Tissue adhesive matrix and uses thereof

Abstract

Disclosed is a composition comprising a first polymer, a second branched polymer, and a third polymer reactive with the second polymer, wherein either the second or third polymer comprises a tissue adhesive group, and the second and third polymers are at least partially crosslinked. Disclosed is a matrix comprising the composition of the present invention and optionally an additional polymer layer. Also disclosed is a process for producing the composition, and its use for bioadhesion and / or repair of damaged tissue.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 876,952, filed July 22, 2019, the contents of which are incorporated herein by reference in their entirety.

[0002] The present invention, in some embodiments thereof, relates to tissue adhesive matrices, their preparation and uses. [Background technology]

[0003] Fluid or air leakage from or into damaged tissue is a potentially life-threatening condition that can occur as a result of a variety of situations, including surgery and trauma.

[0004] Soft tissues are particularly susceptible to injury. Furthermore, these tissues can form various compartments (e.g., lungs, blood vessels, dura mater, bladder, etc.) that retain fluid or air, and when damaged, these disorders can spread to other areas. Furthermore, due to the mechanical properties of these tissues, the attachment of the matrix to the suture or staple can itself cause damage, for example, preventing proper sealing, increasing the likelihood of bacterial infection, or slowing the rate of recovery or healing. Examples of such soft tissues include dura mater, brain tissue, retina, skin tissue, liver tissue, pancreatic tissue, connective tissue, muscle tissue, cardiac tissue, vascular tissue, kidney or urogenital tissue, lung tissue, gonadal tissue, hematopoietic tissue, gastrointestinal tissue (e.g., colon or stomach), and adipose tissue.

[0005] Adhesion to tissues without sutures can be provided by adhesives (e.g., growth factors, extracellular matrix proteins, and / or other proteins) applied to the surface to promote cell growth and adhesion. Polymerizable compositions have been used in a variety of adhesives, for example, as dental materials or as adhesives to hold reconstructed tissues in place. Currently available tissue adhesives have several inherent drawbacks that limit their use in the clinic. For example, cyanoacrylate-based adhesives adhere very strongly to tissue but are associated with severe inflammatory responses and reduced elasticity. On the other hand, hydrogels are considered safe but lack the adhesive strength required to hold tissues together. As a result, the use of cyanoacrylates is limited to external surfaces, and hydrogels such as fibrin glue function as sealants, sealing wounds rather than holding them together. Therefore, there is a great need for new adhesive strategies that provide a viable alternative to sutures and staples. Summary of the Invention

[0006] In one aspect of the present invention, a first polymer; and a second branched polymer; and a third polymer that is reactive with the second polymer and that is at least partially crosslinked with the second branched polymer; Compositions are provided wherein either one of the second and third polymers comprises a tissue adhesive group.

[0007] In one embodiment, the average molecular weight of the first polymer ranges from 10 KDa to 900 KDa.

[0008] In one embodiment, the first polymer is selected from the group comprising polyester, polyanhydride, polyacetal, polyorthoester, polyurethane, polycarbonate, polyphosphazene, polyphosphoester, polyether, silicone, polyamide, polysulfone, polyetheretherketone (PEEK), poly(ethylene glycol), polytetrafluoroethylene, polyethylene, polysaccharide, or any combination or copolymer thereof.

[0009] In one embodiment, the third polymer is branched.

[0010] In one embodiment, the third polymer comprises a nucleophilic group.

[0011] In one embodiment, crosslinking is by reacting the tissue adhesive groups with nucleophilic groups.

[0012] In one embodiment, the branched polymer is selected from the group consisting of a star polymer, a dendrimer, and a hyperbranched polymer, or any combination thereof.

[0013] In one embodiment, the branched polymer comprises 3 to 10 arms.

[0014] In one embodiment, the tissue adhesive group is selected from the group consisting of activated esters (e.g., thioesters, peu-oroalkyl esters, pento-orophenol esters, N-hydroxysuccinimide esters), acyl halides, chloroformates, anhydrides, aldehydes, epoxides, isocyanates, isothiocyanates, maleimides, carbonates, sulfonyl chlorides, haloacetamides, acyl azides, imidoesters, carbodiimides, vinyl sulfones, ortho-pyridyl-disulfides, or any combination thereof.

[0015] In one embodiment, the tissue adhesive group is covalently attached to an arm of the second polymer.

[0016] In one embodiment, the second polymer, the third polymer, or both, are selected from the group consisting of polyethers, polyesters, polydioxanones, polyphosphoesters, polyurethanes, and polyamides, or any combination or copolymer thereof.

[0017] In one embodiment, the second polymer, the third polymer, or both comprise polyethylene glycol, and the first polymer is selected from the group consisting of polylactic acid, poly(L-lactic acid), poly(D-lactic acid), polyglycolic acid, poly(L-glycolic acid), poly(D-glycolic acid), nylon, and polycaprolactone, or any combination or copolymer thereof.

[0018] In one embodiment, the average molecular weight of the second polymer and the third polymer ranges from 500 Da to 100,000 Da.

[0019] In one embodiment, the weight ratio of the third polymer to the second branched polymer ranges from 1:1 to 1:10.

[0020] In one embodiment, the weight ratio of the first polymer to the second branched polymer ranges from 1:1 to 20:1.

[0021] In one embodiment, the first polymer and at least one of the second branched polymer and the third polymer are blended together to form a blended polymer fiber.

[0022] In one embodiment, the blended polymer fibers are biodegradable.

[0023] In one embodiment, the blended polymer fibers are characterized by an average fiber diameter of 0.5 to 10 um.

[0024] In one embodiment, the blended polymer fibers are characterized by a melting point of 50 to 150°C.

[0025] In another aspect, a matrix is ​​provided that includes a tissue adhesive layer, the tissue adhesive layer comprising the blended polymer fibers of the present invention.

[0026] In one embodiment, the matrix further comprises an additional layer of polymer fibers.

[0027] In one embodiment, the additional layer enhances the stability of the tissue adhesive layer.

[0028] In one embodiment, the tissue adhesive layer is characterized by a pore size of 0.5 to 100 um.

[0029] In one embodiment, the tissue adhesive layer is characterized by a tensile strength of at least 0.05 MPa.

[0030] In one embodiment, the tissue adhesive layer is characterized by an adhesive strength of 1 to 10 N, the adhesive strength being measured according to a shear test.

[0031] In one embodiment, the tissue adhesive layer is characterized by a porosity of at least 60%.

[0032] In one embodiment, the tissue adhesive layer is characterized by a thickness of 0.5 to 250 um.

[0033] In one embodiment, the tissue adhesive layer has a viscosity of 1 ml / hr / cm when exposed to an aqueous liquid at a pressure of 40 mmHg. 2 It is characterized by a water permeability of less than

[0034] In one embodiment, the matrix further comprises a pharmaceutical active ingredient.

[0035] In one embodiment, the matrix is ​​for use in (i) bioadhesion of at least one biological tissue, (ii) promotion of blood clotting.

[0036] In one embodiment, the matrix is ​​for use in repairing and / or replacing biological tissue.

[0037] In another aspect, there is a kit comprising: (i) a blended polymer fiber comprising a first polymer and a second polymer; and (ii) a composition comprising a third polymer reactive to the second polymer, wherein the second polymer and the third polymer comprise the second branched polymer or the third polymer, respectively, of the present invention.

[0038] In one embodiment, the first polymer is selected from the group comprising polyesters, polyanhydrides, polyacetals, polyorthoesters, polyurethanes, polycarbonates, polyphosphazenes, polyphosphoesters, polyethers, silicones, polyamides, polysulfones, polyetheretherketones (PEEK), poly(ethylene glycol), polytetrafluoroethylene, polyethylene, polysaccharides, or combinations or copolymers thereof.

[0039] In one embodiment, the second polymer, the third polymer, or both comprise polyethylene glycol, and the first polymer is selected from the group consisting of polylactic acid, poly(L-lactic acid), poly(D-lactic acid), polyglycolic acid, poly(L-glycolic acid), poly(D-glycolic acid), nylon, and polycaprolactone, or any combination or copolymer thereof.

[0040] In one embodiment, the blended polymer fibers in contact with the additional component provide a tissue-adherent layer.

[0041] In one embodiment, the weight ratio of the third polymer to the second polymer ranges from 1:1 to 1:20.

[0042] In one embodiment, the weight ratio of the first polymer to the second polymer ranges from 1:1 to 20:1.

[0043] In another aspect, there is a process for producing a blended polymer fiber of the composition of the invention or the kit of the invention, the process comprising: (i) mixing a first polymer and at least one of a second polymer and a third polymer with a solvent, thereby obtaining a solution; and (ii) providing the solution to an electrospinning apparatus.

[0044] In one embodiment, the process is for producing a layer of polymeric fibers. [Brief explanation of the drawings]

[0045] [Figure 1] 1 shows a schematic diagram of a peel test. [Figure 2] 1 shows a schematic diagram of a shear test. [Figure 3] SEM images of electrospun samples are shown in Figure 3A: Control 1.2 and Figure 3B: Composition 1.2. [Figure 4] 1 shows a bar graph depicting fiber diameters of exemplary electrospun samples, with the control designated as cont. [Figure 5] 1 shows a bar graph illustrating the pore size of exemplary electrospun samples, the control being designated as cont. [Figure 6] 1 shows a bar graph illustrating the tensile strength of exemplary electrospun samples, the control being designated as cont. [Figures 7A-7B] 7A and 7B show bar graphs illustrating adhesive strength determined by peel testing. Figure 7A shows the average peel force exhibited by exemplary samples and controls. Figure 7B shows the maximum force exhibited by exemplary samples and controls. The controls are designated as cont. [Figure 8] 1 shows a bar graph illustrating the adhesive strength of exemplary samples and controls as determined by shear testing. [Figure 9] 1 shows a bar graph illustrating burst pressure strength of exemplary samples and controls. DETAILED DESCRIPTION OF THE INVENTION

[0046] In one aspect, the present invention relates to a composition comprising a first polymer, a second polymer comprising tissue adhesive groups, and a third polymer, wherein the second polymer and the third polymer are at least partially crosslinked. In some embodiments, the present invention relates to a composition in the form of a blended polymer fiber.

[0047] In another aspect, the present invention relates to a tissue adhesive matrix comprising the blended polymer fibers of the present invention. Additionally, the present invention provides a method for producing the matrix and its use for tissue adhesion, etc.

[0048] The present invention is based in part on the surprising discovery that tissue adhesive matrices comprising crosslinked polymers exhibit enhanced adhesive strength compared to matrices comprising linear tissue adhesive polymers.

[0049] composition In some embodiments, a composition is provided comprising a first polymer, a second branched polymer, and a third polymer that is reactive to the second polymer and at least partially crosslinked with the second branched polymer, wherein either one of the second and third polymers comprises a tissue adhesive group.

[0050] In some embodiments, the first polymer is a carrier polymer. In some embodiments, the first polymer provides structural support to a composition comprising it.

[0051] As used herein, the term "structural support" refers to the physical properties of a composition (e.g., blended polymer fiber), such as elasticity. Additionally, the first polymer may be selected to allow for polymer fiber formation by any one of the methods described later herein (e.g., by electrospinning). In some embodiments, the first polymer provides stability to the polymer fiber.

[0052] As used herein, the terms "elastic" and "elastic" refer to the tendency of a material to return to its original shape after being deformed by stress, e.g., tensile and / or shear stress, at the indicated temperature or (in situations where no temperature is indicated) at a temperature of 37° C. Elasticity can be expressed in terms of tensile properties.

[0053] The elongation at break is determined as the maximum strain (elongation) that can occur (upon application of a tensile stress equal to the tensile strength) before failure of the test material occurs (e.g., as a rupture or necking).

[0054] In some embodiments, the first polymer is a synthetic polymer, hi some embodiments, the first polymer is selected from the group including polyesters, polyanhydrides, polyacetals, polyorthoesters, polyurethanes, polycarbonates, polyphosphazenes, polyphosphoesters, polyethers, silicones, polyamides, polysulfones, polyetheretherketones (PEEK), poly(ethylene glycol), polytetrafluoroethylene, polyethylene, and mixtures or copolymers thereof.

[0055] In some embodiments, the first polymer is biodegradable. In some embodiments, the first polymer is at least partially biodegradable and / or bioerodible. In some embodiments, the first polymer is substantially biodegradable and / or bioerodible, substantially as described herein.

[0056] In some embodiments, the first polymer is a copolymer comprising poly(lactic acid). In some embodiments, the first polymer is poly(lactic acid). In some embodiments, the first polymer comprises a polyester. In some embodiments, the first polymer comprises at least one biodegradable polyester.

[0057] Non-limiting examples of polyesters include, but are not limited to, polyglycolide, polylactic acid, polycaprolactone (PCL), polyhydroxyalkanoate, polyhydroxybutyrate, polyethylene adipate, polybutylene succinate, poly(3-hydroxybutyrate-co-3-hydroxyvalerate), polyethylene terephthalate (PET), polybutylene terephthalate, polyethylene naphthalate (PEN), any copolymer or any combination thereof, and the like.

[0058] In some embodiments, the first polymer comprises a poly(alpha-hydroxy)carboxylic acid. In some embodiments, the first polymer is a copolymer comprising a first polymer segment comprising a poly(alpha-hydroxy)carboxylic acid and a second polymer segment comprising a polyester.

[0059] In some embodiments, the first polymer is a copolymer comprising multiple polyesters. In some embodiments, the first polymer is a copolymer comprising a polyester selected from polylactide, polyglycolide, polycaprolactone (PCL), and optionally a polyamide (e.g., nylon). In some embodiments, the first polymer comprises polylactide-co-polycaprolactone (PLA-co-PCL). In some embodiments, the first polymer comprises polyglycolide-co-polycaprolactone. In some embodiments, the first polymer comprises polyglycolide-co-polycaprolactone (PLGA-co-PCL). In some embodiments, the first polymer comprises poly(L-glycolide)-co-polycaprolactone. In some embodiments, the first polymer comprises poly(D-glycolide)-co-polycaprolactone. In some embodiments, the first polymer comprises poly(L-lactide)-co-poly(ε-caprolactone) (PLLA-PCL), poly(D,L-lactide)-co-poly(ε-caprolactone), poly(D-lactide)-co-poly(ε-caprolactone), or any combination thereof. In some embodiments, the first polymer is a biological polymer. In some embodiments, the biological polymer is selected from the group comprising polysaccharides, polypeptides, polynucleic acids, and mixtures or copolymers thereof. In some embodiments, the biological polymer comprises a chemical modification (e.g., crosslinking, acetylation, methylation, hydrolysis).

[0060] In some embodiments, the biological polymer is a polysaccharide. Non-limiting examples of polysaccharides include, but are not limited to, cellulose acetate, gum arabic, gum ghatti, dextran, pullulan, amylopectin, and hyaluronic acid. In some embodiments, the biological polymer induces blood clotting. In some embodiments, the biological polymer includes collagen, oxidized cellulose, or both.

[0061] In some embodiments, the first polymer is characterized by an average molecular weight in the range of 10,000 Da to 900,000 Da, 10,000 Da to 100,000 Da, 10,000 Da to 50,000 Da, 50,000 Da to 100,000 Da, 100,000 Da to 200,000 Da, 200,000 Da to 300,000 Da, 300,000 Da to 400,000 Da, 400,000 Da to 500,000 Da, 500,000 Da to 600,000 Da, 600,000 Da to 900,000 Da (including any range or value therebetween). In some embodiments, the first polymer is characterized by an average molecular weight in the range of 50-70 kDa, 70-100 kDa, 100-150 kDa, 150-200 kDa, 200-250 kDa, 250-300 kDa (including any range or value therebetween).

[0062] In some embodiments, any of the first polymer, the second branched polymer, and the third polymer comprises substantially a single homopolymer or a single copolymer. In some embodiments, any of the first polymer, the second branched polymer, and the third polymer is substantially devoid of particulate matter (e.g., organic or inorganic nanoparticles, microparticles). In some embodiments, any of the first polymer, the second branched polymer, and the third polymer is substantially devoid of non-biodegradable polymers and / or non-biodegradable polymer segments. In some embodiments, the compositions of the present invention consist essentially of the first polymer, the second branched polymer, and the third polymer. In some embodiments, the first polymer, the second branched polymer, and the third polymer comprise at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% by weight of the dry content of the compositions of the present invention. In some embodiments, the first polymer, the second branched polymer, and the third polymer comprise at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% by weight of the blended polymer fiber of the present invention. In some embodiments, any one of the first polymer, the second branched polymer, and the third polymer is substantially devoid of acrylate-modified PEG-PLLA copolymer. In some embodiments, the tissue adhesive group is substantially devoid of acrylate. In some embodiments, the tissue adhesive group is substantially devoid of vinyl sulfone. In some embodiments, the compositions of the present invention are substantially devoid of polyamino acids (e.g., peptides).

[0063] In some embodiments, the first polymer is a high molecular weight polymer, ie, the average molecular weight of the first polymer is at least 100%, at least 200%, at least 300%, at least 400%, at least 500%, at least 600%, at least 700%, at least 800%, at least 900%, or at least 1000% (including any range or value therebetween) higher than the average molecular weight of any one of the second and third polymers.

[0064] In some embodiments, the first polymer is characterized by a tensile strength and elongation at break that is greater than the tensile strength and elongation at break of any one of the second and third polymers, the greater being as described above.

[0065] In some embodiments, the w / w ratio of the first polymer to the total weight of the composition is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45% (including any range or value therebetween).

[0066] In some embodiments, the w / w ratio of the first polymer to the total weight of the composition is at most 20%, at most 25%, at most 30%, at most 35%, at most 40%, at most 45%, at most 50% (including any range or value therebetween). In some embodiments, the w / w ratio of the first polymer to the total weight of the composition is at most 50%.

[0067] In some embodiments, the w / w ratio of the first polymer from the total weight of the composition is 10-60%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60% (including any range or value therebetween). In some embodiments, compositions (e.g., in the form of fibers) having a w / w content of the first polymer of 20-60%, 30-50%, 40-50%, or at most 50% are characterized by sufficient adhesive strength (e.g., greater than 1.1 N), where the adhesive strength is as described herein.

[0068] In some embodiments, the composition comprises a second polymer. In some embodiments, the second polymer is a branched polymer. In some embodiments, the branched polymer is selected from the group consisting of a star polymer, a dendrimer, and a hyperbranched polymer, or any combination thereof. In some embodiments, the terms "second polymer" and "second branched polymer" are used interchangeably herein.

[0069] In some embodiments, the branched polymer (e.g., the second branched polymer and / or the third polymer) comprises a branched core, hi some embodiments, the branched core is covalently linked to at least three arms.

[0070] Non-limiting examples of branching cores include, but are not limited to, pentaerythritol, dipentaerythritol, tripentaerythritol, calix[8]arene, or any combination thereof. [ka]

[0071] In some embodiments, the branched polymer (eg, the second polymer and / or the third polymer) comprises a branched core covalently attached to three or more arms, each one of the arms having the same chemical composition.

[0072] In some embodiments, the branched polymer (eg, the second polymer and / or the third polymer) comprises a branched core covalently attached to three or more arms, at least some of which have different chemical compositions.

[0073] As used herein, the term "chemical composition" describes the composition of any one of the segments (eg, the chemical structure and average number of monomers in a polymer segment).

[0074] In some embodiments, the branched polymer (e.g., the second polymer and / or the third polymer) has 3 to 10, 3 to 5, 5 to 7, 7 to 8, or 8 to 10 arms (including any range or value therebetween). In some embodiments, the branched polymer (e.g., the second polymer and / or the third polymer) has 3 to 8 arms. In some embodiments, the branched polymer (e.g., the second polymer and / or the third polymer) has 4 to 8 arms. In some embodiments, the branched polymer (e.g., the second polymer and / or the third polymer) has 3 to 6 arms. In some embodiments, the branched polymer (e.g., the second polymer and / or the third polymer) has 4 arms. In some embodiments, the branched polymer (e.g., the second polymer and / or the third polymer) has 8 arms. In some embodiments, the branched polymer (e.g., the second branched polymer and / or the third polymer of the present invention) comprises 8 arms. In some embodiments, at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, at least 99% by total weight of the branched polymers (e.g., the second branched polymer and / or the third polymer of the present invention) contain 8 arms.

[0075] In some embodiments, any one of the arms of the branched polymer (e.g., the second polymer and / or the third polymer) independently comprises a polymer segment, hi some embodiments, any one of the arms of the branched polymer (e.g., the second polymer and / or the third polymer) independently comprises at least one polymer segment and at least one tissue-binding group.

[0076] As used herein, the term "polymer segment" refers to a polymer structure of any length. In the field of polymer technology, long polymer structures are often referred to as blocks, and short polymer structures are often referred to as segments. Both of these conventional meanings are understood to be encompassed by the term "segment" as used herein.

[0077] In some embodiments, the polymer segment of the branched polymer (e.g., the second polymer and / or the third polymer) is a copolymer comprising multiple polymer subunits. In some embodiments, the copolymer is selected from the group consisting of a block copolymer, an alternating copolymer, a periodic copolymer, and a random copolymer.

[0078] In some embodiments, the polymer segments of the branched polymer (eg, the second polymer and / or the third polymer) are homopolymers.

[0079] In some embodiments, a polymer segment of a branched polymer (e.g., a second polymer and / or a third polymer) comprises at least one biodegradable subunit. In some embodiments, a polymer segment comprises at least one biocompatible subunit. In some embodiments, a polymer segment comprises at least one biocompatible and biodegradable subunit. In some embodiments, a polymer segment comprises at least one biodegradable subunit and at least one non-biodegradable subunit. In some embodiments, a polymer segment is fully biodegradable. In some embodiments, a polymer segment is fully biocompatible. In some embodiments, a polymer segment is both biodegradable and biocompatible.

[0080] As used herein, the term "biocompatible" is intended to describe a material that is non-toxic to cells in vitro and does not induce undesirable long-term effects when administered in vivo.

[0081] As used herein, the term "biodegradable" is intended to describe materials containing covalent bonds that are degraded in vivo, where degradation of the covalent bonds occurs via hydrolysis. Hydrolysis can involve direct reaction with aqueous media or can be chemically or enzymatically catalyzed. "Aqueous media" refers to water, aqueous solutions, physiological media or biological fluids (e.g., body fluids), and other pharmaceutically acceptable media. Suitable hydrolyzable covalent bonds are selected from the group including esters, amides, urethanes, carbamates, carbonates, ethers, azo bonds, anhydrides, thioesters, and combinations thereof.

[0082] Non-limiting examples of biodegradable polymers include polyethers (e.g., polyethylene glycol (PEG)), polyglycolides, polyesters (e.g., poly-l-lactide (PLLA), polycaprolactone, polyhydroxybutyrate, polyhydroxyvalerate), polydioxanone, polyurethanes, polyphosphoesters, polyurethanes, and polyamides (e.g., polyamino acids, including any copolymers or any combination thereof).

[0083] In some embodiments, the polymer segments of the second polymer and / or the third polymer comprise PEG. In some embodiments, the second polymer, the third polymer, or both comprise polyester. In some embodiments, the second polymer, the third polymer, or both comprise polyether. In some embodiments, the second polymer, the third polymer, or both comprise PEG.

[0084] In some embodiments, the polymer segment of the second polymer is reactive with the third polymer. In some embodiments, the polymer segment of the second polymer comprises a reactive group. In some embodiments, the reactive group of the second polymer is reactive with the reactive group of the third polymer. In some embodiments, the reactive group of the third polymer is reactive with the reactive group of the second polymer. In some embodiments, the reactive group is capable of forming a covalent bond with the third polymer. In some embodiments, the reactive group of the second polymer is an electrophile. In some embodiments, the reactive group of the second polymer is a tissue adhesive group. In some embodiments, the second polymer comprises a tissue adhesive group (e.g., an electrophile or an electrophilic tissue adhesive group), and the tissue adhesive group is reactive with the third polymer. In some embodiments, the tissue adhesive group of the second polymer is reactive with a reactive group of the third polymer (e.g., a nucleophilic group described herein). In some embodiments, the second polymer and the third polymer can form a covalent bond via reaction between the tissue adhesive group of the second polymer and the reactive group of the third polymer. In some embodiments, the second polymer comprises a tissue adhesive group covalently bonded to its polymer segment. In some embodiments, the first polymer is substantially devoid of reactive groups, and the reactive groups are as described herein. In some embodiments, the first polymer is substantially inert (e.g., non-reactive). In some embodiments, the first polymer is substantially inert (e.g., non-reactive) with respect to either the second polymer or the third polymer.

[0085] In some embodiments, the polymer segment of the second polymer comprises one type of tissue adhesive group or more types of tissue adhesive groups.

[0086] The term "tissue adhesive group" encompasses any chemical or functional group that can interact with a biological surface (e.g., tissue) to form a covalent or non-covalent bond. Biological surfaces, such as tissues, generally consist of cells and contain protein molecules on their surfaces, which generally contain thiol and primary amine moieties. Many functional groups, such as activated esters, can covalently bond to biological surfaces by reacting with thiols or primary amines located on cell surfaces. In addition to forming covalent bonds, tissue adhesive groups can also form non-covalent bonds with biological surfaces. The term "non-covalent bond" encompasses ligand-receptor interactions, hydrogen bonds, dipole-dipole interactions, and van der Waals bonds, or any combination thereof. The use of tissue adhesive groups in the present invention provides polymeric materials with bioadhesive properties.

[0087] As used herein, the term "biological surface" refers to any surface that contains cells and / or biological molecules (e.g., proteins, polysaccharides, lipids, nucleic acids). Non-limiting examples of "biological surfaces" include, but are not limited to, tissue surfaces, synthetic graft surfaces, and organ surfaces.

[0088] Non-limiting examples of tissue adhesive groups that form non-covalent bonds with biological surfaces include, but are not limited to, amides, carboxylates, and peptides (eg, RGD).

[0089] Non-limiting examples of tissue adhesive groups that form covalent bonds with biological surfaces include, but are not limited to, activated esters (e.g., thioesters, peu-oroalkyl esters, N-hydroxysuccinimide esters), carboxylic acids, acyl halides, chloroformates, anhydrides, aldehydes, epoxides, isocyanates, isothiocyanates, maleimides, carbonates, sulfonyl chlorides, haloacetamides, acyl azides, imidoesters, carbodiimides, vinyl sulfones, ortho-pyridyl-disulfides, or any combination thereof.

[0090] In some embodiments, the tissue adhesive group is an activated ester.

[0091] In some embodiments, the tissue adhesive group is an N-hydroxysuccinimide (NHS) ester. The mechanism by which an NHS-functionalized polymer reacts with an amine-containing material, such as a tissue protein, is shown below. [ka]

[0092] In some embodiments, the tissue adhesive group is covalently attached to an end group of the polymer segment.

[0093] In some embodiments, the tissue adhesive group is covalently attached to a side chain of the polymer segment.

[0094] In some embodiments, the plurality of tissue adhesive groups provides the second polymer with bioadhesive properties.

[0095] In some embodiments, the polymer segment of the second polymer comprises tissue adhesive monomers that form covalent and / or non-covalent bonds with biological surfaces to provide bioadhesion.

[0096] In some embodiments, the composition comprises a third polymer.

[0097] In some embodiments, the third polymer is biodegradable.

[0098] In some embodiments, the third polymer is selected from the group consisting of polyethers (e.g., polyethylene glycol (PEG)), polyglycolides, polyesters (e.g., poly-l-lactide (PLLA), polycaprolactone, polyhydroxybutyrate, polyhydroxyvalerate), polydioxanone, polyurethanes, polyphosphoesters, polyurethanes, and polyamides (e.g., polyamino acids), or any combination thereof.

[0099] In some embodiments, the second polymer, the third polymer, or both, comprise PEG.

[0100] In some embodiments, the average molecular weight of the third polymer and the second polymer is in the range of 500 to 100,000 Da, 500 to 5,000 Da, 1,000 to 3,000 Da, 1,500 to 2,500 Da, 5,000 to 10,000 Da, 10,000 to 15,000 Da, 15,000 to 18,000 Da, 18,000 to 20,000 Da, 20,000 to 22,000 Da, 22,000 to 25,000 Da, 25,000 to 30,000 Da, 30,000 to 40,000 Da, 40,000 to 60,000 Da, 60,000 to 80,000 Da, 80,000 to 100,000 Da, or any range therebetween.

[0101] In some embodiments, the average molecular weight of at least one of the second polymer and the third polymer is 1,000 to 50,000 Da, 10,000 to 20,000 Da, 20,000 to 30,000 Da, 30,000 to 40,000 Da, or 40,000 to 50,000 Da (including any range or value therebetween). In some embodiments, a composition (e.g., a fiber) includes a first polymer and at least one of a second polymer and a third polymer, wherein at least one polymer has an average molecular weight of 10,000 to 50,000 Da, 10,000 to 20,000 Da, 20,000 to 30,000 Da, 30,000 to 40,000 Da, 40,000 to 50,000 Da (including any range or value therebetween). In some embodiments, a composition (e.g., a fiber) comprises a first polymer and at least one polymer selected from a second polymer and a third polymer, wherein the at least one polymer has an average molecular weight of at least 5,000 Da, at least 7,000 Da, at least 8,000 Da, at least 9,000 Da, at least 10,000 Da, at least 12,000 Da, at least 15,000 Da, at least 20,000 Da (including any range or value therebetween).

[0102] In some embodiments, the third polymer is a branched polymer. In some embodiments, the branched polymer is as described herein above.

[0103] In some embodiments, the third polymer is reactive with the second polymer. In some embodiments, the third polymer comprises a reactive group capable of forming a covalent bond with the second polymer. In some embodiments, the reactive group (e.g., a nucleophilic group) of the third polymer is capable of forming a covalent bond with the reactive group (e.g., an electrophilic group) of the second polymer. In some embodiments, the reactive group of the third polymer is capable of forming a covalent bond with the tissue-adhesive group of the second polymer.

[0104] In some embodiments, the reactive groups of the third polymer are selected from the group consisting of nucleophilic groups (e.g., amines, thiols, phosphines, hydroxyls), dienes, tetrazines, and azides, or any combination thereof. In some embodiments, the reactive groups of the third polymer are nucleophilic groups.

[0105] In some embodiments, the covalent bond formation is referred to as cross-linking.

[0106] In some embodiments, the crosslinks are reciprocal crosslinks. As defined herein, the term "reciprocal" refers to the formation of a bond between two reactive groups present on two polymer chains, as opposed to the formation of an "internal" bond between two reactive groups present within the same polymer chain.

[0107] In some embodiments, the second and third polymers are at least partially crosslinked to form a crosslinked polymer. In some embodiments, the crosslinks are formed by reacting tissue adhesive groups of the third polymer with reactive groups. In some embodiments, the crosslinks are formed via a "click reaction" such as azide-alkyne cycloaddition or a retro-Diels-Alder reaction. In some embodiments, the crosslinks are formed by reacting tissue adhesive groups of the third polymer with nucleophilic groups. In some embodiments, the crosslinks are formed via amide bonds formed by reacting amino groups of the third polymer with NHS of the second polymer. In some embodiments, the crosslinks are formed via thioester bonds formed by reacting thiol groups of the third polymer with NHS of the second polymer.

[0108] In some embodiments, the crosslinked polymer is characterized by a degree of crosslinking ranging from 1% to 80%, 1% to 10%, 10% to 20%, 20% to 30%, 30% to 40%, 40% to 50%, 50% to 60%, 60% to 70%, 70% to 80% (including any range or value therebetween).

[0109] In some embodiments, the degree of crosslinking of the second and third polymers is at most 80%, at most 60%, at most 50%, at most 40%, at most 30%, at most 20%, at most 10% (including any range or value therebetween).

[0110] In some embodiments, as described herein, crosslinks are formed in situ by contacting a composition (e.g., a fiber) comprising (i) a first polymer and one of a second polymer and a third polymer with a composition comprising (ii) a complementary polymer (e.g., of each of the second and third polymers). In some embodiments, the composition (e.g., a fiber) comprising (i) a first polymer and (ii) one of the second and third polymers is substantially devoid of crosslinks.

[0111] In some embodiments, the degree of crosslinking between the second polymer and the third polymer is sufficient to allow for the formation of a polymer fiber by any one of the fiber manufacturing processes disclosed herein, such as electrospinning. In some embodiments, the degree of crosslinking between the second polymer and the third polymer is sufficient to form a stable composition (e.g., a fiber, a matrix, or a layer comprising multiple fibers). In some embodiments, the degree of crosslinking between the second polymer and the third polymer is sufficient to form a composition (e.g., a fiber, a matrix, or a layer comprising multiple fibers) characterized by sufficient adhesive strength, as described herein.

[0112] In some embodiments, at least a portion of the tissue adhesive groups of the second polymer remain unreacted to provide a sufficient amount of binding sites (e.g., covalent bonds) with a biological surface (e.g., tissue). In some embodiments, at least a portion of the tissue adhesive groups remain unreacted (e.g., uncrosslinked) to establish binding and / or adhesion to a biological surface. In some embodiments, at least a portion of the tissue adhesive groups remain unreacted to establish sufficient adhesive strength as described herein. In some embodiments, at least 10 mol%, at least 20 mol%, at least 30 mol%, at least 40 mol%, at least 50 mol%, or at least 60 mol% of the tissue adhesive groups within the composition (e.g., fiber) are unreacted (e.g., intact).

[0113] Crosslinked polymers offer several advantages over non-crosslinked polymers. As shown in Figures 7 and 8, polymer fibers containing crosslinked polymers (Compositions 1.2 and 1.4) and (Composition 2, not shown) exhibited the highest adhesive strength compared to polymer fibers containing non-crosslinked polymers (Composition 1.1, Control 1.1). Without being limited by any particular mechanism or theory, the enhanced adhesive strength may be related to the mesh-like structure of the crosslinked polymer and, optionally, the beneficial orientation of the tissue-adhesive groups relative to the tissue in contact with the outer layer of the polymer fiber.

[0114] In some embodiments, the crosslinked polymer (e.g., a partially crosslinked polymer) undergoes additional crosslinking upon contact with a biological surface. In some embodiments, the crosslinked polymer further forms a gel upon contact with a biological surface. In some embodiments, the gel formation is further due to the enhanced adhesive strength of the matrix comprising the crosslinked polymer. In some embodiments, the crosslinked polymer is characterized by tensile strength and adhesive strength that are higher than the tensile strength and adhesive strength of the non-crosslinked polymer.

[0115] In some embodiments, the weight per weight (w / w) ratio of the third polymer to the second polymer in the composition is in the range of 10:1 to 1:10, 10:1 to 8:1, 8:1 to 6:1, 6:1 to 4:1, 4:1 to 2:1, 2:1 to 1:1, 1:1 to 1:1.5, 1:1.5 to 1:2, 1:2 to 1:2.5, 1:2.5 to 1:3, 1:3 to 1:5, 1:1 to 1:5, 1:1 to 1:4, 1:1 to 1:3, 1:1 to 1:2, 1:5 to 1:7, 1:7 to 1:10 (including any range or value therebetween).

[0116] In some embodiments, the weight per weight (w / w) ratio of the second polymer to the third polymer in the composition is in the range of 0.8:1 to 1:10, 0.8:1 to 1:1, 1:1 to 1:1.5, 1:1.5 to 1:2, 1:2 to 1:2.5, 1:2.5 to 1:3, 1:3 to 1:5, 1:1 to 1:5, 1:1 to 1:4, 1:1 to 1:3, 1:1 to 1:2, 1:5 to 1:7, 1:7 to 1:10 (including any range or value therebetween).

[0117] In some embodiments, the w / w ratio of the third polymer to the second polymer in the composition is in the range of 1:1 to 1:2, 1:1 to 1:1.2, 1:1.2 to 1:1.5, 1:1.5 to 1:1.7, 1:1.7 to 1:2, 1:2 to 1:3, 1:3 to 1:5, 1:5 to 1:10 (including any range or value therebetween).

[0118] In some embodiments, compositions characterized by sufficient adhesive strength and / or sufficient mechanical properties comprise a w / w ratio of a third polymer (e.g., PEG-SH and / or PEG-NH2) to a second polymer (e.g., PEG-NHS) of 1:1 to 1:2, 1:1 to 1:1.2, 1:1.2 to 1:1.5, 1:1.5 to 1:1.7, or 1:1.7 to 1:2 (including any range or value therebetween). In some embodiments, the sufficient adhesive strength and / or mechanical properties are as described herein.

[0119] In some embodiments, compositions characterized by an adhesive strength of greater than 1.1 N comprise a w / w ratio of a third polymer (e.g., PEG-SH and / or PEG-NH2) to a second polymer (e.g., PEG-NHS) of 1:1 to 1:2.

[0120] In some embodiments, the molar ratio of the third polymer to the second polymer in the composition is in the range of 0.8:1 to 1:10, 0.8:1 to 1:1, 1:1 to 1:1.5, 1:1.5 to 1:2, 1:2 to 1:2.5, 1:2.5 to 1:3, 1:3 to 1:5, 1:1 to 1:5, 1:1 to 1:4, 1:1 to 1:3, 1:1 to 1:2, 1:5 to 1:7, 1:7 to 1:10 (including any range or value therebetween). In some embodiments, the molar ratio of the third polymer to the second polymer in the composition is 1:1 to 1:2. In some embodiments, compositions characterized by an adhesive strength of greater than 1.1 N comprise a molar ratio of a third polymer (e.g., PEG-SH and / or PEG-NH2) to a second polymer (e.g., PEG-NHS) of 1:1 to 1:2, 1:2 to 1:3, 1:3 to 1:5, 1:5 to 1:10 (including any range or value therebetween).

[0121] Note that the molar ratio of the third polymer to the second polymer is maintained to ensure a molar excess of tissue adhesive groups over reactive groups on the third polymer. In some embodiments, the molar excess is at least 10 mol%, at least 20 mol%, at least 30 mol%, at least 40 mol%, at least 50 mol%, at least 70 mol%, at least 90 mol%, at least 100 mol%, at least 150 mol%, at least 200 mol%, at least 300 mol%, at least 400 mol%, or at least 500 mol% (including any range or value therebetween).

[0122] Such a molar excess is necessary to ensure that at least a portion of the tissue-adhesive groups remain unreacted, thus allowing the tissue-adhesive properties of the second polymer to be retained. Experimental data obtained by the present inventors showed that compositions comprising polymer fibers composed of PEG-NHS and PEG-SH in a 2:1 w / w ratio of PEG-NHS to PEG-SH exhibited favorable adhesive strength and stability compared to polymer fibers composed of PEG-NHS and PEG-SH in a 1:1 w / w ratio of PEG-NHS to PEG-SH.

[0123] In some embodiments, the w / w ratio of the first polymer to the second polymer in the composition is in the range of 1:1 to 20:1, 1:1 to 3:1, 3:1 to 5:1, 5:1 to 8:1, 8:1 to 10:1, 10:1 to 15:1, 15:1 to 20:1, or any range therebetween.

[0124] In some embodiments, the combined w / w content of the second polymer and the third polymer in the composition is 20-60%, 20-30%, 30-40%, 40-50%, 30-55%, 50-60%, 50-55%, 55-60% (including any range or value therebetween).

[0125] In some embodiments, the second polymer (e.g., polyether-NHS) and the third polymer (e.g., polyether-SH, polyether-NH 2、or both) is at least 30%, at least 40%, at least 50% (including any range or value therebetween).

[0126] In some embodiments, a composition (e.g., in the form of a fiber) comprising a combined w / w content of a second polymer and a third polymer, as described above, is characterized by adequate adhesive strength to establish bonding and / or adhesion to a biological surface.

[0127] In some embodiments, compositions (e.g., compositions of the invention in the form of fibers) having a combined w / w content of the second polymer and the third polymer of 20-70%, 30-50%, or 40-50% are characterized by sufficient adhesive strength (e.g., greater than 1.1 N) to establish bonding and / or adhesion to a biological surface, where the adhesive strength is as described herein.

[0128] In some embodiments, a composition (e.g., in the form of a fiber) having a combined w / w content of the second polymer and the third polymer of 20-60% is characterized by an adhesive strength of at least 1 N, at least 1.1 N, at least 1.2 N, at least 1.3 N, at least 1.4 N, at least 1.5 N, at least 1.6 N, at least 1.7 N, at least 1.8 N, at least 1.9 N, at least 2 N, at least 2.2 N, at least 2.4 N, at least 2.5 N, at least 2.8 N, at least 3 N, at least 3.2 N, at least 4 N (including any range or value therebetween), wherein the adhesive strength is as described herein.

[0129] In some embodiments, the compositions of the present invention are characterized by enhanced mechanical strength (e.g., tensile strength) of greater than 0.3 MPa, greater than 0.5 MPa, greater than 0.7 MPa, greater than 0.9 MPa, greater than 1 MPa, greater than 1.5 MPa, greater than 2 MPa, greater than 2.5 MPa, greater than 3 MPa, greater than 3.5 MPa, greater than 4 MPa (including any range or value therebetween) compared to a control (e.g., a commercially available product), as exemplified herein.

[0130] In some embodiments, compositions (e.g., in the form of fibers) having a combined w / w content of the second polymer and the third polymer of 20-60%, 30-50%, or 40-50% are characterized by enhanced mechanical strength (e.g., tensile strength) of greater than 0.3 MPa, greater than 0.5 MPa, greater than 0.7 MPa, greater than 0.9 MPa, greater than 1 MPa, greater than 1.5 MPa, greater than 2 MPa, greater than 2.5 MPa, greater than 3 MPa, greater than 3.5 MPa, or greater than 4 MPa (including any range or value therebetween) compared to a control (e.g., a commercially available product), as exemplified herein.

[0131] In some embodiments, the compositions of the present invention are solid. In some embodiments, the compositions of the present invention (e.g., solid compositions) are substantially devoid of solvent. In some embodiments, the compositions of the present invention contain trace amounts of residual solvent. In some embodiments, the compositions of the present invention (e.g., solid compositions) contain less than 5% w / w, less than 3% w / w, less than 2% w / w, less than 1% w / w, less than 0.5% w / w, less than 0.1% w / w, less than 0.05% w / w, or less than 0.01% organic solvent. In some embodiments, the compositions of the present invention are in the form of fibers. In some embodiments, the compositions of the present invention are in the form of a matrix comprising a plurality of fibers (as described herein). In some embodiments, the compositions of the present invention are in the form of a fibrous mat. In some embodiments, the compositions of the present invention are in semi-solid or semi-liquid form. In some embodiments, the compositions of the present invention are in the form of a gel. In some embodiments, the compositions of the present invention (e.g., liquid or semi-liquid) are substantially homogeneous. In some embodiments, the compositions of the present invention are substantially stable, where stability refers to the ability of the composition to maintain its structural and / or functional properties (mechanical properties, adhesive properties, etc.).

[0132] It should be understood that the terms "semi-liquid" or "semi-solid" are intended to mean a material that is flowable under pressure and / or shear. In some embodiments, semi-liquid compositions include creams, ointments, gel-like materials, and other similar materials. In some embodiments, the composition is a semi-liquid composition characterized by a viscosity in the range of 31,000 to 800,000 cps.

[0133] In some embodiments, the composition further comprises a solvent. In some embodiments, the solvent is an organic solvent. In some embodiments, the solvent is an aqueous solvent. In some embodiments, the composition of the present invention is a liquid composition. In some embodiments, the composition or liquid composition comprises a solvent and fibers, wherein the fibers are as described herein. In some embodiments, the composition comprising the solvent and fibers is a semi-solid composition or a semi-liquid composition (e.g., a gel). In some embodiments, the w / w concentration of the solvent in the composition is 5-95%, 5-10%, 10-20%, 20-30%, 30-50%, 50-70%, or 70-95% (including any range or value therebetween).

[0134] Non-limiting examples of organic solvents include, but are not limited to, alcohols (e.g., methanol, ethanol), hydrocarbons such as alkanes (e.g., hexane), alkenes and alkynes, ethers (e.g., tetrahydrofuran, dioxane), esters, ketones, oils, polar solvents (e.g., dimethylformamide), and non-polar solvents (e.g., chloroform).

[0135] In some embodiments, the composition comprises multiple solvents.

[0136] In some embodiments, the composition comprises a first polymer and at least one of (i) a second polymer and (ii) a third polymer in the form of a blended polymer fiber (also referred to as a "polymer fiber"). In some embodiments, the polymer fiber comprises a first polymer, a second polymer, and a third polymer, as described herein.

[0137] In some embodiments, at least 20 weight percent (by dry weight) of the polymer fibers are composed of one or more polymers of the present invention. In some embodiments, at least 30 weight percent (by dry weight) of the polymer fibers are composed of one or more polymers of the present invention. In some embodiments, at least 40 weight percent (by dry weight) of the polymer fibers are composed of one or more polymers of the present invention. In some embodiments, at least 50 weight percent (by dry weight) of the polymer fibers are composed of one or more polymers of the present invention. In some embodiments, at least 60 weight percent (by dry weight) of the polymer fibers are composed of one or more polymers of the present invention. In some embodiments, at least 70 weight percent (by dry weight) of the polymer fibers are composed of one or more polymers of the present invention. In some embodiments, at least 80 weight percent (by dry weight) of the polymer fibers are composed of one or more polymers of the present invention. In some embodiments, at least 90 weight percent (by dry weight) of the polymer fibers are composed of one or more polymers of the present invention.

[0138] As used herein, the term "fiber" describes a class of structural elements, similar to a single thread, made of continuous filaments and / or individual, elongated pieces. In some embodiments, a first polymer provides or enhances the stability of the polymer fiber. In some embodiments, a polymer fiber comprising a first polymer and at least one of (i) a second polymer and (ii) a third polymer has enhanced stability compared to a fiber substantially lacking the first polymer. In some embodiments, a polymer fiber is said to be stable if it substantially maintains its structure. In some embodiments, substantially maintaining is over a period of at least 1 day (d), at least 10 d, at least 20 d, at least 30 d, at least 50 d, at least 100 d, at least 200 d, at least 300 d, at least 1 year (y), at least 2 y, or at least 3 y (including any range or value therebetween). In some embodiments, a fiber is said to be stable if it remains structurally intact under physiological conditions (e.g., does not degrade in vivo and is therefore non-biodegradable or non-biodegradable). In some embodiments, a fiber is said to be stable if it remains structurally intact under ambient conditions (e.g., temperatures between 10 and 60°C and moisture contents between 10 and 99%, including any values ​​therebetween).

[0139] In some embodiments, the polymer fiber further comprises an additional biodegradable polymer.

[0140] In some embodiments, the polymer fibers are biodegradable. In some embodiments, the polymer fibers are characterized by an average fiber diameter in the range of 0.5-10 um, 0.5-1.5 um, 1-4 um, 2-4 um, 4-5 um, 5-6 um, 6-7 um, 7-8 um, 8-10 um, or any range therebetween.

[0141] In some embodiments, the polymer fibers are characterized by a melting point of 50-150°C, 50-70°C, 70-100°C, 100-120°C, or 120-150°C.

[0142] As used herein, melting point or glass transition temperature is preferably determined according to differential scanning calorimetry using procedures accepted in the art for such purposes, using cooling and heating rates of 10°C per minute. The glass transition typically appears as the intersection between two linear regions in a plot of heat capacity as a function of temperature.

[0143] In some embodiments, the polymeric fibers are woven or nonwoven. Many suitable techniques for spinning fibers will be known to those skilled in the art.

[0144] In some embodiments, the polymeric fibers are nonwoven.

[0145] In some embodiments, the polymer fibers are electrospun.

[0146] Without being bound by any particular theory, it is believed that electrospun fibers, and structurally similar fibers, are particularly suitable for forming tissue-adhesive layers as described later in this specification. In particular, electrospun fiber layers can be prepared from a wide variety of materials, allowing for control over pore size, fiber size, fiber alignment, hydrophobicity, elasticity, and mechanical strength.

[0147] In some embodiments, the polymer fiber (e.g., a fiber of the present invention) further comprises an additive. In some embodiments, the composition (e.g., a composition of the present invention) further comprises an additive. In some embodiments, the composition (e.g., a liquid composition and / or a semi-liquid composition) further comprises an additive. In some embodiments, the w / w concentration of the additive in the composition of the present invention is 5-95%, 5-10%, 10-20%, 20-30%, 30-50%, 50-70%, 70-95% (including any range or value therebetween).

[0148] Examples of additives include, but are not limited to, adhesive materials, non-adhesive materials (e.g., materials characterized by particularly low adhesion to tissue and / or other substrates), hydrophobic polymer particles, biological and / or bioactive materials, cellular components (e.g., cell signaling proteins, extracellular matrix proteins, cell adhesion proteins, growth factors, protein A, proteases and protease substrates), growth factors, and therapeutically active agents.

[0149] Other additives (e.g., therapeutically active agents) that can be beneficially incorporated into the polymer fibers and / or compositions of the present invention (e.g., liquid or semi-liquid compositions) include natural and / or synthetic polymers (macrobiomolecules, e.g., proteins, enzymes) and non-polymeric (small molecule therapeutic) natural or synthetic drugs.

[0150] Examples of suitable therapeutically active agents include, but are not limited to, antiproliferative agents, cytotoxic factors, or cell cycle inhibitors (including CD inhibitors such as p53, thymidine kinase ("TK"), and other agents useful in disrupting cell proliferation).

[0151] Examples of therapeutically active agents that inhibit cell proliferation and / or angiogenesis (antiproliferative drugs) that are particularly useful in drug eluting systems for anticancer therapy include paclitaxel, sirolimus (rapamycin), farnesylthiosalicylic acid (FTS, salirasib), fluoro-FTS, everolimus, zotarolimus, daunorubicin, doxorubicin, N-(5,5-diacetoxypentyl)doxorubicin, anthracyclines, mitomycin C, mitomycin A, 9-aminocamptothecin, antinomycin, N-aminoperazine, antimycin, anti-inflammatory drugs ... 8-These include acetylspermidine, 1-(2-chloroethyl)-1,2-dimethanesulfonylhydrazine, bleomycin, tallysomucin, etoposide, camptothecin, irinotecan, topotecan, 9-aminocamptothecin, paclitaxel, docetaxel, esperamicin, 1,8-dihydroxy-bicyclo[7.3.1]tridec-4-ene-2,6-diyn-13-one, anguidine, morpholino-doxorubicin, vincristine, vinblastine, and derivatives thereof.

[0152] Additional therapeutically active agents that can be beneficially incorporated into the polymer fibers and / or compositions of the present invention (e.g., liquid or semi-liquid compositions) include antibiotics. Non-limiting examples of suitable antibiotics include gentamicin, ceftazidime, mafenide benzoyl peroxide, octopirox, erythromycin, zinc, silver, tetracycline, triclosan, azelaic acid and its derivatives, phenoxyethanol and phenoxypropanol, ethyl acetate, clindamycin and meclocycline, sebostat such as flavonoids, alpha and beta hydroxy acids, polydiallyldimethylammonium chloride, and bile salts such as simunol sulfate and its derivatives, deoxycholic acid, and cholic acid.

[0153] Additional therapeutically active agents that may be beneficially incorporated into the polymer fibers and / or compositions of the present invention (e.g., liquid or semi-liquid compositions) include analgesics, anesthetics, painkillers, pain relief agents, and the like (including NSAIDs, COX-2 inhibitors, K+ channel openers, opiates, and morphinomimetics), as well as hemostatic and anti-hemorrhagic agents.

[0154] matrix In some embodiments, provided herein is a matrix comprising a tissue-adhesive layer, hi some embodiments, the tissue-adhesive layer comprises a plurality of blended polymer fibers, wherein the blended polymer fibers are as described herein above.

[0155] In some embodiments, the tissue adhesive layer provides bioadhesive properties to the matrix. In some embodiments, the tissue adhesive layer forms covalent bonds or non-covalent interactions with tissue, resulting in tissue adhesion of the matrix.

[0156] In some embodiments, the bioadhesive properties of the tissue adhesive layer are enhanced upon hydration, eg, upon contact with moist tissue.

[0157] In some embodiments, the tissue adhesive layer promotes cell attachment and / or proliferation.

[0158] As used herein, the term "matrix" refers to one or more layers of polymer fibers. The matrix may further include any materials incorporated within and / or interposed between the layers. In some embodiments, the terms "matrix" and "tissue-adhesive layer" are used interchangeably herein.

[0159] In some embodiments, the matrix is ​​a multi-layer matrix comprising a tissue adhesive layer and an additional layer.

[0160] In some embodiments, the additional layer is an elastic layer or a viscoelastic layer. In some embodiments, the additional layer enhances the stability of the tissue adhesive layer. In some embodiments, the stability is as described herein. In some embodiments, the additional layer enhances the mechanical strength of the tissue adhesive layer. In some embodiments, the additional layer enhances at least one mechanical property of the matrix. In some embodiments, the at least one mechanical property is selected from the group consisting of Young's modulus, tensile strength, strain at break, yield point, toughness, work to break, impact strength, tear strength, flexural modulus, flexural strain, and stress at a particular percentage elongation, and abrasion.

[0161] In some embodiments, the additional layer is attached to the tissue adhesive layer or interposed between two tissue adhesive layers.

[0162] As used herein, the term "elastic layer" refers to a layer of material that exhibits elasticity. As used herein, the terms "elastic" and "elastic" are as defined herein above.

[0163] As used herein, the term "viscoelastic layer" refers to a layer of material where the layer exhibits viscoelastic properties.

[0164] An elastic layer according to any one of the embodiments described in this section can be combined with a viscoelastic polymer material and / or a viscoelastic layer according to any one of the respective embodiments described herein.

[0165] As used herein, the term "multilayer" refers to the presence of at least two distinct layers, which may differ, for example, in chemical composition, molecular morphology (e.g., degree and type of crystallinity), physical structure, and / or mechanical properties.

[0166] As exemplified later in this specification (Examples section), matrices as described herein can be formed from biodegradable and biocompatible materials while exhibiting significant mechanical strength, high adhesive strength, a high degree of elasticity and flexibility, high porosity (which can support cell growth and tissue adhesion), and a high degree of water impermeability suitable for forming a seal, bonding a tissue surface to another tissue, preventing fluid leakage, and preventing bacterial and viral infection.

[0167] In some embodiments, the tissue adhesive layer has a thickness in the range of 0.5 to 200 μm, 0.5 to 1 μm, 1 to 100 μm, 1 to 5 μm, 5 to 10 μm, 10 to 20 μm, 20 to 30 μm, 30 to 50 μm, 50 to 70 μm, 50 to 100 μm, 70 to 100 μm, 100 to 150 μm, 150 to 200 μm, 200 to 250 μm (including any range or value therebetween).

[0168] In some embodiments, the tissue adhesive layer is characterized by a tensile strength of at least 0.05 MPa, at least 0.5 MPa, at least 1 MPa, at least 2 MPa, at least 3 MPa, at least 4 MPa, at least 5 MPa, at least 7 MPa, at least 8 MPa, or at least 10 MPa. In some embodiments, the tissue adhesive layer is characterized by a tensile strength of 0.05-1 MPa, 0.5-1 MPa, 1-2 MPa, 2-3 MPa, 3-4 MPa, 4-5 MPa, 5-7 MPa, 7-8 MPa, or 8-10 MPa (including any range or value therebetween). In some embodiments, the tissue adhesive layer is characterized by a tensile strength as exemplified herein.

[0169] The tensile properties (e.g., tensile strength) described herein are determined in accordance with ASTM International Standard D882-12 for Testing Tensile Properties of Thin Plastic Sheets. Tensile testing characterizes the amount of tensile stress applied to a tested material as a function of the material's tensile strain (the increase in length due to the tensile stress as a percentage of the original length).

[0170] Tensile strength is determined as the maximum stress that can be applied to the tested material, so that any further strain at reduced stress is either obtainable (a phenomenon known as "necking") or cannot be obtained because the tensile stress would result in rupture (e.g., tearing, cracking) of the material.

[0171] In some embodiments, the tissue adhesive layer is characterized by an adhesive strength in the range of 10-400 KPa, 10-50 KPa, 20-50 KPa, 50-80 KPa, 80-100 KPa, 100-200 KPa, 200-300 KPa, 300-400 KPa.

[0172] In some embodiments, the tissue adhesive layer is characterized by an adhesive strength in the range of 0.1-2 N, 0.1-0.3 N, 0.3-0.5 N, 0.5-0.7 N, 0.7-0.9 N, 0.9-1.0 N, 1.0-1.2 N, 1.2-1.5 N, 1.5-2 N (including any range or value therebetween). In some embodiments, the adhesive strength refers to the average peel force or maximum peel force measured by a peel test, wherein the peel test is as described herein.

[0173] In some embodiments, the tissue adhesive layer is characterized by an adhesive strength in the range of 1-5 N, 1-1.2 N, 1.2-1.4 N, 1.4-1.6 N, 1.6-2 N, 2-2.5 N, 2.5-3 N, 3-3.5 N, 3.5-4 N, 4-5 N, 5-6 N, 6-10 N (including any range or value therebetween). In some embodiments, the adhesive strength is measured according to a shear test.

[0174] In some embodiments, the tissue adhesive layer is characterized by an adhesive strength of at least 1 N, at least 1.1 N, at least 1.2 N, at least 1.3 N, at least 1.4 N, at least 1.5 N, at least 1.6 N, at least 1.7 N, at least 1.8 N, at least 1.9 N, at least 2 N, at least 2.2 N, at least 2.4 N, at least 2.5 N, at least 2.8 N, at least 3 N, at least 3.2 N, at least 4 N, at least 5 N, at least 6 N, at least 8 N, at least 10 N (including any range or value therebetween). In some embodiments, the adhesive strength is determined by shear testing, as described later herein.

[0175] Adhesion strength is determined in two different ways, a peel test and a shear test, as described later in this specification.

[0176] In some embodiments, the tissue adhesive layer has a viscosity of 1 ml / hr / cm when exposed to an aqueous liquid at a pressure of 40 mmHg. 2In some such embodiments, the water permeability is less than 0.3 ml / hr / cm 2 In some embodiments, the water permeability is less than 0.1 ml / hr / cm 2 In some embodiments, the water permeability is less than 0.03 ml / hr / cm 2 In some embodiments, the water permeability is less than 0.01 ml / hr / cm 2 is less than.

[0177] In some embodiments, the tissue adhesive layer further comprises an additive (e.g., a pharmaceutical active ingredient). In some embodiments, the additive is as described herein above.

[0178] In some embodiments, either tissue adhesive layer or additional layer is porous layer.As used herein, the term " porous layer " refers to a layer that includes voids (for example, in addition to the polymeric material described herein), for example, the space between polymeric materials is not filled by additional material.However, porous layer can optionally include additional material in the space between polymeric materials, as long as at least a part of the volume of voids is not filled by additional material.

[0179] Many suitable techniques for preparing polymeric materials in porous form will be known to those skilled in the art, including, but not limited to, various techniques for spinning fibers, the use of gases to form foams, and drying (e.g., freeze-drying) suspensions of polymers.

[0180] In some embodiments, the porous layer (e.g., tissue adhesive layer) is characterized by a porosity of at least 60% (e.g., 60-99%). In some such embodiments, the porous layer is characterized by a porosity of at least 70% (e.g., 70-99%). In some such embodiments, the porous layer is characterized by a porosity of at least 80% (e.g., 80-99%). In some such embodiments, the porous layer is characterized by a porosity of at least 90% (e.g., 90-99%). In some such embodiments, the porous layer is characterized by a porosity of about 90%.

[0181] As used herein, the term "porosity" refers to the percentage of the volume of a material (eg, a tissue adhesive layer described herein) that consists of voids.

[0182] In some embodiments, the porous layer (e.g., tissue adhesive layer) is characterized by a pore size in the range of 0.5-100 um, 0.5-2 um, 2-4 um, 4-6 um, 6-7 um, 7-8 um, 8-10 um, 10-15 um, 15-20 um, 20-30 um, 30-40 um, 40-50 um, 50-70 um, 70-100 um.

[0183] In some embodiments, compositions (e.g., matrices) of the present invention are characterized by low swelling capacity. In some embodiments, compositions (e.g., matrices) of the present invention are characterized by swelling of about 10%. The inventors tested the swelling capacity of exemplary compositions of the present invention. Even after 8 days, the tested compositions swelled to less than 5% volume, compared to 65% swelling volume for Hemopatch™ (based on published data). In some embodiments, compositions (e.g., matrices) of the present invention are characterized by swelling volumes of less than 10%, less than 8%, less than 6%, less than 5%, less than 4%, or less than 3% (including any range or value therebetween). In some embodiments, compositions (e.g., matrices) of the present invention are characterized by significant water absorption capacity. In some embodiments, compositions (e.g., matrices) of the present invention are characterized by absorbing water 5-10 times, 5-6 times, 6-7 times, 7-8 times, or 8-10 times (including any range or value therebetween) of the initial sample weight.

[0184] The water absorption of exemplary compositions (e.g., matrices) of the present invention was compared to the commercially available Hemopatch™. The tested compositions of the present invention demonstrated the ability to absorb fluids ranging from 5 to 7 times their initial weight. Water absorption is an important property for implants because it is required to absorb unwanted leakage of bodily fluids within the intended implant site. In some embodiments, tested samples less than 0.35 mm thick exhibited similar water absorption capabilities to the commercially available Hemopatch™ at a thickness of 2 mm.

[0185] kit In another aspect, there is a kit comprising a blended polymer fiber and a composition. The blended polymer fiber comprises a first polymer and a second polymer, and the composition comprises a third polymer reactive to the second polymer, wherein one of the second polymer and the third polymer comprises a tissue adhesive group. In some embodiments, the second polymer and the third polymer of the kit comprise a second branched polymer of the present invention or a third polymer of the present invention, respectively. In some embodiments, the blended polymer fiber of the kit comprises a first polymer and a second branched polymer of the present invention, and the composition of the kit comprises a third polymer of the present invention. In some embodiments, the blended polymer fiber of the kit comprises a first polymer and a third polymer of the present invention, and the composition of the kit comprises a second branched polymer of the present invention.

[0186] In some embodiments, the blended polymer fiber of the kit comprises a second branched polymer of the invention and the composition of the kit comprises a third polymer of the invention. In some embodiments, the blended polymer fiber of the kit comprises a third polymer and the composition of the kit comprises a second branched polymer.

[0187] In some embodiments, the composition of the kit further comprises an agent, including a carrier, an additive, a solvent, or any combination thereof, wherein the w / w concentration of the agent in the composition is 5-95%, 5-10%, 10-20%, 20-30%, 30-50%, 50-70%, or 70-95% by weight (including any range or value therebetween). In some embodiments, the carrier, additive, and solvent are as described herein.

[0188] In some embodiments, the composition of the kit is a liquid, where the liquid is as described herein. In some embodiments, the composition of the kit is a semi-liquid (e.g., a gel), where the semi-liquid is as described herein. In some embodiments, the composition of the kit is a solid. In some embodiments, the composition of the kit is substantially homogeneous. In some embodiments, the kit of the invention (e.g., fibers and / or compositions) is substantially stable, where stable is as described herein.

[0189] In some embodiments, the kit composition comprises an aqueous solution or any other pharmaceutically acceptable solvent. In some embodiments, the solvent is an alcohol (e.g., ethanol) or a mixture of an aqueous solution and an alcohol. In some embodiments, the polymer of the kit composition is in liquid form. In some embodiments, the polymer of the kit composition is in viscous liquid or semi-liquid form. In some embodiments, the polymer of the kit composition has sufficient viscosity to be applied onto the fibers of the kit. In some embodiments, the polymer of the kit composition is spreadable. In some embodiments, the polymer of the kit composition is applied by spreading, spraying, casting, or any other method known in the art. In some embodiments, the kit composition is substantially free of solvent and / or carrier. In some embodiments, the kit composition consists essentially of a polymer, wherein the polymer is as described herein.

[0190] In some embodiments, the first polymer of the kit comprises or is selected from polyesters, polyanhydrides, polyacetals, polyorthoesters, polyurethanes, polycarbonates, polyphosphazenes, polyphosphoesters, polyethers, silicones, polyamides, polysulfones, polyetheretherketones (PEEK), poly(ethylene glycol), polytetrafluoroethylene, polyethylene, polysaccharides, or combinations or copolymers thereof. In some embodiments, the first polymer is a first polymer of the present invention.

[0191] In some embodiments, the second branched polymer, the third polymer, or both, comprise or are selected from polyethers, polyesters, polydioxanones, polyphosphoesters, polyurethanes, and polyamides, or any combination thereof.

[0192] In some embodiments, the second polymer of the kit (e.g., the second branched polymer or the third polymer) has an average molecular weight (MW) of at least 10 kDa, at least 20 kDa, at least 15 kDa, at least 30 kDa, or at least 40 kDa (including any range or value therebetween). In some embodiments, blended polymer fibers comprising a second polymer of the kit having a MW of at least 10 kDa are characterized by enhanced mechanical properties compared to blended polymer fibers comprising a second polymer of the kit having a lower MW. In some embodiments, the lower MW is 1-5 kDa, 1-2 kDa, 2-3 kDa, 3-5 kDa, or 5-7 kDa (including any range therebetween).

[0193] In some embodiments, the w / w content of the second polymer within the blended polymer fiber of the kit is at least 20%, at least 30%, at least 40%, at least 50% (including any range or value therebetween).

[0194] In some embodiments, the w / w content of the first polymer in the blended polymer fiber of the kit is at least 20%, at least 30%, at least 40%, at least 50% (including any range or value therebetween).

[0195] In some embodiments, the w / w content of the third polymer in the kit is at least 20%, at least 30%, at least 40%, at least 50% (including any range or value therebetween).

[0196] In some embodiments, the second polymer of the kit, the third polymer of the kit, or both, comprises polyethylene glycol. In some embodiments, the second polymer of the kit, the third polymer of the kit, or both, comprise polyethylene glycol, and the first polymer is selected from the group consisting of polylactic acid, poly(L-lactic acid), poly(D-lactic acid), polyglycolic acid, poly(L-glycolic acid), poly(D-glycolic acid), nylon, and polycaprolactone, or any combination or copolymer thereof.

[0197] In some embodiments, the second polymer of the kit or the third polymer of the kit comprises a nucleophilic group. In some embodiments, the nucleophilic group is as described herein.

[0198] In some embodiments, the weight ratio of the first polymer to the second polymer in the kit is in the range of 1:1 to 20:1, 1:1 to 20:1, 1:1 to 3:1, 3:1 to 5:1, 5:1 to 8:1, 8:1 to 10:1, 10:1 to 15:1, 15:1 to 20:1, or any range therebetween.

[0199] In some embodiments, the molar ratio of the second polymer to the third polymer in the kit is 1:0.8 to 1:20, 1:0.8 to 1:1, 0.8:1 to 1:1, 1:1 to 1:1.5, 1:1.5 to 1:2, 1:2 to 1:2.5, 1:2.5 to 1:3, 1:3 to 1:5, 1:1 to 1:5, 1:1 to 1:4, 1:1 to 1:3, 1:1 to 1:2, 1:5 to 1:7, 1:7 to 1:10, 1:10 to 1:15, 1:15 to 1:20 (including any range or value therebetween), and the second branched polymer comprises a nucleophilic group, and the third polymer comprises a tissue adhesive group.

[0200] In some embodiments, the weight ratio of the third polymer to the second polymer in the kit is 1:1 to 1:10, 1:1 to 1:1.5, 1:1.5 to 1:2, 1:2 to 1:2.5, 1:2.5 to 1:3, 1:3 to 1:5, 1:1 to 1:5, 1:1 to 1:4, 1:1 to 1:3, 1:1 to 1:2, 1:5 to 1:7, or 1:7 to 1:10 (including any range or value therebetween). In some embodiments, the weight ratio of the third polymer (e.g., a tissue-adhesive group-containing polymer such as polyether-NHS) to the second polymer (e.g., a nucleophilic group-containing polymer such as an aminated polyether or a thiolated polyether) in the kit is 1:1 to 1:1.5, 1:1.5 to 1:2, 1:2 to 1:2.5, or 1:2.5 to 1:3 (including any range or value therebetween).

[0201] In some embodiments, the molar ratio of the second polymer (e.g., aminated polyether or thiolated polyether) to the third polymer (e.g., polyether-NHS) in the kit is 1:1 to 1:20, 1:1 to 1:2, 1:5 to 1:7, 1:7 to 1:10, 1:10 to 1:15, 1:15 to 1:20 (including any range or value therebetween).

[0202] In some embodiments, the molar ratio of the third polymer (e.g., aminated polyether or thiolated polyether) to the second polymer (e.g., polyether-NHS) in the kit is 1:1 to 1:20, 1:1 to 1:2, 1:5 to 1:7, 1:7 to 1:10, 1:10 to 1:15, 1:15 to 1:20 (including any range or value therebetween).

[0203] In some embodiments, the polymer comprising a tissue adhesive group is present in the kits and / or compositions of the invention in molar excess relative to the polymer comprising a reactive group (eg, a nucleophile).

[0204] In some embodiments, the blended polymer fibers in contact with the additional component result in a tissue-adhesive layer. In some embodiments, the tissue-adhesive layer is as described above. In some embodiments, the tissue-adhesive layer comprises a second branched polymer at least partially crosslinked with a third polymer. In some embodiments, the tissue-adhesive layer comprises a blended polymer fiber at least partially crosslinked with a third polymer. In some embodiments, the crosslinking is as described herein. In some embodiments, the crosslinking is by reacting a tissue-adhesive group with a reactive group (e.g., a nucleophilic group). In some embodiments, the kit is for utilizing an aminated branched polymer to form a tissue-adhesive layer (e.g., a crosslinked tissue-adhesive matrix), and the tissue-adhesive layer is as described herein. In some embodiments, the aminated branched polymer comprises an aminated polyether, such as PEG-NH2.

[0205] In some embodiments, the third polymer of the kit composition (e.g., the second branched polymer or third polymer of the invention) has a MW of less than 10 kDa, less than 8 kDa, less than 7 kDa, less than 6 kDa, less than 5 kDa, less than 3 kDa, or less than 2 kDa. In some embodiments, a kit composition comprising a third polymer (e.g., the second branched polymer or third polymer of the invention) having a MW of less than 10 kDa, less than 8 kDa, less than 7 kDa, less than 6 kDa, less than 5 kDa, less than 3 kDa, or less than 2 kDa provides a tissue adhesive layer characterized by enhanced adhesive strength compared to a composition comprising a third polymer having a MW of more than 10 kDa.

[0206] In some embodiments, a tissue adhesive layer characterized by an adhesive strength of greater than 1.1 N is formed by contacting a composition of the kit with a blend polymer fiber of the kit, wherein the molar ratio of the second polymer (e.g., PEG-SH, and / or PEG-NH2) to the third polymer (e.g., PEG-NHS) of the kit is 1:1 to 1:20, 1:1 to 1:2, 1:5 to 1:7, 1:7 to 1:10, 1:10 to 1:15, 1:15 to 1:20 (including any range or value therebetween).

[0207] In some embodiments, the w / w ratio of the second polymer (e.g., PEG-SH and / or PEG-NH2) to the third polymer (e.g., PEG-NHS) in the kit is 10:1 to 1:1, 10:1 to 8:1, 8:1 to 6:1, 6:1 to 4:1, 4:1 to 3:1, 3:1 to 2:1, 2:1 to 1:1 (including any range or value therebetween).

[0208] In some embodiments, the kits of the present invention consist essentially of a first polymer, a second branched polymer, and a third polymer. In some embodiments, (i) the first polymer and (ii) either the second branched polymer or the third polymer comprise at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% by weight of the blended polymer fiber of the kit. In some embodiments, the first polymer, the second branched polymer, and the third polymer comprise at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% by weight of the polymer content of the kit and / or the composition of the present invention.

[0209] use In some embodiments, the matrix is ​​a medical device. In some embodiments, the medical device is an implantable medical device.

[0210] In some embodiments, the medical device is for use in the fields of general surgery, neurology, otolaryngology, urology, gynecology / obstetrics, thoracic, dentistry / maxillofacial, gastroenterology, plastic surgery, ophthalmology, cardiovascular and / or orthopedic medicine.

[0211] In some embodiments, the matrices described herein above are for adhering or sealing at least one biological surface. In some embodiments, the matrices described herein above are for promoting or increasing bioadhesion or sealing of a biological surface. In some embodiments, the matrices described herein above are for promoting or increasing blood clotting in a subject in need thereof.

[0212] In some embodiments, the matrix is ​​for use in repairing and / or replacing a biological surface.

[0213] As used herein, the term "biological surface" refers to any surface that contains cells and / or biomolecules (e.g., proteins, polysaccharides, lipids, nucleic acids). Non-limiting examples of "biological surfaces" include, but are not limited to, tissue surfaces, synthetic implant surfaces, and organ surfaces.

[0214] In some embodiments, the biological surface to be repaired and / or replaced is soft tissue. In some embodiments, the biological surface to be repaired and / or replaced is connective tissue. In some embodiments, the biological surface to be repaired and / or replaced is a membrane (e.g., after trauma, hernia, and / or surgical incision of the membrane). In some embodiments, the membrane to be repaired and / or replaced is a dura mater (e.g., after trauma and / or surgical incision of the dura mater).

[0215] In some embodiments, the matrix is ​​for use in forming bonds to a biological surface, the biological surface being selected from the group consisting of a tissue surface, a synthetic graft surface, and an organ surface in a subject in need thereof. In some embodiments, the matrix is ​​for use in bonding a tissue surface to another tissue and sealing a tissue surface in a subject in need thereof. In some embodiments, the matrix is ​​for use in promoting / enhancing wound healing in a subject in need thereof. In some embodiments, the matrix is ​​for use in performing wound closure in a subject in need thereof. In some embodiments, the matrix is ​​for use in sealing connected tubular structures such as blood vessels in a subject in need thereof. In some embodiments, the matrix is ​​for use in sealing air leaks in the lungs in a subject in need thereof.

[0216] The matrices according to the present invention are suitable for application to both internal and external body surfaces; i.e., they can be applied topically to the external body surface (e.g., skin) or to the internal surface, such as the surface of an internal organ exposed during a surgical procedure, including conventional minimally invasive surgery. In some embodiments, the matrices are suitable for maintaining closure of surgical incisions within the body. In some embodiments, the matrices are suitable for surgical applications in the following areas: thoracic and cardiovascular, general surgery, urology, and neurosurgery. In some embodiments, the matrices are suitable for preventing or limiting intraoperative and postoperative bleeding and fluid leakage, for example, after hepatobiliary and pancreatic surgery. In some embodiments, the matrices can be applied to sites requiring tissue repair, tissue sealing, or other treatment. Furthermore, the materials described in the present invention can also be used as coatings, i.e., materials that can adhere to a surface while forming a layer on the surface.

[0217] In some embodiments, a composition or kit of the present invention may be used for the localized delivery of drugs or other therapeutic substances to tissue.

[0218] It should be noted that the term "adhesive" is used herein to describe a material that can adhere to a surface. The term "sealant" is defined as a material that can adhere to a surface to prevent leakage of fluids (such as blood or other biological fluids) from surfaces, particularly internal tissues or organs, and from synthetic grafts and / or implants. Sealant is also referred to as a self-adhesive material.

[0219] Other non-limiting examples of treatments for which the matrix can be used include, but are not limited to, dural repair, hernia repair, placement of another medical implant (such as in breast reconstruction surgery), sealing anastomoses, inhibiting post-operative adhesions between tissues and promoting hemostasis (e.g., when the matrix is ​​coated with thrombin and / or fibrinogen and / or fibrin, or when the carrier polymer is composed of a material that mechanically promotes hemostasis), and administering a therapeutically effective agent (e.g., by incorporating a therapeutically effective agent within and / or on the core matrix according to any of the embodiments described herein relating to the inclusion of additional components).

[0220] In another embodiment, the present invention provides a method for preventing, inhibiting, or reducing fibrosis, scarring, and / or adhesions at a target site, the method comprising the steps of: (a) providing a composition of the present invention; and (b) applying the composition to the target site, thereby forming an adhesion barrier in situ that adheres to the target site, thereby preventing, inhibiting, or reducing fibrosis, scarring, and / or adhesions of the traumatized tissue. In some embodiments, step (b) initiates crosslinking (e.g., between a second branched polymer of the present invention and a third polymer) to form an adhesion barrier or matrix of the present invention.

[0221] In another embodiment, the present invention provides a method for preventing, inhibiting, or reducing fibrosis, scarring, and / or adhesions at a target site, the method comprising the steps of: (a) providing a blended polymer fiber of a kit; (b) applying the blended polymer fiber to the target site; and (c) applying a composition of the kit over the blended polymer fiber, thereby forming an adhesive barrier that adheres in situ to the target site, thereby preventing, inhibiting, or reducing fibrosis, scarring, and / or adhesions in traumatized tissue.

[0222] In another embodiment, the method further comprises mixing the blended polymer fibers with a kit composition to form a composite prior to applying the composite to the traumatic tissue. According to some embodiments, the mixing step initiates crosslinking (e.g., between the second branched polymer and the third polymer) to form the adhesion barrier or matrix of the invention.

[0223] In some embodiments, the target site is a surgical site. In some embodiments, the target site is a post-operative surgical site. In some embodiments, the target site is a biological surface. In some embodiments, the fibrosis, scarring and / or adhesions result from a surgical procedure. In some embodiments, the fibrosis, scarring and / or adhesions result from blunt trauma or a fracture.

[0224] Adhesion formation is known in the art as abnormal fibrous bands of scar tissue that can form within the body as a result of the healing process, often following open or minimally invasive surgical procedures, including abdominal, gynecological, cardiothoracic, spinal, plastic, vascular, ENT, ophthalmological, urological, neurological, or orthopedic surgery. Adhesion formation is typically a connective tissue structure that forms between adjacent damaged areas within the body. Simply put, a localized damaged area triggers a healing response that leads to healing and scar tissue formation. Adhesion formation is said to have occurred when scarring results in the formation of fibrous tissue bands or the attachment of adjacent anatomical structures (which should normally be separate).

[0225] Postoperative adhesions result when damaged or traumatized tissue surfaces fuse to form scar tissue following incision, cauterization, suturing, or other mechanical trauma. Adhesions can also occur in areas of blunt trauma or in tissue surrounding a fracture. The mechanism of adhesion formation in traumatized areas is based on the secretion of tissue exudate, which in turn induces the proliferation of fibroblasts, resulting in the formation of collagenous adhesions. These adhesions can injure tissues and lead to dysfunctional soft tissues.

[0226] Adhesion formation can occur after any surgery or trauma and causes significant morbidity. For example, postoperative intraperitoneal and pelvic adhesions are a major cause of infertility, chronic pelvic pain, and bowel obstruction. Adhesion formation in tissues can also irritate surrounding nerves, disrupting nerve conduction and resulting in significant loss of sensory or motor function.

[0227] In some embodiments, reduction in adhesions includes a reduction in adhesion formation and does not require complete alleviation of signs or symptoms of adhesions and does not require a cure. In various embodiments, reduction in adhesion formation includes even a slight reduction in adhesion formation, for example, by at least a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or more reduction in adhesion formation or compared to a control.

[0228] "Reducing adhesions" refers to administering a first or second composition disclosed herein to cause a decrease in the number of adhesions, the extent (e.g., area), and / or the severity (e.g., thickness, or mechanical or chemical disruption) of adhesions compared to the number, extent, and / or severity of adhesions that would occur in the absence of administration of the first or second composition disclosed herein. In various embodiments, reducing adhesions can be part of a protocol and can also include performing a procedure (e.g., subsequent surgery to reduce adhesions). The composition or procedure can inhibit the formation or growth of adhesions following adhesion-promoting stimulation, inhibit the progression of adhesions, and / or inhibit the recurrence of adhesions after their natural regression or mechanical or chemical disruption.

[0229] As used herein, the term "reduce" in any of its grammatical forms includes a decrease in one or more values ​​or parameters by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 100%, 200%, 500%, 1000% or more (including any ranges therebetween).

[0230] As used herein, the term "enhance" or "increase" in any of its grammatical forms includes an enhancement of one or more values ​​or parameters by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 100%, 200%, 500%, 1000% or more (including any range therebetween).

[0231] "Preventing adhesions" refers to administering the first and second compositions prior to the formation of adhesions to reduce the likelihood of adhesions forming in response to a particular injury, stimulus, or condition. In various embodiments, preventing adhesions can be part of a protocol and can also include performing a procedure (e.g., surgery to reduce adhesions). It will be understood that "preventing adhesions" does not require that the likelihood of adhesion formation be reduced to zero. Instead, "preventing adhesions" refers to a clinically significant reduction in the likelihood of adhesion formation after a particular injury or stimulus, e.g., a clinically significant reduction in the incidence or number of adhesions in response to a particular injury, condition, or stimulus.

[0232] In various embodiments, the adhesion barrier can function as an adhesion barrier that can be administered or applied to a target tissue site preoperatively, intraoperatively, or postoperatively to reduce, prevent, or inhibit adhesions. In some embodiments, the adhesion barrier forms a barrier that separates opposing tissue or tissue-organ surfaces while damaged or traumatized tissue heals. Thus, the growth of scar tissue and the formation or reformation of adhesions immediately adjacent to the adhesion barrier are prevented.

[0233] In another embodiment, the target site is a site of tissue injury, including, but not limited to, incision, dry surgery, suture, excision, abrasion, contusion, laceration, anastomosis, manipulation, prosthetics, curettage, orthopedic surgery, neurosurgery, cardiovascular surgery, and plastic or reconstructive surgery. The target site, as used herein, is also understood to include adjacent uninjured tissue. In another embodiment, the target site is an exposed area of ​​soft tissue surrounding a blunt trauma or fracture.

[0234] In some embodiments, the present invention is applied to various surgical procedures. In another embodiment, the surgical procedure is a gynecological surgical procedure (laparotomy or laparoscopic myomectomy). According to a non-limiting embodiment, during the removal of uterine fibroids, an incision is made in the uterus to form a barrier between the uterus and surrounding tissues to prevent adhesions.

[0235] In another embodiment, the surgical procedure is abdominal surgery. According to non-limiting embodiments, adhesion barriers can be used to prevent peritoneal adhesions and therefore prevent intestinal obstruction.

[0236] In another embodiment, the surgical procedure is cardiac surgery. According to a non-limiting embodiment, the barrier can be used to prevent post-operative adhesions following cardiac surgery.

[0237] In another embodiment, the surgical procedure is craniofacial surgery. According to a non-limiting embodiment, the barrier can protect the cortex exposed during a craniotomy and prevent the skull and cortex from adhering.

[0238] In another embodiment, the surgical procedure is musculoskeletal surgery. According to non-limiting embodiments, the barrier can prevent adhesion of tendons and surrounding tissues.

[0239] In some embodiments, the adhesion barrier is biocompatible, i.e., does not cause substantial tissue irritation or necrosis at the target tissue site.

[0240] In some embodiments, the medical device is configured to elute a therapeutically active agent, e.g., a drug included as an additional component according to any of the respective embodiments described herein. In some such embodiments, the medical device is a stent. Optionally, the composition forms at least a portion of a flexible sleeve of the stent.

[0241] The therapeutically active agent may optionally be incorporated within the matrix and / or on the surface of the matrix. Optionally, the therapeutically active agent is incorporated within a drug-eluting layer within the matrix and / or on the surface of the matrix. Such a drug-eluting layer may be formed from any suitable material known in the art of drug-eluting layers.

[0242] As used herein, the phrase "repair and / or replacement of biological tissue" refers to the repair of tissue that has been physically damaged in any way, including supporting and / or holding damaged tissue together in vivo or ex vivo, and filling the gap created by the lack of tissue (tissue replacement). Damaged tissue can be damaged, for example, by detachment (e.g., tearing, cutting), compressive stress, tensile stress, shear stress, cell dysfunction and / or cell death.

[0243] In some embodiments, methods of repairing and / or replacing biological tissue in a subject in need thereof are provided, the methods comprising contacting the biological tissue with a matrix (e.g., a medical device) described hereinabove. In some embodiments, the subject is an animal subject. In some embodiments, the subject is a human subject. In some embodiments, the subject has suffered trauma and / or injury. In some embodiments, the subject is undergoing surgery. In some embodiments, the subject has suffered bleeding. In some embodiments, the subject has suffered loss of biological fluid from one or more organs.

[0244] In some embodiments, the method includes applying at least a portion of the matrix into / onto biological tissue. In some embodiments, the applying is achieved by curing. In some embodiments, the curing is achieved via covalent bond formation with the tissue adhesive layer, as described herein above.

[0245] In some embodiments, the method is for adhering or sealing at least one biological surface.

[0246] Manufacturing Process In some embodiments, a process for producing polymer fibers is provided according to any of the respective embodiments described herein. In some embodiments, the process includes (i) mixing a solvent with a first polymer and at least one of a branched second polymer and a third polymer, thereby obtaining a solution, and (ii) providing the solution to an electrospinning apparatus. In some embodiments, the polymer fibers are as described above (e.g., in the case of compositions and / or kits of the present invention). In some embodiments, a method for producing polymer fibers of a composition of the present invention includes (i) mixing a solvent with a first polymer, a second branched polymer, and a third polymer, thereby obtaining a solution, and (ii) providing the solution to an electrospinning apparatus. In some embodiments, the first polymer, the second branched polymer, and the third polymer are as described above.

[0247] In some embodiments, the method for producing polymer fibers of the kit of the present invention includes (i) mixing a solvent with a first polymer and one of a second polymer and a third polymer, thereby obtaining a solution; and (ii) providing the solution to an electrospinning apparatus, wherein the first polymer, the second branched polymer, and the third polymer are as described above.

[0248] In some embodiments, a method for producing a composition of the kit of the invention comprises providing a second branched polymer or a third polymer and mixing the second branched polymer or the third polymer with a solvent, thereby obtaining the composition of the kit.

[0249] In some embodiments, the process further comprises drying the polymer fibers, hi some embodiments, the drying is performed at 10 to 90°C.

[0250] In some embodiments, drying comprises vacuum drying. In some embodiments, drying is accomplished by convective drying, such as by applying a hot gas stream to the fiber surface. In some embodiments, drying is accomplished by low temperature drying, such as by applying a dehumidified gas stream to the surface. In some embodiments, drying is accomplished by infrared (IR) drying. In some embodiments, drying is accomplished by microwave drying. Generally, the drying method and exact drying conditions selected will depend, among other things, on the chemical and physical properties of the polymer fiber.

[0251] In some embodiments, the process is for producing a layer of polymer fibers (eg, a tissue adhesive layer according to any of the respective embodiments described herein).

[0252] Any of the fibers described herein can optionally be manufactured by any suitable technique for preparing fibers (including macro-, micro-, and nano-sized fibers), such as conventional fiber spinning techniques. Such techniques include, for example, solution spinning, electrospinning, wet spinning, dry spinning, melt spinning, and gel spinning. Each spinning method imparts specific physical dimensions and mechanical properties to the resulting fiber, which can be tailored to provide desired properties according to the required application of the fibers and fiber layers described herein.

[0253] Simply put, fiber spinning techniques involve the optional use of spinnerets. These essentially resemble a bathroom shower head and can have from one to hundreds of tiny holes. As the filaments or crude fibers emerge from the spinneret holes, the molten or liquefied polymer is first converted to a rubbery state and then solidified. This process of "endless" crude fiber extrusion and solidification is called spinning and should not be confused with the textile operation of the same name, in which short pieces of staple fiber are twisted into yarn.

[0254] Wet spinning uses fiber-forming materials dissolved in a solvent. The spinneret is immersed in a chemical bath, and as filaments emerge, they precipitate from the solution and solidify. This process for making fibers is called wet spinning because the solution is extruded directly into the precipitating liquid. This process can produce fibers such as acrylic, rayon, aramid, modacrylic, and spandex.

[0255] Dry spinning is also used with fiber-forming materials in solution, but instead of precipitating the polymer through dilution or chemical reaction, solidification is achieved by evaporating the solvent in a stream of air or inert gas. Because the filaments do not come into contact with the precipitating liquid, there is no need for drying, and solvent recovery is facilitated. This process can be used, for example, to produce acetate, triacetate, acrylic, modacrylic, PBI, spandex, and vinylon.

[0256] In melt spinning, fiber-forming materials are melted for extrusion through a spinneret, and the crude fibers are then directly solidified by cooling. The melt-spun crude fibers can be extruded from the spinneret in a variety of cross-sectional shapes (round, trilobal, pentagonal, octagonal, etc.). For example, nylon (polyamide), olefin, polyester, saran, and sulfur are produced in this manner. Non-polymeric fibers can also be produced by melt spinning.

[0257] Gel spinning is a specialized process used to obtain high strength or other special fiber properties. During extrusion, the polymer is not in a true liquid state. Instead of being completely separated as in a true solution, the polymer chains are bonded together at various points in the form of liquid crystals. This creates strong interchain forces in the resulting filaments, significantly increasing the tensile strength of the fibers. Furthermore, the liquid crystals are aligned along the fiber axis by shear forces during extrusion. The filaments emerge with an unusually high degree of orientation relative to each other, enhancing their strength. Because the filaments are first passed through air and then further cooled in a liquid bath, this process can also be described as wet-dry spinning. For example, some high-strength polyethylene and aramid fibers are produced by gel spinning.

[0258] Alternatively, the fibers may be of natural or synthetic origin and may be provided ready for use without further manipulation or preparation steps or upon surface treatment thereof.

[0259] In some embodiments, the fibers are formed from electrospun polymeric materials.

[0260] As used herein, the terms "electrospin," "electrospinning," "electrospun," and the like refer to a technique for producing fibers (e.g., nanofibers) from a polymer solution. During this process, one or more polymers of the polymeric materials described herein are liquefied (i.e., melted or dissolved) and placed in a dispenser. An electrostatic field is used to generate a positively charged jet from the dispenser to a collector. Therefore, the dispenser (e.g., a syringe with a metal needle) is typically connected to a high voltage source, preferably of positive polarity, while the collector is grounded, thus creating an electrostatic field between the dispenser and the collector. Alternatively, the dispenser can be grounded while the collector is connected to a high voltage source, preferably of negative polarity. As will be understood by those skilled in the art, any of the above configurations establishes movement of a positively charged jet from the dispenser to the collector. Reverse polarity is also contemplated to establish movement of a negatively charged jet from the dispenser to the collector. At a critical voltage, charge repulsion begins to overcome the surface tension of the droplet. The charged jet leaves the dispenser and moves in the electrostatic field toward the collector. As it moves at high speed through the inter-electrode space, the jet stretches and the solvent therein evaporates, thus forming fibers, which are collected on a collector, for example in the form of a layer of fibers.

[0261] Several parameters can affect the fiber diameter; these include the size of the dispenser's dispensing holes, the dispensing speed, the strength of the electrostatic field, the distance between the dispensers, and / or the concentration of the polymer material used to produce the electrospun fibers.

[0262] The dispenser may be, for example, a syringe with a metal needle or a bath with one or more capillary openings that can extrude the liquefied polymeric material described herein under the action of, for example, hydrostatic pressure, mechanical pressure, air pressure, and high voltage.

[0263] In some embodiments, the collector is a rotating collector that serves to collect the electrospun fibers thereon. Using a rotating collector, a layer of electrospun fibers with a continuous gradient of porosity can be produced. Such a porosity gradient can be achieved by continuously changing the speed of the collector or by vertical movement of the dispenser, which results in a substantial change in the density and / or spatial distribution of the fibers on the collector, thus producing a porosity gradient along the radial or longitudinal direction of the collector, respectively. Typically, but not necessarily, the rotating collector has a cylindrical shape (e.g., a drum). However, it will be understood that the rotating collector can also have a planar shape.

[0264] In some embodiments, the collector is a flat, grounded collector that serves to collect the electrospun scaffold thereon. The use of a flat, grounded collector allows for random nanofiber collection. It will be appreciated that a flat, grounded collector is typically a horizontal or vertical collector.

[0265] In some embodiments, any layer of polymer fiber (including the tissue adhesive layer according to any of the respective embodiments described herein) is optionally prepared by continuous electrospinning.

[0266] In some embodiments, a process for preparing a matrix according to any of the respective embodiments described herein is provided, in some embodiments, the process includes fabricating a layer of polymer fibers (according to any of the respective embodiments described herein) and optionally additional layers by continuous electrospinning, thereby forming a matrix.

[0267] In some embodiments, a process for preparing a multilayer matrix is ​​provided according to any of the respective embodiments described herein. In some embodiments, the process includes providing a first layer of polymer fibers (e.g., a tissue-adhesive layer), disposing an additional layer parallel to the first layer, and pressing the first layer and the additional layer together, thereby forming the multilayer matrix.

[0268] In some embodiments, pressing the first layer and the additional layer together comprises applying a pressure of at least 1 gram / cm. In some embodiments, the pressure is at least 2 grams / cm. In some embodiments, the pressure is at least 4 grams / cm. In some embodiments, the pressure is at least 8 grams / cm.

[0269] In some embodiments, the process further comprises heating any one of the layers prior to, simultaneously with, and / or after pressing the layers, hi some embodiments, the heating is to a temperature above the glass transition temperature and / or melting point (optionally the glass transition temperature) of the polymer fibers forming the layer.

[0270] common terms As used herein, the term "about" refers to ±10%.

[0271] The terms "comprise," "comprising," "includes," "including," "having," and their cognates mean "including but not limited to."

[0272] The term "consisting of" means "including and limited to."

[0273] The term "consisting essentially of" means that a composition, method, or structure may include additional components, steps, and / or moieties, but only if the additional components, steps, and / or moieties do not materially alter the basic and novel characteristics of the claimed composition, method, or structure.

[0274] The word "exemplary" is used herein to mean "serving as an example, instance, or illustration." Any embodiment described as "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments and / or does not necessarily exclude the incorporation of features from other embodiments.

[0275] The word "optionally" is used herein to mean "provided in some embodiments and not provided in other embodiments." Any particular embodiment of the invention may include multiple "optional" features unless such features contradict each other. The words "further" and "optionally" may be used interchangeably.

[0276] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, the terms "one compound" or "at least one compound" can include multiple compounds, including mixtures thereof.

[0277] As used herein, the term "substantially" means at least 80%, at least 90%, at least 92%, at least 95%, at least 97%, at least 98%, at least 99% by weight of the composition (including any ranges or values ​​therebetween).

[0278] Throughout this application, various embodiments of the present invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the present invention. Accordingly, the description of a range should be considered to have specifically disclosed all possible subranges as well as individual numerical values ​​within that range. For example, the description of a range such as 1 to 6 should be considered to have specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0279] Whenever a numerical range is given herein, it is meant to include any recited number (fractional or integer) within the indicated range. The phrases "ranging between" a first indicated number and a second indicated number and "ranging between" a first indicated number and a second indicated number are used interchangeably herein and are meant to include the first and second indicated numbers and all fractional and integer numbers therebetween.

[0280] As used herein, the term "method" refers to manners, means, techniques and procedures for accomplishing a given task, including but not limited to manners, means, techniques and procedures that are either known to or readily developed from known manners, means, techniques and procedures by practitioners in the fields of chemistry, pharmacology, biology, biochemistry and medicine.

[0281] As used herein, the term "treatment" or "treating" includes arresting, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating the clinical or cosmetic symptoms of a condition, or substantially preventing the appearance of clinical or cosmetic symptoms of a condition.

[0282] It will be understood that certain features of the invention that are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination, or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, except to the extent that the embodiment cannot function without those elements.

[0283] Various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below find experimental evidence in the following examples. [Example]

[0284] Reference is now made to the following examples, which together with the above description illustrate, in a non-limiting manner, some embodiments of the present invention.

[0285] material The materials used in the preparation of exemplary compositions of the present invention are summarized in Tables 1A and 1B. [Table 1] [Table 2]

[0286] method 1. Morphological characteristics Morphological characterization of the electrospun samples was obtained by analyzing scanning electron microscope (SEM) images of the electrospun samples using ImageJ software. The samples were sputter-coated with gold. Images of the outer surfaces of the samples were taken at 500-8000x magnification using an environmental scanning electron microscope (SEM) with a tungsten filament (Quonta 200, FEI).

[0287] Fiber and pore diameters were measured on SEM micrographs at 8000x magnification using the ImageJ linear measurement tool, calibrated using the scale bar on the SEM images. Fiber and pore sizes were averaged for each sample (10 fiber and pore measurements were analyzed per image).

[0288] 2. Mechanical properties Tensile Properties: The mechanical properties of each electrospun sample were determined by measuring the tensile strength of each produced sample according to ASTM D882-12: Standard Test Method for Tensile Properties of Thin Plastic Sheets. Testing was performed using a LLOYD LS1 uniaxial tensile machine (equipped with a 100 N load cell). Samples were cut into a dogbone shape, and thickness was measured at three points along the neck of the dogbone. The test sample was then mounted in a clamping force machine. Each sample was stretched until fracture. The ultimate tensile strength was determined.

[0289] 3.Adhesive strength The adhesive strength of each sample produced is determined by two different methods: shear test and peel test. A detailed description of the test conditions is provided later in this specification.

[0290] 4. Burst pressure strength: The burst resistance of the adhesive composition of the present invention was also evaluated and compared with available tissue adhesive materials, such as Hemopatch™. Testing was performed in accordance with ASTM F2392. Collagen strips were used as substrates and prepared as described in the shear test. A 3.0 mm diameter hole was drilled in the center of each collagen piece, and 15 x 15 mm pieces (n = 10) of prototype samples were placed over the collagen hole. The prototype samples were pressed against the collagen for 15 minutes under a weight of less than 160 grams. The bonded / attached pieces were then mounted and fixed in a burst fixture with the central hole centered and exposed to a constant rate of saline as described in ASTM F2392. The burst strength was defined as the average maximum pressure required to cause leakage of the sample.

[0291] 5. Swelling and water absorption properties Dry patches (4x4cm diameter rectangles) were weighed and then immersed in 37°C water for 1 hour until saturated. The samples were removed from the water, their surfaces slightly dried using clean, dry paper, and reweighed at each time point. The dimensions of the patches were measured using calipers at each time point, both in the dry and wet state. Water absorption (%) = (Wf-Wi) / Wi × 100%; Wi = initial weight, Wf = final weight (after immersion in water).

[0292] Example 1 Preparation of exemplary compositions and controls Blended polymer fibers (inventive and control exemplary compositions) were prepared as follows: The electrospinning process was carried out at a temperature of 23 ± 5 °C and a relative humidity of 35 ± 10% using a syringe pump, a 22-gauge needle (inner diameter approximately 0.51 mm), and a high-voltage (30 kV max) DC power supply. The solution flow rate was 2.6 ml / h under a voltage supply of 6 ± 2 kV and a tip-to-collector distance of 5-8 cm. Patches were collected on a 51 mm diameter, 45 mm wide aluminum vertical wheel rotating at 310 rpm. The prepared patches had a thickness of 200 ± 30 µm and were vacuum-dried at room temperature for 24 hours to remove residual solvent.

[0293] Preparation of PLCL fibers containing activated PEG polymers Control 1.1: Electrospin blend PLCL containing methoxy-PEG-NHS (Mw = 20K) at a 1:0.333 (w / w) ratio [6.67E-06 mol and 1.65E-05 mol, respectively]. The polymer was dissolved in a 25:25:50 (w / w) mixture of DMF:dioxane:THF to form a PLCL solution with a final concentration of approximately 15% (w / w) at room temperature.

[0294] Control 1.2: Electrospin blend PLCL containing methoxy-PEG-NHS (20K Mw) and methoxy-PEG-thiol (Mw=20K) in a ratio of 1:0.333:0.167 (w / w / w) [6.67E-06 mol, 1.65E-05 mol, and 8.35E-06 mol, respectively] as described in Control 1.1.

[0295] Control 1.3: Electrospinning of blend PLCL containing methoxy-PEG-NHS (20K Mw) and methoxy-PEG-NH2 (Mw=2KDa) in a ratio of 1:0.333:0.167 [6.67E-06 mol, 1.65E-05 mol, and 8.35E-06 mol, respectively] as described in Control 1.1.

[0296] Composition 1.1: Electrospin a blend PLCL of 4 Arm-PEG-NHS and more preferably 8 Arm PEG-NHS (Mw=40K) in a ratio of 1:0.33 [6.67E-06 moles and 8.25E-06 moles, respectively] as described in Control 1.1.

[0297] Composition 1.2: Electrospun a PLCL blend containing 4 Arm-PEG-NHS, the preferred 8 Arm PEG-NHS (Mw=40K), and 4 Arm PEG-SH (Mw=20K) in a ratio of 1:0.333:0.167 [6.67E-06 mol, 8.25E-06 mol, and 8.35E-06 mol, respectively]. The solution and final patch were produced as described in Control 1.1.

[0298] Composition 1.3: Electrospun a PLCL blend containing 4 Arm-PEG-NHS, the more preferred 8 Arm PEG-NHS (Mw=40K), and mPEG-NH2 (Mw=2KDa) in a ratio of 1:0.333:0.167 [6.67E-06 mol, 8.25E-06 mol, and 8.35E-05 mol, respectively]. The solution and final patch were produced as described in Control 1.1.

[0299] Composition 1.4: Electrospin blend PLCL containing 4 Arm-PEG-NH2, more preferably 8 Arm PEG-NH2 (Mw=40K), in a 2:1 ratio, respectively. Generate solution and final patch as described in Control 1.1. Final polymer concentration is approximately 15%. Patches, supplied in one or more syringes or ampoules filled with 4 Arm-NHS-2KDa solution, more preferably 8 Arm-NHS-2KDa, are applied to the tissue in situ.

[0300] Preparation of PDLCL fibers containing activated PEG polymers Composition 2.1: Electrospin a blend PDLCL containing 4 Arm-PEG-NHS, more preferably 8 Arm PEG-NHS (Mw=2KDa), and 4 Arm-PEG-SH, more preferably 8 Arm PEG-SH (Mw=20KDa), in a ratio of 2.5:2.5:1, respectively. Produce the solution and final patch as described in Control 1.1. The final polymer concentration is approximately 25%.

[0301] Preparation of PDLC films containing activated PEG polymers Composition 3.1: A 4:1 ratio solution of blended PDLC containing 4 Arm-PEG-NHS, preferably 8 Arm PEG-NHS (Mw=10KDa), is spread onto the PLCL fiber layer. The final polymer concentration is approximately 20%.

[0302] This was achieved by spreading a thin layer of the polymer mixture onto a PLCL layer using a thin film applicator, or by depositing two layers of PLCL fibers and 150 microns of PDLC. This could also be achieved by spreading the polymer mixture onto release paper and depositing it onto the PLCL fiber patch, or by electrospraying the blend solution onto the fibers. To improve the covalent bond between the activated PEG and the PLCL fiber patch, the outer layer of the PLCL fiber can be chemically functionalized. Chemical activation of the outer surface of the PLCL fiber can be achieved by treatment with plasma, ozone, gamma radiation, electron beam, laser, and UV light. The patch is then vacuum-dried at room temperature for at least 12 hours to remove residual solvent.

[0303] Composition 3.2: A 20:5:1 ratio solution (approximately 20%) of blend PDLC containing 4 Arm-PEG-NHS, more preferably 8 Arm PEG-NHS (Mw=40KDa), and 4 ArmPEG-SH (Mw=20KDa) is spread onto a patch of PLCL fibers or PLCL fiber layer as described above.

[0304] Composition 3.3: A 1:1 ratio solution (approximately 20%) of blended PDLC containing 4 Arm-PEG-NHS, more preferably 8 Arm PEG-NHS (Mw=2KDa) is spread onto a patch of PLCL fiber or PLCL fiber layer as described in composition 3.1.

[0305] Composition 3.4: A 2.5:2.5:1 ratio solution (approximately 25%) of blended PDLC containing 4 Arm-PEG-NHS, more preferably 8 Arm PEG-NHS (Mw=2KDa), and 4 Arm PEG-SH (Mw=20KDa) is spread onto a patch of PLCL fiber as described in composition 3.1.

[0306] Composition 3.5: A 1.5:1.5:1 ratio solution (approximately 30%) of blended PDLC containing 4 Arm-PEG-NHS, more preferably 8 Arm PEG-NHS (Mw=2KDa), and 4 Arm PEG-SH (Mw=20KDa) is spread onto a patch of PLCL fiber as described in composition 3.1.

[0307] Preparation of PLCL fiber layers coated with activated PEG polymer Composition 4.1: 4 Arm-PEG-NHS (Mw=40KDa), preferably 8 Arm-PEG-NHS (Mw=40KDa), is distributed on the surface of a PLCL fiber patch. This can be done by immersing a portion of the PLCL fiber patch in a PEG polymer melt for a specified time and then cooling, or by spreading the PEG mixture on the surface of a PLCL fiber patch, such as the fiber patch described in Composition 3.1, or on the surface of another PDLC film spread on the PLCL fiber patch. The PEG mixture can be fixed on the surface of the patch / PDLC film by, for example, heating the patch at 40°C for 1-2 hours to melt it.

[0308] Composition 4.2: 20 mg of 4 ARM-PEG-NHS (40 KDa), more preferably 8 ARM-PEG-NHS (Mw=40 KDa) powder is distributed evenly over a 2.5 cm x 4.0 cm surface as described in composition 4.1.

[0309] Composition 4.3: 30 mg of a mixture (2:1) of 4 ARM-PEG-NHS (40 KDa), more preferably 8 ARM-PEG-NHS (Mw=40 KDa), and 4 ARM-PEG-SH (Mw=20 KDa) is distributed evenly over a 2.5 cm x 4.0 cm surface as described in composition 4.1.

[0310] Composition 4.4: 20 mg of 4 ARM-PEG-Isocyanate (Mw=20 KDa) is distributed evenly over a 2.5 cm x 4.0 cm surface as described in composition 4.1.

[0311] Composition 4.5: 30 mg of 4 ARM-PEG-NHS (Mw=40 KDa), more preferably a mixture of 8 ARM-PEG-NHS (Mw=40 KDa) + 4 ARM-PEG-NH2 (Mw=40 KDa) (2:1) is evenly distributed over a 2.5 cm x 4.0 cm surface as described in composition 4.1.

[0312] Composition 4.6: Mix 0.2 ml of 4 Arm-PEG-NHS (Mw=2KDa), more preferably 8 Arm-PEG-NHS (Mw=2KDa) with 0.1 ml of 4 Arm-PEG-SH (Mw=2KDa), more preferably 8 Arm-PEG-SH (Mw=2KDa) (2:1 ratio) and pour onto a 4.0 cm x 5.0 cm surface of a PLCL fiber patch or onto a PDLC film (fibrous PLCL and PDLC film) for a two-layer patch.

[0313] Composition 4.7: Spread only PEG-NHS (30%) solution onto a PEG-NHS fiber patch as described in Composition 3.1, followed by 20 mg of 4 Arm-PEG-NHS, or more preferably 8 Arm-PEG-NHS (Mw=40 KDa) powder evenly distributed over a 2.5 cm x 4.0 cm surface.

[0314] Composition 4.8: Spread only PDLC (30%) solution onto a PLCL fiber patch as described in Composition 3.1, followed by 30 mg of 4 Arm-PEG-NHS, more preferably a 2:1 mixture of 8 Arm PEG-NHS (Mw=40K Da) and 4 Arm PEG-SH (Mw=20K Da) powders, evenly distributed over a 2.5 cm x 4.0 cm surface.

[0315] Composition 4.9: Spread only PDLC (30%) solution onto a PLCL fiber patch as described in Composition 3.1, followed by 30 mg of 4 Arm-PEG-NHS, more preferably a 2:1 mixture of 8 Arm PEG-NHS (Mw=40 KDa) and 4 Arm PEG-NH2 (Mw=40 KDa) powders, evenly distributed over a 2.5 cm x 4.0 cm surface.

[0316] Composition 4.10: Spread only the PDLC (30%) solution onto a PLCL fiber patch as described in Composition 3.1, followed by uniformly distributing 20 mg of 4 Arm-PEG-ISOCYANATE (Mw=20 KDa) powder over a 2.5 cm x 4.0 cm surface.

[0317] Additional exemplary fibers or compositions (Table 2) have been prepared and tested and exhibit properties such as fiber thickness, pore size, tensile strength, and adhesive strength (data not shown) similar to the corresponding fibers or compositions described above. [Table 3]

[0318] The above compositions containing multi-armed PEG refer to exemplary matrices of electrospun fibers according to some embodiments of the present invention, while the above controls refer, inter alia, to matrices of electrospun fibers containing single-armed PEG.

[0319] SEM micrographs showing structural images of the matrix layer of exemplary electrospun fibers of the present invention are shown in Figure 3. SEM images of all samples demonstrated smooth, uniform, bead-free fibers, with no significant effect of each prototype's solution composition on fiber morphology. As shown in Figure 4, electrospun fibers composed of single-arm PEG (Controls 1.1–1.3) with fiber sizes ranging from 1.08 to 2.7 μm were thinner than electrospun fibers composed of multi-arm PEG (Compositions 1.1–1.3) with fiber sizes ranging from 1.22 to 4.88 μm. On the other hand, the larger fiber diameter of Compositions 1.1–1.3 did not affect the overall pore size of the samples, as seen in Figure 5, resulting in similar pore sizes ranging from 7.44 to 9.72 μm for fibers composed of single-arm PEG (Controls 1.1–1.3) and multi-arm PEG (Compositions 1.1–1.3).

[0320] Example 2 Peel Test Procedure Samples of each matrix layer of electrospun fibers were cut into 15 mm x 30 mm strips, half of which were wetted with saline, while the other half was kept dry. As seen in Figure 1, each strip was placed parallel to a wet 15 mm x 30 mm collagen strip to create a minimum bonded area of ​​15 x 15 mm. The wet half of each sample was pressed against the collagen strip for 2 minutes, while the other half was left unbonded to the collagen, creating a peel arm. All samples were allowed to dry at room temperature for easy handling. The force required to break the bond between the collagen and the sample was measured using a LLOYD LS1 universal testing machine. The peel arms were pulled apart at a rate of 10 mm / min, and the force required to break the bond was measured. The adhesive strength was defined as the average of the peel force and maximum force recorded during the test.

[0321] Shear Test Procedure As seen in Figure 2, wet collagen strips were sliced ​​and bonded at the sliced ​​points by pressing the wet sample against the collagen for 2 minutes. The force required to break the bond is measured by stretching the collagen strip at a rate of 10 mm / min using a LLOYD LS1 universal testing machine. Adhesion strength is defined as the maximum force required to separate the collagen strip at the bond point divided by the bond area. Commercially available tissue adhesives, such as Hemopatch™, were also tested to serve as controls.

[0322] The adhesive strengths determined by the peel and shear tests are shown in Figures 7 and 8, respectively. In both tests, Compositions 1.2 and 2 (not shown) exhibited the highest adhesive strengths compared to the other samples. Consequently, blending multi-arm activated PEG into the electrospinning solution results in improved adhesive strength compared to single-arm activated PEG (except for Composition 1.1 in Figure 7). Furthermore, according to the results shown in Figure 7, which show a significant increase in adhesive strength for Composition 1.2 compared to Composition 1.1, the combination of a second branched polymer and a third polymer in the fibers of the present invention (e.g., Composition 1.2) is advantageous over the second branched polymer alone (Composition 1.1). Compared to all the samples tested, Hemopatch™ appears to have the lowest adhesive strength determined by the peel test. All exemplary matrices according to some embodiments of the present invention, having a fibrous structure that maintains its elasticity after wetting and drying, exhibited similar results in both tests.

[0323] The tensile strength values ​​of the electrospun fibers (Controls 1.1–1.3 and Compositions 1.1–1.4) are shown in Figure 6. A clear difference can be seen between the blend polymer fiber samples and the PLCL fiber samples. The electrospun blend polymer fibers containing activated PEG appear to fail at lower stresses. This indicates that the mechanical strength of the electrospun PLCL fibers is compromised by the addition of activated PEG. However, Composition 1.3 exhibited higher tensile strength than its control (Control 1.3). It is speculated that blending m-PEG-NH2 into the electrospinning solution of Composition 1.3, which presents more functional groups (NHS), results in covalent crosslinking between the NHS and NH2 free radicals, resulting in stronger fibers and higher tensile strength compared to its control (Control 1.3). Composition 1.4, which contains multi-arm PEG-NH2 and multi-arm PEG-NHS, also exhibited high tensile strength (average 3.6 MPa), comparable to Composition 1.1, which presents only multi-arm PEG-NHS.

[0324] It is noteworthy that the tensile strength of all exemplary inventive compositions tested was significantly higher than that of DuraGen (a commercially available artificial dura mater), which ranged from 0.084 to 0.131 MPa, and also higher than that of Hemopatch™ (0.118 MPa).

[0325] In summary, the tensile properties, such as tensile strength and elongation at break (data not shown), of the exemplary inventive compositions tested remain significantly higher than those of currently used collagen products.

[0326] The shear test results, represented by Figure 8, suggest that the exemplary inventive composition tested, comprised of multi-arm PEG-NHS with multi-arm PEG-SH, has more favorable adhesive strength than all the prototypes prepared (e.g., Composition 1.2 and Composition 4.3). The addition of multi-arm PEG reagents, such as PEG-NH2 or PEG-SH, increases the cohesive strength of the tested compositions (Figure 9).

[0327] Because PEG-NH2 readily reacts with NHS groups, it was nearly impossible to obtain electrospun fibers. To overcome this limitation, we successfully utilized kits containing electrospun fibers formed by combining a first polymer (PDCL or PLCL) with branched PEG-NHS or branched PEG-NH2. As described above (Composition 1.4), a tissue-reactive component (multi-arm PEG-NHS) was applied in situ onto the fiber layer formed by electrospinning multi-arm PEG-NH2 and PLCL. As seen in Figures 8 and 9, the adhesive strength results achieved with Composition 1.4 were within the range of favorable results.

[0328] As shown in Figure 9, multi-arm PEG-SH improves the cohesive strength without compromising the adhesive strength of the prototypes prepared in Examples 2-4, as seen in the adhesive strength tests presented in both Figure 7 and Figure 8. It can be concluded that blending a combination of multi-arm PEG-SH and PEG-NHS into a patch of PLCL fiber yielded the highest adhesive strength (composition 1.2), and the achieved results were also supported by the significant adhesive strength of composition 1.2 presented in the peel test (Figure 7).

[0329] It can also be concluded that incorporating a tissue-reactive polymer (functionalized PEG reagent) into PLCL-based fibers yields better adhesion results compared to the coating / dispensing method, which may be due to the large surface contact area provided by the PLCL-based fiber structure for optimal tissue adhesion. It is worth noting that all achieved results were compared to a commercially available control, Hemopatch™, consisting of a collagen sponge structure coated with a PEG reagent. The average adhesive strength of Hemopatch™ was approximately 1.15 N. The authors were able to demonstrate that the electrospun fiber-based adhesive layer exhibits enhanced adhesive properties to wet tissues (greater than 1.15 N) compared to currently available commercial products. Furthermore, cast film layers of functionalized PEG polymer blended with PDLC / PLCL (compositions 3.1–4.1) showed impaired adhesive strength compared to the electrospun fiber-based adhesive layer of the present invention.

[0330] While the present invention has been specifically described, those skilled in the art will appreciate that many variations and modifications are possible. Accordingly, the present invention should not be construed as limited to the specifically described embodiments, and the scope and spirit of the present invention will be more readily understood by reference to the following claims.

Claims

1. 1. A matrix comprising a tissue-adhesive layer, the tissue-adhesive layer comprising blended polymer fibers, at least 95% by weight of the blended polymer fibers comprising: (i) a first polymer selected from the group consisting of polylactic acid, poly(L-lactic acid), poly(D-lactic acid), polyglycolic acid, and polycaprolactone, or any combination or copolymer thereof; (ii) a second branched polymer; and (iii) a third polymer, the third polymer being a branched polymer comprising a nucleophilic group reactive towards the second branched polymer, and the third polymer being at least partially crosslinked with the second branched polymer; the second branched polymer and the third polymer comprise polyethylene glycol; the average molecular weights of the second branched polymer and the third polymer are independently from 1,000 Da to 50,000 Da; the second branched polymer comprises a tissue adhesive group selected from the group consisting of an activated ester, an acyl halide, a chloroformate, an anhydride, an aldehyde, an epoxide, an isocyanate, an isothiocyanate, a maleimide, a carbonate, a sulfonyl chloride, a haloacetamide, an acyl azide, an imidoester, a carbodiimide, a vinyl sulfone, an ortho-pyridyl-disulfide, or any combination thereof; the tissue adhesive groups of the second branched polymer are in at least a 10 mol % molar excess relative to the nucleophilic groups of the third polymer; the degree of crosslinking of the second branched polymer and the third polymer is at most 10%; The matrix, wherein the first polymer is inert to both the second branched polymer and the third polymer, and the average molecular weight of the first polymer is in the range of 100 KDa to 900 KDa, and the matrix is ​​a fibrous mat comprising a biocompatible material.

2. The matrix described in claim 1, wherein the tissue adhesive layer is composed of the blended polymer fibers, and at least 50 mol% of the tissue adhesive groups within the polymer fibers are unreacted.

3. The matrix of claim 1 , wherein the nucleophilic group is a thiol.

4. 2. The matrix of claim 1, wherein the molar excess is between 10 and 500 mole percent.

5. 10. The matrix of claim 1, wherein the third polymer is at least partially crosslinked with the second branched polymer by reacting the tissue adhesive group with the nucleophilic group.

6. The matrix of claim 1 , wherein the second branched polymer and the third polymer are selected from the group consisting of star polymers, dendrimers, and hyperbranched polymers, or any combination thereof.

7. The matrix of claim 1, wherein the second branched polymer and the third polymer comprise 3 to 10 arms.

8. The matrix of claim 1 , wherein the tissue adhesive group is an activated ester.

9. The matrix of claim 1 , wherein the tissue adhesive group is covalently bonded to a terminal group of the second branched polymer.

10. 2. The matrix of claim 1, wherein the molar ratio of the third polymer to the second polymer ranges from 1:1 to 1:

3.

11. 10. The matrix of claim 1, wherein the weight ratio of the third polymer to the second branched polymer ranges from 1:1 to 1:

10.

12. 10. The matrix of claim 1, wherein the weight ratio of the first polymer to the second branched polymer ranges from 1:1 to 20:

1.

13. 9. The matrix of claim 8, wherein the activated ester is an N-hydroxysuccinimide ester.

14. The matrix of claim 1 , wherein the blended polymer fibers are biodegradable.

15. 10. The matrix of claim 1, wherein the blended polymer fibers are characterized by an average fiber diameter of 0.5 to 10 um.

16. The matrix of claim 1, wherein the blended polymer fibers are characterized by a melting point of 50 to 150°C.

17. The matrix of claim 1 further comprising an additional layer of polymer fibers.

18. 10. The matrix of claim 1, wherein the tissue-adherent layer is characterized by a pore size of 0.5 to 100 um.

19. 10. The matrix of claim 1, wherein the tissue-adherent layer is characterized by a tensile strength of at least 0.05 MPa.

20. 10. The matrix of claim 1, wherein the polymer fibers of the additional layer and the blended polymer fibers are electrospun fibers, and the tissue adhesive layer is characterized by a porosity of at least 60%, the porosity being the volume of voids relative to the total volume of the tissue adhesive layer.

21. The matrix of claim 1, wherein the tissue-adhesive layer is characterized by a thickness of 0.5 to 250 um.

22. The tissue adhesive layer has a viscosity of 1 ml / hr / cm when exposed to an aqueous liquid at a pressure of 40 mmHg. ２ 10. The matrix of claim 1, characterized by a water permeability of less than 1000 .mu.m.

23. 10. The matrix of claim 1 further comprising a pharmaceutically active ingredient.

24. 10. The matrix of claim 1 for use in promoting (i) bioadhesion of at least one biological tissue, (ii) blood clotting, or both (i) and (ii).

25. A matrix as described in claim 1 for use in (i) repairing and / or replacing biological tissue, (ii) preventing leakage of biological fluids from said biological tissue, or both (i) and (ii).

26. 10. A process for producing the tissue adhesive layer of claim 1, comprising: (i) mixing a first polymer and at least one of the second branched polymer and the third polymer with a solvent, thereby obtaining a solution; and (ii) providing the solution to an electrospinning apparatus to obtain a fibrous mat of electrospun fibers.

27. 27. The process of claim 26, wherein the process is for producing a layer of polymeric fibers.

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