Crosslinked hydrogels with enhanced radiopacity for medical applications

Abstract

In some aspects, the present disclosure provides a hydrogel comprising (a) a reactive multi-armed polymer comprising a plurality of reactive moieties and (b) a crosslinking reaction product of a multifunctional crosslinking compound having a plurality of complementary reactive moieties that react with the reactive moieties of the reactive multi-armed polymer, the hydrogel comprising hydrolysable moieties as described herein dispersed throughout the hydrogel. Other aspects of the present disclosure relate to reactive multi-armed polymers and multifunctional crosslinking compounds for use in forming such hydrogels, as well as crosslinkable systems for forming such hydrolysable hydrogels.

Description

[0001] Cross-references to related applications This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 596,866, filed November 7, 2023, the disclosure of which is incorporated herein by reference. Technical Field

[0002] This disclosure relates to hydrolyzable hydrogels and crosslinkable systems for forming hydrolyzable hydrogels, among other aspects. The hydrogels and crosslinkable systems for forming them can be used in, for example, various medical applications. Background Technology

[0003] SpaceOAR® is a rapidly cross-linked hydrogel that polymerizes in vivo within seconds. It is based on a multi-arm polyethylene glycol (PEG) polymer functionalized with succinimidyl glutarate as the reactive end group and further cross-linked with trilysine. This product has become a highly successful clinical biomaterial in prostate cancer treatment. A further improvement to this structure is the functionalization of a portion of the succinimidyl glutarate end group with a 2,3,5-triiodobenzamide group, providing radiopaqueness. This hydrogel is marketed as SpaceOAR®Vue, a radiopaque version of SpaceOAR® for prostate medical applications. Above a specific pH value, the succinimidyl glutarate groups react rapidly in vivo with a trilysine cross-linking agent to form the hydrogel. The hydrogel decomposes in vivo within approximately 6–9 months. Decomposition primarily occurs through the hydrolysis of the ester bonds on the glutarate groups.

[0004] Currently, the use of glutarate groups in SpaceOAR® products works well because a slowly hydrolyzing hydrogel is needed to maintain the entire duration of prostate treatment. However, developing hydrogels with tunable hydrolysis rates will open the door to many applications utilizing related technologies, such as acute (short-acting) hydrogels. Acute applications here refer to hydrogels that only need to work for a short period (e.g., hours or days) before complete hydrolysis. Summary of the Invention

[0005] This disclosure provides alternatives to the aforementioned SpaceOAR® products.

[0006] In some aspects, this disclosure relates to reactive multi-arm polymers comprising a core region and a plurality of polymer arms having reactive portions, each polymer arm comprising a polymer segment connected to the core region and one of a plurality of reactive portions connected to the polymer segment via hydrolysable linkages selected from carbonate bonds, anhydride bonds, imide bonds, ketal bonds, carbamate linkages, organophosphate bonds, silane bonds, amide bonds, hydrozonium bonds, acylhydrozone bonds, oxime bonds, and amidohydrozone bonds.

[0007] In some aspects, this disclosure relates to a reactive multi-arm polymer comprising a core region and a plurality of polymer arms having reactive portions, each polymer arm comprising a polymer segment connected to the core region, one of a plurality of reactive portions connected to the polymer segment by a hydrolyzable bond, and an activating group located adjacent to the hydrolyzable bond, the activating group increasing the hydrolysis rate of the hydrolyzable bond.

[0008] In some embodiments that can be used in conjunction with the above aspects, the activating group is selected from hydrogen bond donors, hydrogen bond acceptors, lone pair electron donors, lone pair electron acceptors, silicon-containing groups, boron-containing groups, phosphonate groups, and sulfonate groups.

[0009] In some embodiments that can be used in conjunction with the above aspects and embodiments, the activating group is selected from urea bonds, urea side groups, thiourea bonds, thiourea side groups, amine bonds, amine side groups, alcohol side groups, silicon-containing bonds, silicon-containing side groups, boron-containing bonds, boron-containing side groups, phosphonate bonds, phosphonate side groups, and sulfonate side groups.

[0010] In some embodiments that can be used in conjunction with the above aspects and implementation schemes, the activating group is complexed with the hydrolyzable bond to form a 4-9 membered cyclic transition state.

[0011] In some embodiments that can be used in conjunction with the above aspects and embodiments, the reactive portion is selected from reactive portions containing electrophilic groups, reactive portions containing nucleophilic groups, reactive portions containing diene groups, reactive portions containing dienophilic groups, reactive portions containing alkenyl groups, reactive portions containing strained alkyne groups, reactive portions containing azide groups, reactive portions containing ketone groups, reactive portions containing aldehyde groups, and reactive portions containing acrylate groups.

[0012] In some embodiments that can be used in conjunction with the above aspects and embodiments, the polymer segment is selected from polyoxyalkylene segments, polyester segments, polyoxazoline segments, polydioxanone segments, and polypeptide segments.

[0013] In some embodiments that can be used in conjunction with the above aspects and implementation methods, the polymer segment contains 10 to 1000 monomer residues.

[0014] In some embodiments that can be used in conjunction with the above aspects and implementation methods, the core region includes residues of a polyol containing three to twenty hydroxyl groups.

[0015] In some aspects, this disclosure relates to hydrogels formed by covalently crosslinking (a) a reactive multi-arm polymer according to any of the foregoing aspects and embodiments with (b) a multifunctional crosslinking compound comprising a plurality of complementary reactive portions, each of which reacts with a reactive portion of the reactive multi-arm polymer.

[0016] In some aspects, this disclosure relates to a system for forming a hydrogel composition comprising (a) a reactive multi-arm polymer according to any of the foregoing aspects and embodiments, and (b) a multifunctional crosslinking compound comprising a plurality of complementary reactive portions that react with the reactive portion of the reactive multi-arm polymer.

[0017] In some aspects, this disclosure relates to a system for forming a hydrogel composition comprising: (a) a reactive multi-arm polymer having a core region and a plurality of polymer arms having reactive portions, each polymer arm comprising a polymer segment connected to the core region and one of a plurality of reactive portions connected to the polymer segment; and (b) a polyfunctional crosslinking compound comprising a plurality of complementary reactive portions reacting with the reactive portions of the reactive multi-arm polymer, wherein each of the plurality of complementary reactive portions is connected to the remainder of the polyfunctional crosslinking compound by a hydrolyzable bond selected from carbonate bonds, anhydride bonds, imide bonds, ketal bonds, urethane bonds, organophosphate bonds, silane bonds, amide bonds, hydrazone bonds, acylhydrazone bonds, oxime bonds, and amide hydrazone bonds.

[0018] In some aspects, this disclosure relates to a system for forming a hydrogel composition comprising: (a) a reactive multi-arm polymer having a core region and a plurality of polymer arms having reactive portions, each polymer arm comprising a polymer segment connected to the core region and one of a plurality of reactive portions connected to the polymer segment; and (b) a multifunctional crosslinking compound comprising a plurality of complementary reactive portions reacting with the reactive portions of the reactive multi-arm polymer, wherein each of the plurality of complementary reactive portions is connected to the remainder of the multifunctional crosslinking compound via a hydrolyzable bond, and wherein the multifunctional crosslinking compound further comprises an activating group located adjacent to the hydrolyzable bond, which increases the hydrolysis rate of the hydrolyzable bond.

[0019] In some embodiments, the activating group of the multifunctional crosslinked compound is selected from hydrogen bond donors, hydrogen bond acceptors, lone pair electron donors, lone pair electron acceptors, silicon-containing groups, boron-containing groups, phosphonate groups, and sulfonate groups.

[0020] In some embodiments that can be used in conjunction with the above aspects and embodiments, the activating group of the multifunctional crosslinked compound is selected from urea bonds, urea side groups, thiourea bonds, thiourea side groups, amine bonds, amine side groups, alcohol side groups, silicon-containing bonds, silicon-containing side groups, boron-containing bonds, boron-containing side groups, phosphonate bonds, phosphonate side groups, and sulfonate side groups.

[0021] In some embodiments that can be used in conjunction with the above aspects and embodiments, the activating group of the multifunctional crosslinked compound complexes with the hydrolyzable bond to form a 4-9 membered cyclic transition state.

[0022] In some embodiments that can be used in conjunction with the above aspects and embodiments, the plurality of reactive portions are selected from reactive portions containing electrophilic groups, reactive portions containing nucleophilic groups, reactive portions containing diene groups, reactive portions containing dienophilic groups, reactive portions containing alkenyl groups, reactive portions containing tonicynyl groups, reactive portions containing azide groups, reactive portions containing ketone groups, reactive portions containing aldehyde groups, and reactive portions containing acrylate groups.

[0023] In some embodiments that can be used in conjunction with the above aspects and embodiments, the plurality of complementary reactive portions are selected from reactive portions containing electrophilic groups, reactive portions containing nucleophilic groups, reactive portions containing diene groups, reactive portions containing dienophilic groups, reactive portions containing alkenyl groups, reactive portions containing tonicynyl groups, reactive portions containing azide groups, reactive portions containing ketone groups, reactive portions containing aldehyde groups, and reactive portions containing acrylate groups.

[0024] In some embodiments that can be used in conjunction with the above aspects and implementations, the system further includes a delivery device configured to simultaneously deliver the reactive multiarm polymer and the multifunctional crosslinked compound to the patient under conditions of covalent crosslinking of the reactive multiarm polymer and the multifunctional crosslinked compound.

[0025] In some aspects, this disclosure relates to hydrogels formed by covalently crosslinking a reactive multiarm polymer of the system according to any of the foregoing aspects and embodiments with a multifunctional crosslinking compound of the system according to the foregoing aspects and embodiments.

[0026] The above and other aspects, implementations, features and benefits of this disclosure will become apparent from the following detailed description. Attached Figure Description

[0027] Figure 1 A delivery device according to an embodiment of the present disclosure is illustrated schematically.

[0028] Figure 2 A delivery device according to another embodiment of this disclosure is schematically shown. Detailed Implementation

[0029] In some aspects, this disclosure provides a hydrogel comprising: (a) a reactive multi-arm polymer and (b) a crosslinking reaction product of a multifunctional crosslinking compound, wherein the polymer arms of the reactive multi-arm polymer comprise polymer segments with one end connected to a core region and the opposite end connected to a reactive portion, and the multifunctional crosslinking compound has a plurality of complementary reactive portions that react with the reactive portion of the reactive multi-arm polymer.

[0030] In various embodiments, the hydrogel comprises a hydrolyzable portion, as described herein, dispersed throughout the hydrogel. As further described below, the hydrolyzable portion may be provided either in combination with a reactive multi-arm polymer or with a multifunctional crosslinking compound.

[0031] In some embodiments, the hydrolyzable portion comprises a hydrolyzable bond, which may be selected from groups such as carboxylic acid ester bonds. carbonate bonds acid anhydride bond imide bond ketal bond urethane bond Organic phosphate bonds Silane bond amide bond , hydradenoids Acylhydrazone bond oxime or amide hydrazone bond .

[0032] In some embodiments, the hydrolyzable portion may further include an activating group located near the hydrolyzable bond to modulate the hydrolysis rate of the hydrolyzable bond, and in certain embodiments, to increase the hydrolysis rate of the hydrolyzable bond. Examples of activating groups include electron-donating and electron-withdrawing activating groups that can promote hydrolysis, either by binding to and orienting water for subsequent attack, or by directly binding to an easily hydrolyzable linker to accelerate and modulate the reaction rate. These activating groups can function, for example, through mechanisms such as hydrogen bond donation, electrostatic stabilization, metal / ligand interactions, and lone pair electron donation.

[0033] Specific examples of activating groups include hydrogen bond donors / acceptors or lone pair electron donors, which can complex with hydrogen bond acceptors / donors or lone pair electron acceptors. In this regard, it is noted that water is both a hydrogen bond donor and acceptor, with each water molecule possessing two lone pairs of electrons that can act as hydrogen bond acceptors and two OH bonds that provide a pair of hydrogen bond donors. Specific examples of such activating groups are ureas, thioureas, alcohols, and amines, which can provide a urea bond. Urea side group (where R is H), thiourea bond Thiourea side groups (where R is H), amine bond (where R is H), amine side group (where R is H) and alcohol side groups (e.g., hydroxyalkyl groups having 1 to 7 carbon atoms).

[0034] Specific examples of activating groups also include lone pair acceptors in the form of an uncharged portion capable of complexing with lone pair electron donors including water molecules. Specific examples of such activating groups are silicon-containing and boron-containing groups, for example, and can be provided in the form of silicon bonds. (where R is methyl), containing silicon side groups (where R is methyl), boron bond (where R is aryl or alkyl) and boron-containing side groups (where R is an aryl or alkyl functional group, most preferably an electron-deficient aryl or alkyl group).

[0035] Specific examples of activating groups further include water complexes or electrostatic stabilizers (e.g., those that can position water at an adjacent charged portion). Specific examples of such activating groups are phosphonate groups and sulfonate groups, which can be provided in the form of a phosphonate bond. Phosphate side groups (where R is OH, alkyl, or aryl) and sulfonate side groups .

[0036] In some embodiments, activating groups are introduced such that they complex with hydrolyzable bonds to form cyclic transition states, specifically 4-9 membered cyclic transition states. For example, the activating groups may be linked by aromatic ring spacers, cycloaliphatic ring spacers, aliphatic spacers, or heteroatom spacers. The spacer length leading to the 4-9 membered cyclic transition state can be 1-6 atoms.

[0037] The reactive multi-arm polymer according to this disclosure also includes a polymer comprising a plurality of polymer arms connected to a core region. The reactive multi-arm polymer may have two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-five, thirty or more polymer arms.

[0038] As discussed in more detail below, in some embodiments, the core region contains residues of a polyfunctional initiator, specifically, residues of a polyol initiator having two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-five, thirty or more hydroxyl groups, wherein the number of polymer arms corresponds to the number of functional groups in the initiator used to form the reactive multi-armed polymer, specifically, the number of hydroxyl groups.

[0039] The polymer arms of a reactive multi-arm polymer may each contain a polymer chain segment connected to the core region and a terminal reactive portion.

[0040] In some embodiments, a hydrolyzable portion comprising hydrolyzable bonds as described above is provided between the reactive portion and the polymer segment.

[0041] The reactive portion can be selected from reactive portions containing electrophilic groups, reactive portions containing nucleophilic groups, reactive portions containing diene groups, reactive portions containing dienophilic groups, reactive portions containing alkenyl groups, reactive portions containing stress alkyne groups, reactive portions containing azide groups, reactive portions containing ketone groups, reactive portions containing aldehyde groups, and reactive portions containing acrylate groups, etc.

[0042] Electrophilic groups include cyclic imide ester groups, including succinimide ester groups, Maleimide ester group, glutarimide ester group, diethylene glycol imide ester group, phthalimide ester group, and bicyclic [2.2.1]hept-5-ene-2,3-dicarboxylic acid imide ester group, Imidazole ester groups, imidazole carboxylate ester groups, and benzotriazole ester groups, as well as other possibilities. Nucleophilic groups include primary amino groups, thiols, and hydroxyl groups, as well as other possibilities. Diene-containing groups include furanyl and tetraazinyl. Dienophilic groups include norbornenyl and maleimide groups. Alkenyl-containing groups include vinyl, acryloyl, methacryloyl, and tonicenyl, such as groups derived from cyclooctyl-4-en-1-yl. And other possibilities. Strained ynyl groups include (1R,8S,9S)-bicyclo[6.1.0]non-4-yn-9-yl, And other possibilities.

[0043] The polymer segments used for the polymer arm can be selected from a variety of synthetic, natural, or synthetic-natural hybrid polymer segments. Examples of polymer segments include those formed from one or more monomers selected from: C1-C6-epoxides (e.g., ethylene oxide, propylene oxide, tetramethylene oxide, etc.), cyclic ester monomers (e.g., glycolide, lactide, β-propiolactone, β-butyrolactone, γ-butyrolactone, γ-valerolactone, δ-valerolactone, ε-caprolactone, etc.), and oxazoline monomers (e.g., oxazoline and 2-alkyl-2-oxazoline, such as 2-(C1-C6 alkyl)-2-oxazoline, including various isomers such as 2-methyl-2-oxazoline). 2-Ethyl-2-oxazoline, 2-n-propyl-2-oxazoline, 2-isopropyl-2-oxazoline, 2-n-butyl-2-oxazoline, 2-isobutyl-2-oxazoline, 2-hexyl-2-oxazoline, etc.), 2-phenyl-2-oxazoline, polar aprotic vinyl monomers (such as N-vinylpyrrolidone, acrylamide, N-methylacrylamide, dimethylacrylamide, N-vinylimidazolium, 4-vinylimidazolium, sodium 4-vinylbenzenesulfonate, etc.), dioxanehexanone, N-isopropylacrylamide, amino acids and sugars.

[0044] The polymer segments may be selected, for example, from the following polymer segments: polyether segments, including poly(C1-C6-epoxyalkylene) segments, such as poly(ethylene oxide) (PEO) (also known as polyethylene glycol or PEG) segments, poly(propylene oxide) segments, and poly(ethylene oxide-co-propylene oxide) segments; polyester segments, including polyglycolic acid segments, polylactide segments, poly(lactide-co-glycolic acid) segments, poly(β-propiolactone) segments, poly(β-butyrolactone) segments, poly(γ-butyrolactone) segments, poly(γ-valerolactone) segments, poly(δ-valerolactone) segments, and poly(ε-caprolactone) segments; and polyoxazoline segments, including poly(2-C1-C6-alkyl-2-oxazoline) segments, such as poly(2-methyl-2-oxazoline). Polymer segments formed from one or more polar aprotic vinyl monomers, including poly(N-vinylpyrrolidone) segments, poly(acrylamide) segments, poly(N-methacrylamide) segments, poly(dimethacrylamide) segments, poly(N-vinylimidazolium) segments, poly(4-vinylimidazolium) segments, and poly(4-vinylbenzenesulfonate) segments; polydioxane segments, poly(N-isopropylacrylamide) segments, polypeptide segments, and polysaccharide segments.

[0045] The polymer segments used in the reactive multi-arm polymers of this disclosure typically contain 10 to 1000 monomer units or more.

[0046] As previously described, in various embodiments, the reactive multi-arm polymer of this disclosure has two or more polymer arms extending from a core region. In some of these embodiments, the core region includes residues of a polyol containing two or more hydroxyl groups for forming the polymer arms. In some advantageous embodiments, the core region includes residues of a polyol containing two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-five, thirty, or more hydroxyl groups.

[0047] Exemplary polyols may be selected from, for example, straight-chain, branched, and cyclic aliphatic polyols (including straight-chain, branched, and cyclic polyhydroxy alkanes), straight-chain, branched, and cyclic polyhydroxy ethers (including polyhydroxy polyethers), straight-chain, branched, and cyclic polyhydroxy alkyl ethers (including polyhydroxy alkyl polyethers), straight-chain, branched, and cyclic sugars and sugar alcohols (e.g., glycerol, mannitol, sorbitol, inositol, xylitol, styraxyl alcohol, threitol, arabinol, erythritol, pentaerythritol, dipentaerythritol, tripentaerythritol, arabinol, hexamethylenetetramine, galactitol, fucose, ribose, arabinose, xylose, lysolose, rhamnose, galactose, glucose, fructose, etc.). Sorbitol, mannose, pyranose, azoose, tarose, tagatose, pyranoside, sucrose, lactose, and maltose; polymers of linear, branched, and cyclic sugars and sugar alcohols (defined herein as two or more units) (including oligomers of linear, branched, and cyclic sugars and sugar alcohols (defined herein as two to ten units, including dimers, trimers, tetramers, pentamers, hexamers, heptomers, octamers, nonamermers, and decamers); sugars and sugar alcohols including the aforementioned sugars and sugar alcohols; starch, amylose, dextrin, cyclodextrin, polyhedral oligosilsesquioxanes (POSS), catechins, flavanols, anthocyanins, stilbenes, polyphenols, and polyhydroxy crown ethers and polyhydroxyalkyl crown ethers). Exemplary polyols also include aromatic polyols, including 1,1,1-tris(4'-hydroxyphenyl)alkanes, such as 1,1,1-tris(4-hydroxyphenyl)ethane and 2,6-bis(hydroxyalkyl)cresol.

[0048] In some embodiments, iodinated polyols may be employed to impart radiation-impermeable properties to all multi-arm polymers. In some of these embodiments, the iodinated polyol is a compound comprising three or more hydroxyl groups and one or more iodinated aromatic groups. Examples of iodinated aromatic groups include iodine-substituted monocyclic aromatic groups and iodine-substituted polycyclic aromatic groups, such as iodine-substituted phenyl, iodine-substituted naphthyl, iodine-substituted anthraceneyl, iodine-substituted phenanthryl, and iodine-substituted tetraphenyl, etc. The aromatic group may be substituted with one, two, three, four, five, six, or more iodine atoms. In various embodiments, the aromatic group is further substituted with three or more hydroxyl groups, which may be directly substituted to the aromatic group or may be provided in the form of hydroxyalkyl groups (e.g., C1-C4-hydroxyalkyl groups containing 1, 2, 3, or 4 carbon atoms and containing 1, 2, 3, or 4 or more hydroxyl groups). The hydroxyalkyl group may be directly attached to the aromatic group or via any suitable linking moiety selected from, for example, amide, amino, ether, ester, or carbonate groups. Specific examples of iodinated polyols used in this disclosure include known iodinated contrast agents whose biocompatibility has been shown to be quite well tolerated, including iopromide, iopamidol, iohexol, iofluridine, and iodixanol.

[0049] In a specific embodiment where an ester is selected as the hydrolyzable bond, the terminal hydroxyl group of the polymer segment can react with an acyclic anhydride compound (e.g., glutaric anhydride, succinic anhydride, malonic anhydride, adipic anhydride, diethylene glycol anhydride, 1,3-acetone dicarboxylic anhydride, etc.) to form an acid-terminated polymer segment, such as a glutaric acid-terminated segment, a succinic acid-terminated segment, a malonic acid-terminated segment, an adipic acid-terminated segment, a diethylene glycol-terminated segment, a 1,3-acetone dicarboxylic anhydride-terminated segment, etc.

[0050] The aforementioned cyclic anhydrides can react with hydroxyl-terminated multi-arm hydrophilic precursor polymers under alkaline conditions to form carboxylic acid-terminated precursor polymers, which contain carboxylic acid end groups connected to polymer segments via hydrolyzable ester groups.

[0051] The reactive portion can then be attached to a carboxylic acid-terminated precursor polymer. For example, in a specific embodiment employing a cyclic imide ester group as the reactive group, an N-hydroxy cyclic imide compound (e.g., N-hydroxysuccinimide, N-hydroxymaleimide, N-hydroxyglutarimide, N-hydroxyphthalimide, N-hydroxy-5-norbornene-2,3-dicarboxylic acid imide, also known as N-hydroxybicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid imide (HONB), etc.) can be coupled in a suitable coupling agent (e.g., a carbodiimide coupling agent, such as N,N'-dicyclohexylcarbodiimide). In the presence of imines (DCC), 1-ethyl-3-(3-dimethylpropyl)carbodiimide (EDC), N-hydroxybenzotriazole (HOBt), BOP reagent, and / or other coupling agents, a carboxylic acid-terminated precursor polymer is reacted to form reactive cyclic imide ester groups (e.g., succinimide ester groups, maleimide ester groups, glutarimide ester groups, phthalimide ester groups, bicyclic [2.2.1]hept-5-ene-2,3-dicarboxylic acid imide ester groups, etc.), which are linked to polymer segments via hydrolyzable ester groups. In this way, many reactive diester groups can be formed.

[0052] For example, in the specific case of N-hydroxysuccinimide as an N-hydroxycyclic imide compound, exemplary reactive end groups include succinimide malonate group, succinimide glutarate group, succinimide succinate group, succinimide adipate group, succinimide diglycolate group, and succinimide 1,3-acetone dicarboxylate group (the 1,3-acetone dicarboxylate group may also be referred to herein as the 3-oxoglutarate group), etc. In the specific case of HONB as an N-hydroxycyclic imide compound, exemplary reactive end groups include bicyclic [2.2.1]hept-5-ene-2,3-dicarboxylic acid imide malonic acid ester group, bicyclic [2.2.1]hept-5-ene-2,3-dicarboxylic acid imide glutarate ester group, bicyclic [2.2.1]hept-5-ene-2,3-dicarboxylic acid imide succinate group, bicyclic [2.2.1]hept-5-ene-2,3-dicarboxylic acid imide adipic acid ester group, bicyclic [2.2.1]hept-5-ene-2,3-dicarboxylic acid imide diglycol ester group, and bicyclic [2.2.1]hept-5-ene-2,3-dicarboxylic acid imide 1,3-propanone dicarboxylic acid ester group, etc. In the specific case of N-hydroxymaleimide as an N-hydroxy cyclic imide compound, exemplary reactive end groups include maleimide malonate group, maleimide glutarate group, maleimide succinate group, maleimide adipate group, maleimide diglycol ester group, and maleimide 1,3-acetone dicarboxylate group, etc. In the specific case where N-hydroxyphthalimide is an N-hydroxycyclic imide compound, exemplary reactive end groups include phthalimide malonate group, phthalimide glutarate group, phthalimide succinate group, phthalimide adipate group, phthalimide diglycol ester group, and phthalimide 1,3-acetone dicarboxylic acid ester group, etc.

[0053] Hydrolyzable moieties containing hydrolyzable bonds other than the ester bonds described above can also be inserted into the arms of reactive multi-arm polymers using various suitable chemical methods. For example, such hydrolyzable moieties can be inserted between the polymer segments described herein and the reactive moieties described herein. Such hydrolyzable bonds can be selected from, for example, ester bonds, carbonate bonds, anhydride bonds, imide bonds, ketal bonds, urethane bonds, organophosphate bonds, silane bonds, amide bonds, hydrazone bonds, acylhydrazone bonds, oxime bonds, and amide hydrazone bonds other than those described above.

[0054] Furthermore, as described above, such a hydrolyzable portion may further include an activating group located adjacent to the hydrolyzable bond, which increases the hydrolysis rate of the hydrolyzable bond. Specific examples of activating groups include, for example, urea bonds, urea side groups, thiourea bonds, thiourea side groups, amine bonds, amine side groups, alcohol side groups, silicon-containing bonds, silicon-containing side groups, boron-containing bonds, boron-containing side groups, phosphonate bonds, phosphonate side groups, and sulfonate side groups as described above.

[0055] In some aspects, this disclosure provides a hydrogel comprising (a) a reactive multiarm polymer as described herein and (b) a crosslinking reaction product of a multifunctional crosslinking compound having a plurality of complementary reactive moieties that react with the reactive moieties of the reactive multiarm polymer.

[0056] In some aspects, this disclosure provides a hydrogel comprising (a) a reactive multi-arm polymer and (b) a crosslinking reaction product of a multifunctional crosslinking compound, wherein the polymer arms of the reactive multi-arm polymer comprise polymer segments connected at one end to a core region and at the opposite end to a reactive portion, and the multifunctional crosslinking compound has a plurality of complementary reactive portions that react with the reactive portions of the reactive multi-arm polymer.

[0057] In some implementations, the hydrogel decomposes in vivo over a period of 2 days or less to 80 weeks or longer, for example, 2 to 4 days to 1 week to 2 weeks to 4 weeks to 10 weeks to 20 weeks to 40 weeks to 80 weeks (i.e., between any two or more of the aforementioned time periods).

[0058] For example, crosslinking reaction products can be formed from: reactive multi-arm polymers having electrophilic groups and multifunctional crosslinked compounds having nucleophilic groups; reactive multi-arm polymers having nucleophilic groups and multifunctional crosslinked compounds having electrophilic groups; reactive multi-arm polymers having diene groups and multifunctional crosslinked compounds having diene groups; reactive multi-arm polymers having diene groups and multifunctional crosslinked compounds having diene groups; reactive multi-arm polymers having tonicynyl groups and multifunctional crosslinked compounds having azide groups; reactive multi-arm polymers having azide groups and multifunctional crosslinked compounds having tonicynyl groups; reactive multi-arm polymers having tonicene groups and multifunctional crosslinked compounds having tetrazine groups; reactive multi-arm polymers having tetrazine groups and multifunctional crosslinked compounds having tonicene groups; reactive multi-arm polymers having olefin groups and multifunctional crosslinked compounds having thiol groups; and reactive multi-arm polymers having thiol groups and multifunctional crosslinked compounds having olefin groups.

[0059] In some embodiments, the hydrolyzable portion containing the hydrolyzable bond can be positioned within the complementary reactive portion of the multifunctional crosslinked compound (e.g., where the complementary reactive portions are each connected to the remainder of the multifunctional crosslinked compound via a hydrolyzable bond). As described above, the hydrolyzable bond can be selected from, for example, ester bonds, carbonate bonds, anhydride bonds, imide bonds, ketal bonds, urethane bonds, organophosphate bonds, silane bonds, amide bonds, hydrazone bonds, acylhydrazone bonds, oxime bonds, and amide hydrazone bonds.

[0060] Furthermore, such a hydrolyzable portion may further include an activating group located adjacent to the hydrolyzable bond, which increases the hydrolysis rate of the hydrolyzable bond. Specific examples of activating groups include, for example, urea bonds, urea side groups, thiourea bonds, thiourea side groups, amine bonds, amine side groups, alcohol side groups, silicon-containing bonds, silicon-containing side groups, boron-containing bonds, boron-containing side groups, phosphonate bonds, phosphonate side groups, and sulfonate side groups as described above.

[0061] In some embodiments, iodinated polyfunctional crosslinked compounds can be used to provide radiation impermeability. In some of these embodiments, the iodinated polyfunctional crosslinked compound is a compound comprising three or more complementary reactive moieties and one or more iodinated aryl groups, said complementary reactive moieties reacting with the reactive moieties of a reactive multi-arm polymer. Examples of iodinated aromatic groups include iodine-substituted monocyclic aromatic groups and iodine-substituted polycyclic aromatic groups, such as iodine-substituted phenyl, iodine-substituted naphthyl, iodine-substituted anthraceneyl, iodine-substituted phenanthryl, and iodine-substituted tetraphenyl, etc. The aromatic group can be substituted with one, two, three, four, five, six, or more iodine atoms. In various embodiments, the aromatic group is further substituted with three or more hydroxyl groups, which can be directly substituted onto the aromatic group or can be provided in the form of hydroxyalkyl groups (e.g., C1-C4-hydroxyalkyl groups containing 1, 2, 3, or 4 carbon atoms and containing 1, 2, 3, or 4 or more hydroxyl groups). The hydroxyalkyl group can be attached to the aromatic group directly or through any suitable linker, which can be selected from, for example, amide, amino, ether, ester or carbonate groups.

[0062] In some aspects of this disclosure, systems configured to deliver (a) the reactive multi-arm polymer described herein and (b) the polyfunctional crosslinked compound described herein are provided. The reactive multi-arm polymer and the polyfunctional crosslinked compound are blended under certain conditions such that the reactive portion of the reactive multi-arm polymer reacts with the complementary reactive portion of the polyfunctional crosslinked compound to form a covalent bond. Such systems can be used to form crosslinked hydrogels in vivo or in vitro.

[0063] In some aspects of this disclosure, a system is provided comprising: (a) a first composition comprising the reactive multiarm polymer described herein, and (b) a second composition comprising the polyfunctional crosslinking compound described herein. For example, the first and second compositions may be a first fluid composition and a second fluid composition, wherein when the first and second fluid compositions are mixed, covalent bonds are formed between the reactive multiarm polymer and the polyfunctional crosslinking compound, resulting in a crosslinking reaction product of the reactive multiarm polymer and the polyfunctional crosslinking compound.

[0064] In some embodiments, the provided system includes: (a) a first composition comprising a reactive multi-arm polymer and a polyfunctional crosslinking compound, and (b) a second composition comprising an accelerator that accelerates the crosslinking reaction between the reactive multi-arm polymer and the polyfunctional crosslinking compound. For example, the first composition may be a fluid composition wherein the reactive multi-arm polymer and the polyfunctional crosslinking compound are mixed under conditions where crosslinking between the reactive portion of the reactive multi-arm polymer and the complementary reactive portion of the polyfunctional crosslinking compound is inhibited, and the second composition may be a fluid composition that, when mixed with the first fluid composition, results in the formation of covalent bonds between the reactive multi-arm polymer and the polyfunctional crosslinking compound, resulting in a crosslinking reaction product of the reactive multi-arm polymer and the polyfunctional crosslinking compound. In some embodiments, a promoter in the second fluid composition alters the pH of the first fluid composition, leading to crosslinking between the reactive multi-arm polymer and the polyfunctional crosslinking compound.

[0065] The first composition can be a first fluid composition or a first dry composition. A suitable fluid, such as water for injection or a saline solution, can be added to the first dry composition to form the first fluid composition. The second composition can be a second fluid composition independently, or it can be a second dry composition. A suitable fluid, such as water for injection or a saline solution, can be added to the second dry composition to form the second fluid composition. The first and second compositions can be provided independently in vials, syringes, or other containers.

[0066] The first and second compositions may further comprise additives, including therapeutic agents, imaging agents, colorants, tension modifiers, suspending agents, wetting agents, and pH adjusters.

[0067] Examples of therapeutic agents include antithrombotic agents, anticoagulants, antiplatelet agents, thrombolytic agents, antiproliferative agents, anti-inflammatory agents, proliferative inhibitors, anti-restenosis agents, smooth muscle cell inhibitors, antibiotics, antibacterial agents, analgesics, anesthetics, growth factors, growth factor inhibitors, cell adhesion inhibitors, cell adhesion promoters, anti-angiogenic agents, cytotoxic agents, chemotherapeutic agents, checkpoint inhibitors, immunomodulatory cytokines, T-cell agonists, STING (interferon gene stimulator) agonists, antimetabolites, alkylating agents, microtubule inhibitors, hormones, hormone antagonists, monoclonal antibodies, antimitotic drugs, immunosuppressants, tyrosine and serine / threonine kinases, proteasome inhibitors, matrix metalloproteinase inhibitors, Bcl-2 inhibitors, DNA alkylating agents, spindle poisons, poly(DP-ribose) polymerase (PARP) inhibitors, and combinations thereof.

[0068] Other specific examples of imaging agents include (a) fluorescent dyes such as fluorescein, indocyanine green, or fluorescent proteins (e.g., green, blue, and blue-green fluorescent proteins), (b) contrast agents used in conjunction with magnetic resonance imaging (MRI), including contrast agents containing elements that form paramagnetic ions, such as Gd(III), Mn(II), Fe(III), and compounds containing them (including chelates), such as gadolinium ions chelated with diethylenetriaminepentaacetic acid, and (c) contrast agents used in conjunction with ultrasound imaging, including organic and inorganic echogenic particles (i.e., particles that result in increased reflected ultrasound energy) or organic and inorganic echolucent particles. (d) Contrast agents used in conjunction with near-infrared (NIR) imaging, which may be selectively used to impart near-infrared fluorescence to the hydrogel of this disclosure, thereby allowing for deep tissue imaging and device labeling, such as NIR-sensitive nanoparticles, such as gold nanoshells, carbon nanotubes (e.g., nanotubes derived with hydroxyl or carboxyl groups, such as partially oxidized carbon nanotubes), dye-containing nanoparticles, such as dye-doped nanofibers and dye-encapsulated nanoparticles, and semiconductor quantum dots, etc., and NIR-sensitive dyes, such as cyanine dyes. (e) Imageable radioactive isotopes, including 99mTc, 201Th, 51Cr, 67Ga, 68Ga, 111In, 64Cu, 89Zr, 59Fe, 42K, 82Rb, 24Na, 45Ti, 44Sc, 51Cr and 177Lu, and (f) radioactive contrast agents, such as metal particles, such as particles of tantalum, tungsten, rhenium, niobium, molybdenum and their alloys, wherein the metal particles may be spherical or non-spherical. Other examples of contrast agents include nonionic contrast agents such as iohexol, iodixanol, iofluoxetine, iopamidol, ioxilan, or iopromide; ionic contrast agents such as diatrizoate, iothalamate, metrizoate, or ioxaglate; and iodized oils, including ethiodized poppyseed oil (available as Lipiodol®).

[0069] Examples of colorants include Brilliant Blue (e.g., Brilliant Blue FCF, also known as FD&C Blue 1), Indigo Carmine (also known as FD&C Blue 2), Indigo Carmine Lake, FD&C Blue 1 Lake, and Methylene Blue (also known as Methylene Blue Chloride), etc.

[0070] Examples of additives also include tension modifiers such as sugars (e.g., glucose, lactose, etc.), polyols (e.g., glycerol, propylene glycol, mannitol, sorbitol, etc.) and inorganic salts (e.g., potassium chloride, sodium chloride, etc.), suspending agents including various surfactants, wetting agents and polymers (e.g., albumin, PEO, polyvinyl alcohol, block polymers, etc.), and pH adjusters including various buffer solutes.

[0071] In various embodiments, a system is provided that includes one or more delivery devices for delivering a first fluid composition and a second fluid composition to a subject. Preferred subjects include mammalian subjects, particularly human subjects.

[0072] In some embodiments, the system may include a delivery device comprising a first reservoir and a second reservoir. The first reservoir contains a first fluid composition comprising the reactive multiarm polymer as described above, and the second reservoir contains a second fluid composition comprising the polyfunctional crosslinking compound as described above. When the first fluid composition and the second fluid composition are mixed, crosslinking occurs between the reactive multiarm polymer and the polyfunctional crosslinking compound.

[0073] In some embodiments, the system may include a delivery device comprising a first reservoir and a second reservoir. The first reservoir contains a first fluid composition comprising a reactive multi-arm polymer and a multifunctional crosslinking compound, and the second reservoir contains a second fluid composition as a accelerator composition. When mixed with the first fluid composition, the second fluid composition causes crosslinking between the reactive multi-arm polymer and the multifunctional crosslinking compound.

[0074] In either case, during operation, the first composition and the second composition are dispensed from the first reservoir and the second reservoir and combined, thereby crosslinking the multifunctional crosslinked compound and the reactive multiarm polymer with each other to form a crosslinked hydrogel.

[0075] In the specific implementation plan, and referring to Figure 1The system may include a delivery device 110 comprising a dual-tube syringe, the syringe including a first tube 112a having a first tube outlet 114a (the first tube containing a first fluid composition and a first plunger 116a movable within the first tube 112a), and a second tube 112b having a second tube outlet 114b (the second tube 112b containing a second fluid composition and a second plunger 116b movable within the second tube 112b). In some embodiments, the device 110 may further include a mixing section 118 having a first mixing section inlet 118a1 in fluid communication with the first tube outlet 114a, a second mixing section inlet 118b1 in fluid communication with the second tube outlet, and a mixing section outlet 118o. Also shown are a syringe holder 122 configured to maintain a fixed relationship between the first and second syringe tubes 112a, 112b, and a plunger cap 124 configured to maintain a fixed relationship between the first and second plungers 116a, 116b.

[0076] In some embodiments, the delivery device may also include a cannula or conduit configured to receive a first fluid composition and a second fluid composition from a first tube and a second tube. For example, the cannula or conduit may be configured to form a fluid connection with the outlet of the mixing section by attaching the cannula or conduit to the outlet of the mixing section (e.g., via a suitable fluid connector such as a Luer connector).

[0077] As another example, the catheter may be a multi-lumen catheter including a first lumen and a second lumen, the proximal end of the first lumen being configured to form a fluid connection with a first tube outlet, and the proximal end of the second lumen being configured to form a fluid connection with a second tube outlet. In some embodiments, the multi-lumen catheter may include a mixing portion having a first mixing portion inlet in fluid communication with the distal end of the first lumen, a second mixing portion inlet in fluid communication with the distal end of the second lumen, and a mixing portion outlet.

[0078] During operation, when the first and second plungers are depressed, a first fluid composition and a second fluid composition are dispensed from the first and second tubes. The first and second fluid compositions then interact and eventually crosslink to form a crosslinked hydrogel, which is applied to or into the subject's tissue. For example, the first and second fluid compositions may enter a mixing section from the first and second tubes via a first mixing section inlet and a second mixing section inlet, whereby the first and second fluid compositions mix to form a mixture, which exits the mixing section via a mixing section outlet. In some embodiments, a cannula or catheter is attached to the mixing section outlet, thereby allowing the mixture to be applied to the subject after passing through the cannula or catheter.

[0079] As another example, a first fluid composition may enter a first lumen of the multi-lumen catheter from a first tube outlet, and a second fluid composition may enter a second lumen of the multi-lumen catheter from a second tube outlet. In some embodiments, the first fluid composition and the second fluid composition may enter a mixing section at the distal end of the multi-lumen catheter from the first lumen and the second lumen, respectively, via a first mixing section inlet and a second mixing section inlet, whereby the first fluid composition and the second fluid composition mix to form a mixture, which exits the mixing section via a mixing section outlet.

[0080] Regardless of the type of apparatus used to mix the first and second fluid compositions, or how the first and second fluid compositions are mixed, after the mixture of the first and second fluid compositions is formed, the mixture may initially be in a fluid state and can be applied to a subject (e.g., a mammal, particularly a human) by various techniques. Alternatively, the first and second fluid compositions may be applied to the subject independently, and the fluid mixture of the first and second fluid compositions is formed inside or on the surface of the subject. In either method, the fluid mixture of the first and second fluid compositions is formed and used in various medical procedures.

[0081] For example, in applications such as the treatment of diseases and cancers, as well as tissue repair and regeneration, the first fluid composition and the second fluid composition, or a fluid mixture thereof, can be injected to provide spacers between tissues; the first fluid composition and the second fluid composition, or a fluid mixture thereof, can be injected (e.g., in the form of blisters) to provide reference markers; the first fluid composition and the second fluid composition, or a fluid mixture thereof, can be injected for tissue enlargement or regeneration; the first fluid composition and the second fluid composition, or a fluid mixture thereof, can be injected as fillers or replacements for soft tissues; the first fluid composition and the second fluid composition, or a fluid mixture thereof, can be injected to provide mechanical support for damaged tissues; the first fluid composition and the second fluid composition, or a fluid mixture thereof, can be injected as scaffolds; the first fluid composition and the second fluid composition, or a fluid mixture thereof, can be injected as embolic compositions; the first fluid composition and the second fluid composition, or a fluid mixture thereof, can be injected as lifting agents for the removal of internal cysts; and / or the first fluid composition and the second fluid composition, or a fluid mixture thereof, can be injected as carriers of therapeutic agents. The first fluid composition and the second fluid composition, or a fluid mixture thereof, can also be injected into the left atrial appendages during left atrial appendage closure. In some embodiments, the first fluid composition and the second fluid composition, or a fluid mixture thereof, may be injected into the left atrial appendage after the introduction of a closure device, such as the Watchman® left atrial appendage closure device available from Boston Scientific.

[0082] Upon application of the compositions disclosed herein (either as a first fluid composition and a second fluid composition mixed in vivo, or as a fluid mixture of the first fluid composition and the second fluid composition), a cross-linked hydrogel is ultimately formed at the application site.

[0083] After application, the compositions disclosed herein can be imaged using suitable imaging techniques, such as ultrasound or X-ray-based imaging techniques, such as computed tomography or X-ray fluorescence fluoroscopy.

[0084] As can be seen from the above, the compositions disclosed herein can be used in various medical procedures, including the following: procedures for implanting a reference marker comprising a crosslinked product of the first and second fluid compositions; procedures for implanting a tissue regeneration scaffold comprising a crosslinked product of the first and second fluid compositions; procedures for implanting a tissue support comprising a crosslinked product of the first and second fluid compositions; procedures for implanting a tissue expander comprising a crosslinked product of the first and second fluid compositions; procedures for implanting an embolization composition comprising a crosslinked product of the first and second fluid compositions; procedures for implanting a lifter comprising a crosslinked product of the first and second fluid compositions; procedures for implanting a left atrial appendage occlusion composition comprising a crosslinked product of the first and second fluid compositions; procedures for implanting a depot of a release therapeutic agent comprising a crosslinked product of the first and second fluid compositions; procedures for tissue enlargement comprising implanting a crosslinked product of the first and second fluid compositions; and procedures for introducing a crosslinked product of the first and second fluid compositions between a first tissue and a second tissue to separate the first tissue from the second tissue.

[0085] The first fluid composition and the second fluid composition, a fluid mixture of the first fluid composition and the second fluid composition, or a crosslinked product of the first fluid composition and the second fluid composition can be injected in combination with a variety of medical procedures including: injection for septal use between the prostate or vagina and rectum in radiotherapy for rectal cancer; injection for septal use between the rectum and prostate in radiotherapy for prostate cancer; subcutaneous injection for palliative treatment of prostate cancer; transurethral or submucosal injection for female stress urinary incontinence; intravesical injection for urinary incontinence; intrauterine injection for Asherman's syndrome; submucosal injection for anal incontinence; percutaneous injection for heart failure; intramyocardial injection for heart failure and dilated cardiomyopathy; transendocardial injection for myocardial infarction; intra-articular injection for osteoarthritis; and injection for spinal fusion and spinal, oral and maxillofacial, and orthopedic procedures. Spinal injections for traumatic surgery; spinal injections for posterolateral lumbar fusion; intradiscal injections for degenerative disc diseases; injections between the pancreas and duodenum for pancreatic cancer imaging; resection bed injections for oropharyngeal cancer imaging; peritumoral injections for bladder cancer imaging; submucosal injections for gastrointestinal tumors and polyps; visceral pleural injections for lung biopsies; renal injections for type 2 diabetes and chronic kidney disease; renal cortical injections for chronic kidney disease with congenital abnormalities from the kidneys and urethra; intravitreal injections for neovascular age-related macular degeneration; intratympanic injections for sensorineural hearing loss; and dermal injections to correct wrinkles, creases and folds, signs of facial fat loss, volume reduction, superficial to deep contour defects, correction of depressed skin scars, perioral wrinkles, lip augmentation, facial fat atrophy, and stimulate natural collagen production.

[0086] In in vitro formation, the cross-linked hydrogel can be in any desired form, including plates, cylinders, coatings, or granules. In some embodiments, the cross-linked hydrogel is dried and then granulated into particles of suitable size. Granulation can be performed by any suitable method, such as grinding (including cryogenic grinding), homogenization, crushing, milling, or pulverizing. The particles can be sorted and separated using sieving or other known techniques. The size of the cross-linked hydrogel particles formed using the above and other techniques can vary considerably, for example, with an average size of 50-950 micrometers.

[0087] In addition to the cross-linked hydrogels described above, the cross-linked hydrogel compositions according to this disclosure may contain additives, including therapeutic agents, imaging agents, colorants, tension modifiers, suspending agents, wetting agents, and pH adjusters as described above.

[0088] The cross-linked hydrogel composition according to this disclosure comprises an injectable fluid suspension of cross-linked hydrogel particles.

[0089] In various embodiments, kits are provided that include one or more delivery devices for delivering the cross-linked hydrogel to a subject. Such systems may include one or more of the following: a syringe tubing, which may or may not contain the cross-linked hydrogel described herein; a vial, which may or may not contain the cross-linked hydrogel described herein; a needle; a flexible tube (e.g., adapted for fluid connection of the needle to a syringe); or an injectable liquid, such as water for injection, physiological saline, or phosphate-buffered saline. Whether provided in the form of a syringe, vial, or other reservoir, the cross-linked hydrogel may be provided in a dry form (e.g., powder form) or in a ready-for-injection form, such as an injectable hydrogel form (e.g., a suspension of cross-linked hydrogel particles).

[0090] Figure 2 A syringe 10 is shown, which provides a reservoir for the crosslinked hydrogel composition as described above. The syringe 10 may include a tube 12, a plunger 14, and one or more stoppers 16. The tube 12 may include, for example, a Luer adapter (or other suitable adapter / connector) at its distal end 18 for attachment to an injection needle 50 via a flexible conduit 29. The proximal end of the conduit 29 may include a suitable connector 20 for receiving the tube 12. In other examples, the tube 12 may be directly connected to the injection needle 50. The injection tube 12 can be used as a reservoir containing the crosslinked hydrogel composition 15 for injection via the needle 50.

[0091] The cross-linked hydrogel compositions described herein can be used for a variety of purposes.

[0092] For example, in applications such as the treatment of diseases and cancer, as well as the repair and regeneration of tissues, cross-linked hydrogel compositions can be injected to provide spacers between tissues, cross-linked hydrogel compositions (e.g., in the form of blister packs) can be injected to provide reference markers, cross-linked hydrogel compositions can be injected for tissue enlargement or regeneration, cross-linked hydrogel compositions can be injected as fillers or substitutes for soft tissues, cross-linked hydrogel compositions can be injected to provide mechanical support for damaged tissues, cross-linked hydrogel compositions can be injected as scaffolds, and / or cross-linked polymer compositions can be injected as carriers of therapeutic agents for applications such as the treatment of diseases and cancer, as well as the repair and regeneration of tissues.

[0093] The cross-linked hydrogel composition disclosed herein can be used in various medical procedures, including: procedures for implanting a reference marker comprising cross-linked hydrogel, procedures for implanting a tissue regeneration scaffold comprising cross-linked hydrogel, procedures for implanting a tissue support comprising cross-linked hydrogel, procedures for implanting a tissue bulking agent comprising cross-linked hydrogel, procedures for implanting a depot containing a therapeutic agent comprising cross-linked hydrogel, procedures for tissue enlargement comprising implanting cross-linked hydrogel, and procedures for introducing cross-linked hydrogel between a first tissue and a second tissue to separate the first tissue from the second tissue.

[0094] The cross-linked hydrogel composition can be injected with various medical procedures, including: injection as a septum between the prostate or vagina and rectum in radiotherapy for rectal cancer; injection as a septum between the rectum and prostate in radiotherapy for prostate cancer; subcutaneous injection for palliative treatment of prostate cancer; transurethral or submucosal injection for female stress urinary incontinence; intravesical injection for urinary incontinence; intrauterine injection for Asherman's syndrome; submucosal injection for anal incontinence; percutaneous injection for heart failure; intramyocardial injection for heart failure and dilated cardiomyopathy; transendocardial injection for myocardial infarction; intra-articular injection for osteoarthritis; spinal injection for spinal fusion and spinal, maxillofacial, and orthopedic trauma surgery; and spinal injection for posterolateral lumbar fusion. Intradiscal injection for degenerative disc diseases; inter-pancreatic and duodenal injection for pancreatic cancer imaging; resection bed injection for oropharyngeal cancer imaging; peritumoral injection for bladder cancer imaging; submucosal injection for gastrointestinal tumors and polyps; visceral pleural injection for lung biopsy; renal injection for type 2 diabetes and chronic kidney disease; renal cortical injection for chronic kidney disease with congenital abnormalities from the kidneys and urethra; intravitreal injection for neovascular age-related macular degeneration; intratympanic injection for sensorineural hearing loss; correction of wrinkles, creases and folds; signs of facial fat loss; volume reduction; superficial to deep contour defects; correction of depressed skin scars; perioral wrinkles; lip augmentation; facial fat atrophy; dermal injection to stimulate natural collagen production.

[0095] After application, the cross-linked hydrogel composition of this disclosure can be imaged using suitable imaging techniques.

[0096] The cross-linked hydrogel compositions according to this disclosure include smooth compositions for medical applications, compositions for the release of therapeutic agents (e.g., by including one or more therapeutic agents in the matrix of the cross-linked hydrogel), and implants (which can be formed in vitro or in vivo) (e.g., compositions used as tissue markers, compositions acting as spacers to reduce the side effects of off-target radiation therapy, cosmetic compositions, etc.).

[0097] It should be understood that this disclosure is merely illustrative in many respects and that changes in detail may be made without departing from the scope of this disclosure. To the appropriate extent, this may include the use of any feature of one embodiment in other embodiments.

Claims

1. A reactive multi-arm polymer comprising a core region and a plurality of polymer arms having reactive portions, each polymer arm comprising a polymer segment connected to the core region and one of a plurality of reactive portions connected to the polymer segment via hydrolyzable bonds, the hydrolyzable bonds being selected from carbonate bonds, anhydride bonds, imide bonds, ketal bonds, urethane bonds, organophosphate bonds, silane bonds, amide bonds, hydrazone bonds, acylhydrazone bonds, oxime bonds, and amide hydrazone bonds.

2. A reactive multi-arm polymer comprising a core region and a plurality of polymer arms having reactive portions, each polymer arm comprising a polymer segment connected to the core region, one of the reactive portions connected to the polymer segment by a hydrolyzable bond, and an activating group located adjacent to the hydrolyzable bond, the activating group increasing the hydrolysis rate of the hydrolyzable bond.

3. The reactive multi-arm polymer according to claim 2, wherein the activating group is selected from hydrogen bond donors, hydrogen bond acceptors, lone pair electron donors, lone pair electron acceptors, silicon-containing groups, boron-containing groups, phosphonate groups, and sulfonate groups.

4. The reactive multi-arm polymer according to claim 2, wherein the activating group is selected from urea bond, urea side group, thiourea bond, thiourea side group, amine bond, amine side group, alcohol side group, silicon-containing bond, silicon-containing side group, boron-containing bond, boron-containing side group, phosphonate bond, phosphonate side group and sulfonate side group.

5. The reactive multi-arm polymer according to any one of claims 2-4, wherein the activating group is complexed with the hydrolyzable bond to form a 4-9 membered cyclic transition state.

6. The reactive multi-arm polymer according to any one of claims 1-5, wherein the reactive portion is selected from reactive portions containing electrophilic groups, reactive portions containing nucleophilic groups, reactive portions containing diene groups, reactive portions containing dienophilic groups, reactive portions containing alkenyl groups, reactive portions containing tonicynyl groups, reactive portions containing azide groups, reactive portions containing ketone groups, reactive portions containing aldehyde groups, and reactive portions containing acrylate groups.

7. The reactive multi-arm polymer according to any one of claims 1-6, wherein the polymer segment is selected from polyoxyalkylene segments, polyester segments, polyoxazoline segments, polydioxanone segments, and polypeptide segments.

8. The reactive multi-arm polymer according to any one of claims 1-7, wherein the polymer segment contains 10 to 1000 monomer residues.

9. The reactive multi-arm polymer according to any one of claims 1-8, wherein the core region comprises residues of a polyol containing three to twenty hydroxyl groups.

10. A hydrogel formed by covalently crosslinking (a) a reactive multi-arm polymer according to any one of claims 1-9 with (b) a multifunctional crosslinking compound comprising a plurality of complementary reactive portions, each of the complementary reactive portions reacting with a reactive portion of the reactive multi-arm polymer.

11. A system for forming a hydrogel composition comprising: (a) a reactive multi-arm polymer according to any one of claims 1-9, and (b) a multifunctional crosslinking compound comprising a plurality of complementary reactive portions that react with reactive portions of the reactive multi-arm polymer.

12. A system for forming a hydrogel composition comprising: (a) a reactive multi-arm polymer having a core region and a plurality of polymer arms having reactive portions, each polymer arm comprising a polymer segment connected to the core region and one of a plurality of reactive portions connected to the polymer segment; and (b) a polyfunctional crosslinking compound comprising a plurality of complementary reactive portions reacting with the reactive portions of the reactive multi-arm polymer, wherein each of the plurality of complementary reactive portions is connected to the remainder of the polyfunctional crosslinking compound by a hydrolyzable bond selected from carbonate bonds, anhydride bonds, imide bonds, ketal bonds, urethane bonds, organophosphate bonds, silane bonds, amide bonds, hydrazone bonds, acylhydrazone bonds, oxime bonds, and amide hydrazone bonds.

13. A system for forming a hydrogel composition comprising: (a) a reactive multi-arm polymer having a core region and a plurality of polymer arms having reactive portions, each polymer arm comprising a polymer segment connected to the core region and one of a plurality of reactive portions connected to the polymer segment; and (b) a polyfunctional crosslinking compound comprising a plurality of complementary reactive portions reacting with the reactive portions of the reactive multi-arm polymer, wherein each of the plurality of complementary reactive portions is connected to the remainder of the polyfunctional crosslinking compound via a hydrolyzable bond, and wherein the polyfunctional crosslinking compound further comprises an activating group located adjacent to the hydrolyzable bond, which increases the hydrolysis rate of the hydrolyzable bond.

14. The system of claim 13, wherein the activating group is selected from hydrogen bond donors, hydrogen bond acceptors, lone pair electron donors, lone pair electron acceptors, silicon-containing groups, boron-containing groups, phosphonate groups, and sulfonate groups.

15. The system according to claim 13, wherein the activating group is selected from urea bond, urea side group, thiourea bond, thiourea side group, amine bond, amine side group, alcohol side group, silicon-containing bond, silicon-containing side group, boron-containing bond, boron-containing side group, phosphonate bond, phosphonate side group and sulfonate side group.

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