Embolic hydrogels for female sterilization

Abstract

Provided herein are embolic hydrogels for use in methods of female sterilization. An embolic hydrogel may include a maleimide or a maleimide derivative. The embolic hydrogel is administered to a fallopian tube wall, wherein the fallopian tube wall comprises a thiol functional group, said functional group forming a linker moiety between the fallopian tube wall and the maleimide or maleimide derivative, whereby the linker moiety covalently links the embolic hydrogel to the fallopian tube wall.

Description

EMBOLIC HYDROGELS FOR FEMALE STERILIZATIONTECHNICAL FIELD

[0001] The present specification relates generally to hydrogels and methods of making and using said hydrogels, and more specifically to hydrogels used for female sterilization.BACKGROUND

[0002] According to a survey from the Centers for Disease Control and Prevention, approximately 27 percent of American women of reproductive age use female sterilization as their form of birth control. Female sterilization is a permanent procedure to prevent pregnancy by blocking or sealing the fallopian tube. Conventional methods of sterilization include tubal ligation in which the fallopian tubes are cut or tied. Only one non-surgical procedure was approved for patients seeking sterilization. This nonsurgical procedure involves sealing the fallopian tube with a metallic coil. However, patients reported a number of problems and side effects with the device, including displacement of the device. These complications ultimately led to this device being recalled.

[0003] Accordingly, a need exists to develop non-invasive methods of female sterilization that minimize side effects.SUMMARY

[0004] The present disclosure concerns embolic hydrogels for use in methods of female sterilization.

[0005] In some aspects, the present disclosure generally relates to the use of an embolic hydrogel comprising a maleimide or a maleimide derivative in a method for female sterilization by administering the embolic hydrogel to a fallopian tube wall, wherein the fallopian tube wall comprises a thiol functional group, said functional group forming a linker moiety between the fallopian tube wall and the maleimide or maleimide derivative, whereby the linker moiety covalently links the embolic hydrogel to the fallopian tube wall. Optionally, the linker moiety is a thioether bond. Optionally, the embolic hydrogel is prepared by contacting a hydrogel precursor comprising a maleimide-functionalized polymer with a complexing molecule to facilitate the polymerization of the hydrogel precursor to form the embolic hydrogel. In some aspects, the maleimide-functionalized polymer and the complexing molecule are provided at a molar ratio that provides an excess of maleimide functional groups in the embolic hydrogel, optionally forming the linker moiety. Optionally, the fallopian tube wall is denuded prior to administering the embolic hydrogel.

[0006] In other aspects, the present disclosure relates to the use of an embolic hydrogel comprising a bromoacetyl functional group in a method for female sterilization by contacting a hydrogel precursor comprising a bromoacetylated polymer with a complexing molecule to facilitate polymerization of the hydrogel precursor to form the embolic hydrogel; and administering the embolic hydrogel to a fallopian tube wall, wherein the fallopian tube wall comprises a functional group selected from thiols, amines, imidazoles, and thioethers, wherein the functional group reacts with the bromoacetyl functional group to form a linker moiety between the fallopian tube wall and the embolic hydrogel, and wherein the linker moiety covalently links the embolic hydrogel to the fallopian tube wall. Optionally, the bromoacetylated polymer and the complexing molecule are provided at a molar ratio that provides an excess of unreacted bromoacetyl functional groups in the embolic hydrogel.

[0007] In other aspects, the present disclosure relates to the use of an embolic composition comprising l-ethyl-3-[3-dimethylaminopropyl] carbodiimide hydrochloride (EDC) and a monomeric component in a method for female sterilization by administering the embolic hydrogel to a fallopian tube wall, wherein the fallopian tube wall comprises a functional group selected from carboxyls and primary amines, said functional group forming a linker moiety between the fallopian tube wall and an active group of the embolic hydrogel, whereby the linker moiety covalently links the embolic hydrogel to the fallopian tube wall. Optionally, the linker moiety is an amide bond. Optionally, the embolic hydrogel is prepared by contacting a hydrogel precursor comprising a monomer with EDC to facilitate polymerization of the hydrogel precursor to form the embolic hydrogel.

[0008] In another aspect, the present disclosure concerns use of an embolic hydrogel comprising one or more extracellular matrix components and transglutaminase in a method for female sterilization by administering the embolic hydrogel to a fallopian tube wall, wherein the fallopian tube wall comprises a functional group selected from carboxamides and amines, said functional group forming a linker moiety between the fallopian tube wall and an active group of the extracellular matrix component, whereby the linker moiety covalently links the embolic hydrogel to the fallopian tube wall. Optionally, the one or more extracellular matrix components are selected from collagens, collagen derivatives, elastin, proteoglycans, fibronectin, laminins, glycosaminoglycans, or integrins. Optionally, the linker moiety is an isopeptide bond.

[0009] In some aspects, the present disclosure concerns the use of an embolic hydrogel comprising genipin and one or more monomer units in a method for female sterilization by administering the embolic hydrogel to a fallopian tube wall, wherein the fallopian tube wall comprises an amine functional group, said functional group forming a linker moiety between thefallopian tube wall and an active group of the genipin, whereby the linker moiety covalently links the embolic hydrogel to the fallopian tube wall. Optionally, the one or more monomer units are selected from collagen, chitosan, hyaluronate amine, PEG-Amine, polyethyleneimine(PEI), PEI- g-PEG-Amine, PEI-g-PEG-Biotin, PLGA-Diamine, and PLL-PEG-amine.

[0010] Additional features and advantages of the embodiments described herein will be set forth in the detailed description that follows, and in part will be readily apparent to those skilled in the art from that description or recognized by practicing the embodiments described herein, including the detailed description and claims that follow.DETAILED DESCRIPTION

[0011] Aspects described herein are generally directed to embolic hydrogels, methods of forming, and methods of using the same. In some aspects, the embolic hydrogels are administered in a body lumen and form a linker moiety with a wall of the body lumen, thereby linking the embolic hydrogel to the lumen wall and occluding the lumen. In some aspects, the embolic hydrogels are administered into a fallopian tube to occlude the lumen of the fallopian tube as a means of female sterilization. The aspects described herein are non-invasive and prevent migration of the occlusive hydrogel by adhering the gel the wall of the fallopian tube. These and other features and embodiments of the hydrogels are disclosed in greater detail herein.

[0012] While the following terms are believed to be well understood by one of ordinary skill in the art, definitions are set forth to facilitate explanation of the presently-disclosed subject matter.

[0013] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the presently- disclosed subject matter belongs.

[0014] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and claims are approximations that can vary depending upon the desired properties sought to be obtained by the presently- disclosed subject matter.

[0015] As used herein, the term “about,” when referring to a value or to an amount of mass, weight, time, volume, concentration or percentage is meant to encompass variations of in some embodiments ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1% from the specified amount, as such variations are appropriate to perform the disclosed method.

[0016] It should be understood that every maximum numerical limitation given throughout this specification includes every lower numerical limitation, as if such lower numerical limitations were expressly written herein. Every minimum numerical limitation given throughout this specification will include every higher numerical limitation, as if such higher numerical limitations were expressly written herein. Every numerical range given throughout this specification will include every narrower numerical range that falls within such broader numerical range, as if such narrower numerical ranges were all expressly written herein.Hydrogels

[0017] The present disclosure concerns, at least in part, the presence of a hydrogel, either alone or as a body encapsulating other materials and / or agents. A hydrogel refers to a polymerized network of water-insoluble monomer units cross-linked with a complexing molecule that retains water therein. A hydrogel may be of one single type of cross-linked monomer or may be a combination of two or more types of monomer units. A hydrogel may be a cross-linked network of at least one type of monomer, including two, three, four, five, six, seven, eight, and more different monomer units. It will be appreciated that a unit may refer to an assembled molecule of at least two parts, each part providing different functionalities to the monomer. The monomer may also be a natural or synthetic polymer. Illustrative natural polymers include collagen, gelatin, elastin, laminin, fibrin, silk fibroin, lysozymes, BSA, ovalbumin, hyaluronic acid, chitosan, heparin, alginate, combinations thereof, and the like. Illustrative synthetic polymers include polyvinyl alcohol, polyethylene glycol, sodium polyacrylate, acrylate polymers, copolymers thereof, and the like. Additional exemplary information on the hydrogel structure and components may be found in International Patent Application No. PCT / US2023 / 064160, the content of which is incorporated herein by reference.

[0018] The hydrogels include cross-linking between monomers and a complexing molecule within the hydrogel. Cross-linking refers to a bond or attraction point between different moieties and / or different monomers. In aspects, the bond is a chemical bond, such as a covalent bond, an ionic bond, or a metallic bond. In aspects, the bond or attraction may include van der Waal forces, hydrogen bonding, Keesome forces, Coulombic interactions, Pauli repulsions, halogen bonds, and combinations thereof. It will be appreciated that a hydrogel need not contain just one type of bond between moieties, but can instead feature two or more types of bond or attraction throughout the formed hydrogel. In some aspects, the hydrogel may be a chemical hydrogel wherein covalent bonds link strands together. In some aspects, the hydrogel may be a physical hydrogel wherein hydrogen bonds, entanglements, hydrophobic interactions, and similar physical interactions formthe gel. It will be appreciated that a hydrogel may also contain a combination of chemical and physical interactions.

[0019] In aspects, the further include complexing units or macromolecules that polymerize with the monomers. In some aspects, a hydrogel may include complexing molecules such as peptides, polypeptides, or proteins. In aspects, the hydrogel is a polymerized network of crosslinked monomer(s) and complexing unit(s). In aspects, the hydrogel is a polymerized network of cross-linked monomer(s) and peptides / polypeptides / proteins. It will be appreciated that peptide refers to two or more amino acids linked via a peptide bond, with a polypeptide referring to a series of chains of multiple linked amino acids and a protein referring to a full-length expressed gene or chimera thereof.

[0020] In aspects, the complexing unit includes a terminal structure, a linker, and a core. In some aspects, the complexing units of the hydrogel include a structure of a linker or a spacer with available moieties along the length thereof for binding other monomers or water, such as polyethylene glycol or repeats thereof, attached to a core or central moiety at one end and a terminal structure at the opposing end. In aspects, the core is chosen from pentaerythritol, hexaglycerol, tripentaerythritol, or glycerol. The monomeric unit may accordingly have 2, 4, or 8 linker arms extending from the core.

[0021] In some aspects, the terminal structure is an active ester. In some aspects, the terminal structure is an active thiol. In some aspects, the central moiety is a polyol or hydroxyl core. In aspects, one or more linkers may bind the central moiety or core and extend outward therefrom. In aspects, 2, 4, or 8 linkers may be attached to the core or central moiety. Each linker connected to the core or central moiety may accordingly be considered as a figurative appendage or arm extending therefrom. Optionally, the linker is polyethylene glycol. The linker may be of sufficient length to provide the hydrogel with a molecular weight (MW) of between 1 kDa and 100 kDa.

[0022] In aspects, the terminal structure includes a cyclical or ringed organic compound conjugated with a primary amine through a stable amide bond to the carboxyl group of a carboxylic acid, an alkanedioic acid, an alkenedioic acid, or a branched dioic acid. In some aspects, the primary amine is linked to an alkanedioic acid, such as a linear dicarboxylic acid. In some aspects, the terminal structure is a succinimidyl ester. In aspects, the succinimide is N- hydroxysuccinimide (NHS). In other aspects, the succinimide is a further substituted NHS. In aspects, the terminal structure includes a cyclical or ringed organic compound conjugated to the linker through an appended carboxyl group of a carboxylic acid, such as benzoic acid (BA) or a methylated form thereof. In aspects, the terminal structure may include BA, NHS, acrylamide, biotin, COOH, an alkyne, a halogen (such as chloride), an epoxide, hydrazide, norborene,hydroxyl, azide, amine, acrylate, dibenzocyclooctyne (DBCO), glutamic acid, glutaramide acid, succinimidyl glutaramide ester (GAS), maleimide, para-nitrophenyl carbonate (NPC), orthopyridyl disulfide (OPSS), acetic acid, carboxyl methyl, glutaric acid, succinic acid, glutaramide acid, succinamide acid, succinimidyl succinamide ester (SAS), thiol (or SH), tosylate, vinylsulfone, or combinations thereof.

[0023] In aspects, the linear dicarboxylic acid is saturated. In some aspects, the dicarboxylic acid is unsaturated. In aspects, the alkanedioic / alkenedioic / branched acid is selected from oxalic acid, malonic acid, succinic acid, itaconic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, tartaric acid, malic acid, and / or citraconic acid. In some aspects, the primary amine is linked to glycolic acid. In some aspects, the terminal structure is an ester of NHS. In aspects, the terminal structure is a thiol group.

[0024] In some aspects, the linker can be a PEG sufficient to provide a molecular weight (MW) of from about 1,000 Daltons (Da) to about 100,000 Da. The core can be pentaerythritol, hexaglycerol, tripentaerythritol, or glycerol. The monomer can be of 2, 4, 6, or 8 arms, such as NHS-PEG-2, NHS-PEG-4, and NHS-PEG-6, SH-PEG-2, SH-PEG-4, and SH-PEG-8.

[0025] In aspects, the complexing molecules or macromolecules include a central supporting backbone with one or more reactive side chains appended thereto. For example, amino acids include a central peptide bond between the amino and carboxylic acid groups, but also possess side chains. Depending on the amino acid, the side chain can be reactive, such as with arginine, histidine, lysine, aspartate, glutamate, serine, threonine, asparagine, glutamine, cysteine, methionine, and tyrosine provide reactive moieties. Similarly, molecules such as polyethylenimine (PEI) provide reactive amine groups within the complexing molecules that are available for reacting with the monomers. Similarly, polylysine, sulfone, polyphthalamide (PPA), polyphenylene (PPS), polyether ether ketone (PEEK), or combinations thereof can be provided as the complexing molecule.

[0026] In aspects, the complexing molecule is a recombinant protein and / or synthetic protein. In some aspects, the protein can be a commonly found protein in most animal species. Such may provide for minimal reaction by the immune system. In aspects, the protein is albumin. In some aspects, the protein is human albumin, including recombinant human serum albumin (rHSA or rHA) and / or synthetic human serum albumin, such as that formed by solid phase peptide synthesis and solution phase synthesis. In some aspects, the complexing molecule may be poly-lysine or a polypeptide with multiple lysine residues. In some aspects, the complexing molecule is a peptide, polypeptide, or protein located in a tissue at the application site described in greater detail herein.

[0027] In some aspects, the hydrogels include monomers cross-linked with the complexing molecule by bonds or attractions between reactive atoms, sub-molecules, or moieties within each monomer and / or complexing molecule. In some aspects, a monomer may cross-link with another atom or moiety in the same monomer or “self’ cross-link. In some aspects, a moiety or atom within one monomer will bond with or attract another moiety or atom in a different monomer, either of the same type of molecule or of a different molecule.

[0028] In some aspects, the monomer: complexing unit mass ratio is provided at about 48:1.3, 26:1.3, 25:1.3, 13:1.3, 13:54, 1:1, 13:13.5, 13:27, 21 :1.3, 10:1.3, 39:1.3, 64:1.3, 40:0.8, 30:0.6, 40:0.8, 30:0.9, 17:0.6, 40:0.8, 20:0.4, 40:0.8, 40: 1, 40:0.2, 40:0.5, 31 :1.3, 20:1.2, 20:0.2, 10:0.5, 20:0.9, 33:1.2, 33:1.1, 33:1.4, 33:1.5, 33:1.3, 33: 1.6, 33:1.7, 33:1.8, 33:1.9, 33:2, 36:1.4, 29:1.4, 23:1.4, 36:0.9, 20:0.8, 20:0.6, 13:0.4, 18:0.6, 25:0.5, 20:1.2, 25:1.6, 23:1.3, 22:1.6, 22:1.4, 25:0.7, 25:0.8, 23:0.7, 13:0.4, 18:0.6, 22:1.3, or 23:0.7.

[0029] In some aspects, the hydrogels of the present disclosure may include one or more therapeutic agents therein. As described herein, the hydrogels of the present disclosure are formed in situ through the application of one or more solutions that polymerize at a desired site. It is an aspect of the present disclosure that any of these solutions may include one or more additional materials, such as therapeutic agents, therein that become embedded in the hydrogel as it forms.

[0030] Illustrative examples of therapeutic agents include anti-inflammatory agents (e.g., nonsteroidal anti-inflammatory drugs, corticosteroids, cytokine inhibitors); analgesics (e.g., opioids, local anesthetics); antimicrobial agents (e.g., antibiotics, antifungals, antivirals); immunotherapy agents; growth factors; cytokines; antioxidants; radiopharmaceuticals; combinations thereof, and the like.

[0031] In aspects, the hydrogels of the present disclosure can be set to achieve a desired rate of formation and / or elastic modulus and / or rheology and / or viscoelasticity. Factors such as the monomer(s) selected, the concentration of the selected monomer(s), the number of arms and / or the length of the linker, the complexing molecule(s) or macromolecule(s) selected, the concentration of the complexing molecule(s) or macromolecule(s) selected, the degree of crosslinking, the available side chains for cross-linking, the amount of water included or made available, and so forth. As described in greater detail herein, varying the concentrations and the molecular weight can affect the gelling time and / or the degradation time.

[0032] The extent of gelation and the mechanical properties of the hydrogel can be controlled by factors such as the concentration of the enzyme, the duration of the reaction, the temperature, and the concentrations of the substrates. Optionally, the gel time and / or pot life of the hydrogel is modified by adjusting the pH of the precursor solutions, described in greater detail herein.Methods of use

[0033] It is a particular aspect of the present disclosure that the embolic hydrogels as set forth herein can form in situ within a subject, such as in a body lumen. Optionally, the body lumen is a fallopian tube. In other words, a user, such as a medical professional, can prepare the hydrogel solution and have the gel form from the point of application directly within a desired location in a subject. Such malleability in application allows for the hydrogel to properly occupy a desired location within a subject and the gel formed therein to occupy the location. For example, a medical professional can inject an embolic hydrogel into a fallopian tube such that, when the embolic hydrogel polymerizes, the embolic hydrogel crosslinks to the wall of the fallopian tube, thereby occluding the fallopian tube, resulting in female sterilization. In aspects, the embolic hydrogels may permanently occlude the fallopian tube. In other aspects, the embolic hydrogel is biodegradable within a specific time frame, providing a temporary method of sterilization.

[0034] In aspects, the present disclosure concerns methods for preparing the hydrogels as set forth herein. Hydrogel preparation in a clinical / surgical setting starts with forming the hydrogel precursors. Preparing the hydrogel precursors includes hydration of the monomer and / or the complexing molecule, which can be provided in a dried form (e.g., lyophilized, powdered, crystalline, etc.). The monomer and / or the complexing molecule can be hydrated individually by adding a rehydration solution to the dried component. For example, in aspects requiring both the monomer and the complexing molecule to be hydrated, each can be hydrated individually by connecting a first syringe with an aqueous solution and a second syringe with dry materials therein and pushing the aqueous solution back and forth through the connector. A parallel design with dual chamber syringes can be used to hydrate the monomer and the complexing molecule at the same time through a connector using similar manual process. Alternatively, the dry components can be mixed and hydrated together.

[0035] In some aspects, the rehydration solution is the same for each component. In some aspects, a different rehydration solution is used for each solution. In some aspects, the rehydration solution is provided at a specific pH to facilitate crosslinking between the monomer and the complexing unit when administered to the target site. For example, and without being bound by theory, the rehydration solution can be adjusted to a target pH range to prevent polymerization of the monomer and the complexing unit during preparation and delivery. Once the mixed solution is administered to the target site, having physiologic pH, the hydrogel begins to polymerize.

[0036] In some aspects, the rehydration solution includes one or more buffers or pH modifiers, such as HEPES ((4-(2-hydroxyethyl)-l -piperazine ethanesulfonic acid), PIPES (piper azine-N,N- bis(2-ethanesulfonic acid), MES (2-(N-morpholino)-ethanesulfonic acid, TRIS(tris(hydroxymethyl)aminomethane),TBS, sodium bicarbonate-carbonate, sodium ethanoateethanoic, phosphate buffer, bis-tris, tris-hydrochloride, MOPS (3-(N-morpholino)propanesulfonic acid), MES (2-(N-morpholino)ethanesulfonic acid), bicine, HEPPSO (N-(2- hydroxyethyl)piperazine), TAPS (tris(hydroxymethyl)methylamino propanesulfonic acid), maleic acid, malic acid, pyromellitic acid, salicylic acid and / or combinations thereof.

[0037] Generally, administration of the embolic hydrogels can be performed by any suitable means. For example and without being bound by theory, when an embolic hydrogel is administered to a fallopian tube, a dilator is inserted through the vagina and into the cervical opening. Optionally, the luminal surface (i.e., the wall) of the fallopian tube may be denuded prior to administering the embolic hydrogel. In some aspects, a catheter is advanced through the dilator and into the fallopian tube. The embolic hydrogel is administered through the catheter.

[0038] In aspects, the embolic hydrogel will start to form once the two solutions, a hydrated monomeric solution and a hydrated complexing molecule solution, come into contact with each other. As such, a facet of preparing the hydrogels is to allow the gel to form as the solutions fdl the target site. An aspect of the methods of preparing the hydrogels therefore is to contact the two solutions during application at the target site. One such means by which such can be achieved is through a “Y” or “T” connection of two inputs and one output. For example, a syringe or a pump can flow the two solutions to a contact point with the output channel ending in or above the space to be fdled with the hydrogel.

[0039] In other aspects, the embolic hydrogel will start to form once the hydrated monomeric solution comes into contact with a crosslinking agent, described in greater detail herein. In some aspects, the embolic hydrogel partially polymerizes before being administered to the target site. In other aspects, the hydrogel is administered to the target site as a hydrogel precursor(s), where the precursor(s) polymerize at the target site.

[0040] In some aspects, the dried monomeric solution and / or complexing molecule are administered to the treatment site. In such aspects, a bodily fluid at the target site rehydrates the components to form the embolic hydrogel.Maleimide and Maleimide Derivatives

[0041] Aspects of the present disclosure include use of an embolic hydrogel comprising a maleimide or a maleimide derivative in female sterilization by administering the embolic hydrogel to a fallopian tube wall, wherein the fallopian tube wall comprises a thiol functional group, said functional group forming a linker moiety between the fallopian tube wall and the maleimide or maleimide derivative, whereby the linker moiety covalently links the embolic hydrogel to the fallopian tube wall. Optionally, the linker moiety is a thioether bond. In some aspects, the embolichydrogels are permanent. In other aspects, the embolic hydrogels are biodegradable, resulting in temporary sterilization.

[0042] In some aspects, the monomer of the embolic hydrogel is a biocompatible, maleimide- functionalized polymer. As used herein, a maleimide-functionalized polymer incorporates a maleimide or a maleimide derivative functional group into the structure. As used herein, “maleimide or maleimide derivative” refers to the class of chemical compounds prepared by treating maleic anhydride with amines, followed by dehydration and having the general structure:or pharmaceutically-acceptable salts or solvates thereof, in which R is chosen from -H, alkyl groups, and aryl groups. As used herein the term “alkyl” includes both saturated and unsaturated, straight chain (i.e., unbranched) or branched aliphatic hydrocarbons, which are optionally substituted with one or more functional groups. As used herein, the term “aryl” does not differ significantly from the common meaning of the term in the art, and refers to an unsaturated cyclic moiety comprising at least one aromatic ring. In some aspects, “aryl” refers to a monocyclic or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.

[0043] Illustrative, non-limiting, maleimide-functionalized polymers include polyethylene glycol maleimide, maleimide-functionalized polylactic acid, maleimide-modified polycaprolactone, maleimide-functionalized polyvinylpyrrolidone, maleimide-functionalized hyaluronic acid, maleimide-functionalized polystyrene, maleimide-functionalized chitosan, maleimide-functionalized poly(ethylene oxide), maleimide-functionalized polyvinyl alcohol, maleimide-functionalized polyurethane, maleimide-functionalized polyacrylic acid, maleimide- modified poly(N-isopropyl acrylamide), maleimide-functionalized polyphosphazenes, and combinations thereof.

[0044] Maleimide functional groups provide reactive sites that can form covalent bonds with the complexing molecule using Michael addition reactions. In some aspects, complexing units used in conjunction with maleimide-functionalized polymers to form the hydrogel include thiol and / or dithiol functional groups. Optionally, the complexing unit is thiol-PEG. In other aspects, the complexing unit is PEG-NHS. The thiol functional groups react with the maleimide ormaleimide derivative functional groups to form a three-dimensional gel network. Optionally, the hydrogel is formed with a pH range of 6.5 -7.5 described in greater detail herein.

[0045] In aspects of the present disclosure, the hydrogel forms, at least in part, through reactions between the maleimide functional group of the monomer and thiols in the complexing molecule. In some aspects, the maleimide to thiol molar ratio determines certain qualities of the hydrogel. In some aspects, the maleimide :thiol molar ratio is between 0.05 and 3, including 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23,0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40,0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57,0.58, 0.59, 0.60, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.70, 0.71, 0.72, 0.73, 0.74,0.75, 0.76, 0.77, 0.78, 0.79, 0.80, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.90, 0.91,0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1.00, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08,1.09, 1.10, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.20, 1.21, 1.22, 1.23, 1.24, 1.25,1.26, 1.27, 1.28, 1.29, 1.30, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.40, 1.41, 1.42,1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.50, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59,1.60, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68, 1.69, 1.70, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76,1.77, 1.78, 1.79, 1.80, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.90, 1.91, 1.92, 1.93,1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2.00, 2.01, 2.02, 2.03, 2.04, 2.05, 2.06, 2.07, 2.08, 2.09, 2.10,2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2.19, 2.20, 2.21, 2.22, 2.23, 2.24, 2.25, 2.26, 2.27,2.28, 2.29, 2.30, 2.31, 2.32, 2.33, 2.34, 2.35, 2.36, 2.37, 2.38, 2.39, 2.40, 2.41, 2.42, 2.43, 2.44,2.45, 2.46, 2.47, 2.48, 2.49, 2.50, 2.51, 2.52, 2.53, 2.54, 2.55, 2.56, 2.57, 2.58, 2.59, 2.60, 2.61,2.62, 2.63, 2.64, 2.65, 2.66, 2.67, 2.68, 2.69, 2.70, 2.71, 2.72, 2.73, 2.74, 2.75, 2.76, 2.77, 2.78,2.79, 2.80, 2.81, 2.82, 2.83, 2.84, 2.85, 2.86, 2.87, 2.88, 2.89, 2.90, 2.91, 2.92, 2.93, 2.94, 2.95,2.96, 2.97, 2.98, 2.99, and 3.00.

[0046] In some aspects, the maleimide :thiol molar ratio is over 1.00. In some aspects the maleimide :thiol molar ratio is of about 1.1 to about 3.0, about 1.1 to about 2.9, about 1.1, to about 2.8, about 1.1 to about 2.7, about 1.1 to about 2.6, about 1.1 to about 2.5, about 1.1 to about 2.4 about 1.1 to about 2.3, about 1.1 to about 2.2, about 1.1 to about 2.1, about 1.1 to about 2.0, about1.1 to about 1.9, about 1.1 to about 1.8, about 1.1 to about 1.7, about 1.1 to about 1.6, about 1.1 to about 1.5, about 1.1 to about 1.4, about 1.1 to about 1.3, about 1.1 to about 1.2, about 1.2 to about3.0, about 1.2 to about 2.9, about 1.2, to about 2.8, about 1.2 to about 2.7, about 1.2 to about 2.6, about 1.2 to about 2.5, about 1.2 to about 2.4 about 1.2 to about 2.3, about 1.2 to about 2.2, about1.2 to about 2.1, about 1.2 to about 2.0, about 1.2 to about 1.9, about 1.2 to about 1.8, about 1.2 to about 1.7, about 1.2 to about 1.6, about 1.2 to about 1.5, about 1.2 to about 1.4, about 1.2 to about1.3, about 1.3 to about 3.0, about 1.3 to about 2.9, about 1.3, to about 2.8, about 1.3 to about 2.7, about 1.3 to about 2.6, about 1.3 to about 2.5, about 1.3 to about 2.4 about 1.3 to about 2.3, about1.3 to about 2.2, about 1.3 to about 2.1, about 1.3 to about 2.0, about 1.3 to about 1.9, about 1.3 to about 1.8, about 1.3 to about 1.7, about 1.3 to about 1.6, about 1.3 to about 1.5, about 1.3 to about1.4, about 1.4 to about 3.0, about 1.4 to about 2.9, about 1.4, to about 2.8, about 1.4 to about 2.7, about 1.4 to about 2.6, about 1.4 to about 2.5, about 1.4 to about 2.4 about 1.4 to about 2.3, about1.4 to about 2.2, about 1.4 to about 2.1, about 1.4 to about 2.0, about 1.4 to about 1.9, about 1.4 to about 1.8, about 1.4 to about 1.7, about 1.4 to about 1.6, about 1.4 to about 1.5, about 1.5 to about 3.0, about 1.5 to about 2.95, about 1.5 to about 2.9, about 1.5 to about 2.85, about 1.5 to about 2.8, about 1.5 to about 2.75, of about 1.5 to about 2.65, of about 1.5 to about 2.55, of about 1.5 to about 2.5, of about 1.5 to about 2.4, of about 1.5 to about 2.3, of about 1.5 to about 2.2, of about1.5 to about 2.1, of about 1.5 to about 2.0, of about 1.5 to about 1.9, of about 1.5 to about 1.8, of about 1.5 to about 1.7, of about 1.5 to about 1.6, of about 1.6 to about 3.0, about 1.6 to about 2.9, about 1.6, to about 2.8, about 1.6 to about 2.7, about 1.6 to about 2.6, of about 1.6 to about 2.75, of about 1.6 to about 2.65, of about 1.6 to about 2.55, of about 1.6 to about 2.5, of about 1.6 to about 2.4, of about 1.6 to about 2.3, of about 1.6 to about 2.2, of about 1.6 to about 2.1, of about1.6 to about 2.0, of about 1.6 to about 1.9, of about 1.6 to about 1.8, of about 1.6 to about 1.7, about 1.7 to about 3.0, about 1.7 to about 2.9, about 1.7, to about 2.8, about 1.7 to about 2.7, about1.7 to about 2.6, of about 1.7 to about 2.75, of about 1.7 to about 2.65, of about 1.7 to about 2.55, of about 1.7 to about 2.5, of about 1.7 to about 2.4, of about 1.7 to about 2.3, of about 1.7 to about2.2, of about 1.7 to about 2.1, of about 1.7 to about 2.0, of about 1.7 to about 1.9, of about 1.7 to about 1.8, of about 1.8 to about 2.75, of about 1.8 to about 2.65, of about 1.8 to about 2.55, of about 1.8 to about 2.5, of about 1.8 to about 2.4, of about 1.8 to about 2.3, of about 1.8 to about2.2, of about 1.8 to about 2.1, of about 1.8 to about 2.0, of about 1.8 to about 1.9, of about 1.9 to about 2.75, of about 1.9 to about 2.65, of about 1.9 to about 2.55, of about 1.9 to about 2.5, of about 1.9 to about 2.4, of about 1.9 to about 2.3, of about 1.9 to about 2.2, of about 1.9 to about 2.1, of about 1.9 to about 2.0, of about 2.0 to about 2.75, of about 2.0 to about 2.65, of about 2.0 to about 2.55, of about 2.0 to about 2.5, of about 2.0 to about 2.4, of about 2.0 to about 2.3, of about 2.0 to about 2.2, of about 2.0 to about 2.1, of about 2.1 to about 2.75, of about 2.1 to about 2.65, of about 2.1 to about 2.55, of about 2.1 to about 2.5, of about 2.1 to about 2.4, of about 2.1 to about 2.3, of about 2.1 to about 2.2, of about 2.2 to about 2.75, of about 2.2 to about 2.65, of about 2.2 to about 2.55, of about 2.2 to about 2.5, of about 2.2 to about 2.4, of about 2.2 to about2.3, of about 2.3 to about 2.75, of about 2.3 to about 2.65, of about 2.3 to about 2.55, of about 2.3 to about 2.5, of about 2.3 to about 2.4, of about 2.4 to about 2.75, of about 2.4 to about 2.65, ofabout 2.4 to about 2.55, of about 2.4 to about 2.5, of about 2.5 to about 2.75, of about 2.5 to about 2.65, of about 2.5 to about 2.55, of about 2.6 to about 2.75, and of about 2.6 to about 2.65.

[0047] In some aspects, described in greater detail herein, the hydrogels of the present disclosure can be set to achieve a desired rate of formation and / or elastic modulus and / or rheology and / or viscoelasticity and / or degradation profde. Factors such as the monomer(s) selected, the concentration of the selected monomer(s), the complexing molecule(s) or macromolecule(s) selected, the concentration of the complexing unit(s) or macromolecule(s) selected, the degree of crosslinking, the available side chains for cross-linking, the amount of water included or made available, and so forth.

[0048] For example, and without being bound by theory, the degree of adhesion of the embolic hydrogel can be tuned by controlling the molar ratio of maleimide to thiol functional groups. In some aspects, the maleimide-functionalized polymer and the complexing molecule are provided at a molar ratio that provides an excess of maleimide functional groups in the embolic hydrogel. In some aspects, the excess of maleimide functional groups react with a functional group at the target site to form the linker moiety between the embolic hydrogel and the fallopian tube wall.

[0049] In aspects where the hydrogel contains an excess of maleimide functional groups, the hydrogel will adhere to the tissue due to the reaction of the maleimide functional group with a thiol functional group in a peptide, polypeptide, or protein located in a tissue at the application site, forming a linker moiety between the tissue and the embolic hydrogel. Optionally, the linker moiety is a thioether bond. In some aspects, the application site is a fallopian tube.

[0050] In some aspects, the embolic hydrogel may be further tuned by changing the selection of the monomer and / or the complexing molecule. For example, the mechanical property of the hydrogel such as modulus and / or cross-liking density can be tuned by changing from a 2-arm PEG (polyethylene glycol)-SH to 4-arm PEG-SH. Similarly, a change from 4-arm PEG-maleimide to 8-arm PEG-maleimide will increase gelation time and modulus. Accordingly, in addition to varying the amount / concentration of each component, varying the type of component allows for additional levels of tunability.Bromoacetyl Functional Groups

[0051] Aspects of the present disclosure include use of an embolic hydrogel comprising a bromoacetyl group in female sterilization by administering the embolic hydrogel to a fallopian tube wall, wherein the fallopian tube wall comprises a functional group selected from thiols, amines, imidazoles, and thioethers, said functional group reacting with the bromoacetyl functional group to form a linker moiety between the fallopian tube wall and the embolic hydrogel, whereby the linker moiety covalently links the embolic hydrogel to the fallopian tube wall to occlude thefallopian tube. Optionally, the linker moiety is a thioether and / or an amide bond. In some aspects, the embolic hydrogels are permanent. In other aspects, the embolic hydrogels are biodegradable.

[0052] Specifically, the methods for female sterilization described herein include preparing an embolic hydrogel comprising a bromoacetyl functional group by contacting a hydrogel precursor comprising a bromoacetylated polymer with a complexing molecule to facilitate polymerization of the hydrogel precursor to form the embolic hydrogel; administering the embolic hydrogel to a fallopian tube wall, wherein the fallopian tube wall comprises a functional group selected from thiols, amines, imidazoles, and thioethers, wherein the functional group reacts with the bromoacetyl functional group to form a linker moiety between the fallopian tube wall and the embolic hydrogel, and wherein the linker moiety covalently links the embolic hydrogel to the fallopian tube wall.

[0053] In some aspects, the monomer is a biocompatible, bromoacetylated polymer, structure. As used herein, a bromoacetylated polymer incorporates a bromoacetyl functional group into the structure. Illustrative, non-limiting, bromoacetylated polymers include bromoacetylated polyethylene glycol, bromoacetylated polylactic acid, bromoacetylated polycaprolactone, bromoacetylated polyvinylpyrrolidone, bromoacetylated hyaluronic acid, bromoacetylated polystyrene, bromoacetylated chitosan, bromoacetylated poly(ethylene oxide bromoacetylated polyvinyl alcohol, bromoacetylated polyurethane, bromoacetylated polyacrylic acid, bromoacetylated poly(N-isopropyl acrylamide), bromoacetylated polyphosphazenes, and combinations thereof. Optionally, the bromoacetylated polymer is selected from bromoacetamido- dPEGN-TFP ester and bromoacetamido-dPEGi2-Tris(-dPEGii-bromoacetamide)3). Optionally, the number of polyethylene glycol moieties present in dPEGN-TFP ester is from 4 to 24.

[0054] Bromoacetyl functional groups provide reactive sites that can form covalent bonds with the complexing molecule using nucleophilic substitution reactions. In some aspects, complexing molecules used in conjunction with bromoacetyl-functionalized polymers to form the hydrogel include nucleophilic functional groups. Optionally, the nucleophilic functional group is a thiol and / or dithiol functional group. The thiol functional groups react with the bromoacetyl functional groups to form a thioether bond. The thioether bonds formed in the reaction serve as cross-links that tie the polymer chains together, forming a three-dimensional gel network. Optionally, the embolic hydrogel is formed with a pH range of 7.5-9.0 described in greater detail herein.

[0055] In aspects of the present disclosure, the embolic hydrogel forms, at least in part, through reactions between the bromoacetyl functional group of the monomer and thiols in the complexing molecule. In some aspects, the bromoacetyl to thiol molar ratio determines certain qualities of the embolic hydrogel. In some aspects, the bromoacetykthiol molar ratio is between 0.05 and 3,including 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37,0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54,0.55, 0.56, 0.57, 0.58, 0.59, 0.60, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.70, 0.71,0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.80, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88,0.89, 0.90, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1.00, 1.01, 1.02, 1.03, 1.04, 1.05,1.06, 1.07, 1.08, 1.09, 1.10, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.20, 1.21, 1.22,1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.30, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39,1.40, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.50, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56,1.57, 1.58, 1.59, 1.60, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68, 1.69, 1.70, 1.71, 1.72, 1.73,1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.80, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.90,1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2.00, 2.01, 2.02, 2.03, 2.04, 2.05, 2.06, 2.07,2.08, 2.09, 2.10, 2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2.19, 2.20, 2.21, 2.22, 2.23, 2.24,2.25, 2.26, 2.27, 2.28, 2.29, 2.30, 2.31, 2.32, 2.33, 2.34, 2.35, 2.36, 2.37, 2.38, 2.39, 2.40, 2.41,2.42, 2.43, 2.44, 2.45, 2.46, 2.47, 2.48, 2.49, 2.50, 2.51, 2.52, 2.53, 2.54, 2.55, 2.56, 2.57, 2.58,2.59, 2.60, 2.61, 2.62, 2.63, 2.64, 2.65, 2.66, 2.67, 2.68, 2.69, 2.70, 2.71, 2.72, 2.73, 2.74, 2.75,2.76, 2.77, 2.78, 2.79, 2.80, 2.81, 2.82, 2.83, 2.84, 2.85, 2.86, 2.87, 2.88, 2.89, 2.90, 2.91, 2.92,2.93, 2.94, 2.95, 2.96, 2.97, 2.98, 2.99, and 3.00.

[0056] In some aspects the bromoacetyhthiol molar ratio is over 1.00. In some aspects the bromoacetyl :thiol molar ratio is of about 1.5 to about 2.75, of about 1.5 to about 2.65, of about 1.5 to about 2.55, of about 1.5 to about 2.5, of about 1.5 to about 2.4, of about 1.5 to about 2.3, of about 1.5 to about 2.2, of about 1.5 to about 2.1, of about 1.5 to about 2.0, of about 1.5 to about 1.9, of about 1.5 to about 1.8, of about 1.5 to about 1.7, of about 1.5 to about 1.6, of about 1.6 to about 2.75, of about 1.6 to about 2.65, of about 1.6 to about 2.55, of about 1.6 to about 2.5, of about 1.6 to about 2.4, of about 1.6 to about 2.3, of about 1.6 to about 2.2, of about 1.6 to about2.1, of about 1.6 to about 2.0, of about 1.6 to about 1.9, of about 1.6 to about 1.8, of about 1.6 to about 1.7, of about 1.7 to about 2.75, of about 1.7 to about 2.65, of about 1.7 to about 2.55, of about 1.7 to about 2.5, of about 1.7 to about 2.4, of about 1.7 to about 2.3, of about 1.7 to about2.2, of about 1.7 to about 2.1, of about 1.7 to about 2.0, of about 1.7 to about 1.9, of about 1.7 to about 1.8, of about 1.8 to about 2.75, of about 1.8 to about 2.65, of about 1.8 to about 2.55, of about 1.8 to about 2.5, of about 1.8 to about 2.4, of about 1.8 to about 2.3, of about 1.8 to about2.2, of about 1.8 to about 2.1, of about 1.8 to about 2.0, of about 1.8 to about 1.9, of about 1.9 to about 2.75, of about 1.9 to about 2.65, of about 1.9 to about 2.55, of about 1.9 to about 2.5, of about 1.9 to about 2.4, of about 1.9 to about 2.3, of about 1.9 to about 2.2, of about 1.9 to about2.1, of about 1.9 to about 2.0, of about 2.0 to about 2.75, of about 2.0 to about 2.65, of about 2.0 to about 2.55, of about 2.0 to about 2.5, of about 2.0 to about 2.4, of about 2.0 to about 2.3, of about 2.0 to about 2.2, of about 2.0 to about 2.1, of about 2.1 to about 2.75, of about 2.1 to about 2.65, of about 2.1 to about 2.55, of about 2.1 to about 2.5, of about 2.1 to about 2.4, of about 2.1 to about 2.3, of about 2.1 to about 2.2, of about 2.2 to about 2.75, of about 2.2 to about 2.65, of about 2.2 to about 2.55, of about 2.2 to about 2.5, of about 2.2 to about 2.4, of about 2.2 to about 2.3, of about 2.3 to about 2.75, of about 2.3 to about 2.65, of about 2.3 to about 2.55, of about 2.3 to about 2.5, of about 2.3 to about 2.4, of about 2.4 to about 2.75, of about 2.4 to about 2.65, of about 2.4 to about 2.55, of about 2.4 to about 2.5, of about 2.5 to about 2.75, of about 2.5 to about 2.65, of about 2.5 to about 2.55, of about 2.6 to about 2.75, and of about 2.6 to about 2.65.

[0057] In some aspects, described in greater detail herein, the hydrogels of the present disclosure can be set to achieve a desired rate of formation and / or elastic modulus and / or rheology and / or viscoelasticity and / or degradation profde. For example, and without being bound by theory, the degree of adhesion of the embolic hydrogel can be tuned by controlling the molar ratio of thiol functional groups in the complexing molecule with bromoacetyl functional groups in the monomer. In some aspects, the bromoacetylated polymer and the complexing molecule are provided at a molar ratio that provides an excess of unreacted bromoacetyl functional groups in the embolic hydrogel. In some aspects, the excess of unreacted bromoacetyl functional groups react with the functional group to form the linker moiety.

[0058] In aspects where the hydrogel contains an excess of bromoacetyl functional groups, the hydrogel will adhere to the tissue due to the reaction of the bromoacetyl functional group with a functional group in a peptide, polypeptide, or protein located in a tissue at the application site, forming a linker moiety between the tissue and the embolic hydrogel. Optionally, the functional group is a thiol, amine, imidazole, and / or thioether. Optionally, the linker moiety is a thioether and / or an amide bond. In some aspects, the application site is a fallopian tube.

[0059] In some aspects, the embolic hydrogel may be further tuned by changing the selection of the monomer and / or the complexing molecule. (Inventors: can you provide exemplary changes?) For example, the property of hydrogel such as the degree of swelling can be tuned by changing the number units of PEG between the reactive ends. Similarly, a change from a linear structure to a branched structure of bromoacetomide will increase crosslinking density of hydrogel and modulus. Accordingly, in addition to varying the amount / concentration of each component, varying the type of component allows for additional levels of tunability.Crosslinking agents

[0060] In some aspects, the hydrogels include a crosslinking agent with the monomers and / or the complexing molecule. In some aspects, the crosslinking agent facilitates the bonding of the monomers and / or the complexing molecule by activating one or more functional groups, such as a carboxyl group. In some aspects, the complexing molecule is a peptide, polypeptide, or protein located in a tissue at the application site described in greater detail herein. For example, and without being bound by theory, the crosslinking agent may facilitate crosslinking of the monomer with a wall of the fallopian tube to occlude the fallopian tube, thereby providing a method a female sterilization.

[0061] In some aspects of the present disclosure, the monomer is a peptide, polypeptide, or protein located in a tissue at the application site, such as a fallopian tube, described in greater detail herein. In some aspects, a crosslinking agent forms an embolic hydrogel by crosslinking directly with the peptide, polypeptide, or protein in the fallopian tube.

[0062] In some aspects, a functional group on the monomer and / or the complexing molecule reacts with the crosslinking agent to form a reactive intermediate. This reactive intermediate is generally unstable and highly reactive. The reactive intermediate then reacts with a functional group on the monomer and / or the complexing molecule to form a stable bond, generating a three- dimensional gel network. Optionally, this three-dimensional gel network crosslinks with the tissue at a target site. In some aspects, this crosslinking between the three-dimensional gel network and the target site forms the embolic hydrogel. For example, and without being bound by theory, when this embolic hydrogel is administered within a fallopian tube, it occludes the fallopian tube.

[0063] Optionally, the crosslinking agent is mixed with the rehydrated monomer and / or the complexing molecule prior to administration to the target site. In some aspects, the crosslinking agent is mixed with the monomeric solution1 -ethyl-3 -(3 -dimethylaminopropyl) carbodiimide

[0064] Aspects of the present disclosure include use of an embolic hydrogel comprising 1- ethyl-3- [3 -dimethylaminopropyl] carbodiimide hydrochloride (EDC) in female sterilization comprising administering the embolic hydrogel to a fallopian tube wall, wherein the fallopian tube wall comprises a functional group selected from carboxyls and primary amines, said functional group reacting with EDC to form a linker moiety between the fallopian tube wall and an active group of the embolic hydrogel, whereby the linker moiety covalently links the embolic hydrogel to the fallopian tube wall. Optionally, the linker moiety is an amide bond.

[0065] In some aspects, the cross-linking agent is a zero-length crosslinking agent. Optionally, the zero-length crosslinking agent is 1 -ethyl-3 -(3 -dimethylaminopropyl) carbodiimide (EDC). For example, and without being bound by theory, a monomer having one or more carboxyl groupsis crosslinked to a complexing molecule having one or more amine groups. In the presence of EDC, carboxyl groups on the monomer become activated and form an O-acylisourea intermediate. This intermediate is unstable and highly reactive, making it prone to nucleophilic substitution by the amine group, thereby crosslinking the monomer to the complexing molecule. Optionally, the hydrogel is formed at a pH of about 4. In some aspects, the hydrogel precursors contain a buffer or pH modifier that allows the formation of the hydrogel at a pH of about 4. In aspects, the buffer or pH modifier is substantially free from carboxyls and amines.

[0066] In some aspects, the EDC is present in the hydrogel precursor in a concentration of from about 0.5 mM EDC to about 75 mM EDC. Optionally, the EDC is present in the precursor in a concentration of from about 1.0 mM to about 10 mM, including about 1.0 mM, about 1.25 mM, about 1.5 mM, about 1.75 mM, about 2.00 mM, about 2.25 mM, about 2.5 mM, about 2.75 mM, about 3.0 mM, about 3.25 mM, about 3.5 mM, about 3.75 mM, about 4.0 mM, about 4.25 mM, about 4.5 mM, about 4.75 mM, about 5.0 mM, about 5.25 mM, about 5.5 mM, about 5.75 mM, about 6.0 mM, about 6.25 mM, about 6.5 mM, about 6.75 mM, about 7.0 mM, about 7.25 mM, and about 7.5 mM, about 7.75 mM, about 8.0 mM, about 8.25 mM, about 8.5 mM, about 8.75 mM, about 9.0 mM, about 9.25 mM, about 9.5 mM, about 9.75 mM, and about 10.0 mM, including any range defined by any two of the aforementioned endpoints.

[0067] In some aspects, the monomer includes at least one carboxyl functional group. Illustrative, non-limiting examples of monomers suitable for use with EDC include poly(acrylic acid), alginate, carrageenan, carboxymethylcellulose, poly(methacrylic acid), hyaluronic acid, xanthan gum, pectin, and the like. In some aspects, the monomer is a polymer having one or more carboxyl functional groups, such as carboxylic acids, alkanedioic acids, alkenedioic acids, or branched dioic acids.Transglutaminase

[0068] Aspects of the present disclosure include use of an embolic hydrogel comprising one or more extracellular matrix components and transglutaminase in female sterilization by administering the embolic hydrogel to a fallopian tube wall, wherein the fallopian tube wall comprises a functional group selected from carboxamides and amines, wherein the transglutaminase catalyzes the reaction of said functional group and an active group of the extracellular matrix component to form a linker moiety between the fallopian tube wall and the embolic hydrogel, whereby the linker moiety covalently links the embolic hydrogel to the fallopian tube wall. Optionally, the linker moiety is an isopeptide bond.

[0069] In some aspects, the crosslinking agent facilitates the bonding of the monomer to other monomers and / or a tissue at the application site, described in greater detail herein. In some aspects,the crosslinking agent is an enzyme that catalyzes the crosslinking between the monomer and / or the complexing molecule and / or the tissue. Optionally, the enzyme is transglutaminase. In some aspects, the transglutaminase is microbial transglutaminase.

[0070] For example, and without being bound by theory, a monomer having one or more lysine and / or glutamine residues is crosslinked to a complexing molecule having one or more lysine and / or glutamine residues to form s-(y-glutamyl)lysine isopeptide bonds. Specifically, this crosslinking reaction occurs between the ' / -carboxamide group of a glutamine residue in one component and the s-amino group of a lysine residue in another component. The transglutaminase facilitates the formation of covalent bonds between the glutamine and lysine residues of different chains, leading to the formation of a stable gel network.

[0071] In some aspects, the monomer is an extracellular matrix component. Illustrative extracellular matrix components suitable for use with transglutaminase include collagen, collagen derivatives (e.g., gelatin), hyaluronic acid, fibronectin, elastin, laminin, aggrecan, proteoglycans, glycosaminoglycans, integrins combinations thereof, and the like. Optionally, the extracellular matrix component is collagen. In some aspects, the complexing molecule is a peptide, polypeptide, or protein located in a tissue at the application site described in greater detail herein.

[0072] In some aspects, the transglutaminase is present in the hydrogel precursor in a concentration of from about 1% w / v to about 20% w / v relative to the ECM component, including about 2% w / v, about 3% w / v, about 4% w / v, about 5% w / v, about 6% w / v, about 7% w / v, about 8% w / v, about 9% w / v, about 10% w / v, about 11% w / v, about 12% w / v, about 13% w / v, about 14 % w / v, about 15% w / v, about 16% w / v, about 17% w / v about 18% w / v, and about 19% w / v, including any range defined by any two of the aforementioned endpoints.

[0073] In other aspects, the transglutaminase is present in the hydrogel precursor in an amount of about 0.1 U / mg to about 8.0 U / mg relative to the extracellular matrix component, including about 0.25 U / mg, about 0.5 U / mg, about 0.75 U / mg, about 1.0 U / mg, about 1.25 U / mg, about 1.5 U / mg, about 1.75 U / mg, about 2.0 U / mg, about 2.25 U / mg, about 2.5 U / mg, about 2.75 U / mg, about 3.0 U / mg, about 3.25 U / mg, about 3.5 U / mg, about 3.75 U / mg, about 3.0 U / mg, about 3.25 U / mg, about 3.5 U / mg, about 3.75 U / mg, about 4.0 U / mg, about 4.25 U / mg, about 4.5 U / mg, about 4.75 U / mg, about 5.0 U / mg, about 5.25 U / mg, about 5.5 U / mg, about 5.75 U / mg, about 6.0 U / mg, about 6.25 U / mg, about 6.5 U / mg, about 6.75 U / mg, about 7.0 U / mg, about 7.25 U / mg, about 7.5 U / mg, and about 7.75 U / mg, including any range defined by any two of the aforementioned values.Genipin

[0074] In some aspects, the crosslinking agent has an epoxy reactive group that can react with primary amine groups on the monomer and / or the complexing molecule. In some embodiments, the crosslinking agent is genipin or a genipin derivative.

[0075] Aspects of the present disclosure include use of an embolic hydrogel comprising genipin and one or more monomers in female sterilization by administering the embolic hydrogel to a fallopian tube wall, wherein the fallopian tube wall comprises an amine functional group, said functional group forming moiety a linker moiety between the fallopian tube wall and the genipin, whereby the linker moiety covalently links the embolic hydrogel to the fallopian tube wall.

[0076] For example, and without being bound by theory, when genipin encounters an amine group, it undergoes a nucleophilic attack to open the epoxy ring, thereby forming an amide bond with the monomer. Illustrative monomers suitable for use with genipin include collagen, chitosan, aminated hyaluronic acid, PEG-Amines, polyethyleneimine, PLGA-amines, graft copolymers thereof (e.g., PEI-g-PEG-amines, PEI-g-PEG-biotin, PLL-PEG-amines), combinations thereof, and the like. In some aspects, genipin also reacts with an amine functional group in a complexing molecule to cross the link monomer to the complexing molecule. Optionally, the complexing molecule is a peptide, polypeptide, or protein located in a tissue at the application site described in greater detail herein.

[0077] In some aspects, the genipin is present in the hydrogel precursor at a concentration of from about 0.01% to about 5%, including about 0.025%, about 0.05%, about 0.075%, about 0.1%, about 0.2%, about 0.3%, about 0.4% about 0.5%, about 0.6%, about 0.7%, about 0.8% about 0.9%, about 1.0% about 1.25%, about 1.5%, about 1.75%, about 2.0%, about 2.25%, about 2.5%, about 2.75%, about 3.0% about 3.25%, about 3.5%, about 3.75%, about 4.0%, about 4.25%, about 4.5%, about 4.5%, and about 4.75%, including ny range having endpoints defined by any two of the aforementioned values.

[0078] In some aspects, described in greater detail herein, the hydrogels of the present disclosure can be set to achieve a desired rate of formation and / or elastic modulus and / or rheology and / or viscoelasticity and / or degradation profile. For example, and without being bound by theory, when higher elastic modulus is desired, the concentration of the crosslinker (e.g. genipin, transglutaminase, etc.) is increased proportionally. Similarly, when a lower viscoelasticity is desired, the molecular weight of the substrate might be decreased proportionally. Alternatively, the crosslinker might be selected with a lower binding affinity for the substrate. In other aspects, a spacer might be added to the formulation.Items Listing:

[0079] A first item of the present disclosure, alone or in combination with any other item described herein, relates to an embolic hydrogel comprising a maleimide or maleimide derivative for use in a method of female sterilization by administering the embolic hydrogel to a fallopian tube wall, wherein the fallopian tube wall comprises a thiol functional group, said functional group forming a linker moiety between the fallopian tube wall and the maleimide or maleimide derivative, whereby the linker moiety covalently links the embolic hydrogel to the fallopian tube wall.

[0080] A second item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel wherein the embolic hydrogel is prepared by contacting a hydrogel precursor comprising a maleimide-functionalized polymer with a complexing molecule to facilitate polymerization of the hydrogel precursor to form the embolic hydrogel.

[0081] A third item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the maleimide-functionalized polymer and the complexing molecule are provided at a molar ratio that provides an excess of maleimide functional groups in the embolic hydrogel.

[0082] A fourth item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the excess of maleimide functional groups form the linker moiety.

[0083] A fifth item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, further comprising denuding the fallopian tube wall prior to administering the embolic hydrogel.

[0084] A sixth item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the embolic hydrogel further comprises a therapeutic agent.

[0085] A seventh item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the therapeutic agent is an antiinflammatory.

[0086] An eightht item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the embolic hydrogel is formed at a pH of from about 6.5 to about 7.5.

[0087] A ninth item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the linker moiety is a thioether bond.

[0088] A tenth item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the embolic hydrogel is permanent.

[0089] An eleventh item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the embolic hydrogel is biodegradable.

[0090] A twelfth item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel comprising a bromoacetyl functional group in a method for female sterilization by preparing the embolic hydrogel by contacting a hydrogel precursor comprising a bromoacetylated polymer with a complexing molecule to facilitate polymerization of the hydrogel precursor to form the embolic hydrogel; and administering the embolic hydrogel to a fallopian tube wall, wherein the fallopian tube wall comprises a functional group selected from thiols, amines, imidazoles, and thioethers, wherein the functional group reacts with the bromoacetyl functional group to form a linker moiety between the fallopian tube wall and the embolic hydrogel, and wherein the linker moiety covalently links the embolic hydrogel to the fallopian tube wall.

[0091] A thirteenth item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the bromoacetylated polymer and the complexing molecule are provided at a molar ratio that provides an excess of unreacted bromoacetyl functional groups in the embolic hydrogel.

[0092] A fourteenth item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the excess of unreacted bromoacetyl functional groups react with the functional group to form the linker moiety.

[0093] A fifteenth item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, further comprising denuding the fallopian tube wall prior to administering the embolic hydrogel.

[0094] A sixteenth item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the embolic hydrogel further comprises a therapeutic agent.

[0095] A seventeenth item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the therapeutic agent is an anti-inflammatory .

[0096] An eighteenth item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the embolic hydrogel is formed at a pH of from about 7.5 to about 9.0.

[0097] A nineteenth item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the functional group is a thiol.

[0098] A twentieth item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the functional group is one or more of an amine, an imidazole, a thiol, or a thioether.

[0099] A twenty-first item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the linker moiety is a thioether bond.

[0100] A twenty-second item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the linker moiety is an amide bond.

[0101] A twenty-third item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the embolic hydrogel is permanent.

[0102] A twenty-fourth item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the embolic hydrogel is biodegradable.

[0103] A twenty-fifth item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic composition comprising l-ethyl-3-[3- dimethylaminopropyl] carbodiimide hydrochloride (EDC) and a monomeric component in a method for female sterilization by administering the embolic composition to a fallopian tube wall, wherein the fallopian tube wall comprises a functional group selected from carboxyls and primary amines, said functional group forming a linker moiety between the fallopian tube wall and an active group of the embolic composition, whereby the linker moiety covalently links the embolic composition to the fallopian tube wall, forming an embolic hydrogel.

[0104] A twenty-sixth item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the embolic hydrogel is prepared by contacting a hydrogel precursor comprising a monomer with EDC to facilitate polymerization of the hydrogel precursor to form the embolic hydrogel.

[0105] A twenty-seventh item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, further comprising denuding the fallopian tube wall prior to administering the embolic hydrogel.

[0106] A twenty-eighth item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the therapeutic agent is an anti-inflammatory .

[0107] A twenty-ninth item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the embolic hydrogel is formed at a pH of about 4.5.

[0108] A thirtieth item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the active group of the embolic hydrogel is selected from carboxyls and primary amines.

[0109] A thirty-first item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the linker moiety is an amide bond.

[0110] A thirty-second item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel wherein the embolic hydrogel is permanent.

[0111] A thirty-third item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel wherein the embolic hydrogel is biodegradable.

[0112] A thirty-fourth item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel wherein the hydrogel precursor comprises a buffer or pH modifier.

[0113] A thirty-fifth item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the pH modifier is substantially free from carboxyls and amines.

[0114] A thirty-sixth item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel comprising one or more extracellular matrix components and transglutaminase in a method for female sterilization by administering the embolic hydrogel to a fallopian tube wall, wherein the fallopian tube wall comprises a functional group selected from carboxamides and amines, said functional group forming a linker moiety between the fallopian tube wall and an active group of the extracellular matrix component, whereby the linker moiety covalently links the embolic hydrogel to the fallopian tube wall.

[0115] A thirty-seventh item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein transglutaminase catalyzes the formation of the linker moiety.

[0116] A thirty-eighth item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, further comprising denuding the fallopian tube wall prior to administering the embolic hydrogel.

[0117] A thirty-ninth item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the embolic hydrogel further comprises a therapeutic agent.

[0118] A fortieth item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the therapeutic agent is an antiinflammatory.

[0119] A forty-first item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the embolic hydrogel is formed at a pH of from about 7.0 to about 7.8.

[0120] A forty-second item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the one or more extracellular matrix components are selected from collagens, collagen derivatives, elastin, proteoglycans, fibronectin, laminins, glycosaminoglycans, or integrins.

[0121] A forty-third item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the one or more extracellular matrix proteins is collagen.

[0122] A forty-fourth item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the linker moiety is an isopeptide bond.

[0123] A forty-fifth item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the embolic hydrogel is permanent.

[0124] A forty-sixth item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the embolic hydrogel is biodegradable.

[0125] A forty-seventh item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel comprising genipin and one or more monomer units in a method for female sterilization by administering the embolic hydrogel to afallopian tube wall, wherein the fallopian tube wall comprises an amine functional group, said functional group forming a linker moiety between the fallopian tube wall and an active group of the genipin, whereby the linker moiety covalently links the embolic hydrogel to the fallopian tube wall.

[0126] A forty-eighth item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the one or more monomer units are selected from collagen, chitosan, hyaluronate amine, PEG-Amine, polyethyleneimine(PEI), PEI-g-PEG-Amine, PEI-g-PEG-Biotin, PLGA-Diamine, and PLL-PEG- amine.

[0127] A forty-ninth item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the embolic hydrogel is prepared by contacting a hydrogel precursor comprising the monomer with genipin to facilitate polymerization of the hydrogel precursor to form the embolic hydrogel.

[0128] A fiftieth item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the hydrogel precursor partially polymerizes prior to administration to the fallopian tube.

[0129] A fifty-first item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, further comprising denuding the fallopian tube wall prior to administering the embolic hydrogel.

[0130] A fifty-second item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the embolic hydrogel further comprises a therapeutic agent.

[0131] A fifty-third item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the therapeutic agent is an antiinflammatory.

[0132] A fifty-fourth item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the active group on the genipin is an ester.

[0133] A fifty-fifth item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the embolic hydrogel forms an amide bond with the fallopian tube wall.

[0134] A fifty-sixth item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the embolic hydrogel is permanent.

[0135] A fifty-seventh item of the present disclosure, alone or in combination with any other item described herein, relates to use of an embolic hydrogel, wherein the embolic hydrogel is biodegradable.

[0136] It is noted that the terms “substantially” and “about” may be utilized herein to represent the inherent degree of uncertainty that may be attributed to any quantitative comparison, value, measurement, or other representation. These terms are also utilized herein to represent the degree by which a quantitative representation may vary from a stated reference without resulting in a change in the basic function of the subject matter at issue. The term “substantially” is used herein also to represent the degree by which a quantitative representation may vary from a stated reference without resulting in a change in the basic function of the subject matter at issue. Thus, it is used to represent the inherent degree of uncertainty that may be attributed to any quantitative comparison, value, measurement, or other representation, referring to an arrangement of elements or features that, while in theory would be expected to exhibit exact correspondence or behavior, may in practice embody something less than exact.

[0137] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. The terminology used in the description herein is for describing particular embodiments only and is not intended to be limiting. As used in the specification and appended claims, the singular forms “a,” “an,” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0138] It is noted that one or more of the following claims utilize the term “wherein” as a transitional phrase. For the purposes of defining the present technology, it is noted that this term is introduced in the claims as an open-ended transitional phrase that is used to introduce a recitation of a series of characteristics of the structure and should be interpreted in like manner as the more commonly used open-ended preamble term “comprising.”

[0139] It should be understood that where a first component is described as “comprising” or “including” a second component, it is contemplated that, in some embodiments, the first component “consists” or “consists essentially of’ the second component. Additionally, the term “consisting essentially of’ is used in this disclosure to refer to quantitative values that do not materially affect the basic and novel characteristic(s) of the disclosure.

[0140] It should be understood that any two quantitative values assigned to a property or measurement may constitute a range of that property or measurement, and all combinations of ranges formed from all stated quantitative values of a given property or measurement are contemplated in this disclosure.

[0141] While particular embodiments have been illustrated and described herein, it should be understood that various other changes and modifications may be made without departing from scope of the claimed subject matter. Moreover, although various aspects of the claimed subject matter have been described herein, such aspects need not be utilized in combination. It is therefore intended that the appended claims cover all such changes and modifications that are within the scope of the claimed subject matter.

Claims

CLAIMS1. A method for female sterilization comprising administering an embolic hydrogel comprising a maleimide or a maleimide derivative to a fallopian tube wall, wherein the fallopian tube wall comprises a thiol functional group, said functional group forming a linker moiety between the fallopian tube wall and the maleimide or maleimide derivative, whereby the linker moiety covalently links the embolic hydrogel to the fallopian tube wall.

2. The method according to claim 1, wherein the embolic hydrogel is prepared by contacting a hydrogel precursor comprising a maleimide-functionalized polymer with a complexing molecule to facilitate polymerization of the hydrogel precursor to form the embolic hydrogel.

3. The method according to claim 2, wherein the maleimide-functionalized polymer and the complexing molecule are provided at a molar ratio that provides an excess of maleimide functional groups in the embolic hydrogel.

4. The method according to claim 3, wherein the excess of maleimide functional groups form the linker moiety.

5. The method according to any of claims 1-4, further comprising denuding the fallopian tube wall prior to administering the embolic hydrogel.

6. The method according to any of claims 1-4, wherein the embolic hydrogel further comprises a therapeutic agent.

7. The method according to claim 6, wherein the therapeutic agent is an anti-inflammatory.

8. The method according to any of claims 1-4, wherein the embolic hydrogel is formed at a pH of from about 6.5 to about 7.5.

9. The method according to any of claims 1-4, wherein the linker moiety is a thioether bond.

10. The method according to any of claims 1-4, wherein the embolic hydrogel is permanent.

11. The method according to any of claims 1-4, wherein the embolic hydrogel is biodegradable.

12. A method for female sterilization comprising: preparing an embolic hydrogel comprising a bromoacetyl functional group by contacting a hydrogel precursor comprising a bromoacetylated polymer with a complexing molecule to facilitate polymerization of the hydrogel precursor to form the embolic hydrogel; and administering the embolic hydrogel to a fallopian tube wall, wherein the fallopian tube wall comprises a functional group selected from thiols, amines, imidazoles, andthioethers, wherein the functional group reacts with the bromoacetyl functional group to form a linker moiety between the fallopian tube wall and the embolic hydrogel, and wherein the linker moiety covalently links the embolic hydrogel to the fallopian tube wall.

13. The method according to claim 12, wherein the bromoacetylated polymer and the complexing molecule are provided at a molar ratio that provides an excess of unreacted bromoacetyl functional groups in the embolic hydrogel.

14. The method according to claim 13, wherein the excess of unreacted bromoacetyl functional groups react with the functional group to form the linker moiety.

15. The method according to any of claims 12-14, further comprising denuding the fallopian tube wall prior to administering the embolic hydrogel.

16. The method according to any of claims 12-14, wherein the embolic hydrogel further comprises a therapeutic agent.

17. The method according to claim 16, wherein the therapeutic agent is an antiinflammatory.

18. The method according to any of claims 12-14, wherein the embolic hydrogel is formed at a pH of from about 7.5 to about 9.0.

19. The method according to any of claims 12-14, wherein the functional group is a thiol.

20. The method according to any of claims 12-14, wherein the functional group is one or more of an amine, an imidazole, a thiol, or a thioether.

21. The method according to any of claims 12-14, wherein the linker moiety is a thioether bond.

22. The method according to any of claims 12-14, wherein the linker moiety is an amide bond.

23. The method according to any of claims 12-14, wherein the embolic hydrogel is permanent.

24. The method according to any of claims 12-14, wherein the embolic hydrogel is biodegradable.

25. A method for female sterilization comprising administering an embolic composition comprising l-ethyl-3- [3 -dimethylaminopropyl] carbodiimide hydrochloride (EDC) and a monomeric component to a fallopian tube wall, wherein the fallopian tube wall comprises a functional group selected from carboxyls and primary amines, said functional group forming a linker moiety between the fallopian tube wall and an active group of the embolic composition,whereby the linker moiety covalently links the embolic composition to the fallopian tube wall, forming an embolic hydrogel.

26. The method according to claim 25, wherein the embolic hydrogel is prepared by contacting a hydrogel precursor comprising a monomer with EDC to facilitate polymerization of the hydrogel precursor to form the embolic hydrogel.

27. The method according to claim 25 or 26, further comprising denuding the fallopian tube wall prior to administering the embolic hydrogel.

28. The method according to claim 25 or 26, wherein the therapeutic agent is an antiinflammatory.

29. The method according to claim 25 or 26, wherein the embolic hydrogel is formed at a pH of about 4.5.

30. The method according to claim 25 or 26, wherein the active group of the embolic hydrogel is selected from carboxyls and primary amines.

31. The method according to claim 25 or 26, wherein the linker moiety is an amide bond.

32. The method according to claim 25 or 26, wherein the embolic hydrogel is permanent.

33. The method according to claim 25 or 26, wherein the embolic hydrogel is biodegradable.

34. The method according to claim 26, wherein the hydrogel precursor comprises a buffer or pH modifier.

35. The method according to claim 34, wherein the pH modifier is substantially free from carboxyls and amines.

36. A method for female sterilization comprising administering an embolic hydrogel comprising one or more extracellular matrix components and transglutaminase to a fallopian tube wall, wherein the fallopian tube wall comprises a functional group selected from carboxamides and amines, said functional group forming a linker moiety between the fallopian tube wall and an active group of the extracellular matrix component, whereby the linker moiety covalently links the embolic hydrogel to the fallopian tube wall.

37. The method of claim 36, wherein transglutaminase catalyzes the formation of the linker moiety.

38. The method according to claim 35 or 36, further comprising denuding the fallopian tube wall prior to administering the embolic hydrogel.

39. The method according to claim 35 or 36, wherein the embolic hydrogel further comprises a therapeutic agent.

40. The method according to claim 39, wherein the therapeutic agent is an antiinflammatory.

41. The method according to claim 35 or 36, wherein the embolic hydrogel is formed at a pH of from about 7.0 to about 7.8.

42. The method according to claim 35 or 36, wherein the one or more extracellular matrix components are selected from collagens, collagen derivatives, elastin, proteoglycans, fibronectin, laminins, glycosaminoglycans, or integrins.

43. The method according to claim 42, wherein the one or more extracellular matrix proteins is collagen.

44. The method according to claim 35 or 36, wherein the linker moiety is an isopeptide bond.

45. The method according to claim 35 or 36, wherein the embolic hydrogel is permanent.

46. The method according to claim 35 or 36, wherein the embolic hydrogel is biodegradable.

47. A method for female sterilization comprising administering an embolic hydrogel comprising genipin and one or more monomer units to a fallopian tube wall, wherein the fallopian tube wall comprises an amine functional group, said functional group forming a linker moiety between the fallopian tube wall and an active group of the genipin, whereby the linker moiety covalently links the embolic hydrogel to the fallopian tube wall.

48. The method according to claim 46, wherein the one or more monomer units are selected from collagen, chitosan, hyaluronate amine, PEG- Amine, polyethyleneimine(PEI), PEI-g-PEG- Amine, PEI-g-PEG-Biotin, PEGA-Diamine, and PLL-PEG-amine.

49. The method according to claim 46 or 47, wherein the embolic hydrogel is prepared by contacting a hydrogel precursor comprising the monomer with genipin to facilitate polymerization of the hydrogel precursor to form the embolic hydrogel.

50. The method according to claim 49, wherein the hydrogel precursor partially polymerizes prior to administration to the fallopian tube.

51. The method according to claim 46 or 47, further comprising denuding the fallopian tube wall prior to administering the embolic hydrogel.

52. The method according to claim 46 or 47, wherein the embolic hydrogel further comprises a therapeutic agent.

53. The method according to claim 46 or 47, wherein the therapeutic agent is an antiinflammatory.

54. The method according to claim 46 or 47, wherein the active group on the genipin is an ester.

55. The method according to claim 46 or 47, wherein the embolic hydrogel forms an amide bond with the fallopian tube wall.

56. The method according to claim 46 or 47, wherein the embolic hydrogel is permanent.

57. The method according to claim 46 or 47, wherein the embolic hydrogel is biodegradable.

Images