U.S. patent application number 14/877087 was filed with the patent office on 2016-01-28 for bioabsorbable medical device with coating.
The applicant listed for this patent is ORBUSNEICH MEDICAL, INC.. Invention is credited to Robert J. Cottone.
Application Number | 20160022452 14/877087 |
Document ID | / |
Family ID | 39319054 |
Filed Date | 2016-01-28 |
United States Patent
Application |
20160022452 |
Kind Code |
A1 |
Cottone; Robert J. |
January 28, 2016 |
BIOABSORBABLE MEDICAL DEVICE WITH COATING
Abstract
A biodegradable, bioabsorbable medical device with a coating for
capturing progenitor endothelial cells in vivo and delivering a
therapeutic agent at the site of implantation. The coating on the
medical device is provided with a biabsorbable polymer composition
such as a bioabsorbable polymer, copolymer, or terpolymer, and a
copolymer or terpolymer additive for controlling the rate of
delivery of the therapeutic agent.
Inventors: |
Cottone; Robert J.; (Davie,
FL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ORBUSNEICH MEDICAL, INC. |
Ft. Lauderdale |
FL |
US |
|
|
Family ID: |
39319054 |
Appl. No.: |
14/877087 |
Filed: |
October 7, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14158217 |
Jan 17, 2014 |
9211205 |
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14877087 |
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13098850 |
May 2, 2011 |
8642068 |
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14158217 |
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11875887 |
Oct 20, 2007 |
7959942 |
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13098850 |
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60862409 |
Oct 20, 2006 |
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Current U.S.
Class: |
623/1.16 |
Current CPC
Class: |
A61F 2/88 20130101; A61F
2/89 20130101; A61F 2230/0069 20130101; A61L 31/047 20130101; A61L
31/06 20130101; A61L 27/507 20130101; A61L 27/18 20130101; A61L
2420/06 20130101; A61F 2/91 20130101; A61K 9/0024 20130101; A61L
31/044 20130101; A61L 31/06 20130101; A61L 27/34 20130101; A61L
31/046 20130101; A61F 2220/0016 20130101; A61K 2039/505 20130101;
A61F 2/915 20130101; A61K 9/0051 20130101; A61F 2/844 20130101;
A61L 31/125 20130101; A61F 2250/0067 20130101; A61L 2400/16
20130101; A61L 27/58 20130101; A61L 31/16 20130101; A61L 31/148
20130101; A61L 27/18 20130101; A61L 31/042 20130101; A61L 2300/256
20130101; C08L 67/04 20130101; A61F 2/90 20130101; C08L 67/04
20130101; A61L 27/54 20130101; A61F 2210/0004 20130101; A61L 31/10
20130101 |
International
Class: |
A61F 2/915 20060101
A61F002/915; A61L 31/10 20060101 A61L031/10; A61L 31/16 20060101
A61L031/16; A61L 31/14 20060101 A61L031/14; A61L 31/06 20060101
A61L031/06 |
Claims
1. An expandable stent, comprising bioabsorbable material and a
coating, wherein the expandable stent comprises a plurality of
first meandering strut patterns forming an interconnected mesh, and
at least one second strut pattern comprising a hoop circumferential
about the longitudinal axis of the expandable stent, wherein the
second strut pattern crystallizes when the stent is expanded, and
wherein the coating comprises a ligand.
2. The expandable stent of claim 1, wherein the second strut
pattern further comprises a through-void.
3. The expandable stent of claim 1, wherein the bioabsorbable
material comprises at least poly-L-lactide (PLLA).
4. The expandable stent of claim 1, wherein the ligand is
configured to bind target cells in vivo.
5. The expandable stent of claim 4, wherein the ligand is a small
molecule, a peptide, an antibody, antibody fragments, or
combinations thereof and the target cell is a progenitor
endothelial cell antigen.
6. The expandable stent of claim 1, wherein the bioabsorbable
matrix comprises a natural or synthetic biodegradable polymer.
7. The expandable stent of claim 1, wherein the bioabsorbable
matrix comprises at least one of the group consisting of: dextran,
tropoelastin, elastin, laminin, fibronectin, fibrin, collagen,
basement membrane proteins, and cross-linked tropoelastin.
8. The expandable stent of claim 1, comprising a pharmacological
substance.
9. The expandable stent of claim 8, wherein the pharmacological
substance is at least one of the group consisting of: cyclosporin
A, mycophenolic acid, mycophenolate mofetil acid, rapamycin,
rapamycin derivatives, biolimus A9, CCI-779, RAD 001, AP23573,
azathioprene, pimecrolimus, tacrolimus (FK506), tranilast,
dexamethasone, corticosteroid, everolimus, retinoic acid, vitamin
E, rosglitazone, simvastatins, fluvastatin, estrogen,
17.beta.-estradiol, hydrocortisone, acetaminophen, ibuprofen,
naproxen, fluticasone, clobetasol, adalimumab, sulindac,
dihydroepiandrosterone, testosterone, puerarin, platelet factor 4,
basic fibroblast growth factor, fibronectin, butyric acid, butyric
acid derivatives, paclitaxel, paclitaxel derivatives, LBM-642,
deforolimus, and probucol.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. application Ser.
No. 14/158,217, filed Jan. 17, 2014, which is a continuation of
U.S. application Ser. No. 13/098,850, filed May 2, 2011, now U.S.
Pat. No. 8,642,068, which is a continuation of U.S. patent
application Ser. No. 11/875,887, filed on Oct. 20, 2007, now U.S.
Pat. No. 7,959,942, which claims benefit of U.S. Provisional Patent
Application No. 60/862,409, filed Oct. 20, 2006. The disclosures of
all these applications are herein incorporated by reference in
their entirety.
[0002] All references cited in this specification, and their
references, are incorporated by reference herein in their entirety
where appropriate for teachings of additional or alternative
details, features, and/or technical background.
[0003] The invention relates in embodiments disclosed herein to a
novel medical device with a coating. Such device may be configured
for implantation into vessels or luminal structures within the
body. More particularly, the present invention in embodiments
relates to stents and synthetic grafts which are coated with a
controlled-release matrix comprising a medicinal substance for
direct delivery to the surrounding tissues, and a ligand attached
thereto for capturing progenitor endothelial cells that may be
found in the bodily fluids contacting the matrix (e.g.,
blood-contacting surface). The captured cells may result in the
formation of mature endothelium at site of injury. In particular, a
polymer matrix/drug/ligand-coated stent may be used, for example,
in therapy of diseases such as restenosis, artherosclerosis, and
endoluminal reconstructive therapies.
[0004] A medical device of embodiments of the present invention may
comprise a polymer composition comprising a base material formed
from, or including, a bioabsorbable polymer, copolymer, or
terpolymer. The base material may further comprise a copolymer or
terpolymer additive. One advantageous base material allows for a
"soft" breakdown mechanism allowing for the breakdown of the
component polymers to be less injurious to the surrounding
tissue.
[0005] A persistent problem associated with the use of metallic
devices such as stents in treating cardiovascular disease is the
formation of scar tissue coating of the stent at the site of
implantation the so-called process of restenosis. Moreover,
metallic or polymeric non-absorbable stents may prevent vascular
lumen remodeling and expansion. Numerous approaches have been tried
to prevent scar tissue, and reduce complement activation of the
immune response, which may be attendant to such implanted devices.
Furthermore, an advantageous implant with a reduced inflammatory
response and lower potential for trauma upon break-up of an implant
and/or its component materials may be desired. A desirable
improvement target may be found in the need for increased
flexibility of shane and structure of medical devices for
implantation, particularly into blood vessels.
[0006] Reference is made to U.S. Pat. No. 6,607,548 B2 (Inion),
issued Aug. 19, 2003, which discloses compositions that are
biocompatible and bioresorbable using a lactic acid or glycolic
acid based polymer or copolymer blended with one or more copolymer
additives. As a result, implants made from these blends are said to
be cold-bendable without crazing or cracking EP 0401844 discloses a
blend of Poly-L-lactide with Poly D-DL-lactide.
[0007] It may be argued that bioabsorbable medical devices (such as
stents) may be more suitable in the treatment of vascular disease
than non-bioabsorbable medical devices. For example, it is known
that non-biodegrable metallic stents can induce thrombosis by
irritation of the blood vessel after since they are permanently
embedded in the blood vessel. Further, their mechanical properties
may deteriorate impairing blood vessel properties.
[0008] Coated medical devices are available commercially and
approved by the FDA. For example, drug eluting stents containing
anti-cancer drugs such as rapamycin and paclitaxel are commonly
implanted into coronary arteries and have become the preferred
method for used in percutaneous coronary interventions, because of
their significant ability to reduce restenosis rates. One
limitation of drug eluting stents has been that the patient needs
to take supplemental oral drugs, such as aspirin and clopidrogel to
prevent thrombosis from occurring at an early stage after
implantation. Furthermore, the polymers used as a vehicle for drug
delivery in some devices may induce vessel irritation, endothelial
cell dysfunction, vessel hypersensitivity and chronic inflammation
at the site of stent implantation (Waksman 2006).
[0009] The present inventors have recognized that it may be
advantageous to develop a compatible polymer blends for medical
devices, such as stents and vascular synthetic grafts, which
provide a toughening mechanism to the base polymer when deployed
into the body. In one embodiment, the base polymer composition may
be used to impart additional molecular free volume to the base
polymer to affect molecular motion sufficiently to allow for
re-crystallization to occur at physiological conditions, for
example, upon the addition of molecular strain in deployment. They
have further recognized that increased molecular free volume can
also increase the rate of water uptake adding both a plasticizing
effect as well as increasing the bulk degradation kinetics. The
composition may be formulated to allow for a "soft" breakdown
mechanism such that the breakdown proceeds while being friendly to
the surrounding tissue (less inflammatory response, and rendering
lower potential for trauma upon break up of an implant). By
selecting a polymer or copolymer for either the base or the
additive or both, an enhanced hydrophilic property of the polymer
blend may reduce complement activation and minimize or prevent
opsonization. (see Dong and Feng, J of Biomedical Materials
Research part A DOI 10.1002, 2006).
SUMMARY
[0010] Disclosed in embodiments herein are biodegradable,
bioabsorbable medical devices with a coating for the treatment or
amelioration of various diseases, including vascular disease, and
conditions in particular, artherosclerosis and/or restenosis.
[0011] In one embodiment, the medical device comprises a device for
implantation into a patient for the treatment of disease. The
medical device comprises a bioabsorbable, biodegradable material,
which may be a polymer of synthetic or natural origin, which has
the ability to undergo deformation when employed in vivo, for
example, from a solid or rigid state during manufacture to a
flexible and pliable material after implantation in vivo, yet in
its pliable form is capable of maintaining the desired blood vessel
diameter upon deployment in situ.
[0012] In one embodiment, the medical device comprises a polymer
composition and/or formulation, comprising: a polymer such as a
poly(L-lactide), or a poly(D-lactide) as the base polymer, or
copolymers thereof and wherein modifying copolymers including, poly
L(or D)-lactide-co-Tri-methylene-carbonate and poly L(or
D)-lactide-co-.epsilon.-caprolactone can be used to link the base
polymers. These copolymers can be synthesized as block copolymers
or as "blocky" random copolymers wherein the lactide chain length
is sufficiently long enough to crystallize. Such polymer
compositions may allow the development of a crystal morphology that
can enhance the mechanical properties of the medical device;
enhance processing conditions, and provide potential of cross
moiety crystallization, for example, thermal cross-links. In this
embodiment, the polymer composition allows the development of the
lactide racemate crystal structure, between the L and D moieties,
to further enhance the mechanical properties of the medical
device.
[0013] In another embodiment, the medical device may comprise a
polymer composition wherein the properties of the polymer
composition can be engineered to produce a desired degradation time
of the base polymer so that the degradation time can be predicted
after implantation of the device. For example, the medical device
can comprise base polymers having enhanced degradation kinetics. In
this manner, the degradation time of the base polymer can be
shortened. For example, the starting material used as base polymer
can be a lower molecular weight composition and/or a base polymer
that is more hydrophilic or liable to hydrolytic chain
scission.
[0014] In another embodiment, medical device can comprise a polymer
composition which comprises a base copolymer wherein one polymer
moiety is sufficiently long enough and not sterically hindered to
crystallize, such as L-lactide or D-lactide with a lesser or
shorter polymer moiety, for example Glycolide or Polyethylene
Glycol (PEG), or monomethoxy-terminated PEG (PEG-MNE).
[0015] In another embodiment, compositions in addition to the base
polymer, the modifying polymer or co-polymer may also have enhanced
degradation kinetics such as with an e-caprolactone copolymer
moiety wherein the caprolactone remains amorphous with resulting
segments more susceptible to hydrolysis.
[0016] In another embodiment, the composition can incorporate PEG
copolymers, for example either AB diblock or ABA triblock with the
PEG moiety being approximately 1%. In this embodiment, the
mechanical properties of the Lactide (see Enderlie and Buchholz SFB
May 2006) are maintained. In this embodiment the incorporation of
either PEG or PEG-MME copolymers may also be used to facilitate
drug attachment to the polymer, for example in conjunction with a
drug eluding medical device.
[0017] In one embodiment, the polymer compositions are used to
manufacture medical device for implantation into a patient. The
medical devices which may have biodegradable, bioabsorbable
properties as discussed above, may include, but are not limited to
stents, stent grafts, vascular synthetic grafts, catheters,
vascular shunts, valves and the like.
[0018] The coating on the medical device of embodiments of the
present invention can comprise a bioabsorbable, biodegradable
matrix comprising a synthetic or naturally occurring polymer, or
non-polymer material, which can be applied to the medical device,
and can comprise similar base polymers as the medical device. The
coating on the medical device can further comprise a biological
and/or pharmaceutical substance, for example, drugs for delivery to
the adjacent tissues where device is implanted into the body. The
coating may also include a radiopaque material to allow for easier
identification of the medical device when placed in the body. Such
drug or pharmaceutical substances or radioopaque materials may be
bound to the matrix, for example, by reaction of such materials and
substances with end groups of a polymer comprising the matrix,
other chemical linkage (such as through linkers associated with the
polymer), by simple mixing (localized or dispersed) of the
materials and substances into the matrix, and other methods known
in the art. Such coating may be applied to the medical device
itself, or may be applied to material or fabrication from which the
medical device is made--for example applied to a tube structure
from which a stent is cut (e.g. by laser cutting, photolasing,
physical or air knife, etc.).
[0019] In another embodiment, the invention is directed to a method
of coating a medical device with the a bioabsorbable coating
composition, comprising applying one or more layers of a matrix
such as a biobsorbable polymer matrix to the medical device.
Coatings at different portions of the medical device may be the
same or different. For example in a stent, the coating located on
the outer surface of the stent may be different than the coating on
the inner section of the stent. Further, the number of layers of
coating on the outer surface of the stent might be different from
the number of layers of coating on the inside of the stent. For
example, the inner surface of a stent may have coating that breaks
down slower than the coating on the outside of the stent, or have
additional materials, or layers, associated therewith, for example
a ligand that captures cells, than the outer surface (which may for
example have drug eluting layer). Alternatively, or additionally,
the inner layer may have a different drug or biological ligand
associated therewith than the outer layer. Of course, the inner and
outer coatings may be similar or identical to one another in terms
of pharmacological/biological effect.
[0020] In one embodiment, an implantable medical device is
provided, comprising a crystallizable polymer composition and a
coating; said medical device comprising, a base polymer linked with
a modifying copolymer in the form of block copolymer or blocky
random copolymers, wherein the polymer chain length is sufficiently
long enough to allow cross-moiety crystallization; and said coating
comprising a bioabsorbable matrix and a ligand. In this embodiment,
the ligand is configured to bind target cells in vivo. The ligand
can be a small molecule, a peptide, an antibody, antibody
fragments, or combinations thereof and the target cell is a
progenitor endothelial cell antigen. In certain embodiments, the
coating comprises one or more layers, and can comprise a matrix
comprising naturally occurring or synthetic biodegradable polymer.
In this embodiment, matrix can comprise at least one of the group
consisting of: tropoelastin, elastin, laminin, fibronectin,
basement membrane proteins, and cross-linked tropoelastin.
[0021] In one embodiment, the implantable medical device comprises
a coating wherein at least one coating layer, or the implantable
medical device itself, comprises a radioopaque or radio-detectable
material. The radio-opaque material can be for example, tantalum,
iodine, and the like, which can be detected or imaged by X-ray
techniques. In some embodiments, the implantable medical device can
be impregnated with a pharmacological or biological substance. In
this embodiment, the radio-opaque material can be blended with the
pharmaceutical substance or a biological substance and the base
polymers and or attached to the polymer structure during
manufacturing.
[0022] In alternate embodiments, the implantable medical device can
comprise a tube defining a lumen, said tube having an outer surface
and an inner surface, said inner surface surrounding said lumen,
wherein the outer surface can be coated with a composition
comprising a pharmacological substance. In some embodiments, the
outer or inner surface can be coated with a composition comprising
a biological substance. In one embodiment, the pharmacological
substance is at least one of the group consisting of: cyclosporin
A, mycophenolic acid, mycophenolate mofetil acid, rapamycin,
rapamycin derivatives, biolimus A9, CCI-779, RAD 001, AP23573,
azathioprene, pimecrolimus, tacrolimus (FK506), tranilast,
dexamethasone, corticosteroid, everolimus, retinoic acid, vitamin
E, rosglitazone, simvastatins, fluvastatin, estrogen,
17.beta.-estradiol, hydrocortisone, acetaminophen, ibuprofen,
naproxen, fluticasone, clobetasol, adalimumab, sulindac,
dihydroepiandrosterone, testosterone, puerarin, platelet factor 4,
basic fibroblast growth factor, fibronectin, butyric acid, butyric
acid derivatives, paclitaxel, paclitaxel derivatives, LBM-642,
deforolimus, and probucol.
[0023] In embodiments comprising a biological substance, the
biological substance is at least one of the group consisting of:
antibiotics/antimicrobials, antiproliferative agents,
antineoplastic agents, antioxidants, endothelial cell growth
factors, smooth muscle cell growth and/or migration inhibitors,
thrombin inhibitors, immunosuppressive agents, anti-platelet
aggregation agents, collagen synthesis inhibitors, therapeutic
antibodies, nitric oxide donors, antisense oligonucleotides, wound
healing agents, therapeutic gene transfer constructs, peptides,
proteins, extracellular matrix components, vasodialators,
thrombolytics, anti-metabolites, growth factor agonists,
antimitotics, steroids, steroidal antiinflammatory agents,
chemokines, proliferator-activated receptor-gamma agonists,
proliferator-activated receptor-alpha agonists
proliferator-activated receptor-beta agonists,
proliferator-activated receptor-alpha/beta agonists,
proliferator-activated receptor-delta agonists, NF.kappa..beta.,
proliferator-activated receptor-alpha-gamma agonists, nonsterodial
antiinflammatory agents, angiotensin converting enzyme (ACE)
inhibitors, free radical scavangers, inhibitors of the CX3CR1
receptor and anti-cancer chemotherapeutic agents.
[0024] In one embodiment, the implantable medical device can
comprise a crystallizable bioabsorbable polymer composition
comprises a base polymer of from about 70% by weight of poly
(L-lactide) with 30% by weight of modifying copolymer poly
L-lactice-co-TMC.
[0025] In some embodiments, a bioabsorbable implant is provided
comprising: a crystallizable composition comprising a base polymer
of poly L-lactide or poly D-lactide linked with modifying
copolymers comprising poly L(or
D)-lactide-co-Tri-methylene-carbonate or poly L(or
D)-lactide-co-.epsilon.-caprolactone in the form of block
copolymers or as blocky random copolymers wherein the lactide chain
length is sufficiently long enough to allow cross-moiety
crystallization; and a ligand. In this embodiments, the
bioabsorbable implant can have a base polymer composition blend of
70% by weight of poly L-lactide with 30% by weight of modifying
copolymer poly L-lactice-co-TMC.
[0026] In embodiments herein, the bioabsorbable implant comprises a
ligand which can be a small molecule, a peptide, an antibody,
antibody fragments, or combinations thereof and the target cell is
a progenitor endothelial cell. In this embodiment, the
bioabsorbable an antibody or antibody fragments is specific for
binding a progenitor endothelial cell membrane antigen. The
antibodies can bind to progenitor endothelial cell membrane antigen
and can be selected from the group consisting of CD34, CD45, CD133,
CD14, CDw90, CD117, HLA-DR, VEGFR-1, VEGFR-2, CD146, CD130, CD131,
stem cell antigen, stem cell factor 1, Tie-2, MCH-H-2Kk and
MCH-HLA-DR.
[0027] In another embodiment, a bioabsorbable implant is provided,
having a tissue contacting surface and a fluid contacting surface,
said implant comprising a bioabsorbable, biocompatible first
coating for controlled release of one or more pharmaceutical
substances from said tissue contacting surface, and a second
coating comprising one or more ligands which bind to specific
molecules on cell membranes of progenitor endothelial cells on the
fluid contacting surface of the medical device. The bioabsorbable
implant can be a stent, a vascular or other synthetic graft, or a
stent in combination with a synthetic graft. In some embodiments,
the tissue contacting surface coating comprises
poly(DL-lactide-co-glycolide) and one or more pharmaceutical
substances. In other embodiments the tissue contacting surface
coating comprises poly(DL-lactide), or poly(lactide-co-glycolide),
and paclitaxel.
[0028] In one embodiment, the bioabsorbable implant comprises a
pharmaceutical substance is at least one of the group consisting of
antibiotics/antimicrobials, antiproliferative agents,
antineoplastic agents, antioxidants, endothelial cell growth
factors, smooth muscle cell growth and/or migration inhibitors,
thrombin inhibitors, immunosuppressive agents, anti-platelet
aggregation agents, collagen synthesis inhibitors, therapeutic
antibodies, nitric oxide donors, antisense oligonucleotides, wound
healing agents, therapeutic gene transfer constructs, peptides,
proteins, extracellular matrix components, vasodialators,
thrombolytics, anti-metabolites, growth factor agonists,
antimitotics, steroids, steroidal antiinflammatory agents,
chemokines, proliferator-activated receptor-gamma agonists,
proliferator-activated receptor-alpha-gamma agonists,
proliferator-activated receptor-alpha agonists,
proliferator-activated receptor-beta agonists,
proliferator-activated receptor-alpha/beta agonists,
proliferator-activated receptor-delta agonists, NF.kappa..beta.,
nonsterodial antiinfammatory agents, angiotensin converting enzyme
(ACE) inhibitors, free radical scavangers, inhibitors of the CX3CR1
receptor, and anti-cancer chemotherapeutic agents.
[0029] In other embodiments, the bioabsorbable implant comprises a
pharmaceutical substance selected from the group consisting of
cyclosporin A, mycophenolic acid, mycophenolate mofetil acid,
rapamycin, rapamycin derivatives, biolimus A9, CCI-779, RAD 001,
AP23573, azathioprene, pimecrolimus, tacrolimus (FK506), tranilast,
dexamethasone, corticosteroid, everolimus, retinoic acid, vitamin
E, rosglitazone, simvastatins, fluvastatin, estrogen,
17.beta.-estradiol, hydrocortisone, acetaminophen, ibuprofen,
naproxen, fluticasone, clobetasol, adalimumab, sulindac,
dihydroepiandrosterone, testosterone, puerarin, platelet factor 4,
basic fibroblast growth factor, fibronectin, butyric acid, butyric
acid derivatives, paclitaxel, paclitaxel derivatives, LBM-642,
deforolimus, and probucol. In one embodiment, the coating
composition can comprise poly(DL-lactide) polymer comprises from
about 50 to about 99% of the composition.
[0030] In one embodiment, the bioabsorbable implant comprising an
outer coating and an inner coating, either or both coatings
comprise multiple layers of the poly(DL-lactide) polymer,
poly(lactide-co-glycolide) copolymer, or mixture thereof and either
or both coatings comprise multiple layers of the pharmaceutical
substances.
[0031] The invention is also directed to methods of making the
biodegradable polymer compositions and methods for making the
medical devices from the polymer compositions disclosed herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0032] FIG. 1 illustrates an embodiment which consists of a
bioabsorbable medical device with a coating.
[0033] FIG. 2 depicts representative data from experiments wherein
the amount of anti-CD34 antibody was measured on bioabsorbable
polymeric tubes.
[0034] FIG. 3 is a representative example of a fluorescent
micrographs of DAPI stained Kg1a cells bound to bioabsorbable
polymer tube with a coating comprising a matrix and anti-CD34
antibodies.
[0035] FIG. 4 is a representative example of a fluorescent
micrographs of DAPI stained Kg1a cells bound to bioabsorbable
polymer tube without a coating or uncoated bioabsorbable polymer
tube.
[0036] FIG. 5 is a representative example of a fluorescent
micrographs of DAPI stained Kg1a cells bound to bioabsorbable
polymer tube pre-treated with plasma deposition step.
[0037] FIG. 6 is a bar graph which illustrates the data from the
various trials from the cell the Kg1a binding experiments using
coated and uncoated bioabsorbable polymer tubes.
[0038] FIG. 7A is a representative example of a fluorescent
micrographs of DAPI stained Kg1a cells bound to bioabsorbable
polymer stent of the invention. FIG. 7B is a representative example
of a fluorescent micrographs of DAPI stained Kg1a cells bound to a
bioabsorbable polymer stent strut shown in FIG. 7A, seen here at a
higher magnification.
[0039] FIG. 8 is an illustration of a tubular medical device
depicting an inner coating and an outer coating surrounding the
device structure. In this embodiment, the device is depicted with
multiple layers.
[0040] FIG. 9 is an illustration of a stent with a coating showing
a perspective view of a stent strut with the layer in the outer
surface and the inner, luminal surface with a coating.
DETAILED DESCRIPTION
[0041] In embodiments herein there is illustrated bioabsorbable
polymeric medical devices having a coating comprising a
bioabsorbable, biodegradable polymeric composition for delivering a
therapeutic agent, and a ligand for capturing and binding
progenitor endothelial cells. Such polymers and medical devices may
be more biocompatible and less immunogenic than prior art polymeric
medical devices.
[0042] In one embodiment, the medical device comprises a crimpable
polymeric stent, which can be inserted onto a balloon delivery
system for implantation into a tubular organ in the body, for
example, into an artery, a duct or vein. Once deployed into an
organ, the medical A balloon expandable medical device may comprise
a thermal balloon, or non-thermal balloon, and the medical device
can have a structure which is crimpable during loading and
expandable without stress crazing in physiological conditions.
[0043] In another embodiment, the medical device comprises a
structure which can orient and/or crystallize upon strain of
deployment, for example during balloon dilation, in order to
improve its mechanical properties.
[0044] In another embodiment, the products resulting from breakdown
of the polymers comprising a medical device are "friendly" or less
immunogenic to the host, for example to the vascular wall. In yet
another embodiment, the medical device comprises polymers having
slow breakdown kinetics which avoid tissue overload or other
inflammatory responses at the site of implantation. In one
embodiment, a medical device may have a minimum of 30-day retention
of clinically sufficient strength.
[0045] Medical devices of the invention, can be structurally
configured to provide the ability to change and conform to the area
of implantation to allow for the normal reestablishment of local
tissues. The medical devices can transition from solid to a
"rubbery state" allowing for easier surgical intervention, than,
for example a stainless steel stent.
[0046] The polymer composition can comprise a base polymer which
can be present from about 60% to 95% by weight, or from about 70%
to 80% by weight of the composition. In one embodiment, the polymer
formulation can comprise from about 70% by weight poly (L-lactide)
(about 1.5 to 3.5 IV or from about 2.5 to 3 IV) with the poly
L-lactide-co-TMC (80/20 w/w) (1.0 to 2.6 IV, or from about 1.4 to
1.6 IV).
[0047] In another embodiment, the polymer formulation comprises 70%
by weight triblock poly L-lactide-co-PEG (95/05 to 99/01, or from
89/2 to 99/01) (2,000 to 10,000 Mw PEG, or from about 6,000 to
8,000 Mw PEG) with the poly L-lactide-co-TMC (70/30) (1.4 to 1.6
IV).
[0048] The polymer composition can also comprise a formulation of
about 70% by weight diblock poly L-lactide-co-PEG-MME (95/05 to
99/01) (2,000 to 10,000 Mw PEG-MME, or from about 6,000 to 10,000
Mw PEG-MME) with poly L-lactide-co-TMC (70/30 w/w) (1.4 to 1.6
IV).
[0049] In one embodiment, pharmaceutical or biological compositions
can be incorporated with the polymers by for example grafting to
the polymer active sites, or coating. For example, the
pharmaceutical or biological compositions may be bound through the
end groups of a polymer chain Simple admixing into the polymer or
charge-charge interactions may also be employed to associate the
pharmaceutical or biological compositions with the polymers.
[0050] A medical device of the present invention can comprise any
medical device for implantation including stents, grafts, stent
grafts, synthetic vascular grafts, shunts, catheters, and the
like.
[0051] In embodiments disclosed herein, the medical device
comprises a stent, which is structurally configured to be deployed
into, for example, an artery or a vein, and be able to expand in
situ, and conform to the blood vessel lumen to reestablish blood
vessel continuity at the site of injury. The stent can be
configured to have many different arrangements, and may comprise
one or more of the polymeric compositions described herein, so that
it is crimpable when loading and expandable and flexible at
physiological conditions once deployed.
[0052] A biodegradable medical device of the present invention may
comprise a base polymer comprising, for example pply L-Lactide or
poly D-Lactide, a modifying co-polymer, such as poly L(or D)
lactide-co-Tri-methylene-carbonate or poly L(or
D)-lactide-co-e-caprolactone as described above.
[0053] Various embodiments of biodegradable polymeric stents,
and/or stent walls with different configuration are illustrated in
FIGS. 1-42. For example, the stent is a tubular structure
comprising struts operably designed to allow blood to traverse its
walls so that the adjacent tissues are bathed or come in contact
with it as blood flows through the area. The particular stent
design may depend on the size of the stent radially and
longitudinally.
[0054] A method of the invention comprises a method for making a
bioabsorbable polymeric implant comprising:
[0055] blending a polymer composition comprising a crystallizable
composition comprising a base polymer of poly L-lactide or poly
D-lactide linked with modifying copolymers comprising poly L(or
D)-lactide-co-Tri-methylene-carbonate or poly L(or
D)-lactide-co-e-caprolactone in the form of block copolymers or as
blocky random copolymers wherein the lactide chain length is
sufficiently long enough to allow cross-moiety crystallization;
[0056] molding said polymer composition to structurally configure
said implant; and
[0057] cutting said implant to form desired patterns.
[0058] A method for fabricating the medical device comprises:
preparing a biodegradable polymeric structure; designing said
polymeric structure to be configured to allow for implantation into
a patient; cutting said structure into patterns configured to
permit traversing of the device through openings and to allow for
crimping of the device. Of course, the patterns and material
comprising the device may be selected to allow for both crimping
and expansion.
[0059] In another embodiment of the invention, there is provided a
medical device for implanting into the lumen of a blood vessel or
an organ with a lumen, which device provides a biocompatible system
for the delivery of therapeutic agents locally in a safe and
controlled manner, and additionally induces the formation of a
functional endothelium at the site of injury, which stimulates
positive blood vessel remodeling.
[0060] One implantable medical device comprises a coating
comprising a biocompatible matrix, which can be made of a
composition for extended or controlled delivery of a pharmaceutical
substance to adjacent tissue. The coating on the medical device
further may comprise one or more ligands for capturing target cells
on a surface of the medical device (for example, the luminal
surface of a stent). Further, the coating may include native/normal
or genetically modified target cells which secrete a desired
pharmaceutical substance constitutively or when stimulated to do
so. In one embodiment, circulating progenitor endothelial cells are
the target cells which can be captured and immobilized on the
luminal or blood contacting surface of the device to restore,
enhance or accelerate the formation of a functional endothelium at
the site of implantation of the device due to blood vessel
injury.
[0061] In one embodiment, the medical device comprises, for
example, a stent, a synthetic vascular graft or a catheter having a
structure adapted for the introduction into a patient. For example,
in the embodiments wherein the medical device is a stent or graft,
the device is operably configured to have a luminal or blood
contacting surface and an outer surface which is adapted for
contacting adjacent tissue when inserted into a patient.
[0062] The medical device of the invention can be any device that
is implantable into a patient. For example, in one embodiment the
device is for insertion into the lumen of a blood vessels or a
hollowed organ, such as stents, stent grafts, heart valves,
catheters, vascular prosthetic filters, artificial heart, external
and internal left ventricular assist devices (LVADs), and synthetic
vascular grafts, for the treatment of diseases such as cancer,
vascular diseases, including, restenosis, artherosclerosis,
thrombosis, blood vessel obstruction, or any other applications
additionally covered by these devices.
[0063] The medical device of the invention can be any device used
for implanting into an organ or body part comprising a lumen, and
can be, but is not limited to, a stent, a stent graft, a synthetic
vascular graft, a heart valve, a catheter, a vascular prosthetic
filter, a pacemaker, a pacemaker lead, a defibrillator, a patent
foramen ovale (PFO) septal closure device, a vascular clip, a
vascular aneurysm occluder, a hemodialysis graft, a hemodialysis
catheter, an atrioventricular shunt, an aortic aneurysm graft
device or components, a venous valve, a sensor, a suture, a
vascular anastomosis clip, an indwelling venous or arterial
catheter, a vascular sheath and a drug delivery port. The medical
device can be made of numerous bioabsorbable materials depending on
the device, biodegradable materials such as polylactide polymers
and polyglycolide polymers or copolymers thereof are the most
suitable.
[0064] In one embodiment, the medical device comprises a coating
comprising a matrix which comprises a nontoxic, biocompatible,
bioerodible and biodegradable synthetic material. The coating may
further comprise one or more pharmaceutical substances or drug
compositions for delivering to the tissues adjacent to the site of
implantation, and one or more ligands, such as a peptide, small
and/or large molecules, and/or antibodies or combinations thereof
for capturing and immobilizing progenitor endothelial cells on the
blood contacting surface of the medical device.
[0065] In one embodiment, the implantable medical device comprises
a stent. The stent can be selected from uncoated stents available
in the art. In accordance with one embodiment, the stent is an
expandable intraluminal endoprosthesis designed and configured to
have a surface for attaching a coating for controlled or slow
release of a therapeutic substance to adjacent tissues.
[0066] In one embodiment, the controlled-release matrix can
comprise one or more polymers and/or oligomers from various types
and sources, including, natural or synthetic polymers, which are
biocompatible, biodegradable, bioabsorbable and useful for
controlled-released of the medicament. For example, in one
embodiment, the naturally occurring polymeric materials include
proteins such as collagen, fibrin, tropoelastin, elastin,
cross-linked tropoelastin and extracellular matrix component,
fibrin, fibronectin, laminin, derivatives thereof, or other
biologic agents or mixtures thereof. In this embodiment of the
invention, the naturally-occurring material can be made by genetic
engineering techniques from exogenous genes carried by vectors,
such as a plasmid vector and engineered into a host, such as a
bacterium. In this embodiment, desired polymer proteins such as
tropoelastin and elastin can be produced and isolated for use in
the matrix. In alternate embodiments, the naturally occurring
polymeric matrices can be purified from natural sources by known
methods or they can be obtained by chemical synthesis of the
protein polymer. In certain embodiments, the naturally occurring
material can be chemically modified or synthesized, for example, by
cross-linking the material such as proteins, or by methylation,
phosphorylation and the like. In another embodiment, the matrix can
comprise a denuded blood vessel or blood vessel scaffolds and/or
components thereof.
[0067] In one embodiment, the matrix may comprise a synthetic
material which include polyesters such as polylactic acid,
polyglycolic acid or copolymers and or combinations thereof, a
polyanhydride, polycaprolactone, polyhydroxybutyrate valerate, and
other biodegradable polymer, or mixtures or copolymers thereof. In
this embodiment, the matrix may comprise poly(lactide-coglycolide)
as the matrix polymer for coating the medical device. For example,
the poly(lactide-co-glycolide) composition may comprise at least
one polymer of poly-DL-co-glycolide, poly(D,L-lactide-co-glycolide)
or copolymer or mixtures thereof, and it may be mixed together with
the pharmaceutical substances to be delivered to the tissues. The
coating composition may be applied to the surface of the device
using standard techniques such as spraying, dipping, and/or
chemical vaporization. Alternatively, the
poly(lactide-co-glycolide) (PGLA) solution can be applied as a
single layer separating a layer or layers of the pharmaceutical
substance(s).
[0068] In another embodiment, the coating composition further
comprises pharmaceutically acceptable polymers and/or
pharmaceutically acceptable carriers, for example, nonabsorbable
polymers, such as ethylene vinyl acetate (EVAC) and
methylmethacrylate (MMA). The nonabsorbable polymer, for example,
can aid in further controlling release of the substance by
increasing the molecular weight of the composition thereby delaying
or slowing the rate of release of the pharmaceutical substance.
[0069] In certain embodiments, the polymer material or mixture of
various polymers can be applied together as a composition with the
pharmaceutical substance on the surface of the medical device and
can comprise a single layer. Multiple layers of composition can be
applied to form the coating. In another embodiment, multiple layers
of polymer material or mixtures thereof can be applied between
layers of the pharmaceutical substance. For example, the layers may
be applied sequentially, with the first layer directly in contact
with the uncoated surface of the device and a second layer
comprising the pharmaceutical substance and having one surface in
contact with the first layer and the opposite surface in contact
with a third layer of polymer which is in contact with the
surrounding tissue. Additional layers of the polymer material and
drug composition can be added as required, alternating each
component or mixtures of components thereof.
[0070] In another embodiment, the matrix may comprise non-polymeric
materials such as nanoparticles formed of, for example, metallic
alloys or other materials. In this embodiment, the coating on the
medical device can be porous and the pharmaceutical substances can
be trapped within and between the particles. In this embodiment,
the size of the particles can be varied to control the rate of
release of the pharmaceutical substance trapped in the particles
depending on the need of the patient. In one embodiment, the
pharmaceutical composition can be a slow/controlled-release
pharmaceutical composition.
[0071] Alternatively, the pharmaceutical substance can be applied
as multiple layers of a composition and each layer can comprise one
or more drugs surrounded by polymer material. In this embodiment,
the multiple layers of pharmaceutical substance can comprise a
pharmaceutical composition comprising multiple layers of a single
drug; one or more drugs in each layer, and/or differing drug
compositions in alternating layers applied. In one embodiment, the
layers comprising pharmaceutical substance can be separated from
one another by a layer of polymer material. In another embodiment,
a layer of pharmaceutical composition may be provided to the device
for immediate release of the pharmaceutical substance after
implantation.
[0072] In one embodiment, the pharmaceutical substance or
composition may comprise one or more drugs or substances which can
inhibit smooth muscle cell migration and proliferation at the site
of implantation, can inhibit thrombus formation, can promote
endothelial cell growth and differentiation, and/or can inhibit
restenosis after implantation of the medical device. Additionally,
the capturing of the progenitor endothelial cells on the luminal
surface of the medical device may be used to accelerate the
formation of a functional endothelium at the site of injury.
[0073] Examples of compounds or pharmaceutical compositions which
can be incorporated in the matrix, include, but are not limited to
prostacyclin, prostacyclin analogs, .alpha.-CGRP, .alpha.-CGRP
analogs or .alpha.-CGRP receptor agonists; prazosin; monocyte
chemoattactant protein-1 (MCP-1); immunosuppressant drugs such as
rapamycin, drugs which inhibit smooth muscle cell migration and/or
proliferation, antithrombotic drugs such as thrombin inhibitors,
immunomodulators such as platelet factor 4 and CXC-chemokine;
inhibitors of the CX3 CR1 receptor family; antiinflammatory drugs,
steroids such as dihydroepiandrosterone (DHEA) testosterone,
estrogens such as 17.beta.-estradiol; statins such as simvastatin
and fluvastatin; PPAR-alpha ligands such as fenofibrate and other
lipid-lowering drugs, PPAR-delta and PPAR-gamma agonists such as
rosiglitazone; PPAR-dual-.alpha..gamma. agonists, LBM-642, nuclear
factors such as NF-.kappa..beta., collagen synthesis inhibitors,
vasodilators such as acetylcholine, adenosine, 5-hydroxytryptamine
or serotonin, substance P, adrenomedulin, growth factors which
induce endothelial cell growth and differentiation such as basic
fibroblast growth factor (bFGF), platelet-derived growth factor
(PDGF), endothelial cell growth factor (EGF), vascular endothelial
cell growth factor (VEGF); protein tyrosine kinase inhibitors such
as Midostaurin and imatinib or any anti-angionesis inhibitor
compound; peptides or antibodies which inhibit mature leukocyte
adhesion, antibiotics/antimicrobials, and other substances such as
tachykinins, neurokinins or sialokinins, tachykinin NK receptor
agonists; PDGF receptor inhibitors such as MLN-518 and derivatives
thereof, butyric acid and butyric acid derivatives puerarin,
fibronectin, erythropoietin, darbepotin, serine proteinase-1
(SERP-1) and the like.
[0074] In particular embodiments of the invention, one or more of
the pharmaceutical substances can be selected from everolimus,
rapamycin, pimecrolimus, tacrolimus (FK506), biolimus A9, CCI-779,
RAD 001, AP23573, dexamethasone, hydrocortisone, estradiol,
acetaminophen, ibuprofen, naproxen, fluticasone, clobetasol,
adalimumab, sulindac, and combinations thereof. The aforementioned
compounds and pharmaceutical substances can be applied to the
coating on the device alone or in combinations and/or mixtures
thereof.
[0075] In one embodiment, the implantable medical device can
comprise a coating comprising one or more barrier layers in between
said one or more layers of matrix comprising said pharmaceutical
substances. In this embodiment, the barrier layer may comprise a
suitable biodegradable material, including but not limited to
suitable biodegradable polymers including: polyesters such as PLA,
PGA, PLGA, PPF, PCL, PCC, TMC and any copolymer of these;
polycarboxylic acid, polyanhydrides including maleic anhydride
polymers; polyorthoesters; poly-amino acids; polyethylene oxide;
polyphosphazenes; polylactic acid, polyglycolic acid and copolymers
and mixtures thereof such as poly(L-lactic acid) (PLLA),
poly(D,L-lactide), poly(lactic acid-co-glycolic acid), 50/50
(DL-lactide-co-glycolide); polydixanone; polypropylene fumarate;
polydepsipeptides; polycaprolactone and co-polymers and mixtures
thereof such as poly(D,L-lactide-co-caprolactone) and
polycaprolactone co-butylacrylate; polyhydroxybutyrate valerate and
blends; polycarbonates such as tyrosine-derived polycarbonates and
arylates, polyiminocarbonates, and
polydimethyltrimethyl-carbonates; cyanoacrylate; calcium
phosphates; polyglycosaminoglycans; macromolecules such as
polysaccharides (including hyaluronic acid; cellulose, and
hydroxypropylmethyl cellulose; gelatin; starches; dextrans;
alginates and derivatives thereof), proteins and polypeptides; and
mixtures and copolymers of any of the foregoing. The biodegradable
polymer may also be a surface erodable polymer such as
polyhydroxybutyrate and its copolymers, polycaprolactone,
polyanhydrides (both crystalline and amorphous), maleic anhydride
copolymers, and zinc-calcium phosphate. Of course, such materials
may in fabrication of the medical device be disposed in an
appropriate solvent, such as water, ethanol, acetone etc. and may
include materials providing for radioopacity, such as diatrizoate
sodium, tantalum etc. The number of barrier layers that the coating
on a device may have depends on the amount of therapeutic needed as
dictated by the therapy required by the patient. For example, the
longer the treatment, the more therapeutic substance required over
a period of time, the more barrier layers may be needed to provide
the pharmaceutical substance in a timely and continued manner.
[0076] In one embodiment, the ligand is applied to the blood
contacting surface of the medical device and the ligand
specifically recognizes and binds a desired component or epitope on
the surface of target cells in the circulating blood. In one
embodiment, the ligand is specifically designed to recognize and
bind only the genetically-altered mammalian cell by recognizing
only the genetically-engineered marker molecule on the cell
membrane of the genetically-altered cells. The binding of the
target cells immobilizes the cells on the surface of the
device.
[0077] In an alternate embodiment, the ligand on the surface of the
medical device for binding the genetically-altered cell is selected
depending on the genetically engineered cell membrane marker
molecule. That is, the ligand binds only to the cell membrane
marker molecule or antigen which is expressed by the cell from
extrachromosomal genetic material provided to the cell so that only
the genetically-modified cells can be recognized by the ligand on
the surface of the medical device. In this manner, only the
genetically-modified cells can bind to the surface of the medical
device. For example, if the mammalian cell is an endothelial cell,
the ligand can be at least one type of antibody, antibody fragments
or combinations thereof the antibody may be specifically raised
against a specific target epitope or marker molecule on the surface
of the target cell. In this aspect of the invention, the antibody
can be a monoclonal antibody, a polyclonal antibody, a chimeric
antibody, or a humanized antibody which recognizes and binds only
to the genetically-altered endothelial cell by interacting with the
surface marker molecule and, thereby modulating the adherence of
the cells onto the surface of the medical device. The antibody or
antibody fragment of the invention can be covalently or
noncovalently attached to the surface of the matrix, or tethered
covalently by a linker molecule to the outermost layer of the
matrix coating the medical device. In this embodiment, for example,
the monoclonal antibodies can further comprises Fab or F(ab')2
fragments. The antibody fragment of the invention comprises any
fragment size, such as large and small molecules which retain the
characteristic to recognize and bind the target antigen as the
antibody.
[0078] In another embodiment, the antibody or antibody fragment of
the invention recognize and bind antigens with specificity for the
mammal being treated and their specificity is not dependent on cell
lineage. In one embodiment, for example, in treating restenosis
wherein the cells may not be genetically modified to contain
specific cell membrane marker molecules, the antibody or fragment
is specific for selecting and binding circulating progenitor
endothelial cell surface antigen such as CD133, CD34, CD14, CDw90,
CD117, HLA-DR, VEGFR-1, VEGFR-2, Muc-18 (CD146), CD130, stem cell
antigen (Sca-1), stem cell factor 1 (SCF/c-Kit ligand), Tie-2, MHC
such as H-2Kk and HLA-DR antigen.
[0079] In another embodiment, the coating of the medical device
comprises at least one layer of a biocompatible matrix as described
above, the matrix comprises an outer surface for attaching a
therapeutically effective amount of at least one type of small
molecule of natural or synthetic origin. The small molecule
recognizes and interacts with, for example, progenitor endothelial
cells in the prevention, amelioration or treatment of restenosis,
to immobilize the cells on the surface of the device to form an
endothelial layer. The small molecules can be used in conjunction
with the medical device for the treatment of various diseases, and
can be derived from a variety of sources such as cellular
components such as fatty acids, proteins, nucleic acids,
saccharides and the like, and can interact with an antigen on the
surface of a progenitor endothelial cell with the same results or
effects as an antibody. In one aspect of this embodiment, the
coating on the medical device can further comprise a compound such
as a growth factor as described herewith in conjunction with the
coating comprising an antibody or antibody fragment.
[0080] In another embodiment, the coating of the medical device
comprises at least one layer of a biocompatible matrix as described
above, the matrix comprising a luminal surface for attaching a
therapeutically effective amount of at least one type of small
molecule of natural or synthetic origin. The small molecule
recognizes and interacts with an antigen on the target cell such as
a progenitor endothelial cell surface to immobilize the progenitor
endothelial cell on the surface of the device to form endothelium.
The small molecules can be derived from a variety of sources such
as cellular components including, fatty acids, peptides, proteins,
nucleic acids, saccharides and the like and can interact, for
example, with a structure such as an antigen on the surface of a
progenitor endothelial cell with the same results or effects as an
antibody.
[0081] In another embodiment, there is provided a method for
treating, ameloriating, or preventing vascular disease such as
restenosis and artherosclerosis, comprising administering a
pharmaceutical substance locally to a patient in need of such
substance. The method comprises implanting into a vessel or
hollowed organ of a patient a medical device with a coating, which
coating comprises a pharmaceutical composition comprising a drug or
substance for inhibiting smooth muscle cell migration and thereby
restenosis, and a biocompatible, biodegradable, bioerodible,
nontoxic polymer or non-polymer matrix, wherein the pharmaceutical
composition comprises a slow or controlled-release formulation for
the delayed release of the drug. The coating on the medical device
can also comprise a ligand such as an antibody for capturing cells
such as endothelial cells and or progenitor cells on the luminal
surface of the device so that a functional endothelium is
formed.
[0082] In another embodiment, there is provided a method of making
a coated medical device or a medical device with a coating, which
comprises applying to a surface of a medical device a polymer or
non-polymer matrix and a pharmaceutical composition comprising one
or more drugs, and applying a ligand to the medical device so that
the ligand attaches to a surface of the device and is designed to
bind molecules on the cell membrane of circulating native or
genetically engineered cells. In this embodiment, the polymer
matrix comprises a biocompatible, biodegradable, nontoxic polymer
matrix such as collagen, tropocollagen, elastin, tropoelastin,
cross-linked tropoelastin, poly(lactide-co-glycolide) copolymer,
polysaccharides and one or more pharmaceutical substances, wherein
the matrix and the substance(s) can be mixed prior to applying to
the medical device. In this embodiment, at least one type of ligand
is applied to the surface of the device and can be added on top or
on the outer surface of the device with the drug/matrix composition
in contact with the device surface. The method may alternatively
comprise the step of applying at least one layer of a
pharmaceutical composition comprising one or more drugs and
pharmaceutically acceptable carriers, and applying at least one
layer of a polymer matrix to the medical device.
[0083] In one embodiment, the matrix can be applied as one or more
layers and with or without the pharmaceutical substance, and the
ligand can be applied independently to the medical device by
several methods using standard techniques, such as dipping,
spraying or vapor deposition. In an alternate embodiment, the
polymer matrix can be applied to the device with or without the
pharmaceutical substance. In this aspect of the invention wherein a
polymer matrix is applied without the drug, the drug can be applied
as a layer between layers of matrices. In other embodiments, a
barrier layer is applied between the layers comprising the
pharmaceutical substances.
[0084] In one embodiment, the method comprises applying the
pharmaceutical composition as multiple layers with the ligand
applied on the outermost surface of the medical device so that the
ligand such as antibodies can be attached in the luminal surface of
the device. In one embodiment, the method for coating the medical
device comprises: applying to a surface of said medical device at
least one or more layers of a matrix, one or more pharmaceutical
substance(s), and a basement membrane component; applying to said
at least one layer of said composition on said medical device a
solution comprising at least one type of ligand for binding and
immobilizing genetically-modified target cells; and drying said
coating on the medical device, such as a stent, under vacuum at low
temperatures.
[0085] In another embodiment, the coating is comprised of a
multiple component pharmaceutical composition within the matrix
such as containing a fast release pharmaceutical agent to retard
early neointimal hyperplasia/smooth muscle cell migration and
proliferation, and a secondary biostable matrix that releases a
long acting agent for maintaining vessel patency or a positive
blood vessel remodeling agent, such as endothelial nitric oxide
synthase (eNOS), nitric oxide donors and derivatives such as
aspirin or derivatives thereof, nitric oxide producing hydrogels,
PPAR agonist such as PPAR-A ligands, tissue plasminogen activator,
statins such as atorvastatin, erythropoietin, darbepotin, serine
proteinase-1 (SERP-1) and pravastatin, steroids, and/or
antibiotics.
[0086] In another embodiment, there is provided a therapeutic, drug
delivery system and method for treating diseases in a patient. The
therapeutic or drug delivery system comprises a medical device with
a coating composed of a matrix comprising at least one type of
ligand for recognizing and binding target cells such as progenitor
endothelial cells or genetically-altered mammalian cells and
genetically-altered mammalian cells which have been at least singly
or dually-transfected.
[0087] In one embodiment, the coating on the present medical device
comprises a biocompatible matrix and at least one type of
pharmaceutical substance or ligand, which specifically recognizes
and bind target cells such as progenitor endothelial cells such as
in the prevention or treatment of restenosis, or
genetically-altered mammalian cells, onto the surface of the
device, such as in the treatment of blood vessel remodeling and
cancer.
[0088] Additionally, the coating of the medical device may
optionally comprise at least an activating compound for regulating
the expression and secretion of the engineered genes of the
genetically-altered cells. Examples of activator stimulatory
compounds, include but is not limited to chemical moieties, and
peptides, such as growth factors. In embodiments when the coating
comprises at least one compound, the stimulus, activator molecule
or compound may function to stimulate the cells to express and/or
secrete at least one therapeutic substance for the treatment of
disease.
[0089] In one embodiment, the coating on the medical device
comprises a biocompatible matrix which comprises an outer surface
for attaching a therapeutically effective amount of at least one
type of ligand such as an antibody, antibody fragment, or a
combination of the antibody and the antibody fragment, or at least
one type of molecule for binding the engineered marker on the
surface of the genetically-modified cell. The antibody or antibody
fragment present recognizes and binds an antigen or the specific
genetically-engineered cell surface marker on the cell membrane or
surface of target cells so that the cells are immobilized on the
surface of the device. In one embodiment, the coating may
optionally comprise an effective amount of at least one compound
for stimulating the immobilized progenitor endothelial cells to
either accelerate the formation of a mature, functional endothelium
if the target cells are circulating progenitor cells, or to
stimulate the bound cells to express and secrete the desired gene
products if the target are genetically-altered cells on the surface
of the medical device.
[0090] In one embodiment, the compound of the coating of the
invention, for example in treating restenosis, comprises any
compound which stimulates or accelerates the growth and
differentiation of the progenitor cell into mature, functional
endothelial cells. In another embodiment, the compound is for
stimulating the genetically modified cells to express and secrete
the desired gene product. For example, a compound for use in the
invention may be a growth factor such as vascular endothelial
growth factor (VEGF), basic fibroblast growth factor,
platelet-induced growth factor, transforming growth factor beta 1,
acidic fibroblast growth factor, osteonectin, angiopoietin 1
(Ang-1), angiopoietin 2 (Ang-2), insulin-like growth factor,
granulocyte-macrophage colony-stimulating factor, platelet-derived
growth factor AA, platelet-derived growth factor BB,
platelet-derived growth factor AB and endothelial PAS protein
1.
[0091] In another embodiment, for example when using
genetically-altered mammalian cells, the activating agents or
compounds useful for stimulating the cells to express and secrete
the genetically-engineered gene products include, but are not
limited to estrogen, tetracycline and other antibiotics,
tamoxiphen, etc., and can be provided to the patient via various
routes of administration, such as through the skin via a patch and
subcutaneously.
[0092] The invention also provides methods for treating,
amelioriating, and preventing a variety of diseases, such as
vascular disease, cancer, blood vessel remodeling, severe coronary
artery disease artherosclerosis, restenosis, thrombosis, aneurysm
and blood vessel obstruction. In one embodiment, there is provided
a method for retaining or sealing the medical device insert to the
vessel wall, such as a stent or synthetic vascular graft, heart
valve, abdominal aortic aneurysm devices and components thereof,
and for establishing vascular homeostasis, thereby preventing
excessive intimal hyperplasia as in restenosis. In a method of
treating atherosclerosis, the artery may be either a coronary
artery or a peripheral artery such as the femoral artery. Veins can
also be treated using these techniques and medical device.
[0093] With respect to the treatment, amelioration, and prevention
of restenosis, the invention also provides an engineered method for
inducing a healing response. In one embodiment, a method is
provided for rapidly inducing the formation of a confluent layer of
endothelium in the luminal surface of an implanted device in a
target lesion of an implanted vessel, in which the endothelial
cells express nitric oxide synthase and other anti-inflammatory and
inflammation-modulating factors. The invention also provides a
medical device which has increased biocompatibility over prior art
devices, and decreases or inhibits tissue-based excessive intimal
hyperplasia and restenosis by decreasing or inhibiting smooth
muscle cell migration, smooth muscle cell differentiation, and
collagen deposition along the inner luminal surface at the site of
implantation of the medical device.
[0094] In an embodiment, a method for coating a medical device
comprises the steps of: applying at least one layer of a
biocompatible matrix to the surface of the medical device, wherein
the biocompatible matrix comprises at least one component selected
from the group consisting of a polyurethane, a segmented
polyurethane-urea/heparin, a poly-L-lactic acid, a cellulose ester,
a polyethylene glycol, a polyvinyl acetate, a dextran, gelatin,
collagen, elastin, tropoelastin, laminin, fibronectin, vitronectin,
heparin, fibrin, cellulose and carbon and fullerene, and applying
to the biocompatible matrix, simultaneously or sequentially, a
therapeutically effective amounts of at least one type of antibody,
antibody fragment or a combination thereof, and at least one
compound which stimulates endothelial cell growth and
differentiation.
[0095] A bioabsorbable, biocompatible, and biodegradable scaffold
may be operatively configured to afford deliverability,
flexibility, and radial stretchability very suitable for
implantation in the pulsatile movements, contractions and
relaxations of, for example, the cardiovascular system.
[0096] For example, the medical device could comprise a polymer
with low immune rejection properties such as a bioabsorbable
polymer composition or blend, having a combination of mechanical
properties balancing elasticity, rigidity and flexibility. The
polymer composition could produce a low antigenicity by means of a
biocompatible base material, such as, without limitation, a
bioabsorbable polymer, copolymer, or terpolymer, and a copolymer or
terpolymer additive. These kinds of polymer structures may
advantageously undergo enzymatic degradation and absorption within
the body. In particular, the novel composition may allow for a
"soft" breakdown mechanism that is so gradual that the breakdown
products or polymer components are less injurious to the
surrounding tissue and thus reduce restenotic reactions or inhibit
restenosis entirely.
[0097] The present inventors have also proposed novel designs which
may employ such bioabsorbable, biocompatible and biodegradable
material to make advantageous scaffolds, which may afford a
flexibility and stretchability very suitable for implantation in
the pulsatile movements, contractions and relaxations of, for
example, the cardiovascular system.
[0098] Embodiments disclosed herein include, medical devices such
as stents, deformable vascular devices, synthetic grafts and
catheters, which may or may not comprise a bioabsorbable polymer
composition for implantation into a patient.
[0099] In one embodiment, a cardiovascular tube-shaped expandable
scaffold such as a stent is provided, having a low rejection or
immunogenic effect after implantation, which is fabricated from a
bioabsorbable polymer composition or blend having a combination of
mechanical properties balancing vascular scaffolding, elasticity,
rigidity and flexibility, which properties allow bending and
crimping of the scaffold tube onto an expandable delivery system
for vascular implantation. The instant devices can be used in the
treatment of, for example, vascular disease such as
atherosclerosis, restenosis, and vascular remodeling provided as
both a crimped and expanded structure, which can be used in
conjunction with balloon angioplasty.
[0100] In an embodiment, the medical device can be provided as an
expandable scaffold, comprising a plurality of meandering strut
elements or structures forming a consistent pattern, such as
ring-like structures along the circumference of the device in
repeat patterns (e.g., with respect to a stent, without limitation,
throughout the structure, at the open ends only, or a combination
thereof). The meandering strut structures can be positioned
adjacent to one another and/or in oppositional direction allowing
them to expand radically and uniformly throughout the length of the
expandable scaffold along a longitudinal axis of the device. In one
embodiment, the expandable scaffold can comprise specific patterns
such as a lattice structure, dual-helix structures with uniform
scaffolding with optional side branching.
[0101] An embodiment provides an expandable biodegradable tubular
scaffold which includes a plurality of biodegradable first meanders
forming an interconnected mesh, wherein the mesh extends
circumferentially about a longitudinal axis; wherein each of the
biodegradable first meanders are manufactured from a polymer which
crystallizes under the strain of expansion of said tubular
scaffold, and a plurality of biodegradable second meanders, each of
said second meanders being separate from another, and each
extending circumferentially about said longitudinal axis in a
single orthogonal plane. The second meanders nest in, and
interconnect to, the first meanders, and have at least two closed
loop connectors intervening between segments of each second
meanders, which connectors are capable of deformation and
crystallization under full expansion during intravascular
implantation of said tubular scaffold. This extra expansion range
serves to prevent overstretching the second meanders or hoops and
thereby necking or structural integrity of the second meanders or
hoops.
[0102] In one embodiment, a bioabsorbable and flexible scaffold
circumferential about a longitudinal axis so as to form a tube, the
tube having a proximal open end and a distal open end, and being
expandable from an unexpanded structure to an expanded form, and
being crimpable, the scaffold having a patterned shape in expanded
form comprising:
[0103] a plurality of first meandering strut patterns, each of the
first meandering strut pattern being interconnected to one another
to form an interconnected mesh pattern circumferential about the
longitudinal axis;
[0104] at least two second strut patterns nested within the
interconnected mesh pattern, each of said second strut patterns
comprising a hoop circumferential about the longitudinal axis, said
hoop having an inner surface proximal to the longitudinal axis and
an outer
[0105] surface distal to the longitudinal axis, the hoop inner and
outer surfaces about their circumferences being orthogonal to the
longitudinal axis and within substantially the same plane; and
[0106] at least two expansion loops intervening in the second
meanders so as provide extra hoop length when stretched to the
crystallized limit at which the second meanders would neck and
fail.
[0107] In one embodiment, the first meandering strut patterns can
be generally parallel to said longitudinal axis, generally diagonal
to said longitudinal axis, generally orthogonal to said
longitudinal axis, or generally concentric about said longitudinal
axis. The second strut patterns can be made of a material which
substantially crystallizes when said tube is in its expanded state,
but does not substantially crystallize in its unexpanded state. The
second strut patterns can include at least one hoop having a
through-void, wherein said at least one hoop is configured to
permit its radius to be expanded when said at least one hoop is
subject to an expanding force which exceeds its nominal expanded
state, but a force that does not result in hoop failure.
[0108] In one embodiment, each of the first meandering strut
patterns of the scaffold is essentially sinusoidal, and each of the
second strut patterns is substantially non-sinusoidal. The first
meandering strut patterns of a scaffold can extend from the
proximal open end to the distal open end of the tube. in another
embodiment, each of the second strut patterns can be found at the
proximal open end and the distal open end. In one embodiment, each
of the second strut patterns is further found between the proximal
open end and the distal open end.
[0109] In one embodiment, the scaffold comprises a structure
wherein each of the second strut patterns can be found between the
proximal open end and the distal open end but not at the proximal
open end or distal open end. In another embodiment, the scaffold
comprises a structure wherein the second strut patterns can be
found at least one of the proximal open end or the distal open
end.
[0110] In a specific embodiment, the scaffold comprises a stent
having an unexpanded configuration and an expanded configuration;
an outer tubular surface and an inner tubular surface, the stent
comprising: a plurality of biodegradable, paired, separate
circumferential bands having a pattern of distinct undulations in
an unexpanded configuration and substantially no undulations in an
expanded configuration, the undulations of the biodegradable,
paired, separate circumferential bands in the stent in an
unexpanded state being incorporated into a substantially planar
ring in an expanded state, and a plurality of biodegradable
interconnection structures spanning between each pair of
circumferential bands and connected to multiple points on each band
of the paired bands.
[0111] In an embodiment, the stent interconnecting structures
comprise a pattern of undulations both in an unexpanded and
expanded configuration. In an alternate embodiment, the
interconnection structures comprise a pattern containing no
undulations in both an unexpanded and expanded configuration. The
interconnection structures of the stent can expand between
undulations of paired circumferential bands.
[0112] In another embodiment, a biosorbable and flexible scaffold
circumferential about a longitudinal axis and substantially forming
a tube, the tube having a proximal open end and a distal open end,
and being crimpable and expandable, and comprising in expanded
form: a) at least two rings circumferential about the longitudinal
axis, the rings having an inner surface proximal to the
longitudinal axis, an outer surface distal to the longitudinal
axis, a top surface proximal to the proximal open end and a bottom
surface proximal to the distal open end, the ring inner and outer
surfaces about their circumferences being orthogonal to the
longitudinal axis and within substantially the same plane, and b) a
plurality of meandering strut patterns located between the at least
two rings and circumferential coursing about the longitudinal axis;
the plurality of meandering strut patterns connected to the rings
at least two connection points on the circumference of each ring,
and each connection point on the circumference of the ring on both
the top ring surface and the bottom ring surface; wherein each of
the connection points with any particular ring is symmetrical in
structure above and below the upper and lower surface of the
ring.
[0113] In one embodiment, the scaffold comprises a structure
wherein the connection points of the rings, the meandering strut
patterns above the ring upper surface and below the ring lower
surface in conjunction form a stylized, letter H configuration. In
another embodiment, the scaffold can comprise a structure wherein
at the connection points of the rings, the meandering strut
patterns above the ring upper surface and below the ring lower
surface in conjunction form two abutting sinusoids. In an alternate
embodiment, the scaffold can comprise a structure wherein at the
connection points of the rings, the meandering strut patterns above
the ring upper surface and below the ring lower surface in
conjunction form two sinusoids with intervening structure
connecting the same and the ring. In one embodiment, the connection
points of the rings have between 2 through 6 meandering strut
pattern connections at each connection.
[0114] In another embodiment, an expandable biodegradable tubular
scaffold comprising a plurality of biodegradable first meanders
forming an interconnected mesh. The mesh extending
circumferentially about a longitudinal axis; wherein each of the
biodegradable first meanders are manufactured from a racemic
polymer which crystallizes under the strain of expansion of the
tubular scaffold, and also comprising a plurality of biodegradable
second meanders, each of the second meanders being separate from
another, and each extending circumferentially about the
longitudinal axis in a single plane, the second meanders being
nested in, and interconnected to, the first meanders. In this
embodiment, the scaffold's first meanders are generally parallel to
the longitudinal axis, generally diagonal to the longitudinal axis,
generally orthogonal to the longitudinal axis, or are concentric
about the longitudinal axis. The second meanders are made from a
material which crystallizes when the tube is in its expanded state,
but does not substantially crystallize in its unexpanded state, and
at least one of the second meanders includes at least one
through-void, which is configured to permit stretching of the
second member without failure of the member.
[0115] In one embodiment, the first meanders form a strut pattern
that is sinusoidal when the tube is in an expanded form, the second
meanders form a strut pattern that is substantially non-sinusoidal
when the tube is in an expanded form. In this and other
embodiments, the first meanders form a strut pattern that extends
from the proximal open end to the distal open end of the tube, and
the second meanders form a strut pattern that is found at the
proximal open end and the distal open end. The second meanders can
also form a strut pattern that is further found between the
proximal open end and the distal open end, or the second meanders
form a pattern that is found between the proximal open end and the
distal open end but not at the proximal open end or the distal open
end.
[0116] In another embodiment, the stent conformation is variably
adaptable to luminal diameters of the cardiovascular contours such
that the second meander can be flexibly expanded beyond the rigidly
and elastically stretched stable hoop conformation beyond the
maximal crystallization stage, however, without causing collapse of
the hoop structure. This additional built-in flexible expansion is
obtained by the special loop inserts along the second meander
struts. More specifically, such a loop interconnects at least two
segments of the second meander strut, wherein the loop before
expansion forms an oval ring lying in a longitudinal axis
direction. When the second meander at its maximal stretch expansion
to form a hoop structure has to be further expanded for a better
luminal fit or hold in the vascular system in situ, the loop can be
stretched orthogonally forming an oval ring in the direction of the
stretched hoop structure.
[0117] In one embodiment, at least one of the plurality of paired
biodegradable circumferential bands includes along its outer
tubular surface, a radio-opaque material capable of being
detectable by radiography, MRI or spiral CT technology.
Alternatively, at least one of the interconnection structures
includes a radio-opaque material along its outer tubular surface,
which can be detectable by radiography, MRI or spiral CT
technology. The radio-opaque material can be housed in a recess on
one of the circumferential bands, or in a recess on one of the
interconnection structures. In one embodiment, a least one of the
interconnection structures and at least one of the circumferential
bands includes a radio-opaque material along the outer tubular
surface, which is detectable by radiography, MRI or spiral CT
technology.
[0118] In an alternate embodiment, a method for fabricating a
tube-shaped scaffold comprises: preparing a racemic poly-lactide
mixture; fabricating a biodegradable polymer tube of the racemic
poly-lactide mixture; laser cutting the tube until a desired
scaffold is formed. In one option of such embodiment, the
fabrication of the scaffold can be performed using a molding
technique, which is substantially solvent-free, or an extrusion
technique.
[0119] There is also provided a method for fabricating the
tube-shaped scaffold comprising, blending a polymer composition
comprising a crystallizable composition comprising a base polymer
of poly L-lactide or poly D-lactide linked with modifying
copolymers comprising poly L(or
D)-lactide-co-tri-methylene-carbonate or poly L(or
D)-lactide-co-.epsilon.-caprolactone in the form of block
copolymers or as blocky random copolymers wherein the lactide chain
length is sufficiently long enough to allow cross-moiety
crystallization; molding the polymer composition to structurally
configure the scaffold; and cutting the scaffold to form the
desired scaffold patterns. In this embodiment. the blended
composition may comprise a racemic mixture of poly L-lactide and
poly-D lactide. Accordingly, medical devices such as a stent,
produced by this method may consist essentially of a racemic
mixture of a poly-L and poly-D lactide. In this embodiment, the
stent can comprise other polymer materials such as
trimethylcarbonate. In one optional composition of such embodiment
wherein the device comprises trimethylcarbonate, the amount of
trimethylcarbonate does not exceed more than 40% of the weight of
the stent.
[0120] In another embodiment, an expandable tube-shaped scaffold
having a proximal end and a distal end defined about longitudinal
axis is provided. The scaffold comprises: (a) a plurality of first
meandering strut elements interconnected with one another at least
one point in such a manner to form a circumferential tube-shaped
structure, the first meandering strut elements forming a tubular
mesh which is crimpable and expandable; (b) a second meandering
strut element which is operatively configured to be crimpable and
expandable and configured to form a hoop-shaped strut of the
scaffold after expansion; and (c) a locking means permitting the
scaffold to the locked in a crimped position; wherein the scaffold
comprises a expansion crystallizable, bioabsorbable racemate
polymer composition or blend.
[0121] In one lock embodiment, the tube-shaped scaffold can
comprise a structure wherein the locking means is a two-part
portion of one or different meandering strut elements located at or
near both the proximal and distal ends of the tube-shaped scaffold.
In this embodiment, the two-part portion of the locking means can
entail, for example, a snap-fit engagement in the crimped position
of the scaffold, wherein the locking means is disengaged by
scaffold expansion. In alternate embodiments, the tube-shaped
scaffold can comprise a locking means comprising a snap-fit
key-in-lock configuration wherein the design resembles a dovetail
type interlocking means. The tube-shaped scaffold can also comprise
locking means comprising a snap-fit key-in-lock configuration
resembling a ball-joint type interlocking means; a cantilever arm
hooking an oppositely shaped end piece of the plastic scaffold, and
the like.
[0122] The tube-shaped scaffold can be mounted or carried on a
expandable balloon carrier device and can be sized to stretch from
a crimped tube diameter to a diameter sufficient for implantation
inside the lumen of a vascular system.
[0123] In another embodiment, the expandable scaffold comprises a
set of interlocking meandering struts stabilizing the implanted
scaffold in an expanded or implanted configuration, wherein the
scaffold polymer undergoes a molecular reorientation and
crystallization during the radial strain of expansion. The scaffold
can vary from a cylindrical to a conal shape or combination
thereof. In the embodiments described herein, the scaffold's
biodegradable polymer displays breakdown kinetics sufficiently slow
to avoid tissue overload or other inflammatory reactions. The
polymer core material comprising at least one encapsulated drug for
localized treatment of the vascular wall and lumen.
[0124] In certain embodiments, novel stent designs with coatings
are provided which are bioabsorbable, biocompatible, and
biodegradable. Scaffolds made from such material may afford
deliverability, flexibility, and radial stretchability very
suitable for implantation in the pulsatile movements, contractions
and relaxations of, for example, the cardiovascular system. After a
period of implantation, the stent may begin to degrade once normal
endothelium has been established by the presence of the
coating.
[0125] For example, the medical device could comprise a polymer
with low immune rejection properties such as a bioabsorbable
polymer composition or blend, having a combination of mechanical
properties balancing elasticity, rigidity and flexibility. The
polymer composition could produce a low antigenicity by means of a
biocompatible base material, such as, without limitation, a
bioabsorbable polymer, copolymer, or terpolymer, and a copolymer or
terpolymer additive. These kinds of polymer structures may
advantageously undergo enzymatic degradation and absorption within
the body. In particular, the novel composition may allow for a
"soft" breakdown mechanism that is so gradual that the breakdown
products or polymer components are less injurious to the
surrounding tissue and thus reduce restenotic reactions or inhibit
restenosis entirely.
[0126] In certain embodiments, there are provided polymeric
designs, with coatings which may employ bioabsorbable,
biocompatible and biodegradable material to make advantageous
scaffolds, which may afford flexibility and stretchability very
suitable for implantation in the pulsatile movements, contractions
and relaxations of, for example, the cardiovascular system. In
these embodiments, the coatings can be applied prior to or cutting
or making the designs. The coatings can be applied in various
manners, and can vary in content depending on the site of
application on the device. For example, a coating on a luminal
surface of the medical device can comprise ligands for recognizing
and binding endothelial cells to form an endothelium, and can also
comprise one or more pharmaceutical substances for inducing
differentiation of endothelial cells and/or maintaining the
endothelial cells function. In this and other embodiments, the
abluminal coating can comprise one or more pharmaceutical
substances for example, that inhibit restenosis or prevent thrombus
formation.
[0127] The coating can comprise one or more layers of a matrix and
at least one type of ligand such as antibodies, antibody fragments
or combinations or antibodies and antibody fragments; peptides and
small molecules which bind and capture endothelial cells in vivo at
the site of implantation of the device. The coating can further
comprise a pharmaceutical substance for delivery to target tissue.
In this embodiment, pharmaceutical substances, for example, for
reducing restenosis, inhibit smooth muscle cell migration, induce
nitric oxide synthetase, can be used in conjuction with the
coating. The pharmaceutical substances can be applied in various
manner such as in layers.
[0128] FIG. 1 is a photograph of a bioabsorbable medical device of
the invention consisting of a stent design mounted along its
longitudinal axis on a catheter. In this embodiment, the stent is
coated with matrix layer comprising a bioabsorbable polymer and a
ligand consisting of antibodies against CD34 positive cells.
[0129] The figures provided herewith depict embodiments that are
described as illustrative examples that are not deemed in any way
as limiting the present invention.
Example 1
[0130] Bioabsorbable polymer tubes for use to make an embodiment of
the invention were made from polymer compositions as described
above. Uncoated tubes and tubes that had been coated as described
above, comprising a coating with Anti-CD34 antibodies coated on a
polymer matrix were analyzed for the ability to bind antibodies on
their surface. Prior to testing the tubes for cell binding, tubes
that were coated with a layer of antibodies were examined for the
amount of antibody binding on their surface. The experiments were
repeated three times. The results of these studies are shown in
FIG. 2.
[0131] As seen in FIG. 2, the untreated tube, plasma treated with
an oxygen plasma followed by an argon plasma tubes, and tubes
coated with a matrix did not contain any anti-CD34 antibodies per
tube in any of the trials performed. In contrast polymer tube were
coated with a coating solution comprising a bioabsorbable polymer,
followed by a buffered solution containing anti-CD34 antibodies had
approximately 600 to 800 ng of antibodies (per tube) attached to
their surface. The tubes were then tested for cell binding activity
in in vitro experiments using Kg1a, CD34 positive cells. Only those
tubes processed to be coated with solutions containing anti-CD34
were found to contain bound antibody on their surface.
Example 2
[0132] The uncoated and coated tubes and tubes that were plasma
treated were incubated with Kg1a cells. After incubation, the tubes
were rinsed in buffered saline to remove unbound cells and the
tubes were fixed and process to identify cells bound to the
devices. Cell binding to the tubes was determined by staining the
tubes tested after incubation with a fluorescent, nuclear, DAPI
((4',6-diamidino-2-phenylindole)dihydrochloride) staining procedure
and examined under a fluorescent microscope. The results of these
experiments are shown in FIGS. 3 through 6.
[0133] FIG. 3 shows a representative bioabsorbable tube with a
coating comprising a polymer and anti-CD34 antibodies which depicts
numerous Kg1a cells attached to the tube as seen by the
fluorescence emitted from the cells. FIG. 4 is a representative
uncoated tube from the experiments and shows that the uncoated
tubes had very few cells attached thereon. It appeared that the
majority of the signal from these groups was due to background
fluorescence. FIG. 5 is a representative of the plasma treated
tubes which shows that binding of cells also occurred in tubes, but
the binding was confined to one end of the tube. The data for these
experiments is summarized in FIG. 6. FIG. 6 is a table showing that
having a matrix and antibody coating on the bioabsorbable device
enhances the binding of cells to device. Similar experiments were
carried out using bioabsorbable stents made by the present methods.
An exemplary bioabsorbable stent with a coating comprising a
polymer and anti-CD34 antibodies which was exposed to Kg1a cells as
discussed above shows that Kg1a bound to its surface as seen in
FIG. 7.
[0134] One embodiment of the invention is illustrated in FIG. 8,
wherein the bioabsorbable medical device is a tubular structure
comprising a body 5 having a lumen or a conduit 10. In this
embodiment, there is provided an inner coating, comprising one or
more layers, as shown in FIG. 8 as two layers 15 and 20, and an
outer coating, which may comprise one or more layers, as shown in
FIG. 8 as two layers 25, 30 on the surface of the medical device.
For example, the inner coating may comprise at least two layers 15,
20 of a material which for example, can comprise an antibody layer
15 and a pharmaceutical composition 20 with or without a matrix.
Multiple arrangement of layers can be deposited on either surface
of the device and may contain different components or
pharmaceutical substances or the layers can be the same. The outer
coating 25, 30 surrounding the device structure can be the same or
different in composition and can also comprise one or more
pharmaceutical substance or composition depending on the need of
the patient. In this embodiment, the device is depicted with
multiple layers.
[0135] FIG. 9 is an illustration of a stent with a coating showing
a perspective view of a stent strut 55 with the layer in the outer
surface and the inner with a coating with the outermost layer 45
depicting an antibody containing layer, an abluminal layer 50
comprising a biodegradable polymer with a drug load for release
into the vessel wall, and the luminal coating 60 comprising a drug
composition for release into the vessel surface after implantation.
Spaces between the stent struts 40 are also depicted.
[0136] While the invention has been particularly shown and
described with reference to particular embodiments, it will be
appreciated that variations of the above-disclosed and other
features and functions, or alternatives thereof, may be desirably
combined into many other different systems or applications. Also
that various presently unforeseen or unanticipated alternatives,
modifications, variations or improvements therein may be
subsequently made by those skilled in the art which are also
intended to be encompassed by the following claims.
* * * * *