Radiation spacer hydrogels, methods of formation, and methods of use

Abstract

The present disclosure relates to hydrogel compositions designed to fill spaces within a cavity or space in a subject, as well as various additives or combinations thereof that enable the hydrogel to provide a therapeutic substance or physiological effect to the subject in addition to providing structural support.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION

[0001] This specification relates generally to hydrogels and methods of making and using such hydrogels, and more particularly to hydrogels used in tissue separation and treatment. [Background technology]

[0002]

[0002] Patients undergoing radiation therapy are prone to complications due to radiation scatter, which delivers harmful doses of radiation to nearby organs. Radiation toxicity to nearby adjacent organs can cause health problems. Hydrogel spacers, which are used for injection to create space between target and non-target tissues and minimize incidental radiation, can be difficult to deliver. For example, when delivered, the hydrogel can take an excessively long time to polymerize, causing the gel to migrate from the intended delivery site. This situation can result in non-target tissues receiving higher incidental doses of radiation.

[0003]

[0003] Therefore, there is a need to reduce the incidence and severity of these dreaded side effects in patients undergoing radiation therapy by reducing the radiation dose delivered to adjacent organs at risk. Summary of the Invention

[0004]

[0004] The present disclosure relates to hydrogel compositions. In some aspects, the hydrogels are described for use in filling or bridging a space or cavity within a subject, e.g., a human subject. It will be understood that the hydrogels described herein are not limited to this use. The hydrogels described herein may be varied so that they can be formulated to degrade slowly or relatively quickly. Hydrogels may also vary in their rheology or modulus.

[0005] In one aspect, the present disclosure relates to a hydrogel composition for in situ formation within a cavity, comprising a polymerized complex of at least one monomer unit, at least one complexing molecule, and an aqueous solution. The monomer unit may comprise a terminal structure, a linker, and a core, and the complexing molecule is selected from recombinant albumin, polyethyleneimine (PEI), and polylysine. The linker may be polyethylene glycol (PEG). The linker may be of sufficient length to provide a hydrogel having a molecular weight (MW) between 1 kDa and 100 kDa.

[0006] In embodiments, the terminal structure is selected from N-hydroxysuccinimide (NHS) carboxymethyl ester (NHS-SCM), NHS succinate ester (NHS-SS), NHS glutarate (NHS-SG), or triiodobenzoic acid (TIBA).

[0007] In embodiments, the core is selected from pentaerythritol, hexaglycerol, tripentaerythritol, or glycerol. Thus, the monomer unit may have 2, 4, or 8 linker arms extending from the core.

[0008] In embodiments, the hydrogel composition is formed at least in part through esters of the monomer units that complex with amines or imines of the complexing molecule.

[0009] In embodiments, the hydrogel composition may have a molar ratio of ester of the monomer unit to amine or imine of the complexing molecule of 0.05 to 3. In some embodiments, the molar ratio is 1.5 to 2.

[0009]

[0010] In embodiments, the complexing molecule comprises 2% to 60% weight / volume (w / v) of the hydrogel composition. In embodiments, the mass ratio of monomer unit:complexing molecule is 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, or 33:1. Available in 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.

[0010]

[0011] In embodiments, the pH of the hydrogel composition is between 7.5 and 11.0.

[0012] In embodiments, the monomer unit is NHS-PEG-SG-8, NHS-PEG-SG-4, or NHS-PEG-SG-2. In embodiments, the monomer unit is NHS-PEG-SS-8, NHS-PEG-SS-4, or NHS-PEG-SS-2. In embodiments, the monomer unit is NHS-PEG-SCM-8, NHS-PEG-SCM-4, or NHS-PEG-SCM-2.

[0011]

[0013] In embodiments, the complexing molecule is rHA. In embodiments, the complexing molecule is PEI.

[0014] In embodiments, the hydrogel may include embedded components, such as therapeutic agents, radiosensitizers, radioprotectors, gas nanobubbles, peroxides, compounds that generate reactive oxygen species upon radiation therapy, or microparticles.

[0012]

[0015] In some embodiments, the microparticles are biodegradable polymer microparticles. In some embodiments, the microparticles contain a therapeutic agent and / or a tissue marker and / or a radioisotope or a compound containing at least one radioactive element. In some embodiments, the microparticles contain a radiopaque marker, such as methylated TIBA (TIBA-Me).

[0013]

[0016] In some embodiments, the hydrogel composition comprises at least one osmotic component. In some embodiments, the hydrogel comprises two or more layers. In some embodiments, the layers have different osmotic concentrations. In some embodiments, the osmotic concentration of the hydrogel differs from the tissue or cavity of the subject that the hydrogel is expected to fill.

[0014]

[0017] In some aspects, the present disclosure relates to a method of preparing a hydrogel composition by preparing a first solution of reconstituted monomer units in a first aqueous solution, preparing a second solution of reconstituted complexing molecules in a second aqueous solution, and contacting the first and second solutions when both are poured into a cavity space of a subject to form a polymerized complex. In some aspects, the cavity space is located between the rectum and the prostate of the subject. In some aspects, the cavity space is located within breast tissue of the subject.

[0015]

[0018] In some aspects, the present disclosure relates to the use of the hydrogel compositions described herein to separate rectal tissue from prostate tissue in a subject.

[0019] In aspects, the present disclosure also includes kits for preparing the hydrogel compositions described herein. DETAILED DESCRIPTION OF THE INVENTION

[0016]

[0020] Embodiments described herein generally relate to hydrogels, methods of forming them, and methods of using them. The hydrogel generally comprises a polymerized complex of at least one monomer unit, at least one complexing molecule, and an aqueous solution, the monomer unit comprising a terminal structure, a linker, and a core, and the complexing molecule is selected from recombinant albumin, polyethyleneimine (PEI), and polylysine. These and other features and bioreactor embodiments are disclosed in more detail herein.

[0017]

[0021] The present disclosure relates in one aspect to radiation spacer hydrogels incorporating injectable hydrogel spacers for separating tissues for protection from incident radiation, as well as systems and methods incorporating same.

[0018]

[0022] Furthermore, while the radiation spacer hydrogels described herein can be injected over the course of a subject's treatment, additional procedures increase the risk of complications. Therefore, the hydrogels, systems, and methods described herein include biodegradable components that can be adapted to the specific needs of a subject. As used herein, "applying" means that the radiation spacer hydrogel is specifically formulated, shaped, and sized to fit the subject's specific anatomical structure and treatment goals. "Applying" also means that the materials forming the hydrogel are selected with or tailored to a specific degradation profile to match the subject's anticipated treatment duration and / or needs.

[0019]

[0023] The radiation spacer hydrogels disclosed herein are designed to allow the hydrogel to separate target and non-target tissues. As used herein, the terms "separation" and "displacement" refer to filling the gap between the target and non-target tissues or displacing the target and non-target tissues such that the radiation spacer hydrogel creates and fills the gap between the tissues. This space created by the radiation spacer hydrogel protects the non-target tissues from exposure or unintended side effects experienced during treatment. The radiation spacer hydrogel may reduce the adverse effects of radiation therapy on non-target tissues, allow for improved targeting of target tissues, allow for higher radiation doses, provide additional and / or alternative treatments, and / or allow for shorter treatment times.

[0020]

[0024] Radiation therapy is an excellent treatment option for treating various cancers. However, radiation exposure can cause unintended side effects in adjacent organs. Radiation spacer hydrogels can be injected to provide space between the target organ or tissue at risk and nearby organs or tissues, thereby avoiding collateral radiation and minimizing damage to nearby organs.

[0021]

[0025] As used herein, the term "target tissue" refers to a tissue or organ requiring radiation therapy or other treatment. As used herein, the term "non-target tissue" refers to a tissue or organ adjacent to the target tissue, the non-target tissue being at risk of side effects from treatment of the target tissue. In some embodiments, the non-target tissue is at risk of collateral radiation.

[0022]

[0026] Another aspect of the present disclosure is that the hydrogel spacers disclosed herein can also be used in other medical procedures and treatments, such as, but not limited to, vascular occlusion, punctal occlusion, duct occlusion, and other procedures or treatments that require occluding a lumen in a subject. In addition, the hydrogel spacers can be used in medical procedures that require creating space within a subject, such as, but not limited to, orbital volume augmentation, dental procedures, tissue expansion for reconstructive surgery, and vocal cord procedures.

[0023]

[0027] An advantage of the present disclosure is that the biodegradable components reduce the need for follow-up procedures. Additionally, the rapid gelation time of the hydrogel prevents migration of the hydrogel spacer to unintended areas. Additionally, the present disclosure provides a hydrogel spacer that can be adapted to a subject's unique anatomy and location requiring treatment.

[0024] Hydrogel

[0028] The present disclosure relates, at least in part, to the existence of hydrogels, either as bodies that encapsulate other materials and / or substances. Hydrogels refer to polymerized networks of water-insoluble monomer units crosslinked with complexing molecules that retain water therein. Hydrogels can be one single type of crosslinked monomer unit, or a combination of two or more types of monomer units. Hydrogels can also be crosslinked networks of at least one type of monomer unit, e.g., two, three, four, five, six, seven, eight, and more different types of monomer units. It will be understood that a unit can also refer to a molecule that combines at least two parts, each part providing different functionality to the monomer unit.

[0025]

[0029] Hydrogels contain crosslinks between monomer units and complexed molecules within the hydrogel. Crosslinks refer to bonds or points of attraction between different moieties and / or different monomers. In embodiments, the bonds are chemical bonds, such as covalent bonds, ionic bonds, or metallic bonds. In embodiments, the bonds or attractions can include van der Waals forces, hydrogen bonds, Kiesem forces, Coulomb interactions, Pauli repulsion, halogen bonds, and combinations thereof. It will be understood that hydrogels need not contain only one type of bond between moieties, but may instead have two or more types of bonds or attractions throughout the formed hydrogel. In some embodiments, hydrogels can be chemical hydrogels, in which covalent bonds link chains together. In some embodiments, hydrogels can be physical hydrogels, in which hydrogen bonds, entanglements, hydrophobic interactions, and similar physical interactions form the gel. It will also be understood that hydrogels can contain a combination of chemical and physical interactions.

[0026]

[0030] In some embodiments, hydrogels comprise monomeric units crosslinked with complexing molecules through bonding or attractive forces between reactive atoms, submolecules, or moieties within the monomeric units and the complexing molecules, respectively. In some embodiments, a monomeric unit may crosslink with another atom or moiety within the same monomeric unit or may crosslink "with itself." In some embodiments, a moiety or atom within one monomeric unit is expected to bond with or be attracted to another moiety or atom within a different monomeric unit, either of the same type of molecule or of a different molecule.

[0027]

[0031] In some aspects, the bond or attraction leading to the crosslinking can be oxygen, primary / secondary / tertiary amine, peroxide, superoxide, nitrogen, sulfur, phosphorus, boron, lithium, heme, iron, aluminum, silicon, metal ion, carboxyl, thiol, hydroxyl, carbon, carbonyl, carbonate, carboxylate, carboalkoxy, ketone, imide, halogen, acyl halide, hydroperoxy, ether, hemiacetyl, acetal, orthoester, methylenedioxy, carboxamide, amidine, primary / secondary ketimine, primary / secondary aldimine, azide, azo, cyanate / isocyanate, nitrate, nitrogen, or the like. It may be present between nitrate, nitrile, nitrosooxy, nitro, nitroso, oxime, pyridyl, carbamate, sulfhydryl, sulfide, disulfide, sulfinyl, sulfonyl, sulfino, sulfo, thiocyanate, carbonothioyl, carbothioic acid, thiol ester, thionoester, carbodithioic acid, carbodithio, phosphino, phosphono, phosphoric acid, phosphodiester, borono, boronate, borino, borinate, alkyllithium, alkylmagnesium halide, alkylaluminum, or silyl ether.

[0028]

[0032] In some embodiments, the monomer units of the hydrogel comprise linker or spacer structures with available sites along their length for binding other monomers or water, e.g., polyethylene glycol or repeats thereof, connected at one end to a core or central component and at the other end to a terminal structure. In some embodiments, the terminal structure is an active ester. In some embodiments, the central component is a polyol or hydroxyl core. In embodiments, one or more linkers may be attached to and extend outward from the central component or core. In embodiments, two, four, or eight linkers may connect the core or central component. Thus, each linker connected to the core or central component may be interpreted as a symbolic appendage or arm extending therefrom.

[0029]

[0033] In embodiments, the terminal structure comprises a cyclic or cyclic organic compound conjugated to a primary amine through a stable amide bond with the carboxyl group of a carboxylic acid, alkanedioic acid, alkenedioic acid, or branched diacid. In some embodiments, the primary amine is linked to an alkanedioic acid, e.g., a linear dicarboxylic acid. In some embodiments, the terminal structure is a succinimidyl ester. In embodiments, the succinimide is N-hydroxysuccinimide (NHS). In other embodiments, the succinimide is a further substituted NHS. In embodiments, the terminal structure comprises a cyclic or cyclic organic compound conjugated to a linker through a carboxyl group attached to a carboxylic acid, e.g., benzoic acid (BA) or its methylated form. In embodiments, the terminal structure may comprise BA, NHS, acrylamide, biotin, COOH, alkyne, halogen (e.g., chloride), epoxide, hydrazide, norbornene, hydroxyl, azide, amine, acrylate, dibenzocyclooctyne (DBCO), glutamic acid, glutaramic acid, succinimidyl glutaramide ester (GAS), maleimide, para-nitrophenyl carbonate (NPC), orthopyridyl disulfide (OPSS), acetic acid, carboxylmethyl, glutaric acid, succinic acid, glutaramic acid, succinamidic acid, succinimidyl succinamide ester (SAS), thiol (or SH), tosylate ester, vinyl sulfone, or a combination thereof.

[0030]

[0034] In some embodiments, the linear dicarboxylic acid is saturated. In some embodiments, the dicarboxylic acid is unsaturated. In some embodiments, the alkanedioic acid / alkenedioic acid / 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 embodiments, the primary amine is linked to glycolic acid. In some embodiments, the terminal structure is an ester of NHS and one of glycolic acid, succinic acid, and glutaric acid.

[0031]

[0035] In some embodiments, the terminal structure is succinimidyl carboxymethyl ester (SCM). In some embodiments, the terminal structure is succinimidyl succinate ester (SS). In some embodiments, the terminal structure is succinimidyl glutarate (SG). In some embodiments, the terminal structure may include at least one of NHS-SG, NHS-SS, and NHS-SCM.

[0032]

[0036] In an embodiment, the terminal structure can include an acrylate linked to a linker as a methyl ether.

[0037] In some embodiments, the central component comprises a hydroxyl or polyol core. In some embodiments, the polyol core comprises pentaerythritol, hexaglycerol, tripentaerythritol, or glycerol. In some embodiments, the central component is a glycerol-based core, allowing for the presence of "arms" extending therefrom. Linkers can provide connections between the terminal structures and the core. For example, glycerol can provide two arms, pentaerythritol can provide up to four arms, hexaglycerol can provide up to eight arms, and tripentathritol can provide up to eight arms. Further aspects of the linker and / or terminal structure may provide crosslinking reactive sites, such as exposed oxygen, sulfur, and hydroxyl groups, amines, etc. In some embodiments, the linker can include one or more ethylene glycol molecules.

[0033]

[0038] In embodiments, the linker is ethylene glycol or polyethylene glycol (PEG) or a linear or branched chain thereof. In embodiments, the PEG-chain can connect the terminal structure (TS) to the core. Formula I shows the basic structure.

[0034]

[0039] (Terminal structure)-(PEG)n-(core)(I)

[0040] It will be understood that the number n can vary depending on the desired final molecular mass. In embodiments, n is an integer such as 1 to 10, 1 to 100, or 1 to 500, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20. In embodiments, n is 20 or more, 25 or more, 30 or more, 35 or more, 40 or more, 45 or more, 50 or more, 55 or more, 60 or more, 65 or more, 70 or more, 75 or more, 80 or more, 85 or more, 90 or more, 95 or more, or 100 or more.

[0035]

[0041] The hydrogels of the present disclosure comprise end structure-linker-core monomer units. In some embodiments, the core is linked with two or more linkers to provide a multi-armed monomer. In some embodiments, the core may have two arms, or may otherwise be a chain of monomers such as:

[0042] (terminal structure)-(linker)-(core)-(linker)-(terminal structure) (II).

[0036]

[0043] It will be appreciated that in such a two-arm structure, one ethylene glycol molecule may function as the core. In some embodiments, the core may have four arms and have the following structure:

[0037] [ka]

[0038]

[0044] In embodiments, the core may have eight arms with the following structure:

[0039] [ka]

[0040]

[0045] In embodiments, the core allows for 3, 4, 5, 6, 7, or 8 arms. In some embodiments, the number of arms may be further increased through additional modifications to the core. For example, PEG molecules may be pre-reacted to provide a branched structure that provides each arm with an available oxygen for attachment.

[0041]

[0046] In some embodiments, the hydrogel may comprise succinimide terminal structures, a PEG linker, and a glycerol or glycerol-derived core monomer unit. The succinimide may be NHS. The linker may be sufficient PEG to provide a molecular weight (MW) of about 1,000 Da to about 100,000 Da. The core may be pentaerythritol, hexaglycerol, tripentaerythritol, or glycerol. The monomers may be two-, four-, or eight-armed.

[0042]

[0047] In some embodiments, the hydrogel may comprise a succinimidyl glutarate terminal structure, a PEG linker, and a glycerol or glycerol-derived core monomer unit. The succinimidyl glutarate may be NHS-SG. The linker may be sufficient PEG to provide a molecular weight (MW) of about 1,000 Da to about 100,000 Da. The core may be pentaerythritol, hexaglycerol, tripentaerythritol, or glycerol. The monomer may have two, four, or eight arms, or NHS-PEG-SG-2, NHS-PEG-SG-4, and NHS-PEG-SG-8, respectively.

[0043]

[0048] In some embodiments, the hydrogel may comprise a succinimidyl carboxymethyl terminal structure, a PEG linker, and a glycerol or glycerol-derived core monomer unit. The succinimidyl carboxymethyl may be NHS-SCM. The linker may be sufficient PEG to provide a molecular weight (MW) of about 1,000 Da to about 100,000 Da. The core may be pentaerythritol, hexaglycerol, tripentaerythritol, or glycerol. The monomer may have two, four, or eight arms, or NHS-PEG-SCM-2, NHS-PEG-SCM-4, and NHS-PEG-SCM-8, respectively.

[0044]

[0049] In some embodiments, the hydrogel may comprise succinimidyl succinate terminal structures, a PEG linker, and a glycerol or glycerol-derived core monomer unit. The succinimidyl succinate may be NHS-SS. The linker may be sufficient PEG to provide a molecular weight (MW) of about 1,000 Da to about 100,000 Da. The core may be pentaerythritol, hexaglycerol, tripentaerythritol, or glycerol. The monomers may be two-, four-, or eight-armed, or NHS-PEG-SS-2, NHS-PEG-SS-4, and NHS-PEG-SS-8, respectively.

[0045]

[0050] In some embodiments, the terminal structure may be substituted with one or more halogens, such as iodine, to impart radiopacity to the monomer unit. In some embodiments, the terminal structure may be benzoic acid (BA) or a substituted variant thereof. In some embodiments, the benzene ring of BA may be substituted with one or more halogens. In some embodiments, the halogen may be iodine. In some embodiments, the terminal structure may be monoiodoBA, diiodoBA, or triiodoBA. In some embodiments, the terminal structure is triiodobenzoic acid (TIBA). In some embodiments, the monomer is TIBA-SG, TIBA-SS, or TIBA-SCM. In some embodiments, the linker may be sufficient PEG to provide a molecular weight (MW) of about 1,000 Daltons (Da) to about 100,000 Da. The core may be pentaerythritol, hexaglycerol, tripentaerythritol, or glycerol. The monomers may be 2, 4, or 8 arms, for example, TIBA-PEG-2, TIBA-PEG-4, TIBA-PEG-8, TIBA-PEG-SS-2, TIBA-PEGSG-2, TIBA-PEG-SCM-2, TIBA-PEG-SS-4, TIBA-PEG-SG-4, TIBA-PEG-SCM-4, TIBA-PEG-SCM-8, TIBA-PEG-SG-8, and TIBA-PEG-SCM-8.

[0046]

[0051] In embodiments, the hydrogel further comprises a complexing molecule or macromolecule polymerized with the monomer unit. In some embodiments, the hydrogel can comprise a complexing molecule such as a peptide, polypeptide, or protein. In embodiments, the hydrogel is a polymerized network of crosslinked monomers and peptides / polypeptides / proteins. It will be understood that a peptide refers to two or more amino acids linked together via peptide bonds, a polypeptide refers to a chain of multiple linked amino acids, and a protein refers to a full-length expressed gene or chimera thereof.

[0047]

[0052] In embodiments, conjugation molecules or macromolecules comprise a central supporting framework with one or more reactive side chains attached thereto. For example, amino acids contain a central peptide bond between the amino and carboxylic acid groups, but also have side chains. Depending on the amino acid, the side chains may react with, for example, arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, methionine, and tyrosine, providing reactive sites. Similarly, molecules such as polyethyleneimine (PEI) provide reactive amine groups in the conjugation molecule available for reaction with monomer units. Similarly, polylysine, sulfone, polyphthalamide (PPA), polyphenylene (PPS), polyetheretherketone (PEEK), or combinations thereof, may serve as conjugation molecules.

[0048]

[0053] In embodiments, hydrogels can be formed through interactions between primary amide-ester bonds between the end groups and the linker and primary amines in the conjugated molecule, such as amines in PEI or primary amines of amino acid side chains in proteins.

[0049]

[0054] In embodiments, the conjugated molecule is a recombinant protein and / or a synthetic protein. In some embodiments, the protein may be a protein commonly found in most animal species, which may provide a minimal response by the immune system. In embodiments, the protein is albumin. In some embodiments, the protein is human albumin, such as recombinant human serum albumin (rHSA or rHA) and / or synthetic human serum albumin, such as those formed by solid-phase peptide synthesis and solution-phase synthesis. In some embodiments, the conjugated molecule may be polylysine or a polypeptide containing multiple lysine residues.

[0050]

[0055] In some embodiments, the molecular weight of the conjugated molecule is about 1,000 Da to about 100,000 Da. For example, the MW of rHSA is about 66 kDa. The MW of PEI varies depending on the length of the monomer. Similarly, the MW of polylysine polypeptide can be configured based on the desired size.

[0051]

[0056] In some embodiments, the complexing molecule is provided in the hydrogel at about 2 to about 60% weight / volume (w / v), e.g., about 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, and 55% w / v. In some embodiments, the complexing molecule is about 5 to about 50% w / v, about 5 to about 40% w / v, about 5 to about 30% w / v, about 5 to about 20% w / v, about 5 to about 10% w / v, about 10 to about 50% w / v, about 10 to about 40% w / v, about 10 to about 30% w / v, about 10 to about 20% w / v, about 20 to about 50% w / v, about 20 to about 40% w / v, about 20 to about 30% w / v, about 30 to about 50% w / v, about 30 to about 40% w / v, or about 40 to about 50% w / v. In some embodiments, the complexing molecule is albumin (including human albumin) and / or PEI and / or polylysine.

[0052]

[0057] In some embodiments, the mass ratio of monomer units to conjugated molecules is 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: In some embodiments, the monomer units are provided as 2-, 4-, or 8-armed with PEG as a linker. In some embodiments, the MW of the monomer unit is from about 2 kDa to about 40 kDa. In some embodiments, the complexing molecule is PEI and / or rHA.

[0053]

[0058] In embodiments of the present disclosure, hydrogels are formed, at least in part, through a reaction between the oxygen connecting the linker to the end group and a primary amine in the conjugated molecule. For example, NHS-PEG-SG-8 is expected to react with imines in PEI or available primary amines in the side chains of amino acids in rHA, such as lysine, arginine, asparagine, and glutamine. In some embodiments, the molar ratio of esters (also referred to as NHS-esters or NHS) to amines determines the quality of the hydrogel. In some embodiments, the ester:amine (or NHS:amine) ratio is between 0.05 and 3. In some embodiments, the ester / NHS:amine molar ratio is greater than 1.00. In some embodiments, the ester / NHS:amine molar ratio is about 1.5 to about 2 or about 2.75.

[0054]

[0059] In some embodiments, the hydrogel is a combination of PEG-SG-8 (or NHS-PEG-SG-8 or TIBA-SG-8) with rHA or PEI, PEG-SG-4 (or NHS-PEG-SG-4 or TIBA-SG-4) with rHA or PEI, PEG-SG-2 (or NHS-PEG-SG-2 or TIBA-SG-2) with rHA or PEI, PEG-SS-8 (or NHS-PEG-SS-8 or TIBA-SS-8) with rHA or PEI, PEG-SS-4 (or NHS-PEG-SS-4 or combinations of PEG-SS-2 (or NHS-PEG-SS-2 or TIBA-SS-2) with rHA or PEI; combinations of PEG-SCM-8 (or NHS-PEG-SCM-8 or TIBA-SCM-8) with rHA or PEI; combinations of PEG-SCM-4 (or NHS-PEG-SCM-4 or TIBA-SCM-4) with rHA or PEI; or combinations of PEG-SCM-2 (or NHS-PEG-SCM-2 or TIBA-SCM-2) with rHA or PEI.

[0055]

[0060] In some embodiments, the monomer units of the hydrogel are PEG-SG, PEG-SS, or PEG-SCM with a MW of about 10 kDa to about 20 kDa. In some embodiments, the monomer units are added to a solution of about 10 to about 20 wt% / complexation unit volume of rHA, PEI, or polylysine, etc. In some embodiments, increasing the MW of PEG in the linker can enable the hydrogel to retain water.

[0056]

[0061] In embodiments of the present disclosure, hydrogels are prepared with one or more aqueous solutions, such that water is retained and entrapped within the formed hydrogel. In embodiments, the aqueous solutions comprise or are entirely water. The water may be of sufficient quality or purity to minimize the introduction of undesirable contaminants when placed within a space or cavity in a living body, reducing the risk of eliciting or enhancing an immune response. This may include filtered water, deionized water, distilled water, or reverse osmosis water, and combinations thereof. In embodiments, the aqueous solutions may include ions, such as cations, anions, or combinations thereof. In embodiments, the aqueous solutions may include salts or ions thereof, such as sodium, magnesium, manganese, potassium, chloride, boride, iodide, sulfate, sulfite, nitrate, nitrite, carbonate, bicarbonate, ammonia, phosphate, calcium, or combinations thereof. In embodiments, the aqueous solutions may contain one or more buffers. In embodiments, the aqueous solution may include one or more biochemical molecules, such as NADPH (nicotinamide adenine dinucleotide phosphate), NAD (nicotinamide adenine dinucleotide), ATP (adenine triphosphate), CTP (cytosine triphosphate), GTP (guanosine triphosphate), TTP (thymidine triphosphate), acetyl-CoA, amino acids, sugars, monosaccharides, polysaccharides, purines, pyrimidines, cytokines, or growth factors, etc. It will be apparent that the aqueous solution may contain any soluble material, such as, for example, a hydrophilic therapeutic agent, a contrast agent, or a surfactant. These include iohexol, sodium bicarbonate, sodium stearate, docusate sodium, alkyl ether phosphates, benzalkonium chloride, perfluorooctane sulfonate, carboxymethylcellulose (CMC), EO / PO (ethylene oxide and propylene oxide) block copolymers (e.g., PLURONIC®), PEG fatty esters, PEG omega-3 fatty esters and PEG omega-3 fatty alcohols, glycerol fatty esters, sorbitan fatty esters, PEG glyceryl fatty esters, PEG sorbitan fatty esters, sugar fatty esters, PEG sugar esters, polysorbate 20, polysorbate 40, polysorbate 60,p-isononylphenoxypolyglycidol, PEG laurate, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate, polyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate, polyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate, polyglyceryl-10 oleate, polyglyceryl-10 myristate, polyglyceryl-10 palmitate, PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG lauryl ether, octoxynol, monoxynol, Tyloxapol, sucrose monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside, n-hexyl-β-D- glucopyranoside, nonanoyl-N-methylglucamide, n-nonyl-β-D-glucopyranoside, octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside, docusate sodium, sorbitol, urea, BHT, BHA, PEG-sorbitan monolaurate, petrolatum, methyl stearate, or combinations thereof.

[0057]

[0062] In embodiments, the aqueous solution may be prepared or adjusted to a desired pH. In some embodiments, the alkaline pH of the aqueous solution may be between about 7.5 and 11.0, e.g., 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, and 10.9. In some embodiments, the aqueous solution may have an acidic pH between about 3.5 and 6.5, e.g., 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, and 6.4. In some embodiments, the aqueous solution containing the complexing molecule has an alkaline pH. For example, as described in some examples, the pH of the solution containing rHA may be adjusted to about 9.8. In some embodiments, the pH of the rHA solution is greater than 10.2 or greater than 10.6.

[0058] Method of preparation

[0063] In aspects, the present disclosure relates to methods of preparing the hydrogels described herein. In particular aspects of the present disclosure, the hydrogels described herein may be formed in situ within a subject. In other words, a user, e.g., a medical professional, may prepare a hydrogel solution and allow the gel to form directly from the point of application within a desired cavity or space in a subject. This flexibility in application allows the hydrogel to precisely fill the desired space or cavity within the subject, where the gel forms and fills the space.

[0059]

[0064] In some embodiments, the hydrogel forms within seconds to minutes. As described in the Examples, the hydrogels of the present disclosure provide a rapid formation time. Therefore, it is contemplated how the hydrogel solution is prepared and applied to ensure the formation of the hydrogel at the desired location. It is also contemplated that the hydrogel forms rapidly to minimize invasiveness within the subject's body.

[0060]

[0065] Thus, the preparation method involves forming two separate solutions or components. The first solution is formed by combining a first aqueous solution with the monomer units therein. For example, the first solution can be formed by adding water to PEG, PEG-SS, PEG-SG, PEG-SCM, PEG-TIBA, NHS-PEG-SS-2, NHS-PEG-SS-4, NHS-PEG-SS-8, NHS-PEG-SG-2, NHS-PEG-SG-4, NHS-PEG-SG-8, NHS-PEG-SCM-2, NHS-PEG-SCM-4, NHS-PEG-SCM-8, TIBA-PEG-SS-2, TIBA-PEG SG-2, TIBA-PEG-SCM-2, TIBA-PEG-SS-4, TIBA-PEG-SG-4, TIBA-PEG-SCM-4, TIBA-PEG-SS-8, TIBA-PEG-SG-8, TIBA-PEG-SCM-8, and combinations thereof.

[0061]

[0066] The second solution is formed by mixing a second aqueous solution with the complexing molecule. The second aqueous solution can be different from or the same as the first aqueous solution. For example, the second solution can be formed by mixing water with PEI, rHA, polylysine, or any combination thereof, such as those described herein.

[0062]

[0067] In some embodiments, the first and / or second solutions contain additional soluble materials, such as hydrophilic therapeutic agents, contrast agents, surfactants, or those described herein. In some embodiments, the soluble materials are pre-dissolved in the first aqueous solution and / or the second aqueous solution. In other embodiments, the additional soluble materials dissolve when the first aqueous solution is added to the monomer to form a hydrated monomer solution and / or when the second aqueous solution is added to the complexed molecule to form a hydrated complexed molecule solution.

[0063]

[0068] In embodiments, once the two solutions, a hydrated monomer solution and a hydrated complexed molecule solution, are brought into contact with each other, they are expected to begin to form a hydrogel. Therefore, an aspect of preparing a hydrogel is to allow the solutions to fill a space and simultaneously form a gel. Therefore, an embodiment of a method for preparing a hydrogel is to allow the two solutions to contact during application. One means by which this can be accomplished is via a "Y" or "T" junction of two inlets and one outlet. For example, a syringe or pump can flow the two solutions to the contact point, with the outlet channel terminating in or above the space to be filled with the hydrogel.

[0064]

[0069] Two-solution hydrogel chemistry requires that these two components remain isolated from each other prior to use, which may or may require separate packaging. Materials may also be moisture sensitive and may require isolation or separate packaging for long-term storage. Before preparing the gel, dry components such as PEG, rHSA, PEI, and PLGA particles must be reconstituted prior to processing.

[0065]

[0070] Hydrogel preparation in a clinical / surgical setting begins with the hydration of two primary components: the monomer units and the complexing molecules. Each component is hydrated individually. For example, a first syringe containing an aqueous solution can be connected to a second syringe containing dry material, and each can be hydrated individually by pumping the aqueous solution back and forth through the connector. A parallel design with a dual-chamber syringe can be used to simultaneously hydrate two separate portions (i.e., the monomer units and the complexing molecules) through the connector using a similar manual process. In embodiments where microparticles are included in the hydrogel, such a mixing step effectively resuspends them. Alternatively, other hydration methods can be used. For example, a magnetic disk or bar can be pre-loaded into the syringe; once the aqueous solution is introduced and the cap is closed, the syringe can be placed on a magnetic stirring table, where the magnetic disk or bar will stir and mix or blend the hydrated particles. In embodiments where microparticles are included in the hydrogel, such a mixing step effectively resuspends them. Alternatively, the hydration process can be accomplished by placing the syringe in a mechanical vibration system, such as an ultrasonic and / or vortex mixer. A fixture can hold the syringe in place during vibration mixing / hydration. In embodiments in which microparticles are included in the hydrogel, such a shaking step effectively resuspends them. In some embodiments, the solution can contain two or more inert spheres, e.g., stainless steel or polymer, that do not dissolve or react with any of the components. Their presence in the solution can aid in the reconstitution or dissolution of the components therein. In embodiments in which the solution is prepared in a syringe barrel, the spheres can help ensure that the solution is adequately prepared, e.g., by rocking, before mixing with the other solution to provide the hydrogel. For example, two solutions are prepared by reconstituting their respective dry components in a syringe barrel. In some embodiments, a dual-barrel syringe can be used. In some embodiments, the two barrels use a needle configured to mix the two solutions as they reach or near the needle end, so that they mix at or near the point of application.The syringe barrel can be manually shaken, and the sphere within is expected to help ensure the solution is ready, while also providing anti-foaming properties.

[0066]

[0071] After the two components are fully hydrated, mixing and delivery of the hydrogel follows. The mixing process is critical due to the rapid crosslinking rate of the system (short gel time). Incomplete mixing before delivery can result in needle blockage, while insufficient mixing can prevent the gel from achieving structural and morphological integrity during its lifetime.

[0067]

[0072] Mixing of the two components can be achieved during high-speed flow through a long needle, and further mixed by turbulence after exiting the delivery needle tip. Mixing can be assisted by the BD Progel delivery system, which is achieved by spraying at the delivery tip. Alternatively, mixing can be further assisted by a tortuous path mixing section that can be readily attached to the end of a Y-joint or T-joint. The delivery needle can be selected to have the desired length appropriate for the target application.

[0068]

[0073] Once the mixing and delivery process is initiated, it should proceed continuously until completion. The delivery process cannot be stopped or paused, as fast-reacting gels are expected to clog the system. In embodiments where the hydrogel is layered, the formation of a subsequent layer may begin at or near the completion of the gelation process of the previous layer. Applying a subsequent layer before the completion of gelation of the previous layer diffuses the interface between the two layers together, making the two layers appear to be a single hydrogel while providing the functionality of more than one layer.

[0069] adjustability

[0074] In embodiments, the formation and / or modulus and / or rheology and / or viscoelasticity of the hydrogels disclosed herein can be tailored to achieve a desired ratio, such as factors including, for example, the selected monomeric units, the concentration of the selected monomeric units, the number of arms and / or linker length, the selected complexing molecule or macromolecule, the concentration of the selected complexing molecule or macromolecule, the degree of crosslinking, the side chains available for crosslinking, the amount of water present or available, etc. As described in the Examples, varying the concentration and MW can affect gelation time and / or degradation time.

[0070]

[0075] As described in the Examples, providing a mass ratio of monomeric unit to conjugated molecule of about 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, or 33:2 provides hydrogels with degradation times greater than 18 months. In some embodiments, the monomeric units have terminal structures of NHS-SG, SS, or SCM, contain PEG as a linker, and have two, four, or eight arms. In some embodiments, the MW of the monomeric units is about 2 kDa to about 40 kDa. In some embodiments, the conjugated molecule is PEI and / or rHA.

[0071]

[0076] In embodiments of the present disclosure, hydrogels are formed at least in part through a reaction between the oxygens connecting the linkers to the end groups and primary amines in the conjugated molecules. For example, NHS-PEG-SG-8 is expected to react with imines in PEI or available primary amines in the side chains of amino acids in rHA, such as lysine, arginine, asparagine, and glutamine. In some embodiments, the molar ratio of esters (also referred to as NHS-esters or NHS) to amines determines certain qualities of the hydrogel. In some embodiments, the molar ratio of ester:amine (or NHS:amine) is between 0.05 and 3, e.g., 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 7, 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.

[0072]

[0077] In some embodiments, the molar ratio of ester / NHS:amine is greater than 1.00. In some embodiments, the molar ratio of ester / NHS:amine is from about 1.5 to about 2.75, from about 1.5 to about 2.65, from about 1.5 to about 2.55, from about 1.5 to about 2.5, from about 1.5 to about 2.4, from about 1.5 to about 2.3, from about 1.5 to about 2.2, from about 1.5 to about 2.1, from about 1.5 to about 2.0, from about 1.5 to about 1.9, from about 1.5 to about 1.8, from about 1.5 to about 1.7, from about 1.5 to about 1.6, from about 1.6 to about 2.75, from about 1.6 to about 2.65, from about 1.6 to about 2.55, from about 1.6 to about 2.5, from about 1.6 to about 2.4, from about 1.6 to about 2.3, from about 1.6 to about 2.2, about 1.6 to about 2.1, about 1.6 to about 2.0, about 1.6 to about 1.9, about 1.6 to about 1.8, about 1.6 to about 1.7, about 1.7 to about 2.75, about 1.7 to about 2.65, about 1.7 to about 2.55, about 1.7 to about 2.5, about 1.7 to about 2.4, about 1.7 to about 2.3, about 1.7 to about 2.2, about 1.7 to about 2.1, about 1.7 to about 2.0, about 1.7 to about 1.9, about 1.7 to about 1.8, about 1.8 to about 2.75, about 1.8 to about 2.65, about 1.8 to about 2.55, about 1.8 to about 2.5, about 1.8 to about to about 2.4, about 1.8 to about 2.3, about 1.8 to about 2.2, about 1.8 to about 2.1, about 1.8 to about 2.0, about 1.8 to about 1.9, about 1.9 to about 2.75, about 1.9 to about 2.65, about 1.9 to about 2.55, about 1.9 to about 2.5, about 1.9 to about 2.4, about 1.9 to about 2.3, about 1.9 to about 2.2, about 1.9 to about 2.1, about 1.9 to about 2.0, about 2.0 to about 2.75, about 2.0 to about 2.65, about 2.0 to about 2.55, about 2.0 to about 2.5, about 2.0 to about 2.4, about 2.0 to about 2.3, about 2.0 to about 2. 2, about 2.0 to about 2.1, about 2.1 to about 2.75, about 2.1 to about 2.65, about 2.1 to about 2.55, about 2.1 to about 2.5, about 2.1 to about 2.4, about 2.1 to about 2.3, about 2.1 to about 2.2, about 2.2 to about 2.75, about 2.2 to about 2.65, about 2.2 to about 2.55, about 2.2 to about 2.5, about 2.2 to about 2.4, about 2.2 to about 2.3, about 2.3 to about 2.75, about 2.3 to about 2.65, about 2.3 to about 2.55, about 2.3 to about 2.5, about 2.3 to about 2.4, about 2.4 to about 2.75, about 2.4 to about 2.65, about 2.4 to about 2.55, about 2.4 to about 2.5, about 2.5 to about 2.75, about 2.5 to about 2.65, about 2.5 to about 2.55, about 2.6 to about 2.75, and about 2.6 to about 2.65.

[0073]

[0078] In some embodiments, the monomer units of the hydrogel are PEG-SG, PEG-SS, or PEG-SCM with a MW of about 10 kDa to about 20 kDa. In some embodiments, the monomer units are added at about 10 to about 20 wt% / volume of complexation unit, e.g., to a solution of rHA or PEI. In some embodiments, the molar ratio of ester / NHS:amine is about 1.3 to about 2.75.

[0074]

[0079] In some embodiments, hydrogels can be further tuned by varying the selection of monomer units and / or complexing molecules. For example, changing from SCM to SS can result in faster degradation times for the hydrogel. Similarly, changing from PEI to rHA can result in faster degradation times for the hydrogel. Thus, in addition to varying the amount / concentration of each component, varying the type of component allows for an additional level of tunability.

[0075] Layered hydrogel

[0080] As described in the method for preparing the hydrogel, two separate solutions are required, each prepared by hydrating dried monomer units and dried complexing molecules. It is a further aspect of the present disclosure that the hydrogel may comprise multiple layers, such that each layer is independently formulated, tailored, and / or filled, as described in further detail herein. In aspects, the present disclosure relates to methods for preparing the layered hydrogels described herein. In aspects, the layered hydrogels enhance the therapeutic effect of target tissues while preserving and protecting non-target tissues.

[0076]

[0081] In some embodiments, the method for making a layered hydrogel includes creating a first hydrogel layer according to the preparing, mixing, and delivering steps previously described herein. A specific embodiment of the present disclosure is that the layered hydrogels described herein can be formed in situ within a subject. It will be apparent that multiple layers within a layered hydrogel can be formed in situ within a subject. In embodiments, the method further includes creating one or more subsequent layers according to the preparing, mixing, and delivering steps previously described herein, such that the one or more subsequent layers are delivered on top of the first hydrogel layer. In some embodiments, the layered hydrogel includes 2, 3, 4, 5, 6, 7, 8, 9, 10, or more layers.

[0077]

[0082] In embodiments, each layer of a plurality of layers can have a different formulation. For example, each layer can include independently selected monomer units and / or complexing molecules and / or aqueous hydration solutions. In embodiments, each layer of a plurality of layers includes the same monomer units, complexing molecules, and aqueous hydration solutions. In embodiments, each layer of a plurality of layers includes the same monomer units, complexing molecules, and aqueous hydration solutions, but includes one or more additional components independently selected from the other layers of the plurality of layers. In embodiments, the plurality of layers is applied in a staggered formulation.

[0078]

[0083] In embodiments, one or more of the layers are formulated such that they are protective layers and provide a protective effect to adjacent tissues, for example, protective layers may be adjacent to non-target tissues and provide radiation shielding, osmotic balance, etc., as described in more detail herein.

[0079]

[0084] In embodiments, one or more of the layers are therapeutic layers and are formulated to provide a therapeutic effect on adjacent tissue, such as providing radiation enhancement, osmotic imbalance, and medication.

[0080]

[0085] Embodiments of the present disclosure include layered hydrogels having two or more distinct layers, where a first layer protects non-target tissue and a second layer treats and / or enhances treatment of target tissue. In embodiments, the two layers are joined via chemical bonds or attractive forces, such as covalent bonds, ionic bonds, metallic bonds, van der Waals forces, hydrogen bonds, Kiesem forces, Coulomb interactions, Pauli repulsion, halogen bonds, and combinations thereof.

[0081]

[0086] In embodiments, the layered hydrogels can be combined with other embodiments of the hydrogels described herein.

[0082] Penetrating Hydrogel

[0087] As described in the method for preparing a hydrogel, two separate solutions are required, each prepared by hydrating dried monomer units and dried complexing molecules. A further aspect of the present disclosure is that the hydrogel can include one or more osmotic components. Because each of the two solutions required to form the hydrogel requires hydration of monomers and complexing molecules, it will be apparent that the osmotic components may be provided in either a dry form, with the addition of the monomer units and / or complexing molecules, and / or in an aqueous solution in the hydration solution used to hydrate the monomer units and / or complexing molecules. It will also be understood that the one or more osmotic components must be soluble in the hydration solution, regardless of whether the one or more osmotic components are provided in a dry form or in an aqueous solution. In some embodiments, the osmotic components are not added to the monomer units, complexing molecules, or aqueous hydration solution.

[0083]

[0088] In embodiments, the hydrogel is formulated to induce osmotic stress in the target tissue. In embodiments, the hydrogel may contain one or more osmotic components to adjust osmotic pressure to create a hypotonic, hypertonic, and / or isotonic hydrogel. In some embodiments, the osmotically imbalanced hydrogel may be injected to separate a target tissue from a non-target tissue. As used herein, "osmotically imbalanced hydrogel" refers to a hydrogel that has an osmotic pressure different from that of the target tissue, thereby creating an osmotic pressure gradient between the hydrogel and the target tissue. In some embodiments, the osmotically imbalanced hydrogel is a hypertonic hydrogel. In other embodiments, the osmotically imbalanced hydrogel is a hypotonic hydrogel.

[0084]

[0089] In some embodiments, the osmotically imbalanced hydrogel may be a layered hydrogel, as described in more detail herein, having one or more osmotically imbalanced layers. For example, the layered hydrogel may have 2, 3, 4, 5, 6, 7, 8, 9, 10, or more layers. Each layer of the multiple layers may be independently formulated to be hypertonic, hypotonic, or isotonic.

[0085] Hypertonic hydrogel

[0090] In some embodiments, the present disclosure relates to hypertonic hydrogels. In embodiments, the hydrogels can be formulated to be hypertonic with respect to a target tissue and to draw fluid out of the target tissue. In embodiments, the hypertonic hydrogels can be placed adjacent to a cancerous tumor to cause cytotoxic dehydration and induce cell death in the tumor. In embodiments, the osmolality of the target tissue can be greater than 300 mOsm / L. In embodiments, the hypertonic hydrogels can contain one or more osmotic components in an amount sufficient to raise the osmolality of the hydrogel above that of the target tissue.

[0086]

[0091] It will be appreciated that the one or more osmotic components can be provided at any concentration sufficient to raise the osmotic pressure to greater than 300 mOsm / L. In embodiments, the osmotic pressure of the hydrogel is from about 300 mOsm / L to about 10,000 mOsm / L, e.g., about 400, 500, 600, 700, 800, 900, 1000, 1250, 1500, 1750, 2000, 2250, 2500, 2750, 3000, 3250, 3500, 3750, 4000, 4800, 5000, 5100, 5200, 5300, 5400, 5500, 5600, 5700, 5800, 5900, 6000, 6100, 6200, 6300, 6400, 6500, 6600, 6700, 6800, 6900, 7000, 7100, 7200, 7300, 7400, 7500, 7600, 7700, 7800, 7900, 8000, 8100, 8200, 8300, 8400, 8500, 8600, 8700, 8800, 8900, 9000, 9100, 9200, 9300, 9400, 9500, 9600, 9700, 9800, 9900, 1000, The osmolality of the hydrogel may be 250, 4500, 4750, 5000, 5250, 5500, 5750, 6000, 6250, 6500, 6750, 7000, 7250, 7500, 7750, 8000, 8250, 8500, 8750, 9000, 9250, 9500, 9750, and 10000 mOsm / L. In some embodiments, the osmolality of the hydrogel may be within a range having endpoints defined by any two of the foregoing values. In some embodiments, the osmolality is from about 300 to about 9000 mOsm / L, from about 300 to about 8000 mOsm / L, from about 300 to about 7000 mOsm / L, from about 300 to about 6000 mOsm / L, from about 300 to about 5000 mOsm / L, from about 300 to about 4000 mOsm / L, from about 300 to about 3000 mOsm / L, from about 300 to about 2000 mOsm / L, from about 300 to about 1000 mOsm / L, from about 300 to about 500 mOsm / L, from about 300 to about 400 mOsm / L, from about 400 to about 500 mOsm / L, from about 400 to about 600 mOsm / L, from about 4 00 to about 700 mOsm / L, about 400 to about 800 mOsm / L, about 400 to about 900 mOsm / L, about 400 to about 1000 mOsm / L, about 1000 to about 2000 mOsm / L, about 2000 to about 3000 mOsm / L, about 3000 to about 4000 mOsm / L, about 4000 to about 5000 mOsm / L, about 5000 to about 6000 mOsm / L, about 6000 to about 7000 mOsm / L, about 7000 to about 8000 mOsm / L, about 8000 to about 9000 mOsm / L, or about 9000 to about 10000 mOsm / L.

[0087]

[0092] In embodiments, the aqueous solution and / or dry components may include any soluble material at a concentration sufficient to form a hypertonic hydrogel, such as one or more salts, one or more organic acids and / or acid salts thereof, one or more carbohydrates, one or more monohydric alcohols and / or polyhydric alcohols, one or more amino acids and / or peptides and / or proteins, one or more other biocompatible components, and combinations thereof.

[0088]

[0093] In some embodiments, the hypertonic hydrogel may include one or more salts. For example, the aqueous solution and / or dry components may include sodium chloride, calcium chloride, potassium chloride, barium sulfate, magnesium chloride, sodium bicarbonate, sodium phosphate, sodium sulfate, potassium phosphate, potassium sulfate, calcium phosphate, ammonium sulfate, barium chloride, copper sulfate, iron chloride, iron sulfate, lithium chloride, magnesium sulfate, manganese sulfate, nickel sulfate, potassium carbonate, potassium bromide, potassium chloride, potassium iodide, silver nitrate, sodium bromide, sodium carbonate, sodium chlorate, sodium nitrate, sodium pyrophosphate, zinc sulfate, and combinations thereof. In some embodiments, the aqueous solution and / or dry components may include one or more salts whose cations are alkali metals and / or alkaline earth metals, or combinations thereof. In some embodiments, the aqueous solution and / or dry components may include one or more salts whose anions are halides, nonmetals, oxoanions, and / or amides, or combinations thereof. In some embodiments, the salts may be acid salts, as described in more detail below.

[0089]

[0094] In some embodiments, the salt is provided in the hypertonic hydrogel at about 1% to about 60% weight / volume (w / v), e.g., about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 38, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, and 59% w / v. In some embodiments, the salt is present in an amount of about 1 to about 55% w / v, about 1 to about 50% w / v, about 1 to about 45% w / v, about 1 to about 40% w / v, about 1 to about 35% w / v, about 1 to about 30% w / v, about 1 to about 25% w / v, about 1 to about 23% w / v, about 1 to about 22% w / v, about 1 to about 21% w / v, about 1 to about 20% w / v, about 1 to about 19% w / v, about 1 to about 18% w / v, about 1 to about 17% w / v, about 1 to about 16% w / v, about 1 to about 15% w / v, about 1 to about 14% w / v, about 1 to about 13% w / v, about 1 to about 12% w / v, about 1 to about 11% w / v, about 1 to about 10% w / v, about 1 to about 9% w / v, about 1 to about 8% w / v, about 1 to about 7% w / v, about 1 to about 6% w / v, about 1 to about 5% w / v, about 1 to about 4% w / v, about 1 to about 3% w / v, about 1 to about 2% w / v, about 5 to about 60% w / v, about 5 to about 55% w / v, about 5 to about 50% w / v v, about 5 to about 45% w / v, about 5 to about 35% w / v, about 5 to about 30% w / v, about 5 to about 25% w / v, about 5 to about 15% w / v, about 5 to about 10% w / v, about 10 to about 60% w / v, about 10 to about 55% w / v, about 10 to about 50% w / v, about 10 to about 45% w / v, about 10 to about 35% w / v, about 10 to about 30% w / v, about 10 to about 25% w / v, about 10 to about 20% w / v, about 10 to about 15% w / v, about 1 5 to about 60% w / v, about 15 to about 55% w / v, about 15 to about 50% w / v, about 15 to about 45% w / v, about 15 to about 40% w / v, about 15 to about 35% w / v, about 15 to about 30% w / v, about 15 to about 25% w / v, about 15 to about 20% w / v, about 20 to about 60% w / v, about 20 to about 55% w / v, about 20 to about 50% w / v, about 20 to about 45% w / v, about 20 to about 40% w / v, about 20 to about 35% w / v,About 20 to about 30% w / v, about 20 to about 25% w / v, about 25 to about 60% w / v, about 25 to about 55% w / v, about 25 to about 50% w / v, about 25 to about 45% w / v, about 25 to about 40% w / v, about 25 to about 35% w / v, about 25 to about 30% w / v, about 30 to about 60% w / v, about 30 to about 55% w / v, about 30 to about 50% w / v, about 30 to about 45% w / v, about 30 to about 40% w / v, about 30 to about 35% w / v, about 35 to about 60% w / v, about 35 to about 55% w / v, about 35 to about 50% w / v, about 35 to about 45% w / v, about 35 to about 40% w / v, about 40 to about 60% w / v, about 40 to about 55% w / v, about 40 to about 50% w / v, about 40 to about 45% w / v, about 45 to about 60% w / v, about 45 to about 55% w / v, about 45 to about 50% w / v, about 50 to about 60% w / v, about 50 to about 55% w / v, or about 55 to about 60% w / v. In some embodiments, the salt is potassium chloride. In some embodiments, the salt is barium sulfate.

[0090]

[0095] In embodiments, the hypertonic hydrogel can include one or more organic acids or acid salts thereof. For example, the aqueous solution and / or dry components can include acetic acid, adipic acid, ascorbic acid, citric acid, phosphoric acid, tartaric acid, malic acid, succinic acid, fumaric acid, formic acid, gluconic acid, lactic acid, glycolic acid, pyruvic acid, oxalic acid, benzoic acid, cinnamic acid, ferulic acid, butyric acid, propionic acid, gallic acid, itaconic acid, maleic acid, mandelic acid, nicotinic acid, phthalic acid, salicylic acid, shikimic acid, uric acid, and / or valeric acid, and combinations thereof.

[0091]

[0096] In embodiments, the hypertonic hydrogel can include one or more acid salts of the aforementioned organic acids. In some embodiments, the aqueous solution and / or dry components can include one or more acid salts whose cations are alkali metals and / or alkaline earth metals, or combinations thereof. In some embodiments, the hypertonic hydrogel can include one or more acid salts whose anions are lactate, acetate, citrate, malate, pyruvate, citrate, phosphate, ascorbate, succinate, oxalate, gluconate, tartrate, carbonate, and / or combinations thereof.

[0092]

[0097] In some embodiments, the organic acid and / or its acid salt is provided in the hypertonic hydrogel at about 0.1% to 5% weight / volume (w / v), e.g., about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5% w / v. In some embodiments, the organic acid and / or organic salt thereof is from about 0.1 to about 4.5% w / v, from about 0.1 to about 4% w / v, from about 0.1 to about 3.5% w / v, from about 0.1 to about 3% w / v, from about 0.1 to about 2.5% w / v, from about 0.1 to about 2% w / v, from about 0.1 to about 1.5% w / v, from about 0.1 to about 1% w / v, from about 0.5 to about 5% w / v, from about 0.5 to about 4.5% w / v, from about 0.5 to about 4% w / v, from about 0.5 to about 3.5% w / v, from about 0.5 to about 3% w / v w / v, about 0.5 to about 2.5% w / v, about 0.5 to about 2% w / v, about 0.5 to about 1.5% w / v, about 0.5 to about 1% w / v, about 1 to about 5% w / v, about 1 to about 4.5% w / v, about 1 to about 4% w / v, about 1 to about 3.5% w / v, about 1 to about 3% w / v, about 1 to about 2.5% w / v, about 1 to about 2% w / v, about 1 to about 1.5% w / v, about 1.5 to about 2% w / v, about 1.5 to about 2.5% w / v, or about 1.5 to about 5% w / v.

[0093]

[0098] In embodiments, the hypertonic hydrogel may include one or more carbohydrates, such as dextrose, fructose, sucrose, lactose, maltose, trehalose, galactose, dextran, xylose, mannose, ribose, isomaltase, inulin, cyclodextrin, hydroxyethyl starch (HES), pullulan, pectin, xanthan gum, agarose, cellulose, hyaluronic acid, maltodextrin, methylcellulose, alginate, chitosan, heparin, and / or heparan sulfate, and combinations thereof.

[0094]

[0099] In some embodiments, the carbohydrate is provided in the hypertonic hydrogel at about 1% to 20% weight / volume (w / v), e.g., about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and 19% w / v. In some embodiments, the carbohydrate is provided in the hypertonic hydrogel at about 1 to about 19% w / v, about 2 to about 18% w / v, about 3 to about 17% w / v, about 4 to about 16% w / v, about 5 to about 19% w / v, about 5 to about 18% w / v, about 5 to about 17% w / v, about 5 to about 16% w / v, about 5 to about 15% w / v, about 5 to about 14% w / v, about 5 to about 13% w / v, about 5 to about 12% w / v, about 5 to about 11% w / v, about 5 to about 1 0% w / v, about 6 to about 10% w / v, about 7 to about 10% w / v, about 8 to about 10% w / v, about 9 to about 10% w / v, about 10 to about 20% w / v, about 10 to about 19% w / v, about 10 to about 18% w / v, about 10 to about 17% w / v, about 10 to about 16% w / v, about 10 to about 15% w / v, about 10 to about 14% w / v, about 10 to about 13% w / v, or about 10 to about 11% w / v.

[0095]

[0100] In embodiments, the hypertonic hydrogel can include one or more monohydric and / or polyhydric alcohols, such as ethanol, 1-propanol, propylene glycol, ethylene glycol, xylitol, sorbitol, erythritol, mannitol, isomalt, maltitol, lactitol, arabitol, ribitol, glycerol, threitol, dulcitol, inositol, idithiol, adonitol, and / or galactitol, and combinations thereof.

[0096]

[0101] In some embodiments, the monohydric alcohol and / or polyhydric alcohol is provided in the hypertonic hydrogel at about 1 to 40% weight / volume (w / v), e.g., about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, and 39% w / v. In some embodiments, the carbohydrate is about 1 to about 35% w / v, about 2 to about 30% w / v, about 3 to about 25% w / v, about 4 to about 20% w / v, about 5 to about 10% w / v, about 5 to about 15% w / v, about 5 to about 20% w / v, about 5 to about 25% w / v, about 5 to about 30% w / v, about 5 to about 35% w / v, about 5 to about 40% w / v, about 10 to about 15% w / v, about 10 to about 20% w / v, about 10 to about 25% w / v, about 10 to about 30% w / v, about 10 to about 35% w / v, about 1 0 to about 40% w / v, about 15 to about 20% w / v, about 15 to about 25% w / v, about 15 to about 30% w / v, about 15 to about 35% w / v, about 15 to about 40% w / v, about 20 to about 25% w / v, about 20 to about 30% w / v, about 20 to about 35% w / v, about 20 to about 40% w / v, about 25 to about 30% w / v, about 25 to about 35% w / v, about 25 to about 40% w / v, about 30 to about 35% w / v, about 30 to about 40% w / v, or about 35% to about 40% w / v.

[0097]

[0102] In some embodiments, the hypertonic hydrogel may contain one or more amino acids. For example, the aqueous solution and / or dry components may include proline, proline analogs (e.g., hydroxyproline, pipecolic acid, azetidine-2-carboxylic acid), glycine, aspartic acid, taurine, glutamic acid, alanine, histidine, serine, arginine, and / or lysine, and combinations thereof. In some embodiments, the aqueous solution and / or dry components may include polyamino acids of the aforementioned amino acids, such as polyproline, polylysine, polyarginine, polyglutamate, polyhistidine, and combinations thereof. In some embodiments, the aqueous solution and / or dry components may include peptides and / or polypeptides rich in the aforementioned amino acids. For example, the aqueous solution and / or dry components may include proline-rich peptides, such as dehydrin, collagen, proline-rich salivary glycoproteins, and combinations thereof. In some embodiments, the aqueous solution and / or dry ingredients may include one or more peptides, such as glutathione, carnosine, betaine, anserine, leucine-enkephalin, oxytocin, vasopressin, melanin-concentrating hormone, and combinations thereof.

[0098]

[0103] In embodiments, the amino acids and / or peptides and / or proteins are provided in the hypertonic hydrogel at about 1 to 40% weight / volume (w / v), for example, about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, and 39% w / v. In some embodiments, the carbohydrate is from about 1 to about 35% w / v, from about 2 to about 30% w / v, from about 3 to about 25% w / v, from about 4 to about 20% w / v, from about 5 to about 10% w / v, from about 5 to about 15% w / v, from about 5 to about 20% w / v, from about 5 to about 25% w / v, from about 5 to about 30% w / v, from about 5 to about 35% w / v, from about 5 to about 40% w / v, from about 10 to about 15% w / v, from about 10 to about 20% w / v, from about 10 to about 25% w / v, from about 10 to about 30% w / v, from about 10 to about 35% w / v, from about 1 0 to about 40% w / v, about 15 to about 20% w / v, about 15 to about 25% w / v, about 15 to about 30% w / v, about 15 to about 35% w / v, about 15 to about 40% w / v, about 20 to about 25% w / v, about 20 to about 30% w / v, about 20 to about 35% w / v, about 20 to about 40% w / v, about 25 to about 30% w / v, about 25 to about 35% w / v, about 25 to about 40% w / v, about 30 to about 35% w / v, about 30 to about 40% w / v, or about 35% to about 40% w / v.

[0099]

[0104] In embodiments, the hypertonic hydrogel may include one or more other biocompatible compounds. For example, the aqueous solution and / or dry components may include one or more buffers, such as tris(hydroxymethyl)aminomethane (TRIS), bis-tris, tris-hydrochloride, N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid (HEPES), 3-(N-morpholino)propanesulfonic acid (MOPS), 2-(N-morpholino)ethanesulfonic acid (MES), bicine, N-(2-hydroxyethyl)piperazine (HEPPSO), tris(hydroxymethyl)methylaminopropanesulfonic acid (TAPS), and / or piperazine-N,N'-bis(2-ethanesulfonic acid) (PIPES), and combinations thereof; one or more water-soluble polymers, such as polyethylene glycol, polyvinylpyrrolidone, and the like. lolidone, polyethyleneimine, polyacrylic acid, polyvinyl alcohol, and sodium hyaluronate, etc.; one or more quaternary ammonium compounds, such as choline chloride, trimethylamine N-oxide, proline betaine, dimethylsulfoniopropionate, and / or sarcosine betaine, and combinations thereof; and / or one or more surfactants, such as polysorbate 80, polysorbate 20, cetyltrimethylammonium bromide, sodium dodecyl sulfate, poloxamer, Triton X-100, sodium deoxycholate, and / or 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid (CHAPS), and combinations thereof. It will be understood that the one or more biocompatible compounds may be provided at any concentration sufficient to achieve the desired osmolality.

[0100]

[0105] In some embodiments, the hypertonic hydrogel may comprise one or more salts in combination with one or more organic acids and / or acid salts thereof. In some embodiments, the hypertonic hydrogel may comprise one or more salts in combination with one or more carbohydrates. In some embodiments, the hypertonic hydrogel may comprise one or more salts in combination with one or more organic acids and / or acid salts thereof and / or one or more carbohydrates. In some embodiments, the hypertonic hydrogel may comprise one or more salts in combination with one or more monohydric alcohols and / or polyhydric alcohols. In some embodiments, the hypertonic hydrogel may comprise one or more salts in combination with one or more amino acids and / or peptides and / or proteins. In some embodiments, the hypertonic hydrogel may comprise one or more salts in combination with one or more other biocompatible compounds. In some embodiments, the hypertonic hydrogel may comprise one or more salts in combination with one or more organic acids and / or acid salts thereof, one or more carbohydrates, and / or one or more monohydric alcohols and / or polyhydric alcohols. In some embodiments, the hypertonic hydrogel may comprise one or more salts in combination with one or more organic acids and / or acid salts thereof, one or more carbohydrates, one or more monohydric alcohols and / or polyhydric alcohols, and / or one or more amino acids and / or peptides and / or proteins. In some embodiments, the hypertonic hydrogel may comprise one or more salts in combination with one or more organic acids and / or acid salts thereof, one or more carbohydrates, one or more monohydric alcohols and / or polyhydric alcohols, one or more amino acids and / or one or more other biocompatible compounds.

[0101]

[0106] It will be understood that the concentration of the one or more additional materials can vary based on the formulation of the hypertonic hydrogel. For example, if a hypertonic hydrogel is formulated with one or more salts and one or more carbohydrates, the hypertonic solution may contain a lower concentration of the one or more salts than a hypertonic solution formulated with only one or more salts, but may have a similar osmolality.

[0102] Hypotonic hydrogel

[0107] In some embodiments, the present disclosure relates to hypotonic hydrogels. In embodiments, the hydrogels are formulated to be hypotonic with respect to a target tissue, drawing fluid into the target tissue and causing cell lysis. In embodiments, the hypotonic hydrogels can be placed adjacent to cancerous tumors. In embodiments, the hydrogels can be formulated such that the osmolality of the hydrogel is less than 280 mOsm / L.

[0103]

[0108] In embodiments, the osmolality of the hypotonic hydrogel can be from about 0 mOsm / L to about 280 mOsm / L, e.g., about 20, 40, 50, 60, 80, 100, 120, 140, 150, 160, 180, 200, 220, 240, 250, and 260 mOsm / L. In some embodiments, the osmolality of the hydrogel can be within a range having endpoints defined by any two of the foregoing values. In some embodiments, the osmolality is from about 0 to about 260 mOsm / L, from about 0 to about 250 mOsm / L, from about 0 to about 240 mOsm / L, from about 0 to about 220 mOsm / L, from about 0 to about 200 mOsm / L, from about 0 to about 180 mOsm / L, from about 0 to about 160 mOsm / L, from about 0 to about 150 mOsm / L, from about 0 to about 140 mOsm / L, from about 0 to about 120 mOsm / L, from about 0 to about 100 mOsm / L, from about 0 to about 80 mOsm / L, from about 0 to about 60 mOsm / L, L, about 0 to about 50 mOsm / L, about 0 to about 40 mOsm / L, about 0 to about 20 mOsm / L, about 20 to about 280 mOsm / L, about 20 to about 260 mOsm / L, about 20 to about 250 mOsm / L, about 20 to about 240 mOsm / L, about 20 to about 220 mOsm / L, about 20 to about 200 mOsm / L, about 20 to about 180 mOsm / L, about 20 to about 160 mOsm / L, about 20 to about 150 mOsm / L, about 20 to about 140 mOsm / L, about 20 to about 120 mOsm / L, about 20 to about 100 mOsm / L, about 20 to about 80 mOsm / L, about 20 to about 60 mOsm / L, about 20 to about 50 mOsm / L, about 20 to about 40 mOsm / L, about 40 to about 280 mOsm / L, about 40 to about 260 mOsm / L, about 40 to about 250 mOsm / L, about 40 to about 240 mOsm / L, about 40 to about 220 mOsm / L, about 40 to about 200 mOsm / L, about 40 to about 180 mOsm / L, about 40 to about 160 mOsm / L, about 40 to about 150 mOsm / L, about 40 to about 140 mOsm / L, about 40 to about 120 mOsm / L, about 40 to about 100 mOsm / L, about 40 to about 80 mOsm / L, about 40 to about 60 mOsm / L, about 40 to about 50 mOsm / L, about 50 to about 280 mOsm / L, about 50 to about 250 mOsm / L, about 50 to about 200 mOsm / L, about 50 to about 150 mOsm / L, about 50 to about 100 mOsm / L,About 60 to about 280 mOsm / L, about 60 to about 260 mOsm / L, about 60 to about 250 mOsm / L, about 60 to about 240 mOsm / L, about 60 to about 220 mOsm / L, about 60 to about 200 mOsm / L, about 60 to about 180 mOsm / L, about 60 to about 160 mOsm / L, about 60 to about 150 mOsm / L, about 60 to about 140 mOsm / L, about 60 to about 120 mOsm / L, about 60 to about 100 mOsm / L, about 60 to about 80 mOsm / L, about 80 to about 280 mOsm / L, about 80 to about 260 mOsm / L, about 80 to about 250mOsm / L, about 80 to about 240mOsm / L, about 80 to about 220mOsm / L, about 80 to about 200mOsm / L, about 80 to about 180mOsm / L, about 80 to about 160mOsm / L, about 80 to about 150mOsm / L, about 80 to about 140mOsm / L, about 80 to about 120mOsm / L, about 80 to about 100mOsm / L, about 100 to about 280mOsm / L, about 100 to about 260mOsm / L, about 100 to about 250mOsm / L, about 100 to about 240mOsm / L, about 100 to about 220mOsm / L, about 10 0 to about 200 mOsm / L, about 100 to about 180 mOsm / L, about 100 to about 160 mOsm / L, about 100 to about 150 mOsm / L, about 100 to about 140 mOsm / L, about 100 to about 120 mOsm / L, about 120 to about 280 mOsm / L, about 120 to about 260 mOsm / L, about 120 to about 250 mOsm / L, about 120 to about 240 mOsm / L, about 120 to about 220 mOsm / L, about 120 to about 200 mOsm / L, about 120 to about 180 mOsm / L, about 120 to about 160 mOsm / L, about 120 to about 150 mOsm / L, about 120 to about 140 mOsm / L, about 140 to about 280 mOsm / L, about 140 to about 260 mOsm / L, about 140 to about 250 mOsm / L, about 140 to about 240 mOsm / L, about 140 to about 220 mOsm / L, about 140 to about 200 mOsm / L, about 140 to about 180 mOsm / L, about 140 to about 160 mOsm / L, about 140 to about 150 mOsm / L, about 150 mOsm / L to about 280 mOsm / L, about 150 mOsm / L to about 250 mOsm / L, about 150 mOsm / L to about 200 mOsm / L,About 150 mOsm / L to about 180 mOsm / L, about 160 to about 280 mOsm / L, about 160 to about 260 mOsm / L, about 160 to about 250 mOsm / L, about 160 to about 240 mOsm / L, about 160 to about 220 mOsm / L, about 160 to about 200 mOsm / L, about 160 to about 180 mOsm / L, about 180 to about 280 mOsm / L, about 180 to about 260 mOsm / L, about 180 to about 250 mOsm / L, about 180 to about 240 mOsm / L, about 180 to about 220 mOsm / L, about 180 to about 200 mOsm / L, about 200 to about 280 mOsm / L Osm / L, about 200 to about 260 mOsm / L, about 200 to about 250 mOsm / L, about 200 to about 240 mOsm / L, about 200 to about 220 mOsm / L, about 220 to about 280 mOsm / L, about 220 to about 260 mOsm / L, about 220 to about 250 mOsm / L, about 220 to about 240 mOsm / L, about 240 to about 280 mOsm / L, about 240 to about 260 mOsm / L, about 240 to about 250 mOsm / L, about 250 to about 280 mOsm / L, about 250 to about 260 mOsm / L, or about 260 mOsm / L to about 280 mOsm / L.

[0104]

[0109] In embodiments, no osmotic component is added to the monomer units, complexing molecules, or aqueous hydration solution. In some embodiments, the hypotonic hydrogel is formulated using one or more hypotonic aqueous hydration solutions, such as distilled water, reverse osmosis water, ethanol, hypotonic saline, dextrose, and combinations thereof. In some embodiments, the hypotonic hydrogel contains only the monomer units, complexing molecules, and aqueous hydration solution.

[0105]

[0110] In embodiments, the aqueous solution and / or dry components may include any soluble material at a concentration sufficient to form a hypotonic hydrogel. In some embodiments, the aqueous solution and / or dry components may include one or more salts, one or more organic acids and / or acid salts thereof, one or more carbohydrates, one or more monohydric alcohols and / or polyhydric alcohols, one or more amino acids and / or peptides and / or proteins, one or more other biocompatible components, and combinations thereof. It will be understood that the one or more osmotic components may be provided in any concentration or combination that results in a hypotonic hydrogel having an osmolality of less than 280 mOsm / L.

[0106]

[0111] In some embodiments, the hypotonic hydrogel may include one or more salts. For example, the aqueous solution and / or dry components may include sodium chloride, calcium chloride, potassium chloride, barium sulfate, magnesium chloride, sodium bicarbonate, sodium phosphate, sodium sulfate, potassium phosphate, potassium sulfate, calcium phosphate, ammonium sulfate, barium chloride, copper sulfate, iron chloride, iron sulfate, lithium chloride, magnesium sulfate, manganese sulfate, nickel sulfate, potassium carbonate, potassium bromide, potassium chloride, potassium iodide, silver nitrate, sodium bromide, sodium carbonate, sodium chlorate, sodium nitrate, sodium pyrophosphate, zinc sulfate, and combinations thereof. In some embodiments, the aqueous solution and / or dry components may include one or more salts whose cations are alkali metals and / or alkaline earth metals, or combinations thereof. In some embodiments, the aqueous solution and / or dry components may include one or more salts whose anions are halides, nonmetals, oxoanions, and / or amides, or combinations thereof. In some embodiments, the salts may be acid salts, as described in more detail below.

[0107]

[0112] In embodiments, the hypotonic hydrogel can include one or more organic acids or acid salts thereof, such as acetic acid, adipic acid, ascorbic acid, citric acid, phosphoric acid, tartaric acid, malic acid, succinic acid, fumaric acid, formic acid, gluconic acid, lactic acid, glycolic acid, pyruvic acid, oxalic acid, benzoic acid, cinnamic acid, ferulic acid, butyric acid, propionic acid, gallic acid, itaconic acid, maleic acid, mandelic acid, nicotinic acid, phthalic acid, salicylic acid, shikimic acid, uric acid, and / or valeric acid, and combinations thereof.

[0108]

[0113] In embodiments, the hypotonic hydrogel may include one or more acid salts of the aforementioned organic acids. In some embodiments, the aqueous solution and / or dry components may include one or more acid salts whose cations are alkali metals and / or alkaline earth metals, or combinations thereof. In some embodiments, the hypertonic hydrogel may include one or more acid salts whose anions are lactate, acetate, citrate, malate, pyruvate, citrate, phosphate, ascorbate, succinate, oxalate, gluconate, tartrate, carbonate, and / or combinations thereof.

[0109]

[0114] In embodiments, the hypotonic hydrogel can include one or more carbohydrates, such as dextrose, fructose, sucrose, lactose, maltose, trehalose, galactose, dextran, xylose, mannose, ribose, isomaltase, inulin, cyclodextrin, hydroxyethyl starch (HES), pullulan, pectin, xanthan gum, agarose, cellulose, hyaluronic acid, maltodextrin, methylcellulose, alginate, chitosan, heparin, and / or heparan sulfate, and combinations thereof.

[0110]

[0115] In embodiments, the hypotonic hydrogel can include one or more monohydric and / or polyhydric alcohols, such as ethanol, 1-propanol, propylene glycol, ethylene glycol, xylitol, sorbitol, erythritol, mannitol, isomalt, maltitol, lactitol, arabitol, ribitol, glycerol, threitol, dulcitol, inositol, idithiol, adonitol, and / or galactitol, and combinations thereof.

[0111]

[0116] In embodiments, the hypotonic hydrogel may include one or more amino acids. For example, the aqueous solution and / or dry components may include glutamic acid, aspartic acid, cysteine, tyrosine, taurine, histidine, arginine, and / or lysine, and combinations thereof. In some embodiments, the aqueous solution and / or dry components may include polyamino acids of the aforementioned amino acids, such as, but not limited to, polylysine, polyarginine, polyglutamate, polyhistidine, and combinations thereof. In some embodiments, the aqueous solution and / or dry components may include peptides and / or polypeptides rich in the aforementioned amino acids.

[0112]

[0117] In embodiments, the hypotonic hydrogel may include one or more other biocompatible compounds. For example, the aqueous solution and / or dry components may include one or more buffers, such as tris(hydroxymethyl)aminomethane (TRIS), bis-tris, tris-hydrochloride, N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid (HEPES), 3-(N-morpholino)propanesulfonic acid (MOPS), 2-(N-morpholino)ethanesulfonic acid (MES), bicine, N-(2-hydroxyethyl)piperazine (HEPPSO), tris(hydroxymethyl)methylamino]propanesulfonic acid (TAPS), and / or piperazine-N,N'-bis(2-ethanesulfonic acid) (PIPES), and combinations thereof; one or more water-soluble polymers, such as polyethylene glycol, polyvinyl alcohol, or the like. pyrrolidone, polyethyleneimine, polyacrylic acid, polyvinyl alcohol, and sodium hyaluronate, etc.; one or more quaternary ammonium compounds, such as choline chloride, trimethylamine N-oxide, proline betaine, dimethylsulfoniopropionate, and / or sarcosine betaine, and combinations thereof; and / or one or more surfactants, such as polysorbate 80, polysorbate 20, cetyltrimethylammonium bromide, sodium dodecyl sulfate, poloxamer, Triton X-100, sodium deoxycholate, and / or 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid (CHAPS), and combinations thereof. It will be understood that the one or more biocompatible compounds may be provided at any concentration sufficient to achieve the desired osmolality.

[0113]

[0118] In some embodiments, hypotonic hydrogels may include one or more salts in combination with one or more organic acids and / or acid salts thereof. In some embodiments, hypotonic hydrogels may include one or more salts in combination with one or more carbohydrates. In some embodiments, hypotonic hydrogels may include one or more salts in combination with one or more organic acids and / or acid salts thereof and / or one or more carbohydrates. In some embodiments, hypotonic hydrogels may include one or more salts in combination with one or more monohydric alcohols and / or polyhydric alcohols. In some embodiments, hypotonic hydrogels may include one or more salts in combination with one or more amino acids and / or peptides and / or proteins. In some embodiments, hypotonic hydrogels may include one or more salts in combination with one or more other biocompatible compounds. In some embodiments, hypotonic hydrogels can include one or more salts in combination with one or more organic acids and / or acid salts thereof, one or more carbohydrates, and / or one or more monohydric alcohols and / or polyhydric alcohols. In some embodiments, hypotonic hydrogels can include one or more salts in combination with one or more organic acids and / or acid salts thereof, one or more carbohydrates, one or more monohydric alcohols and / or polyhydric alcohols, and / or one or more amino acids and / or peptides and / or proteins. In some embodiments, hypotonic hydrogels can include one or more salts in combination with one or more organic acids and / or acid salts thereof, one or more carbohydrates, one or more monohydric alcohols and / or polyhydric alcohols, one or more amino acids and / or one or more other biocompatible compounds.

[0114] Isotonic hydrogel

[0119] In some embodiments, the present disclosure relates to isotonic hydrogels. In embodiments, the hydrogels are formulated to be isotonic with respect to target and / or non-target tissues, thereby balancing the osmotic pressure between the tissues and the hydrogel spacer. In embodiments, the isotonic hydrogels can be placed adjacent to non-target tissues to provide a protective layer. In embodiments, the hydrogels can be formulated to have an osmotic pressure of about 290 mOsm / L.

[0115]

[0120] In embodiments, the osmolality of an isotonic hydrogel can be from about 280 mOsm / L to about 300 mOsm / L, e.g., about 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, and 299 mOsm / L. In some embodiments, the osmolality of the hydrogel can be within a range having endpoints defined by any two of the foregoing values. In some embodiments, the osmolality is about 280 to about 299 mOsm / L, about 280 to about 298 mOsm / L, about 280 to about 297 mOsm / L, about 280 to about 296 mOsm / L, about 280 to about 295 mOsm / L, about 280 to about 294 mOsm / L, about 280 to about 293 mOsm / L, about 280 to about 292 mOsm / L, about 280 to about 291 mOsm / L, about 280 to about 290 mOsm / L, or about 280 to about 289 mOsm / L. , about 280 to about 288 mOsm / L, about 280 to about 287 mOsm / L, about 280 to about 286 mOsm / L, about 280 to about 285 mOsm / L, about 280 to about 284 mOsm / L, about 280 to about 283 mOsm / L, about 280 to about 282 mOsm / L, about 280 to about 281 mOsm / L, about 281 to about 299 mOsm / L, about 281 to about 298 mOsm / L, about 281 to about 297 mOsm / L, about 281 to about 296 mOsm / L Osm / L, about 281 to about 295mOsm / L, about 281 to about 294mOsm / L, about 281 to about 293mOsm / L, about 281 to about 292mOsm / L, about 281 to about 291mOsm / L, about 281 to about 290mOsm / L, about 281 to about 289mOsm / L, about 281 to about 288mOsm / L, about 281 to about 287mOsm / L, about 281 to about 286mOsm / L, about 281 to about 285mOsm / L, about 281 to about 288mOsm / L to about 284 mOsm / L, about 281 to about 283 mOsm / L, about 281 to about 282 mOsm / L, about 282 to about 299 mOsm / L, about 282 to about 298 mOsm / L, about 282 to about 297 mOsm / L, about 282 to about 296 mOsm / L, about 282 to about 295 mOsm / L, about 282 to about 294 mOsm / L, about 282 to about 293 mOsm / L, about 282 to about 292 mOsm / L, about 282 to about 291 mOsm / L,About 282 to about 290 mOsm / L, about 282 to about 289 mOsm / L, about 282 to about 288 mOsm / L, about 282 to about 287 mOsm / L, about 282 to about 286 mOsm / L, from about 282 to about 285 mOsm / L, about 282 to about 284 mOsm / L, about 282 to about 283 mOsm / L, about 283 to about 299 mOsm / L, about 283 to about 298 mOsm / L, about 283 to about 297 mOsm / L, about 283 to about 296 mOsm / L, about 283 to about 295 mOsm / L, about 283 to about 294 ...6 mOsm / L, about 283 to about 295 mOsm / L, about 283 to about 294 mOsm / L, about 283 to about 299 mOsm / L, about 283 to about 298 mOsm / L, about 283 to about 296 mOsm / L, about 283 to to about 293 mOsm / L, about 283 to about 292 mOsm / L, about 283 to about 291 mOsm / L, about 283 to about 290 mOsm / L, about 283 to about 289 mOsm / L, about 283 to about 288 mOsm / L, about 283 to about 287 mOsm / L, about 283 to about 286 mOsm / L, about 283 to about 285 mOsm / L, about 283 to about 284 mOsm / L, about 284 to about 299 mOsm / L, about 284 to about 298 mOsm / L, about 284 to about 297 mOsm / L, about 284 to about 296 mOsm / L, about 284 to about 295 mOsm / L L, about 284 to about 294 mOsm / L, about 284 to about 293 mOsm / L, about 284 to about 292 mOsm / L, about 284 to about 291 mOsm / L, about 284 to about 290 mOsm / L, about 284 to about 289 mOsm / L, about 284 to about 288 mOsm / L, about 284 to about 287 mOsm / L, about 284 to about 286 mOsm / L, about 284 to about 285 mOsm / L, about 285 to about 299 mOsm / L, about 285 to about 298 mOsm / L, about 285 to about 297 mOsm / L, about 285 to about 296 mOsm / L, about 285 to about 295mOsm / L, about 285 to about 294mOsm / L, about 285 to about 293mOsm / L, about 285 to about 292mOsm / L, about 285 to about 291mOsm / L, about 285 to about 290mOsm / L, about 285 to about 289mOsm / L, about 285 to about 288mOsm / L, about 285 to about 287mOsm / L, about 285 to about 286mOsm / L, about 286 to about 299mOsm / L, about 286 to about 298mOsm / L, about 286 to about 297mOsm / L, about 286 to about 296mOsm / L, about 286 to about 295mOsm / L,About 286 to about 294 mOsm / L, about 286 to about 293 mOsm / L, about 286 to about 292 mOsm / L, about 286 to about 291 mOsm / L, about 286 to about 290 mOsm / L, about 286 to about 289 mOsm / L, about 286 to about 288 mOsm / L, about 286 to about 287 mOsm / L, about 287 to about 299 mOsm / L, about 287 to about 298 mOsm / L, about 287 to about 297 mOsm / L, about 287 to about 296 mOsm / L, about 287 to about 295 mOsm / L, about 287 to about 294 mOsm / L, about 287 to about 298 ...9 mOsm / L, about 287 to about 299 mOsm / L, about 287 to about 299 mOsm / L, about 287 to about 299 mOsm / L, about 287 to about 299 mOsm / L, about 287 to about 93 mOsm / L, about 287 to about 292 mOsm / L, about 287 to about 291 mOsm / L, about 287 to about 290 mOsm / L, about 287 to about 289 mOsm / L, about 287 to about 288 mOsm / L, about 288 to about 299 mOsm / L, about 288 to about 298 mOsm / L, about 288 to about 297 mOsm / L, about 288 to about 296 mOsm / L, about 288 to about 295 mOsm / L, about 288 to about 294 mOsm / L, about 288 to about 293 mOsm / L, about 288 to about 292 mOsm / L, about 288 to about 291 mOsm / L, About 288 to about 290 mOsm / L, about 288 to about 289 mOsm / L, about 289 to about 299 mOsm / L, about 289 to about 298 mOsm / L, about 289 to about 297 mOsm / L, about 289 to about 296 mOsm / L, about 289 to about 295 mOsm / L, about 289 to about 294 mOsm / L, about 289 to about 293 mOsm / L, about 289 to about 292 mOsm / L, about 289 to about 291 mOsm / L, about 289 to about 290 mOsm / L, about 290 to about 299 mOsm / L, about 290 to about 298 ... 97 mOsm / L, about 290 to about 296 mOsm / L, about 290 to about 295 mOsm / L, about 290 to about 294 mOsm / L, about 290 to about 293 mOsm / L, about 290 to about 292 mOsm / L, about 290 to about 291 mOsm / L, about 291 to about 299 mOsm / L, about 291 to about 298 mOsm / L, about 291 to about 297 mOsm / L, about 291 to about 296 mOsm / L, about 291 to about 295 mOsm / L, about 291 to about 294 mOsm / L, about 291 to about 293 mOsm / L, about 291 to about 292 mOsm / L,About 292 to about 299 mOsm / L, about 292 to about 298 mOsm / L, about 292 to about 297 mOsm / L, about 292 to about 296 mOsm / L, about 292 to about 295 mOsm / L, about 292 to about 294 mOsm / L, about 292 to about 293 mOsm / L, about 293 to about 299 mOsm / L, about 293 to about 298 mOsm / L, about 293 to about 297 mOsm / L, about 293 to about 296 mOsm / L, about 293 to about 295 mOsm / L, about 293 to about 294 mOsm / L, about 294 to about 299 mOsm / L, about 294 to about 298 mOsm / L Osm / L, about 294 to about 297 mOsm / L, about 294 to about 296 mOsm / L, about 294 to about 295 mOsm / L, about 295 to about 299 mOsm / L, about 295 to about 298 mOsm / L, about 295 to about 297 mOsm / L, about 295 to about 296 mOsm / L, about 296 to about 299 mOsm / L, about 296 to about 298 mOsm / L, about 296 to about 297 mOsm / L, about 297 to about 299 mOsm / L, about 297 to about 298 mOsm / L, about 298 to about 299 mOsm / L, or about 299 to about 300 mOsm / L.

[0116]

[0121] In embodiments, the aqueous solution and / or dry components may include any soluble material at a concentration sufficient to produce an isotonic hydrogel. In some embodiments, the aqueous solution and / or dry components may include one or more salts, one or more organic acids and / or acid salts thereof, one or more carbohydrates, one or more monohydric alcohols and / or polyhydric alcohols, one or more amino acids and / or peptides and / or proteins, one or more other biocompatible components, and combinations thereof. It will be understood that the one or more osmotic components may be provided in any concentration and / or combination that results in an isotonic hydrogel having an osmolality of between about 280 mOsm / L and 300 mOsm / L.

[0117]

[0122] In some embodiments, the isotonic hydrogel may include one or more salts. For example, the aqueous solution and / or dry components may include sodium chloride, calcium chloride, potassium chloride, barium sulfate, magnesium chloride, sodium bicarbonate, sodium phosphate, sodium sulfate, potassium phosphate, potassium sulfate, calcium phosphate, ammonium sulfate, barium chloride, copper sulfate, iron chloride, iron sulfate, lithium chloride, magnesium sulfate, manganese sulfate, nickel sulfate, potassium carbonate, potassium bromide, potassium chloride, potassium iodide, silver nitrate, sodium bromide, sodium carbonate, sodium chlorate, sodium nitrate, sodium pyrophosphate, zinc sulfate, and combinations thereof. In some embodiments, the aqueous solution and / or dry components may include one or more salts whose cations are alkali metals and / or alkaline earth metals, or combinations thereof. In some embodiments, the aqueous solution and / or dry components may include one or more salts whose anions are halides, nonmetals, oxoanions, and / or amides, or combinations thereof. In some embodiments, the salts may be acid salts, as described in more detail below.

[0118]

[0123] In embodiments, the isotonic hydrogel can include one or more organic acids or acid salts thereof, such as acetic acid, adipic acid, ascorbic acid, citric acid, phosphoric acid, tartaric acid, malic acid, succinic acid, fumaric acid, formic acid, gluconic acid, lactic acid, glycolic acid, pyruvic acid, oxalic acid, benzoic acid, cinnamic acid, ferulic acid, butyric acid, propionic acid, gallic acid, itaconic acid, maleic acid, mandelic acid, nicotinic acid, phthalic acid, salicylic acid, shikimic acid, uric acid, and / or valeric acid, and combinations thereof.

[0119]

[0124] In embodiments, the isotonic hydrogel can include one or more acid salts of the aforementioned organic acids. In some embodiments, the aqueous solution and / or dry components can include one or more acid salts whose cations are alkali metals and / or alkaline earth metals, or combinations thereof. In some embodiments, the isotonic hydrogel can include one or more acid salts whose anions are lactate, acetate, citrate, malate, pyruvate, citrate, phosphate, ascorbate, succinate, oxalate, gluconate, tartrate, carbonate, and / or combinations thereof.

[0120]

[0125] In embodiments, the isotonic hydrogel can include one or more carbohydrates, such as dextrose, fructose, sucrose, lactose, maltose, trehalose, galactose, dextran, xylose, mannose, ribose, isomaltase, inulin, cyclodextrin, hydroxyethyl starch (HES), pullulan, pectin, xanthan gum, agarose, cellulose, hyaluronic acid, maltodextrin, methylcellulose, alginate, chitosan, heparin, and / or heparan sulfate, and combinations thereof.

[0121]

[0126] In embodiments, the isotonic hydrogel can include one or more monohydric and / or polyhydric alcohols, such as ethanol, 1-propanol, propylene glycol, ethylene glycol, xylitol, sorbitol, erythritol, mannitol, isomalt, maltitol, lactitol, arabitol, ribitol, glycerol, threitol, dulcitol, inositol, idithiol, adonitol, and / or galactitol, and combinations thereof.

[0122]

[0127] In embodiments, the isotonic hydrogel may include one or more amino acids. For example, the aqueous solution and / or dry components may include glutamic acid, aspartic acid, cysteine, tyrosine, taurine, histidine, arginine, and / or lysine, and combinations thereof. In some embodiments, the aqueous solution and / or dry components may include polyamino acids of the aforementioned amino acids, such as, but not limited to, polylysine, polyarginine, polyglutamate, polyhistidine, and combinations thereof. In some embodiments, the aqueous solution and / or dry components may include peptides and / or polypeptides rich in the aforementioned amino acids.

[0123]

[0128] In embodiments, the isotonic hydrogel may include one or more other biocompatible compounds. For example, the aqueous solution and / or dry components may include one or more buffers, such as tris(hydroxymethyl)aminomethane (TRIS), bis-tris, tris-hydrochloride, N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid (HEPES), 3-(N-morpholino)propanesulfonic acid (MOPS), 2-(N-morpholino)ethanesulfonic acid (MES), bicine, N-(2-hydroxyethyl)piperazine (HEPPSO), tris(hydroxymethyl)methylamino]propanesulfonic acid (TAPS), and / or piperazine-N,N'-bis(2-ethanesulfonic acid) (PIPES), and combinations thereof; one or more water-soluble polymers, such as polyethylene glycol, polyvinyl alcohol, or the like. pyrrolidone, polyethyleneimine, polyacrylic acid, polyvinyl alcohol, and sodium hyaluronate, etc.; one or more quaternary ammonium compounds, such as choline chloride, trimethylamine N-oxide, proline betaine, dimethylsulfoniopropionate, and / or sarcosine betaine, and combinations thereof; and / or one or more surfactants, such as polysorbate 80, polysorbate 20, cetyltrimethylammonium bromide, sodium dodecyl sulfate, poloxamer, Triton X-100, sodium deoxycholate, and / or 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid (CHAPS), and combinations thereof. It will be understood that the one or more biocompatible compounds may be provided at any concentration sufficient to achieve the desired osmolality.

[0124]

[0129] In some embodiments, isotonic hydrogels can include one or more salts in combination with one or more organic acids and / or acid salts thereof. In some embodiments, isotonic hydrogels can include one or more salts in combination with one or more carbohydrates. In some embodiments, isotonic hydrogels can include one or more salts in combination with one or more organic acids and / or acid salts thereof and / or one or more carbohydrates. In some embodiments, isotonic hydrogels can include one or more salts in combination with one or more monohydric alcohols and / or polyhydric alcohols. In some embodiments, isotonic hydrogels can include one or more salts in combination with one or more amino acids and / or peptides and / or proteins. In some embodiments, isotonic hydrogels can include one or more salts in combination with one or more other biocompatible compounds. In some embodiments, the isotonic hydrogel may comprise one or more salts in combination with one or more organic acids and / or acid salts thereof, one or more carbohydrates, and / or one or more monohydric alcohols and / or polyhydric alcohols. In some embodiments, the isotonic hydrogel may comprise one or more salts in combination with one or more organic acids and / or acid salts thereof, one or more carbohydrates, one or more monohydric alcohols and / or polyhydric alcohols, and / or one or more amino acids and / or peptides and / or proteins. In some embodiments, the isotonic hydrogel may comprise one or more salts in combination with one or more organic acids and / or acid salts thereof, one or more carbohydrates, one or more monohydric alcohols and / or polyhydric alcohols, one or more amino acids and / or one or more other biocompatible compounds.

[0125] Osmotically imbalanced layered hydrogel

[0130] As described in the methods for preparing hydrogels and osmotic hydrogels, osmotically imbalanced layered hydrogels can be provided having one or more osmotically imbalanced layers. A further aspect of the present disclosure is that the hydrogels can include multiple layers, such that the layered hydrogel includes one or more protective layers and one or more therapeutic layers.

[0126]

[0131] In some embodiments, the osmotically imbalanced hydrogel may be a layered hydrogel, as described in more detail herein, and may have one or more osmotically imbalanced layers. For example, the layered hydrogel may have 2, 3, 4, 5, 6, 7, 8, 9, 10, or more layers. Each layer of the multiple layers may be independently formulated to be hypertonic, hypotonic, or isotonic.

[0127]

[0132] In embodiments, the osmotically imbalanced hydrogel protective layer comprises an isotonic hydrogel such that the hydrogel is osmotically balanced with respect to the adjacent tissue. In embodiments, the laminar hydrogel protective layer is delivered adjacent to a non-target tissue.

[0128]

[0133] In embodiments, the therapeutic layer of osmotically imbalanced hydrogel comprises an osmotically imbalanced hydrogel such that the hydrogel is hypertonic and / or hypotonic relative to the adjacent tissue, hi embodiments, the therapeutic layer of layered hydrogel is delivered adjacent to the target tissue.

[0129]

[0134] In embodiments, the therapeutic layer is hypertonic with respect to the target tissue. In embodiments, the therapeutic layer creates an osmotic gradient, creating hyperosmotic stress in the target tissue and causing cell death. In embodiments, the target tissue is a cancerous tumor. In embodiments, the target tissue is a prostate tumor.

[0130]

[0135] In embodiments, the therapeutic layer is hypotonic with respect to the target tissue. In embodiments, the therapeutic layer creates an osmotic gradient, creating hypoosmotic stress in the target tissue and causing cell lysis. In embodiments, the target tissue is a cancerous tumor. In embodiments, the target tissue is a prostate tumor.

[0131] Filled hydrogel

[0136] In embodiments, the hydrogel may contain one or more additional materials, such as additional materials that are released upon degradation of the hydrogel. Such materials may include materials embedded in the hydrogel described herein. In some embodiments, the hydrogel may be embedded with a material that rapidly releases the material after injection of the hydrogel. In some embodiments, the hydrogel may be embedded with a material that delivers a payload of the released material. In some embodiments, the hydrogel may be embedded with a permanent material, such as a marker, that allows for rapid identification of the treated site both during the lifespan of the gel and after the hydrogel has completely degraded.

[0132]

[0137] As described in the method for preparing a hydrogel, two separate solutions are required, each prepared by hydrating dried monomer units and dried complexing molecules. A further aspect of the present disclosure is that the hydrogel may include one or more additional components. Because each of the two solutions required to form the hydrogel requires hydration of monomers and complexing molecules, it will be apparent that the additional components may be provided either in dry form, in addition to the monomer units and / or complexing molecules, and / or in aqueous solution in the hydration solution used to hydrate the monomer units and / or complexing molecules.

[0133] Embedded components

[0138] In some embodiments, the hydrogels of the present disclosure can contain one or more embedded components. As described herein, the hydrogels of the present disclosure are formed in situ through the application of two separate aqueous solutions that are mixed together at a desired location. As described herein, one solution contains monomer units, and the other solution contains complexing molecules. An aspect of the present disclosure is that either of these two solutions can contain one or more additional materials that become embedded within the hydrogel as it forms. For example, the embedded component can include a tissue marker, a therapeutic agent, microparticles and / or nanoparticles, a radiopaque marker, a crystalline therapeutic agent, a radioactive particle, a radioprotector, a radiosensitizer, a reactive oxygen species, or a combination thereof. In some embodiments, both solutions can contain the same embedded component.

[0134]

[0139] In specific aspects of the present disclosure, the embedded component is provided in a hydrogel for delivering a payload of the embedded component, the majority of which is delivered in situ to the patient in a burst release. As specified herein, the burst release can be adjusted or tailored to specific needs, for example, by triggering the release with chemical, electrical, or mechanical stimuli. In some aspects, the burst release can be adjusted or tailored by varying the concentration of the embedded component adsorbed or bound to the surface of the hydrogel.

[0135]

[0140] In particular aspects of the present disclosure, the embedded component is provided in a hydrogel for delivering a payload of the embedded component, the entire concentration of which is delivered in situ to a patient as it is released from the hydrogel through degradation of the hydrogel over time. As specified herein, the degradation time of the hydrogel can be adjusted or tailored to suit particular needs. Thus, the concentration of the embedded component can likewise be adjusted to reflect the rate of degradation of the hydrogel or the corresponding release rate from the hydrogel.

[0136]

[0141] Using PEI and PEG-SCM-2 (or NHS-PEG-SCM-2) as examples of monomer units and complexing molecules, two solutions are formed that keep these components separate until injection. For example, the two solutions are prepared by reconstituting a dry aggregate amount of each in a syringe barrel. In some embodiments, a double-barreled syringe can be used. In some embodiments, the two barrels use a needle designed to mix the two solutions simultaneously as they reach or near the needle end, so that the two solutions mix at or near the point of application. In some embodiments, the embedded component is also aggregated and contains PEG-SCM-2 and / or PEI before its reconstitution. The above may dissolve or suspend the embedded component in the solution.

[0137]

[0142] As described herein, hydrogels can have a set degradation time. It will be understood that the degradation time can vary in certain ways because degradation depends on the specific physiology of the patient receiving the hydrogel. However, the hydrogel is expected to degrade completely overall. Therefore, embedding one or more additional components therein provides an opportunity to deliver a payload of embedded contents to the hydrogel over its lifetime. Whether dissolved or suspended, the embedded contents can be released into the subject as the hydrogel degrades.

[0138]

[0143] In some embodiments, the embedded components include one or more therapeutic substances. The therapeutic substance can be dissolved in one or both solutions, e.g., with a hydrophilic therapeutic substance. The therapeutic substance can also be prepared as a suspension of amorphous or crystalline particles, e.g., with a hydrophobic compound, in one or both solutions. The amount of therapeutic substance embedded in the hydrogel can depend on the desired release rate, taking into account the degradation rate of the hydrogel. For example, loading a hydrogel at a final concentration of 5 μg / mL into a hydrogel that degrades at a rate of 1 mL / day allows for the in situ release of 5 μg of therapeutic substance each day. If the hydrogel fills a 25 mL space, the hydrogel is expected to provide 125 μg to the patient over the lifetime of the hydrogel. This assumes a constant rate of degradation, although it should be apparent that the degradation rate need not be constant. In some embodiments, the degradation rate can be affected by the surface area of ​​the hydrogel exposed to the subject's physiology.

[0139]

[0144] In some embodiments, the total dosage of the therapeutic agent required may be small because it is delivered at or near the desired site to be treated. In some embodiments, the site to be treated is adjacent to or in contact with the hydrogel. Site-specific delivery may allow for greater efficacy and therefore smaller dosages. In some embodiments, site-specific delivery may avoid or delay events, such as drug metabolism. In certain embodiments, the therapeutic agent may require metabolism to be effective. In such embodiments, it may be advantageous to use a therapeutic agent that has been modified to exhibit specific metabolic processes, such as hydroxylation, glutathione conjugation, methylation, acetylation, glucuronidation, or glycine conjugation.

[0140]

[0145] In some embodiments, the implanted therapeutic agent is a chemotherapeutic agent. The choice of chemotherapeutic agent may be determined by the type of tumor, malignancy, or cancer. For example, as described in the Examples, hydrogels may be used to fill the space between the prostate and the intestine of a male subject undergoing treatment for prostate cancer. Incorporation of one or more prostate cancer therapeutic agents therein may provide site-specific drug delivery of the chemotherapeutic agent. For example, hydrogels may contain docetaxel, degarelix, abiraterone, apalutamide, bicalutamide, cabazitaxel, darolutamide, leuprolide, enzalutamide, flutamide, goserelin, lutetium Lu, 177 Bipibotide tetraxetan, olaparib, mitoxantrone, nilutamide, relugolix, cyprocel-T, radium-223, rucaparib camsylate, or combinations thereof may be implanted.

[0141]

[0146] Similarly, hydrogels can be used to fill excised tissue spaces, for example, within breast tissue. In such embodiments, the hydrogel may be implanted with raloxifene, tamoxifen, abemaciclib, paclitaxel, trastuzumab, everolimus, alpelisib, anastrozole, pamidronate, exemestane, capecitabine, cyclophosphamide, docetaxel, doxorubicin, elacestrant, epirubicin, eribulin mesylate, fluorouracil, toremifene, fulvestrant, letrozole, gemcitabine, goserelin, palbociclib, ixabepilone, pembrolizumab, ribociclib, lapatinib, olaparib, margetuximab, megestrol, methotrexate, neratinib, pertuzumab, sacituzumab, talazoparib, thiotepa, tucatinib, vinblastine, or combinations thereof.

[0142]

[0147] Other options for therapeutic agents may also be implanted. For example, therapeutic agents include paclitaxel, rapamycin, daunorubicin, 5-fluorouracil, doxorubicin, sunitinib, sorafenib, irinotecan, bevacizumab, cetuximab, biolimus (biolimus A9), everolimus, zotarolimus, tacrolimus, dexamethasone, prednisolone, corticosterone, cisplatin, vinblastine, lidocaine, bupivacaine, bosutinib, ceritinib, crizotinib, gefitinib, and the like. ruxolitinib, imatinib, axitinib, nilotinib, trametinib, afatinib, ibrutinib, cabozantinib, imatinib, lenvatinib, sunitinib, regorafenib, sorafenib, vandetanib, dasatinib, pazopanib, triamciclone, tranilast, halofuginone, montelukast, zafirlukast, pirfenidone, nintedanib, avapritinib, abemaciclib, eldafi Tinib, fedratinib, nilotinib, nintedanib, palbociclib, pemigatinib, xanthines, aminophylline, sildenafil, tadalafil, vardenafil, udenafil, avanafil, dipyridamole, quinazoline, paraxanthine, papaverine, mesembrenone, rolipram, ibudilast, piclamilast, luteolin, drotaverine, roflumilast, apremilast, crisaborole, ina Murinone, milrinone, enoximone, anagrelide, cilostazol, pimobendan, erythro-9-(2-hydroxy-3-nonyl)adenine, (2-[(3,4-dimethoxyphenyl)methyl]-7-[(1R)-1-hydroxyethyl]-4-phenylbutyl]-5-methyl-imidazo[5,1-f][1,2,4]triazin-4(1H)-one), oxindole, (9-(6-phenyl-2-oxohex-3-yl)-2-(3,4-dimethoxybenzyl)-purin-6-one), 3-isobutyl-1-methylxanthine, pentoxifylline, theobromine, theophylline, resveratrol, quercetin, curcumin, chrysin, myricetin, luteolin, apigenin, anthrocyanin, genistein, epigallocatechin gallate, fisetin, astaxanthin, tetrahydrocurcumin, imatinib, nintedanib, sorafenib, sunitinib, pazopanib, ROCK inhibitor (Y27632), YAP / TAZ inhibitor (CA3 and verteporfin), YAP / TAZ-TEAD interaction inhibitor (verteporfin, VGLL4 peptide), SRC inhibitor (dasatinib), and combinations thereof.

[0143]

[0148] In some embodiments, the therapeutic agent is a compound or molecule that sensitizes cells to radiation, making them more responsive to treatment when exposed to a certain amount of radiation. In some embodiments, the hydrogel is embedded with one or more radiosensitizing agents that sensitize cells in the vicinity of the hydrogel to radiation due to site-specific delivery. Examples of such agents include gemcitabine, fluorouracil or 5-fluorouracil, interferon-α, 13-cis-retinoic acid, doxorubicin, docetaxel, carboplatin, cisplatin, dactinomycin, methotrexate, bleomycin, hydroxyurea, cetuximab, nimotuzumab, AMG102, paraoxonase-2 C-reactive peptide, gold, GSH-modified gold, silver, bismuth, palladium, gadolinium, zinc, curcumin, misonidazole, tirapazamine, paclitaxel, resveratrol, mitomycin C, etanidazole, AQ4N, lidocaine, procaine, chloropromazine, fludarabine, motexafin, nicotinamide, and combinations thereof.

[0144]

[0149] In embodiments, the embedded component is a compound or molecule that sensitizes cells to radiation by creating an oxygen-rich environment; when the target tissue receives a certain amount of radiation, the oxygen generates organic peroxide free radicals, making the target tissue more responsive to treatment while leaving non-target tissue unaffected. In some embodiments, the hydrogel contains one or more reactive oxygen species that, due to site-specific delivery, sensitize the target tissue in the vicinity of the hydrogel to radiation. In some embodiments, non-target tissue is not adversely affected by the reactive oxygen species. Examples of suitable reactive oxygen species include, but are not limited to, peroxides, superoxides, hydroxyl radicals, singlet oxygen, and / or alpha-oxygen, and combinations thereof.

[0145]

[0150] In embodiments, the hydrogel can include one or more peroxides. Suitable peroxides include, but are not limited to, peracids, metal peroxides, main group peroxides, and / or organic peroxides. For example, the aqueous solution and / or dry components can include peroxide formamide, dicumyl peroxide, dibenzoyl peroxide, diacyl peroxide, Caro's acid, pernitrates, perdisulfates, hydrogen peroxide, pernitrites, alkyl peroxides, tert-butyl peroxide, and combinations thereof.

[0146]

[0151] In some embodiments, the presence of gas nanoparticles or gas nanobubbles in the hydrogel can sensitize adjacent tissue to radiation treatment. In some embodiments, nanobubbles can comprise a lipid monolayer or lipid bilayer membrane encapsulating a gas, e.g., oxygen or perfluorocarbon, core. In some embodiments, nanobubbles can be released and accumulate around and within diseased tissue due to their enhanced permeability. Application of energy, e.g., using ultrasound, can then produce hypercavitation and ultimately shear stress in tumor cells.

[0147]

[0152] In some embodiments, the therapeutic agent is a compound or molecule that provides protection to tissue from radiation or is a radioprotectant. In some embodiments, the hydrogels of the present disclosure can be formed, placed within, or in contact with tissue that will be exposed to radiation treatment of adjacent or nearby tissue. The inclusion of a radioprotectant in the hydrogel provides site-specific delivery of radioprotection to potentially radiation-sensitive tissue, thereby reducing the potential for adverse effects on normal or healthy tissue. The radioprotectant can be selected from, or can be selected from, amifostine, palifermin, superoxide dismutase, tetracycline, genistein, captopril, lisinopril, 3,3'-diindolylmethane, rapamycin, CBLB502, ON01210, gamma-tocotrienol, delta-tocotrienol, R-spondin 1, transforming growth factor-β3, mesenchymal stem cells, bone marrow stromal cells, myeloid progenitor cells, antioxidants, or combinations thereof.

[0148]

[0153] In embodiments, the embedded component is a compound or molecule that provides protection to tissue from radiation or is a radioprotector. In some embodiments, the hydrogels of the present disclosure can be formed, placed within, or in contact with tissue that will be exposed to radiation treatment of adjacent or nearby tissue. The inclusion of a radioprotector in the hydrogel provides site-specific delivery of radioprotection to potentially radiation-sensitive tissue, thereby reducing the potential for adverse effects on normal or healthy tissue. In embodiments, the radioprotector is an antioxidant. Examples of suitable antioxidants include, but are not limited to, butylated hydroxytoluene, N-acetyl-DL-tryptophan, butylated hydroxytoluene, propyl gallate, d-alpha tocopheryl acetate, sodium disulfite, ascorbic acid, vitamin E, polyphenols, carotenoids, coenzyme Q10, and combinations thereof.

[0149]

[0154] As mentioned above, the hydrogels of the present disclosure may be layered, for example, two different hydrogels or two similar hydrogels laminated together. It will be apparent that the various layers of the hydrogel may have different embedded materials. For example, in the case where the hydrogel is placed between the prostate and the intestine / rectum of a subject, the radiosensitizer may be embedded in the hydrogel layer that contacts the treated tissue, while the radioprotector may be embedded in the layer that contacts the untreated or healthy tissue.

[0150]

[0155] Example 1

[0156] In some embodiments, one or both solutions contain a suspension of one or more materials, which become embedded throughout the hydrogel as it forms. The materials are typically insoluble or only partially soluble in aqueous solutions. Another embodiment is that the diameter or width of each particle at its largest cross-sectional area is small enough to avoid clogging any delivery method, such as a syringe needle. It should also be clear that, in order to suspend the particles in the hydrogel, the density of each particle must be maintained such that all particles do not slide into the liquid mixture before the hydrogel is fully formed.

[0151]

[0157] In some embodiments of the present disclosure, the particle size is about 300 μm or less, e.g., about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, and 300 μm. In some embodiments, the particles are from about 0.1 μm to about 10 μm, from about 0.1 μm to about 100 μm, from about 0.1 to about 300 μm, from about 0.5 μm to about 1 μm, from about 0.5 μm to about 5 μm, from about 0.5 μm to about 10 μm, from about 0.5 μm to about 50 μm, from about 0.5 μm to about 100 μm, from about 0.5 μm to about 200 μm, from about 0.5 μm to about 300 μm, from about 1 μm to about 5 μm, from about 1 μm to about 10 μm, from about 1 μm to about 50 μm, from about 1 μm to about 100 μm, from about 1 μm to about 200 μm, from about 1 μm to about 300 μm to about 300 μm, 5 μm to about 10 μm, about 5 μm to about 50 μm, about 5 μm to about 100 μm, about 5 μm to about 200 μm, about 5 μm to about 300 μm, about 10 μm to about 50 μm, about 10 μm to about 100 μm, about 10 μm to about 200 μm, about 10 μm to about 300 μm, about 50 μm to about 100 μm, about 50 μm to about 200 μm, about 50 μm to about 300 μm, about 100 μm to about 200 μm, about 100 μm to about 300 μm, or about 200 μm to about 300 μm.

[0152]

[0158] In some aspects, particles may be considered to be microspheres or microparticles or nanoparticles, references thereto being understood to still include all aspects of "particle" as used herein.

[0153]

[0159] In some embodiments, the particles are crystalline and / or amorphous therapeutic agent particles. In other embodiments, the particles are biodegradable polymers embedded with one or more therapeutic agents and / or radiopaque markers. In other embodiments, the particles are biocompatible two-phase or three-phase microparticles containing a radioisotope or a compound containing at least one radioactive element.

[0154] Biodegradable polymer microparticles

[0160] In aspects of the present disclosure, the hydrogel can have embedded or suspended microparticles. In some aspects, the microparticles are biodegradable polymers.

[0155]

[0161] In some embodiments, one or more therapeutic agents may be embedded in biopolymer particles or microparticles. In some embodiments, one or more radiopaque markers may be embedded in biopolymer particles or microparticles. In some embodiments, both a therapeutic agent and a radiopaque marker may be embedded in a microparticle. All of the above may be accomplished by dissolving the therapeutic agent in a solution containing the polymer and evaporating the liquid, such as by emulsion evaporation.

[0156]

[0162] Potential therapeutic agents for the microparticles are discussed herein. If necessary, the hydrophobicity can be adjusted for solubilization, or a more hydrophilic biopolymer can be selected to form the microparticles. It will be understood that the therapeutic agent and / or radiopaque marker must be soluble in the solvent. Using hydrophilic molecules, this can be achieved through chemical modification.

[0157]

[0163] The radiopaque marker of the present disclosure may include methylated triiodobenzoic acid (TIBA-Me). The radiopaque marker TIBA, or triiodobenzoic acid (or 2,3,5 triiodobenzoic acid), can be methylated to TIBA-Me or methyl-2,3,5 triiodobenzoic acid. For example, as described in the Examples, reaction of TIBA with n,n'-dicyclohexylcarbodiimide (DCC) and methanol allows the hydroxyl in the attached carboxylic acid to be replaced with a methyl group. It will be appreciated that methylation of TIBA increases its hydrophobicity.

[0158]

[0164] In some embodiments, the present disclosure relates to radiopaque markers and / or therapeutic substances embedded in biodegradable polymer microparticles, which are themselves embedded in hydrogels of the present disclosure. Degradation of the hydrogel allows for the sustained release of the biodegradable polymer microparticles from the hydrogel. Degradation of the biodegradable polymer allows for the further sustained release of the radiopaque markers and / or therapeutic substances.

[0159]

[0165] Biodegradable polymer microparticles can be prepared by evaporation of a solvent containing a bioabsorbable / biodegradable polymer and at least one therapeutic and / or radiopaque agent. In some embodiments, the solvent is dichloromethane (DCM) or ethyl acetate (EtOAc). The polymer can include networks of polyglycolic acid (PGA), polylactic acid (PLA), and poly-L-lactic acid (PLLA). Other bioabsorbable polymers that can be used in combination or alone in the microparticles include polycaprolactone (PCL), poly DL-lactic acid (PDLLA), poly(trimethylene carbonate) (PTMC), poly(esteramine) (PEA), poly(para-dioxanone) (PPDO), poly 2-hydroxybutyrate (PHB), and copolymers containing these in various ratios. In some embodiments, the bioabsorbable polymer can include polylactic-co-glycolic acid (PLGA), a polymeric combination of lactic acid and glycolic acid, either alone or in combination with other bioabsorbable polymers. Those skilled in the art will appreciate that the percentage of lactic acid and glycolic acid in PLGA can vary, with a higher amount of lactide units providing a longer in situ sustainability for the polymer before degradation. An additional tunable property of PLGA relates to molecular weight, with higher molecular weights exhibiting increased mechanical strength. In some embodiments, the polymer microparticles are also loaded or embedded with an antioxidant, such as BHT.

[0160]

[0166] In some embodiments, the hydrogels of the present disclosure can function as spacers to separate and / or support one or more tissues or organs within a cavity of a subject. In some embodiments, the present disclosure relates to radiopaque hydrogel spacers using encapsulated biodegradable polymer microparticles. Encapsulation of a marker in a polymer microparticle retains the radiopaque marker (e.g., iodine) within the hydrogel without the use of covalent bonds linking the marker within the hydrogel network. Instead, the marker is encapsulated in a biodegradable polymer microparticle, such as PLGA, and physically trapped within the hydrogel network. The biodegradation profile of the hydrogel system, its dimensional stability, and retention of radiopaque molecules can be designed to provide a desirable shelf life suitable for patients with prostate cancer, pancreatic cancer, and other types of cancer, which may be enjoyed by spacers designed to protect adjacent healthy tissues or organs during radiation therapy. The above can also be used in other applications where visibility of the hydrogel during or after gel delivery is important to ensure and confirm that the hydrogel has been accurately applied to the target site.

[0161]

[0167] In some embodiments, the concentration density of the therapeutic agent in the microparticles is 0.1 μg / mm 2 to 10 μg / mm 2 , 0.1 μg / mm 2 to 8 μg / mm 2 , 0.1 μg / mm 2 to 6 μg / mm 2 , 0.1 μg / mm 2 to 4 μg / mm 2 , 0.1 μg / mm 2 to 2 μg / mm 2 , 0.1 μg / mm 2 to 1 μg / mm 2 , 1 μg / mm 2 to 10 μg / mm 2 , 1 μg / mm 2 to 8 μg / mm 2 , 1 μg / mm 2 to 6 μg / mm 2 , 1 μg / mm 2to 4 μg / mm 2 , 1 μg / mm 2 to 2 μg / mm 2 , 2 μg / mm 2 to 10 μg / mm 2 , 2 μg / mm 2 to 8 μg / mm 2 , 2 μg / mm 2 to 6 μg / mm 2 , 2 μg / mm 2 to 4 μg / mm 2 , 4 μg / mm 2 to 10 μg / mm 2 , 4 μg / mm 2 to 8 μg / mm 2 , 4 μg / mm 2 to 6 μg / mm 2 , 6 μg / mm 2 to 10 μg / mm 2 , 6 μg / mm 2 to 8 μg / mm 2 , or 8 μg / mm 2 to 10 μg / mm 2 It is possible.

[0162] radioactive particles

[0168] In embodiments of the present disclosure, the hydrogel may have embedded radioactive microspheres or suspended radioactive microparticles to deliver therapeutic radiation to a target site. In some embodiments, the microparticles comprise a radioisotope or a compound containing at least one radioactive element. The radioisotope or compound may comprise a radioisotope, e.g., a beta-gamma ray emitter or a gamma ray emitter, which emits sufficient gamma radiation to enable imaging. Examples of specific radioisotopes include, but are not limited to, bismuth-213, boron-10, cesium-131, cesium-137, cobalt-60, dysprosium-165, erbium-169, holmium-166, iodine-125, iodine-131, iridium-192, iron-59, lead-212, lutetium-177, molybdenum-99, palladium-103, phosphorus-32, potassium-42, radium-223, rhenium-186, rhenium-188, samarium-153, selenium-75, sodium-24, strontium-89, technetium-99m, thorium-227, xenon-133, ytterbium-169, ytterbium-177, and yttrium-90. Some other examples include actinium-225, astatine-211, bismuth-213, carbon-11, nitrogen-13, oxygen-15, fluorine-18, cobalt-57, copper-64, copper-67, fluorine-18, gallium-67, gallium-68, germanium-68, indium-111, iodine-123, iodine-124, krypton-81m, rubidium-82, strontium-82, and thallium-201. The microparticles can include compounds containing any of the aforementioned radioisotopes. In some embodiments, the microparticles include yttrium-90 or yttrium phosphate ( 90 YPO4), yttrium sulfate ( 90 Y2(SO4)3) or ( 89 Y 90 Y(SO4)3), or yttrium carbonate ( 90 Y2(CO3)3) or ( 89 Y 90 This may include compounds containing yttrium-90 atoms, such as Y(CO3)3).

[0163]

[0169] The two-phase or three-phase microparticles contain a cured first biocompatible resin and may contain a radioisotope or compound thereof within a second and / or third cured resin. The second and third resins may be the same material as the first resin. The two-phase or three-phase microparticles may further contain one or more therapeutic agents described herein. In some embodiments, the radioactive microparticles are as described in WO2019 / 222700, which is incorporated herein by reference in its entirety.

[0164] Tissue marker microparticles

[0170] In embodiments of the present disclosure, the hydrogel may be embedded with a detectable permanent or semi-permanent material to locate it in situ within a subject. While the presence of the hydrogel itself need not be permanent, being able to determine the site where the hydrogel was previously implanted can be beneficial to a physician or medical professional regarding the subject. While the radiopaque markers described herein can locate the hydrogel, additional materials can be embedded to more permanently define the site. Thus, embedding materials such as titanium particles, nitinol particles, or PVA particles in the hydrogel provide a material that can be detected over an extended period of time. In some embodiments, the goal may be to insert a tissue marker simultaneously with the formation of the gel in situ, increasing the available surface area and enhancing the user's ability to detect and locate the tissue marker.

[0165] Kits and Instructions for Use

[0171] In embodiments, the present disclosure also relates to kits that provide hydrogels or allow users to prepare the hydrogels described herein. In some embodiments, the kits can include a first aqueous solution and dried monomer units. As described herein, it is advantageous to reconstitute the monomer units before forming the hydrogel. Similarly, a second aqueous solution can be provided to reconstitute the dried complexed molecules. The first and second aqueous solutions can be the same or different. Thus, the kits can include one or two containers for reconstituting the complex molecules and the monomer units.

[0166]

[0172] As also described herein, the hydrogel may include additional features, such as an embedding component. In some aspects, the kit may also include the above.

[0173] As also described herein, in some embodiments, the hydrogel comprises various osmotic properties. In some embodiments, the kit may include salts or similar components necessary to allow the user to properly prepare the hydrogel.

[0167]

[0174] In some embodiments, the kit may include a means for mixing the two solutions. As described herein, the hydrogels of the present disclosure may form rapidly. Therefore, mixing may be performed at or near the cavity to be filled with the hydrogel. In some embodiments, the kit may include two separate syringe barrels operably connected to a single needle point. Dispensing both solutions from the barrels into a single or shared needle point allows the two to contact each other simultaneously as the fluids dispense from the needle point into the cavity.

[0168]

[0175] It will also be appreciated that the kit may optionally include suitable packaging and / or instructions or a link thereto that will enable the user to prepare the hydrogel.

[0169]

[0176] In some aspects, the present disclosure relates to methods of using the hydrogels described herein, which may include contacting a monomer unit solution with a complexed molecule solution at / in / on a cavity in a subject to form a hydrogel.

[0170]

[0177] As described herein, forming a hydrogel within a cavity allows the hydrogel to provide structural support and / or space between tissues / organs surrounding the cavity. As also described herein, the hydrogel can include one or more specific additional features, such as an osmotic imbalance, a therapeutic agent, a microparticle, a radiosensitizer, a radiopaque marker, and a radioprotector. The inclusion of these additional features in the hydrogel provides additional aspects of treating or treating a subject in addition to the benefits provided by filling the cavity space.

[0171]

[0178] As also described herein, the hydrogels of the present disclosure provide various degradation times, and therefore, methods of use also include providing the hydrogel to a cavity for a specific amount of time without having to remove or discard the hydrogel when its presence is no longer needed. [Example]

[0172]

[0179] Two-component hydrogel chemistry requires two components that are packaged separately before use. For long-term storage, keeping the dry and wet components separated or isolated in separate packages is worth considering due to the moisture sensitivity of some materials. Reconstitution of the dry components, including PEG, PEI, rHSA, and PLGA particles, is required before preparing the hydrogel. In a clinical setting, hydrogel preparation begins with hydration of the two components. Each component can be hydrated individually by connecting the first syringe containing the wet component and the second syringe containing the dry component and pushing the wet component back and forth through the connector. A parallel design with dual-chamber syringes can be used to simultaneously hydrate components 1 and 2 through the connector using a similar manual process. Alternatively, other hydration methods can be used. For example, a magnetic disk or magnetic bar can be pre-loaded into the syringe, and once the wetted components are introduced and the cap is closed, the syringe can be hydrated by placing it on a magnetic stirring table, with the magnetic disk or magnetic bar providing the stirring and mixing, or hydration. Alternatively, the hydration process can be accomplished by placing the syringe in an ultrasonic and / or mechanical vibration system, such as a vortex mixer. A fixture can be used to hold the syringe in place during vortex mixing / hydration.

[0173]

[0180] After the two components are fully hydrated, the PLGA particles disperse, followed by mixing and delivery of the hydrogel. The mixing process is critical due to the rapid crosslinking rate of the system (short gel time). Incomplete mixing before delivery can result in needle blockage, while insufficient mixing can prevent the gel from achieving structural and morphological integrity during its lifetime.

[0174]

[0181] Mixing of the two components can be achieved during high-speed flow within the long needle and further mixed by the turbulence that occurs after exiting the delivery needle tip (diagram in Word document in original IDR filing). Mixing can be assisted with the BD Progel delivery system, which is achieved by spraying at the delivery tip. Alternatively, mixing can be further assisted with a mixing section with a serpentine path that can be readily attached to the end of a Y-joint. Delivery needles can be designed to be the appropriate length for the targeted application.

[0175]

[0182] Once the mixing and delivery process begins, it must proceed continuously until completion: the delivery process cannot be stopped or paused, as the fast-reacting gel would be expected to clog the system.

[0176]

[0183] Hydrogels were prepared with PEI and PEG as linker and conjugation molecule variables, and with the presence of a core or central PEG when the number of arms was only two. Table 1 lists the MW of PEG and PEI, the estimated number of crosslinkable amines, gel formation time, and gel degradation time.

[0177] [Table 1-1]

[0178] [Table 1-2]

[0179] [Table 1-3]

[0180] [Table 1-4]

[0181] [Table 1-5]

[0182]

[0184] Example 2

[0185] PEG-SG hydrogels with different arm numbers, MW, and rHA content were prepared and their degradation was evaluated. It was observed that the higher the MW of SG8, ​​the faster the degradation time, and that SG8 degraded faster than SG4, while the higher the rHA content, the slower the degradation.

[0183] [Table 2]

[0184]

[0186] Example 3

[0187] Efforts have been made to create radiopaque hydrogel spacers using encapsulated biodegradable microparticles, which allow the hydrogel to retain iodine molecules (radiopaque markers) without the use of covalent bonds to link the iodine molecules in the hydrogel network. Instead, the iodine molecules are encapsulated in biodegradable polymer PLGA microparticles and physically trapped inside the hydrogel network.

[0185]

[0188] 2,3,5-Triiodobenzoic acid (TIBA) is a common radiopaque molecule that can be used as a radiopaque marker for applications such as implanted spacers. Chemical modification of the TIBA molecule is necessary to enable consistent and stable encapsulated microparticles. Several TIBA derivatives have been synthesized, and TIBA-Me was selected for encapsulation in PLGA microparticles due to its solubility during the particle manufacturing process, its good retention in the particles, and low toxicity.

[0186]

[0189] Encapsulation of TIBA-Me microparticles in polylactic-co-glycolic acid (PLGA) is achieved by creating a PLGA / TIBA-Me emulsion (oil phase) in an aqueous PVA solution (aqueous phase). A stable emulsion is produced by high-speed homogenization. The emulsion is then stirred at low speed to evaporate the solvent in the oil phase. After the solvent evaporates, the particles are collected after centrifugation, washing, and drying. This scheme illustrates an overview of the process. Alternatively, emulsions can be produced using a microporous membrane process, in which the oil phase is extruded into the aqueous phase through a membrane with uniform pores while continuous shear forces are applied to generate uniform droplets. This results in narrowly distributed dry particles / beads, which undergo the same evaporation, purification, and recovery process as described for the homogenization process. Particle size can be controlled by selecting membranes with different pore sizes. Other parameters, such as the solids concentration of the oil phase, the oil phase flow rate, and the stirring speed, can also be used to control particle size.

[0187]

[0190] Radiopaque hydrogels can be fabricated in situ using a two-component reactive system in which component 1 contains multifunctional polyethylene glycol-SG dissolved in water, and component 2 contains albumin, PLGA / TIBA-me particles, and water, along with an optional surfactant, to control excessive bubble formation during reconstitution. A small amount of PEG can also be added to component 2 to aid in dispersing and stabilizing the ingredients. Components 1 and 2 are then introduced and mixed during the delivery process to the target site, where they crosslink into a three-dimensional network, forming a flexible yet structurally stable radiopaque hydrogel. The radiopaque microparticles do not participate in or alter the crosslinking reaction and are physically trapped within the gel network. The introduction of microparticles is not expected to adversely affect the mechanical properties and stability of the hydrogel compared to chemical coupling approaches.

[0188]

[0191] Radiopaque hydrogels are designed to be bioabsorbed after use. Both PEG hydrogels and PLGA particles can be designed to have tailored degradation profiles, for example, up to 3 months in the context of spacer applications in prostate cancer radiotherapy. The molecular weights of PEG and PLGA, the ratio of lactic acid to glycolic acid in PLGA, and crosslink density / PEG functional groups are key parameters that can be adjusted to achieve the target usable life. The table below shows examples of two-component radiopaque hydrogels.

[0189]

[0192] The properties of the hydrogel are studied at 37°C for an extended period of time. Both the hydrogel structure and radiopacity properties can be maintained throughout its usable life, which is supported by data from modulus measurements and molecular iodine retention / leaching tests. The loss of radiopaque molecules is limited to less than 6% of the original loading.

[0190]

[0193] Three hydrogel samples loaded with different PLGA particles containing TIBA-Me iodine molecules were tested. The samples were sandwiched between 2.54 cm (1 inch) thick pieces of pork with skin. Detection of hydrogels using clinical CT has been demonstrated. At 0.5% and 2.5% iodine concentrations by weight of the hydrogel, the samples all appeared much brighter, whereas the hydrogel without PLGA particles appeared dark and was very difficult to distinguish from the tissue. Hounsfield Units (HU) values ​​were used to assess radiopacity, with results indicating higher values ​​as the iodine content in the hydrogel increased.

[0191]

[0194] It has also been shown that gel time (crosslinking reaction time) can be adjusted to meet mixing and delivery requirements. Sodium bicarbonate concentration is effective in adjusting gel time, which is important when the end use requires an optimal gel time for consistent delivery performance and dimensional control. A gel time that is too short can cause delivery problems, such as premature clogging of the delivery needle. On the other hand, an excessively long gel time can cause inconsistent hydrogel shape and imperfections.

[0192]

[0195] For applications in prostate cancer radiotherapy, the target range for gelation time is approximately 5 to 10 seconds, which can be optimized taking into account other factors such as the mixture delivery method used.

[0193]

[0196] Aspects can be further described with respect to the following embodiments.

[0197] In a first embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition for in situ formation within a cavity, comprising a polymerized complex of at least one monomeric unit, at least one complexing molecule, and an aqueous solution, wherein the monomeric unit comprises a terminal structure, a linker, and a core, and the complexing molecule is selected from recombinant albumin, polyethyleneimine (PEI), and polylysine.

[0194]

[0198] In a second embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the linker comprises polyethylene glycol (PEG).

[0195]

[0199] In a third embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the linker is of sufficient length to provide a hydrogel having a molecular weight (MW) of between 1 kDa and 100 kDa.

[0196]

[0200] In a fourth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the terminal structure is selected from N-hydroxysuccinimide (NHS) carboxymethyl ester (NHS-SCM), NHS succinate ester (NHS-SS), NHS glutarate (NHS-SG), or triiodobenzoic acid (TIBA).

[0197]

[0201] In a fifth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the core is selected from pentaerythritol, hexaglycerol, tripentaerythritol, or glycerol.

[0198]

[0202] In a sixth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to hydrogel compositions in which the monomer units have 2, 4, or 8 linker arms extending from the core.

[0199]

[0203] In a seventh embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition in which an ester of a monomer unit complexes with an amine or imine of a complexing molecule.

[0200]

[0204] In an eighth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the molar ratio of ester of the monomer unit to amine or imine of the complexing molecule is from 0.05 to 3.

[0201]

[0205] In a ninth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the molar ratio of ester of the monomer unit to amine or imine of the complexing molecule is from 1.5 to 2.

[0202]

[0206] In a tenth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the complexing molecule comprises 2% to 60% weight / volume (w / v) of the hydrogel.

[0203]

[0207] In an eleventh embodiment, alone or in combination with any other embodiment herein, the present disclosure provides a method for producing a polymerizable polymer having a mass ratio of monomer unit:conjugated molecule of 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, 10:1.3 ... 20:0.5, 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.

[0204]

[0208] In a twelfth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the pH of the hydrogel is between 7.5 and 11.0.

[0205]

[0209] In a thirteenth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the monomer unit is NHS-PEG-SG-8, NHS-PEG-SG-4, or NHS-PEG-SG-2.

[0206]

[0210] In a fourteenth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the monomer unit is NHS-PEG-SS-8, NHS-PEG-SS-4, or NHS-PEG-SS-2.

[0207]

[0211] In a fifteenth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the monomer unit is NHS-PEG-SCM-8, NHS-PEG-SCM-4, or NHS-PEG-SCM-2.

[0208]

[0212] In a sixteenth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the complexing molecule is rHA.

[0209]

[0213] In a seventeenth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the complexing molecule is PEI.

[0210]

[0214] In an eighteenth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition further comprising an embedding component in the hydrogel.

[0211]

[0215] In a nineteenth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the embedded component comprises a therapeutic agent.

[0212]

[0216] In a twentieth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein a therapeutic agent is dissolved in the hydrogel.

[0213]

[0217] In a twenty-first embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition in which a therapeutic agent is suspended throughout the hydrogel in a crystalline or amorphous solid state.

[0214]

[0218] In a twenty-second embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the therapeutic agent is a chemotherapeutic agent selected from docetaxel, degarelix, abiraterone, apalutamide, bicalutamide, cabazitaxel, darolutamide, leuprolide, enzalutamide, flutamide, goserelin, lutetium Lu177 bipibotide tetraxetan, olaparib, mitoxantrone, nilutamide, relugolix, cyprocel-T, radium-223, rucaparib camsylate, or a combination thereof.

[0215]

[0219] In a twenty-third embodiment, alone or in combination with any other embodiment herein, the present disclosure provides a method for treating a rheumatoid arthritis, wherein the therapeutic agent is raloxifene, tamoxifen, abemaciclib, paclitaxel, trastuzumab, everolimus, alpelisib, anastrozole, pamidronate, exemestane, capecitabine, cyclophosphamide, docetaxel, doxorubicin, elacestrant, epirubicin, eribulin mesylate, fluorouracil, fluticasone, fluoxetine, fluoxetine-10 ... The hydrogel composition relates to a chemotherapeutic agent selected from the group consisting of sil, toremifene, fulvestrant, letrozole, gemcitabine, goserelin, palbociclib, ixabepilone, pembrolizumab, ribociclib, lapatinib, olaparib, margetuximab, megestrol, methotrexate, neratinib, pertuzumab, sacituzumab, talazoparib, thiotepa, tucatinib, vinblastine, or a combination thereof.

[0216]

[0220] In a twenty-fourth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the embedded component is a radiosensitizer selected from gemcitabine, fluorouracil or 5-fluorouracil, interferon-α, 13-cis-retinoic acid, doxorubicin, docetaxel, carboplatin, cisplatin, dactinomycin, methotrexate, bleomycin, hydroxyurea, cetuximab, nimotuzumab, AMG102, paraoxonase-2 C-reactive peptide, gold, GSH-modified gold, silver, bismuth, palladium, gadolinium, xinc, curcumin, misonidazole, tirapazamine, paclitaxel, resveratrol, mitomycin C, etanidazole, AQ4N, lidocaine, procaine, chlorpromazine, fludarabine, motexafin, nicotinamide, and combinations thereof.

[0217]

[0221] In a twenty-fifth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the embedded component is a radioprotector selected from amifostine, palifermin, superoxide dismutase, tetracycline, genistein, captopril, lisinopril, 3,3'-diindolylmethane, rapamycin, CBLB502, ON01210, gamma-tocotrienol, delta-tocotrienol, R-spondin 1, transforming growth factor beta 3, mesenchymal stem cells, bone marrow stromal cells, myeloid progenitor cells, antioxidants, or combinations thereof.

[0218]

[0222] In a twenty-sixth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the embedding component comprises gas nanobubbles.

[0219]

[0223] In a twenty-seventh embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the embedding component comprises a peroxide.

[0220]

[0224] In a twenty-eighth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the embedded component comprises a compound that enables the generation of reactive oxygen species from radiation therapy.

[0221]

[0225] In a twenty-ninth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the embedded component comprises microparticles.

[0222]

[0226] In a thirtieth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the microparticles comprise a biodegradable polymer.

[0223]

[0227] In a thirty-first embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the biodegradable polymer is selected from polyglycolic acid (PGA), polylactic acid (PLA), poly-L-lactic acid (PLLA), polycaprolactone (PCL), poly DL-lactic acid (PDLLA), poly(lactic-co-glycolic) acid (PLGA), poly(trimethylene carbonate) (PTMC), poly(esteramine) (PEA), poly(para-dioxanone) (PPDO), poly 2-hydroxybutyrate (PHB), and copolymers thereof.

[0224]

[0228] In a thirty-second embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the microparticles further comprise a therapeutic agent.

[0225]

[0229] In a thirty-third embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the microparticles further comprise a radioisotope or a compound comprising at least one radioactive element.

[0226]

[0230] In a thirty-fourth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the radioisotope comprises yttrium-90.

[0227]

[0231] In a thirty-fifth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the compound is selected from yttrium phosphate (YPO), yttrium sulfate (Y(SO)) or (Y(SO)), or yttrium carbonate (Y(CO)).

[0228]

[0232] In a thirty-sixth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the microparticles further comprise a radiopaque marker.

[0229]

[0233] In a thirty-seventh embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the radiopaque marker comprises methylated TIBA (TIBA-Me).

[0230]

[0234] In a thirty-eighth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the embedded component comprises a tissue marker.

[0231]

[0235] In a thirty-ninth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the tissue marker is selected from titanium particles, nitinol particles, PVA particles, or a combination thereof.

[0232]

[0236] In a fortieth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the hydrogel comprises a first layer and a second layer.

[0233]

[0237] In a forty-first embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel comprising preparing a first solution of reconstituted monomer units in a first aqueous solution, preparing a second solution of reconstituted complexing molecules in a second aqueous solution, and contacting the first and second solutions when both are poured into a cavity space of a subject to form a polymerized complex.

[0234]

[0238] In a forty-second embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the cavity space is between the rectum and the prostate of a subject.

[0235]

[0239] In a forty-third embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the cavity space is located within breast tissue of a subject.

[0236]

[0240] In a forty-fourth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the complexing molecule is rHA or PEI.

[0237]

[0241] In a forty-fifth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the monomer unit comprises a terminal structure, a linker, and a core, and the complexing molecule is selected from recombinant albumin, polyethyleneimine (PEI), and polylysine.

[0238]

[0242] In a forty-sixth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the linker comprises polyethylene glycol (PEG).

[0239]

[0243] In a forty-seventh embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the linker has a length sufficient to provide the hydrogel with a molecular weight (MW) of between 1 kDa and 100 kDa.

[0240]

[0244] In a forty-eighth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the terminal structure is selected from N-hydroxysuccinimide (NHS) carboxymethyl ester (NHS-SCM), NHS succinate ester (NHS-SS), NHS glutarate (NHS-SG), or triiodobenzoic acid (TIBA).

[0241]

[0245] In a forty-ninth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the core is selected from pentaerythritol, hexaglycerol, tripentaerythritol, or glycerol.

[0242]

[0246] In a fiftieth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel in which the monomer units have 2, 4, or 8 linker arms extending from the core.

[0243]

[0247] In a fifty-first embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel in which an ester of a monomer unit is complexed with an amine or imine of a complexing molecule.

[0244]

[0248] In a fifty-second embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel, wherein the molar ratio of ester of the monomer unit to amine or imine of the complexing molecule is from 0.05 to 3.

[0245]

[0249] In a fifty-third embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel, wherein the molar ratio is from 1.5 to 2.

[0246]

[0250] In a fifty-fourth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the complexing molecule comprises 2% to 60% weight / volume (w / v) of the hydrogel.

[0247]

[0251] In a fifty-fifth embodiment, alone or in combination with any other embodiment herein, the present disclosure provides polymers having a mass ratio of monomer unit:conjugated molecule of 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. 20:0.5, 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.

[0248]

[0252] In a fifty-sixth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the monomer unit is NHS-PEG-SG-8, NHS-PEG-SG-4, or NHS-PEG-SG-2.

[0249]

[0253] In a fifty-seventh embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the monomer unit is NHS-PEG-SS-8, NHS-PEG-SS-4, or NHS-PEG-SS-2.

[0250]

[0254] In a fifty-eighth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the monomer unit is NHS-PEG-SCM-8, NHS-PEG-SCM-4, or NHS-PEG-SCM-2.

[0251]

[0255] In a fifty-ninth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the complexing molecule is rHA.

[0252]

[0256] In a sixtieth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the complexing molecule is PEI.

[0253]

[0257] In a sixty-first embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, further comprising embedding a component in the hydrogel in a first solution and / or a second solution.

[0254]

[0258] In a sixty-second embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the pH of the hydrogel is between 7.5 and 11.0.

[0255]

[0259] In a sixty-third embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to the use of a hydrogel composition to separate rectal tissue from prostate tissue in a subject.

[0256]

[0260] In a sixty-fourth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to the use of a hydrogel composition wherein a cavity space is located between a target tissue and a non-target tissue.

[0257]

[0261] In a sixty-fifth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to the use of a hydrogel composition wherein the cavity space is located between the rectum and the prostate.

[0258]

[0262] In a sixty-sixth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a kit comprising a first aqueous solution, a second aqueous solution, dried monomeric units, and dried complexing molecules, wherein the first aqueous solution reconstitutes the monomeric units and the second aqueous solution reconstitutes the complexing molecules.

[0259]

[0263] In a sixty-seventh embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a kit further comprising a means for mixing the first and second aqueous solutions prior to application to the cavity space of a subject.

[0260]

[0264] In a sixty-eighth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a kit comprising a first syringe barrel and a second syringe barrel, both of which are operably connected to a single needle point.

[0261]

[0265] In a sixty-ninth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition for in situ formation within a cavity, comprising a polymerized complex of at least one monomer unit, at least one complexing molecule, at least one permeation component, and an aqueous solution, wherein the monomer unit comprises a terminal structure, a linker, and a core, and the complexing molecule is selected from recombinant albumin, polyethyleneimine (PEI), and polylysine.

[0262]

[0266] In a seventieth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the linker comprises polyethylene glycol (PEG).

[0263]

[0267] In a seventy-first embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the linker is of sufficient length to provide a hydrogel having a molecular weight (MW) of between 1 kDa and 100 kDa.

[0264]

[0268] In a seventy-second embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the terminal structure is selected from N-hydroxysuccinimide (NHS) carboxymethyl ester (NHS-SCM), NHS succinate ester (NHS-SS), NHS glutarate (NHS-SG), or triiodobenzoic acid (TIBA).

[0265]

[0269] In a seventy-third embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the core is selected from pentaerythritol, hexaglycerol, tripentaerythritol, or glycerol.

[0266]

[0270] In a seventy-fourth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the monomer units have 2, 4, or 8 linker arms extending from the core.

[0267]

[0271] In a seventy-fifth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition in which an ester of a monomer unit complexes with an amine or imine of a complexing molecule.

[0268]

[0272] In a seventy-sixth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the molar ratio of ester of the monomer unit to amine or imine of the complexing molecule is from 0.05 to 3.

[0269]

[0273] In a seventy-seventh embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the molar ratio is from 1.5 to 2.

[0270]

[0274] In a seventy-eighth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the complexing molecule comprises 2% to 60% weight / volume (w / v) of the hydrogel.

[0271]

[0275] In a seventy-ninth embodiment, alone or in combination with any other embodiment herein, the present disclosure provides a method for producing a polymerizable polymer having a mass ratio of monomer unit:conjugated molecule of 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.

[0272]

[0276] In an eightieth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the pH of the hydrogel is between 7.5 and 11.0.

[0273]

[0277] In an eighty-first embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the monomer unit is NHS-PEG-SG-8, NHS-PEG-SG-4, or NHS-PEG-SG-2.

[0274]

[0278] In an eighty-second embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the monomer unit is NHS-PEG-SS-8, NHS-PEG-SS-4, or NHS-PEG-SS-2.

[0275]

[0279] In an eighty-third embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the monomer unit is NHS-PEG-SCM-8, NHS-PEG-SCM-4, or NHS-PEG-SCM-2.

[0276]

[0280] In an eighty-fourth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the complexing molecule is rHA.

[0277]

[0281] In an eighty-fifth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the complexing molecule is PEI.

[0278]

[0282] In an eighty-sixth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the osmotic component comprises one or more components selected from reverse osmosis water, salt, organic acid and / or acid salt thereof, carbohydrate, monohydric alcohol and / or polyhydric alcohol, amino acid and / or peptide and / or protein, and / or biodegradable polymer.

[0279]

[0283] In an eighty-seventh embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the salt is selected from sodium chloride, calcium chloride, potassium chloride, magnesium chloride, sodium bicarbonate, sodium phosphate, sodium sulfate, potassium phosphate, potassium sulfate, calcium phosphate, ammonium sulfate, barium chloride, copper sulfate, iron chloride, iron sulfate, lithium chloride, magnesium sulfate, manganese sulfate, nickel sulfate, potassium carbonate, potassium bromide, potassium chloride, potassium iodide, silver nitrate, sodium bromide, sodium carbonate, sodium chlorate, sodium nitrate, sodium pyrophosphate, zinc sulfate, and combinations thereof.

[0280]

[0284] In an eighty-eighth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the carbohydrate is selected from dextrose, fructose, sucrose, lactose, maltose, trehalose, galactose, dextran, xylose, mannose, ribose, isomaltase, inulin, cyclodextrin, hydroxyethyl starch (HES), pullulan, pectin, xanthan gum, agarose, cellulose, hyaluronic acid, maltodextrin, methylcellulose, alginate, chitosan, heparin, heparan sulfate, and combinations thereof.

[0281]

[0285] In an eighty-ninth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the organic acid and / or acid salt thereof is selected from fumaric acid, formic acid, gluconic acid, lactic acid, glycolic acid, pyruvic acid, oxalic acid, benzoic acid, cinnamic acid, ferulic acid, butyric acid, propionic acid, gallic acid, itaconic acid, maleic acid, mandelic acid, nicotinic acid, phthalic acid, salicylic acid, shikimic acid, uric acid, valeric acid, and combinations thereof.

[0282]

[0286] In a ninetieth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition that is a hypertonic hydrogel and has an osmolality greater than 300 mOsm / L.

[0283]

[0287] In a 91st embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the hydrogel is a hypotonic hydrogel and has an osmotic pressure of less than 280 mOsm / L.

[0284]

[0288] In a 92nd embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the hydrogel is an isotonic hydrogel and has an osmolality between 280 mOsm / L and 300 mOsm / L.

[0285]

[0289] In a ninety-third embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the hydrogel further comprises a radiopaque marker.

[0286]

[0290] In a ninety-fourth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the radiopaque marker comprises methylated TIBA (TIBA-Me).

[0287]

[0291] In a ninety-fifth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the hydrogel comprises a first layer and a second layer.

[0288]

[0292] In a 96th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein a first layer has a first osmotic pressure and a second layer has a second osmotic pressure different from the first osmotic pressure.

[0289]

[0293] In a ninety-seventh embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the first layer is hypertonic and the second layer is isotonic.

[0290]

[0294] In a ninety-eighth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the first layer is hypotonic and the second layer is isotonic.

[0291]

[0295] In a ninety-ninth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the first layer and / or the second layer comprises a therapeutic element.

[0292]

[0296] In a hundredth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel comprising the steps of preparing a first solution of reconstituted monomer units in a first aqueous solution, preparing a second solution of reconstituted complexed molecules in a second aqueous solution, wherein an osmotic component is present in the first solution and / or the second solution, and contacting the first and second solutions when both are poured into a cavity space of a subject to form a polymerized complex.

[0293]

[0297] In a hundred and first embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the cavity space is between the rectum and the prostate of a subject.

[0294]

[0298] In a hundred-second embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the cavity space is located within breast tissue of a subject.

[0295]

[0299] In a hundred and third embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the complexing molecule is rHA or PEI.

[0296]

[0300] In a 104th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel, wherein the monomer unit comprises a terminal structure, a linker, and a core, and the complexing molecule is selected from recombinant albumin, polyethyleneimine (PEI), and polylysine.

[0297]

[0301] In a hundred and fifth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel, wherein the linker comprises polyethylene glycol (PEG).

[0298]

[0302] In a hundred and sixth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the linker has a length sufficient to provide the hydrogel with a molecular weight (MW) of between 1 kDa and 100 kDa.

[0299]

[0303] In a hundred and seventh embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the terminal structure is selected from N-hydroxysuccinimide (NHS) carboxymethyl ester (NHS-SCM), NHS succinate ester (NHS-SS), NHS glutarate (NHS-SG), or triiodobenzoic acid (TIBA).

[0300]

[0304] In a hundred eighth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the core is selected from pentaerythritol, hexaglycerol, tripentaerythritol, or glycerol.

[0301]

[0305] In a hundred and ninth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel in which the monomer units have two, four, or eight linker arms extending from the core.

[0302]

[0306] In a 110th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel in which an ester of a monomer unit is complexed with an amine or imine of a complexing molecule.

[0303]

[0307] In a 111th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel, wherein the molar ratio of ester of the monomer unit to amine or imine of the complexing molecule is from 0.05 to 3.

[0304]

[0308] In a 112th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel, wherein the molar ratio is from 1.5 to 2.

[0305]

[0309] In a 113th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the complexing molecule comprises 2% to 60% weight / volume (w / v) of the hydrogel.

[0306]

[0310] In a 114th embodiment, alone or in combination with any other embodiment herein, the present disclosure provides polymers having a mass ratio of monomer unit:conjugated molecule of 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. 20:0.5, 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.

[0307]

[0311] In a 115th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the pH of the hydrogel is between 7.5 and 11.0.

[0308]

[0312] In a 116th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel, wherein the monomer unit is NHS-PEG-SG-8, NHS-PEG-SG-4, or NHS-PEG-SG-2.

[0309]

[0313] In a 117th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel, wherein the monomer unit is NHS-PEG-SS-8, NHS-PEG-SS-4, or NHS-PEG-SS-2.

[0310]

[0314] In a 118th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel, wherein the monomer unit is NHS-PEG-SCM-8, NHS-PEG-SCM-4, or NHS-PEG-SCM-2.

[0311]

[0315] In a 119th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the complexing molecule is rHA.

[0312]

[0316] In a 120th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the complexing molecule is PEI.

[0313]

[0317] In a 121st embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel, wherein the osmotic component comprises one or more components selected from reverse osmosis water, salt, organic acid and / or acid salt thereof, carbohydrate, monohydric alcohol and / or polyhydric alcohol, amino acid and / or peptide and / or protein, and / or biodegradable polymer.

[0314]

[0318] In a 122nd embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the hydrogel comprises a first layer and a second layer.

[0315]

[0319] In a 123rd embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein a first layer has a first osmotic pressure and a second layer has a second osmotic pressure different from the first osmotic pressure.

[0316]

[0320] In a 124th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein a first layer is hypertonic and a second layer is isotonic.

[0317]

[0321] In a 125th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein a first layer is hypotonic and a second layer is isotonic.

[0318]

[0322] In a 126th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to the use of a hydrogel composition to separate target tissue from non-target tissue of a subject, where the osmotic components of the hydrogel create an osmotic imbalance with the target tissue.

[0319]

[0323] In a 127th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to the use of a hydrogel composition, wherein the hypertonic hydrogel causes a cytotoxic effect on the target tissue.

[0320]

[0324] In a 128th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to the use of a hydrogel composition in which a hypertonic first layer causes a cytotoxic effect on target tissue, while an isotonic second layer protects non-target tissue.

[0321]

[0325] In a 129th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to the use of a hydrogel composition, wherein the hypotonic hydrogel causes lysis of target tissue.

[0322]

[0326] In a 130th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to the use of a hydrogel composition in which a hypotonic first layer causes dissolution of target tissue while an isotonic second layer protects non-target tissue.

[0323]

[0327] In a 131st embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to the use of a hydrogel composition wherein the target tissue is prostate tissue.

[0324]

[0328] In a 132nd embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to the use of a hydrogel composition, wherein the non-target tissue is rectal tissue.

[0325]

[0329] In a 133rd embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a kit comprising a first aqueous solution, a second aqueous solution, dried monomeric units, dried complexing molecules, and one or more permeation components, wherein the first aqueous solution reconstitutes the monomeric units and the second aqueous solution reconstitutes the complexing molecules.

[0326]

[0330] In a 134th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a kit further comprising a means for mixing the first and second aqueous solutions prior to application to the cavity space of a subject.

[0327]

[0331] In a 135th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a kit comprising a first syringe barrel and a second syringe barrel, both of which are operably connected to a single needle point.

[0328]

[0332] In a 136th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition for in situ formation within a cavity, comprising a polymerized complex of at least one monomer unit, at least one complexing molecule, a microparticle, and an aqueous solution, wherein the monomer unit comprises a terminal structure, a linker, and a core, and the complexing molecule is selected from recombinant albumin, polyethyleneimine (PEI), and polylysine.

[0329]

[0333] In a 137th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the linker comprises polyethylene glycol (PEG).

[0330]

[0334] In a 138th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the linker has a length sufficient to provide a hydrogel having a molecular weight (MW) of between 1 kDa and 100 kDa.

[0331]

[0335] In a 139th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the terminal structure is selected from N-hydroxysuccinimide (NHS) carboxymethyl ester (NHS-SCM), NHS succinate ester (NHS-SS), NHS glutarate (NHS-SG), or triiodobenzoic acid (TIBA).

[0332]

[0336] In a 140th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the core is selected from pentaerythritol, hexaglycerol, tripentaerythritol, or glycerol.

[0333]

[0337] In a 141st embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the monomer units have 2, 4, or 8 linker arms extending from the core.

[0334]

[0338] In a 142nd embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition in which an ester of a monomer unit complexes with an amine or imine of a complexing molecule.

[0335]

[0339] In a 143rd embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the molar ratio of ester of the monomer unit to amine or imine of the complexing molecule is from 0.05 to 3.

[0336]

[0340] In a 144th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the complexing molecule comprises 2% to 60% weight / volume (w / v) of the hydrogel.

[0337]

[0341] In a 145th embodiment, alone or in combination with any other embodiment herein, the present disclosure provides a method for producing a polymerizable polymer having a mass ratio of monomer unit:conjugated molecule of 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.

[0338]

[0342] In a 146th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the pH of the hydrogel is between 7.5 and 11.0.

[0339]

[0343] In a 147th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the monomer unit is NHS-PEG-SG-8, NHS-PEG-SG-4, or NHS-PEG-SG-2.

[0340]

[0344] In a 148th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the monomer unit is NHS-PEG-SS-8, NHS-PEG-SS-4, or NHS-PEG-SS-2.

[0341]

[0345] In a 149th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the monomer unit is NHS-PEG-SCM-8, NHS-PEG-SCM-4, or NHS-PEG-SCM-2.

[0342]

[0346] In a 150th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the complexing molecule is rHA.

[0343]

[0347] In a fifty-first embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the complexing molecule is PEI.

[0344]

[0348] In a fifty-second embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the microparticles comprise a biodegradable polymer.

[0345]

[0349] In a 153rd embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the biodegradable polymer is selected from polyglycolic acid (PGA), polylactic acid (PLA), poly-L-lactic acid (PLLA), polycaprolactone (PCL), poly DL-lactic acid (PDLLA), poly(lactic-co-glycolic) acid (PLGA), poly(trimethylene carbonate) (PTMC), poly(esteramine) (PEA), poly(para-dioxanone) (PPDO), poly 2-hydroxybutyrate (PHB), and copolymers thereof.

[0346]

[0350] In a 154th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the microparticles further comprise a therapeutic agent.

[0347]

[0351] In a 155th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the therapeutic agent is a chemotherapeutic agent selected from docetaxel, degarelix, abiraterone, apalutamide, bicalutamide, cabazitaxel, darolutamide, leuprolide, enzalutamide, flutamide, goserelin, lutetium Lu177 bipibotide tetraxetan, olaparib, mitoxantrone, nilutamide, relugolix, cyprocel-T, radium-223, rucaparib camsylate, or a combination thereof.

[0348]

[0352] In a 156th embodiment, alone or in combination with any other embodiment herein, the present disclosure provides a method for treating rheumatoid arthritis, wherein the therapeutic agent is raloxifene, tamoxifen, abemaciclib, paclitaxel, trastuzumab, everolimus, alpelisib, anastrozole, pamidronate, exemestane, capecitabine, cyclophosphamide, docetaxel, doxorubicin, elacestrant, epirubicin, eribulin mesylate, fluorouracil, fluoxetine, fluoxetine, fluoxetine-10 ... and a hydrogel composition, wherein the chemotherapeutic agent is selected from the group consisting of rasil, toremifene, fulvestrant, letrozole, gemcitabine, goserelin, palbociclib, ixabepilone, pembrolizumab, ribociclib, lapatinib, olaparib, margetuximab, megestrol, methotrexate, neratinib, pertuzumab, sacituzumab, talazoparib, thiotepa, tucatinib, vinblastine, or a combination thereof.

[0349]

[0353] In a 157th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the therapeutic agent comprises a radiosensitizer selected from gemcitabine, fluorouracil or 5-fluorouracil, interferon-α, 13-cis-retinoic acid, doxorubicin, docetaxel, carboplatin, cisplatin, dactinomycin, methotrexate, bleomycin, hydroxyurea, cetuximab, nimotuzumab, AMG102, paraoxonase-2 C-reactive peptide, gold, GSH-modified gold, silver, bismuth, palladium, gadolinium, xinc, curcumin, misonidazole, tirapazamine, paclitaxel, resveratrol, mitomycin C, etanidazole, AQ4N, lidocaine, procaine, chlorpromazine, fludarabine, motexafin, nicotinamide, and combinations thereof.

[0350]

[0354] In a 158th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition comprising a therapeutic agent selected from amifostine, palifermin, superoxide dismutase, tetracycline, genistein, captopril, lisinopril, 3,3'-diindolylmethane, rapamycin, CBLB502, ON01210, gamma-tocotrienol, delta-tocotrienol, R-spondin 1, transforming growth factor beta 3, mesenchymal stem cells, bone marrow stromal cells, myeloid progenitor cells, antioxidants, or combinations thereof.

[0351]

[0355] In a 159th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the microparticles further comprise a radioisotope or a compound comprising at least one radioactive element.

[0352]

[0356] In a one hundred and sixtieth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the radioisotope comprises yttrium-90.

[0353]

[0357] In a 161st embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the compound is selected from yttrium phosphate (YPO), yttrium sulfate (Y(SO)) or (Y(SO)), or yttrium carbonate (Y(CO)).

[0354]

[0358] In a 162nd embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the microparticles further comprise a radiopaque marker.

[0355]

[0359] In a 163rd embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the radiopaque marker comprises methylated TIBA (TIBA-Me).

[0356]

[0360] In a 164th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the hydrogel comprises a first layer and a second layer.

[0357]

[0361] In a 165th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein microparticles are not present in the second layer.

[0358]

[0362] In a 166th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the second layer comprises second microparticles, and wherein the composition of the second microparticles is different from that of the microparticles.

[0359]

[0363] In a 167th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, comprising preparing a first solution of reconstituted monomer units in a first aqueous solution, preparing a second solution of reconstituted complexing molecules in a second aqueous solution, suspending microparticles in the first solution and / or the second solution, and contacting the first and second solutions when both are poured into a cavity space of a subject to form a polymerized complex.

[0360]

[0364] In a 168th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the cavity space is between the rectum and the prostate of a subject.

[0361]

[0365] In a 169th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the cavity space is located within breast tissue of a subject.

[0362]

[0366] In a 170th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the complexing molecule is rHA or PEI.

[0363]

[0367] In a 171st embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel, wherein the monomer unit comprises a terminal structure, a linker, and a core, and the complexing molecule is selected from recombinant albumin, polyethyleneimine (PEI), and polylysine.

[0364]

[0368] In a 172nd embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the linker comprises polyethylene glycol (PEG).

[0365]

[0369] In a 173rd embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the linker has a length sufficient to provide the hydrogel with a molecular weight (MW) of between 1 kDa and 100 kDa.

[0366]

[0370] In a 174th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the terminal structure is selected from N-hydroxysuccinimide (NHS) carboxymethyl ester (NHS-SCM), NHS succinate ester (NHS-SS), NHS glutarate (NHS-SG), or triiodobenzoic acid (TIBA).

[0367]

[0371] In a 175th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the core is selected from pentaerythritol, hexaglycerol, tripentaerythritol, or glycerol.

[0368]

[0372] In a 176th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel in which the monomer units have 2, 4, or 8 linker arms extending from the core.

[0369]

[0373] In a 177th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel in which an ester of a monomer unit is complexed with an amine or imine of a complexing molecule.

[0370]

[0374] In a 178th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel, wherein the molar ratio of ester of the monomer unit to amine or imine of the complexing molecule is from 0.05 to 3.

[0371]

[0375] In a 179th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel, wherein the molar ratio is from 1.5 to 2.

[0372]

[0376] In a one hundred and eighty embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the complexing molecule comprises 2% to 60% weight / volume (w / v) of the hydrogel.

[0373]

[0377] In one hundred and eighty-first embodiment, alone or in combination with any other embodiment herein, the present disclosure provides polymers having a mass ratio of monomer unit:conjugated molecule of 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. 20:0.5, 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.

[0374]

[0378] In a one hundred and eighty-second embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the pH of the hydrogel is between 7.5 and 11.0.

[0375]

[0379] In a one hundred and eighty-third embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel, wherein the monomer unit is NHS-PEG-SG-8, NHS-PEG-SG-4, or NHS-PEG-SG-2.

[0376]

[0380] In a 184th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel, wherein the monomer unit is NHS-PEG-SS-8, NHS-PEG-SS-4, or NHS-PEG-SS-2.

[0377]

[0381] In a 185th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the monomer unit is NHS-PEG-SCM-8, NHS-PEG-SCM-4, or NHS-PEG-SCM-2.

[0378]

[0382] In a 186th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the complexing molecule is rHA.

[0379]

[0383] In a 187th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the complexing molecule is PEI.

[0380]

[0384] In a one hundred eighty-eighth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the microparticles comprise a biodegradable polymer.

[0381]

[0385] In one hundred and eighty-ninth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the biodegradable polymer is selected from polyglycolic acid (PGA), polylactic acid (PLA), poly-L-lactic acid (PLLA), polycaprolactone (PCL), poly-DL-lactic acid (PDLLA), poly(lactic-co-glycolic) acid (PLGA), poly(trimethylene carbonate) (PTMC), poly(esteramine) (PEA), poly(para-dioxanone) (PPDO), poly 2-hydroxybutyrate (PHB), and copolymers thereof.

[0382]

[0386] In a one hundred and nineteenth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the microparticles further comprise a therapeutic agent.

[0383]

[0387] In a 191st embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the therapeutic agent is a chemotherapeutic agent selected from docetaxel, degarelix, abiraterone, apalutamide, bicalutamide, cabazitaxel, darolutamide, leuprolide, enzalutamide, flutamide, goserelin, lutetium Lu177 bipibotide tetraxetan, olaparib, mitoxantrone, nilutamide, relugolix, cyprocel-T, radium-223, rucaparib camsylate, or a combination thereof.

[0384]

[0388] In a 192nd embodiment, alone or in combination with any other embodiment herein, the present disclosure provides a method for treating rheumatoid arthritis, wherein the therapeutic agent is raloxifene, tamoxifen, abemaciclib, paclitaxel, trastuzumab, everolimus, alpelisib, anastrozole, pamidronate, exemestane, capecitabine, cyclophosphamide, docetaxel, doxorubicin, elacestrant, epirubicin, eribulin mesylate, fluorouracil, riboflavin, riboflavin, riboflavin mesylate ... The present invention relates to a method for preparing a hydrogel comprising administering to a subject a chemotherapeutic agent selected from the group consisting of pembrolizumab, toremifene, fulvestrant, letrozole, gemcitabine, goserelin, palbociclib, ixabepilone, pembrolizumab, ribociclib, lapatinib, olaparib, margetuximab, megestrol, methotrexate, neratinib, pertuzumab, sacituzumab, talazoparib, thiotepa, tucatinib, vinblastine, or a combination thereof.

[0385]

[0389] In a 193rd embodiment, alone or in combination with any other embodiment herein, the present disclosure provides a method for treating rheumatoid arthritis, wherein the therapeutic agent is gemcitabine, fluorouracil or 5-fluorouracil, interferon-α, 13-cis-retinoic acid, doxorubicin, docetaxel, carboplatin, cisplatin, dactinomycin, methotrexate, bleomycin, hydroxyurea, cetuximab, nimotuzumab, AMG102, paraoxonase-2 The present invention relates to a method for preparing a hydrogel comprising a radiosensitizer selected from C-reactive peptide, gold, GSH-modified gold, silver, bismuth, palladium, gadolinium, xinc, curcumin, misonidazole, tirapazamine, paclitaxel, resveratrol, mitomycin C, etanidazole, AQ4N, lidocaine, procaine, chlorpromazine, fludarabine, motexafin, nicotinamide, and combinations thereof.

[0386]

[0390] In one hundred and ninety-fourth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel, wherein the therapeutic agent comprises a radioprotector selected from amifostine, palifermin, superoxide dismutase, tetracycline, genistein, captopril, lisinopril, 3,3'-diindolylmethane, rapamycin, CBLB502, ON01210, gamma-tocotrienol, delta-tocotrienol, R-spondin 1, transforming growth factor beta 3, mesenchymal stem cells, bone marrow stromal cells, myeloid progenitor cells, antioxidants, or combinations thereof.

[0387]

[0391] In a one hundred and ninety-fifth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel, wherein the microparticles further comprise a radioisotope or a compound comprising at least one radioactive element.

[0388]

[0392] In a one hundred and ninety-sixth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the radioisotope comprises yttrium-90.

[0389]

[0393] In a 197th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the compound is selected from yttrium phosphate (YPO), yttrium sulfate (Y(SO)) or (Y(SO)), or yttrium carbonate (Y(CO)).

[0390]

[0394] In a one hundred and ninety-eighth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the microparticles further comprise a radiopaque marker.

[0391]

[0395] In a one hundred and ninety-ninth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the radiopaque marker comprises methylated TIBA (TIBA-Me).

[0392]

[0396] In a two hundredth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the hydrogel comprises a first layer and a second layer.

[0393]

[0397] In a 201st embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to the use of a hydrogel composition to separate target tissue from non-target tissue of a subject, wherein the embedded component exerts a therapeutic effect on the target tissue and / or enhances treatment of the target tissue.

[0394]

[0398] In a 202nd embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to the use of the hydrogel composition, wherein the treatment of the target tissue is radiation therapy.

[0395]

[0399] In a 203rd embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to the use of a hydrogel composition wherein the target tissue is prostate tissue.

[0396]

[0400] In a 204th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to the use of a hydrogel composition, wherein the non-target tissue is rectal tissue.

[0397]

[0401] In a 205th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a kit comprising a first aqueous solution, a second aqueous solution, dried monomeric units, and dried complexing molecules, wherein the first aqueous solution reconstitutes the monomeric units and the second aqueous solution reconstitutes the complexing molecules and one or more microparticles.

[0398]

[0402] In a 206th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a kit including a means for mixing a first aqueous solution and a second aqueous solution prior to application to a cavity space of a subject.

[0399]

[0403] In a 207th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a kit comprising a first syringe barrel and a second syringe barrel, both of which are operably connected to a single needle point.

[0400]

[0404] In a 208th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition for in situ formation within a cavity, comprising a polymerized complex of at least one monomer unit, at least one complexing molecule, an embedding component, and an aqueous solution, wherein the monomer unit comprises a terminal structure, a linker, and a core, and the complexing molecule is selected from recombinant albumin, polyethyleneimine (PEI), and polylysine.

[0401]

[0405] In a 209th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the linker comprises polyethylene glycol (PEG).

[0402]

[0406] In a 210th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the linker is of sufficient length to provide a hydrogel having a molecular weight (MW) of between 1 kDa and 100 kDa.

[0403]

[0407] In a 211th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the terminal structure is selected from N-hydroxysuccinimide (NHS) carboxymethyl ester (NHS-SCM), NHS succinate ester (NHS-SS), NHS glutarate (NHS-SG), or triiodobenzoic acid (TIBA).

[0404]

[0408] In a 212th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the core is selected from pentaerythritol, hexaglycerol, tripentaerythritol, or glycerol.

[0405]

[0409] In a 213th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the monomer units have 2, 4, or 8 linker arms extending from the core.

[0406]

[0410] In a 214th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition in which an ester of a monomer unit complexes with an amine or imine of a complexing molecule.

[0407]

[0411] In a 215th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the molar ratio of ester of the monomer unit to amine or imine of the complexing molecule is from 0.05 to 3.

[0408]

[0412] In a 216th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the molar ratio is from 1.5 to 2.

[0409]

[0413] In a 217th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the complexing molecule comprises 2% to 60% weight / volume (w / v) of the hydrogel.

[0410]

[0414] In a 218th embodiment, alone or in combination with any other embodiment herein, the present disclosure provides a method for producing a polymerizable polymer having a mass ratio of monomer unit:conjugated molecule of 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.

[0411]

[0415] In a 219th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the pH of the hydrogel is between 7.5 and 11.0.

[0412]

[0416] In a 220th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the monomer unit is NHS-PEG-SG-8, NHS-PEG-SG-4, or NHS-PEG-SG-2.

[0413]

[0417] In a 221st embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the monomer unit is NHS-PEG-SS-8, NHS-PEG-SS-4, or NHS-PEG-SS-2.

[0414]

[0418] In a 222nd embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the monomer unit is NHS-PEG-SCM-8, NHS-PEG-SCM-4, or NHS-PEG-SCM-2.

[0415]

[0419] In a 223rd embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the complexing molecule is rHA.

[0416]

[0420] In a 224th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the complexing molecule is PEI.

[0417]

[0421] In a 225th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the embedding component is dissolved in the hydrogel.

[0418]

[0422] In a 226th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the embedded component material is a therapeutic agent.

[0419]

[0423] In a 227th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the therapeutic agent is a chemotherapeutic agent selected from docetaxel, degarelix, abiraterone, apalutamide, bicalutamide, cabazitaxel, darolutamide, leuprolide, enzalutamide, flutamide, goserelin, lutetium Lu177 bipibotide tetraxetan, olaparib, mitoxantrone, nilutamide, relugolix, cyprocel-T, radium-223, rucaparib camsylate, or a combination thereof.

[0420]

[0424] In a 228th embodiment, alone or in combination with any other embodiment herein, the present disclosure provides a method for treating a rheumatoid arthritis, wherein the therapeutic agent is raloxifene, tamoxifen, abemaciclib, paclitaxel, trastuzumab, everolimus, alpelisib, anastrozole, pamidronate, exemestane, capecitabine, cyclophosphamide, docetaxel, doxorubicin, elacestrant, epirubicin, eribulin mesylate, fluorouracil, fluoxetine, fluoxetine, fluoxetine-10 ... and a hydrogel composition, wherein the chemotherapeutic agent is selected from the group consisting of rasil, toremifene, fulvestrant, letrozole, gemcitabine, goserelin, palbociclib, ixabepilone, pembrolizumab, ribociclib, lapatinib, olaparib, margetuximab, megestrol, methotrexate, neratinib, pertuzumab, sacituzumab, talazoparib, thiotepa, tucatinib, vinblastine, or a combination thereof.

[0421]

[0425] In a 229th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the embedded component is a radiosensitizer selected from gemcitabine, fluorouracil or 5-fluorouracil, interferon-α, 13-cis-retinoic acid, doxorubicin, docetaxel, carboplatin, cisplatin, dactinomycin, methotrexate, bleomycin, hydroxyurea, cetuximab, nimotuzumab, AMG102, paraoxonase-2 C-reactive peptide, gold, GSH-modified gold, silver, bismuth, palladium, gadolinium, xinc, curcumin, misonidazole, tirapazamine, paclitaxel, resveratrol, mitomycin C, etanidazole, AQ4N, lidocaine, procaine, chlorpromazine, fludarabine, motexafin, nicotinamide, and combinations thereof.

[0422]

[0426] In a 230th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the embedded component is a radioprotector selected from amifostine, palifermin, superoxide dismutase, tetracycline, genistein, captopril, lisinopril, 3,3'-diindolylmethane, rapamycin, CBLB502, ON01210, gamma-tocotrienol, delta-tocotrienol, R-spondin 1, transforming growth factor beta 3, mesenchymal stem cells, bone marrow stromal cells, myeloid progenitor cells, antioxidants, or combinations thereof.

[0423]

[0427] In a 231st embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein an embedded component comprises a compound that enables the generation of reactive oxygen species from radiation therapy.

[0424]

[0428] In a 232nd embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the embedding component comprises a peroxide.

[0425]

[0429] In a 233rd embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the peroxide comprises formamide peroxide.

[0426]

[0430] In a 234th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the embedded component comprises a radiopaque compound.

[0427]

[0431] In a 235th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the radiopaque compound comprises methylated TIBA (TIBA-Me).

[0428]

[0432] In a 236th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the embedded component comprises a radioisotope or a compound comprising at least one radioactive element.

[0429]

[0433] In a 237th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the radioisotope comprises yttrium-90.

[0430]

[0434] In a 238th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the compound is selected from yttrium phosphate (YPO), yttrium sulfate (Y(SO)) or (Y(SO)), or yttrium carbonate (Y(CO)).

[0431]

[0435] In a 239th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the hydrogel comprises a first layer and a second layer.

[0432]

[0436] In a 240th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the embedding component is not present in the second layer.

[0433]

[0437] In a 241st embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein a first layer comprises a first embedded component and a second layer comprises a second embedded component.

[0434]

[0438] In a 242nd embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein a first layer comprises a first polymerized complex and a second layer comprises a second polymerized complex that differs from the first polymerized complex in one or more of the monomer units, complexing molecules, embedding components, or aqueous solution.

[0435]

[0439] In a 243 embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, comprising preparing a first solution of reconstituted monomer units in a first aqueous solution, and preparing a second solution of reconstituted complexed molecules in a second aqueous solution, wherein an embedding component is present in the first solution and / or the second solution, and contacting the first and second solutions when both are poured into a cavity space of a subject to form a polymerized complex.

[0436]

[0440] In a 244th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the cavity space is between the rectum and the prostate of a subject.

[0437]

[0441] In a 245th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the cavity space is located within breast tissue of a subject.

[0438]

[0442] In a 246th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the complexing molecule is rHA or PEI.

[0439]

[0443] In a 247th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel, wherein the monomer unit comprises a terminal structure, a linker, and a core, and the complexing molecule is selected from recombinant albumin, polyethyleneimine (PEI), and polylysine.

[0440]

[0444] In a 248th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the linker comprises polyethylene glycol (PEG).

[0441]

[0445] In a 249th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the linker has a length sufficient to provide the hydrogel with a molecular weight (MW) of between 1 kDa and 100 kDa.

[0442]

[0446] In a 250th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the terminal structure is selected from N-hydroxysuccinimide (NHS) carboxymethyl ester (NHS-SCM), NHS succinate ester (NHS-SS), NHS glutarate (NHS-SG), or triiodobenzoic acid (TIBA).

[0443]

[0447] In a 251st embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the core is selected from pentaerythritol, hexaglycerol, tripentaerythritol, or glycerol.

[0444]

[0448] In a 252nd embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel in which the monomer units have 2, 4, or 8 linker arms extending from the core.

[0445]

[0449] In a 253rd embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel in which an ester of a monomer unit is complexed with an amine or imine of a complexing molecule.

[0446]

[0450] In a 254th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel, wherein the molar ratio of ester of the monomer unit to amine or imine of the complexing molecule is from 0.05 to 3.

[0447]

[0451] In a 255th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel, wherein the molar ratio is from 1.5 to 2.

[0448]

[0452] In a 256th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the complexing molecule comprises 2% to 60% weight / volume (w / v) of the hydrogel.

[0449]

[0453] In a 257th embodiment, alone or in combination with any other embodiment herein, the present disclosure provides a method for producing a polymerizable polymer having a mass ratio of monomer unit:conjugated molecule of 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. 20:0.5, 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.

[0450]

[0454] In a 258th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the pH of the hydrogel is between 7.5 and 11.0.

[0451]

[0455] In a 259th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel.

[0456] In a 260th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel, wherein the monomer unit is NHS-PEG-SG-8, NHS-PEG-SG-4, or NHS-PEG-SG-2.

[0452]

[0457] In a 261st embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel, wherein the monomer unit is NHS-PEG-SS-8, NHS-PEG-SS-4, or NHS-PEG-SS-2.

[0453]

[0458] In a 262nd embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel, wherein the monomer unit is NHS-PEG-SCM-8, NHS-PEG-SCM-4, or NHS-PEG-SCM-2.

[0454]

[0459] In a 263rd embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the complexing molecule is rHA.

[0455]

[0460] In a 264th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to the use of a hydrogel composition to separate target tissue from non-target tissue of a subject, wherein the embedded component exerts a therapeutic effect on the target tissue and / or enhances treatment of the target tissue.

[0456]

[0461] In a 265th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to the use of the hydrogel composition, wherein the treatment of the target tissue is radiation therapy.

[0457]

[0462] In a 266th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to the use of a hydrogel composition wherein the target tissue is prostate tissue.

[0458]

[0463] In a 267th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to the use of a hydrogel composition, wherein the non-target tissue is rectal tissue.

[0459]

[0464] In a 268th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a kit comprising a first aqueous solution, a second aqueous solution, dried monomeric units, dried complexing molecules, and one or more embedding components, wherein the first aqueous solution reconstitutes the monomeric units and the second aqueous solution reconstitutes the complexing molecules.

[0460]

[0465] In a 269th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a kit including a means for mixing a first aqueous solution and a second aqueous solution prior to application to a cavity space of a subject.

[0461]

[0466] In a 270th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a kit comprising a first syringe barrel and a second syringe barrel, both of which are operably connected to a single needle point.

[0462]

[0467] In a 271st embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition for in situ formation within a cavity, comprising a polymerized conjugate of at least one monomer unit selected from NHS-PEG-SCM-8, NHS-PEG-SCM-4, or NHS-PEG-SCM-2, at least one conjugation molecule, and an aqueous solution, wherein the conjugation molecule is polyethyleneimine (PEI).

[0463]

[0468] In a 272nd embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition in which an ester of a monomer unit complexes with an amine or imine of a complexing molecule.

[0464]

[0469] In a 273rd embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the molar ratio of ester of the monomer unit to amine or imine of the complexing molecule is from 0.05 to 3.

[0465]

[0470] In a 274th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the molar ratio is from 1.5 to 2.

[0466]

[0471] In a 275th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the molar ratio is from 1.75 to 2.

[0467]

[0472] In a 276th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the complexing molecule comprises 2% to 60% weight / volume (w / v) of the hydrogel.

[0468]

[0473] In a 277th embodiment, alone or in combination with any other embodiment herein, the present disclosure provides a method for producing a polymerizable polymer having a mass ratio of monomer unit:conjugated molecule of 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.

[0469]

[0474] In a 278th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the pH of the hydrogel is between 7.5 and 11.0.

[0470]

[0475] In a 279th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition further comprising an embedding component in the hydrogel.

[0471]

[0476] In a 280th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the embedding component is dissolved in the hydrogel.

[0472]

[0477] In a 281st embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition in which an embedded component is suspended throughout the hydrogel in a crystalline or amorphous solid state.

[0473]

[0478] In a 282nd embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the embedded component comprises a therapeutic agent.

[0474]

[0479] In a 283rd embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the therapeutic agent is a chemotherapeutic agent selected from docetaxel, degarelix, abiraterone, apalutamide, bicalutamide, cabazitaxel, darolutamide, leuprolide, enzalutamide, flutamide, goserelin, lutetium Lu177 bipibotide tetraxetan, olaparib, mitoxantrone, nilutamide, relugolix, cyprocel-T, radium-223, rucaparib camsylate, or a combination thereof.

[0475]

[0480] In a 284th embodiment, alone or in combination with any other embodiment herein, the present disclosure provides a method for treating rheumatoid arthritis, wherein the therapeutic agent is raloxifene, tamoxifen, abemaciclib, paclitaxel, trastuzumab, everolimus, alpelisib, anastrozole, pamidronate, exemestane, capecitabine, cyclophosphamide, docetaxel, doxorubicin, elacestrant, epirubicin, eribulin mesylate, fluorouracil, fluoxetine, fluoxetine, fluoxetine-10 ... and a hydrogel composition, wherein the chemotherapeutic agent is selected from the group consisting of rasil, toremifene, fulvestrant, letrozole, gemcitabine, goserelin, palbociclib, ixabepilone, pembrolizumab, ribociclib, lapatinib, olaparib, margetuximab, megestrol, methotrexate, neratinib, pertuzumab, sacituzumab, talazoparib, thiotepa, tucatinib, vinblastine, or a combination thereof.

[0476]

[0481] In a 285th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the embedded component is a radiosensitizer selected from gemcitabine, fluorouracil or 5-fluorouracil, interferon-α, 13-cis-retinoic acid, doxorubicin, docetaxel, carboplatin, cisplatin, dactinomycin, methotrexate, bleomycin, hydroxyurea, cetuximab, nimotuzumab, AMG102, paraoxonase-2 C-reactive peptide, gold, GSH-modified gold, silver, bismuth, palladium, gadolinium, xinc, curcumin, misonidazole, tirapazamine, paclitaxel, resveratrol, mitomycin C, etanidazole, AQ4N, lidocaine, procaine, chlorpromazine, fludarabine, motexafin, nicotinamide, and combinations thereof.

[0477]

[0482] In a 286th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the embedded component is a radioprotector selected from amifostine, palifermin, superoxide dismutase, tetracycline, genistein, captopril, lisinopril, 3,3'-diindolylmethane, rapamycin, CBLB502, ON01210, gamma-tocotrienol, delta-tocotrienol, R-spondin 1, transforming growth factor beta 3, mesenchymal stem cells, bone marrow stromal cells, myeloid progenitor cells, antioxidants, or combinations thereof.

[0478]

[0483] In a 287th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the embedding component comprises gas nanobubbles.

[0479]

[0484] In a 288th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the embedded component comprises a compound that enables the generation of reactive oxygen species from radiation therapy.

[0480]

[0485] In a 289th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the embedding component comprises a peroxide.

[0481]

[0486] In a 290th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the peroxide comprises formamide peroxide.

[0482]

[0487] In a 291st embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the embedded component comprises microparticles.

[0483]

[0488] In a 292nd embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the microparticles comprise a biodegradable polymer.

[0484]

[0489] In a 293 embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the biodegradable polymer is selected from polyglycolic acid (PGA), polylactic acid (PLA), poly-L-lactic acid (PLLA), polycaprolactone (PCL), poly DL-lactic acid (PDLLA), poly(lactic-co-glycolic) acid (PLGA), poly(trimethylene carbonate) (PTMC), poly(esteramine) (PEA), poly(para-dioxanone) (PPDO), poly 2-hydroxybutyrate (PHB), and copolymers thereof.

[0485]

[0490] In a 294th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the microparticles further comprise a therapeutic agent.

[0486]

[0491] In a 295th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the microparticles comprise a radioisotope or a compound further comprising at least one radioactive element.

[0487]

[0492] In a 296th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the radioisotope comprises yttrium-90.

[0488]

[0493] In a 297th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the compound is selected from yttrium phosphate (YPO), yttrium sulfate (Y(SO)) or (Y(SO)), or yttrium carbonate (Y(CO)).

[0489]

[0494] In a 298th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition.

[0495] In a 299th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition.

[0490]

[0496] In a 300th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition, wherein the microparticles further comprise a radiopaque marker.

[0491]

[0497] In a 301st embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the radiopaque marker comprises methylated TIBA (TIBA-Me).

[0492]

[0498] In a 302 embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the embedded component comprises a tissue marker.

[0493]

[0499] In a 303 embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition.

[0500] In a 304th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the tissue marker is selected from titanium particles, nitinol particles, PVA particles, or a combination thereof.

[0494]

[0501] In a 305th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the embedded component comprises a radiopaque compound.

[0495]

[0502] In a 306th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a hydrogel composition wherein the radiopaque compound comprises methylated TIBA (TIBA-Me).

[0496]

[0503] In a 307th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, comprising preparing a first solution of monomer units selected from NHS-PEG-SCM-8, NHS-PEG-SCM-4, or NHS-PEG-SCM-2, reconstituted in a first aqueous solution; preparing a second solution of complexing molecules reconstituted in a second aqueous solution, wherein the complexing molecule is polyethyleneimine (PEI); and contacting the first and second solutions when both are poured into a cavity space of a subject to form a polymerized complex.

[0497]

[0504] In a 308th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the cavity space is between the rectum and the prostate of a subject.

[0498]

[0505] In a 309th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the cavity space is located within breast tissue of a subject.

[0499]

[0506] In a 310th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the complexing molecule is rHA or PEI.

[0500]

[0507] In a 311th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel, wherein the monomer unit comprises a terminal structure, a linker, and a core, and the complexing molecule is selected from recombinant albumin, polyethyleneimine (PEI), and polylysine.

[0501]

[0508] In a 312th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the linker comprises polyethylene glycol (PEG).

[0502]

[0509] In a 313th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the linker provides a molecular weight (MW) of between 1 kDa and 100 kDa.

[0503]

[0510] In a three hundred and fourteenth embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the terminal structure is selected from N-hydroxysuccinimide (NHS) carboxymethyl ester (NHS-SCM), NHS succinate ester (NHS-SS), NHS glutarate (NHS-SG), or triiodobenzoic acid (TIBA).

[0504]

[0511] In a 315th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the core is selected from pentaerythritol, hexaglycerol, tripentaerythritol, or glycerol.

[0505]

[0512] In a 316th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel in which the monomer units have 2, 4, or 8 linker arms extending from the core.

[0506]

[0513] In a 317th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel in which an ester of a monomer unit is complexed with an amine or imine of a complexing molecule.

[0507]

[0514] In a 318th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel, wherein the molar ratio of ester of the monomer unit to amine or imine of the complexing molecule is from 0.05 to 3.

[0508]

[0515] In a 319th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel, wherein the molar ratio is from 1.5 to 2.

[0509]

[0516] In a 320th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the complexing molecule comprises 2% to 60% weight / volume (w / v) of the hydrogel.

[0510]

[0517] In a 321st embodiment, alone or in combination with any other embodiment herein, the present disclosure provides a method for producing a polymerizable composition comprising a polymerizable monomer having a mass ratio of monomer unit:conjugated molecule of 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. 20:0.5, 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.

[0511]

[0518] In a 322nd embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the pH of the hydrogel is between 7.5 and 11.0.

[0512]

[0519] In a 323rd embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel, wherein the monomer unit is NHS-PEG-SG-8, NHS-PEG-SG-4, or NHS-PEG-SG-2.

[0513]

[0520] In a 324th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel, wherein the monomer unit is NHS-PEG-SS-8, NHS-PEG-SS-4, or NHS-PEG-SS-2.

[0514]

[0521] In a 325th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method for preparing a hydrogel, wherein the monomer unit is NHS-PEG-SCM-8, NHS-PEG-SCM-4, or NHS-PEG-SCM-2.

[0515]

[0522] In a 326th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the complexing molecule is rHA.

[0516]

[0523] In a 327th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel, wherein the complexing molecule is PEI.

[0517]

[0524] In a 328th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a method of preparing a hydrogel further comprising a component embedded in the hydrogel in a first solution and / or a second solution.

[0518]

[0525] In a 329th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to the use of a hydrogel composition to separate target tissue from non-target tissue of a subject, comprising injecting the hydrogel into a cavity space between the target tissue and the non-target tissue.

[0519]

[0526] In a 330th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to the use of a hydrogel composition wherein the cavity space is located between the rectum and the prostate.

[0520]

[0527] In a 331st embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to the use of a hydrogel composition.

[0528] In a 332nd embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a cavity located within breast tissue.

[0521]

[0529] In a 333rd embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to the use of a hydrogel composition, wherein the hydrogel exerts a therapeutic effect on a target tissue and / or enhances treatment of the target tissue.

[0522]

[0530] In a 334th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a kit comprising a first aqueous solution, a second aqueous solution, dried monomer units selected from NHS-PEG-SCM-8, NHS-PEG-SCM-4, or NHS-PEG-SCM-2, and a dried conjugated molecule comprising PEI, wherein the first aqueous solution reconstitutes the monomer units and the second aqueous solution reconstitutes the conjugated molecule.

[0523]

[0531] In a 335th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a kit including a means for mixing a first aqueous solution and a second aqueous solution prior to application to the cavity space of a subject.

[0524]

[0532] In a 336th embodiment, alone or in combination with any other embodiment herein, the present disclosure relates to a kit comprising a first syringe barrel and a second syringe barrel, both of which are operably connected to a single needle point.

[0525]

[0533] While specific embodiments have been illustrated and described herein, it will be understood that various other changes and modifications can be made without departing from the spirit and scope of the claimed subject matter. Moreover, although various embodiments of the claimed subject matter have been described herein, such embodiments 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.

[0526]

[0534] Unless otherwise specified, it is understood that all reagents are available from sources known in the art.

[0535] It is also understood that the present disclosure is not limited to the specific embodiments and methods described herein, as specific components and / or conditions may, of course, vary. Furthermore, the terminology used herein is used solely for the purpose of describing specific embodiments of the present disclosure and is not intended to be limiting in any way. Terms such as "first," "second," and "third" may be used herein to describe various elements, components, regions, layers, and / or sections, but it is understood that these elements, components, regions, layers, and / or sections should not be limited by these terms. These terms are used only to distinguish one element, component, region, layer, or section from another element, component, region, layer, or section. Thus, a "first element," "component," "region," "layer," or "section" discussed below could be referred to as a second (or other) element, component, region, layer, or section without departing from the teachings of the present specification. Similarly, as used herein, the singular forms "a," "an," and "the" are intended to include the plural forms, including "at least one," unless the context indicates otherwise. "Or" means "and / or." As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items. It is further understood that the terms "comprises" and / or "comprising" or "includes" and / or "including," as used herein, specify the presence of stated features, regions, integers, steps, operations, elements, components, and / or components, but do not exclude the presence or addition of one or more other features, regions, integers, steps, operations, elements, components, and / or groups thereof. The term "or a combination thereof" means a combination including at least one of the aforementioned elements.

[0527]

[0536] Unless otherwise defined, all terms used herein (including technical and scientific terms) have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. Terms as defined in commonly used dictionaries should be interpreted to have a meaning consistent with the meaning in the relevant technical field and this disclosure, and it is further understood that they should not be interpreted in an idealized or overly formal sense unless explicitly defined as such in this specification.

[0528]

[0537] Reference will now be made in detail to exemplary compositions, embodiments, and methods of the present disclosure, which constitute the best modes of practicing the present disclosure currently known to the inventors. The figures are not necessarily to scale. However, it is to be understood that the disclosed embodiments are merely exemplary of the present disclosure, which may be embodied in various alternative forms. Accordingly, the specific details disclosed herein should not be construed as limiting, but merely as representative examples of any embodiment of the present disclosure and / or as a means to enable one skilled in the art to utilize the present disclosure in each form.

[0529]

[0538] The patents, publications, and applications mentioned in the specification are indicative of the levels of those skilled in the art to which this disclosure pertains, and are hereby incorporated by reference to the same extent as if each individual patent, publication, or application was specifically and individually incorporated by reference.

[0530]

[0539] The foregoing description illustrates specific embodiments of the present disclosure, but is not intended to limit its practice. The following claims, including all equivalents thereof, are intended to define the scope of the present disclosure.

Claims

1. A hydrogel composition for in-situ formation in a lumen, comprising at least one monomer unit, a polymerized complex of at least one complexing molecule, at least one permeating component, and an aqueous solution, wherein the monomer unit comprises a terminal structure, a linker, and a core, and the complexing molecule is selected from recombinant albumin, polyethyleneimine (PEI), and polylysine.

2. The hydrogel composition according to claim 1, wherein the linker comprises polyethylene glycol (PEG).

3. The hydrogel composition according to claim 1 or 2, wherein the linker has a length sufficient to provide the hydrogel composition having a molecular weight (MW) between 1 kDa and 100 kDa.

4. The hydrogel composition according to claim 1 or 2, wherein the terminal structure is selected from N-hydroxysuccinimide (NHS) carboxymethyl ester (NHS-SCM), NHS succinate ester (NHS-SS), NHS glutarate (NHS-SG), or triiodobenzoic acid (TIBA).

5. The hydrogel composition according to claim 1 or 2, wherein the core is selected from pentaerythritol, hexaglycerol, tripentaerythritol, or glycerol.

6. The hydrogel composition according to claim 5, wherein the monomer unit has two, four, or eight linker arms extending from the core.

7. The hydrogel composition according to claim 5, wherein the ester of the monomer unit forms a complex with the amine or imine of the complexing molecule.

8. The hydrogel composition according to claim 1 or 2, wherein the molar ratio of the monomer unit ester to the amine or imine of the complexed molecule is 0.05 to 3.

9. The hydrogel composition according to claim 8, wherein the molar ratio is 1.5 to 2.

10. The hydrogel composition according to claim 1 or 2, wherein the complexing molecule constitutes 2% to 60% by weight / volume (w / v) of the hydrogel composition.

11. The mass ratio of the monomer unit to the complexed molecule is 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: A hydrogel composition according to claim 1 or 2, provided in the following ratios: 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.

12. The hydrogel composition according to claim 1 or 2, wherein the pH of the hydrogel composition is between 7.5 and 11.

0.

13. The hydrogel composition according to claim 1 or 2, wherein the monomer unit is NHS-PEG-SG-8, NHS-PEG-SG-4, or NHS-PEG-SG-2.

14. The hydrogel composition according to claim 1 or 2, wherein the monomer unit is NHS-PEG-SS-8, NHS-PEG-SS-4, or NHS-PEG-SS-2.

15. The hydrogel composition according to claim 1 or 2, wherein the monomer unit is NHS-PEG-SCM-8, NHS-PEG-SCM-4, or NHS-PEG-SCM-2.

16. The hydrogel composition according to claim 13, wherein the complexing molecule is rHA.

17. The hydrogel composition according to claim 13, wherein the complexing molecule is PEI.

18. The hydrogel composition according to claim 1, wherein the penetrating component comprises one or more components selected from reverse osmosis water, salts, organic acids and / or their acidic salts, carbohydrates, monohydric alcohols and / or polyhydric alcohols, amino acids and / or peptides and / or proteins, and / or biodegradable polymers.

19. The hydrogel composition according to claim 18, wherein the salt is selected from sodium chloride, calcium chloride, potassium chloride, magnesium chloride, sodium bicarbonate, sodium phosphate, sodium sulfate, potassium phosphate, potassium sulfate, calcium phosphate, ammonium sulfate, barium chloride, copper sulfate, iron chloride, iron sulfate, lithium chloride, magnesium sulfate, manganese sulfate, nickel sulfate, potassium carbonate, potassium bromide, potassium chloride, potassium iodide, silver nitrate, sodium bromide, sodium carbonate, sodium chlorate, sodium nitrate, sodium pyrophosphate, zinc sulfate, and combinations thereof.

20. The hydrogel composition according to claim 18, wherein the organic acid and / or its acidic salt is selected from fumaric acid, formic acid, gluconic acid, lactic acid, glycolic acid, pyruvic acid, oxalic acid, benzoic acid, cinnamic acid, ferulic acid, butyric acid, propionic acid, gallic acid, itaconic acid, maleic acid, mandelic acid, nicotinic acid, phthalic acid, salicylic acid, shikimic acid, uric acid, valeric acid, and combinations thereof.

21. The hydrogel composition according to claim 18, wherein the carbohydrate is selected from dextrose, fructose, sucrose, lactose, maltose, trehalose, galactose, dextran, xylose, mannose, ribose, isomaltase, inulin, cyclodextrin, hydroxyethyl starch (HES), pullulan, pectin, xanthan gum, agarose, cellulose, hyaluronic acid, maltodextrin, methylcellulose, alginic acid, chitosan, heparin, heparan sulfate, and combinations thereof.

22. The hydrogel composition according to claim 1 or 18, wherein the hydrogel composition is a hypertonic hydrogel composition and has an osmotic pressure greater than 300 mOsm / L.

23. The hydrogel composition according to claim 1 or 18, wherein the hydrogel composition is a hypotonic hydrogel composition and has an osmotic pressure of less than 280 mOsm / L.

24. The hydrogel composition according to claim 1 or 18, wherein the hydrogel composition is an isotonic hydrogel composition and has an osmotic pressure between 280 mOsm / L and 300 mOsm / L.

25. The hydrogel composition according to claim 1, further comprising a therapeutic substance.

26. The hydrogel composition according to claim 1 or 2, further comprising a radiopaque marker.

27. The hydrogel composition according to claim 26, wherein the radiopaque marker comprises methylated TIBA (TIBA-Me).

28. The hydrogel composition according to claim 1, 18, 19, or 20, wherein the hydrogel composition comprises a first layer and a second layer.

29. The hydrogel composition according to claim 28, wherein the first layer has a first osmotic pressure and the second layer has a second osmotic pressure different from the first osmotic pressure.

30. The hydrogel composition according to claim 28, wherein the first layer is hypertonic and the second layer is isotonic.

31. The hydrogel composition according to claim 28, wherein the first layer is hypotonic and the second layer is isotonic.

32. The hydrogel composition according to claim 28, wherein the first layer and / or the second layer comprises a therapeutic element.

33. A kit comprising a first aqueous solution, a second aqueous solution, dried monomer units, dried complexing molecules, and one or more penetrating components, wherein the first aqueous solution reconstitutes the monomer units and the second aqueous solution reconstitutes the complexing molecules.

34. The kit according to claim 33, further comprising means for mixing the first aqueous solution and the second aqueous solution before applying them to a target cavity.

35. The kit according to claim 33, wherein the means includes a first syringe barrel and a second syringe barrel, both of which are operably connected to a single needle point.