U.S. patent application number 11/276518 was filed with the patent office on 2006-06-22 for autologous growth factors to promote tissue in-growth in vascular device.
This patent application is currently assigned to Medtronic Vascular, Inc.. Invention is credited to Jack Chu, Scott Doig, Brian Fernandes, Trevor Huang, Josiah Wilcox.
Application Number | 20060136050 11/276518 |
Document ID | / |
Family ID | 35853579 |
Filed Date | 2006-06-22 |
United States Patent
Application |
20060136050 |
Kind Code |
A1 |
Chu; Jack ; et al. |
June 22, 2006 |
Autologous Growth Factors to Promote Tissue In-Growth in Vascular
Device
Abstract
Methods and devices for ameliorating stent graft migration and
endoleak using treatment site-specific cell growth promoting
compositions in combination with stent grafts are disclosed. Also
disclosed is coating of autologous growth factor compositions onto
stent grafts prior to stent graft implantation. Additional
embodiments include stent grafts having autologous growth factor
composition coatings useful for treating aneurysms.
Inventors: |
Chu; Jack; (Santa Rosa,
CA) ; Doig; Scott; (Santa Rosa, CA) ;
Fernandes; Brian; (Roseville, MN) ; Huang;
Trevor; (Maple Grove, MN) ; Wilcox; Josiah;
(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.: |
11/276518 |
Filed: |
March 3, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10977545 |
Oct 28, 2004 |
|
|
|
11276518 |
Mar 3, 2006 |
|
|
|
Current U.S.
Class: |
623/1.42 |
Current CPC
Class: |
A61L 2300/414 20130101;
A61L 27/3645 20130101; A61L 27/3616 20130101; A61L 27/54 20130101;
A61L 27/3641 20130101 |
Class at
Publication: |
623/001.42 |
International
Class: |
A61F 2/06 20060101
A61F002/06 |
Claims
1. A method for providing a stent graft and a cell growth-promoting
composition comprising: obtaining autologous platelet rich plasma
(PRP) from a patient in need of a stent graft; activating said PRP
to form autologous growth factor composition; coating said stent
graft with said autologous growth factor composition; and
implanting said autologous growth factor composition-coated stent
graft into a vessel at a treatment site in a patient wherein said
autologous growth factor composition-coated stent graft induces
endothelialization of said stent graft.
2. The method of claim 1 wherein said coating step comprises
injecting autologous growth factor composition through at least one
injection port in a delivery catheter such that said autologous
growth factor composition wets said stent graft disposed within
said delivery catheter.
3. The method of claim 1 further comprising providing a drug in
combination with said autologous growth factor composition wherein
said drug is selected from the group consisting of small molecules,
peptides, proteins, hormones, DNA or RNA fragments, cells,
genetically engineered cells, genes, cell growth promoting
compositions, matrix metalloproteinase inhibitors, antibiotics,
cyclooxygenase-2 inhibitors, angiotensin-converting enzyme
inhibitors, glucocorticoids, beta blockers, nitric acid synthase
inhibitors, antioxidants and cellular adhesion molecules.
4. The method of claim 1 wherein said activating step comprises
mixing said PRP with an activating agent
5. The method of claim 4 wherein said activating agent is a
platelet agonist.
6. The method of claim 5 wherein said platelet agonist is adenosine
diphosphate (ADP) or thrombin receptor activating peptide
(TRAP).
7. The method of claim 6 wherein said platelet agonist is 5 to 20
.mu.M of said ADP.
8. The method of claim 6 wherein said platelet agonist is 5 to 10
.mu.M of said TRAP.
9. The method of claim 1 wherein said autologous growth factor
composition is centrifuged to remove cells and cellular
particulates prior to said coating step.
10. The method of claim 1 wherein said treatment site is an
aneurysm site
11. The method of claim 1 wherein said stent graft is pre-coated
with a base coating material selected from the group consisting of
heparin, hyaluronate, alginate, collagen, fibrin, dextran,
.beta.-cyclodextrin, polyvinyl alcohol and hydrogel prior to
coating with said autologous growth factor composition.
12. A delivery catheter for delivering a stent graft to a vessel in
a patient in need thereof, having disposed therein a stent graft,
comprising at least one injection port through which coating
composition(s) are injected to coat said stent graft.
13. The delivery catheter according to claim 12 wherein said
coating composition(s) is autologous growth factor composition or a
pre-coating material.
14. The delivery catheter according to claim 12 comprising a
plurality of injection ports.
15. The delivery catheter according to claim 14 wherein said
plurality of injection ports are disposed along the length of said
delivery catheter such that the entire stent graft is accessible by
said plurality of injection ports.
16. An endothelialization promoting stent graft for implantation
into a patient in need thereof comprising a stent graft having an
autologous growth factor composition deposited thereon.
17. The endothelialization promoting stent graft according to claim
16 further comprising a base coat between said stent graft and said
autologous growth factor composition coating wherein said base coat
comprises a material selected from the group consisting of heparin,
hyaluronate, alginate, collagen, fibrin, dextran,
.beta.-cyclodextrin, polyvinyl alcohol and hydrogen.
18. The endothelialization promoting stent graft according to claim
16 wherein said autologous growth factor composition is isolated
from said patient at the time of stent graft implantation.
19. The endothelialization promoting stent graft according to claim
16 wherein said stent graft is coated with said autologous growth
factor composition at the time of stent graft implantation.
Description
RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S. patent
application Ser. No. 10/977,545, filed Oct. 28, 2004, which is
herein incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] Methods and devices for preventing vascular device migration
using autologous growth factor composition-coated vascular devices
are disclosed. Specifically, methods for producing autologous
growth factor compositions and coating vascular devices with the
compositions before device implantation are provided.
BACKGROUND OF THE INVENTION
[0003] A variety of implantable vascular devices, including stent
grafts and stents, have been developed to treat abnormalities of
the vascular system. Stent grafts are used to treat aneurysms of
the vascular system and have also emerged as a new treatment for a
related condition, acute blunt aortic injury, where trauma causes
damage to an artery. Stents are used to treat areas of vessel
narrowing or atherosclerosis.
[0004] Aneurysms arise when a thinning, weakening section of vessel
wall balloons out to more than 150% of its normal diameter. These
thinned and 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.
[0005] U.S. surgeons treat approximately 50,000 abdominal aortic
aneurysms each year, typically by replacing the abnormal section of
vessel with a plastic or fabric 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 to provide
support without replacing a section of the vessel. The stent graft,
when placed within the artery at the aneurysm site, acts as a
barrier between blood flow and the weakened wall of the artery,
thereby decreasing pressure on the damaged portion of the artery.
This less invasive approach to treating aneurysms decreases the
morbidity seen with conventional aneurysm repair. Additionally,
patients whose multiple medical comorbidities make them excessively
high risk for conventional aneurysm repair are candidates for stent
grafting.
[0006] Stents are rigid, or semi-rigid, tubular scaffoldings that
are used to treat vessel narrowing or atherosclerosis, the leading
cause of death in the United States. Specifically, atherosclerosis
and other forms of coronary artery narrowing are treated with
percutaneous transluminal angioplasty ("angioplasty"). The
objective of angioplasty is to enlarge the lumen of an affected
vessel by radial hydraulic expansion. The procedure is accomplished
by inflating a balloon within the narrowed lumen of the affected
artery. After (or during) such an angioplasty procedure, stents are
deployed at the treatment site within the vessel to reduce the
risks of reclosure. Stents are generally positioned across the
treatment site, and then expanded to keep the passageway clear. The
stent provides a scaffold which overcomes the natural tendency of
the vessel walls of some patients to renarrow, thus maintaining the
openness of the vessel and resulting blood flow.
[0007] While stent grafts and stents (hereinafter collectively
referred to as "vascular devices") represent improvements over
previously-used vessel treatment techniques, there are still risks
associated with them. The most common of these risks is migration
of the vascular device due to hemodynamic forces within the vessel.
Stent graft migrations lead to endoleaks, a leaking of blood into
the aneurysm sac between the outer surface of the graft and the
inner lumen of the blood vessel. Stent migration can leave a
treated area of a vessel more susceptible to reclosure. Such
migrations of vascular devices are especially possible in curved
portions of vessels where asymmetrical hemodynamic forces in the
area can place uneven forces on the vascular device. Additionally,
the asymmetrical hemodynamic forces can cause remodeling of an
aneurysm sac which leads to increased risk of aneurysm rupture and
increased endoleaks.
[0008] Based on the foregoing, one goal of treating aneurysms and
vessel narrowings is to provide vascular devices that do not
migrate. To achieve this goal, vascular devices with stainless
steel anchoring barbs that engage the vessel wall have been
developed. Additionally, endostaples that fix vascular devices more
readily to the vessel wall have been developed. While these
physical anchoring devices have proven to be effective in some
patients, improvements continue to be sought to assure the position
of stent grafts once placed.
[0009] Additionally, the combination of the metal scaffolding of
most stent grafts and graft migration in a small percentage of
cases has led to the contraindication of magnetic resonance imaging
(MRI) in some patients having stent grafts. The magnetic fields
used in this imaging process, when moving across the body, may
cause insufficiently fixated metal-containing stents to
migrate.
[0010] One way to improve vascular device fixation is to administer
to the treatment site, either before, during or relatively soon
after implantation, a cell growth-promoting factor. This
administration can be beneficial because, normally, the endothelial
cells that make up the portion of the vessel to be treated are
quiescent at the time of vascular device implantation and do not
multiply. As a result, the vascular device rests against a
quiescent endothelial cell layer. If cell growth-promoting
compositions are administered immediately before, during or
relatively soon after vascular device deployment, the normally
quiescent endothelial cells lining the vessel wall, and in intimate
contact with the vascular device, will be stimulated to
proliferate. The same will occur with smooth muscle cells and
fibroblasts found within the vessel wall. As these cells
proliferate they can grow into, on and/or around the vascular
device such that the vascular device becomes physically attached to
the vessel lumen rather than merely resting against it. This
endothelialization helps promote vascular device fixation.
[0011] Endothelialization has been observed to naturally occur in
some human stent grafts within weeks of implantation. This natural
endothelialization is not complete or consistent, however, and
therefore does not in some cases prevent the stent graft migration
and endoleak. Methods to increase endothelialization are sought to
improve clinical outcome after stent grafting.
[0012] Based on the above discussed issues, additional methods for
fixating stent grafts to vessel walls are needed to further prevent
occurrences of endoleaks and stent graft migration.
SUMMARY OF THE INVENTION
[0013] The risk of stent graft migration can be reduced by
delivering to the treatment site, as a coating on the stent graft,
endothelialization factors such as autologous growth factor
compositions. This administration can be beneficial because,
normally, the endothelial cells that make up the portion of the
vessel to be treated are quiescent at the time of stent graft
implantation and do not multiply. As a result, the stent graft
rests against a quiescent endothelial cell layer. If autologous
growth factor compositions are administered to the treatment site
with the stent graft deployment, the normally quiescent endothelial
cells lining the vessel wall, and in intimate contact with the
stent graft, will be stimulated to proliferate. The same will occur
with smooth muscle cells and fibroblasts found within the vessel
wall. As these cells proliferate they can grow into and around the
stent graft lining such that the stent graft becomes physically
attached to the vessel lumen rather than merely resting against it.
This endothelialization helps to prevent stent graft migration.
These methods can promote healing, reduce endoleaks and minimize
device migration by promoting endothelial tissue in-growth.
[0014] Based on the foregoing, embodiments according to the present
invention provide stent grafts having autologous growth factor
compositions coated thereon for the treatment of aneurysms, and
associated methods for using and/or manufacturing the stent grafts.
Additionally, stent grafts are disclosed which provide structural
support for weakened arterial walls while the accompanying
compositions promote tissue in-growth to reduce the chance of graft
migration and endoleaks.
[0015] Therefore, embodiments according to the present invention
provide methods for providing a stent graft and a cell
growth-promoting composition comprising obtaining autologous
platelet rich plasma (PRP) from a patient in need of a stent graft,
activating the PRP to form autologous growth factor composition,
coating the stent graft with the autologous growth factor
composition and implanting the autologous growth factor
composition-coated stent graft into a vessel at a treatment site in
a patient wherein the autologous growth factor composition-coated
stent graft induces endothelialization of the stent graft.
[0016] In one embodiment of the method for providing a stent graft
and a cell growth-promoting composition, the coating step comprises
injecting autologous growth factor composition through at least one
injection port in a delivery catheter such that said autologous
growth factor composition wets the stent graft disposed within the
delivery catheter.
[0017] In another embodiment of the method for providing a stent
graft and a cell growth-promoting composition, the method further
comprises providing a drug in combination with the autologous
growth factor composition wherein the drug is selected from the
group consisting of small molecules, peptides, proteins, hormones,
DNA or RNA fragments, cells, genetically engineered cells, genes,
cell growth promoting compositions, matrix metalloproteinase
inhibitors, antibiotics, cyclooxygenase-2 inhibitors,
angiotensin-converting enzyme inhibitors, glucocorticoids, beta
blockers, nitric acid synthase inhibitors, antioxidants and
cellular adhesion molecules.
[0018] In yet another embodiment of the method for providing a
stent graft and a cell growth-promoting composition, the activating
step comprises mixing said PRP with an activating agent such as,
but not limited to, a platelet agonist. In one embodiment the
platelet agonist is adenosine diphosphate (ADP), preferably at a
concentration of 5 to 20 .mu.M, or thrombin receptor activating
peptide (TRAP), preferably at a concentration of 5 to 10 .mu.M.
[0019] In an embodiment of the method for providing a stent graft
and a cell growth-promoting composition, the autologous growth
factor composition is centrifuged to remove cells and cellular
particulates prior to the coating step.
[0020] In another embodiment of the method for providing a stent
graft and a cell growth-promoting composition, the said treatment
site is an aneurysm site
[0021] In another embodiment of the method for providing a stent
graft and a cell growth-promoting composition, the stent graft is
pre-coated with a base coating material selected from the group
consisting of heparin, hyaluronate, alginate, collagen, fibrin,
dextran, .beta.-cyclodextrin, polyvinyl alcohol and hydrogel prior
to coating with said autologous growth factor composition.
[0022] Another embodiment according to the present invention
provides a delivery catheter for delivering a stent graft to a
vessel in a patient in need thereof, having disposed therein a
stent graft, comprising at least one injection port through which
coating composition(s) are injected to coat the stent graft. In
another embodiment, the coating composition(s) is autologous growth
factor composition or a pre-coating material.
[0023] In another embodiment of the delivery catheter, the delivery
catheter comprises a plurality of injection ports wherein the
plurality of injection ports are disposed along the length of the
delivery catheter such that the entire stent graft is accessible by
the plurality of injection ports.
[0024] One embodiment of the present invention provides an
endothelialization promoting stent graft for implantation into a
patient in need thereof comprising a stent graft having an
autologous growth factor composition deposited thereon.
[0025] In an embodiment of the endothelialization promoting stent
graft, the stent graft further comprises a base coat between the
stent graft and the autologous growth factor composition coating
wherein the base coat comprises a material selected from the group
consisting of heparin, hyaluronate, alginate, collagen, fibrin,
dextran, .beta.-cyclodextrin, polyvinyl alcohol and hydrogen.
[0026] In another embodiment of the endothelialization promoting
stent graft, the autologous growth factor composition is isolated
from the patient at the time of stent graft implantation. In yet
another embodiment, the stent graft is coated with the autologous
growth factor composition at the time of stent graft
implantation.
BRIEF DESCRIPTION OF THE FIGURES
[0027] FIG. 1 depicts a fully deployed stent graft with an exterior
metal scaffolding as used in one embodiment according to the
present invention.
[0028] FIGS. 2a-b depict a stent graft delivery catheter containing
injection ports for coating the stent graft with autologous growth
factor composition(s) immediately prior to deployment in accordance
with the teachings of the present invention. FIG. 2b is a
cross-section of the stent graft delivery catheter depicted in FIG.
2a.
[0029] FIG. 3 depicts the effects of autologous platelet gel on
human microvascular endothelial cell proliferation.
[0030] FIG. 4 depicts the effects of autologous platelet gel on
arterial smooth muscle cell proliferation.
[0031] FIG. 5 depicts the effects of autologous platelet gel on
endothelial cell migration.
DEFINITION OF TERMS
[0032] 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."
[0033] Activating Agent(s): As used herein, "activating agent(s)"
shall include platelet agonist(s) that are capable of inducing
platelet activation which lead to platelet degranulation and
release of growth factors stored within alpha granules. Exemplary,
non-limiting examples of activating agents include adenosine
diphosphate (ADP) and thrombin receptor agonist peptide (TRAP).
[0034] Animal: As used herein, "animal" shall include, without
limitation, mammals, fish, reptiles and birds. Mammals include, but
are not limited to, primates, including humans, dogs, cats, goats,
sheep, rabbits, pigs, horses and cows.
[0035] Autologous Growth Factor Composition: As used herein,
"autologous growth factor composition" includes to growth factors
released from platelets after activation of the platelets with an
activating agent. Autologous growth factor composition can refer to
a composition that either contains, or have been centrifuged to
remove, platelet cellular material after activation.
[0036] Biocompatible: As used herein "biocompatible" refers to any
material that does not cause injury or death to the animal or
induce an adverse reaction in an animal when placed in intimate
contact with the animal's tissues. Adverse reactions include,
without limitation, inflammation, infection, fibrotic tissue
formation, cell death, embolizations and/or thrombosis.
[0037] Bioactive Material: As used herein, "bioactive material(s)"
shall include any compound or composition that creates a
physiological and/or biological effect in an animal. Non-limiting
examples of bioactive materials include small molecules, peptides,
proteins, hormones, DNA or RNA fragments, genes, cells,
genetically-modified cells, cell growth promoting compositions,
matrix metalloproteinase inhibitors, autologous platelet gel,
platelet rich plasma, either inactivated or activated, other
natural and synthetic gels, such as, without limitation, alginates,
collagens, and hyaluronic acid, polyethylene oxide, polyethylene
glycol, and polyesters, as well as combinations of these bioactive
materials.
[0038] Cell Growth Promoting Compositions: As used herein, "cell
growth promoting factors" or "cell growth promoting compositions"
shall include any bioactive material having a growth promoting
effect on vascular cells. Non-limiting examples of cell growth
promoting compositions include vascular endothelial growth factor
(VEGF), platelet-derived growth factor (PDGF), platelet-derived
epidermal growth factor (PDEGF), 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), platelet poor plasma (PPP)
and thrombin.
[0039] 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, cell growth promoting compositions,
matrix metalloproteinase inhibitors, antibiotics, cyclooxygenase-2
inhibitors, angiotensin-converting enzyme inhibitors,
glucocorticoids, beta blockers, nitric acid synthase inhibitors,
antioxidants, cellular adhesion molecules, and autologous platelet
composition.
[0040] Endoleak: As used herein, "endoleak" refers to the presence
of blood flow past the seal between an end of the stent graft and
the vessel wall, and into the aneurysmal sac, when all such flow
should be contained within its lumen.
[0041] Implantable Medical Device: As used herein, "implantable
medical device" includes, without limitation, stents and stent
grafts used in the repair of vascular injuries.
[0042] Migration: As used herein, "migration" refers to
displacement of a stent or stent graft sufficient to be associated
with a complication, for example, endoleak.
[0043] Treatment Site and Administration Site: As used herein, the
phrases "treatment site" and "administration site" includes a
portion of a vessel having a stent or a stent graft positioned in
its vicinity. A treatment site can be, without limitation, an
aneurysm site, the site of an acute traumatic aortic injury, the
site of vessel narrowing or other vascular-associated
pathology.
DETAILED DESCRIPTION
[0044] Embodiments according to the present invention provide
devices and related methods useful for preventing post-implantation
migration of implantable vascular devices using autologous growth
factor composition to promote implantable vascular device
attachment to blood vessel luminal walls. A delivery device, which
allows the application of autologous growth factor compositions to
the stent graft while the stent graft is disposed within the
delivery device, prior to the deployment of the stent graft is
provided.
[0045] For convenience, the devices and related methods according
to the present invention discussed hereinafter will be exemplified
using stent grafts intended to treat aneurysms. As discussed
briefly above, an aneurysm is a swelling, or expansion of a blood
vessel lumen at a defined point and is generally associated with a
vessel wall defect. Aneurysms are often a multi-factorial
asymptomatic vessel disease that if left unchecked may result in
spontaneous rupture, often with fatal consequences. Previous
methods to treat aneurysms involved highly invasive surgical
procedures where the affected vessel region was removed and
replaced with a synthetic graft that was sutured in place. However,
this procedure was extremely risky and was generally only employed
in otherwise healthy vigorous patients who were expected to survive
the associated surgical trauma. Elderly and more feeble patients
were not candidates for many aneurysmal surgeries and remained
untreated and thus at continued risk for sudden death.
[0046] In order to overcome the risks associated with invasive
aneurysmal surgeries, stent grafts were developed that can be
deployed with a cut down procedure or percutaneously using
minimally invasive procedures. Essentially, a catheter having a
stent graft compressed and fitted into the catheter's distal tip is
advanced through an artery to the aneurysmal site. The stent graft
is then deployed within the vessel lumen juxtaposed to the weakened
vessel wall forming an inner liner that insulates the aneurysm from
the body's hemodynamic forces thereby reducing, or eliminating the
possibility of rupture. The size and shape of the stent graft is
matched to the treatment site's lumen diameter and aneurysm length.
Moreover, branched grafts are commonly used to treat abdominal
aortic aneurysms that are located near the iliac branch.
[0047] Stent grafts generally comprise a metal scaffolding having a
biocompatible covering such a Dacron.RTM. (E.I. du Pont de Nemours
& Company, Wilmington, Del.) or a fabric-like material woven
from a variety of biocompatible polymer fibers. Other embodiments
include extruded sheaths and coverings. The scaffolding is
generally on the luminal wall-contacting surface of the stent graft
and directly contacts the vessel lumen. The sheath material is
stitched, glued or molded onto the scaffold. In other embodiments,
the scaffolding may be on the graft's blood flow contacting surface
or interior. When a self-expanding stent graft is deployed from the
delivery catheter, the scaffolding expands to fill the lumen and
exerts circumferential force against the lumen wall. This
circumferential force is generally sufficient to keep the stent-g
raft from migrating and thus preventing endoleak. However, stent
migration and endoleak may occur in vessels that have irregular
shapes or are shaped such that they exacerbate hemodynamic forces
within the lumen. Stent migration refers to a stent graft moving
from the original deployment site, usually in the direction of the
blood flow. Endoleak (as used herein) refers specifically to the
seepage of blood around the stent ends to pressurize the aneurysmal
sac or between the stent graft and the lumen wall. Stent graft
migration may result in the aneurysmal sac being exposed to blood
pressure again and increasing the risk of rupture. Endoleaks occur
in in a small percentage of aneurysms treated with stent grafts.
Therefore, it would be desirable to have devices, compositions and
methods that minimize post implantation stent graft migration and
endoleak.
[0048] Co-pending U.S. patent application Ser. No. 10/977,545,
filed Oct. 28, 2004 discloses injecting autologous platelet gel
(APG) into the aneurysmal sac and/or between an implanted stent
graft and the vessel wall to induce endothelialization of the stent
graft to prevent endoleak and stent graft migration. Autologous
platelet gel is produced by activating autologous platelet-rich
plasma with thrombin to form a gel containing an increased
concentration of growth factors over unactivated platelet rich
plasma (PRP). However, the APG is extremely viscous and cannot be
injected after formation. Therefore, the components of APG, PRP and
thrombin, must be co-injected at the treatment site such that APG
is formed in situ. The present inventors sought to provide an
autologous growth factor-containing composition which is less
viscous than APG and can be used to coat a stent graft prior to
implantation. The autologous growth factor composition of the
present invention, wherein PRP is activated to produce growth
factors in the absence of thrombin, is a liquid composition which
can be used to coat a stent graft prior to deployment and
implantation. This approach is especially beneficial because it
avoids the potential embolization concerns associated with thrombin
use.
[0049] Activation of PRP, either by thrombin or the activating
agents adenosine diphosphate or thrombin receptor activating
peptide, produces a cocktail of growth factors, the composition of
which is not dependent on the type of activation. Therefore
activation of PRP by thrombin or another activating agent, produces
an equivalent composition of growth factors.
[0050] In one embodiment, autologous growth factor compositions are
administered to a treatment site within a vessel lumen as a coating
on a stent graft. The vessel wall's blood-contacting lumen surface
comprises a layer of endothelial cells. In the normal mature vessel
the endothelial cells are quiescent and do not multiply. Thus, a
stent graft carefully placed against the vessel wall's
blood-contacting luminal surface rests against a quiescent
endothelial cell layer. However, if cell growth-promoting
compositions are administered with the stent graft, the normally
quiescent endothelial cells lining the vessel wall, and in intimate
contact with the stent graft luminal wall contacting surface, will
be stimulated to proliferate. The same will occur with smooth
muscle cells and fibroblasts found within the vessel wall. As these
cells proliferate they will grow into and around the stent graft
lining such that the stent graft becomes physically attached to the
vessel lumen rather than merely resting against it. In one example,
the stent graft has a metallic scaffolding on the graft's luminal
wall contacting surface and the cell growth-promoting factor is an
autologous growth factor composition.
[0051] The autologous growth factor composition comprises activated
platelets, unactivated platelets, and platelet releasate(s) and it
is obtained by activating platelets in autologous PRP to release
their contents (i.e., platelet releasates). Platelets are
cytoplasmic portions of marrow megakaryocytes which have no nucleus
for replication and an expected lifetime of five to nine days. Upon
activation by a variety of activating agents, platelets release
pre-formed stores of growth factors from alpha granules. A wide
variety of growth factors are released by activated platelets
including, but not limited to, platelet-derived growth factor
(PDGF), platelet-derived epidermal growth factor (PDEGF),
fibroblast growth factor (FGF), transforming growth factor-beta
(TGF-.beta.), insulin-like growth factor (IGF) and platelet-derived
angiogenesis growth factor (PDAF). These growth factors have been
implicated in wound healing by increasing the rate of collagen
secretion, vascular in-growth and fibroblast proliferation.
Platelet rich plasma also contains a concentrated population of
white blood cells (WBC) which, following activation, secrete a
variety of factors, including but not limited to, growth factors,
cytokines, chemokines, prostaglandins, and matrix
metalloproteinases. Non-limiting examples of growth factors
released from WBCs include IGF, basic FGF, TGF and others.
Non-limiting examples of cytokines released from WBCs include,
granulocyte colony stimulating factor (G-CSF), granulocyte
macrophage colony stimulating factor (GM-CSF) and others. Many of
these WBC-derived factors are also capable of promoting
proliferation and enhancing migration of a variety of cell
types.
[0052] Platelet-rich plasma is generated from variable speed
centrifugation of autologous blood using devices such as, but not
limited to, the Magellan.TM. Autologous Platelet Separator System
(Medtronic, Inc., Minneapolis, Minn.). The Magellan.TM. Separator
is a small, portable platelet separator suitable for use in a
variety of clinical settings, including an operating room.
Additionally, the Magellan.TM. system is particularly suited for
producing PRP from a small amount of autologous blood in a closed
system that minimizes contamination.
[0053] In one embodiment, the autologous growth factor composition
is formed from PRP mixed with one or more activating agents for
about 5, about 10, or about 15 minutes. In one specific example,
the autologous growth factor composition is formed from PRP mixed
with an activating agent for about 10 minutes. In some embodiments,
the autologous growth factor composition is further centrifuged to
remove some or all of the platelets in the mixture after activation
and prior to coating the stent graft.
[0054] Activating agents are platelet agonists such as adenosine
diphosphate (ADP) or thrombin receptor activating peptide (TRAP).
In some embodiments, the autologous growth factor composition is
formed from PRP mixed with about 5 to about 20 .mu.M, about 7 to
about 18 .mu.M, about 9 to about 17 .mu.M, or about 11 to about 15
.mu.M of ADP. In one example, the autologous growth factor
composition is formed from PRP mixed with about 10 .mu.M of ADP. In
some other embodiments, the autologous growth factor composition is
formed from PRP mixed with about 5 to about 10 .mu.M, about 6 to
about 9 .mu.M, or about 7 to about 8 .mu.M of TRAP. In one specific
example, the autologous growth factor composition is formed from
PRP mixed with about 7 .mu.M of TRAP.
[0055] Implantable medical devices, specifically stent grafts, are
advantageously sealed to the vessel lumen using the autologous
growth factor composition. Once associated with the stent graft,
the autologous growth factor composition, with its rich composition
of growth and healing factors, can promote the integration of the
stent graft into the vessel wall. Enhanced healing and tissue
in-growth from the surrounding vessel may lessen the chances of
stent graft migration and endoleak. Additionally, drugs that induce
positive effects at the aneurysm site can also be delivered with
autologous growth factor composition and the methods described.
[0056] Because of the physical properties of the autologous growth
factor composition, it is particularly useful in promoting
endothelialization of vascular stent grafts. The autologous growth
factor composition not only can coat the exterior surface of the
stent graft but also fills the pores of the stent graft, inducing
migrating cells into the stent graft fabric. As a result,
engraftment of endothelial cells will occur preferentially at those
sites where autologous growth factor composition is present.
Previously, vascular prostheses were seeded with non-autologous
materials, enhancing the possibility of graft rejection. Autologous
growth factor composition will not cause antigenicity or rejection
effects.
[0057] Endothelialization may be stimulated by induced angiogenesis
resulting in formation of new capillaries in the interstitial space
and surface endothelialization. This has led to modification of
medical devices with vascular endothelial growth factor (VEGF) and
fibroblast growth factors 1 and 2 (FGF-1, FGF-2). 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 endothelialization. VEGF is
endothelial cell-specific however it is a relatively weak
endothelial cell mitogen. FGF-1 and FGF-2 are more potent mitogens
but are less cell specific. The development of
genetically-engineered growth factors is anticipated to yield more
potent endothelial cell-specific growth factors. Additionally it
may be possible to identify small molecule drugs that can induce
endothelialization.
[0058] Additional embodiments provide coatings for stent grafts
that incorporate endothelialization factors in addition to the
autologous growth factor composition. Stent grafts can be coated
with endothelialization factors, including growth factors and
drugs. The field of medical device coatings is well established and
methods for coating stent grafts with bioactive compositions, with
or without added polymers, are well known to those of skill in the
art.
[0059] The autologous growth factor composition is generated and
applied to the stent graft in the operating room immediately prior
to deployment and implantation of the stent graft. In one
embodiment, activation agents are added to the PRP and the
resultant growth factor-rich plasma, the autologous growth factor
composition, is applied directly to a stent graft loaded within a
delivery device, such as a delivery catheter.
[0060] The stent graft is optionally pre-coated with a material to
enhance growth factor attachment to the stent graft including, but
not limited to, heparin, hyaluronate, alginate, collagen, fibrin,
dextran, .beta.-cyclodextrin, polyvinyl alcohol hydrogel.
[0061] In one embodiment, the stent graft is provided "pre-loaded"
into a delivery catheter and the autologous growth factor
composition is applied to the stent graft while the stent graft is
disposed within the delivery catheter. In normal stent deployment
protocols, a vascular stent graft 100 is fully deployed through the
left iliac artery 114 to an aneurysm site 104 (FIG. 1). Stent graft
100 has a distal end 102 and an iliac leg 108 to anchor the stent
graft in the iliac artery 116. Stent graft 100 is deployed first in
a first delivery catheter and the iliac leg 108 is deployed in a
second delivery catheter. The stent graft 100 and iliac leg 108 are
joined with a 2 cm overlap of the two segments 106.
[0062] A stent graft is pre-loaded into a delivery catheter such as
that depicted in FIG. 2a. Stent graft 100 is radially compressed to
fill the stent graft chamber 218 in the distal end 202 of delivery
catheter 200. The stent graft 100 is covered with a retractable
sheath 220. Catheter 200 has two injection ports 208 and 210 for
delivering the autologous growth factor composition to the
compressed stent graft. In this embodiment, the autologous growth
factor composition is injected through either or both of injection
ports 208 and 210 to wet stent graft 100. Stent graft 100 is then
deployed to the treatment site as depicted in FIG. 1. FIG. 2b
depicts a cross-sectional view of stent graft 100 loaded into the
delivery catheter 200 and the delivery catheter's retractable
sheath 220 illustrating an injection port 208, 210 for delivering
autologous growth factor composition to stent graft 100.
[0063] In an additional embodiment, the stent graft is pre-coated
with a material to enhance attachment of growth factors from
autologous growth factor composition, either prior to or after the
stent graft is loaded into the delivery catheter. The stent graft
can be pre-coated using standard coating methods including, but not
limited to, dipping and spraying. Alternatively, the pre-coat can
be applied through injection ports 208 and/or 210 prior to the
application of the autologous growth factor composition.
[0064] The following examples are meant to illustrate one or more
embodiments according to the invention and are not meant to limit
the scope of the invention to that which is described below.
EXAMPLE 1
Properties of Platelet Rich Plasma
[0065] Aliquots of human peripheral blood (30-60 mL) are passed
through the Magellan.TM. Autologous Platelet Separator System (the
Magellan.TM. system, Medtronic, Inc., Minneapolis, Minn.) and the
concentrated, platelet-rich plasma fraction (PRP) assayed for
platelets (PLT), white blood cells (WBC) and hematocrit (Hct)
(Table 1). The Magellan.TM. system concentrated platelets and white
blood cells six-fold and three-fold respectively. TABLE-US-00001
TABLE 1 Blood cell yields after passing through the Magellan .TM.
system. Mean .+-. SD n = 19 Initial Blood PRP Yield PLT
(.times.1000/.mu.L) 220.03 .+-. 48.58 1344.89 .+-. 302.00 6.14 .+-.
0.73 WBC 5.43 .+-. 1.43 17.04 .+-. 7.01 3.12 .+-. 0.90
(.times.1000.mu./L) Hct (%) 38.47 .+-. 2.95 6.81 .+-. 1.59 Cell
Yield = cell count in PRP/cell count in initial blood = [times
baseline]
[0066] Additionally, PRP was assayed for levels of the endogenous
growth factors platelet-derived growth factor (PDGF), transforming
growth factor-beta (TGF-.beta.), basic fibroblast growth factor
(bFGF), vascular endothelial growth factor (VEGF), and endothelial
growth factor (EGF). As a result of increased platelet and white
blood cell counts in PRP, increased concentrations of growth
factors were found. TABLE-US-00002 TABLE 2 Growth Factor Content of
Blood and PRP Mean .+-. SD; n = 9 Initial Blood PRP PDGF-AB (ng/mL)
10.2 .+-. 1.4 88.4 .+-. 28.8 PDGF-AA (ng/mL) 2.7 .+-. 0.5 22.2 .+-.
4.2 PDGF-BB (ng/mL) 5.8 .+-. 1.4 57.8 .+-. 36.6 TGF-.beta.1 (ng/mL)
41.8 .+-. 9.5 231.6 .+-. 49.1 bFGF (pg/mL) 10.7 .+-. 2.9 48.4 .+-.
25.0 VEGF (pg/mL) 83.1 .+-. 65.5 597.4 .+-. 431.4 EGF (pg/mL) 12.9
.+-. 6.2 163.3 .+-. 49.4
EXAMPLE 2
Autologous Platelet Gel Generation
[0067] Autologous Platelet Gel (APG) is generated from the PRP
fraction produced in the Magellan.TM. system by adding thrombin and
calcium to activate the fibrinogen present in the PRP as well as
causing the platelets to release additional stores of growth
factors. For each approximately 7-8 mL of PRP, approximately 5000
units of thrombin in 5 mL 10% calcium chloride are required for
activation. The APG is formed immediately upon mixing of the
activator solution with the PRP. The concentration of thrombin can
be varied from approximately 1-1,000 U/mL, depending on the speed
required for setting to occur. The lower concentrations of thrombin
will provide slower gelling times.
EXAMPLE 3
Effects of Platelet Releasates on Cell Proliferation
[0068] A series of in vitro experiments were conducted evaluating
the effect of released factors from platelets on the proliferation
of the human microvascular endothelial cells and human coronary
artery smooth muscle cells. Primary cell cultures of both cell
types were established according to protocols well known to those
skilled in the art of cell culture. Autologous platelet gel was
used as the source of platelet releasates. For each cell type, five
culture conditions were evaluated; basal medium (BM)+APG;
BM+platelet-free plasma (PFP); growth medium (GM); BM alone; and
BM+thrombin. Growth medium is the standard culture medium for the
cell type and contains optimal growth factors and supplements.
[0069] Autologous platelet gel had a significant growth effect on
human microvascular endothelial cells after four days of culture
(FIG. 3) and on human coronary artery smooth muscle cells after
five days of culture (FIG. 4).
EXAMPLE 4
Effect of APG on Endothelial Cell Migration
[0070] Human microvascular endothelial cell migration was performed
in a Boyden chemotaxis chamber which allows cells to migrate
through 8 .mu.m pore size polycarbonate membranes in response to a
chemotactic gradient. Human microvascular endothelial cells
(5.times.10.sup.5) were trypsinized, washed and resuspended in
serum-free medium (DMEM) and 400 .mu.L of this suspension was added
to the upper chamber of the chemotaxis assembly. The lower chamber
was filled with 250 .mu.L serum-free DMEM containing either 10%
APG-derived serum, 10% PFP-derived serum or DMEM alone. After a
pre-determined amount of time, the filters were removed and the
cells remaining on the upper surface of the membrane (cells that
had not migrated through the filter) were removed with a cotton
swab. The membranes were then sequentially fixed, stained and
rinsed to enable the visualization and quantification of cells that
had migrated through the pores to the other side of the membrane.
The number of migrated cells was significantly higher in the 10%
APG serum culture than the basal medium or 10% platelet-free serum
cultures (FIG. 5).
[0071] 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. 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 embodiments according
to 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.
[0072] 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.
[0073] Groupings of alternative elements or embodiments 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.
[0074] Embodiments according to the invention are described herein,
variations on those embodiments will become apparent to those of
ordinary skill in the art upon reading the foregoing
description.
[0075] 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.
[0076] It is to be understood that the embodiments according to the
invention disclosed herein are illustrative and that other
modifications may be employed. Thus, by way of example, but not of
limitation, alternative configurations may be utilized in
accordance with the teachings herein.
* * * * *