Tissue adhesion matrix and its use

Abstract

The present invention provides compositions for bioadhesion and / or repair of damaged tissue. [Solution] A composition is provided comprising a first polymer, a second branched polymer, and a third polymer reactive with respect to the second polymer, wherein either the second or third polymer contains tissue-adhering groups, and the second and third polymers are at least partially crosslinked. A matrix comprising the composition of the present invention and optionally an additional polymer layer is provided. A process for producing the composition, as well as its use for bioadhesion and / or repair of damaged tissue, is also provided.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of priority of U.S. Provisional Patent Application No. 62 / 876,952, filed on Jul. 22, 2019, the content of which is incorporated herein by reference in its entirety.

[0002] The present invention, in some of its embodiments, relates to tissue - adhesive matrices, their preparation, and use.

Background Art

[0003] Leakage of liquid or air from or into damaged tissue is a life - threatening condition and can occur as a result of various situations including surgery and trauma.

[0004] Soft tissues are particularly vulnerable to damage. Further, these tissues can form various compartments (e.g., lungs, blood vessels, dura mater, bladder, etc.) that hold liquid or air, and when damaged, their impairment can spread to other areas. Further, due to the mechanical properties of these tissues, the adhesion of a matrix to sutures or staples can cause damage to itself, e.g., prevent proper sealing, increase the likelihood of bacterial infection, or reduce 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, heart tissue, blood vessel tissue, kidney or urogenital tissue, lung tissue, gonadal tissue, hematopoietic tissue, gastrointestinal tract tissue (such as colon or stomach), and adipose tissue.

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

[0006] In one aspect of the present invention, The first polymer and A second branched polymer, A third polymer, which is reactive with respect to the second polymer and is at least partially crosslinked with the second branched polymer, comprises A composition is provided in which one of the second and third polymers contains a tissue-adhesion group.

[0007] In one embodiment, the average molecular weight of the first polymer is in the range of 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, polysaccharides, or any combination or copolymer thereof.

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

[0010] In one embodiment, the third polymer contains a nucleophile.

[0011] In one embodiment, crosslinking is achieved by reacting a tissue-adhering group with a nucleophilic group.

[0012] In one embodiment, the branched polymer is selected from the group consisting of star polymers, dendrimers, and superbranched polymers, or any combination thereof.

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

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

[0015] In one embodiment, the tissue-adhering group is covalently bonded to the 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 contain 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 blended polymer fibers.

[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 μm.

[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 comprising a tissue adhesion layer is provided, the tissue adhesion layer comprising the blend 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 adhesion layer.

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

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

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

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

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

[0033] In one embodiment, the tissue adhesion layer has a water permeability of less than 1 ml / hour / cm when exposed to an aqueous liquid at a pressure of 40 mmHg. 2

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

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

[0036] In one embodiment, the matrix is for use in the repair and / or replacement of living tissue.​

[0037] In another embodiment, there exists 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 with respect to the second polymer, wherein the second polymer and the third polymer each comprise the second branched polymer or the third polymer of the present invention.

[0038] 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, polysaccharides, or combinations or copolymers thereof.

[0039] In one embodiment, the second polymer, the third polymer, or both thereof comprises 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 components provide a tissue-adhesion layer.

[0041] In one embodiment, the weight ratio of the third polymer to the second polymer is in the range of 1:1 to 1:20.

[0042] In one embodiment, the weight ratio of the first polymer to the second polymer is in the range of 1:1 to 20:1.

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

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

[0045] [Figure 1] A schematic diagram of the peel test is shown. [Figure 2] A schematic diagram of the shear test is shown. [Figure 3] SEM images of electrospinned samples are shown. Figure 3A: Control 1.2 Figure 3B: Composition 1.2 [Figure 4] A bar graph showing the fiber diameter of an exemplary electrospinned sample is shown. The control is designated as cont. [Figure 5] A bar graph showing the pore sizes of an exemplary electrospinned sample is displayed. The control is designated as cont. [Figure 6] A bar graph showing the tensile strength of an exemplary electrospinned sample is shown. The control is designated as cont. [Figures 7A-7B] The bar graphs show the adhesive strength determined by the peel test. Figure 7A shows the average peel force shown for exemplary samples and controls. Figure 7B shows the maximum force shown for exemplary samples and controls. The controls are designated as cont. [Figure 8] A bar graph shows the adhesive strength of an exemplary sample and a control, as determined by shear tests. [Figure 9] A bar graph showing the burst pressure strength of an exemplary sample and a control is shown. [Modes for carrying out the invention]

[0046] In one embodiment, the present invention relates to a composition comprising a first polymer, a second polymer containing tissue-adhesion groups, and a third polymer, wherein the second and third polymers are at least partially crosslinked. In some embodiments, the present invention relates to a composition in the form of blended polymer fibers.

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

[0048] This invention is partly based on the surprising discovery that a tissue-adhesive matrix containing a crosslinked polymer exhibited enhanced adhesive strength compared to a matrix containing a linear tissue-adhesive polymer.

[0049] composition In some embodiments, a composition is provided comprising a first polymer, a second branched polymer, and a third polymer which is reactive with respect to the second polymer and is at least partially crosslinked with respect to the second branched polymer, wherein one of the second and third polymers contains a tissue-adhesion group.

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

[0051] As used herein, the term “structural support” refers to physical properties of a composition (e.g., blended polymer fibers) such as elasticity. Furthermore, the first polymer may be selected to enable 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 fibers.

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

[0053] The elongation at fracture is determined as the maximum strain (elongation) that can occur (when a tensile stress equal to the tensile strength is applied) before fracture occurs in the test material (e.g., as rupture or necking).

[0054] In some embodiments, the first polymer is a synthetic polymer. In some embodiments, 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, 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 bioerosive. In some embodiments, the first polymer is substantially biodegradable and / or bioerosive, and substantially as described herein.

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

[0057] Non-limiting examples of polyesters include, but are not limited to, polyglycolides, polylactic acid, polycaprolactone (PCL), polyhydroxyalkanoates, polyhydroxybutyrates, polyethylene adipates, polybutylene succinates, poly(3-hydroxybutyrate-co-3-hydroxyvalerate), polyethylene terephthalate (PET), polybutylene terephthalate, polyethylene naphthalate (PEN), any copolymers or combinations thereof, etc.

[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 a plurality of polyesters. In some embodiments, the first polymer is a copolymer comprising polyesters selected from polylactide, polyglycolide, and polycaprolactone (PCL), and optionally comprising 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 includes 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 including polysaccharides, polypeptides, polynucleic acids, and mixtures or copolymers thereof. In some embodiments, the biological polymer includes chemical modifications (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, ghati gum, dextran, pullulan, amylopectin, and hyaluronic acid. In some embodiments, the biological polymer induces blood coagulation. In some embodiments, the biological polymer comprises collagen, oxidized cellulose, or both.

[0061] Therefore, some first polymers are 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, and 600,000 Da to 900,000 Da (including any range or value between them). 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, and 250-300 kDa (including any range or value between them).

[0062] In some embodiments, any of the first polymer, the second branched polymer, and the third polymer comprises a substantially single homopolymer or a single copolymer. In some embodiments, any of the first polymer, the second branched polymer, and the third polymer substantially lacks 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 substantially lacks non-biodegradable polymers and / or non-biodegradable polymer segments. In some embodiments, the composition of the present invention essentially consists 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 constitute at least 80% by weight, at least 85% by weight, at least 90% by weight, at least 95% by weight, at least 97% by weight, at least 98% by weight, at least 99% by weight, at least 99.5% by weight, and at least 99.9% by weight of the dry content of the composition of the present invention. In some embodiments, the first polymer, the second branched polymer, and the third polymer constitute at least 80% by weight, at least 85% by weight, at least 90% by weight, at least 95% by weight, at least 97% by weight, at least 98% by weight, at least 99% by weight, at least 99.5% by weight, and at least 99.9% by weight of the blended polymer fibers of the present invention. In some embodiments, any one of the first polymer, the second branched polymer, and the third polymer substantially lacks acrylate-modified PEG-PLLA copolymer. In some embodiments, the tissue adhesion groups substantially lack acrylate. In some embodiments, the tissue adhesion groups substantially lack vinyl sulfone. In some embodiments, the composition of the present invention substantially lacks polyamino acids (e.g., peptides).

[0063] In some embodiments, the first polymer is a high molecular weight polymer. In some embodiments, 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%, and at least 1000% (including any range or value in between) 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 fracture greater than that of any one of the second and third polymers, the greater of which is 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%, and at least 45% (including any range or value between them).

[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%, and at most 50% (including any range or value in between). 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 between them). 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), the adhesive strength being 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 star polymers, dendrimers, and superbranched polymers, 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., a second branched polymer and / or a third polymer) includes a branched core. In some embodiments, the branched core is covalently bonded to at least three arms.

[0070] Non-exclusive examples of branched 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 (e.g., a second polymer and / or a third polymer) comprises a branched core covalently bonded to three or more arms, each of which has the same chemical composition.

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

[0073] As used herein, the term “chemical composition” refers to the composition of any one of the segments (e.g., 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 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 in between). In some embodiments, the branched polymer (e.g., the second polymer and / or third polymer) has 3 to 8 arms. In some embodiments, the branched polymer (e.g., the second polymer and / or third polymer) has 4 to 8 arms. In some embodiments, the branched polymer (e.g., the second polymer and / or third polymer) has 3 to 6 arms. In some embodiments, the branched polymer (e.g., the second polymer and / or third polymer) has 4 arms. In some embodiments, the branched polymer (e.g., the second polymer and / or third polymer) has 8 arms. In some embodiments, the branched polymer (e.g., the second branched polymer and / or third polymer of the present invention) includes 8 arms. In some embodiments, at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, and at least 99% of the total weight of the branched polymer (e.g., the second branched polymer and / or third polymer of the present invention) includes eight arms.

[0075] In some embodiments, one of the arms of a branched polymer (e.g., a second polymer and / or a third polymer) independently includes a polymer segment. In some embodiments, one of the arms of a branched polymer (e.g., a second polymer and / or a third polymer) independently includes 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 included in the term “segment” as used herein.

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

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

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

[0080] As used herein, the term “biocompatible” is intended to describe a material that is nontoxic 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 decompose in vivo, and the decomposition of covalent bonds occurs via hydrolysis. Hydrolysis may involve a direct reaction with an aqueous medium or may be chemically or enzymatically catalyzed. “Aqueous medium” refers to water, aqueous solutions, physiological or biological fluids (e.g., body fluids), and other pharmaceutically acceptable mediums. Preferred 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, polyurethane, polyphosphoester, polyurethane, and polyamides (e.g., polyamino acids (including any copolymers or combinations thereof)).

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

[0084] In some embodiments, the polymer segment of the second polymer is reactive with respect to the third polymer. In some embodiments, the polymer segment of the second polymer contains a reactive group. In some embodiments, the reactive group of the second polymer is reactive with respect to the reactive group of the third polymer. In some embodiments, the reactive group of the third polymer is reactive with respect to the reactive group of the second polymer. In some embodiments, the reactive group can form 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-adhesion group. In some embodiments, the second polymer contains a tissue-adhesion group (e.g., an electrophile or an electrophilic tissue-adhesion group), and the tissue-adhesion group is reactive with respect to the third polymer. In some embodiments, the tissue-adhesion group of the second polymer is reactive with respect to the reactive group of the third polymer (e.g., a nucleophile as described herein). In some embodiments, the second and third polymers can form a covalent bond through a reaction between the tissue-adhering groups of the second polymer and the reactive groups of the third polymer. In some embodiments, the second polymer contains tissue-adhering groups covalently bonded to its polymer segments. In some embodiments, the first polymer is substantially devoid of reactive groups, which 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) to either the second or third polymer.

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

[0086] The term "tissue adhesion group" encompasses any chemical or functional group that can interact with a biological surface (e.g., tissue) to result in the formation of covalent or non-covalent bonds. Biological surfaces, such as tissues, generally consist of cells and contain protein molecules on their surface, 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 the cell surface. In addition to forming covalent bonds, tissue adhesion groups can 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 adhesion groups according to the present invention provides polymer materials with bioadhesion properties.

[0087] As used herein, the term “biological surface” refers to any surface containing 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-exclusive examples of tissue adhesion groups that form non-covalent bonds with biological surfaces include, but are not limited to, amides, carboxylates, and peptides (e.g., RGD).

[0089] Non-limited examples of tissue-adhering 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, imide esters, carbodiimides, vinyl sulfones, ortho-pyridyl disulfides, or any combination thereof.

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

[0091] In some embodiments, the tissue adhesion group is an N-hydroxysuccinimide (NHS) ester. The mechanism by which the NHS-functionalized polymer reacts with amine-containing materials such as tissue proteins is described below. [ka]

[0092] In some embodiments, the tissue-adhesion groups are covalently bonded to the terminal groups of the polymer segments.

[0093] In some embodiments, the tissue adhesion groups are covalently bonded to the side chains of the polymer segments.

[0094] In some embodiments, multiple tissue-adhering groups provide bioadherence properties to the second polymer.

[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, resulting in 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, polyurethane, polyphosphoester, polyurethane, and polyamides (e.g., polyamino acids) or any combination thereof.

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

[0100] In some embodiments, the average molecular weights of the third polymer and the second polymer are in the range of 500-100000Da, 500-5000Da, 1000-3000Da, 1500-2500Da, 5000-10000Da, 10000-15000Da, 15000-18000Da, 18000-20000Da, 20000-22000Da, 22000-25000Da, 25000-30000Da, 30000-40000Da, 40000-60000Da, 60000-80000Da, 80000-100000Da, or any range in between.

[0101] In some embodiments, the average molecular weight of either the second polymer or the third polymer is 1000 to 50,000 Da. In some embodiments, the average molecular weight of at least one of the second polymer or the third polymer is 10,000 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 between them). In some embodiments, the composition (e.g., a fiber) comprises a first polymer and at least one of a second polymer and a third polymer, wherein the 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, or 40,000 to 50,000 Da (including any range or value between them). In some embodiments, the 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, and at least 20,000 Da (including any range or value between them).

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

[0103] In some embodiments, the third polymer is reactive with respect to the second polymer. In some embodiments, the third polymer contains reactive groups that can form covalent bonds with the second polymer. In some embodiments, the reactive groups of the third polymer (e.g., nucleophiles) can form covalent bonds with the reactive groups of the second polymer (e.g., electrophiles). In some embodiments, the reactive groups of the third polymer can form covalent bonds with the structural adhesion groups of the second polymer.

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

[0105] In some embodiments, covalent bond formation is referred to as crosslinking.

[0106] In some embodiments, the crosslinking is mutual crosslinking. Whereof herein, the term “mutual” refers to the formation of a bond between two reactive groups present in two polymer chains, as opposed to the formation of an “internal” bond between two reactive groups present in 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 crosslinking is formed by reacting a tissue-adhesion group with a reactive group of the third polymer. In some embodiments, the crosslinking is formed via a "click reaction" such as azido-alkyne cyclization, or a reverse Diels-Alder reaction. In some embodiments, the crosslinking is formed by reacting a tissue-adhesion group with a nucleophilic group of the third polymer. In some embodiments, the crosslinking is via an amide bond formed by reacting an amino group of the third polymer with the NHS of the second polymer. In some embodiments, the crosslinking is via a thioester bond formed by reacting a thiol group of the third polymer with the NHS of the second polymer.

[0108] In some embodiments, the crosslinked polymer is characterized by a degree of crosslinking in the range of 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 in between).

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

[0110] In some embodiments, as described herein, crosslinking is 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 (ii) a composition comprising a complementary polymer (e.g., each of the second polymer and the third polymer). In some embodiments, the composition (e.g., a fiber) comprising (i) a first polymer and (ii) one of a second polymer and a third polymer is substantially crosslinked.

[0111] In some embodiments, the degree of crosslinking between the second polymer and the third polymer is sufficient to enable the formation of polymer fibers 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, matrix, or layer containing 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, matrix, or layer containing multiple fibers) characterized by sufficient adhesive strength as described herein.

[0112] In some embodiments, at least a portion of the tissue-adhesion groups of the second polymer remain unreacted to provide a sufficient amount of bonding sites (e.g., covalent bonds) with a biological surface (e.g., tissue). In some embodiments, at least a portion of the tissue-adhesion groups remain unreacted (e.g., non-crosslinked) to establish bonding and / or adhesion to a biological surface. In some embodiments, at least a portion of the tissue-adhesion 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%, and at least 60 mol% of the tissue-adhesion groups in the composition (e.g., fiber) remain 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-adhering groups to the tissue in contact with the outer layer of the polymer fiber.

[0114] In some embodiments, a 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 attributed to the enhanced adhesive strength of the matrix containing the crosslinked polymer. In some embodiments, the crosslinked polymer is characterized by higher tensile and adhesive strengths than those of a 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 between these).

[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 between them).

[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 in between).

[0118] In some embodiments, compositions characterized by sufficient adhesive strength and / or sufficient mechanical properties include 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, and 1:1.7 to 1:2 (including any range or value between them). In some embodiments, sufficient adhesive strength and / or mechanical properties are as described herein.

[0119] In some embodiments, compositions characterized by an adhesive strength greater than 1.1 N include 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 between these). 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 greater than 1.1 N include 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, and 1:5 to 1:10 (including any range or value in between).

[0121] It should be noted that the molar ratio of the third polymer to the second polymer is maintained to ensure a molar excess of tissue-adhering groups compared to the reactive groups of 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%, and at least 500 mol% (including any range or value between them).

[0122] Such a molar excess is necessary to ensure that at least a portion of the tissue-adhering groups remain unreacted, and thus to allow the tissue-adhering properties of the second polymer to be preserved. According to experimental data obtained by the inventors, a composition containing polymer fibers composed of PEG-NHS and PEG-SH with a w / w ratio of PEG-NHS to PEG-SH of 2:1 showed preferable adhesive strength and stability compared to polymer fibers composed of PEG-NHS and PEG-SH with a w / w ratio of 1:1.

[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 in between.

[0124] In some embodiments, the total w / w content of the second and third polymers 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 between them).

[0125] In some embodiments, the composition contains a second polymer (e.g., polyether-NHS) and a third polymer (e.g., polyether-SH, polyether-NHS). 2、The total w / w content (or both) is at least 30%, at least 40%, and at least 50% (including any range or value in between).

[0126] In some embodiments, as described above, a composition (e.g., in the form of fibers) containing a total w / w content of the second and third polymers is characterized by adequate adhesive strength for establishing bonding and / or adhesion to a biological surface.

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

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

[0129] In some embodiments, the compositions of the present invention feature 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 between them) compared to a control (e.g., a commercially available product), as illustrated herein.

[0130] In some embodiments, compositions (e.g., in the form of fibers) having a total w / w content of the second and third polymers of 20-60%, 30-50%, and 40-50% respectively 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, and greater than 4 MPa (including any range or value between them) compared to a control (e.g., a commercially available product), as illustrated herein.

[0131] In some embodiments, the composition of the present invention is a solid. In some embodiments, the composition of the present invention (e.g., a solid composition) is substantially solvent-free. In some embodiments, the composition of the present invention contains trace amounts of residual solvent. In some embodiments, the composition of the present invention (e.g., a solid composition) contains 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% of an organic solvent. In some embodiments, the composition of the present invention is in the form of fibers. In some embodiments, the composition of the present invention is in the form of a matrix containing multiple fibers (as described herein). In some embodiments, the composition of the present invention is in the form of a fibrous mat. In some embodiments, the composition of the present invention is in the form of a semi-solid or semi-liquid. In some embodiments, the composition of the present invention is in the form of a gel. In some embodiments, the composition of the present invention (e.g., a liquid or semi-liquid) is substantially homogeneous. In some embodiments, the composition of the present invention is substantially stable, where stability refers to the ability of the composition to maintain its structural and / or functional properties (mechanical properties, adhesion, etc.).

[0132] It should be understood that the terms “semi-liquid” or “semi-solid” are intended to mean materials that are fluid under pressure and / or shear force. In some embodiments, semi-liquid compositions include creams, ointments, gel-like materials, and other similar materials. In some embodiments, the compositions are semi-liquid compositions 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, the fibers being 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%, 70-95% (including any range or value between them).

[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 a plurality of 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 blended polymer fibers (also referred to as "polymer fibers"). In some embodiments, the polymer fibers comprise the first polymer, the second polymer, and the third polymer, as described herein.

[0137] In some embodiments, at least 20 weight percent (by dry weight) of the polymer fibers consists of one or more polymers of the present invention. In some embodiments, at least 30 weight percent (by dry weight) of the polymer fibers consists of one or more polymers of the present invention. In some embodiments, at least 40 weight percent (by dry weight) of the polymer fibers consists of one or more polymers of the present invention. In some embodiments, at least 50 weight percent (by dry weight) of the polymer fibers consists of one or more polymers of the present invention. In some embodiments, at least 60 weight percent (by dry weight) of the polymer fibers consists of one or more polymers of the present invention. In some embodiments, at least 70 weight percent (by dry weight) of the polymer fibers consists of one or more polymers of the present invention. In some embodiments, at least 80 weight percent (by dry weight) of the polymer fibers consists of one or more polymers of the present invention. In some embodiments, at least 90 weight percent (by dry weight) of the polymer fibers consists 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 thread, consisting of continuous filaments and / or individual elongated pieces. In some embodiments, the first polymer provides or enhances the stability of the polymer fiber. In some embodiments, a polymer fiber comprising the 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 means 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, at least 3 y (including any range or value between them). In some embodiments, a fiber is said to be stable if it remains structurally intact under physiological conditions (e.g., not decomposed in vivo and therefore non-biodegradable or non-biodegradable). In some embodiments, a fiber is described as stable if it remains structurally intact under ambient conditions (e.g., a temperature of 10–60°C and a moisture content of 10–99% (including any value in between)).

[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 μm, 0.5–1.5 μm, 1–4 μm, 2–4 μm, 4–5 μm, 5–6 μm, 6–7 μm, 7–8 μm, 8–10 μm, or any range in between.

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

[0142] When used herein, the melting point or glass transition temperature is preferably determined by differential scanning calorimetry, using a procedure accepted in the art for such purposes, with a cooling and heating rate of 10°C per minute. The glass transition usually appears as an intersection between two linear regions in a plot of heat capacity as a function of temperature.

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

[0144] In some embodiments, the polymer fibers are a nonwoven fabric.

[0145] In some embodiments, polymer fibers are electrospinned.

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

[0147] In some embodiments, the polymer fibers (e.g., the fibers of the present invention) further comprise additives. In some embodiments, the composition (e.g., the composition of the present invention) further comprises additives. In some embodiments, the composition (e.g., a liquid composition and / or a semi-liquid composition) further comprises additives. In some embodiments, the w / w concentration of the additives 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 between them).

[0148] Examples of additives include, but are not limited to, adhesive materials, non-adhesive materials (e.g., materials characterized by particularly low adhesion to tissues 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 therapeutic activators.

[0149] Other additives (e.g., therapeutic agents) that can be beneficially incorporated into 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) as well as non-polymeric (small molecule therapeutic) natural or synthetic agents.

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

[0151] Examples of therapeutic activators (antiproliferative agents) that inhibit cell proliferation and / or angiogenesis, which are particularly useful in drug elution systems for anticancer treatment, include paclitaxel, sirolimus (rapamycin), farnesylthiosalicylic acid (FTS, salilasib), fluoroFTS, everolimus, zotarolimus, daunorubicin, doxorubicin, N-(5,5-diacetoxypentyl)doxorubicin, anthracyclines, mitomycin C, mitomycin A, 9-aminocamptothecin, aminopertine, antinomycin, N 8-Examples include acetylspermidine, 1-(2-chloroethyl)-1,2-dimethanesulfonylhydrazine, bleomycin, tallysomucin, etoposide, camptothecin, irinotecan, topotecan, 9-aminocamptothecin, paclitaxel, docetaxel, esperamycin, 1,8-dihydroxy-bicyclo[7.3.1]trideca-4-en-2,6-diin-13-one, angidine, morpholino-doxorubicin, vincristine, vinblastine, and their derivatives.

[0152] Additional therapeutic agents that can be beneficially incorporated into 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, maphenide benzoyl peroxide, octopirox, erythromycin, zinc, silver, tetracycline, triclosan, azeraic acid and its derivatives, phenoxyethanol and phenoxypropanol, ethyl acetate, clindamycin and meclocycline, cebostats such as flavonoids, α and β hydroxy acids, polydiallyldimethylammonium chloride and bile salts, such as simunol sulfate and its derivatives, deoxycholic acid and cholic acid.

[0153] Additional therapeutic agents that can be beneficially incorporated into polymer fibers and / or compositions of the present invention (e.g., liquid or semi-liquid compositions) include analgesics, anesthetics, pain relievers, pain reducers, etc. (including NSAIDs, COX-2 inhibitors, K+ channel openers, opioids and morphinometics), as well as hemostatic and antihemorrhagic agents.

[0154] matrix In some embodiments, a matrix comprising a tissue-adhering layer is provided herein. In some embodiments, the tissue-adhering layer comprises a plurality of blended polymer fibers, the blended polymer fibers being as described herein.

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

[0156] In some embodiments, the bioadhesion properties of the tissue-adhesive layer are enhanced during hydration, for example, upon contact with moist tissue.

[0157] In some embodiments, the tissue adhesion layer promotes cell adhesion 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 inserted 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 multilayer matrix comprising a tissue adhesion layer and additional layers.

[0160] In some embodiments, the additional layer is an elastic or viscoelastic layer. In some embodiments, the additional layer enhances the stability of the tissue-adhesion layer. In some embodiments, the stability is as described herein. In some embodiments, the additional layer enhances the mechanical strength of the tissue-adhesion 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 at a particular percentage of elongation, tensile strength, fracture strain, yield point, toughness, work to fracture, impact strength, tear strength, flexural modulus, flexural strain, and stress, as well as wear.

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

[0162] As used herein, the term “elastic layer” refers to a layer of material in which the layer exhibits elasticity. In this specification, the terms “elastic” and “elastic” are defined as described above.

[0163] As used herein, the term “viscoelastic layer” refers to a layer of material that 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 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. These distinct layers may differ, for example, in chemical composition, molecular morphology (e.g., degree and type of crystallinity), physical structure, and / or mechanical properties.

[0166] As will be illustrated later in this specification (see Examples section), matrices such as those described herein can be formed from biodegradable and biocompatible materials while exhibiting considerable mechanical strength, high adhesive strength, high elasticity and flexibility, high porosity (which can support cell proliferation and tissue adhesion), and high water impermeability, making them suitable for forming a seal, bonding tissue surfaces to other tissues, preventing fluid leakage, and preventing bacterial and viral infections.

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

[0168] In some embodiments, the tissue-adhesion 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, and at least 10 MPa. In some embodiments, the tissue-adhesion 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, and 8–10 MPa (including any range or value between them). In some embodiments, the tissue-adhesion layer is characterized by a tensile strength as illustrated herein.

[0169] The tensile properties (e.g., tensile strength) described herein are determined according to ASTM International Standard D882-12 for testing the tensile properties of thin plastic sheets. A tensile test characterizes the amount of tensile stress applied to the tested material as a function of the tensile strain of the material (the increase in length due to 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 any further strain can be obtained with reduced stress (a phenomenon known as "necking"), or it cannot be obtained because the tensile stress will cause the material to rupture (e.g., tear, cracking).

[0171] In some embodiments, the tissue-adhesive layer is characterized by adhesive strengths in the ranges of 10-400 kPa, 10-50 kPa, 20-50 kPa, 50-80 kPa, 80-100 kPa, 100-200 kPa, 200-300 kPa, and 300-400 kPa.

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

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

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

[0175] The adhesive strength is determined by two different methods, peel tests and shear tests, as described later in this specification.

[0176] In some embodiments, the tissue adhesion layer absorbs 1 ml / hour / cm³ of aqueous liquid when exposed to an aqueous liquid at a pressure of 40 mmHg. 2It is characterized by a water permeability of less than 0.3 ml / hour / cm³. In some such embodiments, the water permeability is 0.3 ml / hour / cm³. 2 It is less than 0.1 ml / hour / cm³. In some embodiments, the water permeability is 0.1 ml / hour / cm³. 2 It is less than 0.03 ml / hour / cm³. In some embodiments, the water permeability is 0.03 ml / hour / cm³. 2 It is less than 0.01 ml / hour / cm³. In some embodiments, the water permeability is 0.01 ml / hour / cm³. 2 It is less than.

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

[0178] In some embodiments, either the tissue-adhering layer or the additional layer is a porous layer. As used herein, the term “porous layer” refers to a layer containing voids (in addition to the polymer materials described herein), where, for example, the spaces between the polymer materials are not filled with additional material. However, a porous layer may optionally contain additional material in the spaces between the polymer materials, as long as at least a portion of the volume of the voids is filled with additional material.

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

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

[0181] In this specification, the term "porous" refers to the percentage of volume of a material consisting of voids (for example, the tissue-adhesive layer described herein).

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

[0183] In some embodiments, the compositions of the present invention (e.g., Matrix) are characterized by low swelling capacity. In some embodiments, the compositions of the present invention (e.g., Matrix) 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 swelling volume of the tested compositions was less than 5% compared to the 65% swelling volume of Hemopatch® (based on published data). In some embodiments, the compositions of the present invention (e.g., Matrix) are characterized by swelling volumes of less than 10%, less than 8%, less than 6%, less than 5%, less than 4%, and less than 3% (including any range or value between them). In some embodiments, the compositions of the present invention (e.g., Matrix) are characterized by significant water absorption capacity. In some embodiments, the compositions of the present invention (e.g., Matrix) are characterized by water absorption of 5–10 times, 5–6 times, 6–7 times, 7–8 times, and 8–10 times the initial sample weight (including any range or value between them).

[0184] The water absorption of exemplary compositions of the present invention (e.g., a matrix) was compared to commercially available Hemopatch®. The compositions of the present invention tested showed 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 undesirable leakage of bodily fluids within the implant site of target. In some embodiments, tested samples with a thickness of less than 0.35 mm showed similar water absorption capacity to commercially available Hemopatch® with a thickness of 2 mm.

[0185] kit In another embodiment, there exists a kit comprising blended polymer fibers and a composition. The blended polymer fibers comprise a first polymer and a second polymer, and the composition comprises a third polymer reactive with respect to the second polymer, wherein either the second polymer or the third polymer comprises a tissue-adhering group. In some embodiments, the second polymer and the third polymer of the kit comprise either the second branched polymer or the third polymer of the present invention, respectively. In some embodiments, the blended polymer fibers of the kit comprise the first polymer and the second branched polymer of the present invention, and the composition of the kit comprises the third polymer of the present invention. In some embodiments, the blended polymer fibers of the kit comprise the first polymer and the third polymer of the present invention, and the composition of the kit comprises the second branched polymer of the present invention.

[0186] In some embodiments, the blended polymer fibers of the kit include the second branched polymer of the present invention, and the composition of the kit includes the third polymer of the present invention. In some embodiments, the blended polymer fibers of the kit include the third polymer, and the composition of the kit includes the second branched polymer.

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

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

[0189] In some embodiments, the kit composition of the present invention 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 kit fibers. In some embodiments, the polymer of the kit composition is diffusible. In some embodiments, the polymer of the kit composition is applied by diffusion, spraying, casting, or any other method well 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 polymers, which are as described herein.

[0190] In some embodiments, the first polymer of the kit includes, or is selected from, polyester, polyanhydride, polyacetal, polyorthoester, polyurethane, polycarbonate, polyphosphazene, polyphosphoester, polyether, silicone, polyamide, polysulfone, polyetheretherketone (PEEK), poly(ethylene glycol), polytetrafluoroethylene, polyethylene, polysaccharides, or combinations or copolymers thereof. In some embodiments, the first polymer is the first polymer of the present invention.

[0191] In some embodiments, the second branched polymer, the third polymer, or both thereof include 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., a second branched polymer or a 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 between them). In some embodiments, a blended polymer fiber containing the second polymer of the kit having an MW of at least 10 kDa features enhanced mechanical properties compared to a blended polymer fiber containing the second polymer of the kit having a low MW. In some embodiments, the low MW is 1–5 kDa, 1–2 kDa, 2–3 kDa, 3–5 kDa, or 5–7 kDa (including any range between them).

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

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

[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%, and at least 50% (including any range or value in between).

[0196] In some embodiments, the second polymer of the kit, the third polymer of the kit, or both thereof, comprises polyethylene glycol. In some embodiments, the second polymer of the kit, the third polymer of the kit, or both thereof, comprises 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 or the third polymer of the kit contains a nucleophile. In some embodiments, the nucleophile 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 in between.

[0199] In some embodiments, the molar ratio of the second polymer to the third polymer in the kit is 1:0.8–1:20, 1:0.8–1:1, 0.8:1–1:1, 1:1–1:1.5, 1:1.5–1:2, 1:2–1:2.5, 1:2.5–1:3, 1:3–1:5, 1:1–1:5, 1:1–1:4, 1:1–1:3, 1:1–1:2, 1:5–1:7, 1:7–1:10, 1:10–1:15, 1:15–1:20 (including any range or value between them), where the second branched polymer contains nucleophilic groups and the third polymer contains tissue-adhesion groups.

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

[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 between them).

[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 between them).

[0203] In some embodiments, polymers containing tissue-adhering groups are present in the kit of the present invention and / or in a molar excess relative to polymers containing reactive groups (e.g., nucleophiles) in the composition of the present invention.

[0204] In some embodiments, blended polymer fibers in contact with additional components result in a tissue-adhesion layer. In some embodiments, the tissue-adhesion layer is as described above. In some embodiments, the tissue-adhesion layer comprises a second branched polymer at least partially crosslinked with a third polymer. In some embodiments, the tissue-adhesion layer comprises blended polymer fibers at least partially crosslinked with a third polymer. In some embodiments, the crosslinking is as described herein. In some embodiments, the crosslinking is achieved by reacting tissue-adhesion groups with reactive groups (e.g., nucleophilic groups). In some embodiments, the kit is for utilizing an aminated branched polymer to form a tissue-adhesion layer (e.g., a crosslinked tissue-adhesion matrix), the tissue-adhesion layer being 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 in the kit composition (e.g., the second branched polymer or third polymer of the present 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 present 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 results in a tissue-adhesion layer characterized by enhanced adhesive strength compared to a composition comprising a third polymer having a MW greater than 10 kDa.

[0206] In some embodiments, a tissue-adhesive layer characterized by an adhesive strength greater than 1.1 N is formed by contacting the Kit composition with Kit blend polymer fibers, and 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 between them).

[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) of 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 between them).

[0208] In some embodiments, the kit of the present invention essentially consists 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 constitute at least 80% by weight, at least 85% by weight, at least 90% by weight, at least 95% by weight, at least 97% by weight, at least 98% by weight, at least 99% by weight, at least 99.5% by weight, and at least 99.9% by weight of the blended polymer fibers of the kit. In some embodiments, the first polymer, the second branched polymer, and the third polymer constitute at least 80% by weight, at least 85% by weight, at least 90% by weight, at least 95% by weight, at least 97% by weight, at least 98% by weight, at least 99% by weight, at least 99.5% by weight, and 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 intended for use in the fields of general surgery, neurology, otolaryngology, urology, gynecology / obstetrics, thoracic surgery, dentistry / maxillofacial surgery, gastroenterology, plastic surgery, ophthalmology, cardiovascular surgery and / or orthopedic surgery.

[0211] In some embodiments, the matrix described herein is for bonding or sealing at least one biological surface. In some embodiments, the matrix described herein is for promoting or increasing bioadhesion or sealing of a biological surface. In some embodiments, the matrix described herein is for promoting or increasing blood coagulation in subjects requiring blood coagulation.

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

[0213] As used herein, the term “biological surface” refers to any surface containing 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 graft 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 a membrane). In some embodiments, the membrane to be repaired and / or replaced is the dura mater (e.g., after trauma and / or surgical incision of the dura mater).

[0215] In some embodiments, the matrix is ​​used for bonding to a biological surface, which is selected from the group consisting of tissue surfaces, synthetic graft surfaces, and organ surfaces of the subject requiring it. In some embodiments, the matrix is ​​used in subjects where bonding a tissue surface to another tissue and sealing the tissue surface are required. In some embodiments, the matrix is ​​used in subjects where promoting / enhancing wound healing is required. In some embodiments, the matrix is ​​used in subjects where wound closure is required. In some embodiments, the matrix is ​​used in subjects where sealing bonded tubular structures such as blood vessels is required. In some embodiments, the matrix is ​​used in subjects where sealing air leakage in the lungs is required.

[0216] The matrices according to the present invention are suitable for application to both the internal and external surfaces of the body; that is, they can be applied topically to the external surface of the body (e.g., skin) or to the internal surface, such as the surface of internal organs exposed during surgical procedures, including conventional minimally invasive surgery. In some embodiments, the matrices are suitable for maintaining the 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 surgery on the hepatobiliary tract and pancreas. 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 it.

[0217] In some embodiments, the compositions or kits of the present invention may be used for topical delivery of drugs or other therapeutic substances to tissues.

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

[0219] Other non-limiting examples of treatments in which the matrix can be used include, but are not limited to, dural repair, hernia repair, instruction for another medical implant (such as breast reconstruction surgery), sealing of anastomoses, suppression of postoperative adhesions between tissues and promotion of hemostasis (e.g., if the matrix is ​​coated with thrombin and / or fibrinogen and / or fibrin, or if the carrier polymer is composed of a material that mechanically promotes hemostasis), and administration of therapeutically effective agents (e.g., by incorporating therapeutically effective agents in and / or on the core matrix, as per 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 mitigating fibrosis, scarring and / or adhesion at a target site, the method comprising (a) providing a composition of the present invention, and (b) applying the composition to a target site to form an adhesive barrier that adheres in situ to the target site, thereby preventing, inhibiting or mitigating fibrosis, scarring and / or adhesion of the traumatized tissue. In some embodiments, step (b) involves initiating crosslinking (e.g., between a second branched polymer and a third polymer of the present invention) to form an adhesive barrier or matrix of the present invention.

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

[0222] In another embodiment, the method of the present invention further includes the step of mixing blended polymer fibers and the kit composition to form a composite material before applying the composite material to trauma tissue. According to some embodiments, the mixing step initiates crosslinking (e.g., between a second branched polymer and a third polymer) to form the adhesive barrier or matrix of the present invention.

[0223] In some embodiments, the target site is the surgical site. In some embodiments, the target site is the postoperative surgical site. In some embodiments, the target site is a biological surface. In some embodiments, fibrosis, scarring, and / or adhesions are due to the surgical procedure. In some embodiments, fibrosis, scarring, and / or adhesions are due to blunt trauma or fracture.

[0224] Adhesions are 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 surgery, vascular, ENT, ophthalmic, urological, neurological, or orthopedic surgery. Adhesions are typically connective tissue structures that form between adjacent areas of injury within the body. Simply put, a localized area of ​​injury triggers a healing response, which 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 adhesion of adjacent anatomical structures (which should normally be separate).

[0225] Postoperative adhesions are a consequence of the fusion of damaged or traumatized tissue surfaces to form scar tissue following incision, cauterization, suturing, or other mechanical trauma. Adhesion can also occur in areas of blunt trauma or in tissues surrounding fractures. The mechanism of adhesion formation in the traumatized area is based on the secretion of tissue exudate, which then induces the proliferation of fibroblasts, resulting in the formation of collagenous adhesions. These adhesions damage the tissue and lead to dysfunctional soft tissue.

[0226] Adhesion formation can occur after any surgery or trauma and is a significant cause of morbidity. For example, postoperative intra-abdominal and pelvic adhesions are a major cause of infertility, chronic pelvic pain, and bowel obstruction. Adhesions formed in tissues can also irritate surrounding nerves, disrupt nerve transmission, and lead to a significant decrease in sensory or motor function.

[0227] In some embodiments, adhesion reduction includes a reduction in adhesion formation, without requiring complete relief of the signs or symptoms of adhesion, and without requiring healing. In various embodiments, adhesion reduction includes, for example, a slight reduction in adhesion formation by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or more compared to or with a control in adhesion formation.

[0228] "Adhesion reduction" means administering the first and second compositions disclosed herein to cause a reduction in the number, extent, and / or severity of adhesions (e.g., thickness, or mechanical or chemical breakdown) compared to the number, extent, and / or severity of adhesions that would occur if the first and second compositions disclosed herein were not administered. In various embodiments, adhesion reduction may be part of a protocol and may also include performing a procedure (e.g., a subsequent surgery to reduce adhesions). The compositions or procedures may inhibit the formation or growth of adhesions after adhesion-promoting stimulation, inhibit the progression of adhesions, and / or inhibit the recurrence of adhesions after their spontaneous regression or after mechanical or chemical breakdown.

[0229] As used herein, the term “reduce” in any grammatical form includes a reduction of at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 100%, 200%, 500%, 1000%, or more (including any range in between) of one or more values ​​or parameters.

[0230] As used herein, the terms “strengthen” or “increase” in any grammatical form include strengthening 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 in between).

[0231] "Adhesion prevention" refers to administering the first and second compositions before adhesion formation in order to reduce the likelihood of adhesion formation in response to a particular injury, stimulus, or condition. In various embodiments, adhesion prevention may be part of a protocol and may also include performing a procedure (e.g., surgery to reduce adhesions). It will be understood that "adhesion prevention" does not require a reduction in the likelihood of adhesion formation to zero. Rather, "adhesion prevention" 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 surfaces or tissue organ surfaces while the damaged or traumatized tissue heals. Thus, the growth of scar tissue and the formation or reformation of adhesions directly adjacent to the adhesion barrier are prevented.

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

[0234] In some embodiments, the present invention is applicable to various surgical procedures. In another embodiment, the surgical procedure is a gynecological surgical procedure (open surgery 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 the surrounding tissues to prevent adhesions.

[0235] In another embodiment, the surgical procedure is abdominal surgery. According to a non-limiting embodiment, an adhesion barrier can be used to prevent peritoneal adhesions and thus prevent bowel obstruction.

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

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

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

[0239] In some embodiments, the adhesive barrier is biocompatible; that is, it 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 therapeutic activator, for example, a drug included as an additional component according to any of the embodiments described herein. In some such embodiments, the medical device is a stent. Optionally, the composition forms at least a portion of the flexible sleeve of the stent.

[0241] The therapeutic activator may be optionally incorporated into the matrix and / or on the surface of the matrix. The therapeutic activator may also be optionally incorporated into the drug elution layer within the matrix and / or on the surface of the matrix. Such a drug elution layer can be formed from any suitable material known in the field of drug elution layers.

[0242] In this specification, the phrase “repair and / or replacement of biological tissue” means the repair of tissue that has been physically damaged in any way, including supporting and / or holding together damaged tissue in vivo or ex vivo, and filling gaps formed by the absence of tissue (tissue replacement). Damaged tissue can be damaged, for example, by delamination (e.g., rupture, severance), compressive stress, tensile stress, shear stress, cellular dysfunction and / or cell death.

[0243] In some embodiments, methods are provided for repairing and / or replacing biological tissue in subjects that require such repair and / or replacement, the methods comprising bringing the biological tissue into contact with a matrix described herein (e.g., a medical device). In some embodiments, the subject is an animal subject. In some embodiments, the subject is a human control. In some embodiments, the subject is suffering from trauma and / or injury. In some embodiments, the subject undergoes surgery. In some embodiments, the subject is suffering from bleeding. In some embodiments, the subject is suffering from the loss of biological fluid from one or more organs.

[0244] In some embodiments, this method involves attaching at least a portion of the matrix to / on biological tissue. In some embodiments, attachment is performed by curing. In some embodiments, curing is performed by covalent bond formation with the tissue adhesive layer, as described herein.

[0245] In some embodiments, this method is for bonding 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 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 to obtain a solution, and (ii) providing the solution to an electrospinning apparatus. In some embodiments, the polymer fibers are as described above (for example, in the case of the compositions and / or kits of the present invention). In some embodiments, a method for producing polymer fibers of the compositions of the present invention includes (i) mixing a solvent with a first polymer, a second branched polymer and a third polymer to obtain 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, a method for producing polymer fibers of the kit of the present invention comprises (i) mixing a solvent with a first polymer and one of a second polymer and a third polymer to obtain a solution, and (ii) providing the solution to an electrospinning apparatus, where the first polymer, the second branched polymer and the third polymer are as described above.

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

[0249] In some embodiments, the process further includes drying the polymer fibers. In some embodiments, the drying is carried out at 10-90°C.

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

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

[0252] Any of the fibers described herein can optionally be produced by any suitable technique for preparing fibers (including macro-sized, micro-sized, 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 can impart specific physical dimensions and mechanical properties to the resulting fibers and can be adjusted to impart the desired properties according to the required applications of the fibers and fiber layers described herein.

[0253] Simply put, fiber spinning technology optionally involves the use of spinning nozzles. These, in principle, resemble showerheads in a bathroom and can have one to several hundred tiny holes. As the filament or roving fiber emerges from the holes of the spinning nozzle, the dissolved or liquefied polymer is first converted into a rubbery state and then solidified. This process of "endless" extrusion and solidification of roving fiber 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 together to form yarn.

[0254] Wet spinning is used with fiber-forming materials dissolved in a solvent. A spinneret is immersed in a chemical bath, and as filaments emerge, they precipitate and solidify from the solution. Because the solution is directly extruded into the precipitate, this process for producing fibers is called wet spinning. This process can be used to produce fibers such as acrylic, rayon, aramid, modacrylic, and spandex.

[0255] Dry spinning is also used for fiber-forming materials in solution, but instead of precipitating the polymer by dilution or chemical reaction, solidification is achieved by evaporating the solvent in a stream of air or inert gas. Since the filaments do not come into contact with the precipitate, drying is unnecessary, and solvent recovery is easy. This process can be used, for example, in the production of acetates, triacetates, acrylics, modacryl, PBI, spandex, and vinylons.

[0256] In melt spinning, the fiber-forming material is melted for extrusion through a spinneret, and then the crude fibers are directly solidified by cooling. The melt-spun crude fibers can be extruded from the spinneret in various cross-sectional shapes (circular, trefoil, pentagonal, octagonal, etc.). For example, nylon (polyamide), olefins, polyester, saran, and sulfur are produced in this manner. Non-polymer fibers can also be produced by melt spinning.

[0257] Gel spinning is a specialized process used to obtain high strength or other specific fiber properties. The polymer is not in a true liquid state during extrusion. Because it is not completely separated like a true solution, the polymer chains are bonded together at various points in the form of liquid crystals. This generates 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 the shear forces during extrusion. The filaments emerge with an unusually high degree of orientation relative to each other, increasing their strength. Since the filaments first pass through air and then are further cooled in a liquid bath, this process can also be described as dry-wet 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 immediate use during surface treatment without further processing or preparation.

[0259] In some embodiments, the fibers are formed from an electrospun polymer material.

[0260] As used herein, terms such as “electrospin,” “electrospinning,” and “electrospinned” refer to the technique of producing fibers (e.g., nanofibers) from a polymer solution. During this process, one or more polymers of the polymer 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 the collector. Thus, 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 forming 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, either of the above configurations establishes the motion of a positively charged jet from the dispenser to the collector. Reverse polarity is also intended to establish the motion of a negatively charged jet from the dispenser to the collector. At a critical voltage, the repulsion of charges begins to overcome the surface tension of the droplet. The charged jet moves away from the dispenser and towards the collector within the electrostatic field. As the jet moves at high speed through the space between electrodes, it extends, the solvent within it evaporates, and thus forms fibers, which are collected in the collector, for example, in the form of a layer of fibers.

[0261] Several parameters can affect the diameter of the fiber, including the size of the dispenser's dispensing hole, the dispensing rate, the strength of the electrostatic field, the distance between dispensers, and / or the concentration of the polymer material used in the production of the electrospun fiber.

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

[0263] In some embodiments, the collector is a rotary collector that helps collect electrospun fibers onto it. Using a rotary collector, a layer of electrospun fibers with a continuous porous gradient can be produced. Such a porous gradient can be achieved by a continuous change in the collector's velocity or by the longitudinal movement of the dispenser, which results in substantial changes in the density and / or spatial distribution of the fibers on the collector, thus producing a porous gradient along the radial or longitudinal direction of the collector, respectively. While not strictly necessary, the rotary collector usually has a cylindrical shape (e.g., a drum). However, it will be understood that the rotary collector can also have a planar shape.

[0264] In some embodiments, the collector is a flat, grounded collector that helps collect electrospinned scaffolds onto it. The use of a flat, grounded collector enables the collection of random nanofibers. It will be understood that the flat, grounded collector is typically either a horizontal or vertical collector.

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

[0266] In some embodiments, a process is provided for preparing a matrix according to any of the embodiments described herein. In some embodiments, the process includes the steps of producing a layer of polymer fibers (according to any of the embodiments described herein) and optionally an additional layer 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), arranging an additional layer parallel to the first layer, and pressing the first layer and the additional layer together to form a multilayer matrix.

[0268] In some embodiments, pressing the first layer and the additional layer together involves applying a pressure of at least 1 gram / cm². In some embodiments, the pressure is at least 2 grams / cm². In some embodiments, the pressure is at least 4 grams / cm². In some embodiments, the pressure is at least 8 grams / cm².

[0269] In some embodiments, the process further includes heating one of the layers before, simultaneously with, and / or after, pressing the layers. In 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 "approximately" refers to a range of ±10%.

[0271] The terms "comprise," "comprising," "includes," "including," and "having," as well as their cognates, all mean "to include, but not to limit."

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

[0273] The term “essentially derived from” means that a composition, method, or structure may include additional components, steps, and / or parts, but only if the additional components, steps, and / or parts do not substantially alter the fundamental and novel characteristics of the claimed composition, method, or structure.

[0274] The term “exemplary” is used herein to mean “serving as an example, case, or illustration.” Any embodiment described as “exemplary” should not necessarily be construed as being preferable or advantageous to other embodiments, and / or not necessarily preclude the incorporation of features from other embodiments.

[0275] The phrase “optionally” is used herein to mean “provided in some embodiments and not provided in other embodiments.” Any particular embodiment of the present invention may include several “optional” features, provided that such features do not conflict. The words “furthermore” and “optionally” may be used interchangeably.

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

[0277] As used herein, the term “substantially” means at least 80% by weight, at least 90% by weight, at least 92% by weight, at least 95% by weight, at least 97% by weight, at least 98% by weight, and at least 99% by weight of the composition (including any range or value between them).

[0278] Throughout this application, various embodiments of the invention may be presented in a range format. The description in range format is for mere convenience and brevity and should not be construed as a rigid limitation on the scope of the invention. Accordingly, the description of a range should be considered to specifically disclose all possible sub-ranges as well as the individual numerical values within that range. For example, a description of a range such as 1 to 6 should be considered to specifically disclose sub-ranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as the individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the width of the range.

[0279] When a numerical range is indicated herein, it always means including any cited number (fraction or integer) within the indicated range. The expressions "in the range of / between" the first indicated number and the second indicated number and "in the range of / range" from the first indicated number "~" the second indicated number are used interchangeably herein and mean including the first and second indicated numbers and all fractional and integer numbers between them.

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

[0281] As used herein, the term "treat" or "treatment" includes suppressing the progression of a condition, substantially inhibiting, delaying or reversing, substantially alleviating the clinical or aesthetic symptoms of a condition, or substantially preventing the appearance of the clinical or aesthetic symptoms of a condition.

[0282] To clarify, it is understood that certain features of the invention 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 described in the context of a single embodiment for brevity may also be provided separately, or in any suitable sub-combination, or as suitable in any other described embodiment of the invention. Specific features described in the context of various embodiments are not to be regarded as essential features of those embodiments, except where the embodiments would not function without those elements.

[0283] The various embodiments and aspects of the invention as described above and claimed in the following claims sections find experimental evidence in the following examples.

Examples

[0284] Now, with the above description in mind, reference is made to the following examples which non - limitatively illustrate some embodiments of the invention.

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

Table 1

Table 2

[0286] Methods 1. Morphological characteristics The 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. An environmental - controlled scanning electron microscope (SEM) using a tungsten filament (Quonta 200, FEI) was used to take images of the outer surface of the samples at magnifications of 500 - 8000 times.

[0287] Fiber diameter and pore diameter were measured on 8000x SEM micrographs using the ImageJ Linear Measurement Tool, calibrated with the scale bar of the SEM image. Fiber and pore sizes were averaged across each sample (measurements for 10 fibers and pores per image were analyzed).

[0288] 2. Mechanical properties Tensile Properties: The mechanical properties of each electrospun sample were determined by measuring the tensile strength of each manufactured sample according to ASTM D882-12: Standard test method for tensile properties of thin plastic sheets. The test was performed using a LLOYD LS1 uniaxial tensile machine (equipped with a 100N load cell). The sample was cut into a dogbone shape, and the thickness was measured at three points along the neck of the dogbone. The test sample was then mounted on a clamping machine. Each sample was stretched until it broke. The maximum tensile strength was determined.

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

[0290] 4. Burst pressure strength: The rupture resistance of the adhesive composition of the present invention was also evaluated and compared with available tissue adhesive materials such as Hemopatch®. The tests were conducted according to ASTM F2392. Collagen strips were used as substrates and prepared as described in the shear test. A 3.0 mm diameter hole was formed in the center of each collagen strip, and 15 × 15 mm (n=10) prototype samples were placed on top of the collagen hole. The prototype samples were pressed against the collagen for 15 minutes under a weight of less than 160 grams to adhere. The bonded / adhered pieces were then fixed in a rupture fixation device with the central hole in the center and exposed to a constant rate of saline as described in ASTM F2392. The rupture strength was defined by the average of the maximum pressure required to cause leakage of the sample.

[0291] 5. Swelling and water absorption properties The weight of the dry patches (rectangles measuring 4 x 4 cm in diameter) was measured, and then they were immersed in 37°C water for 1 hour until saturated. The samples were removed from the water, their surfaces were partially dried using clean, dry paper, and they were weighed again at each point in time. The dimensions of the patches were measured using calipers at each period, both in the dry and wet states. Water absorption rate (%) = (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 (exemplary compositions of the present invention and the control) were prepared as follows: The electrospinning process was performed 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 / hour 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 thickness of the prepared patches was 200±30 μm, and they were vacuum-dried from the residual solvent at room temperature for 24 hours.

[0293] Preparation of PLCL fibers containing activated PEG polymer Control 1.1: Blends of PLCL containing methoxy-PEG-NHS (Mw=20K) in a ratio of 1:0.333 (w / w) [6.67 e-0.06 mol and 1.65 e-0.05 mol respectively] were electrospinned. 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 a blend PLCL containing methoxy-PEG-NHS (20K Mw) and methoxy-PEG-thiol (Mw = 20K) at a ratio of 1:0.333:0.167 (w / w / w) [6.67E-06 mol, 1.65E-05 mol, 8.35E-06 mol, respectively], as described in Control 1.1.

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

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

[0297] Composition 1.2: Electrospin a blend PLCL containing 4 Arm-PEG-NHS, more preferably 8 Arm PEG-NHS (Mw = 40K), and 4 Arm PEG-SH (Mw = 20K) at a ratio of 1:0.333:0.167 [6.67E-06 mol, 8.25E-06 mol, 8.35E-06 mol, respectively]. Solutions and final patches were generated as described in Control 1.1.

[0298] Composition 1.3: Electrospin a blend PLCL containing 4 Arm-PEG-NHS, more preferably 8 Arm PEG-NHS (Mw = 40K), and mPEG-NH2 (Mw = 2KDa) at a ratio of 1:0.333:0.167 [6.67E-06 mol, 8.25E-06 mol, 8.35E-05 mol, respectively]. Solutions and final patches were generated as described in Control 1.1.

[0299] Composition 1.4: A blend PLCL containing 4-Arm-PEG-NH2, more preferably 8-Arm-PEG-NH2 (Mw=40K), in a 2:1 ratio is electrospinned. A solution and final patch are produced as described in Control 1.1. The 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 in situ to the tissue.

[0300] Preparation of PDLCL fibers containing activated PEG polymer Composition 2.1: 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 is electrospinned. Solutions and final patches are produced as described in Control 1.1. The final polymer concentration is approximately 25%.

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

[0302] This was done by using a thin film applicator to diffuse a thin film layer of the polymer mixture onto the PLCL layer, or by adhering two layers of PLCL fibers to 150 micron PDLC. This can also be done by diffusing the polymer mixture onto release paper and adhering it to the PLCL fiber patch, or by electrospraying the blend solution onto the fibers. To improve the covalent bonding between activated PEG and the PLCL fiber patch, the outer layer of the PLCL fibers can be chemically functionalized. Chemical activation of the outer surface of the PLCL fibers can be achieved by treatment with plasma, ozone, gamma rays, electron beams, lasers, and UV light. The patch is then vacuum-dried from the residual solvent at room temperature for at least 12 hours.

[0303] A solution (approximately 20%) of a blended PDLC containing composition 3.2:4 Arm-PEG-NHS, more preferably 8 Arm-PEG-NHS (Mw=40kDa), and 4 Arm-PEG-SH (Mw=20kDa) in a 20:5:1 ratio is diffused onto the PLCL fiber or patch of PLCL fiber layer as described above.

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

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

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

[0307] Preparation of PLCL fiber layers coated with activated PEG polymer Composition 4.1: Distribute 4 Arm-PEG-NHS (Mw=40kDa), more preferably 8 Arm-PEG-NHS (Mw=40kDa), onto the surface of the PLCL fiber patch. This can be done by immersing a portion of the PLCL fiber patch in the PEG polymer melt for a specified time and then cooling, or by diffusing the PEG mixture onto the surface of another PDLC film diffused on the surface of the PLCL fiber patch, such as the fiber patch described in Composition 3.1 / PLCL fiber patch. The PEG mixture can be fixed onto 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: Distribute 20 mg of 4 ARM-PEG-NHS (40 kDa), more preferably 8 ARM-PEG-NHS (Mw=40 kDa) powder uniformly on a 2.5 cm × 4.0 cm surface as described in Composition 4.1.

[0309] Composition 4.3: A mixture (2:1) of 30 mg 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 uniformly distributed on a 2.5 cm × 4.0 cm surface as described in Composition 4.1.

[0310] Composition 4.4: Distribute 20 mg of 4 ARM-PEG-isocyanate (Mw=20 kDa) uniformly on a 2.5 cm × 4.0 cm surface as described in Composition 4.1.

[0311] A mixture of 4 ARM-PEG-NHS (Mw=40kDa), more preferably 8 ARM-PEG-NHS (Mw=40kDa) + 4 ARM-PEG-NH2 (Mw=40kDa) (2:1), is uniformly distributed on a 2.5cm × 4.0cm surface as described in Composition 4.1.

[0312] Composition 4.6 is mixed with 0.2 ml of 4 Arm-PEG-NHS (Mw=2kDa), more preferably 8 Arm-PEG-NHS (Mw=2kDa) and 0.1 ml of 4 Arm-PEG-SH (Mw=2kDa), more preferably 8 Arm-PEG-SH (Mw=2kDa) (in a 2:1 ratio), and poured onto a 4.0 cm × 5.0 cm surface of a PLCL fiber patch, or onto a two-layer patch of PDLCL film (fibrous PLCL and PDLC film).

[0313] Composition 4.7: As described in Composition 3.1, only the 30% PDLC solution is diffused onto the yje PLCL fiber patch, followed by a uniform distribution of 20 mg of 4-arm PEG-NHS, more preferably 8-arm PEG-NHS (Mw=40kDa) powder on a 2.5 cm × 4.0 cm surface.

[0314] Composition 4.8: As described in Composition 3.1, only the PDLC)30%) solution is diffused onto the PLCL fiber patch, and then 30 mg of a mixed powder (2:1) of 4-arm PEG-NHS, more preferably 8-arm PEG-NHS (Mw=40kDa) and 4-arm PEG-SH (Mw=20kDa) is uniformly distributed on a 2.5 cm × 4.0 cm surface.

[0315] Composition 4.9: As described in Composition 3.1, only the PDLC)30%) solution is diffused onto the PLCL fiber patch, followed by a uniform distribution of 30 mg of a mixed powder (2:1) of 4-arm PEG-NHS, more preferably 8-arm PEG-NHS (Mw=40kDa) and 4-arm PEG-NH2 (Mw=40kDa) on a 2.5cm × 4.0cm surface.

[0316] Composition 4.10: As described in Composition 3.1, only the PDLC)30% solution is diffused onto the PLCL fiber patch, followed by a uniform distribution of 20 mg of 4 Arm-PEG-ISOCYANATE (Mw=20kDa) powder on a 2.5 cm × 4.0 cm surface.

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

[0318] The above compositions, including multi-arm PEGs, refer to exemplary matrices of electrospun fibers according to several embodiments of the present invention. The above comparisons refer, among other things, to matrices of electrospun fibers including single-arm PEGs.

[0319] Figure 3 shows SEM micrographs illustrating the structural image of the matrix layer of exemplary electrospinned fibers of the present invention. SEM images of all samples showed smooth, uniform, bead-free fibers with no significant influence of the solution composition of each prototype on the fiber morphology. As shown in Figure 4, electrospinned fibers composed of single-arm PEGs with fiber sizes of 1.08–2.7 μm (controls 1.1–1.3) are finer than electrospinned fibers composed of multi-arm PEGs with fiber sizes ranging from 1.22–4.88 μm (compositions 1.1–1.3). 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, and the fibers composed of single-arm PEGs (controls 1.1–1.3) and multi-arm PEGs (compositions 1.1–1.3) represent similar pore sizes in the range of 7.44–9.72 μm.

[0320] Example 2 Peel test procedure Samples from each matrix layer of electrospun fibers were cut into 15mm × 30mm strips, with half of each strip moistened with saline solution and the other half kept dry. As shown in Figure 1, each strip was placed parallel to a moistened 15mm × 30mm collagen strip to create a minimum bonding area of ​​15 × 15mm. The moistened half of each sample was pressed against the collagen strip for 2 minutes, while the other half was left unbonded to the collagen to create a peel arm. All samples were dried at room temperature for easier handling. The force required to break the bond between the collagen and the sample was measured using a LLOYD LS1 universal tester. The peel arm was pulled apart at a speed of 10mm / min, and the force required to break the bond was measured. Adhesion strength was defined by the average of the peel force and maximum force recorded during the test.

[0321] Shear test procedure As shown in Figure 2, a moist collagen strip was thinned, and the moist sample was pressed onto the collagen for 2 minutes to bond the thinned areas. The force required to break the bond was measured by stretching the collagen strip at a speed of 10 mm / min using a LLOYD LS1 universal tester. The adhesive strength was defined as the maximum force required to separate the collagen strip at the bond point divided by the bond area. Commercial tissue adhesives such as Hemopatch® were also tested to serve as controls.

[0322] The adhesive strengths determined by the peel test and shear test are shown in Figures 7 and 8, respectively. In both tests, Composition 1.2 and Composition 2 (not shown) exhibited the highest adhesive strengths compared to the other samples. As a result, 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, as shown by the results in Figure 7, which demonstrate a significant increase in adhesive strength of Composition 1.2 compared to Composition 1.1, the combination of the second branched polymer and the third polymer in the fiber of the present invention (e.g., Composition 1.2) is more advantageous than the second branched polymer alone (Composition 1.1). Compared to all the samples tested, Hemopatch® is considered to have the lowest adhesive strength determined by the peel test. All exemplary matrices having a fiber structure that retains its elasticity after wetting and drying, according to several embodiments of the present invention, showed similar results in both tests.

[0323] Figure 6 shows the tensile strength values ​​of the electrospun fibers (controls 1.1-1.3 and compositions 1.1-1.4). A clear difference is observed between the blended polymer fiber samples and the PLCL fiber samples. The electrospun blended polymer fibers containing activated PEG appear to fail at lower stresses. This indicates that the mechanical strength of the electrospun PLCL fibers is impaired by the addition of activated PEG. However, composition 1.3 showed higher tensile strength compared to its control (control 1.3). It is presumed that blending m-PEG-NH2 into the electrospun solution of composition 1.3, which presents more functional groups (NHS), resulted in covalent crosslinking between the NHS free groups and the NH2 free groups, resulting in stronger fibers and higher tensile strength compared to its control (control 1.3). Composition 1.4, which contains multi-armed PEG-NH2 and multi-armed PEG-NHS, also showed high tensile strength (average 3.6 MPa) comparable to composition 1.1, which presents only multi-armed PEG-NHS.

[0324] It is noteworthy that the tensile strengths of all exemplary compositions of the present invention tested were significantly higher than those of DuraGen (a commercially available artificial dura mater), which ranged from 0.084 to 0.131 MPa, and also higher than those of Hemopatch (trademark) (0.118 MPa).

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

[0326] The results of the shear test shown in Figure 8 suggest that the exemplary composition of the present invention tested, consisting of multi-arm PEG-NHS including multi-arm PEG-SH, has a 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 aggregation strength of the tested composition (Figure 9).

[0327] Because PEG-NH2 reacts immediately with NHS groups, obtaining electrospun fibers from it was virtually impossible. To overcome this limitation, the inventors successfully utilized a kit containing electrospun fibers formed by a combination of a first polymer (PDCL or PLCL) and branched PEG-NHS or branched PEG-NH2. As described above, the tissue-reactive component (multi-arm PEG-NHS) (Composition 1.4) 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 for Composition 1.4 were within the range of favorable results.

[0328] As shown in Figure 9, multi-arm PEG-SH improves 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 Figures 7 and 8. Blending the combination of multi-arm PEG-SH and PEG-NHS into a patch of PLCL fibers yielded the best adhesive strength (composition 1.2), and it can be concluded that the achieved result was also supported by the significant adhesive strength of composition 1.2 presented in the peel test (Figure 7).

[0329] Furthermore, it can be concluded that incorporating tissue-reactive polymers (functionalized PEG reagents) into PLCL-based fibers yields better adhesion results compared to the coating / distribution 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 results achieved were compared to Hemopatch®, a commercially available control consisting of a collagen sponge structure coated with PEG reagents. The average adhesive strength of Hemopatch® was approximately 1.15 N. The authors were able to demonstrate that the electrospun fiber-based adhesive layer enhances the adhesive properties to wet wipes (greater than 1.15 N) compared to commercially available products currently on the market. In addition, a cast film layer 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] Although the present invention is described in detail, those skilled in the art will understand that many modifications and alterations are possible. Therefore, the present invention should not be construed as being limited to the specifically described embodiments, and the scope and concepts of the invention will be more readily understood by referring to the following claims.

Claims

1. (i) The first polymer and (ii) A second branched polymer and (iii) A third polymer which is reactive with respect to the second polymer and is at least partially crosslinked with respect to the second branched polymer, A composition in which either the second or third polymer contains a tissue-adhering group.

2. The composition according to claim 1, wherein the average molecular weight of the first polymer is in the range of 10 kDa to 900 kDa.

3. The composition according to claim 1 or 2, wherein the first polymer is selected from the group consisting of 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.

4. The composition according to any one of claims 1 to 3, wherein the third polymer is branched.

5. The composition according to any one of claims 1 to 4, wherein the third polymer comprises a nucleophile.

6. The composition according to any one of claims 1 to 5, wherein the crosslinking is achieved by reacting the tissue-adhering group with the nucleophile.

7. The composition according to any one of claims 1 to 6, wherein the branching is selected from the group consisting of star polymers, dendrimers, and superbranched polymers, or any combination thereof.

8. The composition according to any one of claims 1 to 7, wherein the branch includes 3 to 10 arms.

9. The composition according to any one of claims 1 to 8, wherein the tissue-adhering group is selected from the group consisting of activated esters (e.g., thioesters, peu-oroalkyl esters, pentolophenol esters, N-hydroxysuccinimide esters), acyl halogenates, chloroformates, anhydrides, aldehydes, epoxides, isocyanates, isothiocyanates, maleimides, carbonates, sulfonyl chlorides, haloacetamides, acyl azides, imide esters, carbodiimides, vinyl sulfones, ortho-pyridyl disulfide, or any combination thereof.

10. The composition according to any one of claims 1 to 9, wherein the tissue-adhering group is covalently bonded to the arm of the second polymer.

11. The composition according to any one of claims 1 to 10, wherein the second branched polymer, the third polymer, or both thereof is selected from the group consisting of polyethers, polyesters, polydioxanones, polyphosphoesters, polyurethanes, and polyamides, or any combination or copolymer thereof.

12. The composition according to any one of claims 1 to 11, wherein the second branched polymer, the third polymer, or both thereof comprises 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.

13. The composition according to any one of claims 1 to 12, wherein the average molecular weight of the second branched polymer and the third polymer is in the range of 500 Da to 100,000 Da.

14. The composition according to any one of claims 1 to 13, wherein the weight ratio of the third polymer to the second polymer is in the range of 1:1 to 1:

10.

15. The composition according to claim 1, wherein the weight ratio of the first polymer to the second polymer is in the range of 1:1 to 20:

1.

16. The composition according to any one of claims 1 to 15, wherein (i) the first polymer and (ii) at least one of the second branched polymer and the third polymer are blended together to form a blended polymer fiber.

17. The composition according to any one of claims 1 to 16, wherein the blended polymer fibers are biodegradable.

18. The composition according to any one of claims 1 to 17, wherein the blended polymer fibers are characterized by having an average fiber diameter of 0.5 to 10 μm.

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

20. A matrix comprising a tissue-adhering layer, wherein the tissue-adhering layer comprises blended polymer fibers according to any one of claims 16 to 19.

21. The matrix according to claim 20, further comprising an additional layer of polymer fibers.

22. The matrix according to claim 20 or 21, wherein the additional layer enhances the stability of the tissue adhesion layer.

23. The matrix according to any one of claims 20 to 22, wherein the tissue-adhering layer is characterized by a pore size of 0.5 to 100 μm.

24. The matrix according to any one of claims 20 to 23, wherein the tissue-adhering layer is characterized by a tensile strength of at least 0.05 MPa.

25. The matrix according to any one of claims 20 to 24, wherein the tissue-adhering layer is characterized by an adhesive strength of 1 to 10 N, and the adhesive strength is measured according to a shear test.

26. The matrix according to any one of claims 20 to 25, wherein the tissue-adhering layer is characterized by at least 60% porosity.

27. The matrix according to any one of claims 20 to 26, wherein the tissue-adhering layer is characterized by a thickness of 0.5 to 250 μm.

28. When the tissue-adhesive layer is exposed to an aqueous liquid at a pressure of 40 mmHg, it absorbs 1 ml / hour / cm². ２ A matrix according to any one of claims 20 to 27, characterized by a water permeability of less than 1.

29. A matrix according to any one of claims 20 to 28, further comprising a pharmaceutically active ingredient.

30. (i) A matrix according to any one of claims 20 to 29 for use in bioadhesion of at least one biological tissue, and (ii) promoting blood coagulation.

31. A matrix according to any one of claims 20 to 30 for use in repairing and / or replacing biological tissue.

32. 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 with respect to the second polymer, wherein the second polymer and the third polymer each comprise a second branched polymer or a third polymer as described in any one of claims 1 to 19.

33. The kit according to claim 32, wherein 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 combinations or copolymers thereof.

34. The kit according to claim 32 or 33, wherein the second polymer, the third polymer, or both thereof comprises 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.

35. The kit according to any one of claims 32 to 34, wherein the blended polymer fibers in contact with the additional components provide a tissue adhesion layer.

36. The kit according to any one of claims 32 to 35, wherein the weight ratio of the third polymer to the second polymer is in the range of 1:1 to 1:

20.

37. The kit according to any one of claims 32 to 36, wherein the weight ratio of the first polymer to the second polymer is in the range of 1:1 to 20:

1.

38. A process for producing a blended polymer fiber of a composition according to any one of claims 1 to 19, or a kit according to any one of claims 32 to 37, comprising: (i) mixing a first polymer and at least one of the second branched polymer and the third polymer with a solvent to obtain a solution; and (ii) providing the solution to an electrospinning apparatus.

39. The process according to claim 38, wherein the process is for producing a layer of polymer fibers.

Images