Patent Publication Number: US-2006009839-A1

Title: Composite vascular graft including bioactive agent coating and biodegradable sheath

Description:
FIELD OF THE INVENTION  
      The present invention relates to implantable medical devices which inhibit or reduce bacterial growth during their use in a living body. More particularly, the present invention relates to composite vascular grafts which incorporate bioactive agents to deliver therapeutic materials and/or to inhibit or reduce bacterial growth during and following the introduction of the graft to the implantation site in the body.  
     BACKGROUND OF THE INVENTION  
      In order to repair or replace diseased or damaged blood vessels it is well known to use implantable vascular grafts in the medical arts. These vascular grafts, which are typically polymeric tubular structures, may be implanted during a surgical procedure or maybe interluminally implanted in a percutaneous procedure.  
      Such medical procedures employing vascular grafts introduce a foreign object into a patient&#39;s vascular system. Therefore, the risk of infection must be addressed in any such procedure.  
      Vascular graft infection is reported to occur in from about 1% to 6% of the procedures. More significantly, vascular graft infections are associated with a high mortality rate of between 25% to 75%. Moreover, morbidity rates for vascular graft infections are in the range of between 40% and 75%. Infections caused by vascular grafts are also known to prolong hospital stays, thereby greatly increasing the cost of medical care.  
      Numerous factors contribute to the risk of vascular graft infection. Such factors include the degree of experience of the surgeon and operating room staff. The age of the patent and the degree to which the patient is immunocompromised also are strong risk factors with respect to vascular graft insertion. Other common factors associated with vascular graft infection risks include sterility of the skin of the patient, as well as the materials being implanted.  
      It has been found that the mechanism of infection for many implanted devices is attributed to local bacterial contamination during surgery. Bacteria on the device produce an extracellular slime matrix/biofilm during colonization, which coats the polymer surface. This biofilm protects the bacteria against the patient&#39;s defense mechanisms. The biofilm layer also reduces the penetration of antibiotics.  
      The most common infectious agents are:  staphylococcus aureus, pseudomonas aeruginosa , and  staphylococcus epidermis . These agents have been identified in over 75% of all reported vascular infections. Both  staphylococcus aureus  and  pseudomonas aeruginosa , show high virulence and can lead to clinical signs of infection early in the post-operative period (less than four months). It is this virulence that leads to septicemia and is one main factor in the high mortality rates.  Staphylococcus epidermis  is described as a low virulence type of bacterium. It is late occurring, which means it can present clinical signs of infection up to five years post-operative. This type of bacterium has been shown to be responsible for up to 60% of all vascular graft infections. Infections of this type often require total graft excision, debridement of surrounding tissue, and revascularization through an uninfected route.  
      Such high virulence organisms are usually introduced at the time of implantation. For example, some of the  staphylococcus  strains (including  staphylococcus aureus ) have receptors for tissue ligands such as fibrinogen molecules which are among the first deposits seen after implantation of a graft. This tissue ligand binding provides a way for the bacteria to be shielded from the host immune defenses as well as systemic antibiotics. The bacteria can then produce polymers in the form of a polysaccharide that can lead to the aforementioned slime layer on the outer surface of the graft. In this protective environment, bacterial reproduction occurs and colonies form within the biofilm that can shed cells to surrounding tissues (Calligaro, K. and Veith, Frank, Surgery, 1991 V110-No. 5, 805-811). Infection can also originate from transected lymphatics, from inter-arterial thrombus, or be present within the arterial wall.  
      There are severe complications as a result of vascular graft infections. For example, anastonomic disruption due to proteolytic enzymes that the more virulent organisms produce can lead to a degeneration of the arterial wall adjacent to the anastomosis. This can lead to a pseudoaneurism which can rupture and cause hemodynamic instability. A further complication of a vascular graft infection can be distal styptic embolisms, which can lead to the loss of a limb, or aortoenteric fistulas, which are the result of a leakage from a graft that is infected and that leads to gastrointestinal bleeding (Greisler, H., Infected Vascular Grafts. Maywood, Ill., 33-36).  
      Desirably, it would be beneficial to prevent any bacteria from adhering to the graft, or to the immediate area surrounding the graft at the time of implantation. It would further be desirable to prevent the initial bacterial biofilm formation described above by encouraging normal tissue ingrowth within the tunnel, and by protecting the implant itself from the biofilm formation.  
      It is known to incorporate antimicrobial agents into a medical device. For example, prior art discloses an ePTFE vascular graft, a substantial proportion of the interstices of which contain a coating composition that includes: a biomedical polyurethane; poly(lactic acid), which is a biodegradable polymer; and the antimicrobial agents, chlorhexidine acetate and pipracil. The prior art further describes an ePTFE hernia patch which is impregnated with a composition including silver sulfadiazine and chlorhexidine acetate and poly(lactic acid).  
      Moreover, prior art is known, which discloses a stent or vascular prosthesis having an overlying biodegradable coating layer that contains a drug. The coating layer is disclosed as including an anticoagulant drug, and, optionally, other additives such as an antibiotic substance.  
      Further prior art describes a medical implant wherein an antimicrobial agent penetrates the exposed surfaces of the implant and is impregnated throughout the material of the implant. The medical implant may be a vascular graft and the material of the implant may be polytetrafluoroethylene (PTFE). The antimicrobial agent is selected from antibiotics, antiseptics and disinfectants.  
      Moreover, there is prior art that discloses that silver, which is a known antiseptic agent, can be deposited onto the surface of a porous polymeric substrate via silver ion assisted beam deposition prior to filling the pores of a porous polymeric material with an insoluble, biocompatible, biodegradable material. This prior art further discloses that antimicrobials can be integrated into the pores of the polymeric substrate. The substrate may be a porous vascular graft of ePTFE.  
      It is also known to provide an anti-infective medical article including a hydrophilic polymer having silver chloride bulk distributed therein. The hydrophilic polymer may be a laminate over a base polymer. Preferred hydrophilic polymers are disclosed as melt processible polyurethanes. The medical article may be a vascular graft. A disadvantage of this graft is that it is not formed of ePTFE, which is known to have natural antithrombogenic properties. A further disadvantage is that the hydrophilic polyurethane matrix into which the silver salt is distributed does not itself control the release of silver into the surrounding body fluid and tissue at the implantation site of the graft.  
      Furthermore, there is prior art describing an implantable medical device that can include a stent structure, a layer of bioactive material posited on one surface of the stent structure, and a porous polymeric layer for controlled release of a bioactive material which is posited over the bioactive material layer. The thickness of the porous polymeric layer is described as providing this controlled release. The medical device can further include another polymeric coating layer between the stent structure and the bioactive material layer. This polymeric coating layer is disclosed as preferably being formed of the same polymer as the porous polymeric layer. Silver can be included as the stent base metal or as a coating on the stent base metal. Alternatively, silver can be in the bioactive layer or can be posited on or impregnated in the surface matrix of the porous polymeric layer. Polymers of polytetrafluoroethylene and bioabsorbable polymers can be used. A disadvantage of this device is that it is not designed to achieve fast tissue ingrowth within the tunnel to discourage initial bacterial biofilm formation.  
      Further prior art describes an antimicrobial vascular graft made with a porous antimicrobial fabric formed by fibers which are laid transverse to each other, and which define pores between the fibers. The fibers may be of ePTFE. Ceramic particles are bound to the fabric material, the particles including antimicrobial metal cations thereon, which may be silver ions. The ceramic particles are exteriorly exposed and may be bound to the graft by a polymeric coating material, which may be a biodegradable polymer. A disadvantage of this device is that the biodegradable coating layer does not provide sufficient rigidity during implantation for an outer graft layer.  
      There is a need for additional antimicrobial vascular grafts. In particular, there is a need for multi-layered vascular grafts which incorporate antimicrobial agents and, optionally, other therapeutic or diagnostic agents that can be controllably released upon implantation from biodegradable materials in the graft to suppress infection and to prevent biofilm formation. It would also be desirable to provide such grafts with sufficient rigidity in the tissue-contacting outer layer and with good cellular communication between the blood and the perigraft tissue in the luminal layer.  
     SUMMARY OF THE INVENTION  
      The present invention provides a composite vascular graft having a bioactive agent incorporated therein. The graft includes a flexible, porous tubular graft member that may be an ePTFE tube and/or a textile. The porous tubular graft member may be covered with one or more biodegradable, bioactive agent coating layers. Desirably, the bioactive agent coating layer includes an antimicrobial agent. The graft further includes a biodegradable sheath disposed over the one or more bioactive agent coating layers. The sheath has a rigidity greater than the flexible tubular graft member; and is biodegradable to expose the bioactive agent coating layer so as to re-establish the flexibility of the tubular graft member. The sheath optionally includes a bioactive agent, such as an antimicrobial agent.  
      The present invention also provides a method for forming a composite vascular graft which incorporates bioactive agents therein. The method can include the steps of providing a porous, flexible tubular graft member; and applying a biodegradable coating material having at least one bioactive agent incorporated therein to the graft member so as to form one or more overlying biodegradable, bioactive agent coating layers. A biodegradable sheath, which optionally includes a bioactive agent, is then disposed over the one or more bioactive agent coating layers overlying the graft member. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       FIG. 1A  is a schematic longitudinal cross-sectional representation of an embodiment of the vascular graft of the present invention, wherein the graft includes a single bioactive agent coating layer.  
       FIG. 1B  is a schematic longitudinal cross-sectional representation of a further embodiment of the vascular graft of the present invention wherein the graft includes multiple bioactive agent coating layers.  
       FIG. 2  is a schematic longitudinal cross-sectional representation of yet another embodiment of the vascular graft of the present invention, wherein the biodegradable sheath of the composite graft includes bioactive agents therewithin.  
       FIG. 3  is a perspective view of a tubular vascular graft according to the present invention.  
       FIG. 4  is a cross-sectional showing of an embodiment of a stent/graft composite of the present invention wherein the inner porous tubular graft member is an ePTFE tube.  
       FIG. 5  is a perspective view of a textile tubular graft member useful in the composite graft of the present invention.  
       FIG. 6  is a schematic showing of a conventional weave pattern useful for the textile tubular graft member in  FIG. 5 .  
       FIG. 7  is a perspective showing of a biodegradable sheath in tubular configuration useful in the composite graft of the present invention.  
       FIG. 8  is a perspective showing of a biodegradable sheath in sheet-like configuration useful in the composite graft of the present invention.  
    
    
     DETAILED DESCRIPTION OF THE INVENTION  
      In preferred embodiments of the present invention, the implantable composite device is a multi-layered tubular structure, which is particularly suited for use as a vascular graft. The prosthesis preferably includes at least one porous, flexible tubular graft member made of a textile and/or ePTFE. Furthermore, the prosthesis preferably includes one or more biodegradable coating layers disposed over the graft member and designed to regulate delivery of an antimicrobial agent associated therewith to the site of implantation. The prosthesis also includes a biodegradable sheath disposed over the one or more coating layers overlying the graft member.  
       FIG. 1A  shows vascular graft  10  of the present invention. As noted above, the present invention takes the preferred embodiment of a tubular graft having a composite structure. The layers shown in  FIG. 1  represent the tubular members forming the composite structure. However, it may be appreciated that the present invention also contemplates other implantable multi-layer prosthetic structures such as vascular patches, blood filters, film wraps for implantable devices such as stents, hernia repair fabrics and plugs and other such devices where such structures may be employed. As shown in  FIG. 1A , the composite device  10  of the present invention includes a tubular flexible vascular graft member  12 , which is porous and made of a textile and/or ePTFE. A biodegradable, bioactive agent coating layer  14  covers the graft member  12 . Biodegradable coating layer  14  permits controlled delivery of bioactive agents  16  associated with coating layer  14  therethrough. These bioactive agents  16  are preferably distributed substantially evenly throughout the bulk of the bioactive agent coating layer  14 , as will be described in greater detail below. Bioactive agents  16  desirably include antimicrobial agents. Device  10  of the present invention further includes a biodegradable sheath  18 , which has a rigidity greater than that of flexible graft member  12 . After implantation, sheath  18  biodegrades upon exposure to blood and/or other physiological fluids. This biodegradation of the sheath  18  decreases the rigidity of the graft so as to re-establish the flexibility of the tubular graft member  12 . Once the sheath has degraded, it exposes bioactive agent coating layer  14 . Desirably, antimicrobial agents are posited on or incorporated within coating layer  14  to reduce infection after implantation. Sheath  18  may be in a tubular configuration and placed over the graft member  12  or may be in a sheet-like configuration and wrapped about the tubular graft member  12 , as further described below. The biodegradable sheath  18  is desirably flexible and slightly elastic in nature to allow it to be placed on top of or wrapped about the vascular graft  12 .  
      With reference now to  FIG. 1B , in one aspect of the present invention the bioactive agent coating is applied to graft member  12  in multiple coating layers, such as  14   a  and  14   b . It is well within the contemplation of the present invention that coating layers  14   a  and  14   b  may contain the same or different bioactive agents  16 . For example, as shown in the embodiment in  FIG. 1B , bioactive agent  16   a  in coating layer  14   a  is an antibiotic agent, whereas bioactive agent  16   b  in coating layer  14   b  is an antiseptic agent. It can be appreciated that these multiple coating layers can be applied onto graft member  12  for a longer term anti-infective effect. Bioactive agent coating layer  14   a  is exposed after bioactive agent coating layer  14   b  has been biodegraded. Desirably, the bioactive agent coating layers are both biodegradable, as well as bioresorbable.  
      Referring now to  FIG. 2 , in another aspect of the present invention, biodegradable sheath  18  also includes one or more bioactive agents. In desired embodiments, the bioactive agents in the biodegradable sheath include at least one antimicrobial agent such that antimicrobial agents are controllably released from the biodegradable sheath immediately upon implantation to reduce infection after implantation. Once the sheath biodegrades and is desirably resorbed, the one or more bioactive agent coating layers  14  are exposed for a longer term anti-infective effect.  
      Referring now to  FIG. 3 , a preferred embodiment of a composite tubular graft of the present invention is shown, wherein the layers shown in  FIG. 1A  represent the tubular members in  FIG. 3  forming the composite structure. Device  20  includes an inner porous tubular graft member  22 , which is flexible; and a medial coating layer  24  disposed coaxially thereover. Medial layer  24  includes bioactive agent  26  which is preferably distributed substantially evenly throughout the bulk of the biodegradable matrix of layer  24 . An outer tubular biodegradable sheath member  28  is disposed coaxially over biodegradable bioactive coating layer  24 . As will be described in further detail below, the porous flexible tubular graft member  22  can be an ePTFE tube and/or a textile. A central lumen  29  extends throughout the tubular composite graft  20  defined further by the inner wall  22   a  of luminal tube  22 , which permits the passage of blood through graft  20  once the graft is properly implanted in the vascular system.  
      It is well within the contemplation of the present invention that a stent can be interposed between the tubular members of the graft of the present invention. With reference to  FIG. 4 , a stent/graft composite device  30  of the present invention is shown. Device  30  includes inner porous tubular graft member  22 , which in the present figure is depicted as an ePTFE tubular member. Device  30  also includes at least one medial, biodegradable, bioactive agent coating layer  24  disposed coaxially over graft member  22 . As described above, coating layer  24  includes at least one bioactive agent which can be controllably released from the biodegradable matrix of coating layer  24 . Composite device  30  further includes a biodegradable tubular sheath member  28  which is disposed coaxially over tubular member  24 . As described above and as shown in  FIG. 2 , sheath member  28  can also include bioactive agents. In desired embodiments, the bioactive agents associated with coating layer  24  and optionally with biodegradable sheath  28 , include an antimicrobial agent that can be controllably released from coating layer  24  and sheath  28  depending on the rate of hydrolysis of the bonds within these biodegradable members. Central lumen  29  extends throughout tubular composite graft  30 . An expandable stent  32  may be interposed between inner ePTFE tubular member  22  and biodegradable coating layer  24 . Stent  32 , which may be associated with the graft of the present invention, is used for increased support of the blood vessel and increased blood flow through the area of implantation. It is noted that increased radial tensile strength at the outer sheath member  28  enables the graft to support, for example, radial expansion of stent  32 , when present. In order to facilitate hemodialysis treatment, a significant number of patients suffering from hypertension or poor glycemic control in diabetes will have a synthetic vascular graft surgically implanted between the venous and arterial systems. Typically, these grafts become occluded over time. In these instances, a covered stent across the venous anastomotic site in patients with significant stenosis may aid in prolonging the patency of these grafts, which would avoid painful and typically expensive surgical revisions. For these reasons, it is well within the contemplation of the present invention that a stent covered with or incorporated within the vascular graft of the present invention may be useful for AV access.  
      The bioactive agents may include antimicrobial agents. In one embodiment, the antimicrobial agents are antibiotic or antiseptic agents, or combinations thereof. The antibiotic agents can be of the type including, but not limited to, ciprofloxacin, vancomycin, minocycline, rifampin and other like agents, as well as combinations thereof.  
      Suitable antiseptic agents include, but are not limited to, the following: silver agents, chlorhexidine, triclosan, iodine, benzalkonium chloride and other like agents, as well as combinations thereof.  
      For example, silver is an antiseptic agent that has been shown in vitro to inhibit bacterial growth in several ways. For example, it is known that silver can interrupt bacterial growth by interfering with bacterial replication through a binding of the microbial DNA, and also through the process of causing a denaturing and inactivation of crucial microbial metabolic enzymes by binding to the sulfhydryl groups (Tweten, K., J. of Heart Valve Disease 1997, V6, No. 5, 554-561). It is also known that silver causes a disruption of the cell membranes of blood platelets. This increased blood platelet disruption leads to increased surface coverage of the implants with platelet cytoskeletal remains. This process has been shown to lead to an encouragement of the formation of a more structured (mature state) pannus around the implant. This would likely discourage the adhesion and formation of the biofilm produced by infectious bacteria due to a faster tissue ingrowth time (Goodman, S. et al, 24 th  Annual Meeting of the society for Biomaterials, April 1998, San Diego, Calif.; pg. 207).  
      The silver agent can be a silver metal ion such as silver iodate, silver iodide, silver nitrate, and silver oxide. These silver ions are believed to exert their effects by disrupting respiration and electron transport systems upon absorption into bacterial or fungal cells. Antimicrobial silver ions are useful for in vivo use because they are not substantially absorbed into the body, and typically pose no hazard to the body.  
      Referring again to  FIG. 1A , the aforementioned antiseptic or antibiotic bioactive agents  16  can be used alone or in combination of two or more of them. These agents  16  can be posited on coating layer  14  or can be dispersed throughout coating layer  14 . The amount of each antimicrobial or antibiotic bioactive agent  16  used to posit onto or to impregnate the coating layer  14  varies to some extent, but is at least of an effective concentration to inhibit the growth of bacterial and fungal organisms.  
      As noted above, in one aspect of the present invention, composite device  10  includes an ePTFE graft member as the porous graft member  12  depicted in  FIG. 1A . PTFE exhibits superior biocompatibility and low thrombogenicity, which makes it particularly useful as vascular graft material. Desirably, the ePTFE graft member is a tubular structure  22 , as depicted in  FIG. 4 . The ePTFE material has a fibrous state, which is defined by interspaced nodes interconnected by elongated fibrils. The space between the node surfaces that is spanned by the fibrils is defined as the internodal distance. In the present invention, the internodal distance in a luminal ePTFE graft member is desirably about 70 to about 90 microns in order to achieve fast tissue ingrowth within the tunnel to discourage initial bacterial biofilm formation. When the term “expanded” is used to describe PTFE, i.e. ePTFE, it is intended to describe PTFE which has been stretched, in accordance with techniques which increase the internodal distance and, concomitantly, porosity. The stretching may be done uni-axially, bi-axially, or multi-axially. The nodes are stretched apart by the stretched fibrils in the direction of the expansion. Methods of making conventional longitudinally expanded ePTFE are well known in the art.  
      It is further contemplated that the ePTFE may be a physically modified ePTFE tubular structure having enhanced axial elongation and radial expansion properties of up to 600% by linear dimension. The physically modified ePTFE tubular structure is able to be elongated or expanded and then returned to its original state without an elastic force existing therewithin. Additional details of physically-modified ePTFE and methods for making the same can be found in commonly assigned Application Title “ePTFE Graft With Axial Elongation Properties”, assigned U.S. application Ser. No. 09/898,418, filed on Jul. 3, 2001, published on Jan. 9, 2003 as U.S. Application Publication No. 2003-0009210A1, the contents of which are incorporated by reference herein in its entirety.  
      As noted above, in another aspect of the present invention, composite device  10  includes a textile graft member as the porous graft member  12  in  FIG. 1A . As will be described in further detail below, virtually any textile construction can be used for the graft  12 , including weaves, knits, braids, filament windings, spun fibers and the like. Any weave pattern in the art, including, simple weaves, basket weaves, twill weaves, velour weaves and the like may be used. With reference to  FIGS. 5 and 6 , the weave pattern of a textile tubular graft member  40  shown in  FIG. 5  includes warp yarns  40   a  running along the longitudinal length (L) of the graft and fill yarns  40   b  running around the circumference (C) of the graft, the fill yarns being at approximately 90 degrees to one another with fabrics flowing from the machine in the warp direction. A central lumen  29  extends throughout the tubular graft member  40 , which permits the passage of blood through the composite vascular graft of the present invention once it is assembled and is properly implanted in the vascular system.  
      Any type of textile products can be used as yarns for a textile graft member. Of particular usefulness in forming a textile graft member for the composite device of the present invention are synthetic materials such as synthetic polymers. Synthetic yarns suitable for use in the textile graft member include, but are not limited to, polyesters, including PET polyesters, polypropylenes, polyethylenes, polyurethanes and polytetrafluoroethylenes. The yarns may be of the mono-filament, multi-filament, spun-type or combinations thereof. The yarns may also be flat, twisted or textured, and may have high, low or moderate shrinkage properties or combinations thereof. Additionally, the yarn type and yarn denier can be selected to meet specific properties desired for the prosthesis, such as porosity and flexibility. The yarn denier represents the linear density of the yarn (number of grams mass divided by 9,000 meters of length). Thus, a yarn with a small denier would correspond to a very fine yarn, whereas a yarn with a large denier, e.g., 1,000, would correspond to a heavy yarn. The yarns used for the textile graft member of the device of the present invention may have a denier from about 20 to about 200, preferably from about 30 to about 100. Desirably, the yarns are polyester, such as polyethylene terephthalate (PET). Polyester is capable of shrinking during a heat-set process, which allows it to be heat-set on a mandrel to form a generally circular shape.  
      After forming the textile layer of the present invention, it is optionally cleaned or scoured in a basic solution of warm water. The textile is then rinsed to remove any remaining detergent, and is then compacted or shrunk to reduce and control in part the porosity of the textile layer. Porosity of a textile material is measured on the Wesolowski scale and by the procedure of Wesolowski. In this test, a textile test piece is clamped flatwise and subjected to a pressure head of about 120 mm of mercury. Readings are obtained which express the number of mm of water permeating per minute through each square centimeter of fabric. A zero reading represents absolute water impermeability and a value of about 20,000 represents approximate free flow of fluid.  
      The porosity of the textile layer is often about 5,000 to about 17,000 on the Wesolowski scale. The textile layer may be compacted or shrunk in the wale direction to obtain the desired porosity. A solution of organic component, such as hexafluoroisopropanol or trichloroacetic acid, and a halogenated aliphatic hydrocarbon, such as methylene chloride, can be used to compact the textile graft by immersing it into the solution for up to 30 minutes at temperatures from about 15° C. to about 160° C.  
      Yarns of the textile layer may be one ply or multi-ply yarns. Multi-ply yarns may be desirable to impart certain properties onto the drawn yarn, such as higher tensile strengths for the textile layer.  
      A further aspect of the composite device of the present invention relates to the biodegradable, bioactive agent coating layer shown as layer  14  in  FIG. 1A . In one embodiment, the bioactive agent coating is applied to the porous tubular graft member as one or more coating layers. For example, a coating material can be applied (prior to polymerization) as a liquid to the outside surface of an ePTFE and/or textile graft member by such means as dipping, spraying or painting.  
      The coating layer may be comprised of natural, modified natural or synthetic polymers, copolymers, block polymers, as well as combinations thereof. It is noted that a polymer is generally named based on the monomer it is synthesized from. Examples of suitable biodegradable polymers or polymer classes include fibrin, collagen, elastin, celluloses, gelatin, vitronectin, fibronectin, laminin, reconstituted basement membrane matrices, starches, dextrans, alginates, hyaluronic acid, poly(lactic acid), poly(glycolic acid), polypeptides, glycosaminoglycans, their derivatives and mixtures thereof. For both glycolic acid and lactic acid, an intermediate cyclic dimer is typically prepared and purified, prior to polymerization. These intermediate dimers are called glycolide and lactide, respectively.  
      Other useful biodegradable polymers or polymer classes for the bioactive agent coating layer include the following: polydioxanones, polyoxalates, poly(α-esters), polyanhydrides, polyacetates, polycaprolactones, poly(orthoesters), polyamino acids, polyamides and mixtures and copolymers thereof.  
      Additional useful biodegradable polymers for the bioactive agent coating layer include, stereopolymers of L- and D-lactic acid, copolymers of bis(p-carboxyphenoxy) propane acid and sebacic acid, sebacic acid copolymers, copolymers of caprolactone, poly(lactic acid)/poly(glycolic acid)/polyethyleneglycol copolymers, copolymers of polyurethane and (poly(lactic acid), copolymers of polyurethane and poly(lactic acid), copolymers of α-amino acids, copolymers of α-amino acids and caproic acid, copolymers of α-benzyl glutamate and polyethylene glycol, copolymers of succinate and poly(glycols), polyphosphazene, polyhydroxy-alkanoates and mixtures thereof. Binary and ternary systems are contemplated.  
      Factors affecting the mechanical performance of in vivo biodegradable polymers are well known to the polymer scientist, and include monomer selection, initial process conditions, and the presence of additives. Biodegradation has been accomplished by synthesizing polymers that have unstable linkages in the backbone, or linkages that can be safely oxidized or hydrolyzed in the body. The most common chemical functional groups having this characteristic are ethers, esters, anhydrides, orthoesters and amides.  
      As described above, the biodegradable coating layer includes a bioactive agent. In one desired embodiment, the bioactive agent is an antimicrobial agent. For example, the antimicrobial agent can be an antibiotic or antiseptic agent. Examples of suitable antibiotic and antiseptic agents for use in the present invention are provided above.  
      The bioactive agent is desirably evenly distributed throughout the bulk of the biodegradable coating layer and is controllably released from the biodegradable coating layer to the site of implantation of the graft by hydrolysis of chemical bonds in the biodegradable polymer. It is also contemplated that a bioactive agent can be posited on the coating layer.  
      A solution of biodegradable material that includes a monomer (or an intermediate cyclic dimer) on which the biodegradable polymer is based can be applied as a coating to the external side of the ePTFE and/or textile graft member. This can be accomplished by such means as dipping, spraying, painting, etc. A bioactive agent can be blended into the wet or fluid biodegradable material to form a coating mixture which is then applied to the porous tubular graft member by a spraying process, for example. Alternatively, the bioactive agent may be applied in powdered form to wet or fluid biodegradable material after the biodegradable material has been applied as a coat to the porous tubular graft member, but prior to its polymerization.  
      In preparing the biodegradable, bioactive agent coating layer, a solution or fluid of a biocompatible, biodegradable material can be formed. For example, extracellular matrix proteins which are used in fluid/solution may be soluble. However, some materials may be difficult to dissolve in water. Collagen, for example, is considered insoluble in water, as is gelatin at ambient temperature. To overcome such difficulties, collagen or gelatin may preferably formed at an acidic pH, i.e. at a pH less than 7 and, preferably, at a pH of about 2 to about 4. The temperature range at which such fluid/solutions are formed is between about 4° C. to about 40° C., and preferably about 30° C.-35° C.  
      In situations where the bioactive agent is insoluble in the wet or fluid biodegradable coating material, the agent may be finely subdivided as by grinding with a mortar and pestle. The finely subdivided bioactive agent can then be distributed desirably substantially evenly throughout the bulk of the wet or fluid biodegradable coating material before cross-linking or cure solidifies the coating layer.  
      It is well within the contemplation of the present invention that the coating layer can be combined with various carrier, drug, prognostic, or therapeutic materials. For example, the coating layer can be combined with any of the following therapeutic agents: antimicrobial agents, such as the antibiotic agents and antiseptic agents listed above; 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); anti-neoplastics/anti-proliferative/anti-miotic agents (such as paclitaxel, 5-flurouracil, 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 anti-platelet peptides); vascular cell growth promoters (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, bi-functional molecules consisting of a growth factor and a cytotoxin, bi-functional molecules consisting of an antibody and a cytotoxin); cholesterol-lowering agents; vasodilating agents; and agents which interfere with andogenous or vascoactive mechanisms. In addition, cells which are able to survive within the body and are dispersed within the coating layer may be therapeutically useful. These cells themselves may be therapeutically useful or they may be selected or engineered to produce and release therapeutically useful compositions.  
      In other embodiments, bioactive agents associated with the composite device of the present invention may be genetic agents. Examples of genetic agents include DNA, anti-sense DNA, and anti-sense RNA. DNA encoding one of the following may be particularly useful in association with an implantable device according to the present invention: (a) tRNA or RRNA to replace defective or deficient endogenous molecules; (b) angiogenic factors including growth factors such as acidic and basic fibroblast growth factors, vascular endothelial growth factor, epidermal growth factor, transforming growth factor α and β, platelet-derived endothelial growth factor, platelet-derived growth factor, tumor necrosis factor α, hepatocyte growth factor and insulin-like growth factor; (c) cell cycle inhibitors; (d) thymidine kinase and other agents useful for interfering with cell proliferation; and (e) the family of bone morphogenic proteins. Moreover, DNA encoding molecules capable of inducing an upstream or downstream effect of a bone morphogenic protein may be useful.  
      A further aspect of the present invention relates to the biodegradable sheath shown as layer  18  in  FIG. 1A . In one embodiment, the biodegradable sheath is comprised of a material selected from, but not limited to, the following: polylactides, polyanhydrides, polyvinyl alcohol, polyvinylpyrolidone, polyglycols, gelatin derivatives and combinations thereof. The biodegradable sheath can have a tubular or sheet-like configuration for disposal over the bioactive coating layer. For example, referring to  FIG. 7  of the present invention, there is shown a biodegradable sheath in a tube-like configuration  50  used in combination with a tubular composite vascular graft of the present invention. Specifically, the tube  50  can be placed over the bioactive coating layer overlying the porous, flexible tubular graft member.  
      Alternatively, the biodegradable sheath can be in a sheet-like configuration as shown in  FIG. 8 . Sheath  60  shown in  FIG. 8  is used in combination with a tubular composite vascular graft of the present invention. Specifically, the sheath  60  can be wrapped about the bioactive coating layer overlying the porous, flexible tubular graft member. The sheet  60  is seamed along the longitudinal axis.  
      The sheath provides a desired degree of initial rigidity to the flexible tubular textile and/or ePTFE graft member during implantation. After implantation, the sheath biodegrades upon exposure to blood and/or other physiological fluids. The biodegradation of the sheath decreases the rigidity of the graft and re-establishes the flexibility of the graft member. After the sheath has degraded, it exposes the underlying bioactive agent coating layer which is desirably incorporated with antimicrobial agents to reduce infection after implantation. In embodiments where multiple bioactive agent coating layers are present, each coating layer controllably releases bioactive agents associated therewith after the coating layer overlying it is resorbed. This provides a longer term anti-infective effect.  
      The biodegradable sheath of the composite graft of the present invention can include bioactive agents. For example, the biodegradable sheath can be incorporated with antimicrobial agents so as to controllably release the antimicrobial agents immediately upon implantation.  
      In one of the embodiments of the present invention, it is contemplated that a dry, finely subdivided antimicrobial agent may be blended with wet or fluid material to form a mixture which is used to impregnate the pores of a porous biodegradable sheath. Alternatively, it is contemplated that air pressure or other suitable means may then be employed to disperse the antimicrobial agent substantially evenly within the filled pores.  
      In one example, a bioactive agent or drug can be incorporated into the sheath in the following manner: mixing into a fluid material used to make the sheath, a crystalline, particulate material like salt or sugar that is not soluble in a solvent used to form the sheath; casting the solution with particulate material into a film or sheet; and then applying a second solvent, such as water, to dissolve and remove the particulate material, thereby leaving a porous sheath. The sheath may then be placed into a solution containing a bioactive agent in order to fill the pores. Preferably, a vacuum would be pulled on the sheath to insure that the bioactive agent applied to it is received into the pores.  
      It is also contemplated that the bioactive agent or drug may be encapsulated in microparticles, such as microspheres, microfibers or microfibrils, which can then be incorporated into or on the sheath. Various methods are known for encapsulating bioactive agents or drugs within microparticles or microfibers (see Patrick B. Deasy, Microencapsulation and Related Drug Processes, Marcel Dekker, Inc., New York, 1984). In one example, a suitable microsphere for incorporation can have a diameter of about 10 microns or less. The microsphere could be contained within the biodegradable polymeric matrix of the sheath. The microparticles containing the bioactive agent can be incorporated within the sheath by adhesively positioning them onto the sheath material or by mixing the microparticles with a fluid or gel and flowing them into the sheath layer. The fluid or gel mixed with the microparticles could, for example, be a carrier agent designed to improve the cellular uptake of the bioactive agent incorporated into the sheath. Moreover, it is well within the contemplation of the present invention that carrier agents, which can include hyaluronic acid, may be incorporated within each of the embodiments of the present invention so as to enhance cellular uptake of the bioactive agent(s) associated with the device.  
      The microparticles may have a polymeric wall surrounding the bioactive agent or a matrix containing the bioactive agent and optional carrier agents, which due to the potential for varying thicknesses of the polymeric wall and for varying porosities and permeabilities suitable for containing a bioactive agent, there is provided the potential for an additional mechanism for controlling the release of a therapeutic agent.  
      Moreover, microfibers or microfibrils, which may be loaded with the bioactive agent by extrusion, can be adhesively layered or woven into the sheath material for drug delivery.  
      The bioactive agents, which can optionally be associated with the biodegradable sheath of the composite graft of the present invention, may be selected from drugs, prognostic agents, carrier agents, therapeutic agents, and genetic agents. Suitable bioactive agents include, but are not limited to, growth factors, anti-coagulant substances, stenosis inhibitors, thrombo-resistant agents, antibiotic agents, anti-tumor agents, anti-proliferative agents, growth hormones, antiviral agents, anti-angiogenic agents, angiogenic agents, anti-mitotic agents, anti-inflammatory agents, cell cycle regulating agents, genetic agents, cholesterol-lowering agents, vasodilating agents, agents that interfere with endogenous vasoactive mechanisms, hormones, their homologs, derivatives, fragments, pharmaceutical salts and combinations thereof. Specific examples of such agents are provided above.  
      As described above, a further aspect of the present invention relates to a method of making the inventive composite vascular graft. The method includes the steps of providing a flexible, porous tubular graft member, such as an ePTFE and/or textile graft member; and applying a biodegradable coating material to the porous tubular graft member so as to form one or more overlying coating layers, wherein the biodegradable coating material has at least one bioactive agent incorporated therein. The method further includes disposing a biodegradable sheath over the one or more coating layers overlying the ePTFE and/or textile graft member.  
      Generally, tubular textile layers are manufactured in a single long tube and cut to a pre-determined length. To cut the textile layer, a laser would be desirably used, which cuts and fuses the ends simultaneously. The textile layer is typically cleaned, desirably with sodium dodecyl sulfate and then rinsed with deionized water. The textile layer can then be placed over a cylindrical mandrel and heat set to precisely set the diameter and to remove any creases or wrinkles. Typically, heat setting is carried out at the temperature range from about 125° C. to about 225° C. using a convection oven for a time of 20 minutes. Any known means for heating may be used.  
      Alternatively, the composite device of the present invention may be formed by expanding a thin wall PTFE inner luminal tube at a relatively high degree of elongation, on the order of approximately between 400% and 2,000% elongation and preferably from about between 700% and 900%. The inner luminal tube is desirably expanded over a cylindrical mandrel, such as a stainless steel mandrel at a temperature of between room temperature and 640° F., preferably about 500° F. The luminal tube is preferably, but not necessarily fully sintered after expansion. Sintering is typically accomplished at a temperature of between 640° F. and 800° F., preferably at about 660° F. and for a time of between about 5 minutes to 30 minutes, preferably about 15 minutes. The resulting luminal tube formed by this method desirably exhibits an IND of greater than 40 microns, and in particular between 40 and 100 microns, most desirably between 70 to about 90 microns, spanned by a moderate number of fibrils. Such a microporous structure is sufficiently large so as to promote enhanced cell endothelization once blood flow is established through the graft. Such cell endothelization enhances the long-term patency of the graft.  
      The combination of the luminal ePTFE and/or textile tube over the mandrel is then employed as a substrate over which the biodegradable, bioactive coating layer can be disposed. In particular, the biodegradable, bioactive coating layer can be applied as a fluid coating material on the external surface of the luminal tube by such means as dipping, spraying or painting. The bioactive agent coating can be applied in a single layer or in multiple layers. Within the bioactive agent coating material is preferably substantially evenly dispersed a bioactive agent, which may be in dry powdered form.  
      The biodegradable sheath, which can be in the form of a tube or sheet, is then disposed over the bioactive agent coating layer(s). For example, the tube or sheet may correspond to a porous, biodegradable polymeric matrix, wherein the pores can optionally be filled with a bioactive agent. The interior diameter of a biodegradable tubular sheath member is selected so that it may be easily, but tightly disposed over the outside diameter of the coated graft member. In one embodiment, the sheath is cross-linked and bonds to the underlying bioactive agent coating layer. It is further contemplated that the biodegradable sheath can be secured to the coated graft member using techniques that would avoid degrading or damaging the bioactive agents in the coating layer(s). For example, where silver metal ions are the bioactive agents, it may be suitable to sinter the composite structure formed between the coated, tubular graft member and the tubular sheath using similar parameters to those described above.  
      Alternatively, the biodegradable sheath may be securably affixed to the coated graft member by means of a bonding agent. The bonding agent may include various biocompatible, elastomeric bonding agents such as urethanes, styrene/isobutylene/styrene block copolymers (SIBS), silicones, and combinations thereof. Once the composite prosthesis is formed, one or more layers of elastic tubing, preferably silicone, can then be placed over this composite structure. This holds the composite structure together and assures that complete contact and adequate pressure is maintained for bonding purposes.  
      While the invention has been described in relation to the preferred embodiments with several examples, it will be understood by those skilled in the art that various changes may be made without deviating from the spirit and scope of the invention as defined in the appended claims.