WO2024119179A1

WO2024119179A1 - Unitary product for addressing arteriovenous fistula stenosis

Info

Publication number: WO2024119179A1
Application number: PCT/US2023/082336
Authority: WO
Inventors: John Mcdermott; Paul BARKOFSKY
Original assignee: Vascular Therapies, Inc.
Priority date: 2022-12-03
Filing date: 2023-12-04
Publication date: 2024-06-06

Abstract

A unitary product is constructed to address stenosis at an arteriovenous fistula. It is tube of appropriate dimensions to be slid over a human vein involved in the fistula. It is constructed of a biocompatible, preferably biodegradable material carrying an amount of an anti- vasculoproliferative drug which may be rapamycin or a rapamycin analogue with similar antiproliferative activity to effectively address the stenosis commonly observed at an arteriovenous fistula. The tube has axial slits extending from one axial end of the tube thus creating tails extending from the intact portion of the tube. It is employed by passing the end distal from which the tails extend over the free end of a vein that has been obtained by severing the vein in preparation for forming a fistula and then, after the vein is secured to the artery, sliding it toward the artery so that the tails can be wrapped about the artery.

Description

UNITARY PRODUCT FOR ADDRESSING ARTERIOVENUS FISTULA STENOSIS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application Serial No. 63/385,966 filed on December 3, 2022, which is incorporated herein by reference in its entirety to the full extent permitted by law.

TECHNICAL FIELD

[0002] The present disclosure relates to devices and methods for preventing and/or treating stenosis at an arteriovenous fistula. The devices comprise a tube or wrap comprising an effective amount of antiproliferative agent to mitigate and/or treat stenosis.

BACKGROUND

[0003] Arteriovenous fistulas are created by surgeons in patients with renal failure. The procedure involves a surgical connection (anastomosis) between a vein and an artery so the vein can be used for 2-needle hemodialysis. However, the surgical trauma of creating the fistula and the redirected blood flow through the vein have led to the development of a narrowing, referred to as a stenosis, in the vicinity of the anastomosis at the juncture of the artery and the vein. Among the approaches to addressing this stenosis is the sleeve approach featured in U.S. Patent No. 6,726,923 and currently in clinical trials. In practical application it has been found appropriate to use two separate sleeve components, one to cover the vein adjacent to the anastomosis and one to cover the anastomosis itself. This creates an additional burden for both the manufacturer of the device and the surgeon creating the fistula. An additional benefit of the present disclosure is to provide structural support around the outside of the vein and an angle for the anastomosis, which may also reduce the amount of the stenosis.

SUMMARY

[0004] The present disclosure involves a product for addressing, preventing and/or treating stenosis at an arteriovenous fistula. It comprises a tube of appropriate dimensions to be slid over a human vein involved in such a fistula. It is constructed of a biocompatible and preferably biodegradable material carrying an adequate amount of an anti-vasculoproliferative drug which may be rapamycin or a rapamycin analogue with similar antiproliferative activity to effectively address, prevent and/or treat the stenosis commonly observed at an arteriovenous fistula. The tube has at least two axial slits extending from one axial end of the tube thus creating tails extending from the intact portion of the tube.

[0005] The present disclosure also involves a process for addressing, preventing and/or treating stenosis at an arteriovenous fistula. A product is obtained which comprises a tube of appropriate dimensions to be slid over a human vein involved in such a fistula. It is constructed of a biocompatible and preferably biodegradable material carrying an adequate amount of an anti- vasculoproliferative drug comprising rapamycin or a rapamycin analogue with similar antiproliferative activity to effectively address, prevent and/or treat the stenosis commonly observed at an arteriovenous fistula. The tube has at least two axial slits extending from one axial end of the tube thus creating tails extending from the intact portion of the tube. The tube is passed over the free end of a vein that has been obtained by severing the vein in preparation for forming a fistula. The free end is attached to an anastomosis in an artery. The tube is then slid towards the artery and the tails of the tube are wrapped around the artery in the vicinity of the anastomosis.

[0006] These and other objects, advantages, and features of the invention will become apparent to those persons skilled in the art upon reading the details of the devices and methodology as more fully described below. Additional embodiments of the present devices, formulations, processes, methods of treatment and the like will be apparent from the following description, drawings, examples, and claims. As can be appreciated from the foregoing and following description, each and every feature described herein, and each and every combination of two or more of such features, is included within the scope of the present disclosure provided that the features included in such a combination are not mutually inconsistent. In addition, any feature or combination of features may be specifically excluded from any embodiment or aspect. Additional aspects and embodiments are set forth in the following description and claims, particularly when considered in conjunction with the accompanying examples and drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

[0007] The invention is best understood from the following detailed description when read in conjunction with the accompanying drawings. It is emphasized that, according to common practice, the various features of the drawings are not to-scale. On the contrary, the dimensions of the various features are arbitrarily expanded or reduced for clarity. [0008] FIG. 1 is a perspective view of a prior art fistula obtained by attaching a vein to an artery.

[0009] FIG. 2 is a perspective view of the fistula of FIG. 1 to which a prior art two-piece product for addressing stenosis has been applied.

[0010] FIG. 3 is a perspective view of a one-piece product for addressing stenosis exemplary of the present invention.

[0011] FIG. 3A is a perspective view of a one-piece product for addressing stenosis exemplary of the present invention in which a shorter slit is visible and a curl has been imparted to the tails obtained from slits in the tubular portion of the product of FIG. 3.

[0012] FIG. 4 is another perspective view of a one-piece product for addressing stenosis exemplary of the present invention in which a longer slit is visible and a curl has been imparted to the tails obtained from slits in the tubular portion of the product of FIG. 3.

[0013] FIG. 5 is a cross-section of FIG. 3 A along section line 5.

[0014] FIG. 6 is a perspective view of the one-piece product FIG. 3A slid over a vein involved in a fistula.

[0015] FIG. 7 is a perspective view of the one-piece product FIG. 4 with the slits from FIG. 5 oriented in such a way that the blood flow through the fistula from the artery to the vein traverses an approximately 120 degree angle.

[0016] FIG. 8 is a perspective view of the one-piece product FIG. 4 with the slits from FIG. 5 oriented in such a way that the blood flow through the fistula from the artery to the vein traverses an approximately 60 degree angle.

[0017] FIG. 9 is a perspective view of the one-piece product of FIG 3 A.

[0018] FIG. 10 is perspective view of the one-piece product of FIG 4 with a printed marking to aid in orienting it before wrapping the tails about the artery.

[0019] FIG. 11 is a perspective view of the one-piece product of FIG 3A with an embossed marking to aid in orienting it before wrapping the tails about the artery.

[0020] FIG. 12 is another perspective view of the one-piece product of FIG 4.

[0021] FIG. 13 is a perspective view of the one-piece product of FIG. 6 in which an axis of curl other than 90 degrees is illustrated. DETAILED DESCRIPTION

[0022] The various aspects and embodiments will now be fully described below. These aspects and embodiments may, however, be embodied in many different forms and should not be construed as limiting; rather, these embodiments are provided so the disclosure will be thorough and complete, and will fully convey the scope of the present subject matter to those skilled in the art. All publications, patents and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety.

[0023] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range, is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where neither, or both, limits are included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0024] FIG. 1 illustrates an arteriovenous fistula commonly created to facilitate 2-needle hemodialysis for patients with renal failure. An anastomosis 30 has been created in an artery 10 and the free end of a vein 20 that has been severed for the purpose of being sutured to the artery 10 at the anastomosis.

[0025] FIG. 2 illustrates a known technique for addressing the potential development of stenosis in the fistula. One sleeve product 40 is wrapped around the vein 20 and a second sleeve product 42 is placed by wrapping in the immediate vicinity of the anastomosis thereby covering portions of the artery 10 and the vein 20. The sleeve products are of the type described in U.S. Patent No. 6,726,923 incorporated by reference herein. Each is constructed of a biocompatible and biodegradable material carrying an anti-vasculoproliferative drug comprising rapamycin or a rapamycin analogue with similar antiproliferative activity.

[0026] FIG. 3 illustrates an improved one-piece product 50 that provides the functions of both of the known sleeve products 40 and 42 illustrated in FIG. 2 as well as providing structural support to the vein 20 as the vein 20 accommodates to the increased blood flow from its direct connection to the artery 10 as illustrated in FIG. 1. It has a portion 52 intended to be placed distal from the anastomosis 30 illustrated in FIG. 1 and a portion 54 intended to be placed proximate to the anastomosis 30 illustrated in FIG. 1. The distal portion 52 has a conical configuration to allow for the expansion of the vein 20 illustrated in FIG. 1 as the fistula to which the product 50 is applied matures. The proximate portion 54 is illustrated as being generally cylindrical in configuration. It is convenient for portion 52 to have a conical configuration and portion 54 to have a tubular configuration, but the more basic concept is simply that portion 52 have an internal diameter that is greater than that of portion 54, though it is also permissible for the portions 52 and 54 to have the same internal diameter. The proximate portion 54 has a shorter slit 56 and a longer slit 57. These two slits 56 and 57 facilitate the creation of tails at the free end of the proximate portion 54. Marks may be embossed or printed on the proximate portion 54 adjacent to the shorter slit 56 to aid a surgeon in extending the length of the shorter slit 56 and thereby creating a custom angle 64 (illustrated in FIG. 5) to achieve a particularly desired positioning of the vein 20 with regard to the artery 10.

[0027] FIG. 3A illustrates the two tails 58 created by the slits 56 and 57 illustrated in FIG. 3 having assumed a curled configuration after hydration of the product. There are well-known techniques for achieving this configuration. For example, if the biocompatible material out of which the product is constructed is collagen-based some useful techniques are disclosed in U.S. Patent No. 9,308,219 (incorporated herein by reference). Briefly, if the tube is comprised of collagen the tails can be formed into curls, subjected to a crosslinking treatment and then mechanically formed into the partial tubular configuration shown in FIG. 3. In this regard, the balance of the tube may be formed in accordance with the teachings of U.S. Patent No. 9,061,464 (incorporated herein by reference) and then the entire product 50 including the tails 58 may be subjected to an appropriate crosslinking treatment.

[0028] FIG. 4 is another view of the one-piece product 50 in which the longer slit 57 is in the foreground.

[0029] FIG. 5 is a cross-section of FIG. 3A along section line 5-5 shown in FIG. 3A. The wall 60 of the proximate portion 54 adjacent to the longer slit 57 illustrated in FIG. 3 and the wall 62 adjacent to the shorter slit 56 also illustrated in FIG. 3 are shown. The angle 64 between the heights of the slits 56 and 57 from the free end of the proximate portion 54 is also illustrated. This angle 64 figures in controlling the angle at which the vein 20 joins the artery 10 as illustrated in FIGs 7 and 8. In the configuration illustrated here the angle 64 is about 60 degrees.

[0030] FIG. 6 illustrates the one-piece product 50 in position on the vein 20 before being slid into contact with the artery 10. It would have been slid over the free end of the vein 20 that is illustrated connected to the artery 10 at the anastomosis 30 before this connection was made. The arrow 66 shows the direction in which the one-piece product is to be slid after vein 20 is connected to the artery 10.

[0031] FIG. 7 illustrates the one-piece product 50 in place over both the artery 10 and the vein 20. The tails 59 have been wrapped about the artery 10 in such a way to provide a path for the blood flow 70 from the artery to the vein that traverses the angle 80. This angle 80 is adjustable by the relative differences between the slits 56 and 57 and the orientation of the one-piece product 50 to the artery 10. In the configuration illustrated here the angle 80 is about 120 degrees.

[0032] FIG. 8 illustrates the one-piece product 50 in place over both the artery 10 and the vein 20 in an alternate configuration. The relative differences in length between slits 56 and 57 create the angle 80 that the blood flow 70 traverses from the artery 10 to the vein 20. In the configuration illustrated here, the angle is about 60 degrees.

[0033] FIG. 9 illustrates the one-piece product 50 with the shorter slit 56 visible.

[0034] FIG. 10 illustrates the one-piece product 50 with the longer slit 57 visible carrying a printed indicia 90 which aids the surgeon in orienting the one-piece product 50 such that when the curled tails 58 are wrapped around the artery 10 as illustrated in FIGs 7 and 8 the desired blood flow angle 80, also illustrated in FIGs 7 and 8, is achieved. The product 50 may conveniently may be accompanied by instructions to the surgeon to orient it so that the indicia 90 is not visible when he has put the product 50 in place.

[0035] FIG 11 illustrates the one-piece product 50 with the shorter slit 56 visible carrying an embossed indicia 92 which aids the surgeon in orienting the one-piece product 50 such that when the curled tails 58 are wrapped around the artery 10 as illustrated in FIGs 7 and 8 the desired blood flow angle 80, also illustrated in FIGs 7 and 8, is achieved. The product 50 may conveniently be accompanied by instructions to the surgeon to orient it so that the indicia 92 is not visible when he has put the product 50 in place. [0036] FIG. 12 illustrates the one-piece product 50 with the longer slit 57 visible.

[0037] FIG. 13 illustrates the one-piece product 50 slid over the vein 20 with the distal portion 52 having an internal diameter that increases in the distal direction from the artery 10 (not shown). The proximate portion 54 carries two tails 102 that are each curled about an axis 100 that is at an angle other than 90 to the axis of the product 50. After the vein 20 is joined to the anastomosis 30 illustrated in FIG. 6 the product 50 is slid in the direction 66. The tails 102 are then wrapped about the artery 10 in a manner similar to that illustrated in FIGs 7 and 8 for tails 59. However, the canted axis of curl 100 facilitates the wrapping of the tails 102 allowing them to assume a helical configuration as they are wrapped.

[0038] In other embodiments, the tails resulting from the slits may be affixed to each other by contact wings or flaps. Further, the one-piece products described herein may be applied to any vessel, i.e., vein, artery, prosthetic vessel, or biological graft.

[0039] The one-piece product is an improvement on the approach taught by U.S. Patent No. 6,726,923 to address the stenosis that develops in the vicinity of the anastomosis used to create an arteriovenous fistula of the type illustrated in FIG. 1. The approach based on this patent that is now in clinical trials is illustrated in FIG. 2 and involves a two-piece wrapped product of pieces 40 and 42 that does not provide the means to adjust the angle between the artery 10 and the vein 20. In addition, it does not provide structural support to the vein 20 as it adapts to the increased blood flow and pressure as a result of its direct connection to the artery 10. The one-piece product adopts the technology of this two-piece product while additionally providing a unitary product that does allow adjustment of the angle between the artery 10 and the vein 20 and also provides structural support to the vein as it adapts to this increased blood flow and pressure. Additionally, it provides the option of providing a deliberate accommodation for the expansion of the vein 20 as the fistula matures.

[0040] The slits 56 and 57 in the proximate portion 54 of the product 50 may have different axial lengths which provides the means for establishing an angle other than 90 between the artery 10 and the vein 20 when the tails created by the slits are wrapped about the artery 10. The product may bear some indication of the length of a given slit relative to the lengths of the other slits. The tube from which the product is formed typically has two slits spaced 180 from each other about the circumference of the tube. The tails formed by the slits may be curled about an axis set at an angle to the axis of the tube, with this angle preferably being other than 90 degrees.

[0041] The one-piece product 50 comprises a biocompatible and preferably biodegradable material carrying an adequate amount of an anti-vasculoproliferative drug comprising rapamycin or a rapamycin analogue with similar antiproliferative activity to effectively address the stenosis commonly observed at an arteriovenous fistula. This drug is conveniently present in an amount between about 20 micrograms and 2 milligrams per cm² of tube planar surface area. The biocompatible and biodegradable material conveniently comprises collagen, or may comprise PTFE (polytetrafluoroethylene), e.g., thin-walled PTFE or expanded-PTFE carrying or impregnated with an anti-vasculoproliferative drug such as rapamycin. Other polymeric materials may also be employed.

[0042] The tube from which the one-piece product 50 is constructed typically has a wall thickness between about 0.3 mm and 2.0 mm. The tube conveniently has a variable inside diameter between about 2.5 mm and 8 mm, conveniently between about 2.5 mm and 6 mm, with the minimum diameter being proximate to the slits 56 and 57, a total length of between about 40 mm and 70 mm, conveniently between about 40 mm and 55 mm and the slits typically have lengths between about 20 mm and 30 mm, conveniently between about 20 mm and 25 mm. Referring to Figure 3A, the inside diameter of the intact portion of the tube may conveniently increase from the end proximate to the slits 54 to the end distal from the slits 52. It may be convenient to have the inside diameter at the distal end 52 be about double of that at the proximate end 54. The increase typically begins somewhere along the length of the product.

[0043] The collagen version of the product is typically used by hydrating it, passing it over a free end of a vein that has been obtained by severing the vein in preparation for forming a fistula with the tails being proximate to this free end. The vein is then sutured to the artery (an anastomosis) and the product is moved towards the artery such that its tails may be wrapped about the artery in the vicinity of the anastomosis. If the tails have different lengths along their longitudinal edges they may be wrapped such that the angle between the artery and the vein is other than 90 degrees. Conveniently, the angle between the portion of the artery upstream of the anastomosis and the vein is about 60 degrees or is about 120 degrees. These two angles have received some attention in the relevant technical literature utilizing other techniques for establishing a desired angle between the artery and the vein; however, the product is designed to allow the surgeon to set the preferred angle based upon the relative lengths of slits 56 and 57.

[0044] Collagen (Type I) is a preferred biocompatible biodegradable resorbable material for the matrix of the drug eluting sleeve of the present invention. The collagen source may be animal or human or may be produced using recombinant DNA techniques. Other types of collagen e.g., types II, III, V, XI singularly or in combination with Type I may be used. Although collagen matrix in the form of a sheet or membrane is the preferred embodiment of this invention, other forms of collagen e.g., gel, fibrilla, sponge, tubular etc., may also be used. As is well known, the rate at which resorption of the collagen occurs can be modified by cross-linking the protein.

[0045] In another embodiment, the unitary product is formed of a collagen matrix having a morphology of condensed laminated film with a textured surface and a range of pore sizes. It can be produced in a wide range of effective pore sizes from 0.001 microns to 100 microns or even larger. This internal pore network (porous material) creates a high surface area and serves as a microreservoir for storage and delivery of the therapeutic agent. Several features make collagen an excellent and ideal matrix material for drug delivery. Collagen exhibits a high degree of flexibility and mechanical durability, as well as intrinsic water wettability, semipermeability, and consistent flow characteristics. More importantly, collagen, a naturally occurring substance is biodegradable and non-toxic. In addition, collagen has favorable biodegradation characteristics and time to complete degradation or resorption (i.e., durability of the collagen matrix for drug delivery) can be modified.

[0046] In order to prevent, suppress, or treat the smooth muscle proliferative response that predominantly contributes to the neointimal hyperplasia, therapeutic agents that have anti- vasculoproliferative properties may be used in this invention. Examples of drugs with significant antiproliferative effects include, but are not limited to, rapamycin, paclitaxel, other taxanes, tacrolimus, actinomycin D, angiopeptin, vassenoids, flavoperidol, hormones such as estrogen, halofuginone, matrix metalloproteinase inhibitors, ribozymes, interferons and antisense compounds. Analogues of the parent compound e.g., those of rapamycin, paclitaxel, and tacrolimus may be used. Examples of other therapeutic agents that may be employed on or in the tube product include anti-inflammatory compounds, dexamethasone and other steroids, antiplatelet agents including aspirin, clopidogrel, glycoprotein Ilb/IIIa antagonists, antithrombins, anticoagulants including unfractionated and fractionated heparin, statins, calcium channel blockers, protease inhibitors, alcohol, botulin and genetic material. Vascular, bone marrow and stem cells may also be used.

[0047] In a further embodiment, the product is an implantable prosthetic device placed on the outer surface of the vessel or graft which then elutes one or more anti-vasculoproliferative drugs or agents such as rapamycin, paclitaxel, tacrolimus, and other cell cycle inhibitor or similarly- functioning agents. In addition to a resorbable matrix material, e.g., protein, 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. This invention provides a method of preventing or treating neo intimal hyperplasia (an expression of the vasculoproliferative response) and calcification by extravascular delivery of an effective amount of an antiproliferative agent with low water solubility alone or in combination with adjuvants, and other antiproliferative agents. Rapamycin is a particularly preferred drug with antiproliferative properties for use with the present invention. A mixture of suitable drugs may be used. 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 within the hemodialysis and other vascular grafts and/or at their anastomotic sites. Thus, in one aspect, the present invention is a method of inhibiting smooth muscle cell proliferation of a vascular access graft or shunt by the gradual elution or timed release of a drug from outside the vascular access site vessel wall to the vessel interior i.e., by extravascular or perivascular delivery.

[0048] In a preferred embodiment, about 120 micrograms/cm² of rapamycin (Range: 50 micrograms to 10 mg/cm²) is combined with a collagen matrix material sheet with a thickness in the dry state between 0.3 and 2.0 mm sheet which is then implanted or wrapped upon the outside of the vascular or graft wall.

LIST OF ADDITIONAL NUMBERED EMBODIMENTS

[0049] The additional numbered embodiments below will be understood to apply to any of the disclosure and claims in this application, and, in determining the subject matter encompassed by these embodiments, the references to the “product” will be understood to also be a reference to any of the embodiments and claims below. Further, the following list of embodiments is intended to supplement the preceding description as well as the claims that follow the list.

[0050] 1. A one-piece product, comprising: a. a tube having dimensions suitable to slide over a human vessel (vein or artery) involved in an arteriovenous fistula and constructed of a biocompatible material carrying an effective amount of an anti-vasculoproliferative drug sufficient to prevent and/or treat stenosis at the fistula; and b. at least two axial slits extending from one axial end of the tube thereby resulting in tails extending from the intact portion of the tube.

[0051] 2 The product of No. 1, wherein the biocompatible material is selected from the group consisting of collagen, PTFE, and mixtures thereof.

[0052] 3. The product of any one of Nos. 1-2, wherein the biocompatible material is collagen having a thickness between about 0.3 and 2.0 mm.

[0053] 4. The product of any one of Nos. 1-3, wherein the biocompatible material is a collagen matrix having a range of effective pore sizes from about 0.001 microns to about 100 microns.

[0054] 5. The product of any one of Nos. 1-4, wherein the tube has an inside diameter between about 2.5 mm and about 8 mm, or between about 2.5 mm and about 6 mm.

[0055] 6. The product of any one of Nos. 1-5, wherein the tube has a minimum diameter proximate to the slits.

[0056] 7. The product of any one of Nos. 1-6, wherein the tube has a total length of between about 40 mm and about 70 mm, or between about 40 mm and about 55 mm.

[0057] 8. The product of any one of Nos. 1-7, wherein the slits have lengths between about 20 mm and about 30 mm, or between about 20 mm and about 25 mm. [0058] 9. The product of any one of Nos. 1-8, wherein the drug is selected from the group consisting of rapamycin, paclitaxel, a taxane, tacrolimus, actinomycin D, angiopeptin, a vassenoid, flavoperidol, estrogen, halofuginone, a matrix metalloproteinase inhibitor, a ribozymes, an interferon, an antisense compound, analogues of any of the foregoing, and combinations of any of the foregoing.

[0059] 10. The product of any one of Nos. 1-9, wherein the drug is rapamycin present in an amount between about 50 micrograms and 10 mg/cm².

[0060] 11. The product of any one of Nos. 1-10, wherein the drug is rapamycin present in an amount of about 120 micrograms/cm² in the biocompatible material comprising a collagen matrix having a thickness in the dry state between about 0.3 mm and about 2.0 mm.

[0061] 12. The product of any one of Nos. 1-11, wherein the slits each extend a different axial distance allowing the tube to position the vein of the fistula at an angle to the artery of the fistula other than 90 degrees, and the biocompatible material is also biodegradable.

[0062] 13. The product of any one of Nos. 1-12, wherein the tube bears some indication of the length of a given slit relative to the lengths of the other slits.

[0063] 14. The product of any one of Nos. 1-13, wherein the tube has two slits positioned approximately 180 degrees from each other about the axis of the tube.

[0064] 15. The product of any one of Nos. 1-14, wherein the material between two successive slits (tail) is curled or will curl upon hydration about an axis set at an angle to the axis of the tube allowing the tails to be wrapped around the vessel.

[0065] 16. The product of any one of Nos. 1-15, wherein the anti-vasculoproliferative drug is present in an amount between about 20 micrograms and 2 milligrams per cm² of tube planar surface area.

[0066] 17. The product of any one of Nos. 1-16, wherein the tails may be affixed to each other by contact wings or flaps. [0067] 18. Use of the product of any one of Nos. 1-17 in the manufacture of a medicament for the prophylactic treatment of vasculoproliferative disease in a vascular structure following the construction of an arterio-venous graft, an arterial -arterial graft or an arterio-venous fistula, the use comprising applying locally and external to the vascular structure, perivascularly, the product of any one of Nos. 1-17 thereby enabling delivery of an antiproliferative effective amount of the drug to the vascular structure wherein the vascular structure may be a vein, artery, prosthetic vessel, or biological graft.

[0068] 19. A method of prophylactically treating vasculoproliferative disease in a vascular structure following the construction of an arterio-venous graft, an arterial-arterial graft or an arterio-venous fistula, the method comprising applying locally and external to the vascular structure, perivascularly, the product of any one of Nos. 1-17 wherein the vascular structure may be a vein, artery, prosthetic vessel, or biological graft.

[0069] While only certain features of the invention have been illustrated and described herein, many modifications and changes will occur to those skilled in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention.

Claims

CLAIMS What is claimed is:

1. A product for preventing and/or treating stenosis at an arteriovenous fistula, comprising a tube of appropriate dimensions to slide over a human vein involved in the fistula and constructed of a biocompatible material carrying an effective amount of an anti-vasculoproliferative drug to prevent and/or treat the stenosis at the fistula, wherein the tube has at least two axial slits extending from one axial end of the tube thus creating tails extending from the intact portion of the tube.

2. The product of claim 1, wherein the slits each extend a different axial distance allowing the tube to position the vein of the fistula at an angle to the artery of the fistula other than 90 degrees, and the biocompatible material is also biodegradable.

3. The product of claim 2, wherein the tube bears some indication of the length of a given slit relative to the lengths of the other slits.

4. The product of claim 2, wherein the tube has two slits positioned approximately 180 degrees from each other about the axis of the tube.

5. The product of claim 1, wherein the material between two successive slits is curled or will curl upon hydration about an axis set at an angle to the axis of the tube allowing the tails to be wrapped around the artery.

6. The product of claim 6, wherein the angle between the curl axis and axis of the tube is other than 90 degrees.

7. The product of any preceding claim, wherein the anti-vasculoproliferative drug is present in an amount between about 20 micrograms and 2 milligrams per cm² of tube planar surface area.

8. The product of any preceding claim, wherein the tube comprises collagen or PTFE.

9. The product of any preceding claim, wherein the tube has a wall thickness between about 0.3 and 2.0 mm.

10. The product of any preceding claim, wherein the tube has an inside diameter between about 2.5 mm and 6 mm, a total length of between 40 mm and 70 mm and the slits have lengths between about 20 mm and 30 mm.

11. The product of any preceding claim, wherein the inside diameter of the intact portion of the tube increases from the end proximate to the slits to the end distal from the slits.

12. The product of claim 11, wherein the inside diameter of the tube at the distal end will be about double of that at the proximate end.

13. A process for preventing and/or treating stenosis at an arteriovenous fistula, comprising: a. providing a product for preventing and/or treating stenosis at an arteriovenous fistula comprising a tube of appropriate dimensions to slide over a human vein involved in the fistula and constructed of a biocompatible material carrying an effective amount of an anti- vasculoproliferative drug to prevent and/or treat the stenosis at the fistula, wherein the tube has at least two axial slits extending from one axial end of the tube thus creating tails extending from the intact portion of the tube; b. passing the tube over the free end of the vein that has been obtained by severing the vein in preparation for forming the fistula; c. forming an anastomosis by attaching the free end of the vein to the artery; d. moving the tube towards the artery; and e. wrapping the tails of the tube around the artery in the vicinity of the anastomosis.

14. The process of claim 13, wherein the two axial slits each extend a different axial distance allowing the tube to position the vein of the fistula at an angle to the artery of the fistula other than 90 degrees.

15. The process of claim 14, wherein the tails are wrapped around the artery in the vicinity of the anastomosis such the vein joins the artery at an angle other than 90 degrees.

16. The process of claim 15, wherein the angle between the portion of the artery upstream of the anastomosis and the vein is about 60 degrees.

17. The process of claim 15, wherein the angle between the portion of the artery upstream of the anastomosis and the vein is about 120 degrees.

18. The process of claim 13, wherein the inside diameter of the intact portion of the tube increases from the end proximate to the slits to the end distal from the slits.

19. The process of claim 18, wherein the inside diameter at the distal end of the tube will be about double of that at the proximate end.

20. A product for preventing and/or treating stenosis at an arteriovenous fistula, comprising a tube with a total length between about 40 mm and 70 mm and a minimum inside diameter of between about 2.5 mm and 6 mm and constructed of collagen carrying between about 20 micrograms and 2 milligrams per cm² of tube planar surface area of an anti-vasculoproliferative drug comprising rapamycin or a rapamycin analogue with similar antiproliferative activity, wherein the tube has two axial slits of different lengths positioned about 180 degrees from each other about the axis of the tube and extending between about 20 mm and 30 mm from one axial end of the tube thus creating tails extending from the intact portion of the tube wherein the tails can be wrapped about the artery in such a way as to hold the vein at an angle to the artery at an angle other than 90 degrees wherein the inside diameter of the intact portion of the tube increases from the end proximate to the slits to the end distal from the slits.