U.S. patent application number 11/279641 was filed with the patent office on 2006-11-23 for methods and devices for contributing to the treatment of aneurysms.
This patent application is currently assigned to Medtronic Vascular, Inc.. Invention is credited to Jack Chu, Prema Ganesan.
Application Number | 20060264368 11/279641 |
Document ID | / |
Family ID | 35853579 |
Filed Date | 2006-11-23 |
United States Patent
Application |
20060264368 |
Kind Code |
A1 |
Ganesan; Prema ; et
al. |
November 23, 2006 |
Methods and Devices for Contributing to the Treatment of
Aneurysms
Abstract
The present invention relates to methods and devices to
contribute to the treatment of aneurysms. More specifically, the
present invention relates to methods and devices to contribute to
contribute to the treatment of aneurysms by delivering bioactive
agents via various delivery devices of collagen III and/or collagen
III and thrombin.
Inventors: |
Ganesan; Prema; (Oakland,
CA) ; Chu; Jack; (Santa Rosa, CA) |
Correspondence
Address: |
MEDTRONIC VASCULAR, INC.;IP LEGAL DEPARTMENT
3576 UNOCAL PLACE
SANTA ROSA
CA
95403
US
|
Assignee: |
Medtronic Vascular, Inc.
Santa Rosa
CA
|
Family ID: |
35853579 |
Appl. No.: |
11/279641 |
Filed: |
April 13, 2006 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10977545 |
Oct 28, 2004 |
|
|
|
11279641 |
Apr 13, 2006 |
|
|
|
Current U.S.
Class: |
604/890.1 ;
514/14.7; 514/17.2; 514/8.1; 514/8.2; 514/8.9; 514/9.1 |
Current CPC
Class: |
A61L 27/3641 20130101;
A61L 27/3616 20130101; A61L 27/54 20130101; A61L 27/3645 20130101;
A61L 2300/414 20130101 |
Class at
Publication: |
514/012 |
International
Class: |
A61K 38/39 20060101
A61K038/39; A61K 38/18 20060101 A61K038/18 |
Claims
1. A method comprising contributing to the treatment of an aneurysm
by placing a ribbon that administers collagen III at the aneurysm
site.
2. A method according to claim 1 wherein said ribbon administers
collagen III and an additional bioactive agent.
3. A method according to claim 2 wherein said additional bioactive
agent is selected from one or more of the group consisting of
collagen I, vascular endothelial growth factor (VEGF),
platelet-derived growth factor (PDGF), plated-derived epidermal
growth factor (PDEGF), basic fibroblast growth factor (bFGF),
fibroblast growth factors (FGFs), transforming growth factor-beta
(TGF-.beta.), platelet-derived angiogenesis growth factor (PDAF)
and autologous platelet gel (APG) including platelet rich plasma
(PRP) and platelet poor plasma (PPP) and thrombin.
4. A method according to claim 1, wherein said ribbon is a polymer
ribbon.
5. A method according to claim 1 wherein said ribbon further
comprises an osmotic mini-pump.
6. A method according to claim 5 wherein said osmotic mini-pump
releases a bioactive agent.
7. A method according to claim 6 wherein said bioactive agent is
selected from one or more of the group consisting of collagen I,
collagen III, vascular endothelial growth factor (VEGF),
platelet-derived growth factor (PDGF), plated-derived epidermal
growth factor (PDEGF), basic fibroblast growth factor (bFGF),
fibroblast growth factors (FGFs), transforming growth factor-beta
(TGF-.beta.), platelet-derived angiogenesis growth factor (PDAF)
and autologous platelet gel (APG) including platelet rich plasma
(PRP) and platelet poor plasma (PPP) and thrombin.
8. A method according to claim 1 further comprising deployment of a
stent graft at said aneurysm site.
9. A method according to claim 1 wherein said method further
comprises administering flowable collagen III to said aneurysm site
through an injection catheter.
10. A method according to claim 9 wherein said method further
comprises administering flowable thrombin to said aneurysm site
through an injection catheter.
11. A method according to claim 9 further comprising deployment of
a stent graft at said aneurysm site.
12. A ribbon comprising collagen III wherein said ribbon is
deployed at an aneurysm site in conjunction with a treatment
selected from the group consisting of the administration of
flowable collagen III to said aneurysm site through an injection
catheter; the deployment of a stent graft at said aneurysm site;
and the administration of flowable collagen III to said aneurysm
site through an injection catheter and the deployment of a stent
graft at said aneurysm site.
13. A ribbon according to claim 12 wherein said ribbon administers
collagen III and an additional bioactive agent.
14. A ribbon according to claim 13 wherein said bioactive agent is
selected from one or more of the group consisting of collagen I,
vascular endothelial growth factor (VEGF), platelet-derived growth
factor (PDGF), plated-derived epidermal growth factor (PDEGF),
basic fibroblast growth factor (bFGF), fibroblast growth factors
(FGFs), transforming growth factor-beta (TGF-.beta.),
platelet-derived angiogenesis growth factor (PDAF) and autologous
platelet gel (APG) including platelet rich plasma (PRP) and
platelet poor plasma (PPP) and thrombin.
15. A ribbon according to claim 12 wherein said ribbon is a polymer
ribbon.
16. A ribbon according to claim 12 wherein said ribbon further
comprises an osmotic mini-pump.
17. A ribbon according to claim 16 wherein said osmotic mini-pump
releases a bioactive agent.
18. A ribbon according to claim 17 wherein said bioactive agent is
selected from one or more of the group consisting of collagen I,
collagen III, vascular endothelial growth factor (VEGF),
platelet-derived growth factor (PDGF), plated-derived epidermal
growth factor (PDEGF), basic fibroblast growth factor (bFGF),
fibroblast growth factors (FGFs), transforming growth factor-beta
(TGF-.beta.), platelet-derived angiogenesis growth factor (PDAF)
and autologous platelet gel (APG) including platelet rich plasma
(PRP) and platelet poor plasma (PPP) and thrombin.
19. A ribbon according to claim 12 wherein when said flowable
collagen III is administered to said aneurysm site through an
injection catheter, flowable thrombin is also administered to said
aneurysm site through an injection catheter.
Description
CROSS REFERENCES TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of co-pending
U.S. patent application Ser. No. 10/977,545 filed Oct. 28, 2004,
which is incorporated by reference herein in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to methods and devices to
contribute to the treatment of aneurysms. More specifically, the
present invention relates to methods and devices to contribute to
the treatment of aneurysms by providing various methods through
which to administer collagen III and/or collagen III and thrombin
compositions to an aneurysm site.
BACKGROUND OF THE INVENTION
[0003] An aneurysm is a localized dilation of a blood vessel wall
usually caused by degeneration of the vessel wall. These weakened
sections of vessel walls can burst, causing an estimated 32,000
deaths in the United States each year. Additionally, aneurysm
deaths are suspected of being underreported because sudden
unexplained deaths, about 450,000 in the United States alone, are
often simply misdiagnosed as heart attacks or strokes while many of
them may be due to aneurysms.
[0004] U.S. surgeons treat approximately 50,000 abdominal aortic
aneurysms each year, typically by replacing the abnormal section of
vessel with a polymeric graft in an open surgical procedure. A
less-invasive procedure that has more recently been used is the
placement of a stent graft at the aneurysm site. Stent grafts are
tubular devices that span the aneurysm site to provide support
without replacing a section of the vessel. The stent graft, when
placed within a vessel at an aneurysm site, acts as a barrier
between blood flow and the weakened wall of a vessel, thereby
decreasing pressure on the damaged portion of the vessel. Patients
whose multiple medical comorbidities make them excessively high
risk for conventional aneurysm repair are candidates for stent
grafting.
[0005] While stent grafts can represent improvements over
previously-used vessel treatment options, there are still risks
associated with their use. The most common of these risks is
migration of the stent graft due to matrix remodeling and/or
hemodynamic forces within the vessel. Stent graft migrations can
lead to endoleaks, or leaking of blood into the aneurysm sac
between the outer surface of the graft and the inner lumen of the
blood vessel which can increase the risk of vessel rupture. Such
migrations of stent grafts are especially possible in curved
portions of vessels where asymmetrical forces place uneven forces
on the stent graft.
[0006] Based on the foregoing, one goal of treating aneurysms is to
provide stent grafts that do not migrate. To achieve this goal,
stent grafts with stainless steel anchoring barbs that engage the
vessel wall have been developed. Additionally, endostaples that fix
stent grafts more securely to the vessel wall have been developed.
While these physical anchoring devices have proven to be effective
in some patients, they have not sufficiently ameliorated stent
graft migration associated with current treatment methods in all
cases.
[0007] An additional way to reduce the risk of stent graft
migration is to administer to the treatment site, either before,
during or relatively soon after implantation, one or more growth
factors. The administration of one or more growth factors can be
beneficial because, normally, the material of the stent graft does
not provide a hospitable environment for cells in the area to grow.
As a result, the stent graft rests against the vessel wall, and may
not be incorporated into the vessel wall. If one or more growth
factors are administered immediately before, during, or relatively
soon after stent graft deployment and implantation, the smooth
muscle cells and fibroblasts will be stimulated to proliferate. As
these cells proliferate they can grow around the stent graft such
that the device becomes physically attached to the vessel wall
rather than merely resting against it. This tissue in-growth can
help to prevent stent graft migration, although it may not be
successful in all circumstances. Therefore, there is still room for
improvement in the treatment of aneurysms.
[0008] Another approach in the treatment of aneurysms, generally
applied to cerebral aneurysms, includes the use of coil
embolization. Coils used in this process are generally comprised of
platinum and coated with a polymer. They are placed within an
aneurysm sac and expected to block blood flow into the aneurysm sac
and eventually lead to clot formation, thus shielding the aneurysm
sac from the pressure of blood flow. In theory, the more organized
clot formation and the more local connective tissue formation that
occurs, the more resistant the aneurysm will be to pressure exerted
by the general circulation.
[0009] Again, while coil embolization has proven beneficial in some
patients, it is not successful in all patients. Coil embolization
is not always successful because if it fails to sufficiently close
off the aneurysm sac from blood flow, a process called
"recanalization" occurs. In this process, blood flow moves into the
area not completely closed off by clot and connective tissue
formation and "reopens" the aneurysm site. Thus, improved aneurysm
treatments are still required. The present invention provides
methods and devices to further contribute to aneurysm
treatment.
SUMMARY OF THE INVENTION
[0010] Embodiments according to the present invention provide
methods and devices through which collagen III or collagen III and
thrombin can be used to contribute to the treatment of aneurysms.
For example, embodiments according to the present invention employ
a collagen III ribbon to reinforce vessel walls and to deliver
therapeutic agents to an aneurysm sac. Embodiments according to the
present invention also provide for flowable collagen III or
flowable collagen III/thrombin administration to an aneurysm site
to mechanically reinforce the vessel walls. Collagen III and
thrombin are excellent candidates for these functions due to their
roles in cell proliferation and tissue in-growth. These various
treatments can be employed alone or in combination and can also be
employed in conjunction with more conventional stent grafting. When
employed with a stent graft, embodiments according to the present
invention can contribute to improved stent graft seal and fixation
thus contributing to a reduction in the risk of endoleaks and stent
graft migration.
[0011] Specifically, one embodiment according to the present
invention comprises a method comprising contributing to the
treatment of an aneurysm by placing a ribbon that administers
collagen III at the aneurysm site.
[0012] In another embodiment the ribbon administers collagen III
and an additional bioactive agent. In another embodiment the
additional bioactive agent is a growth factor. In another
embodiment the bioactive agent is one or more agents selected from
the group consisting of collagen I, vascular endothelial growth
factor (VEGF), platelet-derived growth factor (PDGF),
plated-derived epidermal growth factor (PDEGF), basic fibroblast
growth factor (bFGF), fibroblast growth factors (FGFs),
transforming growth factor-beta (TGF-.beta.), platelet-derived
angiogenesis growth factor (PDAF) and autologous platelet gel (APG)
including platelet rich plasma (PRP) and platelet poor plasma (PPP)
and thrombin.
[0013] In another embodiment the ribbon is a polymer ribbon.
[0014] In another embodiment the ribbon further comprises an
osmotic mini-pump. In another embodiment the osmotic mini-pump
releases a bioactive agent. In another embodiment the bioactive
agent is selected from one or more of the group consisting of
collagen I, collagen III, vascular endothelial growth factor
(VEGF), platelet-derived growth factor (PDGF), plated-derived
epidermal growth factor (PDEGF), basic fibroblast growth factor
(bFGF), fibroblast growth factors (FGFs), transforming growth
factor-beta (TGF-.beta.), platelet-derived angiogenesis growth
factor (PDAF) and autologous platelet gel (APG) including platelet
rich plasma (PRP) and platelet poor plasma (PPP) and thrombin.
[0015] In another embodiment the method further comprises
deployment of a stent graft at the aneurysm site. In another
embodiment the method further comprises administering flowable
collagen III to the aneurysm site through an injection catheter. In
another embodiment the method further comprises administering
flowable collagen III and flowable thrombin to the aneurysm site
through an injection catheter. In another embodiment the method
further comprises deployment of a stent graft at the aneurysm site
and administering flowable collagen III to the aneurysm site
through an injection catheter. In another embodiment the method
further comprises deployment of a stent graft at the aneurysm site,
administering flowable collagen III to the aneurysm site through an
injection catheter and administering flowable thrombin to the
aneurysm site through an injection catheter.
[0016] Embodiments according to the present invention also include
ribbons. In one embodiment the ribbon comprises collagen III and is
deployed at an aneurysm site in conjunction with a treatment
selected from the group consisting of the administration of
collagen III to the aneurysm site through an injection catheter;
the deployment of a stent graft at the aneurysm site; and the
administration of collagen III to the aneurysm site through an
injection catheter and the deployment of a stent graft at the
aneurysm site. In another embodiment of the ribbons, when flowable
collagen III is administered to the aneurysm site through an
injection catheter, flowable thrombin is also administered to the
aneurysm site through an injection catheter.
[0017] In another embodiment of the ribbons, the ribbon administers
collagen III and an additional bioactive agent. In another
embodiment of the ribbons, the additional bioactive agent is a
growth factor. In another embodiment of the ribbons, the bioactive
agent is selected from one or more of the group consisting of
collagen I, vascular endothelial growth factor (VEGF),
platelet-derived growth factor (PDGF), plated-derived epidermal
growth factor (PDEGF), basic fibroblast growth factor (bFGF),
fibroblast growth factors (FGFs), transforming growth factor-beta
(TGF-.beta.), platelet-derived angiogenesis growth factor (PDAF)
and autologous platelet gel (APG) including platelet rich plasma
(PRP) and platelet poor plasma (PPP) and thrombin.
[0018] In another embodiment of the ribbons, the ribbon is a
polymer ribbon.
[0019] In another embodiment of the ribbons, the ribbon further
comprises an osmotic mini-pump. In another embodiment of the
ribbons, the osmotic mini-pump releases a bioactive agent. In
another embodiment of the ribbons, the osmotic mini-pump releases a
bioactive agent selected from one or more of the group consisting
of collagen I, collagen III, vascular endothelial growth factor
(VEGF), platelet-derived growth factor (PDGF), plated-derived
epidermal growth factor (PDEGF), basic fibroblast growth factor
(bFGF), fibroblast growth factors (FGFs), transforming growth
factor-beta (TGF-.beta.), platelet-derived angiogenesis growth
factor (PDAF) and autologous platelet gel (APG) including platelet
rich plasma (PRP) and platelet poor plasma (PPP) and thrombin.
BRIEF DESCRIPTION OF THE FIGURES
[0020] FIG. 1 depicts a schematic diagram of a representative stent
graft as stent grafts are conventionally used in the treatment of
aneurysms.
[0021] FIG. 2 depicts injection catheters at an aneurysm site that
can be used to deliver flowable collagen III and/or flowable
collagen III and thrombin in accordance with the present
invention.
[0022] FIG. 3 depicts a schematic diagram of collagen III ribbons
within aneurysmal sacs in accordance with the present
invention.
[0023] FIG. 4 depicts a schematic diagram of a collagen III ribbon
with an osmotic mini pump within an aneurysm sac in accordance with
the present invention.
[0024] FIGS. 5A and 5B depict injection catheters at an aneurysm
site useful to deliver flowable collagen III and/or flowable
collagen III and thrombin in combination with a stent graft in
accordance with the present invention.
[0025] FIG. 6 depicts a schematic diagram of collagen III ribbons
within aneurysmal sacs in combination with a stent graft in
accordance with the present invention.
DEFINITION OF TERMS
[0026] Prior to setting forth embodiments according to the present
invention, it may be helpful to an understanding thereof to set
forth definitions of certain terms that will be used hereinafter.
Unless otherwise explained, all technical and scientific terms used
herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. The
singular terms "a," "an," and "the" include plural referents unless
context clearly indicates otherwise. Similarly, the word "or" is
intended to include "and" unless the context clearly indicates
otherwise. The term "comprises" means "includes."
[0027] Aneurysm: As used herein "aneurysm" shall include a weak
section of an artery wall in an animal.
[0028] Abdominal aortic aneurysm: As used herein "abdominal aortic
aneurysm" shall include a weak section of an artery wall in the
abdominal section of the aorta of an animal.
[0029] Animal: As used herein "animal" shall include mammals, fish,
reptiles and birds. Mammals include, but are not limited to,
primates, including humans, dogs, cats, goats, sheep, rabbits,
pigs, horses and cows.
[0030] Drug(s): As used herein "drug" shall include any bioactive
compound or composition having a therapeutic effect in an animal.
Exemplary, non limiting examples include small molecules, peptides,
proteins, hormones, DNA or RNA fragments, genes, cells,
genetically-modified cells, growth factors, matrix
metalloproteinase inhibitors and autologous platelet gel.
[0031] Stent graft: As used herein "stent graft" shall include a
tube comprising fabric, metal, composite, and/or derivations and
combinations of these materials that reinforces a weakened or
diseased portion of a vessel (in one instance, an aneurysm).
[0032] "Treatment" or "contributing to the treatment of": As used
herein "treatment" or "contributing to the treatment of" include
preventing the growth or progressoin of an aneurysm, retarding the
progression or growth of an aneurysm, shrinking an aneurysm or
eliminating an aneurysm.
[0033] "Administers": As used herein "administers" shall include
providing a bioactive agent in the vicinity of a target. In one
embodiment the target is the site of an aneurysm. Injection
catheters can be used to administer bioactive agents. Ribbons and
stent grafts can also administer bioactive agents. When a ribbon or
stent graft administers a bioactive agent, the bioactive agent can
remain on the ribbon or stent graft (in one embodiment on the
surface of the ribbon or stent graft) or the bioactive agent can be
released from the ribbon or stent graft through diffusion or other
processes.
[0034] Endoleak: As used herein "endoleak" refers to the presence
of blood flow past the seal between the end of a stent graft and
the vessel wall, and into the aneurysm sac, when all such flow
should be contained within the stent graft's lumen.
[0035] Migration: As used herein "migration" refers to displacement
of a stent graft from its intended implantation site.
[0036] Placed or implanted stent graft: As used herein "placed
stent graft" or "implanted stent graft" shall include a surgically
placed or implanted stent graft, either by invasive or non-invasive
techniques.
[0037] Bioactive Agents: As used herein, "bioactive agents" include
any agent that can promote cell growth and includes, without
limitation, collagen I, collagen III, thrombin, vascular
endothelial growth factor (VEGF), platelet-derived growth factor
(PDGF), plated-derived epidermal growth factor (PDEGF), basic
fibroblast growth factor (bFGF), fibroblast growth factors (FGFs),
transforming growth factor-beta (TGF-.beta.), platelet-derived
angiogenesis growth factor (PDAF) and autologous platelet gel (APG)
including platelet rich plasma (PRP) and platelet poor plasma
(PPP).
DETAILED DESCRIPTION
[0038] Embodiments of the present invention include methods and
devices that are useful in contributing to the treatment of
aneurysms. One embodiment provides methods and devices useful for
contributing to or stimulating thrombosis at an aneurysm site to
reduce the likelihood or occurrence of endoleaks. Embodiments
according to the present invention contribute to stimulating
thrombosis of vessel walls at aneurysm sites by providing various
mechanisms to deliver collagen III and/or collagen III and thrombin
to these sites. In one embodiment a flowable collagen III or
flowable collagen III/thrombin composition is administered through
an injection catheter to promote thrombosis within an aneurysm sac.
In another embodiment a collagen III ribbon is used to deliver
therapeutic agents to an aneurysm sac. Collagen III is an excellent
candidate for these functions due to its roles in cell adhesion and
wound healing. These various treatments can be employed alone or in
combination and can also be employed in conjunction with more
conventional stent grafting. Embodiments according to the present
invention also provide for the delivery of other therapeutic agents
including, without limitation, a variety of bioactive agents. When
stent grafts are employed in combination with embodiments according
to the present invention, these embodiments can also contribute to
enhanced stent graft fixation at the vessel treatment site.
[0039] As discussed above, an aneurysm is a dilation, or expansion
of a vessel lumen at a defined point and is generally associated
with a vessel wall defect. Aneurysms are often multi-factorial
asymptomatic vessel diseases that if left unchecked can result in
spontaneous rupture, often with fatal consequences. One method to
treat aneurysms involves a highly invasive surgical procedure where
the affected vessel region is removed and replaced with a synthetic
graft that is sutured in place. However, this procedure is
extremely risky and generally only employed in patients who can be
expected to survive the associated surgical trauma. Feeble patients
are not candidates for these aneurysmal surgeries, and, before the
development of stent grafts, remained untreated and at continued
risk for sudden death.
[0040] In contrast to the described invasive surgical procedures,
other treatments can be performed using minimally invasive
procedures. Essentially, a catheter having a treatment mechanism
compressed and fitted into the catheter's distal tip is advanced
through an artery to the aneurysmal site. The treatment is then
performed within the vessel lumen juxtaposed to the weakened vessel
wall. One treatment option that adopts this approach is the
implantation of a stent graft at an aneurysm site. In this
procedure, a stent graft is provided "pre-loaded" into a delivery
catheter (not shown). In the embodiment depicted in FIG. 1, the
stent graft 100 has a body section 101 and a leg section 108. In
stent graft deployment protocols, the body section 101 of stent
graft 100 is fully deployed through the right iliac artery 114 to
an aneurysm site through a first delivery catheter (not shown). The
body section 101 of stent graft 100 has a distal end 102. The leg
section 108 of stent graft 100 is deployed in a second delivery
catheter and anchors the stent graft 100 in the iliac artery 116.
The body section 101 and the leg section 108 of stent graft 100 are
joined with an overlap between the two segments 106. Problems with
stent graft migration after implantation, however, prevent this
treatment option from performing adequately in all patients. Thus,
additional treatment options are required.
[0041] Collagen, a major component of the extracellular matrix, is
in some forms a fibrous protein that provides tensile strength to
tissues. It strengthens blood vessels and plays an important role
in tissue development. Collagen can provide a unique ligand for
platelets during endothelialization and tissue in-growth due to the
fact that it both causes platelet activation and supports adhesion
thus leading to platelet aggregate formation.
[0042] Collagen exists in several different forms. Collagen I is
composed of 2 .alpha.1(I) and one .alpha.2(I) chains while collagen
III is a homotrimeric procollagen comprised of three identical
pro-.alpha. (III) chains (NCBI Protein Sequence Listing Accession
Number PO2461). Collagen III is found co-localized with collagen I
in blood vessels, tissues and skin. While collagen I is more
abundant than collagen III, collagen III appears first at wound
sites and initiates hemostatic processes. Collagen III can also
demonstrate superior adhesion strength, larger surface area and
higher hemostatic activity than collagen I. Thus, collagen III
provides an important method to stimulate adhesion and tissue
in-growth at implantable medical device implantation sites.
[0043] Thrombin is a pluripotent serine protease that also plays a
central role in hemostasis following tissue injury by converting
soluble plasma fibrinogen into an insoluble fibrin clot and by
promoting platelet aggregation (Chambers et al., J. Biol. Chem.
275(45):35584-35591, Nov. 10, 2000). In addition to these
procoagulant effects, thrombin also influences a number of cellular
responses that play important roles in subsequent inflammatory and
tissue repair processes. Thrombin influences the recruitment and
trafficking of inflammatory cells and is a potent mitogen for a
number of cell types, including endothelial cells, fibroblasts, and
smooth muscle cells. Thrombin also promotes the production and
secretion of extracellular matrix proteins and influences tissue
remodeling processes. There is increasing in vivo evidence that the
pro-inflammatory and profibrotic effects of thrombin play an
important role in vascular repair.
[0044] Most of the cellular effects elicited by thrombin are
mediated via a family of widely expressed G-protein-coupled
receptors that are activated by limited proteolytic cleavage of the
N-terminal extracellular domain. Once thrombin has interacted with
its receptor, it exerts its cellular effects either directly or via
the induction and release of secondary mediators, including
classical growth factors, pro-inflammatory cytokines, and
vasoactive peptides and amines.
[0045] Due to these complementary effects, collagen III and
thrombin either alone or in combination can provide mechanisms for
the treatment of aneurysms. Administration of these agents at an
aneurysm site can lead to clotting and local organization of
thrombus thus stabilizing the aneurysm sac and diffusing the
pressure from blood flow. Thus, as shown in FIG. 2, one embodiment
according to the present invention involves administering flowable
collagen III and/or flowable collagen III and thrombin to an
aneurysm sac 104 using injection catheters 500, 302 inserted via
the left and/or right iliac artery. If required, a guide wire lumen
can also be included. Bioactive agents including, without
limitation, collagen III and/or collagen III and thrombin can be
injected simultaneously or sequentially between the two injection
catheters 500, 302 to form coatings 211 (note that one injection
catheter can also be used in accordance with the presently
described embodiment). Injection catheters 500, 302 have injection
ports 304, 305 and 306 through which one or more bioactive agents,
including without limitation flowable collagen III and/or flowable
collagen III and thrombin can be delivered to the treatment site
(as will be understood by one of ordinary skill in the art,
injection catheters 500, 302 can include different appropriate
numbers of injection lumens and ports including, without
limitation, one, two, three, four or five). Alternatively, the
catheter could be a multilumen catheter with one lumen reserved for
collagen III injection and the other reserved for thrombin
injection. The injection catheters 500, 302 can then be retrieved.
The administration of these agents can provide a coating 211 on the
weakened vessel walls or the already formed thrombus within the
aneurysm sac that can stimulate organized thrombus formation at the
site thus contributing to the stabilization of the aneurysm sac and
overall aneurysm treatment.
[0046] In this embodiment depicted in FIG. 2, sensors 411, 413 are
also provided on the injection catheters. In embodiments according
to the present invention, these sensors can be one or more of
pressure sensors, temperature sensors, pH sensors, blood sugar
sensors, blood oxygen sensors, motion sensors, flow sensors,
velocity sensors, acceleration sensors, force sensors, strain
sensors, acoustic sensors, moisture sensors, osmolarity sensors,
light sensors, turbidity sensors, radiation sensors,
electromagnetic field sensors, chemical sensors, ionic sensors
and/or enzymatic sensors. In one embodiment, the sensors can employ
wireless telemetry to deliver information from the implantation
site to an instrument external to the body. In another embodiment,
the sensors of the present invention can be constructed in
accordance with the teachings of U.S. Pat. No. 5,704,352 to
Tremblay and Buckles which is incorporated by reference.
Alternatively, sensors as described in U.S. Pat. No. 6,632,196 to
Houser, which is incorporated by reference can also be used. Other
appropriate sensors include, without limitation, optical-fiber
based transducers as manufactured by RJC Enterprises of
Woodinville, Wash. and described in U.S. Pat. No. 6,052,613 to
Takaki or as described in "Fiber-optic Transducer Aids Heart
Monitoring," Engineering News, Jun. 7, 1999, both of which are
incorporated herein by reference. A model FOP-M in vivo pressure
sensor, manufactured by FISO Technologies, of Quebec, Canada, also
can be used in accordance with the present invention as well as
other sensor constructions that are known to those of ordinary
skill in the art.
[0047] FIG. 3 depicts an alternative collagen III and/or collagen
III and thrombin delivery method according the present invention.
In this embodiment a polymer coated with collagen III ribbon(s) are
placed within aneurysmal sac(s). Essentially, a catheter including
a ribbon according to the present invention is advanced to a
treatment site 104, 104' and the ribbon 502, 502' is deployed with
the use of a super-compliant balloon that can be used to press the
ribbon 502, 502' against the aneurysm sac wall. In this embodiment,
the collagen III and/or thrombin combination acts as an adhesive,
to create better adhesion between the ribbon and vessel wall or sac
thrombus. The binding properties of collagen III and/or thrombin
allow it to adhere to the inner aneurysm sac with far superiority
to a polymer ribbon with no coating. In this embodiment the
collagen III can also act as a drug delivery matrix for itself
and/or another therapeutic that can reduce the size or rate of
expansion of the aneurysm sac. As shown in FIG. 4, collagen III
ribbons 502 according to the present invention can also comprise an
osmotic mini pump 522 to deliver additional therapeutic agents to
the treatment sites 104, 104'. Such a pump can be, without
limitation, an appropriate programmable pump from Medtronic P. L.,
(Minneapolis, Minn.) or an Alzet osmotic mini-pump.
[0048] Embodiments according to the present invention can also be
used in conjunction with more conventional stent grafting. For
example, FIGS. 5A and 5B, depict how collagen III and/or collagen
III and thrombin could be administered to provide collagen III
and/or collagen III and thrombin coatings 211 through injection
catheters 500, 302 in conjunction with an independent stent graft
delivery catheter 300. While the administration of collagen III
and/or collagen III and thrombin can be extremely beneficial, this
administration at an aneurysm site where a stent graft will be
deployed can also be problematic, because an increase in volume and
internal pressure caused by the administration of these exogenous
substance can increase internal pressure and the resulting
possibility of further expansion of the aneurysm sac. Thus, the
embodiment depicted in FIGS. 5A and 5B employs injection catheters
500 and 302 that can deliver collagen III and/or collagen III and
thrombin while maintaining nearly-constant pressure in the area.
The depicted injection catheters 500 and 302 achieve
nearly-constant pressure by providing at least one exit lumen 511
as well as injection lumens 304, 306. As collagen III and/or
collagen III and thrombin are administered to the site through the
one or more injection lumens 304, 306, displaced blood or other
fluids in the area that would normally contribute to an increase in
internal pressure at the administration site, instead leaves the
site through exit port and lumen 511. Thus, nearly-constant
pressure at the administration site can be maintained despite the
addition of collagen III and/or collagen III and thrombin within
this confined space. As will be understood by one of ordinary skill
in the art, the exit port(s) and exit lumen(s) used in accordance
with the present invention can adopt various appropriate forms. For
example, in one embodiment, the exit port and lumen can consist of
a tube with a diameter that is larger than the diameter of the
injection catheter that splits off from the injection catheter
within the aneurysm sac.
[0049] In the embodiment depicted in FIGS. 5A and 5B, the body
portion 101 of a stent graft is radially compressed into a stent
graft chamber of stent delivery catheter 300 (second delivery
catheter for leg section not shown). Stent delivery catheter 300 is
then deployed to a treatment site via the right iliac artery 114
(note that it could also be delivered via the left iliac artery).
Multilumen injection catheters 500, 302 are also deployed to the
treatment site through the left iliac artery 116 and the right
iliac artery 114. The multilumen injection catheters 500, 302 can
be coaxial catheters with one or two injection lumens and one or
two exit lumens. If required, a guide wire lumen can also be
included. Injection catheters 500, 302 have injection ports 304 and
306 through which one or more bioactive agents, including without
limitation flowable collagen III and/or flowable collagen III and
thrombin can be delivered to the treatment site. As stated, exit
port 305 provides an avenue for fluids in the area of the treatment
site to exit before a significant increase in internal pressure in
the area occurs.
[0050] In the first step of the deployment scheme depicted in FIG.
5A, the stent delivery catheter 300 and the injection catheters
500, 302 are deployed independently to the treatment site. As shown
in FIG. 5B, the injection catheters 500, 302 can remain at the
treatment site after stent graft 100 deployment and removal of the
delivery catheter. Here, the injection ports are not aligned with
the proximal end 102 of the stent graft 100, but instead are found
within the aneurysm sac 104. In other embodiments, however, these
injection ports could be positioned at any location at the
treatment site including, without limitation, at the proximal end
102 of the body section 101 of the stent graft 100 and/or the
distal end of the leg portion of the stent graft in the iliac
artery. Bioactive agents including, without limitation, collagen
III and/or collagen III and thrombin can be injected simultaneously
or sequentially between the two injection catheters 500, 302 to
form coatings 211. Alternatively, the catheter could be a
multilumen catheter with one lumen reserved for collagen III
injection and the other reserved for thrombin injection. The
injection catheters 500, 302 can then be retrieved. This same
procedure can be repeated as necessary to apply bioactive agents to
the stent graft and/or luminal wall and/or at other locations as
needed.
[0051] FIG. 6 depicts polymer ribbons coated with collagen III
and/or thrombin in accordance with the present invention employed
in conjunction with a stent graft. In this embodiment, the
collagen/thrombin coated ribbons 502, 502' would be used to deliver
a bioactive agent to the aneurysm. The collagen/thrombin coated
ribbons are first deployed to the treatment sites 104, 104' as
previously described. After deployments of the collagen/thrombin
coated ribbons 502, 502, a stent graft 100 can be delivered and
implanted as described in reference to FIG. 1. Employing these
treatment options in combination could provide for better aneurysm
treatment than use of either treatment alone. Importantly, when
stent grafts are employed in combination with embodiments according
to the present invention, collagen III and/or collagen III and
thrombin can be used to deliver therapeutic, bioactive agents that
would contribute to the stabilization of the aneurysm sac.
Stabilization of the aneurysm sac includes preventing or delaying
matrix remodeling within the aneurysm wall. This allows the stent
graft to remain in it originally deployed position, allowing it to
maintain seal and fixation.
[0052] Additional devices and methods related to the use of
collagen III and/or thrombin in the seal and fixation of stent
grafts to vessel wall at an aneurysm site are described in
co-pending U.S. patent application Ser. No. ______, entitled
"Methods and Devices for Contributing to Improved Stent Graft
Fixation" filed on date even with the present application and known
to all by attorney docket number PA1937, which is hereby
incorporated by reference in its entirety.
[0053] Incorporation by tissue in-growth of treatment devices in
accordance with the present invention can be further stimulated by
inclusion of (either by coating onto a stent graft, incorporating
into or coating onto a ribbon or by injection at the treatment
site), without limitation, at least one growth factor including
vascular endothelial growth factor (VEGF) and fibroblast growth
factors 1 and 2 (FGF-1, FGF-2) and basic fibroblast growth factor
(bFGF). The discussion of these factors is for exemplary purposes
only, as those of skill in the art will recognize that numerous
other growth factors have the potential to induce cell-specific
migration and proliferation. Co-pending U.S. patent application
Ser. No. 10/977,545, filed Oct. 28, 2004 which is hereby
incorporated by reference for all it discloses regarding bioactive
agents, discloses injecting autologous platelet gel (APG) into the
aneurysm sac and/or between an implanted stent graft and the vessel
wall to induce incorporation of the stent graft into the vessel
wall to prevent stent graft migration, loss of seal, and resulting
endoleak. The development of genetically-engineered growth factors
also is anticipated to yield more potent cell-specific growth
factors. Delivery of cells that are genetically modified to deliver
specific growth factors are another promising route for growth
factor delivery. Additionally it may be possible to identify small
molecule drugs that can induce cell migration, proliferation, and
chemotaxis. Thus, the stent grafts of the present invention can
improve tissue in-growth through providing substances that induce
cell migration and/or cell proliferation, and possibly promote
inflammatory responses near the ends of the stent graft, and in
some embodiments further by providing and releasing a bioactive
agent at one or more ends or along the length of the stent
graft.
[0054] The field of medical device coatings is well established and
methods for coating stent grafts with drugs, with or without added
polymers, are well known to those of skill in the art. Non-limiting
examples of coating procedures include spraying, dipping, waterfall
application, heat annealing, etc. The amount of coating applied to
a stent graft can vary depending upon the desired effect of the
compositions contained within the coating. The coating may be
applied to the entire stent graft or to a portion of the stent
graft. Thus, various drug coatings applied to the presently-claimed
stent grafts are within the scope of the present invention.
[0055] Unless otherwise indicated, all numbers expressing
quantities of ingredients, properties such as molecular weight,
reaction conditions, and so forth used in the specification and
claims are to be understood as being modified in all instances by
the term "about." Accordingly, unless indicated to the contrary,
the numerical parameters set forth in the following specification
and attached claims are approximations that may vary depending upon
the desired properties sought to be obtained by the present
invention. At the very least, and not as an attempt to limit the
application of the doctrine of equivalents to the scope of the
claims, each numerical parameter should at least be construed in
light of the number of reported significant digits and by applying
ordinary rounding techniques. Notwithstanding that the numerical
ranges and parameters setting forth the broad scope of the
invention are approximations, the numerical values set forth in the
specific examples are reported as precisely as possible. Any
numerical value, however, inherently contains certain errors
necessarily resulting from the standard deviation found in their
respective testing measurements.
[0056] The terms "a" and "an" and "the" and similar referents used
in the context of describing the invention (especially in the
context of the following claims) are to be construed to cover both
the singular and the plural, unless otherwise indicated herein or
clearly contradicted by context. Recitation of ranges of values
herein is merely intended to serve as a shorthand method of
referring individually to each separate value falling within the
range. Unless otherwise indicated herein, each individual value is
incorporated into the specification as if it were individually
recited herein. All methods described herein can be performed in
any suitable order unless otherwise indicated herein or otherwise
clearly contradicted by context. The use of any and all examples,
or exemplary language (e.g. "such as") provided herein is intended
merely to better illuminate the invention and does not pose a
limitation on the scope of the invention otherwise claimed. No
language in the specification should be construed as indicating any
non-claimed element essential to the practice of the invention.
[0057] Groupings of alternative elements or embodiments of the
invention disclosed herein are not to be construed as limitations.
Each group member may be referred to and claimed individually or in
any combination with other members of the group or other elements
found herein. It is anticipated that one or more members of a group
may be included in, or deleted from, a group for reasons of
convenience and/or patentability. When any such inclusion or
deletion occurs, the specification is herein deemed to contain the
group as modified thus fulfilling the written description of all
Markush groups used in the appended claims.
[0058] Certain embodiments of this invention are described herein,
including the best mode known to the inventors for carrying out the
invention. Of course, variations on these described embodiments
will become apparent to those of ordinary skill in the art upon
reading the foregoing description. The inventor expects skilled
artisans to employ such variations as appropriate, and the
inventors intend for the invention to be practiced otherwise than
specifically described herein. Accordingly, this invention includes
all modifications and equivalents of the subject matter recited in
the claims appended hereto as permitted by applicable law.
Moreover, any combination of the above-described elements in all
possible variations thereof is encompassed by the invention unless
otherwise indicated herein or otherwise clearly contradicted by
context.
[0059] Furthermore, numerous references have been made to patents
and printed publications throughout this specification. Each of the
above cited references and printed publications are herein
individually incorporated by reference in their entirety.
[0060] In closing, it is to be understood that the embodiments of
the invention disclosed herein are illustrative of the principles
of the present invention. Other modifications that may be employed
are within the scope of the invention. Thus, by way of example, but
not of limitation, alternative configurations of the present
invention may be utilized in accordance with the teachings herein.
Accordingly, the present invention is not limited to that precisely
as shown and described.
* * * * *