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.

Claims

1. A method for preventing or treating stenosis in a vascular structure having an anastomosis comprising deploying a drug free stent within the lumen of a vascular structure and applying locally and externally to the vascular structure, a biocompatible matrix material that carries an anti-vasculoproliferative drug and is free of biological cells, wherein the anastomosis is a part of an artery, vein or graft.

2. The method of claim 1 wherein the anastomosis results from the formation of an arterio-venous fistula, or an arterio-venous graft or an arterial-arterial graft.

3. The method of claim 1 wherein the matrix material carries about 75 micrograms per cm.sup.2 of the anti-vasculoproliferative drug.

4. The method of claim 1 wherein the anti-vasculoproliferative drug carried by the matrix material is rapamycin or an analogue of rapamycin.

5. The method of claim 1 wherein the analogue of rapamycin is everolimus or zotarolimus.

6. The method of claim 1 wherein the anti-vasculoproliferative drug carried by the matrix material is the only active ingredient carried by the matrix material.

7. The method of claim 1 wherein the matrix material is selected from the group consisting of collagen, fibrin, polysaccharide and mixtures thereof.

8. The method of claim 7 wherein the matrix material comprises collagen.

9. The method of claim 8 wherein the collagen is selected from the group consisting of Type I, Type II, Type III, Type IV, Type XI and mixtures thereof.

10. The method of claim 9 wherein the collagen is Type I Bovine collagen.

11. The method of claim 7 wherein the polysaccharide is chitosan.

12. The method of claim 1 wherein the stent is curved along the longitudinal axis for placement at an anastomosis site.

13. The method of claim 1 wherein the stent is partially or completely covered by a polymer or fabric.

14. The method of claim 13 wherein the cover is PTFE.

15. The method of claim 1 wherein the stent is a self-expanding or a balloon expanding stent.

16. The method of claim 1 wherein the stent is beveled, flared or trumpeted.

17. The method of claim 16 wherein the stent is beveled.

18. A method for preventing or treating stenosis at an anastomosis site comprising deploying a drug free stent within the lumen of a blood vessel and wrapping the exterior surface of the blood vessel with a biocompatible matrix material that carries an anti-vasculoproliferative drug and is free of biological cells.

19. The method of claim 18 wherein the anastomosis site results from the formation of an arterio-venous fistula, an arterio-venous graft or an arterial-arterial graft.

20. A method for preventing or treating stenosis in a vascular structure having an anastomosis comprising deploying a drug free stent within the lumen of a vascular structure and applying locally and externally to the vascular structure a sleeve consisting essentially of a biocompatible matrix material and an anti-vasculoproliferative drug, wherein the anastomosis is a part of an artery, vein or graft.

21. The method of claim 20 wherein the anastomosis results from the formation of an arterio-venous fistula, or an arterio-venous graft or an arterial-arterial graft.

22. The method of claim 20 wherein the matrix material carries about 75 micrograms per cm.sup.2 of the anti-vasculoproliferative drug.

23. The method of claim 22 wherein the anti-vasculoproliferative drug is rapamycin.

Description

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 mm30 mm for the left AV fistula, and 6 mm40 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 mm30 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 mean5%, 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 anglethis 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: 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).

[0071] Results: Contrast Angiography was performed to assess status of the graft, stent and the vessel at 28 and 561 day after initial surgery.

[0072] A. Results of Angiography after 28 Days are Shown in FIG. 12.

[0073] 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.

[0074] 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.

[0075] B. Results of Angiography after 56 Days are Shown in FIG. 13.

[0076] 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.

[0077] 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.

[0078] 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 Minimal Nominal Graft Stent Lumen Stent % Diameter Dimension Diameter Animal ID 28 Days Assigned Treatment (mm) (MLD mm) stenosis 9S003 FIG. 12A AV Graft + Stent 6.0 3.0 50% 9S004 FIG. 12B AV Graft + Stent 6.0 2.4 60% 9S014 FIG. 12C AV Graft + Stent + 6.0 6.0 0 (Collagen matrix + Sirolimus) 9S015 FIG. 12D AV Graft + Stent + 6.0 5.0 17% (Collagen matrix + Sirolimus)

TABLE-US-00002 Minimal Nominal Graft Stent Lumen Stent % Diameter Dimension Diameter Animal ID 56 1 Days Assigned Treatment (mm) (MLD; mm) stenosis 9S003 FIG. 13A AV Graft + Stent 6.0 1.5 75% 9S004 FIG. 13B AV Graft + Stent 6.0 2.1 65% 9S014 FIG. 13C AV Graft + Stent + 6.0 5.4 10% (Collagen matrix + Sirolimus) 9S015 FIG. 13D AV Graft + Stent + 6.0 4.5 25% (Collagen matrix + Sirolimus)

[0079] Conclusions: [0080] 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. [0081] 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. [0082] 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 561 days after the index surgery.

Therapeutic Example (AV Fistula)

[0083] Methods: 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).

[0084] Results: 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.

[0085] A. Results of Angiography on Day 0 (Day of Surgery) are Shown in FIG. 14.

[0086] 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).

[0087] 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 mm30 mm for the left AV fistula, and 6 mm40 mm for the right AV fistula) and Perivascular Sirolimus Eluting Matrix 200. The anastomosis 205 is also visible in each Angiogram.

[0088] B. Results of Follow Up Angiography are Shown in FIG. 15.

[0089] 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.

[0090] 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 mm30 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.

[0091] Conclusions: [0092] 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) [0093] 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. [0094] 3. This benefit is seen in both the 28 day as well as the 62 day angiograms.

[0095] All documents cited herein, including the foregoing, are incorporated herein by reference in their entireties for all purposes.