Abstract:
A method for making an implantable stent includes the steps of (i) providing a plurality of elongate stent wires; (ii) forming said wires into a hollow tubular structure having opposed first and second open ends; (iii) terminating said wires at the second end; (iv) aligning the wires at the second end into a plurality of mated adjacent wires to define a plurality of abutting regions; (v) welding the mated adjacent wires to one and the other at the abutting regions to define a plurality of welds; and optionally (vi) chemically or electro-chemically removing a portion of the welds. The method may further include the steps of (a) extending at least one of the mated stent wires to provide an extended stent wire; (b) looping the extended stent wire so the extended end abuts a proximal pair of stent wires; and (c) welding the extended and looped wire to the proximal pair of wires. The step of looping may include the forming of the wire into a equilaterally arched loop having an apex, but not having other sharp bends.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application is a continuation of U.S. application Ser. No. 10/845844 filed May 14, 2004, the contents of which is incorporated herein by reference. 
     
    
     FIELD OF THE INVENTION 
       [0002]    The present invention relates to stents having welded portions and atraumatic looped ends. The present invention also relates to such stents having their welded portions electro-chemically polished to reduce their profile and/or having a suture loop threaded at one or both extremities and/or being manufactured with a wire having a radiopaque core, and/or being fully or partially covered with a polymer such as silicone. 
       BACKGROUND OF THE INVENTION 
       [0003]    Stents made from interconnecting, often braiding, elongate wires may be made less traumatic, i.e., atraumatic, by closing the loose wire ends at the ends of the stents. The loose wire ends have typically been closed by mechanical means, such as by clamps, for example clamped microtubes, or by welding. Such mechanical means, however, provide regions of high profile as compared to the other regions of the stents, see e.g., U.S. Pat. No. 6,083,257. The high profile regions are undesirable, often leading to deployment concerns, including higher deployment forces. 
         [0004]    Electropolishing or electro-chemical polishing of laser cut nitinol stents to improve surface finishes has been previously mentioned, see e.g. U.S. Pat. No. 6,325,825 B1 and U.S. Patent Application Publication No. 2003/0024534 A1. Further, electro-polishing or electrochemical polishing services are available, see e.g. from Admedes Schuessler GmbH. Such polishing, however, has not been attempted to alleviate the above-discussed deployment concerns. 
         [0005]    The present invention provides a stent made from elongate wires in a closed-end design while avoiding the disadvantages of the prior art. More particularly, the present invention is directed to certain advantageous closed-end stent loop designs having reduced profiles to lower deployment forces and ease deployment of the stent. 
       SUMMARY OF THE INVENTION 
       [0006]    In one aspect of the present invention is a method for making an implantable stent. The method comprises the steps of (i) providing a plurality of elongate stent wires; (ii) forming the wires into a hollow tubular structure having opposed first and second open ends; (iii) terminating the wires at the second end; (iv) aligning the wires at the second end into a plurality of mated adjacent wires to define a plurality of abutting regions; (v) welding the mated adjacent wires to one and the other at the abutting regions to define a plurality of welds; and, optionally, (vi) chemically or electro-chemically removing a portion of the welding material from the plurality of welds. Desirably, the mated adjacent wires are substantially parallel to one and the other at the abutting regions. 
         [0007]    In this aspect of the present invention, the step of welding may include the step of providing an inert gas proximal to the weld areas. Further, the step of welding includes laser welding, electron beam welding, resistance welding, tungsten inert gas welding, metal inert gas welding, and combinations thereof. 
         [0008]    Desirably, the step of forming the tubular structure comprises braiding the wires, winding the wires, knitting the wires, and combinations thereof, preferably braiding the wires. The material of the wires and the material of the welds may be the same type of material. 
         [0009]    Further, the stent wire may include a radiopaque material. 
         [0010]    The step of chemically or electro-chemically removing the portion of the welding material may include chemical polishing or etching, chemical deburring, electrochemical polishing or etching, jet-electropolishing and combinations thereof. The step of electro-chemically removing the portion of the welding material further includes the step of providing an electrolyte, where the electrolyte is selected from the group consisting of NaClO 3  electrolyte, NaNO 3  electrolyte, NaCl electrolyte, Na 2 Cr 2 O 7  electrolyte, HOCH 2 CH 2 OH electrolyte, and combinations thereof. 
         [0011]    In further detail, the step of electro-chemically removing the portion of the welding material may further include the step of (i) providing an electrolyte; (ii) placing a cathode into the electrolyte; (iii) placing a portion of the stent having the welding material into the electrolyte; (iv) providing an electrical voltage or current so that the cathode is negatively charged and the stent portion is positively charged; and (v) partially dissolving the portion of the stent exposed to the electrolyte. 
         [0012]    In another aspect of the present invention, the method of making the stent may further include the steps of (i) extending at least one of the mated stent wires to provide an extended stent wire; (ii) looping the extended stent wire so the extended end abuts a proximal pair of stent wires; and (iii) welding extended and looped wire to the proximal pair of wires. Desirably, the step of looping includes forming the wire into an arch with equilateral sides, having an apex, but not having other sharp bends. Desirably, the step of looping includes forming the wire into an equilateral arch having one vertex having similar curvatures on either side of the one vertex, where the equilateral arch does not contain a second vertex having dissimilar curvatures on either side of the second vertex. 
         [0013]    In another aspect of the present invention, the method of making the stent may further include the steps of (i) extending at least one of the mated stent wires past the abutting regions to provide an extended stent wire; and (ii) looping the extended stent wire at its extended end to form a coil thereat. A plurality of extended wires may also be formed into one coil or pig tail. 
         [0014]    Desirably, the elongate wires comprise biocompatible materials selected from the group consisting of nitinol, stainless steel, cobalt-based alloy such as Elgiloy, platinum, gold, titanium, tantalum, niobium, and combinations thereof, preferably nitinol. The elongate wires may be composite wires for improved radiopacity, such as having an inner core of tantalum, gold, platinum, iridium or combination of thereof and an outer layer or member of nitinol. 
         [0015]    In another aspect of the present invention, an implantable stent is provided. The stent of this aspect of the present invention may include a plurality of wires arranged to form a hollow tubular structure having a tubular wall to define an interior surface and an exterior surface and having opposed open first and second ends, where the wires terminate at the second open end ends and adjacently abutting wires are welded at the second open end with a welding material to provide welds, and further where at least a portion of the welded material has been removed to reduce the profile of the welds. Desirably, the portion of welded material has been removed by chemical or electro-chemical polishing. Preferably, at least 25 to 50% by weight of the stent material at or around the weld location has been removed. The reduced profile of the welds are from about 5 to about 50 linear percent of a diameter of the stent wires. 
         [0016]    The stent includes wires made from bio compatible materials, such as nitinol, stainless steel, cobalt-based alloy such as Elgiloy, platinum, gold, titanium, tantalum, niobium, and combinations thereof. The weld material and the wire material may also be the same, for example nitinol. Further, the elongate wires have an inner core of tantalum gold, platinum, iridium or combination of thereof and an outer member of nitinol. 
         [0017]    In another aspect of the present invention, at least one some of the adjacently abutting stent wires are extended past the welds and looped into an arch with equilateral sides having an apex, but not having other sharp bends, or in other words at least some of the adjacently abutting stent wires are extended past the welds and looped into an arch with equilateral sides having one vertex having similar curvatures on either side of the one vertex, where the arch design does not contain a second vertex having dissimilar curvatures on either side of the second vertex. Alternatively, at least some of the adjacently abutting stent wires are extended past the welds and looped to form a coil thereat in the shape of a pig tail. Still alternatively, at least some of the adjacently abutting stent wires are extended past the welds and looped to form one coil thereat. 
         [0018]    The stent wires may be coated, for example coated with silicone. Further, the stent may be fully or partially covered with a polymeric covering, such as silicone, in order to prevent tissue or tumor ingrowth. 
         [0019]    The stent may further include a hollow tubular graft disposed over the interior or the exterior surface. The graft may be a polymeric material, for example, a polyester, a polypropylene, a polyethylene, a polyurethane, a polynaphthalene, a polytetrafluoroethylene, an expanded polytetrafluoroethylene, a silicone, and combinations thereof. 
         [0020]    Desirably, the stent is a braided stent. 
         [0021]    The stent may further include a polymeric ring disposed over the exterior surface at the second open end. Additionally, the stent may further include a suture secured to one of the open ends. Such suture or sutures are useful for positioning, repositioning, and/or removing the stent. The suture can be a metallic, polymeric or textile suture loop threaded through the stent loops at one or both extremities of the stent. The suture loop may include a protruding part to help facilitate the capture or grabbing of the stent end. 
         [0022]    In another aspect of the present invention, an implantable stent includes a plurality of wires arranged to form a hollow tubular structure having a tubular wall to define an interior surface and an exterior surface and having opposed open first and second ends, where the wires terminate at the second open end ends and adjacently abutting wires are welded at the second open end with a welding material to provide welds, and further where at least a portion of the welded material has been removed by chemical or electrochemical polishing to reduce the profile of the welds. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0023]      FIG. 1  is a perspective view of a hollow, tubular stent according to the present invention. 
           [0024]      FIG. 2  is an expanded view of a wall portion of the stent of  FIG. 1  taken along the  2 - 2  axis showing a plurality of stent wires. 
           [0025]      FIG. 3  depicts a braided stent with a closed-end loop design having a plurality of welds at the closed end according to the present invention. 
           [0026]      FIG. 4  is an expanded view of a weld of  FIG. 3 . 
           [0027]      FIG. 5  depicts a weld adjoining two stent wires according to the present invention. 
           [0028]      FIG. 5A  depicts a weld adjoining two stent wires having an insulator or photoresist on selected stent wire portions according to the present invention. 
           [0029]      FIG. 6  is a cross-sectional view of the adjoining stent wires of  FIG. 5  taken along the  6 - 6  axis. 
           [0030]      FIG. 7  is a cross-sectional view of the welded stent wires of  FIG. 5  taken along the  7 - 7  axis. 
           [0031]      FIG. 8  is a cross-sectional view of the welded stent wires of  FIG. 7  after chemical or electrochemical polishing. 
           [0032]      FIG. 9  is a schematic depiction of an electro-chemical polishing cell according to the present invention. 
           [0033]      FIGS. 10-14  depict an arch with equilateral sides and an apex in a closed-end loop design according to the present invention. 
           [0034]      FIG. 15  depicts another embodiment according to the present invention of a closed-end loop design of the present invention having a plurality of coils at the closed end. 
           [0035]      FIG. 16  depicts yet another embodiment according to the present invention of a closed-end loop design of the present invention having one coil or pigtail at the closed end. 
           [0036]      FIGS. 17-18  depict yet another embodiment according to the present invention of a closed-end design having a band disposed over the stent wires at the closed end. 
           [0037]      FIG. 19  depicts a mandrel having shaped pins for forming the closed loops of  FIGS. 10-14 . 
           [0038]      FIG. 20  depicts a stent having a covering of silicone according to the present invention. 
           [0039]      FIG. 21  is a cross-sectional view if the stent of  FIG. 20  showing an outer covering of silicone about the stent. 
           [0040]      FIG. 22  is a cross-sectional view if the stent of  FIG. 20  showing an inner covering of silicone about the stent. 
       
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT 
       [0041]    The present invention overcomes the deficiencies of the prior art by providing, among other things, low profile stent welds that reduce stent deployment forces.  FIG. 1  depicts stent  10  of the present invention. Stent  10  is a hollow tubular structure having opposed open ends  12 ,  14  and having a tubular wall  16  therebetween. A portion of the tubular wall  16  is depicted in  FIG. 2  as having a plurality of elongate wires  18  formed into the tubular wall  16 . The elongate wires  18  traverse the length of the stent  10  in a direction traverse to the longitudinal length of the stent  10 . The elongate wires  18  may be formed into the tubular wall  16  by braiding the wires  18 , winding the wires  18 , knitting the wires  18 , and combinations. Preferably, the wires  18  are braided to form the tubular wall  16 . 
         [0042]    A welded stent  10 ′ according to the present invention is depicted in  FIG. 3 . The elongate wires  18  terminating at open end  12  are mated and adjacently mated wires are secured to one and the other by welds  20 . The joining of three adjacently mated wires  18  and the welding thereat is depicted in further detailed in  FIG. 4 . The positioning of adjacently mated wires to form closed-loop end designs, excluding the closed-end arch loop design of the present invention which is described below, is further described in U.S. application Ser. No. 60/472,929, filed May 23, 2003, which represents U.S. application Ser. No. 10/852,495 and which published as US 2005/0049682 A1, the contents of which are incorporated herein by reference. The weld  20  may be a low profile weld, i.e., a weld with a reduced welding zone as compared to stent welds of the prior art. The stent  10 ′ depicted in  FIG. 3  includes  24  wires  18  of nitinol or nitinol-containing material. The wires are relatively thin at a diameter of about 0.011 inches. The number of wires and the diameters of the wires, which may be the same or different, depicted in  FIG. 3  are not limiting, and other numbers of wires and other wire diameters may suitably be used. 
         [0043]    A pair of adjacently welded wires according to the present invention is depicted in  FIGS. 5-8 . Weld  24  securably joins adjacently mated stent wires  22 . As compared to the prior art, the weld  24  of the present invention has a significant reduction in the amount of welding material in weld  24 . Desirably, weld  24  has at least about 25% or less welding material than prior art welds, for example from about 25% to about 50% less welding material. Alternatively, the weld  24  desirably has a profile, i.e., a depth d 3  and/or a width d 4 , that is less than the diameter, d.sub. 1 , of the wire  22 . Yet alternatively, or in addition to, the welds  24  of the present invention have a profile of about 150 microns or less, preferably from about 50 microns to about 150 microns. Yet alternatively, or in addition to, the weld  24 ′ of the present invention and portions of the stent wires  22 ′ proximal to the welds  24 ′ have a reduced profile where the profile of weld  24 ′ is lower than the profile of weld  24  and where the diameter, d.sub. 2 , of the proximal stent portions  22 ′ is less than the diameter, d.sub. 1 , of stent wire portions  22 . The mass and volume of the weld  24 ′ and/or stent portions  22 ′ is suitably reduced by chemical or electrochemical polishing. Reduced profile welds  24 ,  24 ′ of the present invention overcome the difficulty of constraining the stent  10 ,  10 ′ on a delivery device (not shown) by removing excess weld material that would otherwise increase localized constraining forces at the weld locations as compared to other portions of the stent  10 ,  10 ′. 
         [0044]    Useful welding methods include, but are not limited to, laser welding, electron beam welding, resistance welding, tungsten inert gas welding, metal inert gas welding and combinations thereof. In laser and electron beam welding the wires are partially melted by the energy provided by the laser or electron beam. In gas tungsten arc welding (GTAW or TIG welding), an arc is formed between an electrode, typically tungsten, and the metal being welded. In metal inert gas (MIG) welding, an arc is generated between a filler electrode and the metal being welded with metal melted from the filler electrode being added to the metal being welded. Resistance welding uses the application of electric current and sometimes mechanical pressure to create a weld between two pieces of metal. The weld areas may be shielded with an inert gas. Suitable, but non-limiting, inert gasses include argon and argon/gas admixtures, such as argon/hydrogen or argon/helium. 
         [0045]      FIG. 9  depicts an electro-chemical cell  30  for removing weld material to thereby form the low profile weld  24 ,  24 ′ of the present invention. The cell  30  includes an electrolyte  32  contained within a container  34 . The stent  10  with welds  24 ,  24 ′ at stent end  12  is placed within the electrolyte  32 . A cathode  36  is also placed within the electrolyte  32 . A wire  38  connects the cathode  36  to the negative terminal  40  of voltage or current source  46 . A wire  42  connects the stent  10  to the positive terminal  44  of the voltage or current source  46 . Upon application of voltage or current from the source  46  the cell  30  becomes operational. Material, such as weld material, is dissolved from the stent  10  into the electrolyte  32 . Useful electrolytes include NaClO 3  electrolyte, NaNO 3  electrolyte, NaCl electrolyte, Na 2 Cr 2 O 7  electrolyte, HOCH 2 CH 2 OH electrolyte and combinations thereof. Typical, but non-limiting, current densities are in the magnitude of about 50 to about 150 amps/cm 2 . The electrolyte  32  may be in motion at low velocities or unstirred. As the anode metal is dissolved electrochemically, the dissolution rate is not influenced by the hardness or other physical characteristics of the metal. 
         [0046]    Desirably, the wires  22  are made from nitinol, stainless steel, cobalt-based alloy such as Elgiloy, platinum, gold, titanium, tantalum, niobium, and combinations thereof. Further, the wires  22  have an inner core of tantalum gold, platinum, iridium or combination of thereof and an outer member or layer of nitinol to provide a composite wire for improved radiocapicity or visibility. Further details of such composite wires may be found in U.S. Patent Application Publication 2002/0035396 A1, the contents of which is incorporated herein by reference. Preferably, the wires  22  are made from nitinol. Further, the filling weld material, if required by welding processes such as MIG, may also be made from nitinol, stainless steel, cobalt-based alloy such as Elgiloy, platinum, gold, titanium, tantalum, niobium, and combinations thereof, preferably nitinol. The material of the cathode is no critical and can be made out of any suitable metal. The filling weld material and the wire  22  may be made of the same material, for example nitinol. 
         [0047]    As the chemical electro-chemical polishing  30  removes material from portions of the stent  10  that are disposed within the electrolyte  32 , there are several means to selectively remove material from the stent  10 , such as welds  24 ,  24 ′, burrs or other imperfections (not shown), and the like. One technique for selectively removing material is through the use of a photoresist or insulator, which is an organic polymer or resin that can be applied to selective areas of the stent  10  to avoid the electrochemical polishing of covered parts  30  as the photoresist insulates the selected from the action of the electrolyte. For example, as depicted in  FIG. 5A , portions of the stent wires  22  may be coated with a photoresist prior to placement in the cell  30 . After chemical or electro-chemical polishing is completed the photoresist may be removed by application of a suitable solvent. Alternatively, jet electro-chemical polishing or etching could be used to specifically etch weld regions. Jet etching includes the localized application of electrolyte at moderate velocity, such as about 3 to about 30 m/s, to selectively polish desired areas, such as stent welds. 
         [0048]    Alternatively, chemical polishing, chemical etching and the like may be used to remove portions of the weld  24 ,  24 ′ and optionally portions of the stent wire  22 . Chemical polishing or etching is similar to the above described electrochemical methods, expect an oxidizing acid is added to the electrolyte and associated equipment (current or voltage source, cathode, etc.) is optionally not necessary. Useful, but not limiting, oxidizing acid-containing electrolytes include electrolytes having hydrofluoric acid, nitric acid, and combinations thereof. 
         [0049]    The present invention, however, is not limited to low profile welds just at terminatingly adjacent wires, such as wires  22  of  FIG. 5  or  5 A. As depicted in  FIGS. 10-14 , certain stent wires  56 ,  62  may be extended beyond adjacent wires  50 ,  64 , and then looped back to proximal wires  52 ,  60  and  58 ,  64 , respectively. Adjacent portions of wires  50  and  56  are abuttingly disposed at abutting region  68 . Similarly, adjacent portions of wires  52  and  60  and the adjacent portion of the extended loop portion  66  are abuttingly disposed at abutting region  70 ; adjacent portions of wires  54  and  62  are abuttingly disposed at abutting region  72 ; and adjacent portions of wires  58  and  64  and the adjacent portion of the extended loop portion  67  are abuttingly disposed at abutting region  74 . Desirably, the abuttingly disposed wire portions in the abutting regions are substantially parallel to one and the other, for example, but not limited to, being within about plus or minus 10 degrees of parallelism to one and the other, preferably, but not limited to within about plus or minus 5 degrees of parallelism. 
         [0050]    As depicted in  FIG. 11 , the wires at the abutting regions  68 ,  70 ,  72 ,  74  may be secured by welds  76 . Desirably, welds  76  are low profile welds having low profiles from electrochemical polishing according to the present invention. 
         [0051]    Desirably, the extended loop portions  66 ,  67  are of an arch with equilateral sides design, which can be referred to as a cathedral type of arch or loop. As depicted in  FIG. 12 , the equilaterally arched loop  78  has an apex or vertex  80 . As used herein, the term “vertex” and its variants refer to the intersection of two geometric lines or curves. As used herein, the term “apex” and its variants refer to a vertex at the top or summit of a loop. Desirably, the equilaterally arched loop  78  does not have any bends, which are defined as areas having dissimilar curvatures on either side of a point, except for the apex  80 . In other words, the equilaterally arched loop  78  has an apex, but not other sharp bends. Desirably, the equilaterally arched loop  78  has one vertex (or apex  80 ) having similar curvatures on either side of the one vertex (or apex  80 ), but does not contain a second vertex having dissimilar curvatures on either side of the second vertex. 
         [0052]    The equilaterally arched loop design offers several advantages, including reduced deployment force, as compared to prior art loop designs having a plurality of vertices or sharp bends. When a stent is constrained on or in a delivery system (not shown) the multiple sharp bends in the end loops of the stent typically impinge on the wall of the delivery system and become slightly imbedded thereat, thereby distorting the outer sheath of the delivery system. This results in significantly greater deployment force values. Further, as the equilaterally arched loop has only one sharp bend, i.e., its apex, and is defined otherwise by a gradual curvature, the gradual curvature portions do not become imbedded in the wall of the delivery system, thereby significantly reducing the resultant deployment force. 
         [0053]    In another aspect of the present invention as depicted in  FIG. 13 , an equilaterally arched loop  82  may have an apex  84  and vertices  86  having substantially straight line portions  88 . In such a case, the vertices  86  and the straight line portions  88  have low profile welds  90  thereover to adjoin other adjacently abutting stent wires (not shown). The equilaterally arched loops  66 ,  67 ,  78 ,  82  of the present invention may be suitably formed by winding their stent wires about shaped pins  98  on a mandrel  100  as depicted in  FIG. 19 . Further, either or both of the ends  12 ,  14  of the stent  10 ,  10 ′, including end  12  with equilaterally arched loops  66 ,  67 ,  78 ,  82 , may have a suture or sutures (not shown) attached thereto. Such sutures are useful for positioning, repositioning, and/or removing the stent  10 ,  10 ′. 
         [0054]    In still a further aspect of the present invention, the stent  10  may have other designs at open end  12  that are useful for positioning, repositioning, and/or removing stent  10 . As depicted in  FIG. 15 , wires may be extended from all or some of the adjacent wire engaging portions  92 . The ends of the extended wires may be formed into coils  90 . As depicted in  FIG. 16 , wires may be extended from all or some of the adjacent wire engaging portions  92 . The ends of the extended wires may be formed into a coil  94 , which is in the shape of a hook and commonly referred to as a pigtail. Still further, the open end  12  of stent  10  may be of reduced diameter as compared to the other portions of the stent  10 . The reduced diameter portion facilitates access to the stent end  12  for positioning, repositioning, and/or removing stent  10 . The stent end  12  of the stent  10  of  FIG. 17  may include any of the previously described loops or coils thereat. Alternatively, or in addition to, the stent end  12 , as depicted in  FIG. 18 , may have a band  96  disposed thereover, which is also useful for positioning, repositioning, and/or removing stent  10 . Band  96  may be made of any biocompatible material, including polymers, plastics and metals. The band  96  may be attached to the stent end  12  by adhesive, mechanical or physical means, such as adhesive bonding, welding, suturing, fusing, and the like. 
         [0055]    As depicted in  FIG. 20 , the stent  10  may be fully, substantially or partially covered with silicone  102  in also the form of a tubular structure. The silicone  102  may be disposed on external surfaces  104  of the stent  10 , as depicted in  FIG. 21 , or disposed on the internal surfaces  106  of the stent  10 , as depicted in  FIG. 22 , or combinations thereof. 
         [0056]    With any embodiment of the stent  10 ,  10 ′ is usable to maintain patency of a bodily vessel, such as in the coronary or peripheral vasculature, esophagus, trachea, bronchi colon, biliary tract, urinary tract, prostate, brain, and the like. Also, the stent  10 ,  10 ′ may be treated with any of the following: anti-thrombogenic agents (such as heparin, heparin derivatives, urokinase, and PPack (dextrophenylalanine proline arginine chloromethylketone); anti-proliferative agents (such as enoxaprin, angiopeptin, or monoclonal antibodies capable of blocking smooth muscle cell proliferation, hirudin, and acetylsalicylic acid); anti-inflammatory agents (such as dexamethasone, prednisolone, corticosterone, budesonide, estrogen, sulfasalazine, and mesalamine); antineoplastic/antiproliferative/anti-miotic agents (such as paclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine, epothilones, endostatin, angiostatin and thymidine kinase inhibitors); anesthetic agents (such as lidocaine, bupivacaine, and ropivacaine); anti-coagulants (such as D-Phe-Pro-Arg chloromethyl keton, an RGD peptide-containing compound, heparin, antithrombin compounds, platelet receptor antagonists, anti-thrombin antibodies, anti-platelet receptor antibodies, aspirin, prostaglandin inhibitors, platelet inhibitors and tick antiplatelet peptides); vascular cell growth promotors (such as growth factor inhibitors, growth factor receptor antagonists, transcriptional activators, and translational promoters); vascular cell growth inhibitors (such as growth factor inhibitors, growth factor receptor antagonists, transcriptional repressors, translational repressors, replication inhibitors, inhibitory antibodies, antibodies directed against growth factors, bifunctional molecules consisting of a growth factor and a cytotoxin, bifunctional molecules consisting of an antibody and a cytotoxin); cholesterol-lowering agents; vasodilating agents; and agents which interfere with endogenous vascoactive mechanisms. 
         [0057]    The invention being thus described, it will now be evident to those skilled in the art that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention and all such modifications are intended to be included within the scope of the following claims.