WO2015051042A2

WO2015051042A2 - Meshes and patches for tissue repair

Info

Publication number: WO2015051042A2
Application number: PCT/US2014/058698
Authority: WO
Inventors: Ron Sostek
Original assignee: Harvard Apparatus Regenerative Technology, Inc.
Priority date: 2013-10-01
Filing date: 2014-10-01
Publication date: 2015-04-09
Also published as: WO2015051042A3

Abstract

Aspects of the disclosure relate to compositions and designs for synthetic material for implantation in a subject to promote tissue repair. In some embodiments, a synthetic mesh or patch is provided for promoting repair of a target tissue. In some embodiments, a synthetic mesh or patch is provided that comprises isotropically-distributed, non-woven electrospun fibers. In some embodiments, a mesh or patch is provided that has a central region that is thicker than one or more edges or comprises one or more perforations.

Description

MESHES AND PATCHES FOR TISSUE REPAIR

RELATED APPLICATIONS

This application claims priority under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application No. 61/885,485, filed on October 1, 2014 and entitled "MESHES AND PATCHES FOR TISSUE REPAIR" and U.S. Provisional Patent Application No. 61/886,106, filed on October 3, 2014 and entitled "MESHES AND PATCHES FOR TISSUE REPAIR". Each of these applications is incorporated herein by reference in its entirety for all purposes.

BACKGROUND OF INVENTION

Synthetic meshes and patches can be used to repair tissue damage including tissue tears (including for example hernias), tissue holes, and anastomoses. Synthetic material can be surgically introduced at a site of tissue damage to provide physical support and also to promote tissue growth at the site. However, conventional synthetic materials often fail due to insufficient cellularization, infection, and/or inflammation at the site of tissue repair. In addition, conventional synthetic materials often shift within the body of a subject. In some cases, the materials may shift, resulting in discomfort, incomplete repair, or failure of the repair. Shifting of meshes may occur as a result of encapsulation. Undesirable shifting or migration of synthetic material within the body of a subject also can promote inflammation, infection, or further damage (e.g. , damage including tissue tears, esophageal and tracheal fistulas) at the surgical site. Also, conventional materials may be relatively flat and rigid causing frictional tissue damage (e.g. , with vaginal meshes and hernia patches).

SUMMARY OF THE INVENTION

Aspects of the disclosure relate to compositions and designs for synthetic material for implantation in a subject to promote tissue repair. In some embodiments, compositions and designs are provided that comprise electrospun fibers arranged in distinct patterns, having distinct combinations of different materials, and/or having two or more layers in a configuration relative to each other to promote tissue regeneration and repair, in which the pattern,

combination of materials, or layering prevents or reduces migration of the composition after implantation into a patient. In some embodiments, electrospun material is provided having properties that enhance its stability when implanted in a subject and its physical interaction at the site of implantation to minimize migration or shifting of all or part of the implant in the subject. Accordingly, in some embodiments, designs or methods of manufacturing electrospun materials are provided herein that incorporate features to prevent migration after implantation. In some embodiments, designs or methods provided herein avoid introducing a grain (e.g. , alignment) into fibers arrangements but rather produce randomly arranged fibers.

According to some aspects of the disclosure, a synthetic mesh or patch is provided that is useful for promoting restoration or repair of a target tissue. In some embodiments, the tissue in need of repair is a tissue that has been damaged during surgery. In some embodiments, the tissue in need of repair is a tissue that has undergone traumatic damage (e.g. , a blunt trauma or cut) or damage associated with a disease (e.g. , cancer) or other condition (e.g. , ischemia, a burn). In some embodiments, the damage is a tissue tear or an esophageal fistula or tracheal fistula) In some embodiments, a synthetic mesh or patch is provided that comprises isotropically- distributed, non-woven electrospun fibers. In some embodiments, isotropically-distributed, non- woven electrospun fibers lack a well-ordered arrangement (e.g. , are randomly arranged). In some embodiments, isotropically-distributed, non-woven electrospun fibers result in a patch or mesh having substantially directionally independent material or structural properties. In some embodiments, isotropically-distributed, non-woven electrospun fibers are configured to accommodate deformation of a synthetic mesh or patch when implanted at a site of a target tissue without substantial migration from the site. In some embodiments, a synthetic mesh or patch is planar, e.g. , for tissue tears, hernias, etc. In some embodiments, a synthetic mesh or patch is tubular or other three-dimensional structure. In some embodiments, a target tissue of a patch or mesh is a trachea or esophagus. In some embodiments, the length of the tubular synthetic mesh or patch for implantation at an esophageal site is 1/8 to 1/4 (e.g. , approximately 1/6) the length of the esophagus (e.g. , an esophagus of a human infant, child or adult). In some embodiments, a tubular synthetic mesh or patch is 2 cm to 6 cm in length. In some embodiments, a tubular synthetic mesh or patch has an internal diameter in a range of 1 cm to 5 cm. In some

embodiments, fibers are polyethylene terephthalate fibers. In some embodiments, a synthetic patch or mesh comprises one or more perforations. In some embodiments, a synthetic mesh or patch is configured to be implanted at a tissue site by sutures. In some embodiments, a synthetic mesh or patch comprises reinforcing structures (e.g. , at one or more ends or edges) to facilitate suturing at the site.

According to some aspects of the disclosure, a synthetic mesh or patch is provided that comprises a non- woven electrospun fiber, in which the mesh or patch has a central region that is thicker than one or more edges of the mesh or patch In some embodiments, the mesh or patch has a smooth transition from the central region to the one or more edges.

According to some aspects of the disclosure, a synthetic mesh or patch is provided that comprises a non- woven electrospun fiber, in which the mesh or patch comprises one or more perforations. In some embodiments, the mesh or patch comprises one or more perforations having an opening in a range of 10 microns to 1 mm in diameter. In some embodiments, the mesh or patch comprises one or more perforations having an opening in a range of 10 microns to 50 microns in diameter.

In some embodiments, a mesh or patch is configured for promoting restoration or repair of a target tissue of a mammalian subject. In some embodiments, a mesh or patch is coated with a decellularized tissue. In some embodiments, the mesh or patch is coated with a decellularized tissue product, such as, for example, Cultrex Basement Membrane Extract, ACELL® Matristem Matrix Products, Geltrex® Matrix Products, Corning® Matrigel® Matrix, or other similar product. In some embodiments, the decellularized tissue is derived from a parenchymal tissue (e.g. , brain, skin, lungs, gastrointestinal tract, liver, pancreas, spleen, kidney, or heart tissue). In some embodiments, the decellularized tissue is derived from a structural tissue (e.g. , tendon, ligament). In certain embodiments, the decellularized tissue is autogenic with respect to the subject. In certain embodiments, the decellularized tissue is allogenic with respect to the subject. In certain embodiments, the decellularized tissue is xenogenic with respect to the subject. In some embodiments, the mesh or patch is populated with cells (e.g. , mammalian cells), for example, before and/or after implantation. In some embodiments, the cells are allogenic with respect to the subject. In some embodiments, the cells are allogenic with respect to the subject. In some embodiments, the cells are xenogenic with respect to the subject.

Aspects of the disclosure relate to a synthetic patch or mesh comprising non-woven electrospun fibers, in which the synthetic patch or mesh comprises one or more internal compartments or conduits and an injection port configured permit a fluid to be injected into the one or more internal compartments or conduits. In some embodiments, the fluid to be injected comprises a drug, cellular nutrients or a cell suspension. Aspects of the disclosure relate to a synthetic patch or mesh comprising non-woven electrospun fibers, in which the synthetic patch or mesh comprises one or more reservoirs, channels, or internal compartments or conduits. In some embodiments, the disclosure relates to a synthetic patch or mesh in which the one or more reservoirs, channels, or internal compartments or conduits are configured to contain a mixture comprising a drug, cellular nutrients or a cell suspension. In some embodiments, the drug is a small molecule or biologic medical product. In some embodiments, the cellular nutrients comprise growth factors (e.g. , angiogenic growth factors, such as VEGF), ligands or cytokines. In some embodiments, the disclosure relates to a synthetic patch or mesh in which the one or more reservoirs, channels, or internal compartments or conduits are configured to contain a bioresorbable material.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 illustrates a non-limiting example of a cross- sectional view of synthetic material that is thicker in the middle and thinner on its outer edges; a hole is depicted as a gap between two bold lines;

FIG. 2A illustrates a non-limiting embodiment of a patch or mesh that includes one or more rectangular shaped perforations in different types of patches or meshes, or one or more star-shaped perforations;

FIG. 2B illustrates a perforated patch that is placed on a damaged tissue;

FIG. 3A illustrates a non-limiting example of a cylindrical synthetic material that includes one or more perforations;

FIG. 3B illustrates a non-limiting example of a cylindrical synthetic material being used to connect two cylindrical tissues in situ;

FIG. 3C illustrates a non-limiting example of a cylindrical synthetic material being used to connect two cylindrical tissues in situ;

FIG. 3D illustrates a non-limiting example of a cylindrical synthetic material being used to connect two cylindrical tissues in situ;

FIG. 4A illustrates a non-limiting example of a rectangular three-dimensional material having an injection port for delivering materials to an internal region;

FIG. 4B illustrates a non-limiting example of a rectangular three-dimensional material having two absorbable or permanent delivery channels;

FIG. 4C illustrates a non-limiting example of a cylindrical material having a

longitudinally aligned concave region and containing an embedded absorbable structure; and

FIG. 4D illustrates a non-limiting example of a three-dimensional material having surface channels connected to a central reservoir (top panel = top view; lower panel = side view). DETAILED DESCRIPTION OF THE INVENTION

Aspects of the disclosure relate to compositions and designs for synthetic material for implantation in a subject to promote tissue damage repair or wound repair. In some

embodiments, non- woven electrospun material is used to produce material for a patch or mesh. As used herein, the term "patch" or "mesh" refers to a material designed and configured to cover, conceal, regenerate, reinforce and/or repair a wound, opening, tear or other aberration of a biological membrane or tissue. In some embodiments, a patch or mesh comprises one or more layers of different materials (e.g. , a backing layer, a drug containing layer, a cellular layer). In some embodiments, a patch or mesh is a relatively flexible material that can be placed over a wound, opening, tear or other aberration of a biological membrane or tissue. In some embodiments, a patch or mesh may be used to connect two or more biological membranes or tissues. In some embodiments, a patch or mesh is configured to be fixed in place on a biological membrane or tissue (e.g. , via one or more sutures, via one or more adhesive surfaces, and combinations thereof.) In some embodiments, a patch or mesh is sufficiently flexible such that when it is sutured or adhered to a biological tissue (e.g. , skin, cartilage, fascia, tracheal tissue, esophageal tissue) it can bend together with the biological tissue such that is does not damage the biological tissue or move out of place. In some embodiments, a patch or mesh is composed of one or more biologically compatible materials that do not elicit an immunogenic,

inflammatory, and/or necrotic response.

Aspects of the disclosure relate to compositions and methods that can be used for wound or tissue damage repair in humans or in any suitable animal (for example, mammals or other animals). Aspects of the disclosure can be used in connection with planar patches or meshes for tissue repair (e.g. , for hernia or other tissue repair) or in connection with cylindrical patches or meshes that can be used for repairing damaged airway tissue for example. In some

embodiments, patches or meshes are configured as three-dimensional constructs (e.g. , tubular, cylindrical or polyhedronic constructs). In some embodiments, electrospun patches are shaped as a mat or sheet. In some embodiments, electrospun patches are shaped as cylinders.

In some embodiments, a patch or mesh (e.g. , containing electrospun material) is produced to have a shape (e.g. , a cross-sectional profile) that reduces the incidence of debris and cell accumulation within the implanted material. In some embodiments, a patch or mesh is thicker in a central region than on one or more outer edge(s). This configuration reduces the presence of "steps" or "shelves" or other edge effects that often occur with current patches or meshes that tend to be thicker around the edges than in their central regions. The resulting ridge can catch food, cellular debris, or other material, and also can form a site at which unwanted bacterial or other microorganismal growth occurs. It has been appreciated that unwanted accumulation of debris or microorganismal growth often degrades the performance of current devices that are characterized by relatively thicker "steps" or "shelves" (e.g. , around their edges). In contrast, devices described herein have one or more edges with relatively thin cross- sections. This reduces the accumulation of unwanted material or microorganisms. In some embodiments, the one or more edges have cross-sections having a thickness in a range of up to 10 , up to 20 , up to 30 , up to 40 , up to 50 , up to 60 , up to 70 , up to 80 , up to 90 , or up to 95% of the thickness of the central region of the patch or mesh. It should be appreciated that cross-sections of the one or more edges can be a variety of different shapes. In some embodiments, the one or more edges have circular, elliptical, rounded, or polygonal cross- sections.

FIG. 1 illustrates a non-limiting example of a cross- sectional view (100) of a synthetic material that is thicker in the middle and thinner on its outer edges. However, it should be appreciated that devices described herein do not need to be symmetrically designed and any combination of cross-sectional shapes can be used provided that at least one edge (or at least a portion of an edge) is thinner than a central region (or a portion thereof) of the device. Upon implantation, a patch or mesh can be sutured over a hole in a tissue of a host. For example, in FIG. 1, a patch or mesh as described herein (101) is used to repair a hole in a tissue (102). FIG. l also shows a patch or mesh (104) that is essentially of uniform thickness over a hole in a tissue (103). It should be appreciated that the hole depicted in FIG. 1 is merely illustrative and that many different shapes of rips, tears, cuts or other forms of tissue damage may be present and/or suitable for repair by a mesh or patch.

Similar design considerations can be used for cylindrical patches or meshes. For example, one or more ends of a cylindrical patch or mesh can have a low profile (e.g. , be thinner relative to a central region of the cylindrical device), such that the cross-section of the wall of the cylindrical patch or mesh (e.g. , rather than the diameter of the cylindrical patch or mesh) is thinner at the ends.

In some embodiments, a patch or mesh has a geometric aspect ratio of a thin object. In some embodiments, a patch has a relatively large dimension (e.g. , length, width, diameter, etc.) in a range of 1 mm to 10 mm, 5 mm to 10 mm, 10 mm to 15 mm, 15 mm to 20 mm, 20 mm to 25 mm, 25 mm to 30 mm, 30 mm to 35 mm, 35 mm to 40 mm, 40 mm to 45 mm, 45 mm to 50 mm, 50 mm to 100 mm, 100 mm to 500 mm, 100 mm to 1 cm, 1 cm to 5 cm, 5 cm to 10 cm, 10 cm to 100 cm, or more. In some embodiments, a patch or mesh has a relatively small dimension of up to 1 μιη, up to 10 μιη, up to 5 mm, 10 mm, 15 mm, 20 mm, 25 mm, 50 mm, 100 mm, 500 mm, 1 cm, 10 cm, 40 cm to 50 cm, 40 cm to 100 cm, 50 cm to 100 cm, 100 cm or more. In some embodiments, the ratio (the aspect ratio) of a large dimension (e.g. , length, width, diameter) to small dimension (thickness) of the patch is about 10,000 to 1, about 5000 to 1, about 2000 to 1, about 1000 to 1, about 500 to 1, about 200 to 1, about 100 to 1, about 10 to 1.

In some embodiments, a patch or mesh has a cross sectional shape of a polygon (e.g. , square, rectangle). In some embodiments a patch or mesh has a cross sectional shape of a rounded object (e.g. , circle, oval, ellipse). In some embodiments, a patch has a cross sectional shape having a combination of straight and rounded edges.

In some embodiments, a patch has a small dimension (thickness) in a range of about 1 μιη to about 10 μιη, about 10 μιη to about 100 μιη, about 100 μιη to about 1 mm, about 0.005 mm to about 0.05 mm, about 0.05 mm to about 0.1 mm, about 0.1 mm to about 0.5 mm, about 0.5 mm to about 1 mm, about 1 mm to about 5 mm, about 1 mm to about 10 mm, or about 5 mm to about 20 mm. In some embodiments, a patch has a relatively small dimension (e.g. , thickness) of about 1 μιη, about 10 μιη, about 0.05 mm, about 0.1 mm, about 0.2 mm, about 0.5 mm, about 1 mm, about 5 mm, about 10 mm or more. In some embodiments, a patch has a central region of a uniform thickness and a thinner surrounding or peripheral region. In some embodiments, the transition from the central uniform thickness to the thinner surrounding or peripheral region is a smooth tapered transition. In some embodiments, a patch has a thin dimension having a smooth tapered transition from a relatively thick inner region to a relatively thin outer region or periphery. In some embodiments, the thin outer region or periphery has a cross- sectional thickness that is in a range of up to 10 , up to 20 , up to 30 , up to 40 , up to 50 %, up to 60 %, up to 70 %, up to 80 %, up to 90 %, or up to 95% of the inner region.

In some embodiments, a patch or mesh can include, or consist essentially of, or consist of, spun nanofibers (e.g. , electrospun nanofibers), spun microfibers (e.g. , electrospun microfibers), printed material (e.g. , printed fibers), extruded material (e.g. , extruded fibers), molded material (e.g. , molded fibers), chemically formed material (e.g. , chemically formed fibers), or any combination of two or more thereof. In some embodiments, a patch or mesh comprises a synthetic material (e.g. , a synthetic membrane) that is coated with nanofibers or microfibers (e.g. , spun nanofibers (e.g. , electrospun nanofibers), spun microfibers (e.g. , electrospun microfibers).) For example, a commercially available material (e.g. , synthetic materials composed of VICRYL™ (Ethicon, Inc., Somerville, NJ) or DEXON™ (Covidien, Mansfield, MA) materials, GORE® BIO- A® Tissue Reinforcement material, TIGR® Matrix material, Marlex knitted polypropylene material, etc.) or other woven or knitted materials can be covered, at least partially, by a layer of nanofibers or microfibers. In some embodiments, the surface area of the at least partially covered material is less than 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90% covered by the layer of nanofibers or microfibers.

In some embodiments, the nanofibers or microfibers are more biologically compatible than the underlying patch material and cause less inflammation than the underlying patch alone after implantation in a subject.

In some embodiments, a patch or mesh comprises a hydrogel portion. In some embodiments, a patch or mesh comprises a drug delivery layer that is configured and arranged for controlled release of a drug or other therapeutic agent from the patch or mesh. In some embodiments, the drug delivery layer comprises a hydrogel or other material that is loaded with a drug or therapeutic agent for controlled release. In some embodiments, a patch or mesh includes a relatively impermeable backing layer (e.g. , that is impermeable to the drug or therapeutic agent). In some embodiments, the backing layer is adjacent to the drug delivery layer and the drug delivery layer interfaces with the biological membrane or tissue; in this manner the backing layer confines (or substantially confines) delivery of the drug to a region within the patch or membrane coverage area.

In some embodiments, a patch or mesh is designed and configured to achieve and/or maintain desired mechanical (e.g. , elastic, viscoelastic) properties of the patch or mesh. For example, in some embodiments, a patch or mesh comprises a layer of fibers (e.g. , nanofibers) deposited over a material (e.g. , a woven material) in order to achieve and/or maintain desired mechanical (e.g. , elastic, viscoelastic) properties of the woven material (e.g. , polypropylene, tetrafluoroethylene, polyglycolic acid, polyglactin 910, polylactic acid, polycaprolactone) while reducing inflammatory responses caused by the woven material. In some embodiments, the desired mechanical (e.g. , elastic, viscoelastic) properties of the patch or mesh are similar to or identical to a biological tissue or membrane that the patch or mesh is designed to cover. In some embodiments, a patch or mesh comprises absorbable, biodegradable or bioresorbable materials (e.g. , fibers). However, in some embodiments, a patch or mesh comprises non-absorbable, nonbiodegradable or non-bioresorbable materials (e.g. , fibers).

In some embodiments, a patch or mesh may have one or more channels (e.g. , perfusion channels) for delivering drugs and/or cells. In some embodiments, the flow of material and/or cells from the channels can be controlled (e.g. , via pressure or other force applied to the patch).

It should be appreciated that meshes or patches can be prepared under sterile conditions and/or sterilized after production so that they are suitable for cellularization. It should be appreciated that the types of cells that are used for cellularization will depend on the tissue type that is being produced or repairs. In some embodiments, one or more different tissue-specific (e.g. , tissue-specific stem or progenitor) cells may be used. In some embodiments, different combinations of epithelial, endothelial, and/or structural cell types may be used to populate an elastic scaffold. In some embodiments, cells are selected to be compatible (e.g. ,

histocompatible) with the host into which the mesh or patch is being transplanted. In some embodiments, one or more cell types that are isolated from the host are used to seed the mesh or patch. In some embodiments, the seeded mesh or patch is incubated to allow the cells to grow and further populate the mesh or patch prior to surgical implantation.

In some, embodiments, fibers used in or for coating patches or meshes described herein range from around 1 nm to around 10 microns in diameter (e.g. , less than 10 microns, less than 5 microns, less than 1 micron, less than 500 nm, less than 100 nm, less than 10 nm, or any intermediate range or size). In some embodiments, a patch or mesh includes an even (e.g. , homogeneous) or uneven (e.g. , heterogeneous) distribution of one or more fiber types. In some embodiments, a combination of one or more thin fiber types (e.g. , for promoting cellularization) and one or more thick fiber types (e.g. , to physically strengthen the material) can be used. Thin fibers can be, for example, 800 nm thick or less. Thick fibers can be, for example, 10-20 microns thick or more. In some embodiments, fibers of different dimensions can be mixed. For example, in some embodiments, fibers over 10 μιη can be mixed with fibers below 1 nm to make a patch or mesh stronger while retaining its ability to cellularize and/or vascularize sufficiently.

In some embodiments, non- woven fibers are used to produce a patch or mesh that does not have any significant grain (e.g. , directionality of fibers) that could cause the patch or mesh to shift after implantation in a subject. Accordingly, in some embodiments, a patch or mesh has isotropic material properties. However, in some embodiments, a patch or mesh has anisotropic material properties.

In some embodiments, a patch or mesh described herein (e.g. , a low profile patch or mesh that is thicker in the center relative to the outside edges) can be electrospun on an electro spinning device (e.g. , using electro spinning to deposit material on a mandrel or other electro spinning collector). In some embodiments, a desired distribution of electrospun fiber thickness can be obtained by using a collector that is more conductive in areas where thicker layers of fiber is desired. In some embodiments, a collector (e.g. , mandrel) can include one or more shapes (e.g. , dimples) having a shallow outside and a deeper inside. In some

embodiments, one or more regions of higher conductivity are used (e.g. , on a collector such as a mandrel) to control the relative amount of material that is deposited in different areas of a patch or mesh. In some embodiments, the speed and frequency of deposition by an electro spinning sprayer over a surface area of a collector can be adjusted (e.g. , to control the relative amounts of material that is deposited in different areas of the material being synthesized). For example, an electro spinning device can be adjusted to tune the relative rate of deposition to be faster (and less frequency) over the edges of a patch than in the middle. This can be done by adjusting the voltage, speed of transition of the sprayer, speed of rotation of a collector (e.g. , mandrel) of the electro spinning device. In some embodiments, a mandrel can be designed to produce low profile tubes and sheets. Similarly, the relative amount of fibers deposited in different regions of the tubes and sheets may be adjusted or controlled.

In some embodiments, patches or meshes (e.g. , electrospun patches or meshes) include one or more regions that are welded or otherwise connected together. These regions can be useful to prevent delamination of the different layers of the material, and/or to provide physical support (e.g. , to protect against tearing, stretching, or to provide an anchor for sutures or other attachment to the tissue of a subject). It should be appreciated that any suitable technique can be used to introduce connections (e.g. , welds) at one or more sites. Non-limiting techniques include heating, ultrasonic, laser, electrical or chemical (e.g. , chemical melting) techniques, or a combination thereof. In some embodiments, a side edge (e.g. , the entire peripheral edge of a mesh or patch), or a portion thereof can be welded or otherwise connected (e.g. , fused).

In some embodiments, a mesh or patch can be sutured in place. In some embodiments, one or more suture holes are provided (e.g. , around the edges or periphery of the patch, or anywhere on the patch) to assist in suturing the patch into place in a subject. In some embodiments, the suture holes are reinforced around their edges (e.g. , using laser, thermal, ultrasonic, or chemical welds, or chemical adhesives, or other reinforcement).

In some embodiments, reinforcing structures can be provided in a mesh or patch for purposes of strengthening the mesh or patch. For example, a reinforcing structure, such as a suturing bar, can be provided in the middle or edges of a mesh or patch to form physical reinforcements for suturing or other purposes. A reinforcing structure may be fixed in place using an adhesive or welds (e.g. , via a laser, ultrasound, or chemicals). Reinforcing structure(s) may be composed of the same or different materials used in the corresponding mesh or patch. In some embodiments, reinforcing structure(s), when provided in a patch or mesh, confer(s) on the patch or mesh a greater resistance to bending, stretching, compression or tearing. In some embodiments, reinforcing structure(s), when provided in a patch or mesh, confer(s) on the patch or mesh a resistance to bending, stretching, compression or tearing that is in a range of 1.5 to 100 times, 1.5 to 50 times, 5 to 50 times, or 5 to 25 times greater than the resistance to bending, stretching, compression or tearing exhibited by a patch or mesh of similar or equivalent size and shape that does not have reinforcing structure(s).

In some embodiments, a mesh or patch can be fixed in place with one or more adhesive layers. In some embodiments, one or more adhesive layers are provided (e.g. , at the periphery of the mesh or patch) to secure the mesh or patch in place. In some embodiments, a mesh or patch is fixed in place through a combination of one or more sutures and one or more adhesive layers. In some embodiments, one or more sutures and/or adhesive layer(s) provide a seal that isolates a tissue for which the mesh or patch is configured to cover from a surrounding environment. In some embodiments, the mesh or patch is relatively permeable to water and certain solutes. In some embodiments the mesh or patch is relatively permeable to water and but impermeable to certain solutes.

In some embodiments, one or more regions of a mesh or patch can be strengthened by fusing fibers and/or layers of fibers (e.g. , electrospun fibers). In some embodiments, fusion can be accomplished via welding, for example by heating, or using ultrasonic or laser techniques, and/or by chemical melting, or a combination thereof. In some embodiments, welds or other regions of material fusion can be introduced at one or more positions within a mesh or patch (or around the mesh or patch) to provide support (e.g. , for suturing, etc.). In some embodiments, a weld or other region of fiber fusion is used to produce a reinforcing region around and/or over at least a portion of the mesh or patch. In some embodiments, a reinforcing layer provides a structure through or around which a suture may be passed to secure the mesh or patch in place at a tissue site.

In some embodiments, one or more openings (e.g. , holes, slits, or other perforations of any shape can be introduced into a patch or mesh). FIG. 2 A illustrates a non-limiting embodiment of a patch or mesh (201, 204, 209, 212) that includes one or more rectangular shaped perforations (202, 206, 210 and 211) in different types of patches or meshes, or one or more star-shaped perforations (203). However, it should be appreciated that other perforation shapes can be incorporated into a patch or mesh. For example, perforations of other geometric shapes can be incorporated into a patch or mesh such as, for example, circular, oval, rectangular, star, other shapes, including irregular shapes, and combinations of different shapes.

FIG. 2B illustrates a perforated patch (216) that is placed on a damaged tissue (217). It should be appreciated that perforated patches or meshes may be used in connection with damaged tissue where regions of healthy tissue remain (as opposed to non-perforated patches or meshes that are typically treated with non-perforated material). In some embodiments, perforated patch or mesh may be used to cover a hole or other condition where no significant amount of host tissue remains. However, it should be appreciated that perforated and non- perforated patches or meshes can be used in other contexts too.

In some embodiments, one or more openings can be introduced into a patch or mesh during synthesis (e.g. , by adapting an electro spinning technique to avoid depositing fibers in one or more areas). In some embodiments, one or more openings can be introduced after synthesis. In some embodiments, one or more openings be in a range of 1 to 10 microns, 5 to 50 microns, 10 to 50 microns, 25 to 100 microns, 25 microns to 1 mm, 50 microns to 1 mm, 100 microns to 1 mm, 500 microns to 5 mm or more across (e.g. , in diameter).

In some embodiments, the edges (or portions thereof) of the one or more openings can be reinforced by welding or other material fusion techniques described herein, for example. For example, star shape (203) in FIG. 2A is not illustrated as having a reinforced edge in contrast to the other star- shaped perforations in material (204).

FIG. 3 illustrates a non-limiting example of a cylindrical synthetic material (301, 303) includes one or more perforations (302), and can be used to connect two cylindrical tissues in situ (304, and 305). FIG. 3 also depicts steps (307-309) for connecting two cylindrical tissues (304 and 305) together with a cylindrical synthetic material (303). For example, the cylindrical tissues can be parts of the airway (e.g. , of a human subject) or other cylindrical tissue. In some embodiments, an electrical weld technique may be used to produce a hole or perforation (e.g. , in a range of 20 to 50 microns or 35 to 40 microns across (e.g. , in diameter)) in a patch or mesh that involves passing an electrical current through a mesh or patch sufficient to produce a hole or perforation through the patch or mesh. The process may be repeated at different positions in the patch or mesh to create a pattern of holes or perforations in the patch or mesh.

It should be appreciated that in some embodiments perforations allow cells at the site of implantation to more quickly and efficiently populate the synthetic material (for example, this allows tissue to grow from the perforations in addition to the ends of a cylindrical material).

In some embodiments, perforations (e.g. , holes, slits) can range from small micron-sized holes to millimeter- sized holes. In some embodiments, perforations (e.g. , holes, slits) can have at least one dimension (e.g. , diameter, length, width) in a range of 1 micron to 10 microns, 5 microns to 25 microns, 10 micros to 50 microns, 25 microns to 75 microns, 50 microns to 1 mm, 500 microns to 5 mm, 1 mm to 5 mm, or more. In some embodiments, perforations (e.g. , holes, slits) are spaced approximately 50 microns to 1 mm from each other (e.g. , on center). However, other sizes of holes or relative positioning can be used. In some embodiments, perforations (e.g. , holes, slits) can be welded (e.g. , heat welded) on their periphery or edges to make them stronger. In some embodiments, perforations (e.g. , holes, slits) can be cut out from a patch or mesh using laser, heat, electrical shock- welding or ultrasonic techniques.

It should be appreciated that a patch or mesh can be of any suitable size or shape (e.g. , square, rectangular, oval, circular, or other regular or irregular shape), and can be positioned at any suitable location in a subject. In some embodiments, a synthetic patch or mesh is designed to form a cylinder (e.g. , it is electrospun onto a cylindrical mandrel or is synthesized as a sheet that then rolled to form a cylinder).

In some embodiments, patches or meshes are formed as tubular structures that can be seeded with cells (e.g. , before and/or after implantation into a host) to form tubular tissue regions (e.g. , segments of tracheal, bronchial, or other tubular regions). It should be appreciated that a tubular region can be a hollow cylinder with a uniform passage (e.g. , inner diameter). However, in some embodiments, a tubular region can have any appropriate tubular shape (for example, including portions with different diameters along the length of the tubular region). In some embodiments, a tubular patch or mesh is produced having an opening at one end, both ends, or a plurality of ends. However, a tubular patch or mesh may be closed at one, both, or all ends, as aspects of the disclosure are not limited in this respect.

In some embodiments, a patch or mesh has a porous structure. In some embodiments, a patch or mesh has pores ranging from around 10 nm to about 100 micron in diameter that can promote cellularization. However, it should be appreciated that pores of other sizes also can be included. In some embodiments, a surface layer, channel, conduit or other feature of a patch or mesh is synthesized using fibers that include one or more dissolvable components that can be dissolved during or after synthesis (e.g. , by exposure to a solvent, an aqueous solution, for example, water or a buffer) to leave behind pores, channels or conduits the size of the dissolvable components. In some embodiments, the components are dissolvable particles included in a polymer mix that is pumped to the nozzle of an electro spinning device. As a result the particles are deposited along with the fibers. In some embodiments, dissolvable components are provided as a base on or around which a polymer is deposited, e.g. , by electro spinning.

In some embodiments, the electro spinning procedure is configured to deposit thick fibers (e.g. , having an average diameter of several microns, about 10 microns, and thicker). In some embodiments, if the fibers are deposited in a dense pattern, one or more fibers may merge prior to curing to form larger macrostructures (e.g. , 10- 100 microns thick or more). In some embodiments, these macrostructures can entangle two or more layers of fibers and or portions (e.g. , fibers) from two or more different components of a patch or mesh thereby augmenting (e.g. , increasing) the mechanical integrity of the patch or mesh. In some embodiments, when such macrostructures are formed (e.g. , via electro spinning as described herein) at one or more stages during synthesis (e.g. , to connect two or more layers and/or components), the surface of the macrostructure(s) can be treated (e.g. , etched or made porous using dissolvable particles as described herein) in order to provide a structure suitable for cellularization. In some

embodiments, cavities or depressions can be created to provide a structure suitable for cellularization.

In some embodiments, a patch or mesh is provided with an injection port configured for accessing an inner compartment or conduit or series of conduits or compartments of the patch or mesh. In some embodiments, an injection port enables injection of a drug, nutrient mix, cell suspension or other material into the inner compartment or conduit or series of conduits or compartments of the patch or mesh. In some embodiments, injection may be performed prior to implanting or positioning the patch or mesh in or on a subject. However, in some embodiments, injection may be performed after implanting or positioning (e.g. , adhering) the patch or mesh in or on a subject. FIG. 4A illustrates a composition (400) comprising a rectangular three- dimensional material (402) having an injection port (403) for delivering materials to an internal region via an injector (401) having a injector tip suitable for placement in the injection port (403).

In some embodiments, one or more components of a patch or mesh (e.g. , a structural component such as a channel or conduit) can function as a delivery device for a drug or other compound. In some embodiments, the one or more components can be coated and/or include one or more reservoirs of a drug or other compound (e.g. , one or more growth factors that promote cell growth and/or differentiation, a therapeutic drug or compound, an

immunomodulatory drug or compound, a drug or compound that acts on the patch or mesh or a portion thereof, a drug or compound that acts on the circulatory system of the host, a drug or compound that promotes vascularization and or other tissue growth in the host, or other drug or compound, or any combination thereof). FIG. 4B illustrates a composition (404) comprising a rectangular three-dimensional material (405) having two absorbable or permanent delivery channels (406, 407). FIG. 4C illustrates a composition (408) comprising cylindrical structure (409) having a longitudinally aligned concave region and containing an embedded structure (407) (e.g. , an absorbable / bioresorbable structure). FIG. 4D illustrates a composition (410) comprising a three-dimensional material (411, 414) having surface channels (412, 413) connected to a central reservoir (415).

In some embodiments, a drug or compound is delivered by elution from a coating, impregnation, or surface treatment of a patch or mesh. In some embodiments, a drug or compound is delivered by liquid injection from a reservoir within a patch or mesh. In some embodiments, a drug or compound is delivered from one or more reservoirs (e.g. , bladders) in a patch or mesh. It should be appreciated that the one or more reservoirs can deliver similar or different volumes of one or more different drugs or compounds. In some embodiments, a drug or compound is delivered by immediate release, delayed release, extended release, or a combination thereof. In some embodiments, a drug or compound can be delivered from an external reservoir.

In some embodiments, a patch or mesh is coated with a nutrient mix that promotes cellularization, cell growth or differentiation or that prevents or inhibits an immune response or immune rejection. In some embodiments, materials (e.g. , patch or mesh materials) can include one or more different types or natural or synthetic fibers (including for example, one or more collagens, inorganic polymers, PET, high molecular weight polyethylenes, or polyurethanes, etc.). In some embodiments, one or more types of fiber (e.g. , nanofibers) are used. In some embodiments, materials comprise one or more natural fibers, one or more synthetic fibers, one or more polymers, or any combination thereof. It should be appreciated that different materials (e.g. , including different fibers) can be used in methods and compositions described herein. In some embodiments, the material is biocompatible so that it can support cell growth. In some embodiments, the material is permanent (e.g. , PET), semi-permanent (e.g. , it persists for several years after implantation into the host, or rapidly degradable (e.g. , it is resorbed within several months after implantation into the host).

In some embodiments, materials contain or consist of electrospun material (e.g. macro or nanofibers). In some embodiments, the electrospun material contains or consists of PET (polyethylene terephthalate (sometimes written poly(ethylene terephthalate)). PET is a thermoplastic polymer resin of the polyester family. PET consists of polymerized units of the monomer ethylene terephthalate, with repeating

units. Depending on its processing and thermal history, polyethylene terephthalate may exist both as an amorphous (transparent) and as a semi-crystalline polymer. The semicrystalline material might appear transparent (particle size < 500 nm) or opaque and white (particle size up to a few microns) depending on its crystal structure and particle size. Its monomer (bis-P-hydroxyterephthalate) can be synthesized by the esterification reaction between terephthalic acid and ethylene glycol with water as a byproduct, or by transesterification reaction between ethylene glycol and dimethyl terephthalate with methanol as a byproduct. Polymerization is through a polycondensation reaction of the monomers (done immediately after esterification/transesterification) with water as the byproduct. In some embodiments, the electrospun material contains or consists of polyurethane (PU). In some embodiments, the electrospun material contains or consists of PET and PU.

In some embodiments, the artificial material may consist of or include one or more of any of the following materials: elastic polymers (e.g. , one or more polyurethanes (PU), for example polycarbonates and/or polyesters), acrylamide polymers, Nylon, resorbable materials (e.g. , PLGA, PLA, PGA, PCL), synthetic or natural materials (e.g. , silk, elastin, collagen, carbon, gelatin, chitosan, hyaluronic acid, etc.) or any combination thereof. In some

embodiments, the material may consist of or include addition polymer and/or condensation polymer materials such as polyolefin, polyacetal, polyamide, polyester, cellulose ether and ester, polyalkylene sulfide, polyarylene oxide, polysulfone, modified polysulfone polymers and mixtures thereof. In some embodiments, the material may consist of or include polyethylene, polypropylene, poly(vinylchloride), polymethylmethacrylate (and other acrylic resins), polystyrene, and copolymers thereof (including ABA type block copolymers), poly(vinylidene fluoride), poly(vinylidene chloride), polyvinylalcohol in various degrees of hydrolysis (e.g. , 87% to 99.5%) in cross-linked and non-cross-linked forms. In some embodiments, the material may consist of or include block copolymers. In some embodiments, addition polymers like polyvinylidene fluoride, syndiotactic polystyrene, copolymer of vinylidene fluoride and hexafluoropropylene, polyvinyl alcohol, polyvinyl acetate, amorphous addition polymers, such as poly(acrylonitrile) and its copolymers with acrylic acid and methacrylates, polystyrene, poly(vinyl chloride) and its various copolymers, poly(methyl methacrylate) and its various copolymers, and PET (polyethylene terephthalate (sometimes written poly(ethylene

terephthalate))) can be solution spun or electrospun and combined with any other material disclosed herein to produce a patch or mesh. In some embodiments, highly crystalline polymers like polyethylene and polypropylene may be solution spun or combined with any other material disclosed herein to produce a patch or mesh.

In some embodiments, aspects of the disclosure relate to meshes and patches that are produced or coated via electro spinning. Methods of electro spinning polymers are known in the art (see, e.g. (Doshi and Reneker. Electro spinning process and application of electrospun fibers. J Electrostat. 1995;35: 151-60.; Reneker DH, Chun I. Nanometer diameter fibers of polymer produced by electro spinning. Nanotechnology. 1996;7:216-23; Dzenis Y. Spinning continuous fibers for nanotechnology. Science. 2004;304: 1917-19; or Vasita and Katti. Nanofibers and their applications in tissue engineering. Int J. Nanomedicine. 2006; 1(1): 15-30).

Electro spinning is a versatile technique that can be used to produce either randomly oriented or aligned fibers with essentially any chemistry and diameters ranging from nm scale (e.g. , around 15 nm) to micron scale (e.g. , around 10 microns).

In some embodiments, electro spinning and electro spraying techniques used herein involve using a high voltage electric field to charge a polymer solution (or melt) that is delivered through a nozzle (e.g. , as a jet of polymer solution) and deposited on a target surface. The target surface can be the surface of a static plate, a rotating drum (e.g. , mandrel), or other form of collector surface that is both electrically conductive and electrically grounded so that the charged polymer solution is drawn towards the surface.

In some embodiments, the electric field employed is typically on the order of several kV, and the distance between the nozzle and the target surface is usually several cm or more. The solvent of the polymer solution evaporates (at least partially) between leaving the nozzle and reaching the target surface. This results in the deposition of polymer fibers on the surface.

Typical fiber diameters range from several nanometers to several microns. The relative orientation of the fibers can be affected by the movement of the target surface relative to the nozzle. For example, if the target surface is the surface of a rotating mandrel, the fibers will align (at least partially) on the surface in the direction of rotation. In some cases, the nozzle can be scanned back and forth between both ends of a rotating mandrel. This can produce a mesh of fibers that forms a cylinder covering at least a portion of the surface of the mandrel.

In some embodiments, the size and density of the polymer fibers, the extent of fiber alignment, and other physical characteristics of an electrospun material can be impacted by factors including, but not limited to, the nature of the polymer solution, the size of the nozzle, the electrical field, the distance between the nozzle and the target surface, the properties of the target surface, the relative movement (e.g. , distance and/or speed) between the nozzle and the target surface, and other factors that can affect solvent evaporation and polymer deposition. In some embodiments, isotropically-distributed non- woven fibers may be deposited using electro- spinning techniques. In some embodiments, isotropically-distributed fibers are deposited by controlling the distance of the nozzle from the target surface to achieve a random whipping action of the fibers being laid down upon the target surface. In some embodiments, the speed of a rotating mandrel comprising a target surface is controlled to facilitate a deposition of randomly oriented fibers.

Having thus described several embodiments with respect to aspects of the disclosure, it is to be appreciated various alterations, modifications, and improvements will readily occur to those skilled in the art. Such alterations, modifications, and improvements are intended to be part of this disclosure, and are intended to be within the spirit and scope of the disclosure.

Accordingly, the foregoing description and drawings are by way of example only.

The indefinite articles "a" and "an," as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean "at least one." The phrase "and/or," as used herein in the specification and in the claims, should be understood to mean "either or both" of the elements so conjoined, e.g. , elements that are conjunctively present in some cases and disjunctively present in other cases. Other elements may optionally be present other than the elements specifically identified by the "and/or" clause, whether related or unrelated to those elements specifically identified unless clearly indicated to the contrary. Thus, as a non-limiting example, a reference to "A and/or B," when used in conjunction with open-ended language such as "comprising" can refer, in one embodiment, to A without B (optionally including elements other than B); in another embodiment, to B without A (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

As used herein in the specification and in the claims, "or" should be understood to have the same meaning as "and/or" as defined above. For example, when separating items in a list, "or" or "and/or" shall be interpreted as being inclusive, e.g. , the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as "only one of or "exactly one of," or, when used in the claims, "consisting of," will refer to the inclusion of exactly one element of a number or list of elements. In general, the term "or" as used herein shall only be interpreted as indicating exclusive alternatives (e.g. "one or the other but not both") when preceded by terms of exclusivity, such as "either," "one of," "only one of," or "exactly one of." "Consisting essentially of," when used in the claims, shall have its ordinary meaning as used in the field of patent law.

As used herein in the specification and in the claims, the phrase "at least one," in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase "at least one" refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B," or, equivalently "at least one of A and/or B") can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

In the claims, as well as in the specification above, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," and the like are to be understood to be open-ended, e.g. , to mean including but not limited to. Only the transitional phrases "consisting of and "consisting essentially of shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

Use of ordinal terms such as "first," "second," "third," etc., in the claims to modify a claim element does not by itself connote any priority, precedence, or order of one claim element over another or the temporal order in which acts of a method are performed, but are used merely as labels to distinguish one claim element having a certain name from another element having a same name (but for use of the ordinal term) to distinguish the claim elements.

Claims

What is claimed is:

1 A synthetic mesh or patch for promoting restoration or repair of a target tissue, the synthetic mesh or patch comprising isotropically-distributed, non- woven electrospun fibers configured to accommodate deformation of the synthetic mesh or patch when implanted at a site of a target tissue without substantial migration from the site.

2 The synthetic mesh or patch of claim 1, wherein the synthetic mesh or patch is tubular.

3 The synthetic mesh or patch of claim 2, wherein the target tissue is a trachea or esophagus.

4 The synthetic mesh of patch of claim 3, wherein the target tissue is an esophagus and the length of the tubular synthetic mesh or patch is 1/8 to 1/4 the length of the esophagus.

5 The synthetic mesh or patch of claim 4, wherein the tubular synthetic mesh or patch is 2 cm to 6 cm in length.

6 The synthetic mesh or patch of claim 5, wherein the tubular synthetic mesh or patch has an internal diameter in a range of 1 cm to 5 cm.

7 The synthetic mesh or patch of any one of claims 1 to 6, wherein the fibers are polyethylene terephthalate fibers.

8 The synthetic mesh of patch of any one of claims 1 to 7, wherein the synthetic patch or mesh comprises one or more perforations.

9 The synthetic mesh or patch of claim 8, wherein the one or more perforations have an opening in a range of 10 microns to 1 mm in diameter.

10 The synthetic mesh or patch of claim 9, wherein the one or more perforations have an opening in a range of 10 microns to 50 microns in diameter.

11 The synthetic mesh or patch of any one of claims 1 to 10, wherein the synthetic mesh or patch is configured to be implanted at the site by sutures.

12 The synthetic mesh or patch of claim 11 further comprising reinforcing structures at one or both ends to facilitate suturing at the site.

13. A synthetic mesh or patch comprising a non- woven electrospun fiber, wherein the mesh or patch has a central region that is thicker than one or more edges or comprises one or more perforations.

14. The synthetic mesh or patch of claim 13, wherein the mesh or patch has a central region that is thicker than one or more edges, having a smooth transition from the central region to the one or more edges.

15. The synthetic mesh or patch of claim 13 or 14, wherein the mesh or patch comprises one or more perforations having an opening in a range of 10 microns to 1 mm in diameter.

16. The synthetic mesh or patch of claim 13 or 14, wherein the mesh or patch comprises one or more perforations having an opening in a range of 10 microns to 50 microns in diameter.

17. The synthetic mesh or patch of claim 13, wherein the mesh or patch is coated with a decellularized tissue.

18. The synthetic mesh or patch of claim 17, wherein the decellularized tissue is derived from a parenchymal tissue.

19. The synthetic mesh or patch of claim 17, wherein the decellularized tissue is derived from a structural tissue.

20. The synthetic mesh or patch of claim 18 or 19, wherein the mesh or patch is configured for promoting restoration or repair of a target tissue of a mammalian subject, wherein the decellularized tissue is autogenic with respect to the subject.

21. The synthetic mesh or patch of claim 18 or 19, wherein the mesh or patch is configured for promoting restoration or repair of a target tissue of a mammalian subject, wherein the decellularized tissue is allogenic with respect to the subject.

22. The synthetic mesh or patch of claim 18 or 19, wherein the mesh or patch is configured for promoting restoration or repair of a target tissue of a mammalian subject, wherein the decellularized tissue is xenogenic with respect to the subject.

23. The synthetic mesh or patch of claim 21 or 22, and wherein the mesh or patch is further populated with mammalian cells.

24. The synthetic mesh or patch of claim 23, wherein the mammalian cells are allogenic with respect to the subject.

25. A synthetic patch or mesh comprising non- woven electrospun fibers, the synthetic patch or mesh comprising one or more internal compartments or conduits and an injection port configured permit a fluid to be injected into the one or more internal compartments or conduits.

26. The synthetic patch or mesh of claim 25, wherein the fluid to be injected comprises a drug or cellular nutrient.

27. A synthetic patch or mesh comprising non- woven electrospun fibers, the synthetic patch or mesh comprising one or more reservoirs, channels, or internal compartments or conduits, wherein the one or more reservoirs, channels, or internal compartments or conduits are configured to contain a mixture comprising a drug or cellular nutrient.

28. The synthetic patch or mesh of claim 27, wherein the one or more reservoirs, channels, or internal compartments or conduits contain a mixture comprising a drug or cellular nutrient.

29. The synthetic patch or mesh of claim 26, 27 or 28, wherein the drug is a small molecule or biologic medical product.

30. The synthetic patch or mesh of claim 26, 27 or 28, wherein the cellular nutrients comprise growth factors (e.g. , angiogenic growth factors, such as VEGF), ligands or cytokines.