bath by use of a clamp. Each end of a medical implant (e.g.,
aneurysm coil or hernia mesh) is dipped rotated into the molten
formulation, so that a ring of that a coating of the material is
deposited on the bottom 5 mm of the exterior surface of the medical
implant. The medical implant is then cooled and stored at 4.degree.
C. until use. Alternatively, to enable dipping immediately prior to
surgery the PEG/angiotensin mixture is stored at 4.degree. C. until
use. Immediately prior to surgery, the vial of PEG/angiotensin is
warmed to 50.degree. C. for 2 minutes to melt and the medical
implant is coated as described above.
Example 11
Coating of Medical Implants with Transforming Growth Factor-9
(TGF-9) in Crosslinked Hyaluronic Acid
[11226] A medical implant is coated according to the procedure
described in Example 1. A 1% solution of hyaluronic acid (HA)
(Sodium salt, Sigma) in water, containing 30% glycerol (w/w to HA)
(Fisher Scientific) and 8 mM 1-ethyl-3-(-3
dimethylaminopropyl)carbodiimide (EDAC) is prepared by dissolution
overnight. TGF-9 (Calbiochem, San Diego, Calif.) is dissolved at
0.01 mg/ml in this solution. Two hundred microliters of this
solution is slowly pipetted as a 3 mm wide ring located 5 mm from
the end of the medical implant fixed in the conical steel head over
a period of 2 minutes as the medical implant rotates. The
HA/glycerol/TGF-9 solution is dried under a stream of nitrogen as
the medical implant continues to rotate. When dry, the medical
implant is removed, turned around and the other end coated in the
same manner. Using this method a flexible ring of HA/glycerol/TGF-9
is deposited on both ends of the medical implant without compromise
of the physical characteristics of the medical implant.
Example 12
Coating of Medical Implants with Fibroblast Growth Factor (FGF) in
Crosslinked Chitosan
[11227] A medical implant is coated according to the procedure
described in Example 1. A 1% solution of chitosan (Medical grade,
Carbomer, Westborough, Mass.) in dilute acetic acid (pH 5),
containing 30% glycerol (w/w to chitosan) (Fisher Scientific) and
0.5% glutaraldehyde (Sigma, St. Louis, Mo.) is prepared by
dissolution overnight. FGF (Calbiochem, San Diego, Calif.) is
dissolved at 0.01 mg/ml in this solution. Two hundred microliters
of this solution is slowly pipetted as a 3 mm wide ring located 5
mm from the end of the medical implant fixed in the conical steel
head over a period of 2 minutes as the medical implant rotates. The
chitosan/glycerol/FGF solution is dried under a stream of nitrogen
as the medical implant continues to rotate. When dry, the medical
implant is removed, turned around and the other end coated in the
same manner. Using this method a flexible ring of
chitosan/glycerol/FGF is deposited on both ends of the medical
implant without compromise of the physical characteristics of the
medical implant.
Example 13
Screening Procedure for Assessment of Perigraft Reaction
[11228] A rabbit perivascular model is described for identifying
arterial vessel wall irritants. Large domestic rabbits are placed
under general anesthetic. Using aseptic precautions, the infrarenal
abdominal aorta is exposed and clamped at its superior and inferior
aspects. A longitudinal arterial wall arteriotomy is performed and
a 2 millimeter diameter, 1 centimeter long segment of PTFE graft is
inserted within the aorta and the proximal and distal aspect of the
graft is sewn so that the entire aortic blood flow is through the
graft which is contained in the abdominal aorta in the manner of
open surgical abdominal aortic repair in humans (except that no
aneurysm is present in this model). The aortotomy is then
surgically closed and the abdominal wound closed and the animal
recovered.
[11229] The animals are randomized to receive standard PTFE grafts
or grafts of which the middle 1 cm is coated alone
circumferentially with nothing (control), or with an agent that
induces a vessel wall reaction or adhesion between a stent graft
and vessel wall alone or contained in a slow release, polymer such
as polycaprolactone or polylactic acid.
[11230] The animals are sacrificed between 1 and 6 weeks post
surgery, the aorta is removed en bloc and the area in relation to
the graft is grossly examined for adhesive reaction. Any difference
in morphology or histology of the vessel wall from portions of the
artery which contain no graft, portion which contain graft without
coating, and portion which contained graft with coating is
noted.
Example 14
Animal Abdominal Aortic Aneurysm Model
[11231] An animal model is described for determining whether a
stent graft containing a biologically active or irritative
substance stimulates fibrosis. Pigs or sheep are placed under
general anesthetic. Using aseptic precautions the abdominal aorta
is exposed. The animal is heparinized and the aorta is cross
clamped below the renal arteries and above the bifurcation.
Collaterals are temporarily controlled with vessel loops or clips
that are removed upon completion of the procedure. A longitudinal
aortotomy is created in the arterial aspect of the aorta, and an
elliptical shaped patch of rectus sheath from the same animal is
sutured into the aortotomy to create an aneurysm. The aortic clamps
from the lumbar arteries and collaterals are removed and the
abdomen closed. After 30 days, the animal is reanesthesized and the
abdominal wall again opened. A cutdown is performed on the iliac
artery and through this, a stent graft is positioned across the
infrarenal abdominal aorta aneurysm extending from normal
infrarenal abdominal aorta above to normal infrarenal abdominal
aorta below the surgically created aneurysm and the device is
released in a conventional way.
[11232] Animals are randomized into groups of 5 receiving uncoated
stent grafts, stent graft containing slow release polymer alone,
and stent graft containing a biologically active or irritative
substance as determined by the previously mentioned screening exam.
After closure of the arteriotomy and of the abdominal wound, the
animal is allowed to recover. At 6 weeks and 3 months post stent
graft insertion, the animal is sacrificed and the aorta removed en
bloc. The infrarenal abdominal aorta is examined for evidence of
histologic reaction and perigraft leaking.
Example 15
Screening Assay for Assessing the Effect of Cyclosporine a on Cell
Proliferation
[11233] An in vitro assay is described for determining whether a
substance stimulates cell (fibroblast) proliferation (see, In Vitro
Toxicol. (1990) 3: 219; Biotech. Histochem. (1993) 68: 29; Anal.
Biochem. (1993) 213: 426). Smooth muscle cells at 70-90% confluency
are trypsinized, replated at 600 cells/well in media in 96-well
plates and allowed to attachment overnight. Cyclosporine A is
prepared in DMSO at a concentration of 10.sup.-2 M and diluted
10-fold to give a range of stock concentrations (10.sup.-8 M to
10.sup.-2 M). Drug dilutions are diluted 1/1000 in media and added
to cells to give a total volume of 200 .mu.L/well. Each drug
concentration is tested in triplicate wells. Plates containing
smooth muscle cells and cyclosporine A are incubated at 37.degree.
C. for 72 hours.
[11234] To terminate the assay, the media is removed by gentle
aspiration. A 1/400 dilution of CYQUANT 400.times.GR dye indicator
(Molecular Probes; Eugene, Oreg.) is added to 1.times. cell lysis
buffer, and 200 .mu.L of the mixture is added to the wells of the
plate. Plates are incubated at room temperature, protected from
light for 3-5 minutes. Fluorescence is read in a fluorescence
microplate reader at -480 nm excitation wavelength and .about.520
nm emission maxima. Activation of proliferation is determined by
taking the average of triplicate wells and comparing average
relative fluorescence units to the DMSO control (see FIG. 1).
[11235] The assay was repeated for the following proliferative
therapeutic agents: dexamethasone (FIG. 2), all-trans retinoic acid
(FIG. 3), isotretinoin (FIG. 4), 17-.beta.-estradiol (FIG. 5), and
1a,25-dihydroxy-vitamin D.sub.3 (FIG. 6).
Example 16
Screening Assay for Assessing the Effect of PDGF on Smooth Muscle
Cell Migration
[11236] An in vitro assay is described for determining whether a
substance stimulates cell (fibroblast) migration. Primary human
smooth muscle cells are starved of serum in smooth muscle cell
basal media containing insulin and human basic fibroblast growth
factor (bFGF) for 16 hours prior to the assay. For the migration
assay, cells are trypsinized to remove cells from flasks, washed
with migration media and diluted to a concentration of
2-2.5.times.10.sup.5 cells/ml in migration media. Migration media
consists of phenol red free Dulbecco's Modified Eagle Medium (DMEM)
containing 0.35% human serum albumin. A 100 .mu.L volume of smooth
muscle cells (approximately 20,000-25,000 cells) is added to the
top of a Boyden chamber assembly (Chemicon QCM CHEMOTAXIS 96-well
migration plate). To the bottom wells, the chemotactic agent,
recombinant human platelet derived growth factor (rhPDGF-BB) is
added at a concentration of 10 ng/ml in a total volume of 150
.mu.L. Paclitaxel is prepared in DMSO at a concentration of
10.sup.-2 M and serially diluted 10-fold to give a range of stock
concentrations (10.sup.-8 M to 10.sup.-2 M). Paclitaxel is added to
cells by directly adding paclitaxel DMSO stock solutions, prepared
earlier, at a 1/1000 dilution, to the cells in the top chamber.
Plates are incubated for 4 hours to allow cell migration.
[11237] At the end of the 4 hour period, cells in the top chamber
are discarded and the smooth muscle cells attached to the underside
of the filter are detached for 30 minutes at 37.degree. C. in Cell
Detachment Solution (Chemicon). Dislodged cells are lysed in lysis
buffer containing the DNA binding CYQUANT GR dye and incubated at
room temperature for 15 minutes. Fluorescence is read in a
fluorescence microplate reader at .about.480 nm excitation
wavelength and .about.520 nm emission maxima. Relative fluorescence
units from triplicate wells are averaged after subtracting
background fluorescence (control chamber without chemoattractant)
and average number of cells migrating is obtained from a standard
curve of smooth muscle cells serially diluted from 25,000
cells/well down to 98 cells/well. Inhibitory concentration of 50%
(IC.sub.50) is determined by comparing the average number of cells
migrating in the presence of paclitaxel to the positive control
(smooth muscle cell chemotaxis in response to rhPDGF-BB). See FIG.
7. References: Biotechniques (2000) 29: 81; J. Immunol Methods
(2001) 254: 85.
Example 17
In Vivo Evaluation of Silk Coated Perivascular Pu Films to Assess
Scarring
[11238] A rat carotid artery model is described for determining
whether a substance stimulates fibrosis. Wistar rats weighing 300 g
to 400 g are anesthetized with halothane. The skin over the neck
region is shaved and the skin is sterilized. A vertical incision is
made over the trachea and the left carotid artery is exposed. A
polyurethane film covered with silk strands or a control uncoated
PU film is wrapped around a distal segment of the common carotid
artery. The wound is closed and the animal is recovered. After 28
days, the rats are sacrificed with carbon dioxide and
pressure-perfused at 100 mmHg with 10% buffered formaldehyde. Both
carotid arteries are harvested and processed for histology. Serial
cross-sections can be cut every 2 mm in the treated left carotid
artery and at corresponding levels in the untreated right carotid
artery. Sections are stained with H&E and Movat's stains to
evaluate tissue growth around the carotid artery. Area of
perivascular granulation tissue is quantified by computer-assisted
morphometric analysis. Area of the granulation tissue is
significantly higher in the silk coated group than in the control
uncoated group. See FIG. 8.
Example 18
In Vivo Evaluation of Perivascular PU Films Coated with Different
Silk Suture Material to Assess Scarring
[11239] A rat carotid artery model is described for determining
whether a substance stimulates fibrosis. Wistar rats weighing 300 g
to 400 g are anesthetized with halothane. The skin over the neck
region is shaved and the skin is sterilized. A vertical incision is
made over the trachea and the left carotid artery is exposed. A
polyurethane film covered with silk sutures from one of three
different manufacturers (3-0 Silk--Black Braided (Davis &
Geck), 3-0 SOFSILK (U.S. Surgical/Davis & Geck), and 3-0
Silk-Black Braided (LIGAPAK) (Ethicon, Inc.) is wrapped around a
distal segment of the common carotid artery. (The polyurethane film
can also be coated with other agents to induce fibrosis.) The wound
is closed and the animal is allowed to recover.
[11240] After 28 days, the rats are sacrificed with carbon dioxide
and pressure-perfused at 100 mmHg with 10% buffered formaldehyde.
Both carotid arteries are harvested and processed for histology.
Serial cross-sections are be cut every 2 mm in the treated left
carotid artery and at corresponding levels in the untreated right
carotid artery. Sections are stained with H&E and Movat's
stains to evaluate tissue growth around the carotid artery. Area of
perivascular granulation tissue is quantified by computer-assisted
morphometric analysis. Thickness of the granulation tissue is the
same in the three groups showing that tissue proliferation around
silk suture is independent of manufacturing processes. See FIG.
9.
Example 19
In Vivo Evaluation of Perivascular Silk Powder to Assess
Scarring
[11241] A rat carotid artery model is described for determining
whether a substance stimulates fibrosis. Wistar rats weighing 300 g
to 400 g are anesthetized with halothane. The skin over the neck
region is shaved and the skin is sterilized. A vertical incision is
made over the trachea and the left carotid artery is exposed. Silk
powder is sprinkled on the exposed artery that is then wrapped with
a PU film. Natural silk powder or purified silk powder (without
contaminant proteins) is used in different groups of animals.
Carotids wrapped with PU films only are used as a control group.
The wound is closed and the animal is allowed to recover. After 28
days, the rats are sacrificed with carbon dioxide and
pressure-perfused at 100 mmHg with 10% buffered formaldehyde. Both
carotid arteries are harvested and processed for histology. Serial
cross-sections can be cut every 2 mm in the treated left carotid
artery and at corresponding levels in the untreated right carotid
artery. Sections are stained with H&E and Movat's stains to
evaluate tissue growth around the carotid artery. Area of tunica
intima, tunica media and perivascular granulation tissue is
quantified by computer-assisted morphometric analysis.
[11242] The natural silk caused a severe cellular inflammation
consisting mainly of a neutrophil and lymphocyte infiltrate in a
fibrin network without any extracellular matrix or blood vessels.
In addition, the treated arteries were seriously damaged with
hypocellular media, fragmented elastic laminae and thick intimal
hyperplasia. Intimal hyperplasia contained many inflammatory cells
and was occlusive in 2/6 cases. This severe immune response was
likely triggered by antigenic proteins coating the silk protein in
this formulation. On the other end, the regenerated silk powder
triggered only a mild foreign body response surrounding the treated
artery. This tissue response was characterized by inflammatory
cells in extracellular matrix, giant cells and blood vessels. The
treated artery was intact. These results show that removing the
coating proteins from natural silk prevents the immune response and
promotes benign tissue growth. Degradation of the regenerated silk
powder was underway in some histology sections indicating that the
tissue response can likely mature and heal over time. See FIG.
10.
Example 20
In Vivo Evaluation of Perivascular Talcum Powder to Assess
Scarring
[11243] A rat carotid artery model is described for determining
whether a substance stimulates fibrosis. Wistar rats weighing 300 g
to 400 g are anesthetized with halothane. The skin over the neck
region is shaved and the skin is sterilized. A vertical incision is
made over the trachea and the left carotid artery is exposed.
Talcum powder is sprinkled on the exposed artery that is then
wrapped with a PU film. Carotids wrapped with PU films only are
used as a control group. The wound is closed and the animal is
recovered. After 1 or 3 months, the rats are sacrificed with carbon
dioxide and pressure-perfused at 100 mmHg with 10% buffered
formaldehyde. Both carotid arteries are harvested and processed for
histology. Serial cross-sections are cut every 2 mm in the treated
left carotid artery and at corresponding levels in the untreated
right carotid artery. Sections are stained with H&E and Movat's
stains to evaluate tissue growth around the carotid artery.
Thickness of tunica intima, tunica media and perivascular
granulation tissue is quantified by computer-assisted morphometric
analysis. Histopathology results and morphometric analysis showed
the same local response to talcum powder at 1 month and 3 months. A
large tissue reaction trapped the talcum powder at the site of
application around the blood vessel. This tissue was characterized
by a large number of macrophages within a dense extracellular
matrix with few neutrophiles, lymphocytes and blood vessels. The
treated blood vessel appeared intact and unaffected by the
treatment. Overall, this result showed that talcum powder induced a
mild long-lasting fibrotic reaction that was subclinical in nature
and did not harm any adjacent tissue. See FIG. 11.
Example 21
Preparation of Silk Powder
[11244] Several pieces of silk braid (Ethicon, 4-0, 638) are cut
into lengths of approx 0.4 cm. These cut pieces are placed in a 100
ml round bottom flask that contains 50 ml 2M NaOH. The sample is
stirred using a magnetic stirrer at room temperature for 24 h. The
sample is neutralized using concentrated HCl. The neutralized
contents are then dialyzed against deionized water using
cellulose-based dialysis tubing (WMCO approx 3000; Spectrum). The
sample is dialyzed for 48 hours with 5 water changes. The dialyzed
sample is then poured into a 100 ml round bottom flask. The sample
is frozen and freeze-dried to yield a fluffy powdered material.
Example 22
Coating of Medical Implants with a Powdered Silk/PLGA Coating
[11245] A medical device (e.g., aneurysm coil) attached to a
stainless steel rod (with the aid of a bulldog clip) that is
attached to a Fisher overhead stirrer that is orientated
vertically. The stirrer is set to rotate at 30 rpm. A 2% PLGA (9K,
50:50, Birmingham Polymers) solution (ethyl acetate) that contains
the powdered silk is sprayed onto the rotating implant using an
airbrush spray device. The concentration of the powdered silk in
the PLGA solution is altered from 0.1% to 50%. After the spraying
process, the device is allowed to air dry for 30 minutes while
still rotating. The device is then removed from the pipette tip and
is further dried under vacuum for 24 h.
Example 23
Coating of Tube with a Powdered Silk/Polyurethane Coating
[11246] A polyurethane tube is pushed onto a 1 ml plastic pipette
tip. The open end of the pipette tip is attached to a stainless
steel rod that is attached to a Fisher overhead stirrer that is
orientated horizontally. The stirrer is set to rotate at 30 rpm. A
2% CHRONOFLEX AL 85A (CT Biomaterials) solution (THF) that contains
powdered silk (prepared using a cryomill) is sprayed onto the
rotating tube using a TLC spray device. The concentration of the
powdered silk in the polyurethane solution is altered from 0.1% to
50%. After the spraying process, the tube is allowed to air dry for
30 minutes while still rotating. The tube is then removed from the
pipette tip and is further dried under vacuum for 24 h.
Example 24
Top-Coating of a Coated Tube with a Degradable Coating
[11247] The coated tube from Example 24 is reattached to the
overhead stirrer and is rotated at 30 rpm. A 10% 20:80
MePEG(750)-PLA block copolymer solution (acetone) is sprayed onto
the rotating tube using an TLC spray device. After the spraying
process, the tube is allowed to air dry for 30 minutes while still
rotating. The spray coating process can be repeated until the
desired thickness or uniformity of coating is obtained. The tube is
then removed from the pipette tip and is further dried under vacuum
for 24 h.
Example 25
Top-Coating of a Coated Tube with a Heparin-Containing Degradable
Coating
[11248] The coated tube from Example 24 is reattached to the
overhead stirrer and is rotated at 30 rpm. A 10% 20:80
MePEG(750)-PLA block copolymer solution (acetone) that contains
various amounts of a heparin benzalkonium chloride complex
(PolySciences) is sprayed onto the rotating tube using an TLC spray
device. After the spraying process, the tube is allowed to air dry
for 30 minutes while still rotating. The spray coating process can
be repeated until the desired thickness or uniformity of coating is
obtained. The tube is then removed from the pipette tip and is
further dried under vacuum for 24 h.
Example 26
Coating of a Coated Tube with a Heparin Coating
[11249] The coated tube from Example 24 is reattached to the
overhead stirrer and is rotated at 30 rpm. A solution that contains
various amounts of a Heparin benzalkonium chloride complex
(PolySciences) in IPA is sprayed onto the rotating tube using a TLC
spray device. After the spraying process, the tube is allowed to
air dry for 30 minutes while still rotating. The spray coating
process can be repeated until the desired thickness or uniformity
of coating is obtained. The tube is then removed from the pipette
tip and is further dried under vacuum for 24 h.
Example 27
Coating of Tube with a Powdered Silk/Cyclosporine a/Polyurethane
Coating
[11250] A polyurethane tube is pushed onto a 1 ml plastic pipette
tip. The open end of the pipette tip is attached to a stainless
steel rod that is attached to a Fisher overhead stirrer that is
orientated horizontally. The stirrer is set to rotate at 30 rpm. A
2% CHRONOFLEX AL 85A solution (THF) that contains the powdered silk
and cyclosporine A is sprayed onto the rotating tube using an TLC
spray device. The concentration of the powdered silk in the
polyurethane solution is altered from 0.1% to 50% (w/w relative to
the polymer) and the concentration of the Cyclosporine A is altered
from 0.1% to 10% (w/w relative to the polymer). Afterthe spraying
process, the tube is allowed to air dry for 30 minutes while still
rotating. The tube is then removed from the pipette tip and is
further dried under vacuum for 24 h.
Example 28
Film Impregnated with Silk Fibers
[11251] A 20% CHRONOFLEX AL 85A solution (THF) was cast onto a
silicone-coated release liner. The solvent allowed to dry. Pieces
of 3-0 Silk-Black Braided (LIGAPAK) (Ethicon, Inc.) were placed on
the surface of the polyurethane film. Drops of THF were then added
to the surface of the polyurethane film. Using a glass
scintillation vial as a roller, the silk strands were embedded into
the surface of the polyurethane film.
Example 29
In Situ Forming Silk--Containing Gel
[11252] Methylated collagen is prepared by the following process:
bovine corium collagen is solubilized using pepsin and purified as
described in U.S. Pat. No. 4,233,360. This purified, solubilized
collagen is precipitated by neutralization into 0.2 M sodium
phosphate, pH 7.2. The precipitate is isolated by centrifugation to
a final concentration of 70 mg/ml. The material is dried for two
days, and then pulverized. Dry methanol containing HCl (to 0.1 N)
is added (40 ml) and stirred for four days. Collagen is separated
from the acidic methanol, vacuum dried and sterilized by
irradiation. The final product is dissolved in water at a pH of
3-4.
[11253] For delivery as a gel, 10 mg of the methylated collagen,
100 mg of a tetra-functional sulfhydryl-PEG (pentaerythritol
poly(ethylene glycol)ether tetra-sulfhydryl), 10,000 MW, and 100 mg
of a tetra-functional succinimidyl PEG (pentaerythritol
poly(ethylene glycol)ether tetra-succinimidyl glutarate), 10,000
MW, are dissolved in water at pH 3-4 to a final volume of 1 ml
(first component). The second component is 1 ml of
phosphate/carbonate buffer (300 mM sodium monobasic phosphate is
mixed with 300 mM sodium carbonate. If required, the pH is adjusted
with NaOH or HCl to achieve pH 9.6. The final molarity is
approximately 117 mM phosphate and 183 mM carbonate). Various
amounts (1 mg to 100 mg) of silk powder (prepared using a cryomill)
is added to the phosphate/carbonate buffer. Each component is
placed in a syringe and mixed and sprayed on the desired test site
using a manual dual-syringe delivery system or a air-assisted dual
syringe delivery system (FibriJet, Micromedics).
Example 30
Coating of the Silk Braid with a Polymer/Biologically Agent--Direct
Dipping
[11254] Silk braid (Ethicon, 4-0, 638) is cut into approximately 10
cm lengths. The silk braid is dipped into a chloroform solution of
poly(lactide-co-glycolide) (PLGA) (9K, 50:50, Birmingham Polymers)
and cyclosporine A. The concentration of the PLGA is altered from
0.1% to 20% (w/v) and concentration of the cyclosporine A in the
solution is altered from 0.1% to a saturated solution. The silk
braid is immersed in the PLGA/cyclosporine A solution for 5
minutes. The silk braid is then removed and air-dried. The
cyclosporine A loaded silk braid is then further dried under
vacuum. The silk braid is then attached to a polyurethane film by
placing the coated-braids on the polyurethane film and then
pressing the film/braids in a heat press for about 10 seconds such
that the coated braid is embedded in the polyurethane film.
Example 31
In Situ Forming Silk--Containing Gel
[11255] For delivery as a gel, 200 mg of a tetra-functional
succinimidyl PEG (pentaerythritol poly(ethylene glycol)ether
tetra-succinimidyl glutarate) 10,000 MW s dissolved in water at pH
2.5 (adjusted with HCl) to a final volume of 1 ml (first
component). The second component is 1 ml of phosphate/carbonate
Buffer (300 mM sodium monobasic phosphate is mixed with 300 mM
sodium carbonate. If required, the pH is adjusted with NaOH or HCl
to achieve pH 9.6. The final molarity is approximately 117 mM
phosphate and 183 mM carbonate) that contains 200 mg of a
tetra-functional amino-PEG (pentaerythritol poly(ethylene
glycol)ethertetra-amino), 10,000 MW. Various amounts (1 mg to 200
mg) of the silk powder are added to the acidic buffer. Each
component is placed in a syringe and is sprayed on the desired test
site using a manual dual-syringe delivery system or a air-assisted
dual syringe delivery system (FibriJet, Micromedics).
Example 32
Cyclosporine A--Containing Coating
[11256] A 5% CHRONOFLEX AL 85A solution (chloroform) containing
from 0.1% to 10% cyclosporine A is prepared. A piece of
polyurethane tubing is immersed in and then withdrawn from the
coating solution. The coated sample is air-dried in the fume-hood.
Samples of different coating thicknesses are prepared by repeating
the dip-coating process. The coated sample is then dried under
vacuum for 24 hours.
Example 33
Collagen Synthesis Assay
[11257] An in vitro assay is described for determining whether a
substance promotes deposition of extracellular matrix (ECM). Normal
human dermal fibroblasts were trypzanized, then re-plated in medium
containing ascorbic acid-2-phosphate at 150,000 cells per well in a
12-well plate. The cells were cultured at 37.degree. C. and 5%
CO.sub.2 for 2-3 weeks with media changes every three days so that
they formed a 3-D matrix of cells and collagen. After 14-21 days of
culture, the medium was replaced with serum free medium and the
cells allowed to rest for 24 hours.
[11258] Drug was diluted in DMSO at 10.sup.-2M, then diluted 10
fold to give a range of stock concentrations from 10.sup.-2M to
10.sup.-8M. Drug was then diluted 1000 times in fresh serum free
medium and added to the wells in a total volume of 3 ml per well.
The plate(s) were then incubated for 72 hrs at 37.degree. C. After
72 hrs the media was removed from the wells and put into
microcentrifuge tubes and frozen at -20.degree. C. until
assayed.
[11259] The amount of collagen synthesized was measured using a
Procollagen Type 1 C-Peptide (PIP) EIA kit (Takara), where the
amount of collagen produced is stoichiometrically represented by
the amount of pro-peptide cleaved from the collagen when it is
secreted. Anti-PIP monoclonal antibodies are immobilized on an
ELISA plate, the samples added, then a second PIP monoclonal
antibody conjugated to horseradish peroxidase is added to the wells
and incubated. Following incubation, the wells are washed, a
substrate solution is added, and the absorbance measured in a plate
reader at 450 nm and compared to a standard curve of PIP
(ng/ml).
Example 34
Chick Chorioallantoic Membrane ("CAM") Assay
[11260] This example describes an in vitro assay for determining
whether a substance promotes angiogenesis. Fertilized, domestic
chick embryos are incubated for 3 days prior to shell-less
culturing. In this procedure, the egg contents are emptied by
removing the shell located around the air space. The interior shell
membrane is then severed and the opposite end of the shell is
perforated to allow the contents of the egg to gently slide out
from the blunted end. The egg contents are emptied into
round-bottom sterilized glass bowls and covered with petri dish
covers. These are then placed into an incubator at 90% relative
humidity and 3% CO.sub.2 and incubated for 3 days. (Alternatively,
egg contents can remain in the shell with the opening covered with
parafilm.)
[11261] The agent (e.g., paclitaxel) (Sigma) can be mixed at
concentrations of 0.25, 0.5, 1, 5, 10, 30 .mu.g per 10 ul aliquot
of 0.5% aqueous methylcellulose. Concentrations can be altered
depending on the agent. Agents can be mixed with other compatible
materials as appropriate depending on the solubility of the agent.
Ten microliter aliquots of this solution are dried on parafilm for
1 hour forming disks 2 mm in diameter. The dried disks containing
agent are then carefully placed at the growing edge of each CAM at
day 6 of incubation. The day of disc placement can be altered
depending on the amount of angiogenesis stimulation by the agent
beyond control. Controls are obtained by placing agent-free
methylcellulose disks on the CAMs over the same time course. After
a 2 day exposure (day 8 of incubation) the vasculature is examined
with the aid of a stereomicroscope. Liposyn II, a white opaque
solution, is injected into the CAM to increase the visibility of
the vascular details. The vasculature of unstained, living embryos
were imaged using a Zeiss stereomicroscope which is interfaced with
a video camera (Dage-MTI Inc., Michigan City, Ind.). These video
signals are then displayed at 160.times. magnification and captured
using an image analysis system (Vidas, Kontron; Etching, Germany).
Image negatives are then made on a graphics recorder (Model 3000;
Matrix Instruments, Orangeburg, N.Y.).
[11262] The membranes of the 8 day-old shell-less embryo are
flooded with 2% glutaraldehyde in 0.1M sodium cacodylate buffer;
additional fixative is injected under the CAM. After 10 minutes in
situ, the CAM is removed and placed into fresh fixative for 2 hours
at room temperature. The tissue is then washed overnight in
cacodylate buffer containing 6% sucrose. The areas of interest are
postfixed in 1% osmium tetroxide for 1.5 hours at 4.degree. C. The
tissues are then dehydrated in a graded series of ethanols, solvent
exchanged with propylene oxide, and embedded in Spurr resin. Thin
sections are cut with a diamond knife, placed on copper grids,
stained, and examined in a Joel 1200EX electron microscope.
Similarly, 0.5 mm sections are cut and stained with toluene blue
for light microscopy.
[11263] At day 11 of development, chick embryos are used for the
corrosion casting technique. Mercox resin (Ted Pella, Inc.,
Redding, Calif.) is injected into the CAM vasculature using a
30-gauge hypodermic needle. The casting material consists of 2.5
grams of Mercox CL-2B polymer and 0.05 grams of catalyst (55%
benzoyl peroxide) having a 5 minute polymerization time. After
injection, the plastic is allowed to sit in situ for an hour at
room temperature and then overnight in an oven at 65.degree. C. The
CAM is then placed in 50% aqueous solution of sodium hydroxide to
digest all organic components. The plastic casts are washed
extensively in distilled water, air-dried, coated with
gold/palladium, and viewed with the Philips 501B scanning electron
microscope.
[11264] At day 6 of incubation, the embryo is centrally positioned
to a radially expanding network of blood vessels; the CAM develops
adjacent to the embryo. These growing vessels lie close to the
surface and are readily visible making this system an idealized
model for the study of angiogenesis. Living, unstained capillary
networks of the CAM can be imaged non-invasively with a
stereomicroscope.
[11265] Transverse sections through the CAM show an outer ectoderm
consisting of a double cell layer, a broader mesodermal layer
containing capillaries which lie subjacent to the ectoderm,
adventitial cells, and an inner, single endodermal cell layer. At
the electron microscopic level, the typical structural details of
the CAM capillaries are demonstrated. Typically, these vessels lie
in close association with the inner cell layer of ectoderm.
[11266] After 48 hours exposure to an agent at concentrations of
0.25, 0.5, 1, 5, 10, or 30 .mu.g, each CAM is examined under living
conditions with a stereomicroscope equipped with a video/computer
interface to evaluate the effects on angiogenesis. This imaging
setup is used at a magnification of 160.times. which permits the
direct visualization of blood cells within the capillaries; thereby
blood flow in areas of interest can be easily assessed and
recorded. The change in the amount of angiogenesis is defined as an
area of the CAM (measuring 2-6 mm in diameter) with increased
capillary network and vascular blood flow. Throughout the
experiments, zones are assessed on a 4 point gradient (Table 1).
This scale represents the degree of increase in angiogenesis with
maximal increase represented as a 3 on the vascular gradient scale.
Scores of agents are compared with scores of controls.
7TABLE 1 VASCULAR GRADIENT 0 no vascularity 1 some microvascular
movement 2* richly vascularized zone approximately 2 mm in diameter
3* richly vascularized zone extending beyond the disk (6 mm in
diameter) *indicates a positive angiogenesis response
Example 35
Silk Suture Coated with Magnetically Active Particles
[11267] The end of a piece of silk 5-0 suture was immersed in a THF
solution of CHRONOFLEX AL 85A polyurethane solution (about 10%
w/v). The silk was removed, and the coated end was dipped into a
vial containing magnetically active microparticles. The coated silk
end was removed, and the particles were further embedded into the
polyurethane coating by rolling the end between two fingertips. The
solvent was removed by air-drying.
Example 36
Silk Suture Coated with Magnetically Active Beads
[11268] The end of a piece of silk 5-0 suture was immersed in a THF
solution of CHRONOFLEX AL 85A polyurethane solution (about 10% w/v)
that contained approximately 5% w/w (beads to polymer) magnetic
beads. The silk was removed, and the coated end was dipped into a
vial containing magnetically active microparticies. The coated silk
end was removed, and the particles were further embedded into the
polyurethane coating by rolling the end between two fingertips. The
solvent was removed by air-drying.
Example 37
In-Vivo Evaluation of Perivascular Pu Films Coated with Degummed or
Virgin Silk Strands
[11269] Wistar rats weighing 300 g to 400 g are anesthetized with
halothane. The skin over the neck region is shaved and the skin is
sterilized. A vertical incision is made over the trachea and the
left carotid artery is exposed. A polyurethane film covered with
degummed silk strands, virgin silk strands or a control uncoated PU
film is wrapped around a distal segment of the common carotid
artery. The wound is closed and the animal is recovered.
[11270] After 28 days, the rats are sacrificed with carbon dioxide
and pressure-perfused at 100 mmHg with 10% buffered formaldehyde.
Both carotid arteries are harvested and processed for histology.
Serial cross-sections will be cut every 2 mm in the treated left
carotid artery and at corresponding levels in the untreated right
carotid artery. Sections are stained with H&E and Movat's
stains to evaluate tissue growth around the carotid artery.
Thickness of perivascular granulation tissue is quantified by
computer-assisted morphometric analysis. Both types of silk
markedly increased granulation tissue growth around the blood
vessel to the same extent. The silk strands in both groups has
broken down into small particles (approximately 30 um in diameter)
scattered around the blood vessel and surrounded by giant cells,
macrophages, proteoglycan matrix and blood vessels. These features
are typical of a foreign body response. The area covered by the
foreign body response was more variable in the virgin silk group
than in the degummed silk group. See FIGS. 12, 13 and 14.
Example 38
Preparation of Silk Powder Using a Cryomill
[11271] Fibers of degummed silk were cut into pieces approximately
1-2 cm in length. The material was then milled to a powder using a
cryomill (Spex Certiprep Freezer/Mill--Model 6850). A portion of
the milled powder was then sieved through a series of different
sized metal sieves to obtain silk powder of different size
ranges.
Example 39
Electrospinning of Silk-Loaded Material
[11272] 20% solutions of PLGA (50:50, Mw.sup..about. 54,000) are
prepared by dissolving 2 g PLGA into 10 mL DCM. Various amounts of
silk powder (25-53 um) are added to each solution such that the
silk percentage of the polymers ranges from 2% to 50%. Each
solution is then loaded into a 10 ml syringe fitted with a 18 gauge
needle. The syringe is then loaded into a syringe pump and 20 kV
positive high voltage (by Glassman High Voltage, Inc.) is applied
on the syringe needle. The grounded target drum is a rotating drum
that has a diameter of about 12 cm. The syringe pump is set to pump
at 25 uL per minute and the drum is rotated at approximately 250
rpm. The distance from the tip of the needle to the outside of the
drum surface is about 14 cm. The rotating drum is moved from side
to side during the spinning process such that the drum is virtually
completely covered in the spun material. After the spinning process
is completed, a razor blade is used to make a cut through the
entire length of the spun material. The material is removed from
the drum and is further dried in a vacuum oven for 24 hours.
Example 40
MIC (Minimum Inhibitory Concentration) Determination by Microtitre
Broth Dilution Method
[11273] A. MIC Assay of Various Gram Negative and Positive
Bacteria
[11274] MIC assays were conducted essentially as described by
Amsterdam, D. 1996, "Susceptibility testing of antimicrobials in
liquid media," p. 52-111. In Loman, V., ed. Antibiotics in
laboratory medicine, 4th ed. Williams and Wilkins, Baltimore, Md.
Briefly, a variety of compounds were tested for antibacterial
activity against isolates of P. aeruginosa, K. pneumoniae, E. coli,
S. epidermidus and S. aureus in the MIC (minimum inhibitory
concentration assay under aerobic conditions using 96 well
polystyrene microtitre plates (Falcon 1177), and Mueller Hinton
broth at 37.degree. C. incubated for 24 h. (MHB was used for most
testing except C721 (S. pyogenes), which used Todd Hewitt broth,
and Haemophilus influenzae, which used Haemophilus test medium
(HTM)) Tests were conducted in triplicate. The results are provided
below in Table 2.
8TABLE 2 MINIMUM INHIBITORY CONCENTRATIONS OF THERAPEUTIC AGENTS
AGAINST VARIOUS GRAM NEGATIVE AND POSITIVE BACTERIA Bacterial
Strain P. aeruginosa K. pneumoniae E. coli S. aureus PAE/K799
ATCC13883 UB1005 ATCC25923 S. epidermidis S. pyogenes H187 C238
C498 C622 C621 C721 Wt wt wt wt wt wt Drug Gram - Gram - Gram -
Gram + Gram + Gram + doxorubicin 10.sup.-5 10.sup.-6 10.sup.-4
10.sup.-5 10.sup.-6 10.sup.-7 mitoxantrone 10.sup.-5 10.sup.-6
10.sup.-5 10.sup.-5 10.sup.-5 10.sup.-6 5-fluorouracil 10.sup.-5
10.sup.-6 10.sup.-6 10.sup.-7 10.sup.-7 10.sup.-4 methotrexate N
10.sup.-6 N 10.sup.-5 N 10.sup.-6 etoposide N 10.sup.-5 N 10.sup.-5
10.sup.-6 10.sup.-5 camptothecin N N N N 10.sup.-4 N hydroxyurea
10.sup.-4 N N N N 10.sup.-4 cisplatin 10.sup.-4 N N N N N
tubercidin N N N N N N 2- N N N N N N mercaptopurine 6- N N N N N N
mercaptopurine Cytarabine N N N N N N Activities are in Molar
concentrations Wt = wild type N = No activity
[11275] B. MIC of Antibiotic-Resistant Bacteria
[11276] Various concentrations of the following compounds,
mitoxantrone, cisplatin, tubercidin, methotrexate, 5-fluorouracil,
etoposide, 2-mercaptopurine, doxorubicin, 6-mercaptopurine,
camptothecin, hydroxyurea and cytarabine were tested for
antibacterial activity against clinical isolates of a methicillin
resistant S. aureus and a vancomycin resistant pediocoocus clinical
isolate in an MIC assay as described above. Compounds which showed
inhibition of growth (MIC value of <1.0.times.10-3) included:
mitoxantrone (both strains), methotrexate (vancomycin resistant
pediococcus), 5-fluorouracil (both strains), etoposide (both
strains), and 2-mercaptopurine (vancomycin resistant
pediococcus).
Example 41
Coating of a Hip Implant with Silk/PLGA
[11277] A solution of 5 g PLGA (50:50, IV=0.15, Birmingham
Polymers, Inc.) is dissolved in 100 mL dichloromethane. 1 g of
powdered silk (25-53 um, prepared using the cryomill as sieving as
described above) is mixed into the solution. The hip implant
(SECUR-FIT HA, Stryker Orthopaedics) is placed in a clamp system
such that the ball segment of the hip implant is secured in the
clamp. The clamp is then secured to an overhead stirrer (Fisher
Scientific). The stirrer is set to a speed of about 30 rpm. The
silk/PLGA solution is placed in a glass TLC spray device
(Sigma-Aldrich Corp). Approx. 1/3 of the implant below the polished
section of the implant is coated with the silk/PLGA using the TLC
spray device (connected to a nitrogen tank). The spray device is
swirled during the spraying process to ensure that the silk is
evenly dispersed in the PLGA solution. The rate of spray
application is controlled such that the solution does not drip off
the device. Once an initial coating is accomplished, the spraying
process is stopped and the device is air dried. If required the
spray coating/drying process can be repeated until the desired
thickness is accomplished. After the final air drying step, the
device is removed from the clamp and is placed in a vacuum oven.
The implant is dried for 6 hours under vacuum. Other examples of
fibrosing agents that may be similarly coated onto a hip implant
device include: fibronectin, talc, silica, starch, poly(ethyl
cyanoacrylate), polylysine, bleomycin, and CTGF. Other implant
devices such as a knee implant, shoulder implant and a digit
implant can be coated in a manner similar to that described
above.
Example 42
Coating of a Hip Implant with Silk/Cyclosporine A/PLGA
[11278] A solution of 5 g PLGA (50:50, IV=0.15, Birmingham
Polymers, Inc.) is dissolved in 100 mL chloroform. 1 g of powdered
silk (25-53 um, prepared using the cryomill as sieving as described
above) is mixed into the solution. 0.5 mg cyclosporine A is added
to the solution. The hip implant (SECUR-FIT HA, Stryker
Orthopaedics) is placed in a clamp system such that the ball
segment of the hip implant is secured in the clamp. The clamp is
then secured to an overhead stirrer (Fisher Scientific). The
stirrer is set to a speed of about 30 rpm. The silk/PLGA solution
is placed in a glass TLC spray device (Sigma-Aldrich Corp). Approx.
1/3 of the implant below the polished section of the implant is
coated with the silk/PLGA using the TLC spray device (connected to
a nitrogen tank). The spray device is swirled during the spraying
process to ensure that the silk is evenly dispersed in the PLGA
solution. The rate of spray application is controlled such that the
solution does not drip off the device. Once an initial coating is
accomplished, the spraying process is stopped and the device is air
dried. If required the spray coating/drying process can be repeated
until the desired thickness is accomplished. After the final air
drying step, the device is removed from the clamp and is placed in
a vacuum oven. The implant is dried for 6 hours under vacuum. Other
examples of fibrosing agents that may be similarly coated onto a
hip implant device include: talc, silica, starch, fibronectin,
poly(ethyl cyanoacrylate), polylysine, bleomycin, and CTGF. Other
implant devices such as a knee implant, shoulder implant and a
digit implant can be coated in a manner similar to that described
above.
Example 43
Coating of a Hip Implant with Silk
[11279] A silk solution is prepared by adding 10 g virgin silk
fibers to 100 mL hexafluoroisopropanol (HFIP). The solution is
allowed to stir for 48 hours at room temperature. The hip implant
(SECUR-FIT HA, Stryker Orthopaedics) is placed in a clamp system
such that the ball segment of the hip implant is secured in the
clamp. The clamp is then secured to an overhead stirrer (Fisher
Scientific). The stirrer is set to a speed of about 30 rpm. A
Pasteur pipette is used to drip the silk/HFIP solution onto the
hydroxyapatite (HA) coated portion of the hip implant. The volume
added with each drop is such that the solution does not drip from
the implant. Once the HA coating is wetted with the silk/HFIP
solution, the material application is stopped and the implant is
allowed to air dry. The process is repeated again and after the
drying step, the device is removed from the clamp and is placed in
a vacuum oven. The implant is dried for 6 hours under vacuum. Other
examples of fibrosing agents that may be similarly coated onto a
hip implant device include: talc, silica, starch, fibronectin,
poly(ethyl cyanoacrylate), polylysine, bleomycin, and CTGF. Other
implant devices such as a knee implant, shoulder implant and a
digit implant can be coated in a manner similar to that described
above.
Example 44
Coating of an Endosteal Implant with Silk/Plga
[11280] A solution of 5 g PLGA (50:50, IV=0.15, Birmingham
Polymers, Inc.) is dissolved in 100 mL dichloromethane. 1 g of
powdered silk (25-53 um, prepared using the cryomill as sieving as
described above) is mixed into the solution. The endosteal implant
is placed in a clamp system such that the threaded section is
readily accessible. The clamp is then secured to an overhead
stirrer (Fisher Scientific). The stirrer is set to a speed of about
30 rpm. The silk/PLGA solution is placed in a glass TLC spray
device (Sigma-Aldrich Corp). The threaded section of the implant is
coated with the silk/PLGA using the TLC spray device (connected to
a nitrogen tank). The spray device is swirled during the spraying
process to ensure that the silk is evenly dispersed in the PLGA
solution. The rate of spray application is controlled such that the
solution does not drip off the device. Once an initial coating is
accomplished, the spraying process is stopped and the device is air
dried. If required the spray coating/drying process can be repeated
until the desired thickness is accomplished. After the final air
drying step, the device is removed from the clamp and is placed in
a vacuum oven. The implant is dried for 6 hours under vacuum. Other
examples of fibrosing agents that may be similarly coated onto the
implant device include: talc, silica, starch, fibronectin,
poly(ethyl cyanoacrylate), polylysine, bleomycin, and CTGF.
Example 45
Coating of an Endosteal Implant with Silk/PLGA
[11281] A solution of 10 g PLGA (50:50, IV=0.15, Birmingham
Polymers, Inc.) is dissolved in 100 mL dichloromethane. The
threaded portion of the endosteal implant is dipped into the PLGA
solution. The coated device is partially dried and then the silk
powder is sprinkled onto the coated section of the coated implant.
The implant is then rolled on a TEFLON sheet such that the silk
particles are embedded into the PLGA coating. The implant is then
air dried for 3 hours. After the air drying step, the device is
placed in a vacuum oven. The implant is dried for 6 hours under
vacuum. Other examples of fibrosing agents that may be similarly
coated onto the implant device include: talc, silica, starch,
fibronectin, poly(ethyl cyanoacrylate), polylysine, bleomycin, and
CTGF.
Example 46
Coating of an Intramedullary Pin with Silk/PLGA
[11282] A solution of 10 g PLGA (50:50, IV=0.25, Birmingham
Polymers, Inc.) is dissolved in 100 mL dichloromethane. The lower
half of a intramedullary pin (cat #: 167430000, Sanatmetal) implant
is dipped into the PLGA solution. The coated device is partially
dried and then the silk powder is sprinkled onto the coated section
of the coated implant. The implant is then rolled on a Teflon sheet
such that the silk particles are embedded into the PLGA coating.
The implant is then air dried for 3 hours. After the air drying
step, the device is placed in a vacuum oven. The implant is dried
for 6 hours under vacuum. Other examples of fibrosing agents that
may be similarly coated onto the implant device include: talc,
silica, starch, fibronectin, poly(ethyl cyanoacrylate), polylysine,
bleomycin, and CTGF.
Example 47
Coating of an Intramedullary Pin with Silk/POLYURETHANE
[11283] A solution of 10 g CHRONOFLEX AL 85A (CT Biomaterials) is
dissolved in 100 mL THF. The lower half of a intramedullary pin
(cat #: 167430000, Sanatmetal) implant is dipped into the
polyurethane solution. The coated device is partially dried and
then the silk powder is sprinkled onto the coated section of the
coated implant. The implant is then rolled on a TEFLON sheet such
that the silk particles are embedded into the polyurethane coating.
The implant is then air dried for 3 hours. After the air drying
step, the device is placed in a vacuum oven. The implant is dried
for 6 hours under vacuum. Other examples of fibrosing agents that
may be similarly coated onto the implant device include: talc,
silica, starch, fibronectin, poly(ethyl cyanoacrylate), polylysine,
bleomycin, and CTGF.
Example 48
Coating of an Intramedullary Pin with Silk/PLGA
[11284] A solution of 10 g PLGA (50:50, IV=0.25, Birmingham
Polymers, Inc.) is dissolved in 100 mL dichloromethane. A stainless
steel wire is looped through the top hole of a broad bone plate
(cat #: 934016005, Sanatmetal). The implant is dipped into the PLGA
solution. The coated device is partially dried and then the silk
powder is sprinkled onto the coated section of the coated implant.
The implant is then air dried for 3 hours. After the air drying
step, the device is placed in a vacuum oven. The implant is dried
for 6 hours under vacuum. Other examples of fibrosing agents that
may be similarly coated onto the implant device include: talc,
silica, starch, fibronectin, poly(ethyl cyanoacrylate), polylysine,
bleomycin, and CTGF.
Example 49
Coating of a Gastric Restriction Device with TALC/Polyurethane
[11285] A solution of 10 g CHRONOFLEX AL 85A (CT Biomaterials) is
dissolved in 100 mL THF. The outer surface of the ring portion of a
BIOENTERICS LAP-BAND System (Inamed Health) is dipped into the
polyurethane solution. The coating is air dried until it is tacky
at which point talc (hydrous magnesium silicate, powder particle
size 10 .mu.m, Aldrich Corp.) is sprinkled over the tacky coating.
The device is gently shaken to remove the excess material. A TEFLON
rod is then gently rolled over the surface to further embed the
talc into the coating. The implant is then air dried for 2 hours.
After the air drying step, the device is placed in a vacuum oven.
The implant is dried for 24 hours under vacuum. Other examples of
fibrosing agents that may be similarly coated onto the implant
device include: silica, fibronectin, starch, silk, poly(ethyl
cyanoacrylate), polylysine, bleomycin, and CTGF.
Example 50
Coating of a Gastric Restriction Device with Silk/PLGA
[11286] A solution of 10 g PLGA (50:50, IV=0.25, Birmingham
Polymers, Inc.) is dissolved in 100 mL ethyl acetate. The outer
surface of the ring portion of the BioEnterics LAP-BAND System
(Inamed Health) is dipped into the polyurethane solution. The
coating is air dried until it is tacky at which point silk powder
(25-53 um, Prepared using a cryomill and sieves) is sprinkled over
the tacky coating. The device is gently shaken to remove the excess
material. A TEFLON rod is then gently rolled over the surface to
further embed the silk into the coating. The implant is then air
dried for 2 hours. After the air drying step, the device is placed
in a vacuum oven. The implant is dried for 24 hours under vacuum.
Other examples of fibrosing agents that may be similarly coated
onto the implant device include: talc, silica, fibronectin, starch,
poly(ethyl cyanoacrylate), polylysine, bleomycin, and CTGF.
Example 51
Coating of a Soft Palate Implant Device with Silk/PLGA
[11287] A solution of 2 g PLGA (50:50, IV=0.15, Birmingham
Polymers, Inc.) is dissolved in 100 mL ethyl acetate. The end of a
PILLAR palatal implant (Restore Medical, Inc) is held using clamp.
The clamp is then secured to an overhead stirrer (Fisher
Scientific). The stirrer is set to a speed of about 30 rpm. The
PLGA solution is placed in a glass TLC spray device (Sigma-Aldrich
Corp) and the device is sprayed with the PLGA solution until a thin
coating of PLGA covered the device. The coating is air dried until
it is tacky. Using a pair of tweezers, the device is removed from
the clamp and silk powder (25-53 um, prepared using a cryomill and
sieves) is sprinkled over the tacky coating. The device is gently
shaken to remove the excess material. The implant is then air dried
for 2 hours. After the air drying step, the device is placed in a
vacuum oven. The implant is dried for 24 hours under vacuum. Other
examples of fibrosing agents that may be similarly coated onto the
implant device include: talc, silica, starch, poly(ethyl
cyanoacrylate), polylysine, bleomycin, and CTGF.
Example 52
Coating of a Surgical Mesh with Talc/Polyurethane
[11288] A solution of 10 g CHRONOFLEX AL 85A (CT Biomaterials) is
dissolved in 100 mL THF. 1 g talc (hydrous magnesium silicate,
powder particle size 10 .mu.m, Aldrich Corp.) is then added to the
solution. A PROCEED Surgical Mesh (Ethicon) layed flat onto a piece
of silicone coated release liner. The silk/PLGA solution is placed
in a glass TLC spray device (Sigma-Aldrich Corp). The surface of
the mesh is then coated with the polyurethane/talc solution using
the TLC spray device (connected to a nitrogen tank). The spray
device is swirled during the spraying process to ensure that the
talc is evenly dispersed in the polyurethane solution. The rate of
spray application is controlled such that the solution does not
drip off the device. Once an initial coating is accomplished, the
spraying process is stopped and the device is air dried. If
required the spray coating/drying process can be repeated until the
desired thickness is accomplished. After the final air drying step,
the device is removed from the clamp and is placed in a vacuum
oven. The implant is dried for 6 hours under vacuum. Other examples
of fibrosing agents that may be similarly coated onto a hip implant
device include: talc, silica, starch, silk, poly(ethyl
cyanoacrylate), polylysine, bleomycin, and CTGF.
Example 53
Coating of a Surgical Mesh with Silk/PLGA
[11289] A solution of 2 g PLGA (50:50, IV=0.15, Birmingham
Polymers, Inc.) is dissolved in 100 mL ethyl acetate. 1 g of
powdered silk (25-53 um, prepared using the cryomill as sieving as
described above) is mixed into the solution. A Bard Mesh (Flat
Sheets, Cat # 0112680 3".times.6" (7.5 cm.times.15 cm), DAVOL) laid
flat onto a piece of silicone coated release liner. The silk/PLGA
solution is placed in a glass TLC spray device (Sigma-Aldrich
Corp). The surface of the mesh is then coated with the PLGA/silk
solution using the TLC spray device (connected to a nitrogen tank).
The spray device is swirled during the spraying process to ensure
that the silk is evenly dispersed in the PLGA solution. Once an
initial coating is accomplished, the spraying process is stopped
and the device is air dried. If required the spray coating/drying
process can be repeated. After the final air drying step, the mesh
is placed in a vacuum oven and is dried for 6 hours under vacuum.
Other examples of fibrosing agents that may be similarly coated
onto the mesh include: talc, fibronectin, silica, starch,
poly(ethyl cyanoacrylate), polylysine, bleomycin, and CTGF.
Example 54
Incorporation of Silk into a Surgical Mesh
[11290] A Bard Hernia Mesh (Flat Sheets, Cat # 0112680 3".times.6"
(7.5 cm.times.15 cm), DAVOL) is laid flat in a sheet of glass.
Several silk sutures (PERMA-HAND Silk Suture--Taper Point, Cat:
7730G, Ethicon) are then sewn onto the mesh by inserting the needle
through the mesh from one side if the mesh to the other side of the
mesh. The silk is traversed through the mesh at least 4 times for
each suture. The excess suture material is the cut away.
Example 55
Incorporating Silk onto an Embolization Coil
[11291] A 2 ply silk thread is looped around the platinum wire of a
detachable TORNADO embolization coil (Cook, Inc) and then a knot is
tied to secure the silk to the platinum coil. This process is
repeated several times until the amount of silk present accounts
for about 5% of the fibers present.
Example 56
Coating of a Septal Occlusion Device with Silk
[11292] A 5% silk solution in HFIP is prepared by adding 1 g virgin
silk yard to 20 mL HFIP. The solution is stirred for 48 hours. The
resultant solution is then dripped onto the PTFE portion of a HELEX
septal occluder device (W. L. Gore). Once most of the PTFE protion
of the device had been in contact with the HFIP/Silk solution, the
device is air dried and is then vacuum dried for 24 hours.
Example 57
Coating of a Septal Occlusion Device with Polylysine
[11293] A 2% solution of poly(Lysine) [poly-D-lysine hydrobromide,
mol wt 150,000-300,000 Sigma-Aldrich] is prepared by dissolving 0.1
g in 2 mL deionized water. The solution is poured into a small
metal tray. An AMPLATZER septal occluder (AGA Medical Corporation,
USA) is then dipped into the solution and is covered in the
solution by using a Pasteur pipetted squirt the solution over the
device. The device is then removed from the tray and is placed on a
TEFLON sheet and is allowed to air dry. The device is then dried
under vacuum for 24 hours.
Example 58
Coating of a Fallopian Tube Implant with Silk/PLGA
[11294] A solution of 2 g PLGA (50:50, IV=0.15, Birmingham
Polymers, Inc.) is dissolved in 100 mL ethyl acetate. 1 g of
powdered silk (25-53 um, prepared using the cryomill as sieving as
described above) is mixed into the solution. The "stent" portion of
the ECLIPSE permanent contraceptive device (Ovion, Redwood City,
Calif.) is clamped using a pair of tweezers and a wire strand. The
tweezers are then secured to an overhead stirrer (Fisher
Scientific). The stirrer is set to a speed of about 45 rpm. The
silk/PLGA solution is placed in a glass TLC spray device
(Sigma-Aldrich Corp). Approximately {fraction (1/3)} of the implant
below the polished section of the implant is coated with the
silk/PLGA using the TLC spray device (connected to a nitrogen
tank). The spray device is swirled during the spraying process to
ensure that the silk is evenly dispersed in the PLGA solution. The
rate of spray application is controlled such that the solution does
not drip off the device. Once an initial coating is accomplished,
the spraying process is stopped and the device is air dried. If
required the spray coating/drying process can be repeated until the
desired thickness is accomplished. After the final air drying step,
the device is removed from the clamp and is placed in a vacuum
oven. The implant is dried for 6 hours under vacuum. Other examples
of fibrosing agents that may be similarly coated onto a device
include: talc, silica, starch, fibronectin, poly(ethyl
cyanoacrylate), polylysine, bleomycin, and CTGF.
Example 59
Coating of a Vas Deferens Clip with Silk/PLGA
[11295] A solution of 2 g PLGA (50:50, IV=0.15, Birmingham
Polymers, Inc.) is dissolved in 100 mL ethyl acetate. A vas
deferens clip (VASCLIP, VMBC, LLC, Roseville, Minn.) is dipped into
the PLGA solution and is air dried until it is tacky. The clip is
then added to powdered silk (25-53 um, prepared using the cryomill
as sieving) that is in a beaker. The clip is shaken in the beaker
with the powdered silk. The clip is removed from the beaker of silk
and gently shaken to remove excess silk. A TELFON rod is rolled
over the surface of the coated clip to embed the silk powder
further into the coating. The clip is then air dried for 6 hours
after which it is vacuum dried for 24 hours.
[11296] Other examples of fibrosing agents that may be similarly
coated onto a device include: talc, silica, starch, fibronectin,
poly(ethyl cyanoacrylate), polylysine, bleomycin, and CTGF.
Example 60
Incorporation of Silk into a Bulking Agent
[11297] 50 mg powdered silk (25-53 um, prepared using the cryomill
as sieving) is added to 2.5 mL of a glutaradehyde crosslinked
bovine collagens solution (35 mg/mL) [CONTIGEN, CR Bard]. The
solution is vortexed to produce the final suspension. Other
examples of fibrosing agents that may be similarly coated onto a
device include: talc, silica, fibronectin, starch, poly(ethyl
cyanoacrylate), polylysine, bleomycin, and CTGF.
Example 61
Coating of Silk onto a Prosthetic Anal Sphincter Device
[11298] A solution of 10 g CHRONOFLEX AL 85A (CT Biomaterials) is
dissolved in 100 mL THF. The cuff portion of an ACTICON
NEOSPHINCTER is placed on a TELFON sheet. The silk/polyurethane
solution is placed in a glass TLC spray device (Sigma-Aldrich
Corp). The cuff portion of the implant is coated with a thin
coating of the silk/polyurethane using the TLC spray device
(connected to a nitrogen tank). Once an initial coating is
accomplished, the spraying process is stopped and the device is air
dried to produce a tacky coating. Powdered silk (25-53 um, prepared
using the cryomill as sieving) is then sprinkled over the tacky
coating. A TELFON rod is then rolled over the surface of the device
to aid in the embedding of the silk into the coating. The excess
silk powder is then shaken off the device. The device is air dried
for 24 hours after which it is dried under vacuum for 24 hours.
Other examples of fibrosing agents that may be similarly coated
onto a device include: talc, silica, fibronectin, starch,
poly(ethyl cyanoacrylate), polylysine, bleomycin, and CTGF.
Example 62
Incorporation of Silk onto an External Fixation Device
[11299] A solution of 10 g PLGA (50:50, IV=0.15, Birmingham
Polymers, Inc.) is dissolved in 100 mL dichloromethane. 1 g of
powdered silk (25-53 um, prepared using the cryomill as sieving as
described above) is mixed into the solution. The through skin
components (The HOFFMANN II HYBRID EXTERNAL FIXATION System,
Stryker) that screw into the bone are dipped into the PLGA/Silk
solution. The lower 1/5 of these pins are coated. The coated pins
are air dried and then vacuum dried.
Example 63
Incorporation of Silk into Surgical Film Implant
[11300] A 10% solution of a 70:30 PLLA:PDLLA polymer (RESOMER LR
708, Boehringer Ingelheim, KG, Germany) is prepared by dissolving 1
g of the polymer in 10 mL DCM. 1 g powdered silk (25-53 um,
prepared using the cryomill and sieving) is added to the solution.
The solution is stirred for 1 hour. The solution is cast into a
film on a release liner using a 40 mil casting knife. The film is
dried in forced-air oven (50.degree. C., 3 hours) and then in a
vacuum oven for 24 hours.
Example 64
Dripped-on Cyclosporine a Samples
[11301] A polyurethane (PU) (CHRONOFLEX AL 85A) is dissolved in
tetrahydrofuran (THF) to form a 20% solution (20 mL). The PU film
is prepared by casting the PU solution on release liner (using
40MIL opening knife). The film is dried in forced-air oven
(50.degree. C.) and then in a vacuum oven. The final film thickness
is about 100-120 .mu.m). Cyclosporin-A is dissolved in ethanol (500
ug/mL) to form a cyclosporin-A ethanol solution. A 50 .mu.l aliquot
of cyclosporin-A solution is dripped onto the 8.times.8 mm2
(precut) PU film. The ethanol is evaporated in fume hood and the PU
samples are further dried in vacuum oven.
Example 65
Encapsulated Cyclosporine A Samples
[11302] A 20% polyurethane (CHRONOFLEX AL 85A) solution in THF (2 g
PU in 10 mL THF, 20 mL glass scintillation vial) is prepared. 230
uL of a 100 ug/mL cyclosporine A/chloroform solution is added to
the PU solution. The solution is stirred using a magnetic stirrer
for 2 hours. The PU/cyclosporine A solution is cast into a film on
a release liner using a 40 mil casting knife. The film is dried in
forced-air oven (50.degree. C.) and then in a vacuum oven. The
final film thickness is about 100-120 .mu.m).
Example 66
Release Study and Total Concent Analysis for Cyclosporin from
Polyurethane Film
[11303] The release of cyclosporine A from a polyurethane film is
analyzed by HPLC using the following parameters.
9 Mobile Phase 35:65:5:0.1 (water/acetonitrile,
tert-butylmethylether, phosphoric acid) Wavelength 210 nm Column
ACE C18 150 .times. 4.6 mm 5 .mu.m Flow rate 1.2 mL/min Diluent for
1:1 (acetonitrile/water) samples
[11304] Standards are prepared as follows: Approximately 25 mg of
cyclosporine is weighted into a 25 mL volumetric flask. A diluent
(1:1 acetonitrile/water) is added to dissolve the cyclosporine and
diluent is added to achieve the correct volume. The following
dilustions (shown in the table below) are made to obtain standards
of 0.2, 0.5, 2, 5, 10 and 20 .mu.g/mL.
10 Stock solution Dilution Final volume Final concentration
concentration (.mu.g/mL) volume (mL) (mL) (.mu.g/mL) 1000 8 10 800
1000 5 10 500 1000 3 10 300 1000 2 10 200 1000 1 10 100 100 1 10 10
500 1 10 50 50 1 10 0.5 800 1 10 80 80 1 10 0.8 200 1 10 20 20 1 10
2
[11305] Release Studies:
[11306] Release studies are performed as follows. A PU film is cut
into 1 cm.times.1 cm piece, if not already this size, and weighed
accurately into a 15 cm test tube. 14 mL of release media are
dispensed into each test tube containing the sample, capped, and
placed on a rotator at 37.degree. C. until next time point. The
time points are 5 hours, 1 day, 2 days, 3 days, 4 days, 5 days and
then every other day after the first week until drug is not
detected or until otherwise decided. At each time point, the sample
is transferred into a new test tube and 14 mL of release media are
added. The sample is placed back into the 37.degree. C. oven until
the next time point. The release media solution is injected at
various time points directly onto the HPLC column for analysis.
[11307] Total Content Analysis:
[11308] A PU film is cut into 1 cm.times.1 cm piece, if not already
this size, and weigh accurately into a 15 cm test tube. 0.5 mL of
choloform is added to each test tube and completely dissolve the
sample. Once the sample is dissolved, 6.0 mL of acetonitrile is
added to each sample. The sample is capped and shaken vigorously to
precipitate the polyurethane. The sample is centrifuged at 2500 rpm
for 10 minutes. 5.0 mL of the supernatant is transferred into a
clean test tube and dried under nitrogen at 35.degree. C. The dried
samples are reconstituted in 1.0 mL of acetonitrile and injected
into the HPLC. The results of the release study for polyurethane
films loaded with 1.25% and 0.125% cyclosporine are shown in FIG.
15.
[11309] From the foregoing, it is appreciated that, although
specific embodiments of the invention have been described herein
for purposes of illustration, various modifications may be made
without deviating from the spirit and scope of the invention.
Accordingly, the invention is not limited except as by the appended
claims.
[11310] All of the above U.S. patents, U.S. patent application
publications, U.S. patent applications, foreign patents, foreign
patent applications and non-patent publications referred to in this
specification and/or listed in the Application Data Sheet are
incorporated herein by reference, in their entirety.
* * * * *
References