U.S. patent application number 13/850450 was filed with the patent office on 2014-03-27 for device and method for preventing stenosis at an anastomosis site.
The applicant listed for this patent is Gerald Dorros, Sriram Iyer. Invention is credited to Gerald Dorros, Sriram Iyer.
Application Number | 20140088681 13/850450 |
Document ID | / |
Family ID | 44319785 |
Filed Date | 2014-03-27 |
United States Patent
Application |
20140088681 |
Kind Code |
A1 |
Iyer; Sriram ; et
al. |
March 27, 2014 |
DEVICE AND METHOD FOR PREVENTING STENOSIS AT AN ANASTOMOSIS
SITE
Abstract
The present invention relates to treating or preventing stenosis
at an anastomosis site. In one embodiment, the present invention is
a stent is curved along the longitudinal axis for placement in and
adjacent to the graft orifice. In a further embodiment, the stent
is drug coated to allow delivery of antivasculoproliferative drugs
directly to the vicinity of the graft orifice. In a further
embodiment, the stent is expandable by use of an external wire. In
another embodiment, the present invention is a kit comprising the
specially configured stent together with a sleeve comprising a
biocompatible matrix material and a pharmaceutical agent, wherein
the sleeve is applied to the external surface of the vessel or
graft, resulting in extravascular delivery of a pharmaceutical
agent. Methods for treating or preventing stenosis at an
anastomosis site by applying the extravascular sleeve and the
intravascular stent are also provided.
Inventors: |
Iyer; Sriram; (New York,
NY) ; Dorros; Gerald; (Wilson, WY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Iyer; Sriram
Dorros; Gerald |
New York
Wilson |
NY
WY |
US
US |
|
|
Family ID: |
44319785 |
Appl. No.: |
13/850450 |
Filed: |
March 26, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13015571 |
Jan 27, 2011 |
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13850450 |
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61298631 |
Jan 27, 2010 |
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Current U.S.
Class: |
623/1.11 ;
623/1.15; 623/1.42 |
Current CPC
Class: |
A61F 2/82 20130101; A61F
2002/821 20130101; A61F 2250/0067 20130101; A61L 2300/204 20130101;
A61F 2/966 20130101; A61F 2250/006 20130101; A61L 31/16 20130101;
A61F 2/856 20130101; A61F 2/064 20130101; A61F 2230/0041 20130101;
A61L 27/54 20130101; A61F 2/844 20130101; A61F 2/90 20130101; A61L
31/125 20130101; A61F 2/954 20130101; A61F 2/962 20130101; A61F
2230/0043 20130101; A61K 31/436 20130101; A61F 2210/0004 20130101;
A61F 2/852 20130101 |
Class at
Publication: |
623/1.11 ;
623/1.15; 623/1.42 |
International
Class: |
A61L 27/54 20060101
A61L027/54; A61F 2/966 20060101 A61F002/966; A61F 2/82 20060101
A61F002/82 |
Claims
1. A stent, comprising: a structure defining an essentially tubular
body having a tubular wall with a longitudinal axis and a
circumferential diameter, the structure being expandable from a
contracted configuration to an expanded configuration, wherein the
stent is curved along the longitudinal axis for placement at an
anastomosis site.
2. The stent of claim 1, wherein the degree of curvature in the
stent is approximately 5 degrees.
3. The stent of claim 1, wherein the degree of curvature in the
stent is approximately 10 degrees.
4. The stent of claim 1, wherein the degree of curvature in the
stent is approximately 15 degrees.
5. The stent of claim 1, wherein the degree of curvature in the
stent is approximately 20 degrees.
6. The stent of claim 1, wherein the degree of curvature in the
stent is approximately 25 degrees.
7. The stent of claim 1, wherein the degree of curvature in the
stent is approximately 30 degrees.
8. The stent of claim 1, wherein the degree of curvature in the
stent is approximately 35 degrees.
9. The stent of claim 1, wherein the degree of curvature in the
stent is approximately 40 degrees.
10. The stent of claim 1, wherein the degree of curvature in the
stent is approximately 45 degrees.
11. The stent of claim 1, wherein the degree of curvature in the
stent is approximately 50 degrees.
12. The stent of claim 1, wherein the degree of curvature in the
stent is approximately 55 degrees.
13. The stent of claim 1, wherein the degree of curvature in the
stent is approximately 60 degrees.
14. The stent of claim 1, wherein the degree of curvature in the
stent is approximately 65 degrees.
15. The stent of claim 1, wherein the degree of curvature in the
stent is approximately 70 degrees.
16. The stent of claim 1, wherein the degree of curvature in the
stent is approximately 75 degrees.
17. The stent of claim 1, wherein the degree of curvature in the
stent is approximately 80 degrees.
18. The stent of claim 1, wherein the degree of curvature in the
stent is approximately 85 degrees.
19. The stent of claim 1, wherein the degree of curvature in the
stent is approximately 90 degrees.
20. The stent of claim 1, wherein the degree of curvature in the
stent is approximately 95 degrees.
21. The stent of claim 1, wherein the degree of curvature in the
stent is approximately 100 degrees.
22. The stent of claim 1, wherein the degree of curvature in the
stent is approximately 105 degrees.
23. The stent of claim 1, wherein the degree of curvature in the
stent is approximately 110 degrees.
24. The stent of claim 1, wherein the degree of curvature in the
stent is approximately 115 degrees.
25. The stent of claim 1, wherein the degree of curvature in the
stent is approximately 120 degrees.
26. The stent of claim 1, wherein the degree of curvature in the
stent is approximately 125 degrees.
27. The stent of claim 1, wherein the degree of curvature in the
stent is approximately 130 degrees.
28. The stent of claim 1, wherein the degree of curvature in the
stent is approximately 135 degrees.
29. The stent of claim 1, wherein the degree of curvature in the
stent is approximately 140 degrees.
30. The stent of claim 1, wherein the stent is a drug eluting
stent.
31. The stent of claim 30, wherein the drug is an
anti-proliferative drug.
32. The stent of claim 30, wherein the drug is rapamycin.
33. The stent of claim 30, wherein the drug is an analogue of
rapamycin.
34. The stent of claim 30, wherein the drug is everolimus.
35. The stent of claim 30, wherein the drug is dexamethasone.
36. The stent of claim 30, wherein the drug is paclitaxel.
37. The stent of claim 30, wherein the drug is tacrolimus.
38. The stent of claim 1, further comprising a wire affixed to the
outer surface of the stent in its compressed state, wherein
manipulating the wire pulls the exterior surface of the stent
toward the internal surface of the vessel, expanding the stent to
abut the interior vascular or graft wall.
39. The stent of claim 38, wherein the stent is a drug eluting
stent.
40. The stent of claim 39, wherein the drug is an
anti-proliferative drug.
41. The stent of claim 39, wherein the drug is rapamycin.
42. The stent of claim 39, wherein the drug is an analogue of
rapamycin.
43. The stent of claim 39, wherein the drug is everolimus.
44. The stent of claim 39, wherein the drug is dexamethasone.
45. The stent of claim 39, wherein the drug is paclitaxel.
46. The stent of claim 39, wherein the drug is tacrolimus.
47. A method for preventing stenosis at an anastomosis site,
comprising the steps of: a. Providing a stent comprising a
structure defining an essentially tubular body having a tubular
wall with a longitudinal axis and a circumferential diameter, the
structure being expandable from a contracted configuration to an
expanded configuration, wherein the stent is curved along the
longitudinal axis for placement in an anastomosis site; b.
Providing a sleeve comprising a biocompatible matrix material
imbibed with a therapeutic agent; c. Applying the sleeve to the
extravascular surface of an anastomosis site; and d. Inserting the
stent into the vein and graft orifice of an anastomosis site.
48. The method of claim 47, wherein the therapeutic agent is
rapamycin.
49. The method of claim 47, wherein the therapeutic agent is an
analogue of rapamycin.
50. The method of claim 47, wherein the therapeutic agent is
everolimus.
51. The method of claim 47, wherein the therapeutic agent is
dexamethasone.
52. The method of claim 47, wherein the therapeutic agent is
paclitaxel.
53. The method of claim 47, wherein the therapeutic agent is
tacrolimus.
54. The method of claim 47, wherein the matrix material comprises
collagen.
55. The method of claim 54, wherein the collagen is Type I Bovine
collagen.
56. The method of claim 54, wherein the collagen is selected from
the group consisting of Type I, Type II, Type III, Type IV, Type
XI, and mixtures thereof.
57. The method of claim 47, wherein the matrix material comprises
fibrin.
58. The method of claim 47, wherein the matrix material comprises a
polysaccharide.
59. The method of claim 58, wherein the polysaccharide is
chitosan.
60. The method of claim 47, wherein the matrix material is selected
from the group consisting of collagen, fibrin, chitosan, and
mixtures thereof.
61. The method of claim 47, wherein the stent is a drug eluting
stent.
62. The method of claim 61, wherein the drug is an
anti-proliferative drug.
63. The method of claim 61, wherein the drug is rapamycin.
64. The method of claim 61, wherein the drug is an analogue of
rapamycin.
65. The method of claim 61, wherein the drug is everolimus.
66. The method of claim 61, wherein the drug is dexamethasone.
67. The method of claim 61, wherein the drug is paclitaxel.
68. The method of claim 61, wherein the drug is tacrolimus.
69. The method of claim 47, wherein the provided stent further
comprises a wire affixed to the external surface of the stent in
its compressed state, and wherein inserting the stent further
comprises the steps of: a. Inserting the stent in its contracted
state into the vein and graft orifice of an anastomosis site; b.
Manipulating the external wire to pull the external surface of the
stent toward the internal surface of the vessel, expanding the
stent to abut the interior vascular or graft wall.
70. The method of claim 69, wherein the stent is a drug eluting
stent.
71. The method of claim 70, wherein the drug is an
anti-proliferative drug.
72. The method of claim 70, wherein the drug is rapamycin.
73. The method of claim 70, wherein the drug is an analogue of
rapamycin.
74. The method of claim 70, wherein the drug is everolimus.
75. The method of claim 70, wherein the drug is dexamethasone.
76. The method of claim 70, wherein the drug is paclitaxel.
77. The method of claim 70, wherein the drug is tacrolimus.
78. A method for preventing stenosis at an anastomosis site
comprising the steps of: a. Providing a stent delivery system
comprising: i. a stent in its contracted configuration, wherein the
stent is a web structure defining an essentially tubular body
having a tubular wall with a longitudinal axis and a
circumferential diameter, the web structure being expandable from a
contracted configuration to an expanded configuration, wherein the
stent is curved along the longitudinal axis for placement in an
anastomosis site; and ii. a sheath surrounding said stent to
constrict the stent to its contracted state; b. Providing a sleeve
comprising a biocompatible matrix material imbibed with a
therapeutic agent; c. Applying the sleeve to the extravascular
surface of an anastomosis site; d. Directing the stent delivery
system to an anastomosis site; e. Retracting the sheath, wherein
retraction of said sheath causes the stent to expand and abut the
internal vascular or graft wall.
79. The method of claim 78, wherein the stent is a drug eluting
stent.
80. The method of claim 79, wherein the drug is an
anti-proliferative drug.
81. The method of claim 79, wherein the drug is rapamycin.
82. The method of claim 79, wherein the drug is an analogue of
rapamycin.
83. The method of claim 79, wherein the drug is everolimus.
84. The method of claim 79, wherein the drug is dexamethasone.
85. The method of claim 79, wherein the drug is paclitaxel.
86. The method of claim 79, wherein the drug is tacrolimus.
87. A kit for preventing stenosis at an anastomosis site,
comprising: a. a stent comprising a web structure defining an
essentially tubular body having a tubular wall with a longitudinal
axis and a circumferential diameter, the web structure being
expandable from a contracted configuration to an expanded
configuration, wherein the stent is curved along the longitudinal
axis for placement in an anastomosis site; and b. a sleeve
comprising a biocompatible matrix material imbibed with a
therapeutic agent.
88. The kit of claim 87, wherein the therapeutic agent is
rapamycin.
89. The kit of claim 87, wherein the therapeutic agent is an
analogue of rapamycin.
90. The kit of claim 87, wherein the therapeutic agent is
everolimus.
91. The kit of claim 87, wherein the therapeutic agent is
dexamethasone.
92. The kit of claim 87, wherein the therapeutic agent is
paclitaxel.
93. The kit of claim 87, wherein the therapeutic agent is
tacrolimus.
94. The kit of claim 87, wherein the matrix material comprises
collagen.
95. The kit of claim 94, wherein the collagen is Type I Bovine
collagen.
96. The kit of claim 94, wherein the collagen is selected from the
group consisting of Type I, Type II, Type III, Type IV, Type XI,
and mixtures thereof.
97. The kit of claim 87, wherein the matrix material comprises
fibrin.
98. The kit of claim 87, wherein the matrix material comprises a
polysaccharide.
99. The kit of claim 98, wherein the polysaccharide is
chitosan.
100. The kit of claim 87, wherein the matrix material is selected
from the group consisting of collagen, fibrin, chitosan, and
mixtures thereof.
101. The kit of claim 78, wherein the stent is a drug eluting
stent.
102. The kit of claim 101, wherein the drug is an
anti-proliferative drug.
103. The kit of claim 101, wherein the drug is rapamycin.
104. The kit of claim 101, wherein the drug is an analogue of
rapamycin.
105. The kit of claim 101, wherein the drug is everolimus.
106. The kit of claim 101, wherein the drug is dexamethasone.
107. The kit of claim 101, wherein the drug is paclitaxel.
108. The kit of claim 101, wherein the drug is tacrolimus.
109. A method for preventing stenosis at an anastomosis of an AV
fistula, comprising the steps of: a. Providing a stent comprising a
structure defining an essentially tubular body having a tubular
wall with a longitudinal axis and a circumferential diameter, the
structure being expandable from a contracted configuration to an
expanded configuration, wherein the stent is curved along the
longitudinal axis for placement at the anastomosis; and b.
Inserting the stent into the vein and graft orifice of the
anastomosis, wherein the placement of the stent at or around the
anastomosis prevents the narrowing of the outflow vein.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 13/015,571, filed Jan. 27, 2011, which claims
priority to U.S. Provisional Patent Application No. 61/298,631
filed Jan. 27, 2010.
FIELD
[0002] The present invention relates generally to therapeutic
implants, devices, and methods useful for preventing, suppressing,
or treating stenosis(es) at and around the site of an anastomosis.
The invention also relates to stents specifically configured for
placement at an anastomosis or a fistula, and methods for combining
those sites with extravascular therapeutic implants comprising a
matrix material and a therapeutic agent. The specifically
configured stents are also useful for treatment of stenosis or
narrowings remote from an anastomosis, e.g., treatment of an ostial
stenosis in a side branch, treatment of a stenosis in a central
vein (e.g. cephalic arch) and the like.
BACKGROUND
[0003] Vascular procedures such as construction of arterio-venous
grafts and arterio-venous fistulae are performed to provide
vascular access to facilitate hemodialysis in patients with end
stage renal disease. Interventions like angioplasty are performed
to treat, for example, narrowing (stenosis) or occlusion resulting
from vasculoproliferative conditions such as obstructive intimal
hyperplasia or atherosclerosis. Vascular access for hemodialysis
can be constructed as an arterio-venous fistula (AVF) (e.g.,
Brecisa-Cimino), or as a graft (AVG) interposing prosthetic
material (e.g., polytetrafluoroehtylene, "PTFE") between an artery
and a vein. During the construction of an AV fistula, a vein is
joined or attached to an artery to enable direct communication
between the arterial and venous lumen. In one method for creating
an arterio-venous fistula, a vein in the forearm, arm or thigh is
joined or attached to an adjacent artery so that there is a direct
communication between the arterial and venous lumen. During the
construction of an AV fistula, the severed end of the vein is
dislodged from its natural location and the vein curved along its
longitudinal axis so that the vein may be connected directly to the
artery. The site(s) of vascular union, e.g. artery and vein or
graft and artery or graft and vein are referred to as the vascular
anastomotic(s) site or vascular anastomosis. The anastomosis can be
completed using sutures or clips, or with the help of devices
specially designed for creation and completion of such anastomosis.
The graft can be made of synthetic materials, like
polytetrafluoroethylene (PTFE) for example, or can be comprised of
autologous tissue (e.g. saphenous vein, mammary artery, etc.).
[0004] Subsequent to the construction of a fistula or graft, the
anastomotic site connecting the artery and the vein (e.g. in case
of a fistula) and the graft/artery and the graft/venous anastomotic
sites (e.g. in case of AV graft) undergo healing. However, a
certain proportion of these vascular access and vascular graft
surgeries fail as a result of narrowing or stenosis at and around
the anastomotic sites. As many as 60 percent of AV fistulae do not
develop ("failure to mature") into a vascular access suitable to
support dialysis; an important reason for this maturation failure
is luminal narrowing, or an obstructive stenosis, at and around the
venous end, commonly referred to as a Juxta Anastomotic Stenosis
(JAS). Stenosis can also occur at sites remote from the anastomosis
(e.g. cephalic arch stenosis, stenosis at the site of needle
punctures, etc). In the case of AV grafts, the anastomotic site of
the PTFE graft and the vein often develop a stenosis resulting in
slow flow and thrombosis of the graft making it unusable as a
vascular access for dialysis. Similar lesions develop in grafts
placed in the arterial circulation, (e.g. peripheral arterial
bypass using prosthetic PTFE grafts or coronary artery or
peripheral artery bypass using biological tissue conduits like
saphenous vein). Failure or dysfunction of grafts used in coronary
artery bypass graft surgery as well as peripheral vascular surgery
(e.g., aorta-iliac, femoral-femoral, femoral-popliteal,
femoral-tibial, etc.) are also well known. In general, stenosis in
grafts used to bypass pathology in the arterial system develops at
a slower rate when compared to the failure of hemodialysis access
grafts or fistulae described above.
[0005] An important cause of failure of vascular grafts is usually
related to luminal narrowing of the vessel or prosthetic conduit,
at or around the vascular anastomotic site(s). One reason for this
narrowing is a consequence of a vasculoproliferative response and
frequently results in graft thrombosis and fistula failure. Other
pathologies can also affect the performance of a graft or fistula,
e.g. infection, pseudo-aneurysm, bleeding etc. Although the
discussion above has focused on anastomosis involving blood vessels
(vascular anastomosis), other examples of anastomosis, which in
broad terms includes the site or region of union of two hollow
tubes or conduits include: anastomosis involving the ureter,
trachea/bronchi, fallopian tubes, segments of bowel, etc., and
problems of luminal narrowing can also be seen at and around these
anastomotic sites. The methods and devices described in this
application are intended for use in both vascular as well as these
non-vascular applications.
[0006] Neointimal hyperplasia, a manifestation of the
vasculoproliferative response, affects the anastomotic orifice and
adjacent vessel. The vessel wall thickens and the lumen narrows
often due to migration and proliferation of smooth muscle cells.
Left untreated, stenosis eventually leads to occlusion and graft or
fistula failure. The etiology of graft and fistula failures may
relate to a variety of physical stimuli (e.g., shear stress causing
hemodynamic disturbances such as increased resistance from a
non-dilated vein, turbulent flow replacing laminar flow), chemical
stimuli, or biological stimuli, as well as infection or foreign
body rejection. For example, in an arterio-venous fistula,
dislodging the vein from its natural location can cause stress and
injury, which can lead to an increased risk of stenosis. As
stenosis in the graft or fistula becomes progressively more severe,
the graft or fistula becomes dysfunctional and access for medical
procedures becomes suboptimal or absent, and precludes use of that
vascular access to perform hemodialysis. Diminished blood flow in
grafts connecting two arteries (e.g. grafts used for coronary
artery bypass graft surgery or peripheral arterial bypass surgery)
leads to problems related to diminished or lack of blood supply
(ischemia) to the organ supplied by the bypassed artery.
[0007] Once the stenosis has occurred, one of the treatment options
involves reduction or obliteration of the narrowing and restoration
of blood flow through the graft (thereby permitting resumption of
adequate hemodialysis) by means of non-surgical, percutaneous
catheter-based treatments such as balloon angioplasty. Balloon
angioplasty, in one aspect, involves deployment of a balloon
catheter at the site of the blockage, and inflating the balloon to
increase the minimum luminal diameter (MLD) of the vessel by
compressing the material causing the restriction against the
interior of the vessel wall. Depending on the length, severity and
characteristics of the restriction (e.g. degree of stenosis
resulting in the blood flow restriction, and amount of
calcification) the balloon may have to be repositioned and inflated
and deflated more than once in order to attain optimal lumen
expansion. When completed, the balloon catheter is withdrawn from
the system.
[0008] Although balloon angioplasty can be used as a "stand alone"
procedure, it is frequently accompanied by deployment of a stent.
As is known in the art, a stent is an expandable scaffolding or
support device which is placed within the vasculature (endovascular
implant). Following angioplasty, mechanical (elastic) recoil and
negative vascular remodeling can be important contributors to
re-narrowing (restenosis) at the site of the original restrictions.
An endovascular stent is effective in countering recoil and also
very effective in preventing a dissection flap, which can result
following balloon angioplasty of the restriction or stenosis, from
falling back into the vascular lumen. Such a dissection flap has
the potential to completely obstruct blood flow soon after
angioplasty, resulting in acute vessel closure. The stent is very
effective in preventing acute closure. The stents known in the
prior art are either "balloon expandable" or "self expanding," and
when deployed endovascularly, the stent after expansion abuts
directly against the inner lining of the vessel wall (intimal
surface). Balloon-expandable stents are disclosed in U.S. Pat. No.
4,733,665 to Palmaz. Self-expanding stents are disclosed in U.S.
Pat. No. 5,443,500 to Sigwart, U.S. Pat. No. 4,655,771 to Wallsten,
U.S. Pat. No. 5,061,275 to Wallsten et al., and U.S. Pat. No.
5,645,559 to Hachtman et al. Despite using a plain stent (i.e. bare
metal, partially or completely biodegradable, non-drug-coated
stent) following angioplasty, this form of treatment (endovascular
stent placement) has an important risk of failure, i.e., the risk
of re-narrowing (restenosis) or occlusion at the treatment site. In
other words, the scaffolding effect of the bare metal stent by
itself, cannot completely overcome the problem of restenosis at the
treatment site. The use of drug eluting stents in vascular
procedures to overcome or reduce the problem of restenosis is also
well known to those skilled in the art. Drug eluting stents are,
for example, disclosed generally in U.S. Pat. No. 5,545,208 to
Wolff, U.S. Pat. No. 6,899,731 to Li et al., U.S. Pat. No.
6,273,913 to Wright et al., and U.S. Pat. Pub. No. 2009/0182404 to
Shookoohi.
[0009] Unless stenosis(es) at the treatment sites (e.g. at and
around the site of vascular anastomosis) can be effectively
treated, graft or fistula failure tends to follow. In the event of
hemodialysis AV graft or fistula failure, the patient has to
undergo an immediate/urgent endovascular procedure (i.e., a
non-surgical, catheter-based percutaneous procedure such as a
thrombectomy) to "declot (remove the thrombus within)" or undergo
repeat vascular surgery to place another vascular access, which
could be another graft or fistula, at a different site, or undergo
placement of a catheter, unless the patient receives a kidney
transplant. Given the obvious problems of repeat procedures and
surgery (e.g. mortality, morbidity, cost, prolonged
hospitalizations, infections, etc.), and the limited availability
of transplants, there is a need for a treatment that is both
effective and long lasting (i.e. durable) in the prevention and
treatment of dialysis vascular access and graft anastomotic
stenosis.
[0010] The configurations of traditional stents have limitations
for treating stenosis at and adjacent to an anastomosis site of
fistula and grafts. Adjacent to the anastomotic orifice of an
arterio-venous fistula or graft, the vein or graft protrudes from
the artery or blood vessel at an angle, curving along its
longitudinal axis toward its origin in the body ("candy cane
configuration"). (FIGS. 1-3). Because currently available stents
are not curved along the longitudinal axis, they are not well
suited for placement at and adjacent to the anastomotic site of a
fistula or graft because they cannot extend into the curvature of
the blood vessel. In addition, these stents cannot be easily
maneuvered through the graft orifice and into the artery at an
arterio-venous fistula because of the angulation, U-turn or hairpin
configuration of the vessels at the anastomotic site.
[0011] Yet another limitation of currently available stents relates
to the configuration at the anastomosis. Two blood vessels, or a
graft and a blood vessel, can be joined at a right angle (see FIG.
1A). If the anastomosis is at a right angle, the edge of a
cylindrical stent can be positioned such that the stent edge can be
aligned and lined up to match the edge of the blood vessel at the
right angle anastomosis (see FIG. 1B). However, in most instances,
the operator bevels the edge of the blood vessel prior to creating
the anastomosis (see FIG. 1C). In this case, it can be appreciated
that a cylindrical stent edge cannot be exactly lined up against
the edge of the beveled blood vessel. Either the stent will be a
"little short" of the anastomosis (see FIG. 2D, 16A) or it will
protrude across the anastomosis into the other vessel (see FIG.
16B). Accordingly, there is a need for a stent that will address
both undesirable conditions related to the placement of a stent
having a square-cut, right angled end/edge at the site of an
anastomosis where the vessels of the anastomosis are not
perpendicular to each other.
[0012] The diameter of the two blood vessels that are being joined
at the anastomosis may be different; similarly the diameter of the
blood vessel at the level of the anastomosis and the diameter at a
point away from the anastomosis may be different. Hence, the stents
used herein may need to be tapered. The term tapered indicates that
the diameter of the expanded stent at one end differs when compared
to the diameter of the expanded stent at the opposite end. This
difference in diameter may occur gradually over the length of the
stent or it may occur abruptly at some point along the length of
the stent.
[0013] Another known method for treating and preventing stenosis is
the implantation of a prosthetic device, or "sleeve" on the outer
surface of the vessel or graft which then elutes
antivasculoproliferative drugs or agents such as rapamycin
(sirolimus), paclitaxel, tacrolimus, everolimus, zotarolimus and
other cell cycle inhibitors or similarly-functioning agents. Such a
sleeve is disclosed in U.S. Pat. No. 6,726,933, entitled "Apparatus
and Methods for Preventing or Treating Failure of Hemodialysis
Vascular Access and Other Vascular Grafts," and co-pending U.S.
Patent Application Publication No. 2005/0004158, entitled "Medical
Implants and Methods For Regulating the Tissue Response to Vascular
Closure Devices," filed on Jun. 18, 2004.
[0014] There is therefore a need for a stent that can be used
together with the above-described wrap or sleeve to prevent,
suppress or treat stenosis at and around an anastomosis site or
fistula. And there is a need for methods for combining such
extravascular therapeutic implants comprising a matrix material
together with an endovascular stent implant. There is also a need
to combine a traditional self expanding nitinol stent or a balloon
expandable stent together with a perivascular drug eluting sleeve.
Any of the stents described herein can be used in combination with
a perivascular wrap in order to prevent, suppress, or treat
stenosis. (See FIGS. 18 and 19).
SUMMARY
[0015] In one embodiment, the present invention is a stent that is
specially configured for placement at an anastomosis site in that
the stent is curved along the longitudinal axis for placement at
and/or adjacent to the anastomosis. Such a stent can also be used
away from an anastamosis site; for example, at a curved part of a
vessel remote from the anastomosis, or at the bifurcation of a
vessel. In another embodiment, the stent is specially configured
for placement at an anastomosis site in that the stent is beveled,
flared or trumpeted at the edge to facilitate deployment at the
anastomosis. In another embodiment the stent is tapered so that the
diameter at one end of the expanded stent is different from the
other end. In another embodiment the stent is coated with a polymer
like PTFE; the coating may extend along the entire length and
circumference of the stent or it may partially cover the stent. In
a further embodiment, the stent is drug coated to allow local
delivery of anti-vasculoproliferative drugs directly to the
vicinity at and around the site of anastomosis. In a further
embodiment a combination of a drug eluting balloon expandable stent
and a self expandable is used; the balloon expandable drug eluting
stent is sandwiched between the self expanding stent and the vessel
wall. In a further embodiment, a wire or wire like delivery system
with a handle is attached to the exterior surface of the stent in
its compacted state, wherein manipulating the wire or another
release mechanism pulls the exterior surface of the stent toward
the interior surface of the vessel, resulting in expansion and
deployment of the stent.
[0016] In another embodiment, a combination of a balloon expandable
drug eluting stent and a non drug coated self expanding stent is
used. In this case, the balloon expandable drug eluting stent is
first deployed at and around the anastomosis of an AV fistula or
graft. The self expanding nitinol stent is then deployed such that
the balloon expandable drug eluting stent is sandwiched between the
expanded self expanding nitinol stent and the inner lining of the
graft and/or the inner wall of the blood vessel. The balloon
expandable drug eluting stent can be made of a biodegradable
material or a biostable material like stainless steel or cobalt
chromium.
[0017] In another embodiment, the balloon expandable or self
expandable stent may be partially or completely covered by a
polymer, fabric or biological coating. An example of such a
covering that may be used for the stent is polytetrafluoroethylene
(PTFE).
[0018] In another embodiment, the present invention is a kit
comprising a stent specially configured for placement at an
anastomosis site in that the stent is curved along the longitudinal
axis (endovascular implant), together with a sleeve comprising a
biocompatible matrix material and a pharmaceutical agent, wherein
the sleeve is applied to the external surface of the vessel or
graft (perivascular implant), resulting in extravascular delivery
of a pharmaceutical agent. The biocompatible matrix may be applied
after the stent is deployed by a simple delivery device that
permits folding of the limbs of the matrix to enable covering of
the anastomosis. In another embodiment both the endovascular stent
and the perivascular drug eluting biocompatible matrix material can
be implanted during the time of surgery for creation of the
anastomosis (e.g. AV graft, AV Fistula)
[0019] In another embodiment, the present invention is a kit
comprising a stent specially configured for placement at an
anastomosis site in that the stent is beveled, flared or trumpeted
at the edge, together with a sleeve comprising a biocompatible
matrix material and a pharmaceutical agent, wherein the sleeve is
applied to the external surface of the vessel or graft, resulting
in extravascular delivery of a pharmaceutical agent. The
biocompatible matrix may be applied after the stent is deployed by
a simple delivery device that permits folding of the limbs of the
matrix to enable covering of the anastomosis. In another embodiment
both the endovascular stent and the perivascular drug eluting
biocompatible matrix material can be implanted during the time of
surgery for creation of the anastomosis (e.g. AV graft, AV
Fistula).
[0020] In another embodiment, the present invention is a kit
comprising a stent specially configured for placement at an
anastomosis site in that the stent is tapered together with a
sleeve comprising a biocompatible matrix material and a
pharmaceutical agent, wherein the sleeve is applied to the external
surface of the vessel or graft, resulting in extravascular delivery
of a pharmaceutical agent. The biocompatible matrix may be applied
after the stent is deployed by a simple delivery device that
permits folding of the limbs of the matrix to enable covering of
the anastomosis. In another embodiment both the endovascular stent
and the perivascular drug eluting biocompatible matrix material can
be implanted during the time of surgery for creation of the
anastomosis (e.g. AV graft, AV Fistula).
[0021] In another embodiment, the present invention is a kit
comprising a stent specially configured for placement at an
anastomosis site in that the stent is a covered stent (e.g. covered
by PTFE) together with a sleeve comprising a biocompatible matrix
material and a pharmaceutical agent, wherein the sleeve is applied
to the external surface of the vessel or graft, resulting in
extravascular delivery of a pharmaceutical agent. The biocompatible
matrix may be applied after the stent is deployed by a simple
delivery device that permits folding of the limbs of the matrix to
enable covering of the anastomosis. In another embodiment both the
endovascular stent and the perivascular drug eluting biocompatible
matrix material can be implanted during the time of surgery for
creation of the anastomosis (e.g. AV graft, AV Fistula).
[0022] In another embodiment, the present invention is a kit
comprising a drug eluting balloon expandable stent and a self
expanding nitinol stent specially configured for placement at an
anastomosis site. The special features of the stent may include one
or more of the following: curvature along the long axis of the
stent, beveled, flared or trumpeted edge(s), tapered design,
covering with a fabric (e.g. PTFE). Traditionally designed stents
(e.g. balloon expandable stents such as stainless steel or cobalt
chromium balloon expandable stents, self expanding stents such as
nitinol self expanding stents, partially or completely
biodegradable stents, stents that are partially or completely
covered with a synthetic material such as PTFE or other
biodegradable or non biodegradable polymers, or stents that are
covered with a segment of biological tissue like a segment of vein,
etc.) that do not have any of the features described above may also
be included in the kit.
[0023] Methods for treating or preventing stenosis at an
anastomosis site by applying the extravascular sleeve and the
intravascular stent are also provided (FIGS. 12-15, 18 and 19). In
one embodiment, the stent is inserted in its contracted state and
manipulating a wire attached to the external surface of the stent
pulls the exterior surface of the stent toward the interior wall of
the vessel, resulting in expansion of the stent. In another
embodiment, the stent is inserted in its contracted state and
covered with a sheath, wherein retracting the sheath results in
expansion of the stent. The system may be configured such that
retraction of the sheath starts from the distal end (i.e. the
distal end of the stent is deployed first), or, the system may be
configured so that the retraction of the sheath begins from the
proximal end (i.e. the proximal end of the stent is deployed
first). (FIGS. 17A and 17B). In additional embodiments, the stent
may be held in its compact, restrictive (non-expanded) state by
other means (e.g. a wire wrapped around the stent, a membrane
restricting expansion of the stent) prior to deployment. In one
embodiment, the stent is a balloon-expandable stent. In another
embodiment, the stent is self-expanding. In another embodiment, the
stent delivery device permits the proximal end of the stent
(closest to the operator's fingers) to be deployed first. Once the
proximal end is released, it enables the operator to pull back and
recognize that a few millimeters of the partially deployed stent
are now on the arterial side of the anastomosis. At this point, the
second mechanism of release allows the remaining portion of the
stent to be released. In one iteration, the proximal end of the
stent is released first, while in another iteration the distal end
of the stent is released first.
[0024] The delivery system containing the stent may be introduced
into the body percutaneously. The delivery system containing the
stent may be introduced into the body during an open surgical
procedure. The delivery system containing the stent may be
introduced into the body using a robotic system
[0025] The sleeve comprising a biocompatible matrix material and a
pharmaceutical agent, may be implanted at the intended position
during an open surgical procedure. The sleeve comprising a
biocompatible matrix material and a pharmaceutical agent may also
be implanted percutaneously. The sleeve comprising a biocompatible
matrix material and a pharmaceutical agent may be implanted using a
robotic system
BRIEF DESCRIPTION OF THE DRAWINGS
[0026] FIGS. 1A-1D illustrate the difference between a "non
beveled" right angled anastomosis (FIGS. 1A and 1B) and a beveled,
angled anastomosis (FIGS. 1C and 1D).
[0027] FIGS. 2A-2E illustrate how the stent design requirements
(FIGS. 2A and 2B) are different for a right angled, non beveled
anastomosis (FIG. 2C) and a beveled angled anastomosis (FIGS. 2D
and 2E).
[0028] FIG. 3 is a side view of an arterio-venous fistula.
[0029] FIG. 4 is a side view of one embodiment of the stent of the
present invention.
[0030] FIGS. 5-7 are side views of embodiments of the stent of the
present invention in place at an arterio-venous fistula or across
the anastomotic site of a graft, which has been transected along
the longitudinal axis.
[0031] FIG. 8 is a side view of the kit of the present invention in
use at an arterio-venous fistula, where the fistula and the wrap
have been transected along the longitudinal axis to reveal
placement of the stent.
[0032] FIG. 9 is a side view of one embodiment of the method of the
present invention, where the arterio-venous fistula has been
transected to reveal placement of the stent delivery system.
[0033] FIG. 10 is a side view of a covered stent, which has been
transected along the longitudinal axis.
[0034] FIG. 11 is a side view of the embodiment of the stent of the
present invention in place at a natural bend in a vessel, which has
been transected along the longitudinal axis.
[0035] FIGS. 12A and 12B are 28 Day Angiograms from the two animals
that received the endovascular self expanding nitinol stent 100
without the sirolimus eluting collagen matrix, which was placed at
the anastomosis of the PTFE graft and the Vein. Narrowing within
the stent is seen in both animals.
[0036] FIGS. 12C and 12D are 28 Day Angiograms are from the two
animals that received the endovascular self expanding nitinol stent
plus the Sirolimus eluting collagen matrix 200, which was placed at
the anastomosis of the PTFE graft and the Vein.
[0037] FIGS. 13A and 13B are 56 Day Angiograms from the two animals
that received the endovascular self expanding nitinol stent 100
without the Sirolimus eluting collagen matrix, which was placed at
the anastomosis of PTFE graft 105 and the Vein 110. Narrowing of
the stent is seen and is more pronounced compared to the appearance
at 28 days.
[0038] FIGS. 13C and 13D are 56 Day Angiograms from the two animals
that received the endovascular self expanding nitinol stent plus
the Sirolimus eluting collagen matrix 200, which was placed at the
anastomosis of the PTFE graft 105 and the Vein 110. In FIG. 13C,
the Proximal Vein 115 is also visible. There is minimal narrowing
of the stent.
[0039] FIGS. 14A and 14B are Angiograms of control AV fistulae (the
left and right AV fistula, respectively) in Animal ID No. 9S005,
which do not include a stent or siroliums eluting matrix, from the
day of surgery (Day 0).
[0040] FIGS. 14C and 14D are Angiograms from the day of surgery
(Day 0) for Animal ID No. 9S019, which was treated with an
endovascular self-expanding stent (6 mm.times.30 mm for the left AV
fistula, and 6 mm.times.40 mm for the right AV fistula) and
Perivascular Sirolimus Eluting Matrix 200. The anastomosis 205 is
also visible in each Angiogram.
[0041] FIGS. 15A and 15B are Angiograms of control AV fistulae (the
left and right AV fistula, respectively) in Animal ID No. 9S005,
which do not include a stent or sirolimus eluting matrix, taken 28
days following surgery that show severe stenosis of the outflow
vein 210 (juxta anastomotic segment) as well as the anastomosis
205.
[0042] FIGS. 15C and 15D are Angiograms of the left AV fistula
performed on day 28 (FIG. 15C) and day 62 (FIG. 15D) in Animal ID
No. 9S019 that was treated with endovascular self-expanding stent
(6 mm.times.30 mm and Perivascular Sirolimus Eluting Matrix 200. On
day 28, significant improvement in lumen dimensions of the
anastomosis 205 as well as the outflow vein (improved patency) is
seen in comparison to controls. The improvement is maintained on
the angiogram performed on day 62.
[0043] FIG. 16A-16D shows the difference between a beveled stent
edge and a traditional right angled stent edge and illustrates why
the beveled edge provides optimal coverage of the anastomosis.
[0044] FIGS. 17A-17F illustrates the difference between the
traditional, conventional deployment system for a self expanding
stent (distal end deployed first, proximal end deployed last) and
the proposed deployment system, which allows "proximal end first
distal end last" deployment of the stent.
[0045] FIGS. 18A-18B and 19A-19B illustrate the concept of
combining an endovascular stent together with a perivascular drug
eluting matrix, both implants placed at and around the
anastomosis.
DETAILED DESCRIPTION
[0046] While the present invention is capable of being embodied in
various forms, the description below of several embodiments is made
with the understanding that the present disclosure is to be
considered as an exemplification of the invention, and is not
intended to limit the invention to the specific embodiments
illustrated.
[0047] The use of numerical values in the various ranges specified
in this application, unless expressly indicated otherwise, are
stated as approximations as though the minimum and maximum values
within the stated ranges were both preceded by the word "about." In
this manner, slight variations above and below the stated ranges
can be used to achieve substantially the same results as values
within the ranges. As used herein, the terms "about" and
"approximately" when referring to a numerical value shall have
their plain and ordinary meanings to one skilled in the art of
cardiology and pharmaceutical sciences or the art relevant to the
range or element at issue. The amount of broadening from the strict
numerical boundary depends upon several factors. For example, some
of the factors to be considered may include the criticality of the
element and/or the effect a given amount of variation will have on
the performance of the claimed subject matter, as well as other
considerations known to those of skill in the art. Thus, as a
general matter, "about" or "approximately" broaden the numerical
value, yet cannot be given a precise limit. For example, in some
cases, "about" or "approximately" may mean.+-.5%, or .+-.10%, or
.+-.20%, or .+-.30% depending on the relevant technology. Also, the
disclosure of ranges is intended as a continuous range including
every value between the minimum and maximum values.
[0048] The medical devices of the present invention broadly
comprise stents and sleeves used for treating stenosis at and
around an anastomosis site. The present invention is unique in at
least six respects: (1) the stent of the present invention is
curved along its longitudinal axis ("candy cane shape") for special
placement at a fistula or an anastomosis site, or to accommodate a
vessel remote from the anastomosis site that has a curve (e.g.
cephalic arch), (2) the stent of the present invention is beveled,
flared or trumpeted for special placement and to facilitate
alignment at a beveled anastomosis site, vessel origin (ostium) or
vessel bifurcation wherein the side branch vessel originates at an
angle other than a right angle from the parent vessel, (3) the
stent of the present invention is tapered to facilitate placement
wherein the diameter of the two structures are different, (4) the
present invention includes a combination of drug-eluting balloon
expandable or self-expanding stent and a plain, non-drug-eluting
balloon expandable or self-expanding stent, (5) the stents of the
present invention may be partially or completely covered with a
fabric or polymer (e.g. PTFE), and (6) the methods and kits of the
present invention combine the specially-configured stent with a
sleeve that elutes a pharmaceutical agent directed to preventing
stenosis. The drug-eluting sleeve may be used in combination with
other self expanding and/or balloon expandable stents (i.e. it is
not necessary to have a specifically configured stent to practice
this invention).
[0049] Referring to FIG. 1A, the edge 10 of the vessel or graft 15
may be cut (shown with the dashed lines) perpendicular to the
longitudinal axis of the blood vessel or graft 10. In this
instance, the anastomosis created by joining the two vessels, or a
vessel and a graft, 15 and 20 (shown in FIG. 1B) will be at right
angles. FIG. 1C shows that the edge 25 of the vessel or graft 15
may be also cut at an angle--this confers a beveled configuration
to the end of the vessel 15. Notice that because of this bevel, the
eventual size of the anastomosis (shown in FIG. 1D) is larger in
terms of both length as well as the area of the anastomosis when
compared to the right angled anastomosis shown in FIG. 1B. FIGS.
2A-2E illustrate some of the stent designs discussed in the present
disclosure, that make the stent particularly suited for implant at
and around the anastomosis. FIG. 2A shows a stent 30 that is
essentially a tubular body with a longitudinal axis and a circular
cross-section. The stent 30 has a degree of curvature along the
longitudinal axis. The stent 30 has a first, proximal end 35 and a
second, distal end 40, each of the ends 30, 35 having a different
diameter 45, 50, conferring a tapered appearance to the stent 30.
FIG. 2B shows the first end 35 of the stent 30 is flared or
trumpeted. FIG. 2C illustrates how the stent 30 shown in FIG. 2A
can be implanted in a right angled anastomosis. FIG. 2D illustrates
that the stent 30 shown in FIG. 2A is not well suited for
implantation around an anastomosis wherein the vein or graft 15 is
beveled. FIG. 2E illustrates how a beveling, flaring, or trumpeting
of the first end 35 of the stent 30 allows a more precise
implantation at the anastomosis. FIG. 3 illustrates an anastomosis
viewed from the side. The structure marked A represents an artery.
The structure marked V represents a graft or vein. A and V can
represent any hollow tube or conduit in the body undergoing an
anastomosis.
[0050] Referring to FIG. 4, in one embodiment, the stent 30 of the
present invention has a web-like structure 55 defining an
essentially tubular body having a tubular wall 60 with a
longitudinal central axis 65 and a first end diameter 70, the web
structure 55 being expandable from a contracted configuration to an
expanded configuration, wherein the stent 30 is specially
configured for placement at a fistula or an anastomosis site or a
vessel with a curvature. The stent has a degree of curvature 75
along the longitudinal axis 65 between about 5 and 160 degrees.
Referring to FIG. 5, the stent 30 is placed in the internal lumen
80 of the vein, graft or blood vessel 15 and the proximal end 35 of
the stent 30 holds open the anastomosis orifice 85 at the junction
of the vein, graft or blood vessel 15 and the artery, graft or
blood vessel 20. The exact degree of curvature 75 of the stent 30
may be determined based upon the degree of curvature occurring in
the vein 15. In cases other than fistula, reference numeral 15 can
represent a graft or other blood vessel or conduit. The stent 30 is
thus specially configured to maintain the structure of the
anastomotic orifice 85 and the curvature of the vein or artery or
other blood vessel 15 at a fistula or graft anastomosis site.
[0051] Referring to FIG. 6, the curved portion of the stent 30 may
also be placed across the anastomosis or the graft orifice 85. In
this placement, the stent 30 passes from the vein, graft or blood
vessel 15, through the anastomosis orifice 85, and into the artery,
graft or blood vessel 20. In the case of an AV graft, the structure
labeled 20 will be a vein and the structure labeled 15 will be the
prosthetic graft. In this instance (i.e. in the case of an AV
graft), the stent 30 extends from the graft 15 across the
anastomosis 85 and into the vein 20. In the case of an arterial
bypass graft, the structure labeled 15 represents a prosthetic
graft (e.g. PTFE), arterial conduit (e.g. the mammary artery) or a
venous conduit (e.g. saphenous vein) and the structure marked 20
represents the recipient artery which may be a coronary artery or
peripheral artery that is being bypassed. The degree of curvature
75 of the stent is between about 5 and 160 degrees and is selected
based upon the degree of orientation between the vein, blood vessel
or graft 15 and the artery, graft or other vascular structure 20.
All embodiments described herein apply to either stent
placement.
[0052] Referring to FIG. 11, the body of the stent 30 can also be
placed at the natural bend of a blood vessel 15 at a location away
from an anastomosis site. The degree of curvature 75 is between
about 5 and 160 degrees and is selected based upon the degree of
curvature in the vessel.
[0053] In a further embodiment of the present invention, the stent
30 is tapered so that the diameter decreases along the longitudinal
axis 65 of the stent 30. Referring to FIG. 2A, the stent 30 is
comprised of a first proximal end 35 and a second, distal end 40
opposite the proximal end 35. The diameter of the stent 30 at the
proximal end 35 is greater than the diameter of the stent at the
opposite, distal end 40. As is shown in FIG. 2C, this embodiment is
particularly suited for placement in vessels where the diameter of
the vessel changes from one segment to another.
[0054] In a further embodiment, the stent has a "beveled,"
"flared," or "trumpeted" edge 25. Referring to FIG. 2B, the stent
30 is comprised of a first proximal end 35 and a second, distal end
40 opposite the proximal end 35. At the proximal end 35 the web
structure 55 expands outwardly, resulting in an increased diameter
45 at that end 35 of the stent 30, giving the proximal end 35 of
the stent 30 a "beveled," "flared," or "trumpeted" appearance. As
is seen in FIG. 2E, such an embodiment is particularly suited for
placement at an anastamotic orifice 85. The beveled edge 25 allows
the stent to abut the orifice 85 without protruding into the
artery, vessel, or graft 20.
[0055] In a further embodiment, the stent elutes
anti-vasculoproliferative drugs or agents such as rapamycin,
paclitaxel, tacrolimus, everolimus, zotarolimus and other cell
cycle inhibitor or similarly-functioning agents. This in
combination with the special configuration of the stent 30, that
allows accurate placement at the anastomosis (e.g. by beveling,
flaring or trumpeting the edge) and close apposition to the inner
surface of the curved blood vessel (by curving the stent along its
longitudinal axis 65) allows for local delivery of
antivasculoproliferative drugs directly to the immediate vicinity
of the anastomosis orifice 85, preventing or suppressing or
treating neointimal hyperplasia by delivery directly to the
vascular structure an effective amount of an antiproliferative
agent alone or in combination with adjuvants and other
antiproliferative agents. Rapamycin (Sirolimus) is a preferred drug
with antiproliferative properties for use with the present
invention.
[0056] In one embodiment of the present invention, the stent 30 in
its contracted state 90 is equipped with an external wire ("rip
cord") to release and expand the stent. Referring to FIG. 7, the
stent 30 in its contracted state is attached to a guidewire 95. A
further wire 100 is attached to the external surface of the stent
in its contracted state 90. Wire 100 may also be attached to the
leading edge of the stent and not its surface. This wire 100 is
configured so that, after the stent 30 is placed at the graft
orifice or at the anastomosis site 85, manipulating the attached
wire 100 pulls the external surface of the stent 30 toward the
interior surface of the vessel or graft 15, causing the stent to
expand and abut the interior surface 105 of the vessel or graft
wall.
[0057] Referring to FIG. 8, a further embodiment of the present
invention is a kit for treating or preventing stenosis at an
anastomosis site containing the previously described curved stent
30 specially configured for placement in an anastomosis site
(bevel, flaring or trumpeting, tapering not shown in this figure)
or any other type of balloon expandable or self-expanding stent,
together with a wrap or sleeve 110, or an implantable prosthetic
device for placement on the area surrounding the anastomotic
orifice 85 and anastomosis site, on the outer surface of the vessel
or graft 15 or 20, wherein the sleeve then elutes one or more
antivasculoproliferative drugs or agents such as rapamycin
(sirolimus), paclitaxel, tacrolimus, everolimus, zotarolimus and
other cell cycle inhibitor or similarly-functioning agents. In
addition to a biocompatible matrix material, e.g., protein,
collagen, fibrin, chitosan, cellulose etc and an antiproliferative
agent, this implantable device contains, optionally, agents that
inhibit collagen accumulation in the tunica media and adventitia of
the vascular wall and pharmaceuticals that help reduce
calcification of the vascular wall. Rapamycin is a preferred drug
with antiproliferative properties for use with the present
invention. The rapamycin diffuses from the outside and through the
vessel and/or graft wall to the interior of the vein and/or artery
and/or graft. Elution of rapamycin (and other drugs with
antiproliferative effect) into and through the vascular wall from
the outside starts soon after the device is implanted and the drug
will inhibit smooth muscle cell proliferation at the anastomosis
site.
[0058] The kit of the present invention thus improves the treatment
and/or prevention of stenosis by providing a novel treatment
originating from within the vascular or graft lumen in combination
with an extravascular pharmaceutical application. This combination
can prevent stenosis of the vein, graft, artery and anastomotic
orifice as well as treat the restenosis that commonly follows stent
implantation. In another embodiment of the invention, the specially
configured stent is drug eluting, resulting in intravascular
delivery of pharmaceutical agents directly to the vicinity of the
graft orifice in addition to the extravascular pharmaceutical
treatment provided by the sleeve.
[0059] The entire contents of U.S. Pat. No. 6,726,933, entitled
"Apparatus and Methods for Preventing or Treating Failure of
Hemodialysis Vascular Access and Other Vascular Grafts," and U.S.
Patent Application Publication No. 2005/0004158, entitled "Medical
Implants and Methods For Regulating the Tissue Response to Vascular
Closure Devices" are hereby incorporated by this reference.
[0060] The method of the present invention discloses providing a
stent 30 that is specially configured for placement at an
anastomosis site as described above, providing a sleeve 110
comprising a biological matrix imbibed with a pharmaceutical agent,
applying the sleeve to the extravascular surface of an anastomosis
site, and inserting the stent 30 to the vein, vessel and graft 15
and orifice 85 of an anastomosis site. In one embodiment, the stent
30 is configured with an external wire 100 affixed to the outer
surface of the stent 30. As to FIG. 7, the stent 30 in its
contracted state 90, is then inserted into the vein, graft or blood
vessel 15 through the use of a guide wire 95. After the proximal
end 35 of the stent is in place at the anastomotic orifice 85 or at
the anastomosis site, the wire 100 affixed to the external surface
of the stent is manipulated, pulling the external surface of the
stent toward the interior surface 105 of the vessel, causing the
stent 30 to expand and abut the interior surface 105 of the wall of
the vessel or graft 15.
[0061] As to FIG. 9, in another embodiment, the stent 30 is
inserted its contracted state 90, and is held in its contracted
state by a sheath 115 surrounding the contracted stent 90. After
the proximal end 35 of the stent 30 is placed at the anastomotic
orifice 85 or anastomosis site, the sheath 115 is retracted.
Retraction of the sheath 115 causes the stent 30 to expand and abut
the interior surface 105 of the wall of the vessel or graft 15.
Finally, the sheath 115 is removed, leaving the expanded stent 30
in place at the anastomosis site.
[0062] In one embodiment, the stent is a balloon-expandable stent.
In anther embodiment, the stent is a self-expanding stent.
[0063] As to FIG. 10, in another embodiment, the external surface
of the web structure 55 of the balloon expandable or self
expandable stent 30 may be partially or completely covered by a
polymer, fabric or biological coating 120. An example of such a
covering that may be used for the stent is polytetrafluoroethylene
(PTFE).
[0064] In another embodiment, the invention relates to the use of a
plain stent (i.e., non-drug coated self-expanding or balloon
expanding stent) at and around the anastomotic site of an AV
fistula as a stand-alone treatment for fistula outflow stenosis.
Such method may be used to treat outflow stenosis prophylactically
shortly after the surgery with a plain stent without the
perivascular application of a drug-eluting sleeve. In other words,
the use of the sleeve is optional. Such plain stent can be an
existing stent design or any of the novel stent designs described
elsewhere herein.
[0065] Additionally, the order of the steps of the methods is not
critical to the novelty thereof.
[0066] FIGS. 16A-16D show the difference between a beveled stent
edge and a traditional right angled, square-cut stent edge and
illustrates why the beveled edge provides optimal coverage of the
anastomosis when the vessels of the anastomosis are not joined
perpendicular to each other. Since neither of the situations in
FIG. 16A (i.e. the square ended stent is placed at a location such
that it is too short to completely contact the full circumference
of the anastomosis orifice and does not extend all the way down to
the site of the anastomosis) or FIG. 16 B (i.e. in order to reach
the full circumference of the anastomosis orifice, the stent must
protrude into the vessel past the anastomosis) is desirable, a
stent with a "beveled," "flared" or "trumpeted" edge can overcome
this problem. The "bevel" helps in providing optimal coverage of
the anastomosis and will facilitate stent deployment such that the
anastomosis is completely covered without protrusion into the
adjacent vessel (see FIG. 16C).
[0067] FIGS. 17A-17E illustrate the difference between the
traditional, conventional deployment system for a self expanding
stent (see FIGS. 17A-17C, depicting conventional delivery method in
which the distal end of the stent is deployed first and the
proximal end is deployed last) and the proposed delivery system
(see FIGS. 17D-17F, depicting proposed delivery method in which the
proximal end of the stent is deployed first and the distal end is
deployed last).
[0068] FIG. 18 illustrates how an endovascular stent 30 will be
used with a perivascular drug eluting matrix 110 with an AV Graft.
The AV graft is constructed by anastomosing a piece of PTFE graft
15 between an artery 20 and a vein 20. The stent 30 is placed
internally at and around the site of anastomosis (see FIG. 18A).
The drug eluting matrix 110 is placed on the external aspect of the
blood vessel 20 and graft 15 (see FIG. 18B). FIG. 18 illustrates
this use at the graft venous anastomosis. The implants can also be
done at the graft arterial anastomosis or elsewhere in the AV graft
system. This stent 30 and dug eluting matrix 110 configuration was
used in the therapeutic example discussed in Sections 64-73 under
Therapeutic Example (AV Graft)
[0069] FIG. 19 illustrates how an endovascular stent will be used
with a perivascular drug eluting matrix for an AV Fistula. The AV
fistula is constructed by anastomosing the end of a segment of vein
15 to the side of an artery 20. The stent 30 shown in this
illustration is a traditional non beveled stent, placed internally
at and around the site of anastomosis and extending into the
outflow vein 15 (see FIG. 19A). The drug eluting matrix 110 is
placed on the external aspect of the blood vessel (see FIG. 19B).
These same concepts can be practiced with the specially designed
stents disclosed in this invention. This stent 30 and dug eluting
matrix 30 configuration was used in the therapeutic example
discussed in Sections 74-82 under Therapeutic Example (AV
Fistula)
Therapeutic Example (AV Graft)
[0070] Methods:
[0071] A proof of principle study was performed using an ovine
model. A 6 mm PTFE vascular graft was anastomosed between the
carotid artery on one side and the contralateral jugular vein,
creating an arterio venous (AV) loop graft that is similar in
construction to the human hemodialysis access loop. A total of four
animals were studied, two animals (two AV grafts) received an
endovascular self expanding nitinol stent at the PTFE graft-venous
anastomosis, the other two animals (two AV grafts) received an
endovascular self expanding nitinol stent at the PTFE-venous graft
anastomosis plus a perivascular sirolimus (rapamycin) eluting
collagen matrix. The sirolimus eluting collagen matrix was
implanted on the external surface of the PTFE graft venous
anastomosis location, such that the matrix on the external aspect
roughly corresponded to the location of the endovascular nitinol
endovascular stent. The stent used was a self expanding nitinol
stent, 30 mm in length and fully expanded had a diameter of 8.0 mm.
The collagen matrix was combined with a known dose of sirolimus
(approximately 75 microgram/cm.sup.2).
[0072] Results:
[0073] Contrast Angiography was performed to assess status of the
graft, stent and the vessel at 28 and 56.+-.1 day after initial
surgery.
[0074] A. Results of Angiography after 28 Days are Shown in FIG.
12.
[0075] FIGS. 12A, 12B: These figures are 28 Day Angiograms from the
two animals that received the endovascular self expanding nitinol
stent 100 without the sirolimus eluting collagen matrix, which was
placed at the anastomosis of the PTFE graft and the Vein. Narrowing
within the stent is seen in both animals.
[0076] FIGS. 12C, 12D: These figures are 28 Day Angiograms are from
the two animals that received the endovascular self expanding
nitinol stent plus the Sirolimus eluting collagen matrix 200, which
was placed at the anastomosis of the PTFE graft and the Vein. There
is no angiographically obvious narrowing in FIG. 1C and minimal
narrowing of the stent lumen in FIG. 1D.
[0077] B. Results of Angiography after 56 Days are Shown in FIG.
13.
[0078] FIGS. 13A, 13B: These figures are 56 Day Angiograms from the
two animals that received the endovascular self expanding nitinol
stent 100 without the Sirolimus eluting collagen matrix, which was
placed at the anastomosis of PTFE graft 105 and the Vein 110.
Narrowing of the stent is seen and is more pronounced compared to
the appearance at 28 days.
[0079] FIGS. 13C, 13D: These figures are 56 Day Angiograms from the
two animals that received the endovascular self expanding nitinol
stent plus the Sirolimus eluting collagen matrix 200, which was
placed at the anastomosis of the PTFE graft 105 and the Vein 110.
In FIG. 13C, the Proximal Vein 115 is also visible. There is
minimal narrowing of the stent.
[0080] Approximate measurements based on offline measurements are
shown in the Table below. All stent dimensions were normalized to
the known graft dimension of 6.0 mm.
TABLE-US-00001 Nominal Graft Minimal Stent Stent Animal 28 Assigned
Diameter Lumen Dimension % Diameter ID Days Treatment (mm) (MLD mm)
stenosis 9S003 FIG. AV Graft + Stent 6.0 3.0 50% 12A 9S004 FIG. AV
Graft + Stent 6.0 2.4 60% 12B 9S014 FIG. AV Graft + Stent + 6.0 6.0
0 12C (Collagen matrix + Sirolimus) 9S015 FIG. AV Graft + Stent +
6.0 5.0 17% 12D (Collagen matrix + Sirolimus) Nominal Graft Minimal
Stent Stent Animal 56 .+-. 1 Assigned Diameter Lumen Dimension %
Diameter ID Days Treatment (mm) (MLD; mm) stenosis 9S003 FIG. AV
Graft + Stent 6.0 1.5 75% 13A 9S004 FIG. AV Graft + Stent 6.0 2.1
65% 13B 9S014 FIG. AV Graft + Stent + 6.0 5.4 10% 13C (Collagen
matrix + Sirolimus) 9S015 FIG. AV Graft + Stent + 6.0 4.5 25% 13D
(Collagen matrix + Sirolimus)
[0081] Conclusions: [0082] 1. The degree of narrowing (% stent
diameter stenosis) is more in the animals that received the stent
without the drug eluting collagen matrix in comparison to the
animals that received both the stent as well as the drug eluting
stent matrix. [0083] 2. The residual minimal stent lumen dimension
(MLD) is greater in the animals that received the stent with the
drug eluting collagen matrix in comparison to the animals that
received the stent without the drug eluting stent matrix. [0084] 3.
These differences in stent % diameter stenosis as well as the
minimal stent lumen dimensions (MLD) are seen at both 28 days as
well as at 56.+-.1 days after the index surgery.
Therapeutic Example (AV Fistula)
[0085] Methods:
[0086] A proof of principle study was performed using an ovine
arterio-venous fistula model. Bilateral arterio venous fistula were
created by anastomosing the femoral vein to the femoral artery in
an end (of vein) to side (of artery) fashion. The method of
anastomosis (end to side) mimics the configuration of the AV
fistulae created for providing dialysis access in humans (e.g.
radio-cephalic, brachio-cephalic). The concept of using the
endovascular stent plus the perivascular drug eluting (e.g.
sirolimus) can be applied to other anastomotic configurations as
well (e.g. end to end, side to side etc) as well as other surgeries
were a vein and an artery are anastomosed (e.g. Coronary artery
bypass graft surgery, peripheral vascular bypass surgery) or other
surgeries where two conduits are anastomosed (e.g. fallopian tubes,
ureter, biliary duct, bronchial airways, intestinal loops etc)
Control fistulae received neither the endovascular self-expanding
nitinol stent nor the perivascular sirolimus (rapamycin) eluting
collagen matrix. Treated fistulae received an endovascular self
expanding nitinol stent starting from the anastomosis and extending
out to the outflow vein (in this instance covering the
juxta-anastomotic segment) plus a perivascular sirolimus
(rapamycin) eluting collagen matrix. The sirolimus eluting collagen
matrix was implanted on the external surface of the fisulae, such
that the matrix on the external aspect roughly corresponded to the
anastomotic location of the endovascular nitinol endovascular
stent. A sirolimus eluting matrix was also implanted at the
anastomosis such that the matrix wrapped both the artery as well as
the vein at that location. The illustrative example discussed below
shows the use of a self-expanding stent 30 mm or 40 mm in length
and a fully expanded diameter of 6 mm. The collagen matrix was
combined with a known dose of sirolimus (approximately 75
microgram/cm.sup.2).
[0087] Results:
[0088] Contrast Angiography was performed to assess status of the
fistulae, anastomosis, stent and the vessel (controls and treated)
on day 0 (day of surgery) and 28 days after surgery. An angiogram
was also performed 62 day after surgery in the treated animal
example discussed below.
[0089] A. Results of Angiography on Day 0 (Day of Surgery) are
Shown in FIG. 14.
[0090] FIGS. 14A, 14B: These figures are Angiograms of control AV
fistulae (the left and right AV fistula, respectively) in Animal ID
No. 9S005, which do not include a stent or siroliums eluting
matrix, from the day of surgery (Day 0).
[0091] FIGS. 14C, 14D: These figures are Angiograms from the day of
surgery (Day 0) for Animal ID No. 9S019, which was treated with an
endovascular self-expanding stent (6 mm.times.30 mm for the left AV
fistula, and 6 mm.times.40 mm for the right AV fistula) and
Perivascular Sirolimus Eluting Matrix 200. The anastomosis 205 is
also visible in each Angiogram.
[0092] B. Results of Follow Up Angiography are Shown in FIG.
15.
[0093] FIGS. 15A, 15B: These figures are Angiograms of control AV
fistulae (the left and right AV fistula, respectively) in Animal ID
No. 9S005, which do not include a stent or sirolimus eluting
matrix, taken 28 days following surgery that show severe stenosis
of the outflow vein 210 (juxta anastomotic segment) as well as the
anastomosis 205.
[0094] FIGS. 15C, 15D: These figures are Angiograms of the left AV
fistula performed on day 28 (FIG. 15C) and day 62 (FIG. 15D) in
Animal ID No. 9S019 that was treated with endovascular
self-expanding stent (6 mm.times.30 mm and Perivascular Sirolimus
Eluting Matrix 200. On day 28, significant improvement in lumen
dimensions of the anastomosis 205 as well as the outflow vein
(improved patency) is seen in comparison to controls. The
improvement is maintained on the angiogram performed on day 62.
[0095] Conclusions: [0096] 1. 28-day angiograms of the
Arterio-venous fistulae in the control animal (no endovascular
stent or perivascular sirolimus eluting collagen matrix) show
severe stenosis at the anastomosis as well as the juxta anastomotic
segment of the outflow vein. This pattern of stenosis mimics the
situation in humans (e.g. stenosis in radio-cephalic fistulae
created for supporting dialysis, anastomotic stenosis of vein
grafts in coronary artery and peripheral artery bypass graft
surgery) [0097] 2. Treated animal (endovascular stent plus
perivascular sirolimus eluting collagen matrix) shows significant
improvement in lumen dimensions (improved lumen patency) at the
anastomosis as well as the outflow vein. [0098] 3. This benefit is
seen in both the 28 day as well as the 62 day angiograms.
[0099] All documents cited herein, including the foregoing, are
incorporated herein by reference in their entireties for all
purposes.
* * * * *