WO2011127478A1

WO2011127478A1 - Sleeve for graft and method

Info

Publication number: WO2011127478A1
Application number: PCT/US2011/031982
Authority: WO
Inventors: Craig Hashi; Daniel Francis Davidson; Robert O'reilly; Ajitkumar B. Nair
Original assignee: Nanovasc, Inc.
Priority date: 2010-04-09
Filing date: 2011-04-11
Publication date: 2011-10-13

Abstract

The invention provides a biocompatible device including a porous, flexible tube, and a sleeve positioned around a portion of the circumference of the graft. The sleeve may be formed of a plurality of biocompatible fibers configured to be in fluid communication with the tube and seal the tube to essentially completely prevent leakage of fluid flowing therethrough. Various aspects of the invention are directed to providing the sleeve on a catheter, AV graft, and other similar device. Methods of forming and using the device in accordance with the invention are also provided.

Description

SLEEVE FOR GRAFT AND METHOD

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 61/322,507, filed on April 9, 2010, the disclosure of which is incorporated herein by reference in its entirety for all purposes.

[0002] The present application relates to U.S. Provisional Patent Application No. 61/174,767, filed May 1, 2009 and entitled SLEEVE FOR GRAFT AND

METHOD; U.S. Patent Application No. 11/668,448, filed January 29, 2007 and entitled BIOMIMETIC SCAFFOLDS; U.S. Patent Application No. 11/811,923, filed June 11, 2007 and entitled BIOMOLECULE-LINKED BIOMIMETIC SCAFFOLDS; U.S. Patent Application No. 12/137,504, filed June 11, 2008 and entitled STENTS; and U.S. Patent Application No. 12/630,682, filed December 3, 2009 and entitled IMPLANTABLE MEDICAL DEVICE, the disclosures of which are incorporated herein by reference in their entirety for all purposes.

BACKGROUND OF THE INVENTION

Field of the Invention

[0003] The present invention relates to methods for making bio-compatible materials and devices, and in various aspects, a biocompatible polymer sleeve for tissue grafts and catheters.

Description of Related Art

[0004] Medical procedures commonly involve the use of instruments and devices in a sensitive biological environment. There is a continuing need to develop materials and structures having increased biocompatibility to reduce the risk of problems associated with such procedures. [0005] For example, dialysis is typically used to treat renal failure by means of a flexible catheter implanted to pass directly through the skin and tissue wall into an organ cavity. In its most common practice, continuous dialysis involves connecting the body exterior end of the catheter to a plastic bag of dialysate solution which is drained into the cavity. Because the catheter is placed into the body, conventional catheter devices carry operative and post-operative risks such as risk of infection and uncontrolled bleeding. Despite extensive protocols for maintaining sterile conditions, infection frequently occurs as a result of dialysis. The most common infection pathway is through the interior of the catheter, but exit site infection may be caused by bacteria invasion along the exterior surfaces of the catheter as well.

[0006] Other invasive medical procedures carry similar risks. Implanting a dialysis A-V shunt graft or autologous A-V fistula typically requires penetrating vessels with needles to establish blood flow through the catheters. This often creates unwanted bleeding. Moreover, it takes a significant amount of time to clot off the wound and stop the bleeding, which increases the risk of complications and inconvenience to the patient.

[0007] Conventional devices in many medical procedures likewise carry a high risk of infection and trauma. Conventional grafting and dialysis devices are typically difficult to position, lack stability, and do not respond well to the biological environment.

[0008] Conventional grafts, shunts, dialysis tubes, and the like also have the disadvantage of having a lag time between placement and homeostasis. In the case of dialysis, for example, the time to homeostasis after cannulation can be significant.

[0009] There is also a continuing need for materials and structures which promote the growth of new tissue or replace damaged tissue in a subject. There is the need for materials and structures which improve access to graft sites. There is a need for devices composed of materials and structures that can replace or improve biological functions in a subject. [0010] There is the need for devices and methods which address these and other problems. These and other needs are addressed by the invention(s) described herein.

[0011] The information disclosed in this Background of the Invention section is only for enhancement of understanding of the general background of the invention and should not be taken as an acknowledgement or any form of suggestion that this information forms the prior art already known to a person skilled in the art.

BRIEF SUMMARY OF THE INVENTION

[0012] Various aspects and embodiments of the present invention(s) are directed to devices including materials and structures described herein.

[0013] Various aspects and embodiments of the invention(s) are directed to a biocompatible device for positioning over a conduit. The device comprises a sleeve configured to receive a porous conduit therethrough. The sleeve is configured to be implanted in a subject such that at least a portion of the sleeve is disposed within and essentially completely sealed to the surface of the body of the subject when emplaced. In various embodiments, the sleeve is formed of a plurality of biocompatible polymer fibers.

[0014] In various embodiments, the conduit receives a fluid flow therethrough. In various embodiments, the conduit is sufficiently porous to allow fluid engagement with the sleeve. The sleeve may be configured to seal the conduit to essentially completely prevent leakage from the conduit of the fluid flowing therethrough.

[0015] In various embodiments, the conduit and the sleeve are substantially tubular and concentric. In various embodiments, the sleeve has an inner diameter

substantially corresponding to an outer diameter of the conduit. The sleeve may be configured to be removable from the conduit.

[0016] In various embodiments, the sleeve comprises fibers of one or more of: polyurethane, silicon rubber, poly(lactide), poly(glycolide), and poly(capro lactone). In those embodiments in which the fibers include fibers of different compositions, the fibers can be combined after formation of the fibers or they can be produced together. In an exemplary embodiment, the fibers of different compositions are electrospun on the same mandrel.

[0017] In various embodiments, the conduit used in conjunction with the sleeve of the invention is a vascular graft device, a synthetic graft (conduit), an autologous vein, a catheter, a blood vessel, a biological duct including a lymphedema vein graft, a hydrocephalus shunt, a nerve wrap, a nerve regeneration duct, an optical nanofiber nerve, a urinal and prostate expansion stent, a stent graft, an intestine (e.g. colon) duct prosthesis, or a dialysis fistula. In various embodiments, the conduit may be a conduit or duct in the body of a subject. Exemplary conduits for use in conjunction with the sleeve of the invention are described in WO/2007/090102, WO/2007/146261, WO/2008/154608, and US 2010/0070020 Al .

[0018] In various embodiments, the graft device comprises ePTFE, polyurethane, PET, or combinations of the same. The device may be treated with or conjugated to an anti-coagulation agent. The device may be treated with or conjugated to a pro- thrombotic agent to promote blood clotting and reduce hematoma formation. The device may be treated with or conjugated to heparin, hirudin or a combination thereof. The device may be treated with or conjugated to an antimicrobial and/or antibiotic to reduce cell proliferation. The device may be treated with or conjugated to at least one of sirolimus and paclitaxel.

[0019] In various embodiments, the device is a drug-eluting device. In various embodiments, the device is configured to deliver a plaque dissolving drug to a site internal to the subject.

[0020] Various aspects of the invention(s) are directed to a biocompatible dialysis device. Exemplary devices include a porous, flexible tube and a sleeve positioned around a portion of the circumference of the graft. In various embodiments, the sleeve is formed of a plurality of biocompatible fibers configured to be in fluid communication with the tube and to seal the tube to substantially prevent leakage of fluid flowing therethrough.

[0021] Various aspects of the invention(s) are directed to an implantable, biocompatible device for insertion through the epidermis of a subject (e.g., an animal or human subject) for dialysis. The device comprises an access conduit having a insertion end configured to be implanted at an access site of the epidermis to access a body through the access conduit interior. The device further includes a sleeve member positioned on at least a portion of the access conduit adjacent the insertion end. In various embodiments, the sleeve member is configured to be at least partially disposed within and essentially completely sealed to the inner surface of the epidermis of the subject when emplaced. In exemplary embodiments, the sleeve member is formed of a biocompatible polymeric material.

[0022] In various embodiments, the device further comprises an axially movable needle configured to extend through the conduit to the insertion end and provide an access opening at the site for the conduit and sleeve member. In an exemplary embodiment, the sleeve member is configured to maintain the access opening after removal of the needle. The access conduit may be removable and the sleeve member may be configured to maintain the access opening after removal of the conduit.

[0023] Various aspects of the invention(s) are directed to a method of performing dialysis using a device of the invention. In an exemplary embodiment, the method includes inserting a porous access conduit through an implant site to access the interior of a subject. In exemplary aspects, before or after the inserting, a sleeve member is formed on at least a portion of the access conduit adjacent to the insertion end such that the sleeve member is at least partially disposed within the access site when emplaced. In various embodiments, the sleeve member is configured to be in fluid communication with the conduit interior and to seal the conduit to essentially completely prevent leakage of the fluid flowing therethrough. In an exemplary embodiment, a fluid is flowed through the conduit and sleeve member for dialysis of the subject. In various embodiments, the sleeve member is formed of biocompatible polymer fibers.

[0024] Various aspects of the invention(s) are directed to a method of forming a biocompatible device for a conduit. An exemplary method of forming this device includes electrospinning biocompatible fibers on an exterior surface of a conduit configured for insertion into the body of a subject. In various embodiments, the fibers are spun to a sufficient thickness such that the fibers are rigidly formed around the surface of the conduit. In various embodiments, the fibers are secured to the conduit to form the biocompatible device. In an exemplary embodiment, the plurality of fibers are configured to be fluid communication with fluid flowing through the conduit and to seal the conduit to essentially completely prevent leakage of the fluid.

[0025] The methods and apparatuses of the present invention(s) have other features and advantages which will be apparent from or are set forth in more detail in the accompanying drawings, which are incorporated herein, and the following Detailed Description of the Invention, which together serve to explain certain principles of the present invention(s).

BRIEF DESCRIPTION OF THE DRAWINGS

[0026] FIG. 1 is a schematic view of an exemplary vascular graft in accordance with the present invention, illustrating the graft with a pair of biocompatible nano fibrous polymer sleeves.

[0027] FIG. 2 is a top view of the vascular graft of FIG. 1.

[0028] FIG. 3 A is a top view of an exemplary device similar to that of FIG. 1, illustrating the graft with a biocompatible nanofibrous polymer sleeve spirally wrapped around a central portion of the graft body. FIG. 3B is a cross-sectional view of the device illustrating the sleeve around the conduit circumference. [0029] FIG. 4 is a top view of an exemplary device of FIG. 1, illustrating multiple biocompatible nanofibrous polymer sleeves and a relatively more rigid conduit.

[0030] FIGs. 5A-5D are views of the fibers forming the sleeve and conduit of FIG. 4 under a scanning electron microscope, illustrating the graft with a pair of biocompatible nanofibrous polymer sleeves.

[0031] FIG. 6 A is a scanning electron microscope (SEM) image of the surface structure of an electrospun vascular access sleeve. FIG. 6B is an illustration of an exemplary surface modification of a sleeve. See Example 1.

[0032] FIG. 7A is a view of an exemplary vascular access sleeve placed over a vascular graft, the sleeve and graft combination punctured with a 16-gage

hemodialysis syringe needle. FIG. 7B is a cross sectional SEM image of the sleeve and graft punctured by the syringe needle. FIG. 7C is a SEM image of the sleeve after puncture with the needle. FIG. 7D is a SEM image of the graft after puncture with the needle. See Example 1.

[0033] FIG. 8A is a graphical representation of the nitrogen composition (analyzed by ESCA) of the heparin modified sleeve of Example 1 and an unmodified control. FIG. 8B is an image of the unmodified control surface after staining with Toluidine blue. FIG. 8C is an image of the heparin modified sleeve surface after staining with toluidine blue. See Example 2.

[0034] FIG. 9 is a schematic view of an in vitro blood recirculation model for the assessment of the thrombogenicity and hemocompatibility of a sleeve. See Example 3.

[0035] FIG. 10A is an image of the luminal surface of vascular prostheses that were exposed to bovine whole blood in a recirculation loop for 90 minutes. FIG. 10B is a graphical representation of adhered ¹¹ indium lableled platelets on each graft. See Example 3. DEFINITIONS AND ABBREVIATIONS

[0036] The abbreviations used herein generally have their conventional meaning within the chemical, biological and mechanical arts unless otherwise noted.

[0037] As used herein the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

[0038] "Fibrous" refers to structures formed of one or more fibers. The term "fiber" includes the singular and plural referents unless the context clearly dictates otherwise.

[0039] As used herein, and unless otherwise indicated, a material that is "essentially free" of a component means that the material contains less than about 20% by weight, such as less than about 10%> by weight, less than about 5% by weight, or less than about 3% by weight of that component.

[0040] "Peptide" refers to a polymer in which the monomers are amino acids and are joined together through amide bonds, alternatively referred to as a polypeptide. Additionally, unnatural amino acids, for example, β-alanine, phenylglycine and homoarginine are also included. Amino acids that are not gene-encoded may also be used in the present invention. Furthermore, amino acids that have been modified to include reactive groups, glycosylation sites, polymers, therapeutic moieties, biomolecules and the like may also be used in the invention. All of the amino acids used in the present invention may be either the D- or L-isomer. In addition, other peptidomimetics are also useful in the present invention. As used herein, "peptide" refers to both glycosylated and unglycosylated peptides. Also included are peptides that are incompletely glycosylated by a system that expresses the peptide. For a general review, see, Spatola, A. F., in CHEMISTRY AND BIOCHEMISTRY OF AMINO ACIDS, PEPTIDES AND PROTEINS, B. Weinstein, eds., Marcel Dekker, New York, p. 267 (1983). [0041] The term "amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an a carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups {e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that function in a manner similar to a naturally occurring amino acid.

[0042] As used herein, "nucleic acid" means DNA, RNA, single-stranded, double- stranded, or more highly aggregated hybridization motifs, and any chemical modifications thereof. Modifications include, but are not limited to, those providing chemical groups that incorporate additional charge, polarizability, hydrogen bonding, electrostatic interaction, points of attachment and functionality to the nucleic acid ligand bases or to the nucleic acid ligand as a whole. Such modifications include, but are not limited to, peptide nucleic acids (PNAs), phosphodiester group modifications {e.g., phosphorothioates, methylphosphonates), 2'-position sugar modifications, 5- position pyrimidine modifications, 8-position purine modifications, modifications at exocyclic amines, substitution of 4-thiouridine, substitution of 5-bromo or 5-iodo- uracil; backbone modifications, methylations, unusual base-pairing combinations such as the isobases, isocytidine and isoguanidine and the like. Nucleic acids can also include non-natural bases, such as, for example, nitroindole. Modifications can also include 3' and 5' modifications such as capping with a fluorophore {e.g., quantum dot) or another moiety. [0043] As used herein, the term "copolymer" describes a polymer which contains more than one type of subunit. The term encompasses polymer which include two, three, four, five, or six types of subunits.

[0044] The term "isolated" refers to a material that is substantially or essentially free from components, which are used to produce the material. The lower end of the range of purity for the materials is about 60%, about 70% or about 80%> and the upper end of the range of purity is about 70%>, about 80%>, about 90%> or more than about 90%.

[0045] The term "conjugated," as used herein encompasses interaction including, but not limited to, covalent bonding, ionic bonding, chemisorption, physisorption and combinations thereof.

[0046] The term "bioactive agent" as used herein refers to an organic molecule that has activity to produce a desired effect in a biological system. The organic molecule can be of biological origin, made by living organisms, or made synthetically. This includes, but is not limited to, antithrombogenic agents such as heparin.

[0047] "Small molecule," refers to species that are less than 1 kD in molecular weight, preferably, less than 600 D.

[0048] "Material of the invention," as used herein refers to the materials discussed herein.

[0049] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they optionally equally encompass the chemically identical substituents, which would result from writing the structure from right to left, e.g., -CH₂0- is intended to also recite -OCH₂-.

[0050] By "effective" amount of a drug, formulation, or permeant is meant a sufficient amount of a active agent to provide the desired local or systemic effect. A "topically effective," "cosmetically effective," "pharmaceutically effective," or "therapeutically effective" amount refers to the amount of drug needed to effect the desired therapeutic result.

[0051] The term, "aligned", as used herein, refers to the orientation of fibers in a fibrous polymer scaffold wherein at least 50% of the fibers are oriented in a general direction and their orientation forms an average axis of alignment. The orientation of any given fiber can deviate from the average axis of alignment and the deviation can be expressed as the angle formed between the alignment axis and orientation of the fiber. A deviation angle of 0° exhibits perfect alignment and 90° (or -90°) exhibits orthogonal alignment of the fiber with respect to the average axis of alignment. In an exemplary embodiment, the standard deviation of the fibers from the average axis of alignment can be an angle selected from between 0° and 1°, between 0° and 3°, between 0° and 5°, between 0° and 10°, between 0° and 15°, between 0° and 20°, or between 0° and 30°.

[0052] The term 'rod', as used herein, refers to a fibrous polymer scaffold which is essentially in the shape of a filled cylinder. Spaces and channels can be present between the individual fibers which compose the rod.

[0053] The term 'conduit', as used herein, refers to an object that is essentially cylindrical in shape. The conduit has an inner wall and an outer wall, an interior diameter, an exterior diameter, and an interior space which is defined by the inner diameter of the conduit as well as its length. Spaces and channels can be present between the individual fibers which compose the conduit.

[0054] The term 'filled conduit', as used herein, refers to a conduit in which a portion of the interior space is composed of filler material. This filler material can be a fibrous polymer scaffold. Spaces and channels can be present between the individual fibers which compose the filled conduit.

[0055] The term 'seam' or 'seamed', as used herein, refers to a junction formed by fitting, joining, or lapping together two sections. These two sections can be held together by mechanical means, such as sutures, or by chemical means, such as annealing or adhesives. For example, a seam is formed by joining one region of a sheet to another region.

[0056] The term 'seamless', as used herein, refers to an absence of a seam.

[0057] The term "cell" can refer to either a singular ("cell") or plural ("cells") situation.

[0058] The term "extracellular matrix component", as used herein, is a member selected from laminin, collagen, fibronectin and elastin.

[0059] The term "stent", as used herein, is a tube which can be made of, among other things, metal and organic polymers. When the stent is made of an organic polymer, the polymer is not a nanofibrous or microfibrous polymer scaffold as described herein. In other words, if the stent is made from a fibrous polymer scaffold, the average diameter of the fibers will be between 100 microns and about 50 centimeters. In some instances, the entire stent is capable of expanding from a first diameter to a second diameter, wherein the second diameter is greater than the first diameter.

[0060] The term "hirudin", as used herein, refers to the 65 amino acid wild-type peptide or analogs thereof. The 65 amino acid wild-type peptide has a sequence described in Folkers et al., Biochemistry, 28(6): 2601-2617 (1989). Analogs of hirudin include peptides with one or more mutations, fewer amino acids, more amino acids, chemical modifications to one or more amino acid residues, and combinations thereof. Examples of hirudin include wild-type hirudin, bivalirudin, lepirudin, desirudin, non-sulfated Tyr-63 hirudin, hirudin with the N-terminus modified (ie acetylated), hirudin with the C-terminus modified (ie acetylated), a hirudin fragment with the N-terminal domain deleted (approximately residues 1-53), a hirudin fragment with the C-terminal domain deleted (approximately residues 54-65), [Tyr(S0₃H)-63]- hirudin fragment 54-65, [Tyr(S0₃H)-63]-hirudin fragment 55-65, acetyl [Tyr(S0₃H)-

63]-hirudin fragment 54-65, acetyl [Tyr(S0₃H)-63] -hirudin fragment 55-65. Hirudin for use in this invention can be produced from a variety of sources. In some instances, hirudin is isolated from leeches. In others, hirudin is recombinantly produced from bacteria, yeast or fungi. In still others, hirudin is chemically synthesized. Recombinant and chemical syntheses tend to produce homogenous products, while hirudin isolated from leeches can include more than one hirudin analog. Hirudin is commercially available from companies such as Sigma- Aldrich (St. Louis, MO).

[0061] The symbol vwo _? whether utilized as a bond or displayed perpendicular to a bond, indicates the point at which the displayed moiety is conjugated to the remainder of the molecule, for example, a polymer.

[0062] As used herein, and unless otherwise specified, the term "subject" is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In specific embodiments, the subject is a human.

[0063] The term "poly(urethane)" and "polyurethane" as used herein refers to modified or unmodified polyurethanes, any co-polymer thereof, and blends or mixtures comprising said modified or unmodified polyurethanes and/or any copolymer thereof. This includes, for example, thermoplastic and thermoset polyurethane elastomers, poly(ester urethane), poly(ester urethane)urea, polyether urethane, poly(ether ester urethane)urea, silicone polyether urethane, polycarbonate urethane, silicone polycarbonate urethane, segmented polycaprolactone polyurethane, and segmented polyethylene oxide polyurethane.

[0064] The term "poly(lactide)" and "polylactide" as used herein refers to poly(lactide) and blends including, but not limited to, poly(L-lactide), poly(D-lactide), poly(DL-lactide), poly(lactic acid) and combinations thereof. In various

embodiments, the term "poly(lactide)" and "polylactide" encompasses copolymers of L-lactide, D-lactide, and/or DL-lactide with other types of subunits including, for example, poly(L-lactide-co-glycolide), poly(DL-lactide-co-glycolide), poly(DL- lactide-co-caprolactone), poly(L-lactide-co-caprolactone-co-glycolide), and combinations thereof.

[0065] The term "fibrous polymer scaffold", as used herein refers to any material or structure comprising at least one fiber. This includes, for example, a single fibrous polymer layer or multiple fibrous polymer layers.

DETAILED DESCRIPTION OF THE INVENTION

[0066] Reference will now be made in detail to various embodiments of the present invention(s), examples of which are illustrated in the accompanying drawings and described below. While the invention(s) are described in conjunction with exemplary embodiments, it will be understood that the present description is not intended to limit the invention(s) to those exemplary embodiments. On the contrary, the invention(s) is/are encompass not only the exemplary embodiments, but also various alternatives, modifications, equivalents and other embodiments, which are included within the spirit and scope of the invention as defined by the appended claims.

[0067] Turning now to FIGs. 1-2, various aspects of the invention are directed to a device, generally designated 130, which comprises materials and structures such as those described herein. In various embodiments, device 130 comprises one or more of such materials configured to enhance tissue growth and reduce biological trauma.

[0068] In various embodiments, exemplary device 130 is a biocompatible vascular graft. In various embodiments, the device is configured as an implantable, biocompatible device for insertion through the epidermis of a subject (e.g., an animal or human subject) for dialysis.

[0069] Device 130 includes a lumen or conduit 132 having an insertion end 133 for insertion into the body of a subject. The exemplary conduit is similar to a

conventional synthetic graft. Although described in terms of a graft, one will appreciate that the conduit may be a catheter, shunt, or other medical device. [0070] The exemplary device is configured to be implanted through an access site of the epidermis. The device optionally includes a needle axially movable within the conduit to guide the device or pierce the epidermis and/or tissue in a conventional manner. In various embodiments, conduit 132 is configured to extend into the body of a subject through the access site such that it provides access to the body. In other words, fluids and solids may pass from one end of the conduit to the insertion end positioned inside the body.

[0071] In various embodiments, the device is configured to be inserted through a permanent stoma, fistula or a temporary puncture.

[0072] In various embodiments, conduit 132 is shaped and configured similar to conventional grafts or catheters. In the exemplary embodiment, conduit 132 is configured to receive a fluid flow therethrough. The fluid may be blood or other biological fluids depending on the application. In an exemplary embodiment, the fluid is blood flowing to and/or from the subject (such as during renal dialysis).

[0073] Suitable materials for conduit 132 include, but are not limited to, PTFE, electrospun fibers of PTFE, ePTFE, polyurethane, PET, and combinations of the same. An exemplary conduit 132 is formed of ePTFE. Although the exemplary conduit 132 is hollow and tubular, one will appreciate that the conduit may have other shapes and configurations depending on the application. In various embodiments, the conduit is a solid body. In various embodiments, the conduit is relatively rigid such that it can be shaped and has a "memory." In various embodiments, the conduit is configured for enabling guiding of the device through a vessel or body of a subject.

[0074] Device 130 further includes at least one sleeve member 135 positioned on an outer surface of at least a portion of conduit 132. In an exemplary embodiment, conduit 132 and sleeve 135 are substantially tubular and concentric. In various embodiments, the sleeve is attached to a body other than the conduit. For example, the sleeve may be positioned over a blood vessel. [0075] An exemplary device includes two sleeve members, one of which is positioned adjacent an end of the conduit and the other of which is positioned inwardly of an opposite end. The sleeve members may be positioned along any portion of the length of the conduit or along the whole conduit. In various

embodiments, the sleeve is configured to be at least partially disposed within the inner surface of the epidermis when emplaced. In various embodiments, the position of the sleeve is based on the treatment location. For example, the sleeve may be positioned along a portion of the conduit corresponding to a desired treatment site inside the subject. The position of the sleeve in the subject may thus be determined relative to sleeve's position on the conduit.

[0076] Exemplary device 130 is configured to be inserted into the body of a subject such that conduit 132 accesses the interior. In various embodiments, sleeve 135 is positioned around a circumference of the conduit adjacent insertion end 133 such that it is positioned within the inner walls of the epidermis when emplaced. In various embodiments, sleeve 135 is configured to promote sealing to the opening in the epidermis or tissue walls such that fluids are inhibited from escaping around the outer periphery of the device when emplaced. In various embodiments, sleeve 135 is configured to attach to the tissue walls for sealing thereto.

[0077] In various embodiments, sleeve 135 is removable from conduit 132. The sleeve member may be configured to maintain the access opening after removal of the conduit. In various embodiments, the sleeve is substantially rigid such that it limits closing of the opening in the tissue walls.

[0078] In various embodiments, device 130 does not include conduit 132. Instead, the device includes sleeve 135 without an inner conduit. The sleeve may be relatively rigid or include other devices to maintain a desired shape.

[0079] In various embodiments, sleeve 135 is formed of a biocompatible elastomeric material. The material may have sufficient elasticity to promote engagement with the outer surface of the conduit and bending during use. [0080] In various embodiments, the conduit and sleeve are in fluid engagement. By "fluid engagement" it is meant that at least some fluid from one body contacts the other body. The amount of fluid between the conduit and sleeve will generally vary depending on the application. In some applications, it will be desirable to have a higher proportion of fluid passing through the sleeve to promote tissue growth along the sleeve. The fluid may contact only the inner surface of the sleeve, may pass completely through the sleeve, or may only permeate a portion of the sleeve walls.

[0081] Exemplary conduit 132 is sufficiently porous to allow at least a portion of the fluid flowing therethrough to leak through the conduit walls to sleeve 135. The conduit may be formed of a porous material or may be configured with openings or the like to allow fluid to pass through the walls.

[0082] In various embodiments, sleeve 135 is configured to seal porous conduit 132 to prevent leakage of the fluid flowing therethrough. By "seal" it is meant that the sleeve substantially, or mostly, prevents the fluid from flowing through the sleeve walls to the environment as would be understood in the mechanical or biochemical arts. In some aspects, "seal" may refer to preventing more than about 10% of the fluid from escaping. Although some fluid may pass through, it will be understood that the amount of fluid leakage will be functionally negligible and dependent on the parameters of the application. For example, in the case of dialysis, leakage will generally negatively affect performance and lead to complications. In some applications, it may be desirable for fluid to permeate all or a part of the sleeve but not exit from the sleeve. By "leakage" it is meant that the fluid or substance passes through the material. In various embodiments, the sleeve is configured to allow the fluid to pass through and retain the fluid on the sleeve's outer surface. "Seal" may also refer to the ability to contain or maintain pressure inside the body of the conduit.

[0083] The porosity of device 130 refers to the amount of fluid that escapes from the device. While exemplary conduit 132 has a porosity allowing at least some fluid to pass through and contact sleeve 135, the overall porosity of the device is largely affected by the sealing of the sleeve. In applications where the sleeve is directly emplaced on a target conduit, such as diseased vessel, the porosity of the device is the generally the same as the porosity of the sleeve. The application of treatments and use of other components may also affect the porosity of the device. In various embodiments, the device has a sufficient porosity to reduce seroma formation. In various embodiments, the device is essentially not porous thereby preventing seroma formation.

[0084] In various embodiments, sleeve 135 is only loosely sealed to conduit 132 or biological body. In this case, the sleeve is attached to the surface of the conduit such that fluid is generally directed through the interior of the conduit or body with only minimal fluid passing in a direction transverse to the fluid flow and into the sleeve body. In various embodiments, the sleeve and/or conduit are configured to regulate the amount of fluid leakage through the conduit walls.

[0085] In various embodiments, the sleeve is configured to promote or allow a determined amount of fluid to leak. For example, the fluid passing through the device may have medical benefits at the target site, such as for healing. The amount of fluid to be released may be an absolute amount or a rate of flow.

[0086] In various embodiments, sleeve 135 is configured to allow a sufficient amount of fluid to permeate the sleeve for tissue in-growth but an insufficient amount of fluid to permit substantial or a harmful amount of fluid leakage into the

surrounding tissue. In various embodiments, the sleeve is deployed to a vessel or tissue wall and is configured to be in fluid engagement with the body to which it is attached.

[0087] Suitable materials for sleeve 135 include, but are not limited to, the biabsorbable and biocompatible materials and structures described herein. Various aspects of device 130 are directed to employing materials and structures such as those described herein. Tissue engineering involves the use of materials and structures to improve or replace biological functions. An example of these materials and structures are polymer scaffolds such as those described herein. These polymer scaffolds can be fibrous polymer scaffolds, such as micro fiber polymer scaffolds or nanofiber polymer scaffolds. These polymer scaffolds can also be micropatterned polymer scaffolds. The materials or polymer scaffolds of the invention can optionally be aligned or can optionally be formed into a shape, such as a sheet, conduit, rod or filled conduit. The materials or polymers of the invention can also optionally include materials such as cells, bioactive agents, and/or a pharmaceutically acceptable excipient. These alignments, shapes, and additional components can aid in the improvement or replacement of biological function.

[0088] To this end, various components of device 130 may be formed of and/or various surfaces of the device may be wrapped with a biocompatible polymer layer composed of one or more polymers such as those described herein. In various embodiments, the device is composed entirely of a biocompatible polymer.

[0089] In various embodiments, device 130 is formed of a biocompatible polymer similar to those described in greater detail herein. In various embodiments, sleeve 135 comprises one or more of: polyurethane, silicon rubber, poly(lactide),

poly(glycolide), and poly(caprolactone). The exemplary sleeve is formed of poly(lactide) nanofibers. In various embodiments, the polymer fibers are aligned to adjust arterial/venous pressure. In various embodiments, the fibers of the fibrous polymer may be aligned in the longitudinal direction or the circumferential direction.

[0090] In an exemplary embodiment, the sleeve is made from one monomer or subunit, for example, lactic or polylactic acid, or glycolic or polyglycolic acid can be utilized to form materials made of poly(lactide) (PLA) or poly(L-lactide) (PLLA) or poly(glycolic acid). The polymer layer can also be made from more than one polymer thus forming a co-polymer, terpolymer, etc. For example, lactic or polylactic acid and be combined with glycolic acid or polyglycolic acid to form the copolymer poly(glycolide-co-lactide) (PGLA). Other copolymers of use in the invention include poly(ethylene-co-vinyl) alcohol). [0091] In various embodiments, the sleeve comprises a monomer or subunit which is a member selected from polydimethylsiloxane, polylactic acid, polyglycolic acid, polycaprolactone, polyethylene glycol, collagen, elastin, alginate, fibrin, hyaluronic acid. In various embodiments, the polymer layer comprises two different monomers or subunits which are members selected from polydimethylsiloxane, polylactic acid, polyglycolic acid, polycaprolactone, polyethylene glycol, collagen, elastin, alginate, fibrin and hyaluronic acid. In various embodiments, the sleeve comprises three different monomers or subunits which are members selected from

polydimethylsiloxane, polylactic acid, polyglycolic acid, polycaprolactone, polyethylene glycol, collagen, elastin, alginate, fibrin and hyaluronic acid.

[0092] In various embodiments, the conduit is formed of one of the above polymer materials. In various embodiments, the sleeve and/or conduit is formed of a fibrous polymer scaffold comprising a number of different types of fibers, and this number is a member selected from one, two, three, four, five, six, seven, eight, nine and ten.

[0093] In various aspects, the invention provides a device formed of a composition comprising a fibrous polymer scaffold such as those further described herein. A fibrous polymer scaffold includes a fiber or fibers which can have a range of diameters.

[0094] In various embodiments, the polymer fibers forming sleeve 135 and/or conduit 132 have an average diameter which is a member selected from between about 100 microns and about 50 centimeters, or between about 100 microns and about 5 millimeters, or between about 0.3 millimeters and about 1 millimeter, or between about 0.5 millimeters and about 4 millimeters, or between about 0.3 millimeters and about 3 millimeters. In an exemplary embodiment, the device is mechanically durable. By "mechanically durable" it is meant an object or material having relatively high hardness and strength. For example, the device may comprise a rigid structured material, such a rigid nanostructured material. In various embodiments, a portion of the walls of the device comprise a rigid laminate structure. [0095] In various embodiments, at least one of sleeve 135 and conduit 132 is formed of polymer fiber scaffolds that are biodegradable. The biodegradable polymers may comprise a monomer which is a member selected from lactic acid and glycolic acid. In an exemplary embodiment, the biodegradable polymers are poly(lactic acid), poly(glycolic acid) or a copolymer thereof. The biodegradable polymers may be those which are approved by the FDA for clinical use, such as poly(lactic acid) and poly(gly colic acid). In an exemplary embodiment, the biodegradable polymer materials can be used to guide the morphogenesis of engineered tissue and gradually degrade after the assembly of the tissue. The degradation rate of the polymers can be tailored by one of skill in the art to match the tissue generation rate. For example, if a polymer that biodegrades quickly is desired, an approximately 50:50 PLGA combination can be selected. Additional ways to increase polymer scaffold biodegradability can involve selecting a more hydrophilic copolymer (for example, polyethylene glycol), decreasing the molecular weight of the polymer, as higher molecular weight often means a slower degradation rate, and changing the porosity or fiber density, as higher porosity and lower fiber density often lead to more water absorption and faster degradation. In an exemplary embodiment, the tissue is vascular tissue.

[0096] In various embodiments, the inner surface of the sleeve is configured with an enhanced mechanical surface to promote engagement with an outer surface of the target conduit. For example, the inner surface of the sleeve may be relatively rigid or have a texture to promote engagement. The enhanced mechanical surface promotes positioning and/or fixation on the target conduit while reducing the time to homeostasis after cannulation.

[0097] In various embodiments, device 130 is treated with or conjugated to additional materials. In various embodiments, the device is treated with or conjugated to an anti-coagulation agent, pro-thrombotic agent to promote blood clotting and reduce hematoma formation, and/or antibiotic to reduce cell proliferation. In various embodiments, the device is treated with or conjugated to at least one of heparin and hirudin or an antimicrobial composition. In various embodiments, the device is treated with or conjugated to heparin. In various embodiments, the device is treated with at least one of sirolimus and paclitaxel. In one embodiment, sleeve 135 carries a biochemical or pharmaceutical agent and conduit 132 is configured to deliver the sleeve to a precise location within a vessel or body of a subject.

[0098] In various embodiments, the device— the sleeve and/or conduit— is covered with electrospun nanofibers of extracellular matrix (ECM), collagen, or both. The nanofiber layer may be configured to increase the sealability upon puncturing or piercing of the conduit. The nanofiber coating may also enhance adventitial tissue growth thereby improving sealing and healing.

[0099] In various embodiments, sleeve 135 is configured to be relatively rigid to promote stability of the device for tissue growth. The sleeve may also be configured to be relatively hard to protect the conduit thereby reducing the risk of infection and the like from accidental disconnection or damage to conduit 132.

[0100] In various embodiments, the sleeve is configured to be removed from the conduit at a treatment site. As described herein, the sleeve may be formed of biocompatible polymer material to promote tissue growth thereby providing a stable, fixed device for further treatment. For example, the sleeve may provide a permanent or temporary location for subsequent connection of catheters, dialysis tubes, and the like without having to make further incisions.

[0101] The method of making the device in accordance with the present invention can now be described. In an exemplary embodiment, device 130 is formed by electrospinning polymer fibers. A detailed description of an electrospinning apparatus is provided in Zong, et al, Polymer, 43(16):4403-4412 (2002). In short, the polymer solution is delivered by a programmable pump to the exit hole of the electrode (spinneret) which is connected with a positive high- voltage supply to generate a high electric field between the spinneret and a grounded substrate such as a collecting plate, mandrel, or contact surface. Additional electrospinning techniques are described in Rosen et al, Annals of Plastic Surgery., 25:375-87 (1990); Kim, K., Biomaterials 2003, 24, (27), 4977-85; and Zong, X., Biomaterials 2005, 26, (26), 5330-8. After electrospinninng, extrusion and molding can be utilized to further fashion the polymers. To modulate the organization of nanofibers into an aligned fibrous structure, post-processing methods may be performed as described herein. Further details regarding the electrospinning process and post-processing methods may be found in WO/2007/090102, WO/2007/146261, WO/2008/154608, and US 2010/0070020 Al .

[0102] In various embodiments, biocompatible sleeve 135 is formed by

electrospinning biocompatible fibers on an exterior surface of conduit 132 to a sufficient thickness such that the fibers form a substantially rigid member around the conduit. Alternatively, the sleeve may be formed on a mandrel and thereafter assembled on the conduit.

[0103] The sleeve may be attached to the conduit using various techniques. The term "attached," as used herein, encompasses interaction including, but not limited to, covalent bonding, ionic bonding, chemisorption, physisorption, mechanical fastening and combinations thereof.

[0104] In various embodiments, the sleeve is removably and/or adjustably secured to the conduit. In various embodiments, the sleeve is secured to the conduit by a mechanical fastener such as interference fit, hook-and-loop fasteners, sutures, and the like. Such techniques include, but are not limited to, mechanical expansion of the sleeve and deployment over the conduit and use of lubricants to facilitate sliding of the sleeve over the conduit.

[0105] The sleeve may also be configured such that it can be expanded from a first size to a larger second size, positioned over the conduit, and then shrunk to the first size for attachment. In various embodiments, the sleeve is secured to the conduit by chemical bonding or affinity, adhesives, and the like. In various embodiments, the sleeve is split open and wrapped around a body or the conduit. In this manner, the sleeve may be configured to fit devices of a variety of sizes and shapes.

[0106] The sleeve may be secured to the conduit using biocompatible glue. In various embodiments, the sleeve is secured to a vascular conduit by applying biocompatible glue over a predetermined length of the conduit.

[0107] In various embodiments, the sleeve is configured to fasten to conduit 132 by interference fit. In various embodiments the sleeve is formed of an elastic, tacky material and has an inner diameter slightly smaller than the outer diameter of the conduit such that the sleeve clings to the conduit.

[0108] As noted above, device 130 does not necessarily include conduit 132. The sleeve may be configured to be placed over other materials or devices, such as an artery wall. In various embodiments, sleeve 135 is positioned directly at a treatment site. For example, the sleeve may be placed over a blood vessel or on a tissue wall. The sleeve may be attached using techniques similar to those above.

[0109] Exemplary sleeve 135 is thermo-reactive. The sleeve is positioned on conduit 132 and tightens and/or binds to the conduit by the application of heat.

[0110] In the exemplary embodiment, conduit 132 is formed of ePTFE and sleeve 135 is formed of polyurethene nanofibers. The sleeve is positioned over the conduit and placed in an environment about 120°C to form device 130.

[0111] At various stages in the manufacturing process, the conduit and/or sleeve may be treated with a drug treatment or other treatment. In various embodiments, at least one of the conduit and the sleeve are treated with a low concentration of polyurethane solution.

[0112] One will appreciate that the configuration of device 130 may vary. In various embodiments, the polymer fibers forming the sleeve are integrated with/into the conduit to form a substantially monolithic device. [0113] One will further appreciate from the foregoing that the application of device 130 may be varied simply and easily by positioning the sleeve over different types of surgical and medical devices that would benefit from the enhanced biocompatibility of the sleeve. For example, sleeve 135 may be configured for use with a catheter, stent, fistula, or other device instead of exemplary conduit 132.

[0114] Referring to FIGs. 3A-3B, a device 130' similar to that of device 130 is shown. Device 130' is a vascular graft including a sleeve 135' similar to that of sleeve 130 and positioned over a conduit 132'. In the exemplary device, a single sleeve 135' is provided over the conduit. The sleeve is formed into a tape and spirally wrapped around the conduit. As shown in FIG. 3B, the conduit is hollow and the sleeve is formed as a separate member around the conduit wall. Alternatively, the sleeve may be wrapped around a graft, blood vessel or other body.

[0115] FIG. 4 illustrates a device 130" similar to that of device 130. Device 130" is a vascular graft including a sleeve 135" similar to that of sleeve 130 positioned over a sleeve delivery conduit 132". In the exemplary device, sleeve 135" and conduit 132" are configured similar to sleeve 135 and conduit 132 except that the device includes a polyurethane (PU) coating 137 over about 2%-3% of the thickness of the graft. The coating thus forms an intermediate layer between the conduit and sleeve. Additionally, device 130" has been heated to a temperature of about 141°C for approximately 45 minutes in contrast to device 130. Exemplary device 130" exhibits improved performance for regeneration of connective tissue such as adventitia.

[0116] FIGs. 5A-5B illustrate the polymer fibers comprising the sleeve of device 130'. FIG. 5C illustrates the fibers conduit forming conduit 132" and PU coating 137. FIG. 5D illustrates the fibers of conduit 132".

[0117] The device in accordance with the present invention may be used in a variety applications. One will appreciate that the configuration of device 130 may vary depending on the application. [0118] In various embodiments, the device is a drug-eluting device including a drug agent provided on at least one surface of the device. In various embodiments, the conduit is configured to be guided to a treatment location where the drug may be released. In various embodiments, the device is configured to deliver a plaque- dissolving drug to a site internal to the subject.

[0119] In various embodiments, the device is configured to be positioned at an anastomotic suture site. In this case, the conduit is configured similar to a

conventional PTFE graft which is sutured to the site, and the sleeve is configured to promote blood clotting. The provision of the sleeve thus reduces bleeding associated with the procedure, reduces medical complications, and enhances tissue growth among other advantages.

[0120] In various embodiments, the sleeve is configured to reduce bleeding and the device is configured for use in a trauma procedures. This can be useful in emergency rooms or where hospital services are not readily available such as in the battlefield. In lieu of attaching sleeve 135 to conduit 132, the sleeve is delivered to a treatment site, such as a portion of a native artery. The sleeve may be wrapped or otherwise attached to the artery. The sleeve may be delivered using the conduit or other techniques.

[0121] In various embodiments, sleeve 135 is used as an "Introducer Sheath" for Percutaneous Intraspinal Navigation (PIN) access. The sleeve of the present inventions may be used as a safety sheath for navigational devices including, but not limited to, a guide wire, catheter, and fenestration device without replacing or removing CSF. The porosity of the device helps the fluid flowing through the conduit to soak in and thus reduces the risk of CSF displacement.

[0122] The device in accordance with the present invention provides several advantages including: (1) The fibrous polymer scaffold mimics the native matrix fibrils for cell adhesion and migration; (2) The fibrous polymer scaffold allows vessel remodeling and restoration; (3) The aligned fibrous polymer scaffold limits overgrowth of smooth muscle cells; (4) The aligned fibrous polymer scaffold promotes endothelial migration and wound healing; (5) The aligned fibrous polymer scaffold increases the surface/volume ratio and drastically increases the efficiency and capacity of drug delivery; and (6) The fibrous polymer scaffold can be used as a platform to deliver stem cells.

[0123] Additionally, the device in accordance with the present invention provides other advantages over conventional devices, such as vascular grafts and dialysis tubes. In comparison to conventional grafts and catheters, the sleeve and device in accordance with the present invention exhibits reduced time to homeostasis after cannulation.

[0124] Furthermore, the device in accordance with the invention may reduce the risk of biological trauma and mechanical tissue abrasion involved with insertion into a biological body. The materials and structures forming the device may also provide enhanced tissue growth and reduced risk of infection.

[0125] For convenience in explanation and accurate definition in the appended claims, the terms "upper" or "lower", "front" or "rear", "inside" or "outside", and etc. are used to describe features of the inventions with reference to the positions of such features as displayed in the figures.

Fibrous Sleeve

[0126] In various embodiments, sleeve 135 is a fibrous polymer sleeve. "Fibrous" and "fibrous structure" refer to an element formed of one or more fibers. In various embodiments, the sleeve is formed of electrospun poly(urethane) fiber. "Fiber" refers to one or more fibers. In various embodiments, the sleeve is formed of polymer fibers in random alignment. In various embodiments, the sleeve is formed from a continuous fiber. In various embodiments, the plurality of polymer fibers are aligned in the longitudinal direction or the circumferential direction. In various embodiments, the sleeve is monolithically formed. [0127] A variety of materials can be used to form the sleeve including synthetic and/or natural sources. In an exemplary embodiment, the sleeve is formed from electrospun poly(urethane) fibers.

[0128] Sleeve 135 is defined by a wall structure. One will appreciate that the sleeve may be formed of a single electrospun fiber, such as a continuous filament, or may be formed of a plurality of fibers. One will appreciate that the actual wall thickness of the sleeve may not be uniform because of the inherent nature of the fibrous structure. The electrospinning system may be adjusted to increase or decrease the variation in the wall structure.

[0129] In various embodiments, the wall structure has an average thickness of approximately 0.9 mm. In various embodiments, the wall structure has an average thickness of approximately 0.7 mm. In various embodiments, the wall structure is homogenous and has substantially uniform porosity. In various embodiments, the wall structure is formed by two or more layers of materials, such as two layers of electrospun polymer fibers.

[0130] In a first aspect, the invention provides a sleeve which comprises at least one layer composed of plurality of polymer fibers. A fibrous polymer layer includes a fiber or fibers which can have a range of diameters. In an exemplary embodiment, the average diameter of the fibers in the fibrous polymer layer is in the nanodiameter range. In various embodiments, the diameter is from about 0.1 nanometers to about 50000 nanometers. In another exemplary embodiment, the average diameter of the fibers in the fibrous polymer layer is from about 25 nanometers to about 25,000 nanometers. In an exemplary embodiment, the average diameter of the fibers in the fibrous polymer layer is from about 50 nanometers to about 20,000 nanometers. In an exemplary embodiment, the average diameter of the fibers in the fibrous polymer layer is from about 100 nanometers to about 5,000 nanometers. In an exemplary embodiment, the average diameter of the fibers in the fibrous polymer layer is from about 1,000 nanometers to about 20,000 nanometers. In an exemplary embodiment, the average diameter of the fibers in the fibrous polymer layer is from about 10 nanometers to about 1,000 nanometers. In an exemplary embodiment, the average diameter of the fibers in the fibrous polymer layer is from about 2,000 nanometers to about 10,000 nanometers. In an exemplary embodiment, the average diameter of the fibers in the fibrous polymer layer is from about 0.5 nanometers to about 100 nanometers. In an exemplary embodiment, the average diameter of the fibers in the fibrous polymer layer is from about 0.5 nanometers to about 50 nanometers. In an exemplary embodiment, the average diameter of the fibers in the fibrous polymer layer is from about 1 nanometer to about 35 nanometers. In an exemplary

embodiment, the average diameter of the fibers in the fibrous polymer layer is from about 2 nanometers to about 25 nanometers. In an exemplary embodiment, the average diameter of the fibers in the fibrous polymer layer is from about 90 nanometers to about 1,000 nanometers. In an exemplary embodiment, the average diameter of the fibers in the fibrous polymer layer is from about 500 nanometers to about 1,000 nanometers.

[0131] In an exemplary embodiment, the fibrous sleeve is formed from one or more a nano fiber or micro fiber polymer layers. Micro fiber polymer layers have micron- scale features (an average fiber diameter between about 1 ,000 nanometers and about 50,000 nanometers, and in various embodiments between about 1,000 nanometers and about 20,000 nanometers), while nanofiber polymer layers generally have submicron- scale features (an average fiber diameter between about 10 nanometers and about 1,000 nanometers, and in various embodiments between about 50 nanometers and about 1,000 nanometers).

[0132] In an exemplary embodiment, the average diameter of the fibers in the fibrous polymer layer is in the microdiameter range. In an exemplary embodiment, the fibers have an average diameter in the range selected from between about 100 nanometers to about 8 micrometers, from about 500 nanometers to about 5 micrometers, and from about 1 micrometer to about 3 micrometers. One will appreciate that the dimensions and configuration of the fibers in the fibrous polymer elements of the device may vary depending on the application. Each of these polymer layers can resemble the physical structure at the area of treatment, such as native collagen fibrils or other extracellular matrices.

[0133] In some embodiments, the fibrous sleeve is composed of a single continuous fiber. In other embodiments, the fibrous sleeve is composed of at least two, three, four, five, or more fibers. In an exemplary embodiment, the number of fibers in the fibrous sleeve is a member selected from 2 to 100,000. In an exemplary embodiment, the number of fibers in the fibrous sleeve is a member selected from 2 to 50,000. In an exemplary embodiment, the number of fibers in the fibrous sleeve is a member selected from 50,000 to 100,000. In an exemplary embodiment, the number of fibers in the fibrous sleeve is an integer between about 10 and about 20,000. In an exemplary embodiment, the number of fibers in the fibrous sleeve is an integer between about 15 and about 1,000.

[0134] The fibrous polymer sleeve can comprise a fiber of at least one composition. In an exemplary embodiment, the fiber or fibers of the fibrous polymer sleeve are biodegradable.

[0135] In an exemplary embodiment, the device includes biodegradable polymers. Biodegrable polymers are those which are approved by the FDA for clinical use. In another exemplary embodiment, biodegradable polymer layers are used to guide the morphogenesis of engineered tissue and gradually degrade after the assembly of the tissue. The degradation rate of the polymers can be tailored by one of skill in the art to match the tissue generation rate. Additional ways to increase polymer layer biodegradability can involve selecting a more hydrophilic copolymer (for example, polyethylene glycol), decreasing the molecular weight of the polymer, as higher molecular weight often means a slower degradation rate, and changing the porosity or fiber density, as higher porosity and lower fiber density often lead to more water absorption and faster degradation. In another exemplary embodiment, the tissue is vascular tissue. Covering Composition and Bioactive Agent

[0136] Exemplary device 130 includes a covering composition 35 which covers at least one of the electrospun fibers of sleeve 135. The exemplary covering

composition includes polymer primer 36 which covers or coats the fibers. In various embodiments, the covering composition further includes a bioactive agent 41

conjugated to the polymer primer through a linker molecule 43. Thus, the exemplary linker molecule and bioactive agent effectively coat the fibers via the polymer primer. See FIG. 6B.

[0137] In various embodiments, the polymer primer coats all of the fibers of the sleeve. In various embodiments, each individual fiber is coated or encapsulated by the polymer primer.

[0138] In various embodiments, the covering composition covers all of the fibers of the sleeve. In various embodiments, each individual fiber is coated, encapsulated, or covered by the covering composition.

[0139] Suitable materials for the polymer primer include, but are not limited to, bioabsorbable polymers. In various embodiments, the polymer primer is formed of a poly(lactide). In various embodiments, the polymer primer includes poly (D,L- lactide) ("PDLA"). In various embodiments, at least one of the polymer primer and sleeve is biodegradable.

[0140] Exemplary bioactive agent 41, which is conjugated to polymer primer 36, serves to functionalize the coated fiber. In various embodiments, the bioactive agent and linker molecule are referred to as layers formed on top of the polymer primer layer.

[0141] In various embodiments, the bioactive agent is conjugated to the polymer primer through a linker molecule. As will be discussed below, the conjugation may be accomplished by the use of linker molecules, catalysts, and/or coupling agents. In various embodiments, a heparin residue is conjugated to a PDLA polymer primer through at least one linker. In various embodiments, heparin is covalently bonded to a PDLA polymer primer through a di-amino poly(ethylene glycol) ("PEG") linker.

[0142] In various embodiments, the covering composition includes a polymer primer functionalized with a bioactive agent. In various embodiments, the covering composition comprises poly(lactide) and has the formula:

wherein A is a heparin residue, n is an integer between about 1000 and about 10000, and m is an integer between about 50 and about 100. One will appreciate that m and n can be chosen based on a variety of commercially available products. In various embodiments, m is an integer in a range selected from between about 1 and about 500, between about 50 to about 100, about 60 to about 85, and about 66 to about 83. In various embodiments, the average value of m is about 74. In various embodiments, n is an integer in a range selected from between about 1000 to about 700000, between about 3000 to about 10000, between about 4000 to about 8500, and between about 4100 and about 7300. In various embodiments, the average value of n is about 7250. In various embodiments, n is of a sufficient number to provide an average inherent viscosity midpoint in a range selected from between about 0.1 to about 6.0 dL/g, between about 1 to about 4 dL/g, and between about 1.6 to about 2.4 dL/g, at room temperature. In various embodiments, n is of a sufficient number to provide an average inherent viscosity midpoint of about 2.0 dL/g at room temperature.

[0143] In various embodiments, the polymer primer comprises PDLA and a linker molecule is immobilized to an end of the PDLA. In various embodiments, the linker molecule has a molecular weight in a range selected from the group consisting of between about 1000 g/mol and about 10000 g/mol, between about 2500 g/mol and about 4500 g/mol, between about 2800 g/mol and about 4000 g/mol, between about 3000 g/mol and about 3700 g/mol. In various embodiments, the linker is PEG and has a molecular weight of about 3350 g/mol. In various embodiments, the polymer primer has a molecular weight in a range selected from the group consisting of between about 1000 g/mol and about 800000 g/mol, between about 200000 g/mol and about 600000 g/mol, between about 250000 g/mol and about 550000 g/mol, between about 290000 g/mol and about 530000 g/mol. In various embodiments, the polymer primer has a molecular weight of about 406000 g/mol.

[0144] Exemplary bioactive agent 41 is conjugated to the polymer primer 36 through a linker. In various embodiments, the linker is a polymer or subunit which is a member selected from an aliphatic polyester, a polyalkylene oxide, and

combinations thereof.

[0145] In an exemplary device, each fiber is coated with poly(lactide) (PLA) and functionalized with a heparin residue via a linker molecule. In various embodiments, the linker molecule is PEG. The PEG is immobilized to the surface of the

poly(lactide) primer layer using carbodiimide chemistry (i.e., activation of free carboxylic acid residues of the PLA coating with a coupling agent and subsequent reaction with one of the functional ends of di-amino PEG). In various embodiments, the heparin residue is conjugated to the linker molecule using carbodiimide chemistry (i.e., activation of free carboxylic acid residues on the heparin and subsequent reaction with the remaining functional end of the immobilized linker molecule). In various embodiments, the linker molecule tethers the heparin from the surface of the respective polymer fiber.

[0146] In various embodiments, the linker molecule is PEG, and the PEG is immobilized to the surface of the poly(lactide) coating layer. The PEG is of linear structure and has an average molecular weight of 3350 g/mol. The average molecular weight of the PEG may be between about 1000 and 10,000 g/mol. In various embodiments, the heparin residue is conjugated to the linker molecule using carbodiimide chemistry. In various embodiments, the linker molecule tethers the heparin from the surface of the respective polymer fiber.

[0147] In an exemplary embodiment, poly(lactide) primer layer 36 is conjugated to the fibrous sleeve by adsorption. In various embodiments, the poly(lactide) layer is integrated into the fibrous sleeve. In various embodiments, the poly(lactide) layer forms a covalent bond with the linker molecule. In various embodiments, the linker molecule forms a covalent bond with the heparin residue. In various embodiments, the bioactive agent is covalently associated with the poly(lactide) polymer primer through at least one linker molecule.

[0148] In various embodiments, polymer primer 36 is an aliphatic polyester that is linear or branched. In an exemplary embodiment, the linear aliphatic polyester is a member selected from lactic acid (D- or L-), lactide, poly(lactic acid), poly(lactide) glycolic acid, poly(lactide-co-glycolide), poly(lactic acid-co-glycolic acid), and combinations thereof. In another exemplary embodiment, the aliphatic polyester is branched and comprises at least one member selected from lactic acid (D- or L-), poly(D,L-lactide), lactide, poly(lactic acid), poly(lactide), poly(lactide-co-glycolide), poly(lactic acid-co-glycolic acid), and combinations thereof which is conjugated to a linker or a bioactive agent. In an exemplary embodiment, the polyalkylene oxide is a member selected from polyethylene oxide, polyethylene glycol, polypropylene oxide, polypropylene glycol and combinations thereof.

[0149] In some embodiments, the bioactive agent is utilized to promote the growth of new tissue. In an exemplary embodiment, the bioactive agent is a member selected from heparin, heparin sulfate, heparin sulfate proteoglycan and combinations thereof. In various embodiments, "heparin residue" may refer to clinical analogs such as antiplatelet agents. Other agents that are useful in conjunction with the present invention will be readily apparent from the description herein to those of skill in the art. In various embodiments, the bioactive agent is a heparin residue such as heparin sodium. Heparin is a biological substance, sometimes made from pig intestines. It works by activating antithrombin III, which blocks thrombin from clotting blood. In an exemplary embodiment, the bioactive agent is heparin or a prodrug of heparin. In an exemplary embodiment, the device includes a heparin analog or a prodrug of a heparin analog. In an exemplary embodiment, the heparin analog is a member selected from Antithrombin III, Bemiparin, Dalteparin, Danaparoid, Enoxaparin, Fondaparinux (subcutaneous), Nadroparin, Parnaparin, Reviparin, Sulodexide, and Tinzaparin.

[0150] In various embodiments, the bioactive agent that is capable of retarding or arresting the formation of intimal hyperplasia is appropriate for incorporation into the fiber of the invention. Although the discussion thus far has focused on vascular reconstructive surgery involving implanting a vascular graft, those of skill will readily appreciate that the discussion is generally applicable to other forms of vascular reconstructive surgery, angioplasty and preventing the formation of post-surgical adhesions in other organs and/or internal structures.

[0151] Polymer primer 36 may coat each or most of the respective fibers of device 130 or may be incorporated or impregnated into the fibrous structure. For example, the polymer primer may fill interstices between the fibers. "Fill interstices" refers to the polymer primer existing in the space between adjacent fibers. In an exemplary embodiment, the polymer primer covers or coats essentially all of each of the fibers and thereby fills interstices between the fibers. "Cover" is to be understood as commonly used in the chemical and biological arts and refers to covering a portion or all of an element. In an exemplary embodiment, the polymer primer covers essentially all of the fibers of the sleeve, and each fiber is substantially coated by the polymer primer. One will appreciate from the description herein that the covering composition is associated with the device by virtue of the polymer primer.

[0152] One or more of the many art-recognized techniques for immobilizing, coating, adhering, or attaching one molecule with another molecule or surface can be used to prepare the device. These methods include, but are not limited to, covalent bonding to the respective molecule or a derivative of the molecule bearing a "handle" allowing it to react with a component of the fiber having a complementary reactivity.

[0153] In various embodiments, the bioactive agent is covalently bonded to a linker molecule which is covalently bonded to the polymer primer. In various embodiments, the polymer primer is non-covalently associated with fibrous sleeve 135. Non- covalent association can also be termed "embedded" or "impregnated" and includes, but is not limited to, chemisorption, physisorption and combinations thereof.

Method of Coating with Polymer Primer and Conjugation of Bioactive Agent

[0154] An exemplary method of coating the sleeve with a polymer primer and subsequent conjugation of a bioactive agent to the polymer primer will now be described. Referring to FIG. 6B, covering composition 35 is applied to the uncoated sleeve. The uncoated sleeve is first treated with polymer primer 36 and then functionalized with a heparin residue. The exemplary covering composition includes poly(lactide) (PLA) conjugated to a heparin residue through a linker molecule. In various embodiments, the sleeve is allowed to completely dry after the

electrospinning process before coating the sleeve with the polymer primer. In various embodiments, the sleeve is allowed to partially dry after the electrospinning process before coating the sleeve with the polymer primer. The method for conjugating the polymer primer will be described in more detail below.

[0155] In various embodiments, the steps for coating the sleeve with a polymer primer and subsequent conjugation of a bioactive molecule to the polymer primer are accomplished by successive dip coating of the sleeve. FIG. 6B illustrates an exemplary fiber "F" of the fibrous sleeve which is covered with polymer primer 36 in accordance with the present invention. In general, the dip coating operations are performed with a reagent under sufficient conditions to achieve sufficient conjugation for the particular clinical application. Further details regarding the exemplary dip coating operations are provided below and in the Examples.

[0156] In the first step, the exemplary sleeve is dip coated in a polymer primer solution including poly(lactide) (PLA) in acetonitrile. The sleeve is dipped in the PLA coating under sufficient conditions to cause conjugation to a respective fiber or fibers "F". The dipped sleeve is then dried at low temperature, relatively low humidity and normal atmospheric pressure until the acetonitrile has evaporated. [0157] The exemplary sleeve is dipped in the polymer primer solution under sufficient conditions to cause the polymer primer to conjugate to the sleeve thereby forming a layer of polymer primer on the fibers (see, e.g., FIG. 6B). In various embodiments, the polymer primer layer is conjugated to the sleeve by adsorption. In the exemplary embodiment, the polymer primer layer is integrated into the sleeve and coats one or more of the fiber components of the sleeve. In various embodiments, essentially all the fibers in the sleeve are coated with the polymer primer. In various embodiments, some of the fibers in the sleeve are coated with the polymer primer.

[0158] In the second step, the exemplary coated sleeve is dip coated in a linker molecule solution including poly(ethylene glycol) ("PEG"). The sleeve is placed in the solution under sufficient conditions to cause the PEG to be immobilized to the sleeve. In various embodiments, the PEG is immobilized to the surface of the polymer primer. The PEG can be immobilized by treating it with EDC (i.e., 1-ethyl- 3(3-dimethylaminopropylcarbodiimide) to facilitate covalent bonding with the carboxyl group of the exemplary polymer primer.

[0159] The sleeve is dipped in the solution including PEG and a reagent under sufficient conditions to cause the PEG to conjugate to the polymer primer. In various embodiments, the reagent is forced to evaporate from the sleeve after the dipping. In an exemplary embodiment, EDC is added to the solution of PEG shortly before treating the sleeve. In the exemplary embodiment, the PEG is integrated into the sleeve. The PEG may conjugate to the polymer primer covering the fibers of the sleeve. In various embodiments, PEG is conjugated to essentially all of the free ends of the poly(lactide) forming the polymer primer. In various embodiments, PEG is conjugated to only a portion of the free ends.

[0160] In the third step, the sleeve is dip coated in a solution of heparin sodium. In an exemplary embodiment, EDC is added to the solution of heparin sodium shortly before treating the sleeve. In various embodiments, the heparin sodium is covalently bonded to the PEG. In an exemplary case, the PLA primer is conjugated to a surface of a fiber of sleeve 135, one end of the PEG linker is conjugated to an end of a respective PLA molecule, and an opposite end of the PEG linker is conjugated to an end of the respective heparin residue.

[0161] One will appreciate that the level and amount of conjugation of the polymer primer and/or covering composition to the respective fibrous component, the linkers to the polymer primer, and the bioactive agent to the linkers may vary depending on the application. In various embodiments, essentially all of the fibers are coated with polymer primer. "Essentially all" refers to substantially or most of the fibers and may include, for example, 100%, 95%, 90%, 80%, 70%, and 60%.

[0162] In various embodiments, the linkers are conjugated to about 100% of the polymer primer. In various embodiments, the linkers are conjugated to about 95% of the polymer primer. In various embodiments, the linkers are conjugated to about 90% of the polymer primer. Conjugation of the linkers refers to conjugation of a linker molecule to a unit of the polymer primer such as a poly(lactide) molecule. In various embodiments, linkers are conjugated to essentially all of the polymer primer.

[0163] In various embodiments, essentially 100% of each of the linkers is conjugated to a bioactive agent. In various embodiments, essentially 95% of each of the linkers is conjugated to a bioactive agent. In various embodiments, essentially 90% of each of the linkers is conjugated to a bioactive agent. In various

embodiments, essentially all of the linkers are conjugated to a bioactive agent.

[0164] In various embodiments, the linker molecule is PEG, and the PEG is immobilized to the surface of the poly(lactide) primer layer using carbodiimide chemistry (i.e., activation of free carboxylic acid residues of the PLA polymer primer with l-ethyl-3-[3-dimethylaminopropyl] carbodiimide ("EDC") and subsequent reaction with one of the functional ends of di-amino PEG). In various embodiments, the heparin residue is conjugated to the linker molecule using carbodiimide chemistry (i.e., activation of free carboxylic acid residues on the heparin with EDC and subsequent reaction with the remaining functional end of the immobilized linker molecule). In various embodiments, the linker molecule tethers the heparin from the surface of the respective polymer fiber (best seen in FIG. 6B). [0165] After addition of the bioactive agent, the sleeve is washed with Phosphate Buffered Saline and Molecular Biology Grade Water to remove any excess heparin. The sleeve may also be optionally washed after applying the polymer primer, the linker molecule layer, or both.

[0166] The exemplary coated sleeve has an intraluminal and an extraluminal surface coated by the polymer primer. In various embodiments, the covering composition is integrated into the sleeve and fills interstices between the fibers of the sleeve. The sleeve includes a first longitudinal terminus and a second longitudinal terminus.

[0167] The process for making the sleeve in accordance with the invention may include further processing operations between any of the above steps or postprocessing. For example, the sleeve may be cut and laid out into a flat sheet. The finished sleeve is dried, packaged and sterilized.

[0168] The sleeve of the invention can be formed into a variety of shapes, depending on the nature of the problem to be solved.

Conjugation of Bioactive Agent

[0169] The bioactive agent can be conjugated to the fiber(s) of the device and/or sleeve in a variety of ways. In various embodiments, the bioactive agent is conjugated to the fiber(s) of the device and/or sleeve through non-covalent mechanisms, such as hydrophobic/hydrophilic interactions, ionic bonding, physisorption etc. In various embodiments, the bioactive agent is covalently bonded to a reactive group located on one or more components of the polymer primer or fibers of the device and/or sleeve directly or through a linker molecule. Approaches for conjugating the bioactive agent include the use of coupling agents that serve as conjugation vehicles for coupling reactive groups of biologically active molecules to reactive groups on a monomer or a polymer.

[0170] Complementary reactive functional groups and classes of reactions useful in practicing the present invention are generally those in the art of bioconjugate chemistry. In various embodiments, the classes of reactions available with reactive functional groups of the invention are those which proceed under relatively mild conditions. These include, but are not limited to nucleophilic substitutions (e.g., reactions of amines and alcohols with acyl halides, active esters), electrophilic substitutions (e.g., enamine reactions) and additions to carbon-carbon and carbon- heteroatom multiple bonds (e.g., Michael reaction, Diels-Alder addition). These and other useful reactions are discussed in, for example, March, ADVANCED ORGANIC CHEMISTRY, 3rd Ed., John Wiley & Sons, New York, 1985; Hermanson,

BIOCONJUGATE TECHNIQUES, Academic Press, San Diego, 1996; and Feeney et al., MODIFICATION OF PROTEINS; Advances in Chemistry Series, Vol. 198, American Chemical Society, Washington, D.C., 1982.

[0171] Useful reactive functional groups include, for example:

(a) carboxyl groups and various derivatives thereof including, but not limited to, N-hydroxysuccinimide esters, N-hydroxybenztriazole esters, acid halides, acyl imidazoles, thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl and aromatic esters;

(b) hydroxyl groups, which can be converted to esters, ethers, aldehydes, etc.

(c) haloalkyl groups, wherein the halide can be later displaced with a

nucleophilic group such as, for example, an amine, a carboxylate anion, thiol anion, carbanion, or an alkoxide ion, thereby resulting in the covalent bonding of a new group at the site of the halogen atom;

(d) dienophile groups, which are capable of participating in Diels-Alder

reactions such as, for example, maleimido groups;

(e) aldehyde or ketone groups, such that subsequent derivatization is possible via formation of carbonyl derivatives such as, for example, imines, hydrazones, semicarbazones or oximes, or via such mechanisms as Grignard addition or alkyllithium addition;

(f) sulfonyl halide groups for subsequent reaction with amines, for example, to form sulfonamides; (g) thiol groups, which can be converted to disulfides or reacted with acyl halides;

(h) amine or sulfhydryl groups, which can be, for example, acylated,

alkylated or oxidized;

(i) alkenes, which can undergo, for example, cycloadditions, acylation,

Michael addition, etc;

(j) epoxides, which can react with, for example, amines and hydroxyl

compounds; and

(k) phosphoramidites and other standard functional groups useful in nucleic acid synthesis.

[0172] In an exemplary embodiment, the reactive functional groups are members selected from:

(a) carboxyl groups and various derivatives thereof including, but not limited to, N-hydroxysuccinimide esters, N-hydroxybenztriazole esters, acid halides, acyl imidazoles, thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl and aromatic esters; and

(b) amine groups.

[0173] The reactive functional groups can be chosen such that they do not participate in, or interfere with, the reactions necessary to assemble the compound of the invention. Alternatively, a reactive functional group can be protected from participating in the reaction by the presence of a protecting group. Those of skill in the art understand how to protect a particular functional group such that it does not interfere with a chosen set of reaction conditions. For examples of useful protecting groups, see, for example, Greene et al, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, John Wiley & Sons, New York, 1991.

[0174] In an exemplary embodiment, a carboxylic acid moiety is being conjugated to an amine moiety. First the carboxylic acid moiety is reacted with a carbodiimide to generate an O-acylisourea, which can react with the amine moiety to produce an amide which then links the two moieties. [0175] In an exemplary embodiment, conjugation of bioactive agents to the fibrous sleeve described herein can be achieved by any of several methods. For example, a bioactive agent can be conjugated by treatment with EDC (i.e., l-ethyl-3(3- dimethylaminopropylcarbodiimide), which will facilitate linkage of, for example, the amino end of linker 43 to the carboxyl group of the PLA primer layer 36 or bioactive agent 41. The linkages may be on the opposite species as well (e.g. the amino group could be on an end of the fibrous polymer). One will appreciate from the description herein that other coupling agents may be used.

[0176] Reactive groups contemplated in the practice of the present invention include functional groups, such as carboxyl, carboxylic acid, amine groups, and the like, that promote physical and/or chemical interaction with the bioactive material. The particular compound employed as the modifier will depend on the chemical functionality of the biologically active agent and can readily be deduced by one of skill in the art. In the present embodiment, the reactive site binds a bioactive agent by covalent means. It will, however, be apparent to those of skill in the art that these reactive groups can also be used to adhere bioactive agents to the polymer by hydrophobic/hydrophilic, ionic and other non-covalent mechanisms.

Bioabsorbable, Biodegradable, and Bioresorbable Fiber Materials

[0177] Polymer compositions, such as sleeve 135 and covering composition 35 may have intrinsic and controllable biodegradability, so that they persist for about a week to about six months. The fibers may also be biocompatible, non-toxic, contain no significantly toxic monomers and degrade into non-toxic components. In various embodiments, one or more of the polymer compositions is chemically compatible with the substances to be delivered and tends not to denature the active substance. In various embodiments, one or more of the polymer compositions becomes sufficiently porous to allow the incorporation of biologically active molecules and their subsequent liberation from the fiber by diffusion, erosion or a combination thereof. The polymer compositions may remain at the site of application by adherence or by geometric factors, such as by being formed in place or softened and subsequently molded or formed into fabrics, wraps, gauzes, particles (e.g., microparticles), and the like.

Linkers

[0178] In an exemplary embodiment, the linker includes a member selected from a water-soluble polymer and a water-insoluble polymer. In another exemplary embodiment, the linker includes a member selected from polyphosphazines, poly(vinyl alcohols), polyamides, polycarbonates, polyalkylenes, polyacrylamides, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate),

poly(octadecyl acrylate) polyethylene, polypropylene, poly(ethylene glycol), poly(ethylene oxide), poly(ethylene terephthalate), poly(vinyl acetate), polyvinyl chloride, polystyrene, polyvinyl pyrrolidone, pluronics, polyvinylphenol, saccharides

(e.g., dextran, amylose, hyalouronic acid, poly(sialic acid), heparans, heparins, etc.); poly (amino acids), e.g., poly(aspartic acid) and poly(glutamic acid); nucleic acids and copolymers thereof. In an exemplary embodiment, the linker includes a member selected from polyethylene glycol (PEG) and polypropylene glycol (PPG) , or a mixture thereof. In another exemplary embodiment, the PEG or PPG comprises a number of monomeric subunits which is an integer from 1 to 5000. In an exemplary embodiment, said number of monomeric subunits is an integer from about 10 to about

1000. In an exemplary embodiment, said number of monomeric subunits is an integer from about 10 to about 500. In an exemplary embodiment, said number of monomeric subunits is an integer from about 20 to about 400. In an exemplary embodiment, said number of monomeric subunits is an integer from about 20 to about

250. In an exemplary embodiment, said number of monomeric subunits is an integer from about 50 to about 200. In an exemplary embodiment, said number of monomeric subunits is an integer from about 50 to about 125. In an exemplary embodiment, said number of monomeric subunits is an integer from about 50 to about 100. In an exemplary embodiment, said number of monomeric subunits is an integer from about 60 to about 90. In an exemplary embodiment, said number of monomeric subunits is an integer from about 60 to about 90. In an exemplary embodiment, said linker is a member selected from di-amino poly(ethylene glycol), poly(ethylene glycol) and combinations thereof.

Materials and Structures

[0179] These materials and structures can comprise polymer scaffolds. These polymer scaffolds can be fibrous polymer scaffolds, such as microfiber polymer scaffolds or nanofiber polymer scaffolds. These polymer scaffolds can also be micropatterned polymer scaffolds. The materials and/or polymer scaffolds of the invention can optionally be unaligned or they can be aligned, such as longitudinally or circumferentially. The materials and/or polymer scaffolds of the invention can optionally be formed into a shape, such as a sheet, criss-cross sheet, conduit, rod or filled conduit. The materials and/or polymer scaffolds of the invention can have a seam or they can be seamless. The materials or polymers of the invention can also optionally include materials such as a cell, a bioactive agent, or a pharmaceutically acceptable excipient. These alignments, shapes, and additional components can aid in the improvement or regeneration or replacement of biological function. The materials of the invention do not include a stent. The materials can be used in tissue engineering to improve, regenerate or replace biological functions.

Fibrous Polymer Scaffolds

[0180] In a first aspect, the invention provides a material which comprises a fibrous polymer scaffold. A fibrous polymer scaffold includes a fiber or fibers which can have a range of diameters. In an exemplary embodiment, the average diameter of the fibers in the fibrous polymer scaffold is from about 0.1 nanometers to about 50000 nanometers. In another exemplary embodiment, the average diameter of the fibers in the fibrous polymer scaffold is from about 25 nanometers to about 25,000

nanometers. In an exemplary embodiment, the average diameter of the fibers in the fibrous polymer scaffold is from about 50 nanometers to about 20,000 nanometers. In an exemplary embodiment, the average diameter of the fibers in the fibrous polymer scaffold is from about 100 nanometers to about 5,000 nanometers. In an exemplary embodiment, the average diameter of the fibers in the fibrous polymer scaffold is from about 1,000 nanometers to about 20,000 nanometers. In an exemplary embodiment, the average diameter of the fibers in the fibrous polymer scaffold is from about 10 nanometers to about 1,000 nanometers. In an exemplary embodiment, the average diameter of the fibers in the fibrous polymer scaffold is from about 2,000 nanometers to about 10,000 nanometers. In an exemplary embodiment, the average diameter of the fibers in the fibrous polymer scaffold is from about 0.5 nanometers to about 100 nanometers. In an exemplary embodiment, the average diameter of the fibers in the fibrous polymer scaffold is from about 0.5 nanometers to about 50 nanometers. In an exemplary embodiment, the average diameter of the fibers in the fibrous polymer scaffold is from about 1 nanometer to about 35 nanometers. In an exemplary embodiment, the average diameter of the fibers in the fibrous polymer scaffold is from about 2 nanometers to about 25 nanometers. In an exemplary embodiment, the average diameter of the fibers in the fibrous polymer scaffold is from about 90 nanometers to about 1,000 nanometers. In an exemplary embodiment, the average diameter of the fibers in the fibrous polymer scaffold is from about 500 nanometers to about 1,000 nanometers.

[0181] In an exemplary embodiment, the fibrous polymer scaffold is a member selected from a nano fiber polymer scaffold and a micro fiber polymer scaffold.

Micro fiber polymer scaffolds have micron-scale features (an average fiber diameter between about 1,000 nanometers and about 50,000 nanometers, and especially between about 1,000 nanometers and about 20,000 nanometers), while nano fiber polymer scaffolds have submicron-scale features (an average fiber diameter between about 10 nanometers and about 1,000 nanometers, and especially between about 50 nanometers and about 1,000 nanometers). Each of these polymer scaffolds can resemble the physical structure at the area of treatment, such as native collagen fibrils or other extracellular matrices.

[0182] A variety of polymers from synthetic and/or natural sources can be used to compose these fibrous polymer scaffolds. A fiber can be made from one monomer or subunit. For example, lactic or polylactic acid or glycolic or polyglycolic acid can be utilized to form poly(lactide) (PLA) or poly(L-lactide) (PLLA) nanofibers or poly(glycolide) (PGA) nanofibers. Fibers can also be made from more than one monomer or subunit thus forming a co-polymer, terpolymer, etc. For example, lactic or polylactic acid and be combined with glycolic acid or polyglycolic acid to form the copolymer poly(lactide-co-glycolide) (PLGA). Other copolymers of use in the invention include poly(ethylene-co-vinyl) alcohol). In an exemplary embodiment, a fiber comprises a polymer or subunit which is a member selected from an aliphatic polyester, a polyalkylene oxide, polydimethylsiloxane, polyvinylalcohol, polylysine, collagen, laminin, fibronectin, elastin, alginate, fibrin, hyaluronic acid, proteoglycans, polypeptides and combinations thereof. In another exemplary embodiment, a fiber comprises two different polymers or subunits which are members selected from an aliphatic polyester, a polyalkylene oxide, polydimethylsiloxane, polyvinylalcohol, polylysine, collagen, laminin, fibronectin, elastin, alginate, fibrin, hyaluronic acid, proteoglycans, polypeptides and combinations thereof. In another exemplary embodiment, a fiber comprises three different polymers or subunits which are members selected from an aliphatic polyester, a polyalkylene oxide,

polydimethylsiloxane, polyvinylalcohol, polylysine, collagen, laminin, fibronectin, elastin, alginate, fibrin, hyaluronic acid, proteoglycans, polypeptides and

combinations thereof. In an exemplary embodiment, the aliphatic polyester is linear or branched. In another exemplary embodiment, the linear aliphatic polyester is a member selected from lactic acid (D- or L-), lactide, poly(lactic acid), poly(lactide) glycolic acid, poly(glycolic acid), poly(glycolide), glycolide, poly(lactide-co- glycolide), poly(lactic acid-co-glycolic acid), polycaprolactone and combinations thereof. In another exemplary embodiment, the aliphatic polyester is branched and comprises at least one member selected from lactic acid (D- or L-), lactide, poly(lactic acid), poly(lactide) glycolic acid, poly(glycolic acid), poly(glycolide), glycolide, poly(lactide-co-glycolide), poly(lactic acid-co-glycolic acid), polycaprolactone and combinations thereof which is conjugated to a linker or a bioactive agent. In an exemplary embodiment, wherein said polyalkylene oxide is a member selected from polyethylene oxide, polyethylene glycol, polypropylene oxide, polypropylene glycol and combinations thereof.

[0183] In some embodiments, the fibrous polymer scaffold is composed of a single continuous fiber. In other embodiments, the fibrous polymer scaffold is composed of at least two, three, four, or five fibers. In an exemplary embodiment, the number of fibers in the fibrous polymer scaffolds is a member selected from 2 to 100,000. In an exemplary embodiment, the number of fibers in the fibrous polymer scaffolds is a member selected from 2 to 50,000. In an exemplary embodiment, the number of fibers in the fibrous polymer scaffolds is a member selected from 50,000 to 100,000. In an exemplary embodiment, the number of fibers in the fibrous polymer scaffolds is a member selected from 10 to 20,000. In an exemplary embodiment, the number of fibers in the fibrous polymer scaffolds is a member selected from 15 to 1,000.

[0184] The fibrous polymer scaffold can comprise a fiber of at least one

composition. In an exemplary embodiment, the fibrous polymer scaffold comprises a number of different types of fibers, and this number is a member selected from one, two, three, four, five, six, seven, eight, nine and ten.

[0185] In another exemplary embodiment, the fiber or fibers of the fibrous polymer scaffold are biodegradable. In another exemplary embodiment, the fibers of the fibrous polymer scaffold comprise biodegradable polymers. In another exemplary embodiment, the biodegradable polymers comprise a monomer which is a member selected from lactic acid and glycolic acid. In another exemplary embodiment, the biodegradable polymers are poly(lactic acid), poly(glycolic acid) or a copolymer thereof. Preferred biodegradable polymers are those which are approved by the FDA for clinical use, such as poly(lactic acid) and poly(glycolic acid). In another exemplary embodiment, biodegradable polymer scaffolds of the invention can be used to guide the morphogenesis of engineered tissue and gradually degrade after the assembly of the tissue. The degradation rate of the polymers can be tailored by one of skill in the art to match the tissue generation rate. For example, if a polymer that biodegrades quickly is desired, an approximately 50:50 PLGA combination can be selected. Additional ways to increase polymer scaffold biodegradability can involve selecting a more hydrophilic copolymer (for example, polyethylene glycol), decreasing the molecular weight of the polymer, as higher molecular weight often means a slower degradation rate, and changing the porosity or fiber density, as higher porosity and lower fiber density often lead to more water absorption and faster degradation. In another exemplary embodiment, the tissue is a member selected from muscle tissue, vascular tissue, nerve tissue, spinal cord tissue and skin tissue. In another exemplary embodiment, the biodegradable fibrous scaffolds can be used to guide the morphogenesis of engineered muscular tissue and gradually degrade after the assembly of myoblasts, myotubes, and skeletal muscle tissue.

[0186] In an exemplary embodiment, any of the materials described herein has a first fibrous polymer scaffold which is seamless. In another exemplary embodiment, any of the materials described herein has a first fibrous polymer scaffold which is monolithically formed. In another exemplary embodiment, any of the materials described herein is designed to be placed as an end-to-end anastomosis or an end-to- side anastomosis. For end-to-end anastomosis, each side of the graft is placed such that the native artery is matched to the diameter of the graft. Interrupted or continuous sutures can be used to hold the two ends of the graft and artery together. For end-to-side anastomosis, the graft would be cut at an angle (usually around 45 degrees, but can vary from 0 to 90 degrees) and it would be placed onto the side of the native artery.

[0187] In an exemplary embodiment, any of the materials described herein comprises a second polymer which comprises a member selected from PTFE and Dacron. In an exemplary embodiment, any of the materials described herein further comprising a sleeve which surrounds the exterior surface of the first fibrous polymer scaffold conduit or filled conduit, but is not located within the lumen of the first fibrous polymer scaffold conduit or filled conduit. In an exemplary embodiment, any of the materials described herein said sleeve comprises a polymer or subunit which is a member selected from polyethylene terephthalate and polytetrafluoroethylene.

[0188] In an exemplary embodiment, for any of the materials described herein, said first fibrous polymer scaffold is seamless, circumferentially aligned and at least one of the fibers of the first fibrous polymer scaffold comprises poly(lactide-co- glycolide) (PLGA), said hirudin is covalently bonded to said first fibrous polymer scaffold by a linker which is a member selected from di-amino poly(ethylene glycol) and poly(ethylene glycol).

[0189] In an exemplary embodiment, any of the materials described herein has a length of between about 1 mm and about 50 cm. In an exemplary embodiment, any of the materials described herein has a length of between about 0.5 cm and about 10 cm. In an exemplary embodiment, any of the materials described herein has a length of between about 3 mm and about 6 mm. In an exemplary embodiment, any of the materials described herein has an inner diameter of between about 0.01 mm and 6 mm. In an exemplary embodiment, any of the materials described herein has a length of between about 3 mm and about 6 mm. In an exemplary embodiment, any of the materials r described herein has a length of between about 4 cm and about 8 cm. In an exemplary embodiment, any of the materials described in this Summary or described herein are used as a member selected from an A/V shunt and a hemodialysis access graft.

Methods of Making a Fibrous Polymer Scaffold

[0190] The polymer scaffolds of the invention can be produced in a variety of ways. In an exemplary embodiment, the polymer scaffold can be produced by

electrospinning. Electrospinning is an atomization process of a conducting fluid which exploits the interactions between an electrostatic field and the conducting fluid. When an external electrostatic field is applied to a conducting fluid (e.g., a semi-dilute polymer solution or a polymer melt), a suspended conical droplet is formed, whereby the surface tension of the droplet is in equilibrium with the electric field. Electrostatic atomization occurs when the electrostatic field is strong enough to overcome the surface tension of the liquid. The liquid droplet then becomes unstable and a tiny jet is ejected from the surface of the droplet. As it reaches a grounded target, the material can be collected as an interconnected web containing relatively fine, i.e. small diameter, fibers. The resulting films (or membranes) from these small diameter fibers have very large surface area to volume ratios and small pore sizes. A detailed description of electrospinning apparatus is provided in Zong, et al., Polymer,

43(16):4403-4412 (2002); Rosen et al., Ann Plast Surg., 25:375-87 (1990) Kim, K., Biomaterials 2003, 24, (27), 4977-85; Zong, X., Biomaterials 2005, 26, (26), 5330-8. After electrospinninng, extrusion and molding can be utilized to further fashion the polymers. To modulate fiber organization into aligned fibrous polymer scaffolds, the use of patterned electrodes, wire drum collectors, or post-processing methods such as uniaxial stretching has been successful. Zong, X., Biomaterials 2005, 26, (26), 5330- 8; Katta, P., Nano Lett 2004, 4, (11), 2215-2218; Li, D., Nano Lett 2005, 5, (5), 913-6. Further details regarding the electrospinning process and post-processing methods may be found in WO/2007/090102, WO/2007/146261, WO/2008/154608, and US 2010/0070020 Al .

Micropattemed Polymer Scaffolds

[0191] In a second aspect, the invention provides a material which comprises a micropattemed polymer scaffold. With micropatterning, soft lithography is used to topographically or chemically alter the spatial and geometric organization of the polymer and create micron-scale features on substrate surfaces. Taylor, A.M., Nat

Methods 2005, 2, (8), 599-605; Dow, LA., J Cell Sci Suppl 1987, 8, 55-79; Kane,

R.S., Biomaterials 1999, 20, (23-24), 2363-76. The polymer scaffolds created by this technique can be used to control many aspects of cellular behavior, including cell size, shape, spatial organization, proliferation and survival. Chen, C.S., Science 1997,

276, (5317), 1428-8; Bhatia, SN., Faseb J 1999, 13, (14), 1883-900; Deutsch, J., J

Biomed Mater Res 2000, 53, (3), 267-76; Folch, A., Annu Rev Biomed Eng 2000, 2,

227-56; Whitesides, G.M., Annu Rev Biomed Eng 2001, 3, 335-73.

Poly(dimethylsiloxane) (PDMS) is an elastomer that can be micropattemed with high reproducibility and provides a flexible substrate for cell conjugation. Wang, N., Cell Motil Cytoskeleton 2002, 52, (2), 97-106.

Alignment of the Polymer Scaffolds

[0192] The polymer scaffolds of the invention can have an aligned orientation or a random orientation. In an aligned orientation, at least 50% of the fibers comprising the polymer scaffold are oriented along an average axis of alignment.

[0193] In an exemplary embodiment, the material has an alignment which is a member selected from essentially longitudinal, essentially circumferential, and 'crisscross'. A longitudinal alignment is present when the fibers are aligned in the direction of the long axis of the conduit, filled conduit or rod shaped polymer scaffolds. A circumferential alignment is present when the fibers are aligned along the short axis of the polymer scaffold. A criss-cross alignment is present when the fibers of one polymer scaffold in the material are aligned in such a manner that the average alignment axis of a first polymer scaffold is at an angle relative to the average alignment axis of a second polymer scaffold which is adjacent to the first polymer scaffold. A longitudinally aligned or circumferentially aligned polymer scaffold can have more than one layer of fibers. A criss-cross aligned polymer scaffold requires more than one layer of fibers.

[0194] In another exemplary embodiment, the polymer fibers can have a standard deviation from the central axis of the fiber bundle. In an exemplary embodiment, the standard deviation of the fiber is a member selected from between about 0° and about 1°, between about 0° and about 3°, between about 0° and about 5°, between about 0° and about 10°, between about 0° and about 15°, between about 0° and about 20°, and between about 0° and about 30°.

[0195] Aligned polymer scaffolds have profound effects on cell cytoskeletal alignment, cell migration and cellular function. Aligned polymer scaffolds can induce and direct cell migration thus enhancing tissue regeneration. Such scaffolds are a promising solution for a variety of tissue regeneration, such as muscle, skin, vascular tissue, nerve and spinal cord regeneration. For example, the longitudinally aligned fibrous polymer scaffolds can enhance and specifically direct nerve, skin, muscle and/or vascular tissue growth across an injury gap.

[0196] The direction in which the aligned polymer scaffold is situated may affect the biological function that the aligned polymer scaffold is replacing or improving. For instance, when an aligned polymer scaffold is situated in a wound, wound healing is more rapid when the aligned polymer scaffold is perpendicular, rather than parallel, to the long axis of the wound. In an exemplary embodiment, the central long axis of the bundle of an aligned polymer scaffold is situated perpendicular to the direction of the material which the aligned polymer scaffold is improving or replacing. In another exemplary embodiment, the central long axis of the bundle of an aligned polymer scaffold is situated parallel to the direction of the material which the aligned polymer scaffold is improving or replacing.

[0197] In another exemplary embodiment, the aligned materials of the invention (such as polymer scaffolds) can comprise biodegradable polymers. These materials can be used to guide the morphogenesis of other types of tissues with anisotropic structure, e.g., nerve, skin, blood vessel, skeletal muscle, cardiac muscle, tendon and ligament. These aligned, biodegradable materials of the invention can also be used in the development of three-dimensional tissues. Using electrospun biodegradable fibrous polymer scaffolds, three-dimensional constructs of nerve tissue, spinal cord tissue, skin tissue, vascular tissue and muscle tissue can be created.

[0198] In an exemplary embodiment, the materials described herein can comprise more than one polymer scaffold. Each of those polymer scaffolds can have an alignment which is the same or different from the other polymer scaffold or scaffolds in the material.

[0199] In an exemplary embodiment, the material comprises two polymer scaffolds. The first polymer scaffold has the shape of a conduit and is longitudinally aligned. The second polymer scaffold surrounds the exterior of the first polymer scaffold and has an orientation which is a member selected from random, circumferential, criss- cross, and longitudinal. In an exemplary embodiment, the orientation of the second polymer scaffold is a member selected from random and circumferential.

Shapes of the Polymer Scaffolds /Methods of Making the Polymer Scaffolds

[0200] The polymer scaffolds of the invention can be formed into a variety of shapes, depending on the nature of the problem to be solved.

[0201] The materials and/or polymer scaffolds of the invention can have a variety of dimensions. In an exemplary embodiment, the polymer scaffold is 0.1 mm to 50 cm long. In another exemplary embodiment, the polymer scaffold is 0.1 mm to 1 mm long. In another exemplary embodiment, the polymer scaffold is 1mm to 1 cm long. In another exemplary embodiment, the polymer scaffold is 1 cm to 10 cm long. In another exemplary embodiment, the polymer scaffold is 10 cm to 50 cm long. In another exemplary embodiment, the polymer scaffold is 1 cm to 5 cm long. In another exemplary embodiment, the polymer scaffold is 2.5 cm to 15 cm long. In another exemplary embodiment, the polymer scaffold is 5mm to 6 cm long. In another exemplary embodiment, the polymer scaffold is 8mm to 3 cm long. In another exemplary embodiment, the polymer scaffold is 10 cm to 25 cm long. In another exemplary embodiment, the polymer scaffold is 0.5 cm to 2 cm long. In another exemplary embodiment, the polymer scaffold is 0.1 cm to 2 cm long.

[0202] The materials and/or polymer scaffolds of the invention can be composed of a variety of fibrous layers. In an exemplary embodiment, the material has between about 1 and about 2,000 fibrous layers. In an exemplary embodiment, the material has between about 1 and about 1,000 fibrous layers. In an exemplary embodiment, the material has between about 1 and about 500 fibrous layers. In an exemplary embodiment, the material has between about 1 and about 20 fibrous layers. In an exemplary embodiment, the material has between about 1 and about 10 fibrous layers. In an exemplary embodiment, the material has between about 5 and about 25 fibrous layers. In an exemplary embodiment, the material has between about 500 and about 1,500 fibrous layers. In an exemplary embodiment, the material has between about 10 and about 20 fibrous layers. In an exemplary embodiment, the material has between about 35 and about 80 fibrous layers. In an exemplary embodiment, the material has between about 10 and about 100 fibrous layers. In an exemplary embodiment, the material has between about 5 and about 600 fibrous layers. In an exemplary embodiment, the material has between about 10 and about 80 fibrous layers. In an exemplary embodiment, the material has between about 2 and about 12 fibrous layers. In an exemplary embodiment, the material has between about 60 and about 400 fibrous layers. In an exemplary embodiment, the material has between about 1,200 and about 1,750 fibrous layers.

[0203] In an exemplary embodiment, the polymer scaffold has the shape of a sheet or membrane. Polymer scaffold membranes can be made through electrospinning. The individual fibers within the membrane can be aligned either during

electrospinning using a rotating drum as a collector or after by mechanical uniaxial stretching.

[0204] In another exemplary embodiment, the polymer scaffold has the shape of a 'criss-cross' sheet. To form a criss-cross sheet, layers of aligned polymer sheets or membranes can be arranged in relation to each other, at an angle which is a member selected from greater than 20 degrees but less than 160 degrees, greater than 30 degrees but less than 150 degrees, greater than 40 degrees but less than 140 degrees, greater than 50 degrees but less than 130 degrees, greater than 60 degrees but less than 120 degrees, greater than 70 degrees but less than 110 degrees, and greater than 80 degrees but less than 100 degrees.

[0205] There are a variety of ways to make a 'criss-cross' sheet. In one exemplary embodiment, a rotating metal drum collector is used that does not contain a nonconducting region. An aligned layer of fibers is created on the drum, which is then peeled off the drum. The aligned layer is rotated 90 degrees and then placed back on the drum. Next an additional layer of electrospun fibers is added while the drum rotates at a high speed. Additional criss-cross layers can be added by repeating these steps. In another exemplary embodiment, a drum is used that has a non-conducting region. Here, the drum is rotated slowly for a first period of time so the fibers deposit and align longitudinally on the non-conducting section. Then the drum is spun fast so the fibers are forced to align circumferentially. Additional criss-cross layers can be added by repeating these steps.

Additional Material or Polymer Scaffold Components Bioactive Agents

[0206] A bioactive agent (such as a pharmaceutical drug, nucleic acid, amino acid, sugar or lipid) can be covalently bonded or non-covalently associated with the material and/or polymer scaffolds described herein. In an exemplary embodiment, the bioactive agent is a member selected from a pharmaceutical drug, receptor molecule, extracellular matrix component or a biochemical factor. In another exemplary embodiment, the biochemical factor is a member selected from a growth factor and a differentiation factor. In an exemplary embodiment, the bioactive agent is a member selected from glycosaminoglycans and proteoglycans. In an exemplary embodiment, the bioactive agent is a member selected from heparin, heparan sulfate, heparan sulfate proteoglycan and combinations thereof.

[0207] In another exemplary embodiment, a first molecule (which may or may not be a bioactive agent) is covalently bonded to the material and/or polymer scaffold of the invention. This first molecule can be used to interact with a second bioactive agent. In an exemplary embodiment, the first molecule is a linker, and the second bioactive agent is a member selected from a receptor molecule, biochemical factor, growth factor and a differentiation factor. In an exemplary embodiment, the first molecule is a member selected from heparin, heparan sulfate, heparan sulfate proteoglycan, and combinations thereof. In an exemplary embodiment, the second bioactive agent is a member selected from a receptor molecule, biochemical factor, growth factor and a differentiation factor. In another exemplary embodiment, the first molecule is covalently bonded through a linker. In an exemplary embodiment, the linker includes a member selected from a water-soluble polymer and a water- insoluble polymer. In another exemplary embodiment, the linker includes a member selected from polyphosphazines, poly( vinyl alcohols), polyamides, polycarbonates, polyalkylenes, polyacrylamides, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate) polyethylene,

polypropylene, poly(ethylene glycol), poly(ethylene oxide), poly(ethylene

terephthalate), poly(vinyl acetate), polyvinyl chloride, polystyrene, polyvinyl pyrrolidone, pluronics, polyvinylphenol, saccharides (e.g., dextran, amylose, hyalouronic acid, poly(sialic acid), heparans, heparins, etc.); poly (amino acids), e.g., poly(aspartic acid) and poly(glutamic acid); nucleic acids and copolymers thereof. In an exemplary embodiment, the linker includes a member selected from polyethylene glycol (PEG) and polypropylene glycol (PPG) , or a mixture thereof. In another exemplary embodiment, the PEG or PPG comprises a number of monomeric subunits which is an integer from 1 to 5000. In an exemplary embodiment, said number of monomeric subunits is an integer from about 10 to about 1000. In an exemplary embodiment, said number of monomeric subunits is an integer from about 10 to about 500. In an exemplary embodiment, said number of monomeric subunits is an integer from about 20 to about 400. In an exemplary embodiment, said number of monomeric subunits is an integer from about 20 to about 250. In an exemplary embodiment, said number of monomeric subunits is an integer from about 50 to about 200. In an exemplary embodiment, said number of monomeric subunits is an integer from about 50 to about 125. In an exemplary embodiment, said number of monomeric subunits is an integer from about 50 to about 100. In an exemplary embodiment, said number of monomeric subunits is an integer from about 60 to about 90. In an exemplary embodiment, said number of monomeric subunits is an integer from about 60 to about 90. In an exemplary embodiment, said linker is a member selected from di-amino poly(ethylene glycol), poly(ethylene glycol) and combinations thereof. For bioactive agents that do not bind to heparin, direct conjugation to the polymer scaffold or through a linker (such as PEG, amino-PEG and di-amino-PEG) is also feasible.

[0208] In another exemplary embodiment, the bioactive agent is an extracellular matrix component which is a member selected from laminin, collagen, fibronectin, elastin, vitronectin, fibrinogen, polylysine, other cell adhesion promoting polypeptides and combinations thereof. In another exemplary embodiment, the bioactive agent is a growth factor which is a member selected from acidic fibroblast growth factor, basic fibroblast growth factor, nerve growth factor, brain-derived neurotrophic factor, insulin-like growth factor, platelet derived growth factor, transforming growth factor beta, vascular endothelial growth factor, epidermal growth factor, keratinocyte growth factor and combinations thereof. In another exemplary embodiment, the bioactive agent is a differentiation factor which is a member selected from stromal cell derived factor, sonic hedgehog, bone morphogenic proteins, notch ligands, Wnt and combinations thereof.

[0209] The first molecules which are covalently bonded to the polymer scaffold of the invention can be used to interact with a bioactive agent (for example, a growth factor and/or ECM component) in order to stimulate neurite growth. In another exemplary embodiment, the polymer scaffold can be used for wound healing, and the bioactive agent which is a member selected from an extracellular matrix component, growth factors and differentiation factors. Examples of potential factors for wound healing enhancement include epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF).

[0210] Bioactive agents can be incorporated within the materials of the invention during electrospinning or post-fabrication. These bioactive agents can be

incorporated via blending, covalent bonding directly or through various linkers or by adsorption. Antiplatelet Agents

[0211] In an exemplary embodiment, the bioactive agent is an antiplatelet agent. Non-limiting examples of antiplatelet agents that may be used in the materials of the invention include adenosine diphosphate (ADP) antagonists or P2Y12 antagonists, phosphodiesterase (PDE) inhibitors, adenosine reuptake inhibitors, Vitamin K antagonists, heparin, heparin analogs, direct thrombin inhibitors, glycoprotein IIB/IIIA inhibitors, aspirin, non-aspirin NSAIDs, anti-clotting enzymes, as well as pharmaceutically acceptable salts, isomers, enantiomers, polymorphic crystal forms including the amorphous form, solvates, hydrates, co-crystals, complexes, active metabolites, active derivatives and modifications, pro-drugs thereof, and the like.

[0212] ADP antagonists or P2Y12 antagonists block the ADP receptor on platelet cell membranes. This P2Y12 receptor is important in platelet aggregation, the cross- linking of platelets by fibrin. The blockade of this receptor inhibits platelet aggregation by blocking activation of the glycoprotein Ilb/IIIa pathway. In an exemplary embodiment, the antiplatelet agent is an ADP antagonist or P2Y12 antagonist. In another exemplary embodiment, the antiplatelet agent is a

thienopyridine. In another exemplary embodiment, the ADP antagonist or P2Y12 antagonist is a thienopyridine.

[0213] In another exemplary embodiment, the ADP antagonist or P2Y12 antagonist is a member selected from sulfinpyrazone, ticlopidine, clopidogrel, prasugrel, R- 99224 (an active metabolite of prasugrel, supplied by Sankyo), R-1381727, R-125690 (Lilly), C-1330-7, C-50547 (Millennium Pharmaceuticals), INS-48821, INS-48824, INS-446056, INS-46060, INS-49162, INS-49266, INS-50589 (Inspire

Pharmaceuticals) and Sch-572423 (Schering Plough). In another exemplary embodiment, the ADP antagonist or P2Y12 antagonist is ticlopidine hydrochloride (TICLID™). In another exemplary embodiment, the ADP antagonist or P2Y12 antagonist is a member selected from sulfinpyrazone, ticlopidine, AZD6140, clopidogrel, prasugrel and mixtures thereof. In another exemplary embodiment, the ADP antagonist or P2Y12 antagonist is clopidogrel. In another exemplary embodiment, the ADP antagonist or P2Y12 antagonist is a member selected from clopidogrel bisulfate (PLAVIX™), clopidogrel hydrogen sulphate, clopidogrel hydrobromide, clopidogrel mesylate, cangrelor tetrasodium (AR-09931 MX), ARL67085, AR-C66096 AR-C 126532, and AZD-6140 (AstraZeneca). In another exemplary embodiment, the ADP antagonist or P2Y12 antagonist is prasugrel. In another exemplary embodiment, the ADP antagonist or P2Y12 antagonist is a member selected from clopidogrel, ticlopidine, sulfmapyrazone, AZD6140, prasugrel and mixtures thereof.

[0214] A PDE inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase (PDE), preventing the inactivation of the intracellular second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), by the respective PDE subtype(s). In an exemplary embodiment, the antiplatelet agent is a PDE inhibitor. In an exemplary embodiment, the antiplatelet agent is a selective cAMP PDE inhibitor. In an exemplary

embodiment, the PDE inhibitor is cilostazol (Pletal™).

[0215] Adenosine reuptake inhibitors prevent the cellular reuptake of adenosine into platelets, red blood cells and endothelial cells, leading to increased extracellular concentrations of adenosine. These compounds inhibit platelet aggregation and cause vasodilation. In an exemplary embodiment, the antiplatelet agent is an adenosine reuptake inhibitor. In an exemplary embodiment, the adenosine reuptake inhibitor is dipyridamole (Persantine™).

[0216] Vitamin K inhibitors are given to people to stop thrombosis (blood clotting inappropriately in the blood vessels). This is useful in primary and secondary prevention of deep vein thrombosis, pulmonary embolism, myocardial infarctions and strokes in those who are predisposed. In an exemplary embodiment, the anti-platelet agent is a Vitamin K inhibitor. In an exemplary embodiment, the Vitamin K inhibitor is a member selected from acenocoumarol, clorindione, dicumarol (Dicoumarol), diphenadione, ethyl biscoumacetate, phenprocoumon, phenindione, tioclomarol and warfarin. [0217] Heparin is a biological substance, sometimes made from pig intestines. It works by activating antithrombin III, which blocks thrombin from clotting blood. In an exemplary embodiment, the antiplatelet agent is heparin or a prodrug of heparin. In an exemplary embodiment, the antiplatelet agent is a heparin analog or a prodrug of a heparin analog. In an exemplary embodiment, the heparin analog a member selected from Antithrombin III, Bemiparin, Dalteparin, Danaparoid, Enoxaparin, Fondaparinux (subcutaneous), Nadroparin, Parnaparin, Reviparin, Sulodexide, and Tinzaparin.

[0218] Direct thrombin inhibitors (DTIs) are a class of medication that act as anticoagulants (delaying blood clotting) by directly inhibiting the enzyme thrombin. In an exemplary embodiment, the antiplatelet agent is a DTI. In another exemplary embodiment, the DTI is univalent. In another exemplary embodiment, the DTI is bivalent. In an exemplary embodiment, the DTI is a member selected from hirudin, bivalirudin (IV), lepirudin, desirudin, argatroban (IV), dabigatran, dabigatran etexilate (oral formulation), melagatran, ximelagatran (oral formulation but liver

complications) and prodrugs thereof.

[0219] Glycoprotein IIB/IIIA inhibitors work by inhibiting the GpIIb/IIIa receptor on the surface of platelets, thus preventing platelet aggregation and thrombus formation. In an exemplary embodiment, the antiplatelet agent is a glycoprotein IIB/IIIA inhibitor. In an exemplary embodiment, the glycoprotein IIB/IIIA inhibitor is a member selected from abciximab, eptifibatide, tirofiban and prodrugs thereof. Since these drugs are only administered intravenously, a prodrug of a glycoprotein IIB/IIIA inhibitor is useful for oral administration.

[0220] Anti-clotting enzymes may also be used in the invention. In an exemplary embodiment, the antiplatelet agent is an anti-clotting enzyme which is in a form suitable for oral administration. In another exemplary embodiment, the anti-clotting enzyme is a member selected from Alteplase, Ancrod, Anistreplase, Brinase, Drotrecogin alfa, Fibrinolysin, Protein C, Reteplase, Saruplase, Streptokinase, Tenecteplase, Urokinase. [0221] In an exemplary embodiment, the anti-platelet agent is a member selected from aloxiprin, beraprost, carbasalate calcium, cloricromen, defibrotide, ditazole, epoprostenol, indobufen, iloprost, picotamide, rivaroxaban (oral FXa inhibitor) treprostinil, triflusal, or prodrugs thereof.

[0222] In another exemplary embodiment, the antiplatelet agent is a direct thrombin inhibitor. In another exemplary embodiment, the antiplatelet agent is a member selected from hirudin, bivalirudin, lepirudin, desirudin, argatroban, dabigatran, dabigatran etexilate, melagatran, ximelagatran, prodrugs and analogs thereof. In another exemplary embodiment, the antiplatelet agent is a member selected from hirudin, bivalirudin, lepirudin, desirudin, prodrugs and analogs thereof. In another exemplary embodiment, the antiplatelet agent comprises a thrombin binding site. In another exemplary embodiment, the antiplatelet agent comprises a protein sequence which is a member selected from FPRP and LYEEPIEEFDGN. In an exemplary embodiment, the first fibrous polymer scaffold is a member selected from a rod, a conduit and a filled conduit.

Methods of Conjugating a Bioactive Agent and/or a Cell to a Polymer Scaffold

[0223] The bioactive agents and/or cell can be conjugated to the polymer scaffold in a variety of ways. In one embodiment, the bioactive agent can be non-covalently embedded or absorbed into a first fibrous polymer scaffold described herein.

[0224] In another exemplary embodiment, the bioactive agent is covalently bonded, either directly or through a linker, to a first fibrous polymer scaffold. This covalent bonding is made from the reaction of complementary reactive groups on the first fibrous scaffold and the bioactive agent or cell, or between the linker on the first fibrous scaffold and the bioactive agent or cell, or between the first fibrous scaffold and the linker on the bioactive agent or cell.

[0225] Complementary reactive functional groups and classes of reactions useful in practicing the present invention are generally those that are well known in the art of bioconjugate chemistry. Currently favored classes of reactions available with reactive functional groups of the invention are those which proceed under relatively mild conditions. These include, but are not limited to nucleophilic substitutions (e.g., reactions of amines and alcohols with acyl halides, active esters), electrophilic substitutions (e.g., enamine reactions) and additions to carbon-carbon and carbon- heteroatom multiple bonds (e.g., Michael reaction, Diels-Alder addition). These and other useful reactions are discussed in, for example, March, ADVANCED ORGANIC CHEMISTRY, 3rd Ed., John Wiley & Sons, New York, 1985; Hermanson,

[0226] Useful reactive functional groups include, for example:

(b) hydroxyl groups, which can be converted to esters, ethers, aldehydes, etc.

(c) haloalkyl groups, wherein the halide can be later displaced with a

(d) dienophile groups, which are capable of participating in Diels-Alder

reactions such as, for example, maleimido groups;

(h) amine or sulfhydryl groups, which can be, for example, acylated, alkylated or oxidized;

(i) alkenes, which can undergo, for example, cycloadditions, acylation,

Michael addition, etc;

(j) epoxides, which can react with, for example, amines and hydroxyl compounds; and

[0227] In an exemplary embodiment, the reactive functional groups are members selected from

wherein R³¹ and R³² are members independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

[0228] Additional examples of reactive functional groups, as well as the corresponding functional groups with which they react, are provided in the following table:

Table 1

Possible Reactive Substituents and Sites Reactive Therewith

Reactive Functional Groups Corresponding Functional Groups Succinimidyl esters primary amino, secondary amino,

hydroxyl

Anhydrides primary amino, secondary amino,

hydroxyl

Acyl azides primary amino, secondary amino

Isothiocyanates, isocyanates amino, thiol, hydroxyl

sulfonyl chlorides amino, hydroxyl

sulfonyl fluorides

hydrazines, aldehydes, ketones

substituted hydrazines

hydroxylamines, amino, hydroxyl

substituted hydroxylamines

acid halides amino, hydroxyl haloacetamides, maleimides thiol, imidazoles, hydroxyl, amino carbodiimides carboxyl groups phosphoramidites hydroxyl azides alkynes

For example, in order to conjugate a compound of the invention to the hydroxyl moiety on a serine amino acid, exemplary reactive functional groups include, succinimidyl esters, anhydrides, isothiocyanates, thiocyanates, sulfonyl chlorides, sulfonyl fluorides, acid halides, haloacetamides, maleimides and phosphoramidites.

[0229] The reactive functional groups can be chosen such that they do not participate in, or interfere with, the reactions necessary to assemble the compound of the invention. Alternatively, a reactive functional group can be protected from participating in the reaction by the presence of a protecting group. Those of skill in the art understand how to protect a particular functional group such that it does not interfere with a chosen set of reaction conditions. For examples of useful protecting groups, see, for example, Greene et al., PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, John Wiley & Sons, New York, 1991.

[0230] In an exemplary embodiment, a carboxylic acid moiety is being conjugated to an amine moiety. First the carboxylic acid moiety is reacted with a carbodiimide to generate an O-acylisourea, which can react with the amine moiety to produce an amide which then links the two moieties.

[0231] In an exemplary embodiment, conjugation of bioactive agents to a fibrous polymer scaffold described herein can be achieved by any of several methods. For example, a bioactive agent (such as an antiplatelet agent) can be conjugated to a polymer scaffold described herein optionally containing a linking group by treatment with EDC (i.e., l-ethyl-3(3-dimethylaminopropylcarbodiimide), which will facilitate linkage of, for example, the amino end of the fibrous polymer to the carboxyl group of the bioactive agent, or to an amine-containing linker bound to the fibrous polymer. The linkages may be on the opposite species as well (the carboxyl group could be on the fibrous polymer and the amine group could be on the bioactive agent). One will appreciate from the description herein that other coupling agents may be used.

[0232] The foregoing descriptions of specific exemplary embodiments of the present invention have been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the invention to the precise forms disclosed, and obviously many modifications and variations are possible in light of the above teachings. The exemplary embodiments were chosen and described in order to explain certain principles of the invention and their practical application, to thereby enable others skilled in the art to make and utilize various exemplary embodiments of the present invention, as well as various alternatives and

modifications thereof. It is intended that the scope of the invention be defined by the Claims appended hereto and their equivalents.

[0233] The invention is further illustrated by the Examples that follow. The Examples are not intended to define or limit the scope of the invention.

EXAMPLES

[0234] The following examples describe the preparation and testing of an exemplary vascular access sleeve, created as a supplemental medical device to address current complications related to the use of ePTFE graft for vascular access. The nano fibrous structure will surround the ePTFE graft and is designed to allow for multiple needle punctures without resulting in major defects. The surface modification of the nanofibers provides excellent hemocompatibility and

biocompatibility. EXAMPLE 1

Non-woven, vascular access sleeve

[0235] A 6mm, vascular access sleeve was electrospun using medical implant grade polyurethane from DSM-Polymer Technology Group (Berkeley, CA), applying an electrospinning technique essentially as descibed in US 2010/0070020 Al . SEM images reveal that the electrospinning technique produces a biomimetic surface (FIG. 6A).

[0236] The sleeve was then treated with a polymer primer and bioactive agent. The sleeve was first dipped in a coating solution of 1% w/v poly(lactide) (PLA) (PURAC America of Lincolnshire, Illinois, 2.0 dL/g inherent viscosity midpoint) in a solvent. Following the above-described process, each individual fiber of the respective layers was coated or encapsulated by a layer of PLA primer. The solvent was then left in normal atmospheric pressure at below room temperature until the solvent evaporated from the sleeve.

[0237] The sleeve was then dipped in a solution including a linker molecule to cause the linker molecules to become immobilized to the surface of the PLA primer using carbodiimide chemistry (e.g., activation of free carboxylic acid residues of the PDLA covering with l-ethyl-3-[3-dimethylaminopropyl] carbodiimide ("EDC") and subsequent reaction with one of the functional ends of polyoxyethylene bis(amine)). The linker molecule solution included polyoxyethylene bis(amine) (poly(ethylene glycol) (PEG)) (Sigma Aldrich (P/N P9906)). EDC was added to the linker molecule solution in a 0.1M 2-(N-morpholino)ethanesulfonic ("MES") acid buffer shortly before treatment of the sleeve. The PEG was of a linear structure and had an average molecular weight of 3350 g/mol. The average molecular weight of the PEG may be between about 1000 and 10,000 g/mol. The PEG was reacted to the dried sleeve for at least about two hours at room temperature and then washed.

[0238] Thereafter, the sleeve including the PLA primer and PEG conjugated to the fibers was dipped in a third solution including heparin for several hours. Reagents were put into the heparin solution shortly before treatment of the sleeve. The heparin was conjugated to the polyoxyethylene bis(amine) using carbodiimide chemistry (e.g., activation of free carboxylic acid residues on the heparin with EDC and subsequent reaction with the remaining functional end of the immobilized amino PEG).

[0239] The solution included Heparin Sodium (Scientific Protein Laboratories, LLC of Waunakee, WI, 182 U/mg). EDC was added to the solution with pH 7.4 phosphate buffered saline ("PBS") shortly before treatment. The linker (PEG) was found to tether the heparin from the surface of the respective polymer fiber as illustrated in FIG. 6B. The coated product was left in the heparin solution at room temperature long enough to allow the heparin to react with the PEG.

[0240] PEG is capable of creating a brush-like layer onto target surfaces, reducing the amount of protein and platelet binding. Heparin is a well-known, anti-thrombotic agent used in various applications and medical devices to improve hemocompatibility.

[0241] The sleeve was then washed with Phosphate Buffered Saline and Molecular Biology Grade Water at room temperature to remove any excess heparin.

[0242] As shown in FIG. 7A and 7B, the sleeve 135 was then placed over a 5mm ePTFE vascular graft 132 (C.R. Bard, Tempe, AZ). A 16-gage, hemodialysis syringe needle 44 was used to puncture the device and the resulting puncture site was characterized by a Hitachi TM-1000 scanning electron microscope. After puncturing the sleeve and graft combination, it was evident that the sleeve was capable of self- sealing to reduce bleeding through the puncture-site (FIG. 7C), while the ePTFE material was cored out by the needle puncture, leaving a major defect in the graft (FIG. 7D). As mentioned in the background section, ePTFE grafts suffer greatly from needle punctures; prolonged hemostasis times and the development of pseudo- aneurysms. The vascular access sleeve would reduce the time to hemostasis and reduce pseudo-aneurysm formation by sealing the defect left in the ePTFE. EXAMPLE 2

Covalent Bonding Verification

[0243] Electron Spectroscopy for Chemical Analysis (ESCA) was used to verify the covalent bonding of heparin to the vascular access sleeve described in Example 1 above. The contribution of nitrogen from heparin was used as an indicator of successful covalent conjugation (FIG. 8A). The nitrogen contribution on the unmodified control is from the polyurethane.

[0244] Further, toluidine blue, a chemical dye, was used to qualitatively assess the heparin coverage on the unmodified control and the sleeve (FIG. 8B and FIG. 8C, respectively). The unmodified control demonstrated no heparin presence, while the sleeve with covalently bound heparin underwent a dramatic color shift to a deep purple, indicative of heparin presence on the surface of the sleeve.

EXAMPLE 3

In Vitro Hemocompatibility Assay

[0245] The vascular access sleeve described in Example 1 above was examined in an in vitro test model to investigate the response of blood (i.e. - deposition of thrombi and adhesion of cells) to the sleeve. In this test model, fresh bovine blood was circulated at 150mL/min, which is analogous to conditions that would be encountered by a vascular access graft in vivo. This test model permits the study of blood-material interactions and reproducibly identifies sites where thrombi may form. This model has been used extensively and successfully to determine the hemocompatibility of a wide range of medical devices, including stents, catheters, blood pumps etc. Fresh bovine blood was obtained under controlled conditions and very mildly heparizined with 0.5U/mL for collection purposes only. Autologous platelets were labeled with ¹¹ indium separately and then added to the blood pool in order to quantify the amounts of bound platelets to each graft. The blood flowed through the sleeve for 90 minutes at 37°C (FIG. 9). The radioactivity levels of the platelets bound to the sleeve were read with a liquid scintillation counter.

[0246] The following 5mm internal diameter, 10cm long vascular prostheses were evaluated (FIG. 10):

• vascular access sleeve with covalently bound heparin (discribed in Example 1 above)

• Perma-Pass ePTFE graft by Possis (control)

[0247] The luminal surface of the sleeve was thrombus-free at 90 minutes. The luminal surfaces of the ePTFE control graft had appreciable thrombi formation. See FIG. 10A. ePTFE and the sleeve with covalently bound heparin exhibit similar amounts of adhered platelets. See FIG. 10B.

[0248] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference for all purposes.

[0249] As described above, the present invention is exemplified by the following aspects and embodiments.

[0250] A biocompatible device for positioning over a conduit. In an exemplary embodiment, the device comprises a sleeve configured to receive a porous conduit therethrough. In an exemplary embodiment, the sleeve is configured to be implanted in a subject such that at least a portion of the sleeve essentially completely seals off fluid leakage of the conduit when emplaced in the subject. In an exemplary embodiment, the sleeve is formed of a plurality of biocompatible polymer fibers. [0251] In an exemplary embodiment, a device according to the preceding paragraph, wherein the conduit receives a fluid flow therethrough. In an exemplary embodiment, the conduit and the sleeve are sufficiently porous to allow fluid engagement.

[0252] In an exemplary embodiment, a device according to any of the preceding paragraphs, wherein the sleeve is configured to seal the conduit to the body of the subject to reduce leakage of the fluid flowing therethrough.

[0253] In an exemplary embodiment, a device according to any of the preceding paragraphs, wherein the conduit and the sleeve are substantially tubular and concentric. In an exemplary embodiment, the sleeve has an inner diameter substantially corresponding to an outer diameter of the conduit.

[0254] In an exemplary embodiment, a device according to any of the preceding paragraphs, wherein the sleeve is configured to be removable from the conduit.

[0255] In an exemplary embodiment, a device according to any of the preceding paragraphs, wherein the sleeve is permanently attached to the conduit.

[0256] In an exemplary embodiment, a device according to any of the preceding paragraphs, wherein the conduit is a member selected from a vascular graft device, a synthetic graft, an autologous vein, a catheter, a blood vessel, a biological duct, a hydrocephalus shunt, a nerve wrap, a nerve regeneration duct, an optical nanofiber nerve, an urinal and prostate expansion stent, a stent graft, an intestine duct prosthesis, and a dialysis fistula.

[0257] In an exemplary embodiment, a device according to any of the preceding paragraphs, wherein the sleeve comprises fibers of a member selected from

polyurethane, silicon rubber, poly(lactide), poly(glycolide), poly(caprolactone), and combinations thereof. [0258] In an exemplary embodiment, a device according to any of the preceding paragraphs, wherein the polymer fibers are a member selected from aligned fibers, random aligned fibers, and a mixture of random and aligned fibers.

[0259] In an exemplary embodiment, a device according to the preceding paragraph, wherein the alignment is a member selected from circumferential, longitudinal, and helical.

[0260] In an exemplary embodiment, a device according to any of the preceding paragraphs, wherein the polymer fibers are aligned to adjust arterial/venous pressure.

[0261] In an exemplary embodiment, a device according to any of the preceding paragraphs, wherein the device comprises a member selected from ePTFE, polyurethane, PET, electrospun PET, PET-polyurethane, collagen, elastin, and combinations thereof.

[0262] In an exemplary embodiment, a device according to any of the preceding paragraphs, wherein the device is a graft device. In an exemplary embodiment, the device is treated with or conjugated to an anti-coagulation agent.

[0263] In an exemplary embodiment, a device according to any of the preceding paragraphs, wherein the device is a graft device. In an exemplary embodiment, the device is treated with or conjugated to a pro-thrombotic agent to promote blood clotting and reduce hematoma formation.

[0264] In an exemplary embodiment, a device according to any of the preceding paragraphs, wherein the device is treated with or conjugated to a member selected from heparin, hirudin and a combination thereof.

[0265] In an exemplary embodiment, a device according to any of the preceding paragraphs, wherein the device is treated with or conjugated to an antimicrobial and/or antibiotic to reduce cell proliferation. [0266] In an exemplary embodiment, a device according to any of the preceding paragraphs, wherein the device is treated with or conjugated to a cell non-proliferation compound.

[0267] In an exemplary embodiment, a device according to any of the preceding paragraphs, wherein the device is treated with or conjugated to at least one of sirolimus and paclitaxel.

[0268] In an exemplary embodiment, a device according to any of the preceding paragraphs, wherein the device is a drug-eluting device.

[0269] In an exemplary embodiment, a device according to any of the preceding paragraphs, wherein the device is configured to deliver a plaque-dissolving drug to a site internal to the subject.

[0270] In an exemplary embodiment, a device according to any of the preceding paragraphs, wherein at least a portion of the device is covered with electrospun nanofibers of a member selected from extracellular matrix (ECM), collagen, and combinations thereof.

[0271] In an exemplary embodiment, a device according to any of the preceding paragraphs, wherein the device has a sufficient porosity to reduce seroma formation.

[0272] In an exemplary embodiment, a device according to any of the preceding paragraphs, wherein the porosity of the device is substantially uniform throughout the walls of the device.

[0273] A method of accessing a subject. In an exemplary embodiment, the method comprises positioning a device according to any of the preceding paragraphs around a target conduit. In an exemplary embodiment, the method further comprises piercing the body wall of the subject thereby accessing an interior of the subject through the device. In an exemplary embodiment, the method further comprises flowing a fluid through the device. [0274] A method of treating a diseased vessel. In an exemplary embodiment, the method comprises positioning a device according to any of the preceding paragraphs around the diseased vessel. In an exemplary embodiment, the method further comprises flowing a fluid to the device.

[0275] A biocompatible dialysis device. In an exemplary embodiment, the device comprises a porous, flexible tube. In an exemplary embodiment, the device further comprises a sleeve positioned around a portion of the circumference of the tube. In an exemplary embodiment, the sleeve is formed of a plurality of biocompatible fibers configured to be in fluid communication with the tube and to seal the tube to essentially completely prevent leakage of fluid flowing therethrough.

[0276] In an exemplary embodiment, a device according to the preceding paragraph, wherein the porous, flexible tube comprises a hollow, vascular graft configured to allow a fluid to flow therethrough for dialysis.

[0277] In an exemplary embodiment, a device according to the preceding paragraph, wherein the porosity of the vascular graft is sufficient such that the sleeve is in fluid engagement with the fluid.

[0278] An implantable, biocompatible device for insertion into a subject. In an exemplary embodiment, the device comprises an access conduit having an insertion end configured to be implanted to access the interior of the subject through the access conduit interior. In an exemplary embodiment, the device further comprises a sleeve member positioned on at least a portion of the access conduit adjacent the insertion end. In an exemplary embodiment, the sleeve member is configured to be at least partially disposed within and essentially completely sealed to the inner surface of the body of the subject when emplaced. In an exemplary embodiment, the sleeve member is formed of a biocompatible polymeric material.

[0279] In an exemplary embodiment, a device according to the preceding paragraph, further comprising an axially movable needle configured to extend through the conduit to the insertion end and provide an access opening at the site for the conduit and sleeve member. In an exemplary embodiment, the sleeve member is configured to maintain the access opening after removal of the needle.

[0280] In an exemplary embodiment, a device according to any of the preceding paragraphs, wherein the access conduit is removable. In an exemplary embodiment, the sleeve member is configured to maintain the access opening after removal of the conduit.

[0281] In an exemplary embodiment, a device according to any of the preceding paragraphs, wherein the sleeve member is configured to be in fluid communication with conduit interior and to seal the conduit to reduce leakage of the fluid flowing therethrough.

[0282] In an exemplary embodiment, a device according to any of the preceding paragraphs, wherein the conduit is formed of ePTFE.

[0283] A method of administering a treatment. In an exemplary embodiment, the method comprises inserting a porous access conduit through an implant site to access a subject. In an exemplary embodiment, the method further comprises, before or after the inserting, forming a sleeve member on at least a portion of the access conduit adjacent the insertion end such that the sleeve member is at least partially disposed within the access site when emplaced, wherein the sleeve member is configured to be in fluid communication with conduit interior and to seal the conduit to essentially completely prevent leakage of the fluid flowing therethrough. In an exemplary embodiment, the method further comprises positioning the conduit and sleeve at a target site. In an exemplary embodiment, the method further comprises flowing a fluid through the conduit and sleeve member for dialysis of the subject.

[0284] In an exemplary embodiment, a method according to the preceding paragraph, wherein the sleeve member is formed of biocompatible polymer fibers.

[0285] In an exemplary embodiment, a method according to any of the preceding paragraphs, wherein the positioning is accomplished by a surgical robot. [0286] A method of forming a biocompatible device for a conduit. In an exemplary embodiment, the method comprises providing a conduit for insertion into a subject, the conduit having a porous surface. In an exemplary embodiment, the method further comprises electrospinning biocompatible fibers on an exterior surface of the conduit to a sufficient thickness such that the fibers are rigidly formed around the surface. In an exemplary embodiment, the method furher comprises securing the fibers to the conduit to form the biocompatible device, wherein the plurality of fibers are configured to be fluid communication with fluid flowing through the conduit and seal the conduit to essentially completely prevent leakage of the fluid.

[0287] In an exemplary embodiment, a method according to the preceding paragraph, further comprising treating at least one of the conduit and the plurality of fibers with a drug treatment.

[0288] In an exemplary embodiment, a method according to any of the preceding paragraphs, further comprising treating at least one of the conduit and the plurality of fibers with a low concentration of polyurethane solution.

[0289] In an exemplary embodiment, a method according to any of the preceding paragraphs, wherein the securing is accomplished by mechanical fasteners.

[0290] In an exemplary embodiment, a method according to any of the preceding paragraphs, wherein the securing is accomplished by application of an adhesive compound over a predetermined length of the conduit and sleeve.

[0291] In an exemplary embodiment, a method according to the preceding paragraph, wherein the adhesive compound is a biocompatible glue.

Claims

WHAT IS CLAIMED IS:

1. A biocompatible device for positioning over a conduit, the device comprising: a sleeve configured to receive a porous conduit therethrough, the sleeve being configured to be implanted in a subject such that at least a portion of the sleeve essentially completely seals off fluid leakage of the conduit when emplaced in the subject, wherein the sleeve is formed of a plurality of biocompatible polymer fibers.

2. The device according to claim 1, wherein the conduit receives a fluid flow therethrough, the conduit and the sleeve being sufficiently porous to allow fluid engagement.

3. The device according to claims 1 or 2, wherein the sleeve is configured to seal the conduit to the body of the subject to reduce leakage of the fluid flowing therethrough.

4. The device according to any one of the preceding claims, wherein the conduit and the sleeve are substantially tubular and concentric, the sleeve having an inner diameter substantially corresponding to an outer diameter of the conduit.

5. The device according to any one of the preceding claims, wherein the sleeve is configured to be removable from the conduit.

6. The device according to any one of the preceding claims, wherein the sleeve is permanently attached to the conduit.

7. The device according to any one of the preceding claims, wherein the conduit is a member selected from a vascular graft device, a synthetic graft, an autologous vein, a catheter, a blood vessel, a biological duct, a hydrocephalus shunt, a nerve wrap, a nerve regeneration duct, an optical nanofiber nerve, an urinal and prostate expansion stent, a stent graft, an intestine duct prosthesis, and a dialysis fistula.

8. The device according to any one of the preceding claims, wherein the sleeve comprises fibers of a member selected from polyurethane, silicon rubber, poly(lactide), poly(glycolide), poly(caprolactone), and combinations thereof.

9. The device according to any one of the preceding claims, wherein the polymer fibers are a member selected from aligned fibers, random aligned fibers, and a mixture of random and aligned fibers.

10. The device according to claim 9, wherein the alignment is a member selected from circumferential, longitudinal, and helical.

11. The device according to any one of the preceding claims, wherein the polymer fibers are aligned to adjust arterial/venous pressure.

12. The device according to any one of the preceding claims, wherein the device comprises a member selected from ePTFE, polyurethane, PET, electrospun PET, PET -polyurethane, collagen, elastin, and combinations thereof.

13. The device according to any one of the preceding claims, wherein the device is a graft device, and the device is treated with or conjugated to an anticoagulation agent.

14. The device according to any one of the preceding claims, wherein the device is a graft device, and the device is treated with or conjugated to a pro- thrombotic agent to promote blood clotting and reduce hematoma formation.

15. The device according to any one of the preceding claims, wherein the device is treated with or conjugated to a member selected from heparin, hirudin and a combination thereof.

16. The device according to any one of the preceding claims, wherein the device is treated with or conjugated to an antimicrobial and/or antibiotic to reduce cell proliferation.

17. The device according to any one of the preceding claims, wherein the device is treated with or conjugated to a cell non-proliferation compound.

18. The device according to any one of the preceding claims, wherein the device is treated with or conjugated to at least one of sirolimus and paclitaxel.

19. The device according to any one of the preceding claims, wherein the device is a drug-eluting device.

20. The device according to any one of the preceding claims, wherein the device is configured to deliver a plaque-dissolving drug to a site internal to the subject.

21. The device according to any one of the preceding claims, wherein at least a portion of the device is covered with electrospun nanofibers of a member selected from extracellular matrix (ECM), collagen, and combinations thereof.

22. The device according to any one of the preceding claims, wherein the device has a sufficient porosity to reduce seroma formation.

23. The device according to any one of the preceding claims, wherein the porosity of the device is substantially uniform throughout the walls of the device.

24. A method of accessing a subject comprising: positioning a device according to any one of the preceding claims around a target conduit; piercing the body wall of the subject thereby accessing an interior of the subject through the device; and flowing a fluid through the device.

25. A method of treating a diseased vessel comprising: positioning a device according to any one of the preceding claims around the diseased vessel; and flowing a fluid to the device.

26. A biocompatible dialysis device, the device comprising: a porous, flexible tube; and a sleeve positioned around a portion of the circumference of the tube, the sleeve being formed of a plurality of biocompatible fibers configured to be in fluid communication with the tube and to seal the tube to essentially completely prevent leakage of fluid flowing therethrough.

27. The device according to claim 26, wherein the porous, flexible tube comprises a hollow, vascular graft configured to allow a fluid to flow therethrough for dialysis.

28. The device according to claim 27, wherein the porosity of the vascular graft is sufficient such that the sleeve is in fluid engagement with the fluid.

29. An implantable, biocompatible device for insertion into a subject, the device comprising: an access conduit having an insertion end configured to be implanted to access the interior of the subject through the access conduit interior; a sleeve member positioned on at least a portion of the access conduit adjacent the insertion end, the sleeve member being configured to be at least partially disposed within and essentially completely sealed to the inner surface of the body of the subject when emplaced; wherein the sleeve member is formed of a biocompatible polymeric material.

30. The device according to claim 29, further comprising an axially movable needle configured to extend through the conduit to the insertion end and provide an access opening at the site for the conduit and sleeve member, wherein the sleeve member is configured to maintain the access opening after removal of the needle.

31. The device according to claims 29 or 30, wherein the access conduit is removable and the sleeve member is configured to maintain the access opening after removal of the conduit.

32. The device according to any one of claims 29-31 , wherein the sleeve member is configured to be in fluid communication with conduit interior and to seal the conduit to reduce leakage of the fluid flowing therethrough.

33. The device according to any one of claims 29-32, wherein the conduit is formed of ePTFE.

34. A method of administering a treatment, the method comprising: inserting a porous access conduit through an implant site to access a subject; before or after the inserting, forming a sleeve member on at least a portion of the access conduit adjacent the insertion end such that the sleeve member is at least partially disposed within the access site when emplaced, wherein the sleeve member is configured to be in fluid communication with conduit interior and to seal the conduit to essentially completely prevent leakage of the fluid flowing therethrough; positioning the conduit and sleeve at a target site; and flowing a fluid through the conduit and sleeve member for dialysis of the subject.

35. The method according to claim 34, wherein the sleeve member is formed of biocompatible polymer fibers.

36. The method according to claims 34 or 35, wherein the positioning is accomplished by a surgical robot.

37. A method of forming a biocompatible device for a conduit, the method comprising: providing a conduit for insertion into a subject, the conduit having a porous surface; electrospinning biocompatible fibers on an exterior surface of the conduit to a sufficient thickness such that the fibers are rigidly formed around the surface; securing the fibers to the conduit to form the biocompatible device, wherein the plurality of fibers are configured to be fluid communication with fluid flowing through the conduit and seal the conduit to essentially completely prevent leakage of the fluid.

38. The method according to claim 37, further comprising treating at least one of the conduit and the plurality of fibers with a drug treatment.

39. The method according to claims 37 or 38, further comprising treating at least one of the conduit and the plurality of fibers with a low concentration of polyurethane solution.

40. The method according to any one of claims 37-39, wherein the securing is accomplished by mechanical fasteners.

41. The method according to any one of claims 37-40, wherein the securing is accomplished by application of an adhesive compound over a

predetermined length of the conduit and sleeve.

42. The method according to claim 41, wherein the adhesive compound is a biocompatible glue.