U.S. patent application number 10/977545 was filed with the patent office on 2006-05-04 for autologous platelet gel on a stent graft.
This patent application is currently assigned to Medtronic Vascular, Inc.. Invention is credited to Jack Chu, Brian Fernandes.
Application Number | 20060095121 10/977545 |
Document ID | / |
Family ID | 35853579 |
Filed Date | 2006-05-04 |
United States Patent
Application |
20060095121 |
Kind Code |
A1 |
Fernandes; Brian ; et
al. |
May 4, 2006 |
Autologous platelet gel on a stent graft
Abstract
Methods for ameliorating stent graft migration and endoleak
using treatment site-specific cell growth promoting compositions in
combination with stent grafts are disclosed. Also disclosed are
application of cell growth promoting compositions such as, but not
limited to, autologous platelet gel compositions directly to
treatment sites before, during or after stent graft implantation.
Additional embodiments include medical devices having autologous
platelet gel coatings and/or autologous platelet gel delivery
devices useful for treating aneurysms.
Inventors: |
Fernandes; Brian;
(Roseville, MN) ; 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.: |
10/977545 |
Filed: |
October 28, 2004 |
Current U.S.
Class: |
623/1.46 |
Current CPC
Class: |
A61L 2300/414 20130101;
A61L 27/3641 20130101; A61L 27/54 20130101; A61L 27/3616 20130101;
A61L 27/3645 20130101 |
Class at
Publication: |
623/001.46 |
International
Class: |
A61F 2/06 20060101
A61F002/06 |
Claims
1. A stent graft comprising: a luminal wall contacting surface; a
blood flow contacting surface; and a cell growth promoting
composition on said luminal wall contacting surface.
2. The stent graft of claim 1 wherein said cell growth promoting
composition is applied directly to the exterior of said stent graft
by spraying, dipping or rolling.
3. The stent graft of claim 1 wherein said cell growth promoting
composition is applied to the exterior of said stent graft in a
biocompatible polymer.
4. The stent graft of claim 3 wherein said cell growth promoting
composition containing-biocompatible polymer is applied to the
exterior of said stent graft by spraying, dipping or rolling.
5. The stent graft of claim 1 wherein said cell growth promoting
composition is applied directly to said luminal wall contacting
surface of said stent graft in situ.
6. The stent graft of either of claims 1 or 5 wherein said cell
growth promoting composition is autologous platelet gel (APG).
7. The stent graph of 6 wherein said APG or components of APG, such
as platelet rich plasma (PRP), platelet poor plasma (PPP) or
thrombin, are dispersed in a biocompatible polymer.
8. The stent graft of claim 6 wherein said stent graft is coated
with APG prior to deployment by depositing PRP and thrombin on said
stent graft in the stent graft chamber of a stent deployment
catheter.
9. The stent graft of claim 1 wherein said cell growth promoting
composition is an endothelial cell promoting factor.
10. The stent graft of claim 9 wherein said endothelial cell
promoting factor consists of a vascular growth factor or a heparin
binding growth factor.
11. The stent graft of claim 10 wherein said endothelial cell
promoting factor is a vascular growth factor.
12. The stent graft of claim 10 wherein said endothelial cell
promoting factor is a heparin binding growth factor.
13. The stent graft of claim 1 wherein said cell growth promoting
composition is a smooth muscle cell promoting factor.
14. The stent graft of claim 13 wherein said smooth muscle cell
promoting factor consists of a vascular growth factor or a heparin
binding growth factor.
15. The stent graft of claim 1 wherein said cell growth promoting
composition is a fibroblast promoting factor.
16. The stent graft of claim 15 wherein said fibroblast promoting
factor consists of a vascular growth factor or a heparin binding
growth factor.
17. The stent graft of any one of claims 11, 14 or 16 wherein said
vascular growth factor is selected from the group consisting of
vascular endothelial growth factor A, vascular endothelial growth
factor B, vascular endothelial growth factor C, vascular
endothelial growth factor D and placental growth factor.
18. The stent graft of claim 17 wherein said vascular growth factor
is vascular endothelial growth factor A.
19. The stent graft of claim 17 wherein said vascular growth factor
is vascular endothelial growth factor B.
20. The stent graft of claim 17 wherein said vascular growth factor
is vascular endothelial growth factor C.
21. The stent graft of claim 17 wherein said vascular growth factor
is vascular endothelial growth factor D.
22. The stent graft of claim 17 wherein said vascular growth factor
is placental growth factor.
23. The stent graft of any one of claims 12, 14 or 16 wherein said
heparin binding growth factor is selected from the group consisting
of fibroblast growth factor 1, fibroblast growth factor 2 and
insulin-like growth factor.
24. The stent graft of claim 23 wherein said heparin binding factor
is fibroblast growth factor 1.
25. The stent graft of claim 23 wherein said heparin binding factor
is fibroblast growth factor 2.
26. The stent graft of claim 23 wherein said heparin binding factor
is insulin-like growth factor.
27. The stent graft of claim 1 wherein said stent graft further
comprises a metal scaffolding attached to said luminal wall
contacting surface.
28. A method for providing a stent graft and a cell growth
promoting composition comprising: administering said cell growth
promoting composition directly to a lumen of a blood vessel wall
adjacent to a treatment site; and contacting said cell growth
promoting composition with said luminal wall contacting surface of
said stent graft and said blood vessel luminal wall at said
treatment site.
29. The method for providing a stent graft and a cell growth
promoting composition according to claim 28 wherein said cell
growth promoting composition is autologous platelet gel.
30. The method for providing a stent graft and a cell growth
promoting composition according to claim 29 further comprising the
step of providing a drug in combination with said autologous
platelet gel.
31. The method for providing a stent graft and a cell growth
promoting composition according to claim 30 wherein said providing
step further comprises said drug selected from the group consisting
of small molecules, peptides, proteins, hormones, DNA or RNA
fragments, cells, genetically engineered cells, genes, cell growth
promoting compositions and matrix metalloproteinase inhibitors.
32. The method for providing a stent graft and a cell growth
promoting composition according to claim 31 wherein said drug is a
matrix metalloproteinase inhibitor.
33. The method for providing a stent graft and a cell growth
promoting composition according to claim 28 further comprising:
advancing a stent deploying catheter containing a vascular stent to
a treatment site; advancing at least one injection catheter
containing said cell growth promoting composition to said treatment
site; deploying said stent graft at said treatment site; and
applying said cell growth promoting composition from said at least
one injection catheter to said inner lumen of said blood vessel at
said treatment site; such that said luminal wall contacting surface
of said stent graft engages said cell growth promoting composition
at said treatment site.
34. The method for providing a stent graft and a cell growth
promoting composition according to claim 33 wherein said injection
catheter is selected from the group comprising single lumen
injection catheter and multilumen injection catheter.
35. The method for providing a stent graft and a cell growth
promoting composition according to claim 34 wherein said injection
catheter is a single lumen injection catheter.
36. The method for providing a stent graft and a cell growth
promoting composition according to claim 34 wherein said injection
catheter is a multilumen injection catheter.
37. The method for providing a stent graft and a cell growth
promoting composition according to claim 33 wherein a first of said
at least one injection catheter reaches said treatment site through
a different route than a second of said at least one injection
catheter.
38. The method for providing a stent graft and a cell growth
promoting composition according to claim 33 wherein said first of
said at least one injection catheter reaches said treatment site
through a blood vessel bisecting the treatment site thereby
delivering said cell growth promoting composition directly to the
aneurysm sac.
39. The method for providing a stent graft and a cell growth
promoting composition according to claim 28 wherein said treatment
site is the area where the distal end of the stent graft contacts
the vessel lumen wall.
40. The method for providing a stent graft and a cell growth
promoting composition according to claim 28 wherein said treatment
site is the junction between a stent graft and an iliac limb
section.
41. The method for providing a stent graft and a cell growth
promoting composition according to claim 28 wherein said treatment
site is the aneurysm sac.
42. A delivery catheter for delivering a stent graft and a cell
growth promoting composition to an aneurysm site comprising: a
stent graft chamber in which said stent graft is radially
compressed; an injection catheter disposed within said delivery
catheter; and at least one injection port at the distal end of said
injection catheter capable of delivering said cell growth promoting
composition.
43. The delivery catheter of claim 42 wherein said injection
catheter is selected from the group comprising single lumen
injection catheter and multilumen injection catheter.
44. The delivery catheter of claim 43 wherein said injection
catheter is a single lumen injection catheter.
45. The delivery catheter of claim 43 wherein said injection
catheter is a multilumen injection catheter.
46. The delivery catheter according to claim 42 wherein said
injection catheter further comprises a vent for expressing air or
excess cell growth promoting composition.
47. A method for treating abdominal aortic aneurysms comprising:
delivering a stent graft to a treatment site; and promoting
endothelialization of said stent graft by depositing a cell growth
promoting composition on said inner lumen of said blood vessel
contacting said luminal wall contacting surface of said stent graft
and said inner lumen of said blood vessel; and promoting
strengthening and fixation of stent graft by enhancing
proliferation of smooth muscle cells and fibroblasts.
48. The method for treating abdominal aortic aneurysms according to
claim 47 wherein said cell growth promoting composition is
autologous platelet gel.
Description
FIELD OF THE INVENTION
[0001] Methods for preventing stent graft migration and endoleak
using treatment site-specific cell growth promoting factor
application devices and related methods are disclosed.
Specifically, methods for applying cell growth promoting
compositions such as, but not limited to, autologous platelet gel
compositions directly to treatment sites before, during or after
stent graft implantation are provided. More specifically, medical
devices having autologous platelet gel coatings and/or autologous
platelet gel delivery devices useful for treating aneurysms are
provided.
BACKGROUND OF THE INVENTION
[0002] Aneurysms arise when a thinning, weakening section of an
artery wall balloons out to more than 150% of the artery's normal
diameter. The most common and deadly of these occur in the aorta,
the large blood vessel stretching from the heart to the lower
abdomen. A normal aorta is between 1.6 to 2.8 centimeters wide; if
an area reaches as wide as 5.5 centimeters, the risk of rupture
increases such that surgery is recommended. Aneurysms are
asymptomatic and they often burst before the patient reaches the
hospital.
[0003] Aneurysms are estimated to cause approximately 32,000 deaths
each year in the United States. 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. Aneurysms most often occur in the aorta, the
largest artery in the body. Most aortic aneurysms, approximately
15,000/year, involve the abdominal aorta while approximately 2,500
occur in the chest. Cerebral aneurysms occur in the brain and
present a more complicated case because they are more difficult to
detect and treat, causing approximately 14,000 U.S. deaths per
year. Aortic aneurysms are detected by standard ultrasound,
computerized tomography (CT) and magnetic resonance imaging (MRI)
scans and the increased use of these scanning techniques for other
diseases has produced an estimated 200% increase in the diagnosis
of intact aortic aneurysms. Approximately 200,000 intact aortic
aneurysms are diagnosed each year due to this increased screening
alone.
[0004] U.S. surgeons treat approximately 50,000 abdominal aortic
aneurysms each year, typically replacing the abnormal section with
a plastic or fabric graft in an open surgical procedure. A
less-invasive procedure that has more recently been used is the
stent graft which threads a compressed tubular device to the
aneurysm and is expected to span the aneurysm to provide support
without replacing a section of the aorta. A vascular graft
containing a stent (stent graft) is placed within the artery at the
site of the aneurysm and acts as a barrier between the blood and
the weakened wall of the artery, thereby decreasing pressure on
artery. The less invasive approach of stent grafting 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. Stent grafts have also emerged as a
new treatment for a related condition, acute blunt aortic injury,
where trauma causes damage to the artery. There are, however, risks
associated with endovascular repair of abdominal aortic aneurysms.
The most common of these risks is migration of the stent graft due
to hemodynamic forces within the artery. 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.
[0005] The abdominal aorta between the renal artery and the iliac
branch is the most susceptible arterial site to aneurysms. While
this area of the aorta is ideally straight, in many patients the
aorta is curved leading to asymmetrical hemodynamic forces. When a
stent graft is deployed in this curved portion of the aorta,
hemodynamics place uneven forces on the graft, leading to graft
migration. Additionally, the asymmetrical hemodynamic forces can
cause remodeling of the aneurysm sac which leads to increased risk
of aneurysm rupture and increased endoleaks.
[0006] The goal of endovascular repair of aorta aneurysms is to
provide a graft which comes in close contact with the vessel wall,
in fact sealed to the vessel wall. The greater the area of the
stent graft in contact with the artery wall, the better graft
fixation, and the tighter seal leads to a decreased risk of
migration and endoleak. Endoleaks present a risk factor for
post-surgical rupture of the aneurysm due to increased blood
pressure within the aneurysm sac.
[0007] Stent grafts have been designed with stainless steel
anchoring barbs that engage the aortic wall directly to prevent
migration. Additionally, endostaples have been developed to fix the
graft more readily to the treatment site. These physical anchoring
have proven to be effective in some patients however they have not
sufficiently ameliorated the graft migration and endoleak problems
associated with current stent-grafting methods and devices in all
cases.
[0008] The combination of the metal scaffolding of most stent
grafts and a predilection to graft migration 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 endothelialized metal-containing stents to migrate.
Anchoring the stent graft into the vessel wall may be expected to
ameliorate this problem to the extent that sufficient tissue
in-growth occurs. Inducing significant endothelialization of the
stent graft may allow patients access to this vital medical
diagnostic procedure.
[0009] Therefore there exists a medical need for compositions
useful for coating stent grafts or direct application to the
aneurysm wall at the time of stent implantation that promote
healing, reduce endoleaks and minimize device migration by
promoting endothelial tissue in-growth.
SUMMARY OF THE INVENTION
[0010] Compositions are provided in combination with vascular stent
grafts for the treatment of aneurysms. Additionally, devices are
described which provide structural support for weakened arterial
walls while the accompanying compositions seal the support to the
tissue wall and promote tissue in-growth to reduce graft migration
and prevent endoleaks.
[0011] In one embodiment according to the present invention, a
stent graft is provided comprising a luminal wall contacting
surface; a blood flow contacting surface; and a cell growth
promoting composition on the luminal wall contacting surface. The
stent graft can optionally have a metal scaffold attached to the
luminal wall contacting surface of the stent graft. The cell growth
promoting compositions may be applied directly to the exterior of
the stent graft either alone or dispersed in a biocompatible
polymer by spraying, dipping or rolling.
[0012] In another embodiment according to the present invention,
the cell growth promoting composition is autologous platelet gel
(APG).
[0013] In yet another embodiment according to the present
invention, the stent graft is coated with APG prior to deployment
by depositing platelet poor plasma and thrombin on the stent graft
in the stent graft chamber of a stent deployment catheter.
[0014] In an embodiment according to the present invention, the
cell growth promoting composition is an endothelial cell promoting
factor, a smooth muscle cell promoting factor or a fibroblast
promoting factor such as a vascular growth factor or a heparin
binding growth factor.
[0015] In another embodiment according to the present invention,
the cell growth promoting factors is selected from the group
including vascular endothelial growth factor A, vascular
endothelial growth factor B, vascular endothelial growth factor C,
vascular endothelial growth factor D, placental growth factor,
fibroblast growth factor 1, fibroblast growth factor 2 and
insulin-like growth factor.
[0016] In an embodiment according to the present invention, a
method is claimed for providing a stent graft and a cell growth
promoting composition comprises administering a cell growth
promoting composition directly to a lumen of a blood vessel wall
adjacent to a treatment site; and contacting the cell growth
promoting composition with the luminal wall contacting surface of
the stent graft and the blood vessel luminal wall at the treatment
site. The cell growth promoting composition may be autologous
platelet gel.
[0017] In another embodiment according to the present invention, a
further step is included wherein a drug is delivered in combination
with the autologous platelet gel. The drug can be selected from the
group consisting of small molecules, peptides, proteins, hormones,
DNA or RNA fragments, cells, genetically engineered cells, genes,
cell growth promoting compositions and matrix metalloproteinase
inhibitors.
[0018] In yet another embodiment according to the present invention
includes a method for providing a stent graft and a cell growth
promoting composition comprising advancing a stent deploying
catheter containing a vascular stent to a treatment site; advancing
at least one injection catheter containing the cell growth
promoting composition to the treatment site; deploying the stent
graft at the treatment site; and applying the cell growth promoting
composition from the injection catheter to the inner lumen of the
blood vessel at the treatment site; such that the luminal wall
contacting surface of the stent graft engages the cell growth
promoting composition at the treatment site. The stent deployment
catheter and the injection catheter can be deployed to the
treatment site via the same or a different route. Additionally, the
injection catheter can reach the treatment site via a blood vessel
which bisects the treatment site. The injection catheter can be a
single lumen injection catheter or a multilumen injection
catheter.
[0019] In an embodiment according to the present invention, the
treatment site is the area where the distal end of the stent graft
contacts the vessel lumen wall. In another embodiment according to
the present invention, the treatment site is the junction between a
stent graft and an iliac limb section. In yet another embodiment
according to the present invention, the treatment site is the
aneurysm sac.
[0020] In one embodiment according to the present invention, a
delivery catheter is provided for delivering a stent and a cell
growth promoting composition to an aneurysm site which comprises a
stent graft chamber in which the stent graft is radially
compressed; an injection catheter disposed within the delivery
catheter; and at least one injection port at the distal end of the
injection catheter capable of delivering a cell growth promoting
composition. The injection catheter can be a single lumen injection
catheter or a multilumen injection catheter. The injection catheter
may further comprise a vent for expressing air or excess cell
growth promoting composition.
[0021] In an embodiment according to the present invention, a
method is provided for treating abdominal aortic aneurysms
comprising delivering a stent graft to a treatment site; promoting
endothelialization of the stent graft by depositing a cell growth
promoting composition on the inner lumen of the blood vessel
contacting the luminal wall contacting surface of the stent graft
and the inner lumen of the blood vessel; and promoting
strengthening and fixation of stent graft by enhancing
proliferation of smooth muscle cells and fibroblasts. The cell
growth promoting composition for treating abdominal aortic
aneurysms may be autologous platelet gel.
BRIEF DESCRIPTION OF THE FIGURES
[0022] FIG. 1 depicts a fully deployed stent graft with an exterior
metal scaffolding as used in one embodiment according to the
present invention.
[0023] FIG. 2a-b depict a stent graft delivery catheter containing
a multilumen injection catheter for coating the stent graft with
autologous platelet gel immediately prior to deployment in
accordance with the teachings according to the present
invention.
[0024] FIG. 3a-c depicts deployment of a stent graft and an
multilumen injection catheter suitable for injection of a cell
growth promoting factor simultaneously in accordance with the
teachings according to the present invention.
[0025] FIG. 4a-d depicts a method of injection of APG directly into
the aneurysm sac after deployment of a stent graft in accordance
with the teachings according to the present invention.
[0026] FIG. 5a-c depicts an alternate method of injection of APG
directly into the aneurysm sac after deployment of a stent graft in
accordance with the teachings according to the present
invention.
[0027] FIG. 6 depicts an alternate method of injection of APG
directly into the aneurysm sac after deployment of a stent graft in
accordance with the teachings according to the present
invention.
[0028] FIG. 7 depicts the effects of the autologous platelet gel
according to the present invention on arterial smooth muscle cell
proliferation.
[0029] FIG. 8 depicts the effects of the autologous platelet gel
according to the present invention on endothelial cell
proliferation.
[0030] FIG. 9 depicts the effects of the autologous platelet gel
according to the present invention on fibroblast cell
proliferation.
[0031] FIG. 10 depicts the effects of platelet poor plasma on human
dermal fibroblast growth.
[0032] FIG. 11 depicts the effects of the autologous platelet gel
according to the present invention on endothelial cell
migration.
[0033] FIG. 12 depicts the tissue response to implantation of the
autologous platelet gel according to the present invention or
Matrigele in athymic mice.
DEFINITION OF TERMS
[0034] 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:
[0035] 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.
[0036] Biocompatible: As used herein "biocompatible" shall mean 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
inflammation, infection, fibrotic tissue formation, cell death, or
thrombosis.
[0037] Cell Growth Promoting Compositions: As used herein "cell
growth promoting factors" or "cell growth promoting compositions"
shall include any bioactive compound having a growth promoting
effect on vascular cells. Exemplary, non limiting examples include,
vascular endothelial growth factor (VEGF), platelet-derived growth
factor (PDGF), plated-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).
[0038] 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 and autologous platelet
gel.
[0039] Endoleak: As used herein "endoleak" refers to Type I
endoleak, i.e., the presence of flow of blood past the seal between
the proximal end of the stent graft and the vessel wall, and into
the aneurysmal sac, when all such flow should be contained within
its lumen.
[0040] Heparin Binding Growth Factor Family: As used herein
"heparin binding growth factor family shall include factors binding
heparin and having a positive growth effect on vascular cells.
Exemplary, non limiting examples include fibroblast growth factor 1
(FGF-1), FGF-2 and insulin-like growth factor.
[0041] Migration: As used herein "migration" refers to displacement
of the stent graft sufficient to be associated with another
complication, for example, endoleak.
[0042] Treatment Site: As used herein "treatment site" shall mean
an aneurysm site, acute traumatic aortic injury or other
vascular-associated pathology.
[0043] Vascular Growth Factor: As used herein "vascular growth
factor" shall include factors having a positive effect on growth of
vascular cells. Exemplary, non limiting examples include vascular
endothelial growth factor A (VEGF-A), VEGF-B, VEGF-C, VEGF-D and
placental growth factor.
DETAILED DESCRIPTION
[0044] Embodiments according to the present invention provide
compositions, devices and related methods useful for preventing
implantable medical device post-implantation migration and
endoleak. More specifically, compositions, devices and related
methods promote implantable medical device attachment to blood
vessel luminal walls. One embodiment provides methods and
compositions useful for minimizing post-implantation stent graft
migration following deployment at an aneurysmal treatment site and
is also useful in preventing or minimizing post-implantation
endoleak following stent-graft deployment at an aneurysmal
treatment site.
[0045] For convenience, the devices, compositions 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 swelling, or expansion
of the 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 is removed and
replaced with a synthetic graft that is sutured in place. However,
this procedure is extremely risky and is generally only employed in
otherwise healthy vigorous patients who are 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 (see 114
in FIG. 1) having a biocompatible covering such a Dacron.RTM. 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-graft from migrating and to minimize 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 (Type I) refers to the
seepage of blood around the stent ends to pressurize the aneurismal
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 (of
all types) occur in 10-25% of aneurysms treated with stent grafts.
Some surgeons believe that endoleaks increase the risk of aneurysm
expansion or rupture. Therefore, it would be desirable to have
devices, compositions and methods that minimize post implantation
stent graft migration and endoleak.
[0048] In one embodiment according to the present invention, cell
growth promoting compositions are administered to a treatment site
within a vessel lumen, either before, during or after stent graft
implantation. 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 immediately before, during or
immediately after stent graft deployment, 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 embodiment
according to the present invention, the stent graft has a metallic
scaffolding on the graft's luminal wall contacting surface and the
cell growth promoting factor is autologous platelet gel (APG).
[0049] Autologous platelet gel is formed from autologous platelet
rich plasma (PRP) mixed with thrombin and calcium. The PRP is
generated from variable speed centrifugation of autologous blood
using devices such as, but not limited to, Medtronic Inc.'s
Magellan.TM. Autologous Platelet Separation System. The PRP
contains sufficient fibrinogen to allow a fibrin gel to form when
mixed with calcium and thrombin. In addition, the PRP contains a
high concentration of platelets that can aggregate for plugging, as
well as release cytokines, growth factors or enzymes following
activation by thrombin. Some of the many factors released by the
platelets and the white blood cells present that constitute the PRP
include platelet-derived growth factor (PDGF), plated-derived
epidermal growth factor (PDEGF), fibroblast growth factor (FGF),
transforming growth factor-beta (TGF-.beta.) and platelet-derived
angiogenesis growth factor (PDAF). These factors have been
implicated in wound healing by increasing the rate of collagen
secretion, vascular in-growth and fibroblast proliferation.
[0050] Implantable medical devices, specifically stent grafts, are
advantageously sealed to the vessel lumen using APG. The APG
comprises platelet aggregates which help mechanically seal the
stent graft to the lumen wall in addition to providing a rich
source of growth factors. Briefly, following activation by
thrombin, platelets release thromboxane A2, adenosine diphosphate
and thrombin, factors that attract additional platelets to the
developing clot. Once associated with the stent graft, APG, 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 for graft migration and endoleak. Additionally, drugs
that inhibit matrix metalloproteinases, or other pathological
processes involved in aneurysm progression, can be incorporated
into the gel to enhance wound healing and/or stabilize and possibly
reverse the pathology. Drugs that induce positive effects at the
aneurysm site can also be delivered by APG and the methods
described.
[0051] Autologous platelet gel is injectable and can be generated
and applied to the stent graft in the operating room immediately
prior to deployment. The stent graft can be coated with APG by
dipping the stent in a receptacle containing the forming gel; using
a modified version of a standard delivery catheter to deliver the
APG or injecting the APG directly into the aneurysm site to prevent
pressure build-up. Single lumen catheters may be used to deliver
either the components of APG or pre-formed APG or multilumen
catheters may be used to deliver the PRP and calcium/thrombin
activating solution concurrently to the aneurysm site.
[0052] Because of the physical properties of APG, it may be
particularly useful in promoting endothelialization of vascular
stent grafts. The APG not only can coat the exterior surface of the
stent graft but also fills the pores, inducing migrating cells into
the stent graft fabric. As a result, engraftment of autologous
endothelial cells will occur preferentially at those sites where
APG was injected. Previously, vascular prostheses were seeded with
non-autologous materials, enhancing the possibility of graft
rejection. Autologous platelet gel will not cause antigenicity or
rejection effects. Additionally the APG may fill gaps between the
stent graft outer wall and the inner lumen of the aneurysm sac
further preventing endoleaks and providing structural support for
weakened arterial walls within the aneurysm sac.
[0053] Endothelialization has been observed to naturally occur in
few human coronary stents within weeks of implantation. This
natural endothelialization is not complete or consistent, however,
and does not prevent the stent graft side effects of graft
migration and endoleak. Methods to increase endothelialization are
sought to improve clinical outcome after stent grafting.
[0054] 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.
[0055] Therefore embodiments according to the present invention
provide coatings for stent grafts that incorporate
endothelialization factors other than APG. Drug-eluting stents have
been developed for treatment of restenosis, which results from
cardiac stent implantation. 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, is well known to those of skill in the
art.
[0056] In some embodiments, the stent graft is provided
"pre-loaded" into a deployment catheter and thus cannot be
pre-coated with APG. Consequently, APG must be applied to the stent
graft, luminal wall or both, contemporaneous with stent graft
deployment. 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.
Stent graft 100 is deployed first in a first deployment catheter
and iliac leg 108 is deployed in a second deployment catheter. The
stent graft 100 and iliac leg 108 are joined with a 2 cm overlap of
the two segments
[0057] In an embodiment according to the present invention, 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 of catheter 200. The
stent graft 100 is covered with a retractable sheath 220. Within
the lumen of catheter 200 is a multilumen injection catheter 206.
Injection catheter 206 (FIG. 2b) has a guide wire lumen 212, a
lumen 214 for delivery of PRP and a lumen 216 for delivery of
thrombin. Catheter 206 has two injection ports 208 and 210 for
delivering the PRP and thrombin (or other cell growth promoting
factors) contemporaneously with stent graft deployment. In this
embodiment, PRP is injected through injection port 208 to wet stent
100. Thrombin is next injected through injection port 210 to react
with PRP to form APG on the surface of stent graft 100 within stent
graft chamber 218. Stent graft 100 is then deployed to the
treatment site as depicted in FIG. 1.
[0058] In another embodiment, APG is injected between the stent
graft and the vessel wall during stent graft placement. As depicted
in FIG. 3a, a stent graft 100 is radially compressed to fill the
stent graft chamber 218 of stent delivery catheter 300 which is
then deployed to the treatment site via the left iliac artery 114.
A multilumen injection catheter 302 is also deployed to the
treatment site through the right iliac artery 116. The multilumen
injection catheter 302 can be a coaxial catheter with two injection
lumens or a dual lumen catheter or alternatively a three lumen
catheter if a guide wire lumen is required. Injection catheter 302
has injection ports 304 and 306 through which PRP and thrombin may
be deposited. In the first step of this deployment scheme (FIG.
3a), the stent delivery catheter 300 and the injection catheter 302
are deployed independently to the treatment site and the stent 100
is deployed. Delivery catheter 300 is removed and the iliac limb
108 is deployed as in FIG. 1 while the injection catheter 302
remains in place (FIG. 3b) with its injection ports 304 and 306
aligned with the distal end 102 of stent graft 100. Thrombin and
PRP are injected simultaneously between the vessel lumen wall and
the stent graft at the distal end 102 of stent graft 100 to form
APG 308 (FIG. 3c). The injection catheter 302 is then retrieved.
This same procedure can be repeated as necessary to apply APG to
the stent graft and/or luminal wall at other locations as depicted
in FIG. 1 (102, 112 and 106).
[0059] In another embodiment, APG is delivered directly to the
aneurysm sac. As previously described, stent graft 100 is radially
compressed to fill the stent graft chamber 218 of stent delivery
catheter 300 which is then deployed to the treatment site via the
left iliac artery 114 (FIG. 4a). An injection catheter 302 is also
deployed to the aneurysm sac through the right iliac artery 116
(FIG. 4b). The injection catheter 302 can be a coaxial catheter
with two injection lumens or a dual lumen catheter or alternatively
a three lumen catheter if a guide wire lumen is required. Injection
catheter 302 has injection ports 304 and 306 through which PRP and
thrombin may be deposited. Delivery catheter 300 is removed and the
iliac limb 108 is deployed as in FIG. 1 while the injection
catheter 302 remains in place (FIG. 4c) with its injection ports
304 and 306 in the aneurysm sac 400. The iliac limb segment of the
stent graft seals the aneurysm sac at the proximal end. Thrombin
and PRP are injected simultaneously between the vessel lumen wall
and the stent graft within the aneurysm sac to form APG 308 (FIG.
4d). An amount of PRP and thrombin necessary to produce enough APG
to fill the aneurysm sac is then deployed. The injection catheter
302 is then retrieved.
[0060] In another embodiment, single lumen injection catheters can
be used in the place of multilumen injection catheter 302. After
the guide wire is retrieved from the lumen, PRP and thrombin can be
delivered to the treatment site sequentially through the same lumen
of the single lumen injection catheter. In an alternate embodiment,
more than one single lumen injection catheters can be deployed in
each iliac artery with the distal ends of the catheters meeting in
the aneurysm sac. Thrombin and PRP can then each be injected
through the single lumen injection catheters to form APG in the
aneurysm sac.
[0061] In an alternative embodiment, more than one injection
catheter can be used to form APG within the aneurysm sac (FIG. 5).
As previously described, stent graft 100 is radially compressed to
fill the stent graft chamber 218 of stent delivery catheter 300
which is then deployed to the treatment site via the left iliac
artery 114 (FIG. 5a). Multiple single lumen or multilumen injection
catheters 302 and 500 are also deployed to the aneurysm sac through
the right iliac artery 116 and left iliac artery 118 (FIG. 4a).
Injection catheters 302 and 500 have injection ports through which
PRP and thrombin may be deposited. Delivery catheter 300 is removed
and the iliac limb 108 is deployed as in FIG. 1 while injection
catheters 302 and 500 remain in place (FIG. 5b) with their
injection ports 304 and 306 in the aneurysm sac 400. The iliac limb
segment of the stent graft seals the aneurysm sac at the proximal
end. Thrombin and PRP are injected simultaneously between the
vessel lumen wall and the stent graft within the aneurysm sac to
form APG 308 (FIG. 5c). An amount of PRP and thrombin necessary to
produce enough APG to fill the aneurysm sac and seal the ends is
determined radiographically by measuring the size of the aneurysm
sac prior to surgery. The injection catheters 302 and 500 are then
retrieved.
[0062] In yet another embodiment, depending on stent placement, a
collateral artery can be used to access the luminal wall-contacting
surface of a deployed stent graft (FIG. 6). For example, and not
intended as a limitation, stent graft 100 may be deployed such that
the distal end 102 is in the abdominal aorta near, but below the
renal artery. After deployment of stent graft 100, deployment
catheter 200 is removed and an injection catheter 302 is advanced
up the aorta past the treatment site 104 to the superior mesenteric
artery. The injection catheter 302 is then advanced through the
superior mesenteric artery and down into the inferior mesenteric
artery where it originates at the aorta immediately distal to the
treatment site 104 and the distal end of the stent graft 102. The
APG is then injected at a site adjacent the lumen wall/stent graft
interface (see FIG. 1 at 112) or into the aneurysm sac 400 and
allowed to diffuse into and around the stent graft 100.
[0063] Once the APG, or alternate cell growth promoting factor, or
combinations thereof, has been administered to the stent
graft/vessel lumen interface, cell growth will be activated and
cells will proliferate and adhere to the stent graft (a condition
or process referred to herein after as "tissue in-growth" or
endothelialization) thus anchoring the stent graft securely to the
vessel lumen and preventing stent graft migration. Moreover, tissue
in-growth will also provide a seal between the distal end of the
luminal wall contacting surface of stent graft 102 or other
locations at risk for endoleak (102, 112 and 106).
[0064] In another embodiment, the cell growth promoting
compositions are stably pre-coated on stent grafts. Drug-eluting
vascular stents are well known in the field for preventing and
treating restenosis secondary to cardiac stent implantation.
Delivery of solubilized drugs to sites within the vasculature has
been attempted using weeping balloon and injection catheters
without success. The blood flow quickly flushes the drug down
stream and away from the treatment site. For this reason, methods
of delivery of drugs coated on stents or administered in a gel were
developed. Drug-coated stent grafts are manufactured by spraying,
rolling or dipping the stent in a solution containing the drug.
Alternatively, depending on the characteristics of the drug, it may
be desirable to coat the stent graft with the composition dispersed
in a suitable polymer coating. Biocompatible and hemocompatible
polymers, including, but not limited to, poly(ethylene glycol)
(PEG)-containing polymers, are known to those of skill in the
polymer coating art. Cell growth promoting compositions including,
but not limited to, VEGF, FGF-1 and FGF-2, can be stably coated
onto stent grafts by spraying, rolling or dipping the stent graft
in solutions containing the cell growth promoting factor with or
without coating polymers.
[0065] 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
[0066] Aliquots of human peripheral blood (30-60 mL) are passed
through the Magellan.TM. Autologous Platelet Separation System (the
Magellan.TM. system) 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 (.times. 1000 .mu./L) 5.43
.+-. 1.43 17.04 .+-. 7.01 3.12 .+-. 0.90 Hct (%) 38.47 .+-. 2.95
6.81 .+-. 1.59 Cell Yield = cell count in PRP/cell count in initial
blood = [times baseline]
[0067] 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
[0068] Autologous Platelet Gel (APG) is generated from the PRP
fraction produced in the Magellan system by adding thrombin and
calcium to activate the fibrinogen present in the PRP. 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 APG on Cell Proliferation
[0069] A series of in vitro experiments were conducted evaluating
the effect of released factors from APG on the proliferation of the
human microvascular endothelial cells, human coronary artery smooth
muscle cells and human dermal fibroblasts. Primary cell cultures of
the three cell types were established according to protocols well
known to those skilled in the art of cell culture. For each cell
type, three culture conditions were evaluated. For APG cultures,
APG was added to cells in basal medium. A second group of cells
were cultured in growth medium. Growth medium is the standard
culture medium for the cell type and contains optimal growth
factors and supplements. The control cultures contain cells
cultured only in basal medium which contains no growth factors.
[0070] Autologous platelet gel had a significant growth effect on
human coronary artery smooth muscle cells after five days of
culture (FIG. 7), human microvascular endothelial cells after four
days of culture (FIG. 8) and on human dermal fibroblasts after five
days of culture (FIG. 9).
EXAMPLE 4
Effect of Platelet Poor Plasma on Human Dermal Fibroblast
Growth
[0071] In addition to the platelet-rich plasma fraction, the
Magellan system generates a platelet-poor plasma (PPP) fraction as
well. This PPP fraction was further processed by centrifuging at
10,000.times.g for 10 minutes. The PPP fractions were then
activated with the CaCl.sub.2/thrombin activator solution used in
the APG generation. Human dermal fibroblasts were then cultured in
basal medium containing PRP gel or PPP gel. Culture condition for
proliferation of human dermal fibroblasts are well known to those
of ordinary skill in the art of cell culture.
[0072] Human dermal fibroblasts cultured in the presence of PPP gel
proliferated to a similar extent as those cultured in the presence
of PRP gel (FIG. 10).
EXAMPLE 5
Effect of APG on Endothelial Cell Migration
[0073] 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% platelet-free plasma (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. Autologous platelet gel-derived serum
induced significantly more migration in human microvascular
endothelial cells than either PFP or basal medium (FIG. 11).
EXAMPLE 5
Effect of APG on Neovascularization in Athymic Mice
[0074] Autologous platelet gel was injected subcutaneously in nude
(athymic) mice to determine if the APG is detectable and
retrievable after a seven day implantation period. Athymic mice
were injected with 500 .mu.L of either APG or an inert Matrigele
control. Each animal was injected with Matrigel.RTM. in the left
flank and APG in the right flank. After seven days the implants and
the surrounding tissue were subjected to histological analysis
(FIG. 12). In the area of the Matrigele control implant there was
minimal reaction to the material and a very thin capsule of loose
connective tissue rimmed the mass (FIG. 12a). In the area of the
APG implant, the APG was deeply infiltrated by spindle shaped cells
(fibroblasts and macrophages) along with moderate numbers of
neutrophils (FIG. 12b). The entire mass was rimmed by a thick layer
of fibrovascular tissue and the tissue showed significant
neovascularization.
[0075] Those skilled in the art will further appreciate that the
embodiments according to the present invention may include other
specific forms without departing from the spirit or central
attributes thereof. In that the foregoing description discloses
only exemplary embodiments, it is to be understood that other
variations are contemplated as being within the scope of the
present invention. Accordingly, the present invention is not
limited in the particular embodiments which have been described in
detail therein. Rather, reference should be made to the appended
claims as indicative of the scope and content of the present
invention.
* * * * *