Thermogelling polymers, functionalized forms thereof, and related methods

Abstract

Provided is a thermally gelling polymer comprising one or more repeating units derived from a hydrophilic polymer, one or more repeating units derived from a thermally responsive polymer, and one or more repeating units derived from a vinyl group-containing diol monomer, wherein the one or more repeating units derived from a hydrophilic polymer, the one or more repeating units derived from a thermally responsive polymer, and the one or more repeating units derived from a vinyl group-containing diol monomer are bonded by a urethane / urethane bond, a carbonate bond, a vinyl group-containing diol monomer, and a vinyl group-containing diol monomer, at least one of an ester bond or a combination thereof is chemically coupled together. A method of making the thermogelling polymer and a functionalized form of the thermogelling polymer are also provided.

Description

TECHNICAL FIELD

[0001] The present disclosure relates broadly to a thermogelling polymer, functionalized versions thereof, and methods related thereto. BACKGROUND

[0002] Thermogels or thermogelling copolymers are a class of thermoresponsive amphiphiles that undergo a temperature-dependent spontaneous sol-gel transition and self-assemble into supramolecular gels when the temperature is raised, i.e. when in contact with the human body. This offers unique advantages such as injectability, sprayability and the ability to encapsulate temperature-sensitive therapeutics, drugs, proteins or cells. To date, thermogels have been used for drug delivery and tissue engineering.

[0003] Currently, the ability to tailor the chemical composition of these synthetic gels is limited to the incorporation of hydrolysable polyesters such as poly(ε-caprolactone)-diols and poly(lactic-co-glycolic acid) (PLGA) to promote biodegradability. The high reactivity of isocyanates would preclude the facile incorporation of many chemical moieties along the polymer backbone while controlling the functional group density, and without the cumbersome protection and deprotection of functional groups. For example, existing protocols such as chain-end modification result in low functional group densities or lack of synthetic versatility that would allow facile but high-yield functionalization of thermogels. Furthermore, these methods often require harsh conditions (e.g. concentrated corrosive acids).

[0004] In view of the above, there is a need to address or at least ameliorate the above problems. In particular, there is a need to provide a method to conveniently allow post-synthetic chemical functionalization of thermogelling polymers, which would allow them to possess new properties. SUMMARY

[0005] In one aspect, there is provided a thermogelling polymer comprising one or more repeating units derived from a hydrophilic polymer, one or more repeating units derived from a thermoresponsive polymer, and one or more repeating units derived from a vinyl-containing diol monomer,

[0006] wherein the one or more repeating units derived from a hydrophilic polymer, the one or more repeating units derived from a thermoresponsive polymer, and the one or more repeating units derived from a vinyl-containing diol monomer are chemically coupled together by at least one of a urethane / carbamate linkage, a carbonate linkage, an ester linkage, or a combination thereof.

[0007] In one embodiment, the one or more repeating units derived from a hydrophilic polymer is represented by Formula (1); the one or more repeating units derived from a thermoresponsive polymer is represented by Formula (2); the one or more repeating units derived from a vinyl-containing diol monomer is represented by Formula (3); and the at least one of a urethane / urethane linkage, a carbonate linkage, an ester linkage, or a combination thereof is represented by Formula (5):

[0008]

[0009] wherein

[0010] R 1 -R 10 each is independently selected from H, alkyl, or optionally substituted alkyl;

[0011] m > 1 ;

[0012] n > 1 ;

[0013] R 11 is alkyl or optionally substituted alkyl.

[0014] In one embodiment, Formula (1) comprises poly(ethylene glycol) (PEG), Formula (2) comprises poly(propylene glycol) (PPG), Formula (3) comprises 1,5-hexadiene-3,4-diol (HDDO), and Formula (5) comprises hexamethylene diisocyanate (HMDI).

[0015] In one embodiment, Formula (1) is present in an amount of 0 mass% - 90 mass% of the thermogelling polymer, Formula (2) is present in an amount of 0 mass% - 90 mass% of the thermogelling polymer, Formula (3) is present in an amount of 0.1 mass% - 40% of the thermogelling polymer, and Formula (5) is present in an amount of 10 mass% - 60 mass% of the thermogelling polymer.

[0016] In one embodiment, the thermogelling polymer comprises 0.01 mmol / g - 7 mmol / g of vinyl groups (e.g., -CH=CH2).

[0017] In one embodiment, the thermogelling polymer has a polydensity index (PDI) in the range of 1 - 2.

[0018] In one embodiment, one or more of the vinyl groups of the thermogelling polymer are further functionalized.

[0019] In one aspect, a functionalized thermal-gelling polymer is provided, comprising one or more repeating units derived from a hydrophilic polymer, one or more repeating units derived from a thermally-responsive polymer, and one or more repeating units derived from a functionalized vinyl-containing diol monomer,

[0020] wherein the one or more repeating units derived from a hydrophilic polymer, the one or more repeating units derived from a thermally-responsive polymer, and the one or more repeating units derived from a functionalized vinyl-containing diol monomer are chemically coupled together by at least one of a urethane / urea linkage, a carbonate linkage, an ester linkage, or a combination thereof.

[0021] In one embodiment, the one or more repeating units derived from a hydrophilic polymer is represented by Formula (1); the one or more repeating units derived from a thermally-responsive polymer is represented by Formula (2); the one or more repeating units derived from a functionalized vinyl-containing diol monomer is represented by Formula (4); and the at least one of a urethane / urea linkage, a carbonate linkage, an ester linkage, or a combination thereof is represented by Formula (5):

[0022]

[0023] wherein

[0024] R 1 -R 10 , m and n are as defined above;

[0025] X 1 -S and X 2 -S each independently is a thiol-containing functional group;

[0026] R 11 is an alkyl group or an optionally substituted alkyl group.

[0027] In one embodiment, Formula (1) comprises poly(ethylene glycol) (PEG), Formula (2) comprises poly(propylene glycol) (PPG), Formula (3) comprises 1,5-hexadiene-3,4-diol (HDDO), and Formula (5) comprises hexamethylene diisocyanate (HMDI).

[0028] In one embodiment, X 1 and X 2 each independently is a moiety comprising a carboxylic acid, an amino acid, a sulfonate, an alkyl sulfonate, an amine hydrochloride, an alcohol, a diol, benzene, an alkyl benzene, or a derivative thereof.

[0029] In one embodiment, X 1 and X 2each independently selected from the following structures or derivatives thereof:

[0030]

[0031] In an embodiment, the functionalized thermogelling polymer has one or more of the following properties: a pH value in the range of 1-10; a gelation temperature in the range of 4°C-60°C; a cross- modulus in the range of 5 Pa-1000 Pa; a storage modulus (G') in the range of 4 Pa-5000 Pa at about 37°C; or a complex viscosity in the range of 1 Pa.s-500 Pa.s at about 37°C.

[0032] In an embodiment, X of the functionalized thermogelling polymer is 1 and / or the functional group density of X 2 is in the range of 0.01 mmol / g-7 mmol / g.

[0033] In an aspect, a method of preparing a thermogelling polymer is provided, the method comprising:

[0034] coupling one or more hydrophilic polymers, one or more thermoresponsive polymers and one or more vinyl-containing diol monomers in the presence of a coupling agent to obtain a thermogelling polymer,

[0035] wherein the coupling agent comprises a carbamate / carbamate-forming agent, a carbonate-forming agent, an ester-forming agent or a combination thereof.

[0036] In an embodiment, the one or more hydrophilic polymers are represented by general formula (6); the one or more thermoresponsive polymers are represented by general formula (7); and the one or more vinyl-containing diol monomers are represented by general formula (8),

[0037]

[0038] wherein R 1 -R 10 , m and n are as defined above.

[0039] In an embodiment, general formula (6) comprises poly(ethylene glycol) (PEG), general formula (7) comprises poly(propylene glycol) (PPG), and general formula (8) comprises 1,5-hexadiene-3,4-diol (HDDO).

[0040] In an embodiment, the one or more hydrophilic polymers represented by general formula (6), the one or more thermoresponsive polymers represented by general formula (7) and the one or more vinyl-containing diol monomers represented by general formula (8) are mixed in a mass ratio of 1-20: 1-10: 0.01-3.

[0041] In an embodiment, the coupling step is carried out at an elevated temperature in the range of 60 °C to 150 °C.

[0042] In an embodiment, the coupling step is carried out for at least 2 hours.

[0043] In an embodiment, the coupling agent is a diisocyanate selected from the group consisting of hexamethylene diisocyanate (HMDI), tetramethylene diisocyanate, cyclohexane diisocyanate, tetramethyl xylene diisocyanate, dodecane diisocyanate, tolylene 2,4-diisocyanate and tolylene 2,6-diisocyanate.

[0044] In an embodiment, the coupling agent is added in a ratio of 1-2: 1-2 with respect to one or more vinyl containing diol monomers of general formula (8).

[0045] In an embodiment, the coupling step is carried out in the presence of an anhydrous solvent selected from the group consisting of toluene, benzene and xylene.

[0046] In an embodiment, the coupling step is carried out in the presence of a metal containing or non-metal containing catalyst capable of catalyzing the formation of urethane / urethane bond, carbonate bond, ester bond or combinations thereof from an alcohol and a suitable isocyanate precursor or derivatives thereof.

[0047] In an embodiment, the metal containing catalyst can be a tin catalyst selected from the group consisting of alkyl tin compounds, aryl tin compounds, dialkyl tin compounds such as dibutyl tin dilaurate (DBTL) and zinc based catalysts such as zinc diethyl dithiocarbamate.

[0048] In an embodiment, X 1 -S and X 2 -S each independently is a thiol containing functional group.

[0049] In an embodiment, the method further comprises functionalizing the thermally gelled polymer with one or more thiols to obtain a functionalized thermally gelled polymer having thiol containing functional groups X 1 -S and X 2 -S, wherein X 1 and X 2 each independently comprises a functional group.

[0050] In an embodiment, X 1 and X 2 each independently is a moiety comprising a carboxylic acid, an amino acid, a sulfonate, an alkyl sulfonate, an amine hydrochloride, an alcohol, a diol, benzene, an alkyl benzene or derivatives thereof.

[0051] In an embodiment, X 1 and X 2 each is independently selected from the following structures or derivatives thereof:

[0052]

[0053] In an embodiment, functionalizing the thermogelling polymer is performed in the presence of a free radical initiator, a photoinitiator, and / or ultraviolet (UV) light.

[0054] In an embodiment, functionalizing the thermogelling polymer is performed in the presence of UV light for at least 30 minutes.

[0055] In an embodiment, functionalizing the thermogelling polymer is performed in the presence of an anhydrous solvent, optionally wherein the anhydrous solvent is selected from anhydrous tetrahydrofuran (THF) and anhydrous methanol.

[0056] In an embodiment, the one or more thiols are added in a molar ratio of 20-1 : 1-20, optionally 3: 1, relative to the vinyl groups in the thermogelling polymer.

[0057] In an embodiment, the photoinitiator is added in a molar ratio of at least 3-1 : 1-3, optionally 2: 1, relative to the vinyl groups in the functionalized thermogelling polymer.

[0058] In an embodiment, the photoinitiator comprises 2-hydroxy-4'-(2-hydroxyethoxy)-2- methylpropiophenone.

[0059] In an embodiment, the functionalization efficiency of functionalizing the thermogelling polymer with one or more thiols is in the range of 5% - 100%.

[0060] Definitions

[0061] The terms "coupled" or "connected," as used in this specification, are intended to cover both direct connections and indirect connections.

[0062] The term "alkyl" as a group or part of a group refers to a straight or branched chain aliphatic hydrocarbon group having 1 to 20 carbon atoms, 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. Examples of suitable straight chain and branched alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, hexyl, pentyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, pentyl, isopentyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2-trimethylpropyl, 1,1,2-trimethylpropyl, 2-ethylpentyl, 3-ethylpentyl, heptyl, 1-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, 1,2,3-trimethylbutyl, 1,1,2-trimethylbutyl, 1,1,3-trimethylbutyl, 5-methylheptyl, 1-methylheptyl, octyl, nonyl, decyl, and the like. The group can be a terminal group or a bridging group.

[0063] The term "optionally substituted" when used to describe a chemical structure or moiety means that one or more hydrogen atoms of the chemical structure or moiety are optionally replaced with a chemical moiety or functional group, such as an alcohol, alkoxy, alkanoyloxy, alkoxycarbonyl, alkenyl, alkyl (e.g., methyl, ethyl, propyl, t-butyl), alkynyl, alkylcarbonyloxy (-OC(O)alkyl), amide (-C(O)NH-alkyl- or -alkylNHC(O)alkyl), amine (e.g., alkylamino, arylamino, arylalkylamino), aryl, aryloxy, azo, carbamoyl (-NHC(O)O-alkyl- or -OC(O)NH-alkyl), carbamoyl (e.g., CONH2and CONH-alkyl, CONH-aryl, and CONH-arylalkyl), carboxyl, carboxylic acid, cyano, ester, ether (e.g., methoxy, ethoxy), halogen, haloalkyl (e.g., -CCl3, -CF3, -C(CF3)3), heteroalkyl, isocyanate, isothiocyanate, nitrile, phosphodiester, sulfide, sulfonamido (e.g., SO2NH2), sulfone, sulfonyl (including alkylsulfonyl, arylsulfonyl, and arylalkylsulfonyl), sulfoxide, thiol (e.g., sulfhydryl, thioether), or urea (-NHCONH-alkyl-).

[0064] As used herein, the term "derivative" refers to a compound derived from another compound and which retains the general structure of the compound from which it is derived.

[0065] As used herein, the term "functional group" refers to a group of atoms arranged in a manner that determines the chemical properties of the group and the molecule to which it is attached. Examples of functional groups include, but are not limited to, carboxylic acid groups, amino acid groups, sulfonate groups, alkyl sulfonate groups, amine hydrochloride groups, alcohol groups, diol groups, phenyl groups, alkyl phenyl groups, halogen atom containing groups, and the like.

[0066] The term "adjacent" as used herein when referring to two elements means that one element is immediately next to the other element, and can be, but is not limited to, elements that are in contact with each other, or can also include elements that are separated by one or more additional elements located therebetween.

[0067] The term "and / or" such as "X and / or Y" shall be understood to mean either "X and Y" or, alternatively, "X or Y", and shall be taken to provide explicit support for both meanings or for either meaning.

[0068] Further, in the description herein, the word "substantially" is used to mean that a thing is largely but not wholly what is described as the thing. In other words, the word "substantially" describes closely but not perfectly, typically allowing for some errors; as understood by those of ordinary skill in the art, the word "substantially" is thus consistent with examples of "entirely" or "completely" or "fully" or "perfectly" or "completely" or "wholly" or "totally" or "almost entirely" or "almost completely" or "almost fully" or "almost perfectly" or "almost wholly" or "almost totally." In addition, the words "comprise," "comprising," "comprise," "comprising," "comprise," "comprising," and the like are to be understood to be open-ended and not limiting, unless otherwise noted or as otherwise apparent from context. Thus, use of such terms is meant to include anything that follows in the list of nomenclature that such term directly or indirectly precedes, as well as those items integral in the application as a whole. For example, when a system is described as "comprising" a component, it is understood that the system can further comprise other components, even if such other components are not explicitly recited. Further, the words "comprise," "comprising," "comprise," "comprising," "comprise," "comprising," and the like are to be understood to be open-ended and not limiting, unless otherwise noted or as otherwise apparent from context. Thus, use of such terms is meant to include anything that follows in the list of nomenclature that such term directly or indirectly precedes, as well as those items integral in the application as a whole. For example, when a system is described as "comprising" a component, it is understood that the system can further comprise other components, even if such other components are not explicitly recited. Further, the terms "about," "approximately," and the like, as used herein when used in a context to refer to a numerical value, are typically intended to mean a reasonable variation, such as + / - 5% of the value disclosed, or + / - 4% of the value disclosed, or + / - 3% of the value disclosed, or + / - 2% of the value disclosed, or + / - 1% of the value disclosed.

[0069] Further, in the description herein, certain values can be disclosed in a range. The intention is that the lower and upper end points of the range are to be interpreted as a preference. Whenever a range is recited, it is intended to include all possible sub-ranges and individual values within that range. That is, the end points of the range are not to be interpreted as inflexible limitations. For example, a recitation of a range of 1% to 5% is intended to have the specific disclosed sub-ranges of 1% to 2%, 1% to 3%, 1% to 4%, 2% to 3%, etc., as well as individual values within that range, such as 1%, 2%, 3%, 4%, and 5%. The specific disclosure of the above is intended to apply to any depth / wideness of range.

[0070] In addition, the disclosure can have disclosed methods and / or processes as a particular sequence of steps. However, unless otherwise required, the disclosed methods or processes should not be limited to the specific sequence of steps disclosed. Other sequences of steps can also be possible. The specific sequence of steps disclosed herein should not be construed as a limitation on the scope of the disclosure. Unless otherwise required, the methods and / or processes disclosed herein should not be limited to the steps performed in the written order.

[0071] Further, it will be understood that while the disclosure provides embodiments having one or more features / characteristics discussed herein, one or more of these features / characteristics can also be abandoned in other alternative embodiments, and the disclosure provides support for such abandonment and these related alternative embodiments.

[0072] It will also be understood that, where priority is claimed to an earlier application, the content of the entire earlier application is considered part of the disclosure, and can be used to support the embodiments disclosed herein. SUMMARY

[0073] Illustratively, non-limiting embodiments of thermogelling polymers, functionalized versions thereof, and related methods of making these polymers are disclosed below.

[0074] In various embodiments, thermogelling polymers are provided that include one or more repeating units derived from a hydrophilic polymer, one or more repeating units derived from a thermally responsive / thermosensitive polymer, and one or more repeating units derived from a vinyl-containing diol monomer.

[0075] In various embodiments, the one or more repeating units derived from a hydrophilic polymer are represented by Formula (1), the one or more repeating units derived from a thermally responsive polymer are represented by Formula (2), and the one or more repeating units derived from a vinyl-containing diol monomer are represented by Formula (3):

[0076] In various embodiments, the one or more repeating units derived from a hydrophilic polymer are represented by Formula (1), the one or more repeating units derived from a thermally responsive polymer are represented by Formula (2), and the one or more repeating units derived from a vinyl-containing diol monomer are represented by Formula (3):

[0077] wherein

[0078] R 1 -R 10 each is independently selected from H, alkyl, or optionally substituted alkyl;

[0079] m is 1-400, 5-395, 10-390, 15-385, 20-80, 25-375, 30-370, 35-365, 40-360, 45-355, 50-350, 60-340, 70-330, 80-320, 90-310, 100-300, 110-290, 120-280, 130-270, 140-260, 150-250, 160-240, 170-230, 180-220, 190-210, or 200;

[0080] n is 1-400, 5-395, 10-390, 15-385, 20-80, 25-375, 30-370, 35-365, 40-360, 45-355, 50-350, 60-340, 70-330, 80-320, 90-310, 100-300, 110-290, 120-280, 130-270, 140-260, 150-250, 160-240, 170-230, 180-220, 190-210, or 200.

[0081] In various embodiments, when m is about 340, the molecular weight of the general formula (1) (e.g., PEG) is about 15 kDa.

[0082] In various embodiments, the vinyl-containing diol monomer includes, but is not limited to, 1,5-hexadiene-3,4-diol (HDDO), 3-(allyloxy)propane-1,2-diol, 2,3-dihydroxypropyl methacrylate, and the like. The vinyl-containing diol monomer can be a compound that is proprietary / synthetic or commercially available.

[0083] In various embodiments, the thermal gelation polymer is a multi-block polymer. The multi-block polymer can have at least one unit of the following structure sequence A-B-C, where A is a polymer block comprising at least one repeating unit of Formula (1), B is a polymer block comprising at least one repeating unit of Formula (2), and C is a polymer block comprising at least one repeating unit of Formula (3). It is understood that in some embodiments, the positions of A, B, and C can be interchanged among them. In various embodiments, the multi-block polymer can comprise a plurality of repeating units of Formula (1), a plurality of repeating units of Formula (2), and / or a plurality of repeating units of Formula (3). In various embodiments, the multi-block copolymer comprises greater than 3 polymer blocks. The blocks can be randomly distributed / arranged within the polymer.

[0084] In various embodiments, the one or more repeating units derived from a hydrophilic polymer are part of a hydrophilic polymer block, and the one or more repeating units derived from a thermally responsive / thermosensitive polymer are part of a thermally responsive / thermosensitive polymer block.

[0085] In various embodiments, the polymer block comprising at least one repeating unit of Formula (1), the polymer block comprising at least one repeating unit of Formula (2), and the polymer block comprising at least one repeating unit of Formula (3) are chemically coupled together by at least one of a urethane / urea linkage, a carbonate linkage, an ester linkage, or a combination thereof. For example, each polymer block is linked to its respective adjacent block by at least one of a urethane / urea linkage, a carbonate linkage, an ester linkage, or a combination thereof.

[0086] In various embodiments, the at least one of a urethane / urea linkage, a carbonate linkage, an ester linkage, or a combination thereof is of the general Formula (5):

[0087]

[0088] where R 11 is an alkyl group or an optionally substituted alkyl group.

[0089] In various embodiments, the general Formula (1) is different from the general Formula (2) in the thermal gelation polymer. For example, the general Formula (1) can comprise PEG, while the general Formula can comprise PPG. In various embodiments, the general Formula (5) comprises a urethane / urea. Thus, in various embodiments, the general Formula (1) comprises poly(ethylene glycol) (PEG), the general Formula (2) comprises poly(propylene glycol) (PPG), the general Formula (3) comprises 1,5-hexadiene-3,4-diol (HDDO), and the general Formula (5) comprises hexamethylene diisocyanate (HMDI).

[0090] In various embodiments, the amount of Formula (1) is present in a range of about 0 mass % to about 90 mass %, about 5 mass % to about 85 mass %, about 10 mass % to about 80 mass %, about 15 mass % to about 75 mass %, about 20 mass % to about 70 mass %, about 25 mass % to about 65 mass %, about 30 mass % to about 60 mass %, about 35 mass % to about 55 mass %, about 40 mass % to about 50 mass %, about 41 mass %, about 42 mass %, about 43 mass %, about 44 mass %, about 45 mass %, about 46 mass %, about 47 mass %, about 48 mass %, about 49 mass %, about 50 mass %, about 51 mass %, about 52 mass %, about 53 mass %, about 54 mass %, about 55 mass %, about 56 mass %, about 57 mass %, about 58 mass %, about 59 mass %, about 60 mass %, about 61 mass %, about 62 mass %, about 63 mass %, about 64 mass %, or about 65 mass % of the thermogelling polymer.

[0091] In various embodiments, the amount of Formula (2) is present in a range of about 0 mass % to about 90 mass %, about 5 mass % to about 85 mass %, about 10 mass % to about 80 mass %, about 15 mass % to about 75 mass %, about 20 mass % to about 70 mass %, about 25 mass % to about 65 mass %, about 30 mass % to about 60 mass %, about 35 mass % to about 55 mass %, about 40 mass % to about 50 mass %, about 10 mass % to about 25 mass %, about 11 mass % to about 24 mass %, about 12 mass % to about 23 mass %, about 13 mass % to about 22 mass %, about 14 mass % to about 21 mass %, about 15 mass % to about 20 mass %, about 16 mass % to about 19 mass %, about 17 mass % to about 18 mass %, or about 17.5 mass % of the thermogelling polymer.

[0092] In various embodiments, the amount of Formula (3) present is in the range of about 0.1 mass % to about 40 mass %, about 0.15 mass % to about 35 mass %, about 0.2 mass % to about 30 mass %, about 0.2 mass % to about 25 mass %, about 0.2 mass % to about 20 mass %, about 0.2 mass % to about 15 mass %, about 0.2 mass % to about 10 mass %, about 0.2 mass % to about 9.5 mass %, about 0.2 mass % to about 9.0 mass %, about 0.2 mass % to about 8.5 mass %, about 0.2 mass % to about 8.0 %, about 0.5 mass % to about 7.5 %, about 1.0 mass % to about 7.0 %, about 1.5 mass % to about 6.5 %, about 2.0 mass % to about 6.0 %, about 2.5 mass % to about 5.5 %, about 3.0 mass % to about 5.0 %, about 3.5 mass % to about 4.5 %, about 4.0 mass %, about 0.3 mass %, about 0.31 mass %, about 0.32 mass %, about 0.33 mass %, about 0.34 mass %, about 0.35 mass %, about 0.36 mass %, about 0.37 mass %, about 0.38 mass %, about 0.39 mass %, about 0.4 mass %, about 8.0 mass %, about 7.9 mass %, about 7.8 mass %, about 7.7 mass %, about 7.6 mass %, about 7.5 mass % of the thermogelling polymer. It will be understood that the mass % of Formula (3) present in the thermogelling polymer can vary depending on the molecular weight of the vinyl containing diol monomer and crosslinker used.

[0093] In various embodiments, the amount of Formula (5) present is about 10 mass % to about 60 mass %, about 12 mass % to about 55 mass %, about 15 mass % to about 50 mass %, about 15 mass % to about 45 mass %, about 15 mass % to about 40 mass %, about 16 mass % to about 39 mass %, about 17 mass % to about 38 mass %, about 18 mass % to about 37 mass %, about 19 mass % to about 36 mass %, about 20 mass % to about 35 mass %, about 21 mass % to about 34 mass %, about 22 mass % to about 33 mass %, about 23 mass % to about 32 mass %, about 24 mass % to about 31 mass %, about 25 mass % to about 30 mass %, about 26 mass % to about 29 mass %, about 27 mass % to about 28 mass %, or about 27.5 mass % of the thermogelling polymer. It will be understood that the mass % of Formula (5) present in the thermogelling polymer can vary depending on the molecular weight of the monomers and crosslinker used.

[0094] In various embodiments, the thermogelling polymer comprises about 0.01 mmol / g to about 7.0 mmol / g, about 0.02 mmol / g to about 6.0 mmol / g, about 0.03 mmol / g to about 5.0 mmol / g, about 0.04 mmol / g to about 4.0 mmol / g, about 0.05 mmol / g to about 3.0 mmol / g, about 0.05 mmol / g to about 2.0 mmol / g, about 0.05 mmol / g to about 1.5 mmol / g, about 0.10 mmol / g to about 1.45 mmol / g, about 0.15 mmol / g to about 1.40 mmol / g, about 0.20 mmol / g to about 1.35 mmol / g, about 0.25 mmol / g to about 1.30 mmol / g, about 0.30 mmol / g to about 1.25 mmol / g, about 0.35 mmol / g to about 1.20 mmol / g, about 0.40 mmol / g to about 1.15 mmol / g, about 0.45 mmol / g to about 1.10 mmol / g, about 0.50 mmol / g to about 1.05 mmol / g, about 0.55 mmol / g to about 1.00 mmol / g, about 0.60 mmol / g to about 0.95 mmol / g, about 0.65 mmol / g to about 0.90 mmol / g, about 0.70 mmol / g to about 0.85 mmol / g, about 0.75 mmol / g to about 0.80 mmol / g, about 0.06 mmol / g, about 0.07 mmol / g, about 0.08 mmol / g, about 0.09 mmol / g, about 0.1 mmol / g, about 1.35 mmol / g, about 1.34 mmol / g, about 1.33 mmol / g, about 1.32 mmol / g, or about 1.31 mmol / g of vinyl groups (e.g., -CH=CH2). Advantageously, in various embodiments, the vinyl groups allow for flexibility in the synthesis of the functionalized thermogelling polymer. For example, the vinyl groups can be used as reactive handles / functional groups to enable incorporation of chemical moieties that impart additional functional properties or mechanical enhancements to the thermogelling polymer. In various embodiments, the weight percent of vinyl groups incorporated into the thermogelling polymer can be adjusted by controlling the initial amount of general formula (3) (e.g., HDDO) used in the reaction. It will be appreciated that general formula (3) can comprise modified vinyl-containing diol monomers, such as modified HDDO. As modifying the vinyl-containing diol monomers allows for tunable hydrophilic-For example, when General Formula (3) comprises HDDO, the HDDO can be adjusted to different polarities such that the resulting polymer from these polymers can have higher vinyl content than shown in the examples provided herein, while maintaining thermal gelation properties.

[0095] In various embodiments, the thermal gelation polymer has a polydispersity index (PDI) in the range of about 1.0 to about 2, about 1.1 to about 1.9, about 1.2 to about 1.8, about 1.3 to about 1.7, about 1.4 to about 1.6, about 1.45 to about 1.50, about 1.31 to about 1.49, about 1.32 to about 1.48, about 1.33 to about 1.47, about 1.34 to about 1.46, about 1.35 to about 1.45, about 1.36 to about 1.44, about 1.37 to about 1.43, about 1.38 to about 1.42, about 1.39 to about 1.40, or about 1.395. In various embodiments, the upper limit of the PDI is in accordance with the Carother's equation for polymeric reactions. Thus, due to the nature of the type of polymerization occurring, various embodiments of the presently disclosed polymers result in generally larger dispersities (e.g., PDI of up to 2).

[0096] In various embodiments, the thermal gelation polymer can further comprise other polymers and / or monomers that impart other desired properties to the thermal gelation polymer. For example, the thermal gelation polymer can comprise poly(caprolactone). Advantageously, in various embodiments, the poly(caprolactone) can provide biodegradability to the thermal gelation polymer.

[0097] In various embodiments, a functionalized thermal gelation polymer is provided that comprises one or more repeating units derived from a hydrophilic polymer, one or more repeating units derived from a thermally responsive polymer, and one or more repeating units derived from a functionalized vinyl-containing diol monomer.

[0098] In various embodiments, the one or more repeating units derived from a hydrophilic polymer are represented by General Formula (1), the one or more repeating units derived from a thermally responsive polymer are represented by General Formula (2), and the one or more repeating units derived from a functionalized vinyl-containing diol monomer are represented by General Formula (4):

[0099]

[0100] wherein

[0101] R 1 -R 10 , m and n are as defined above;

[0102] X 1 -S and X 2-S each independently comprises a thiol-containing functional group.

[0103] In various embodiments, the one or more repeating units derived from a hydrophilic polymer, the one or more repeating units derived from a thermoresponsive polymer, and the one or more repeating units derived from a functionalized, vinyl-containing diol monomer are chemically coupled together by at least one of a urethane / urea linkage, a carbonate linkage, an ester linkage, or a combination thereof.

[0104] In various embodiments, the at least one of a urethane / urea linkage, a carbonate linkage, an ester linkage, or a combination thereof is represented by general formula (5):

[0105]

[0106] where R 11 is an alkyl group or an optionally substituted alkyl group.

[0107] In various embodiments, X 1 and X 2 may each independently be a moiety comprising one or more of a carboxylic acid, an amino acid, a sulfonate, an alkyl sulfonate, an amine hydrochloride, an alcohol, a diol, benzene, alkyl benzene, etc., or a derivative thereof. In various embodiments, X 1 and X 2 each independently is selected from the following structures or a derivative thereof:

[0108]

[0109] In various embodiments, derivatives of the structures disclosed above include ionized forms thereof. It will be understood that other commercially available thiols, such as mercaptoethanol, aromatic thiols (e.g., benzene thiol), etc., or derivatives thereof can also be used to obtain X 1 -S and X 2 -S.

[0110] It will be understood that the functionalized thermogelling polymer can comprise one or more properties and / or characteristics of the thermogelling polymers described previously above or described herein below.

[0111] In various embodiments, the pH of the functionalized thermogelling polymer can be in the range of about 1 to about 10, about 1.5 to about 9.5, about 2.0 to about 8.0, about 2.5 to about 7.5, about 3.0 to about 7.0, about 3.5 to about 6.5, about 4.0 to about 6.0, about 4.5 to about 5.5, or about 5.0.

[0112] In various embodiments, the functionalized thermogelling polymer can have a pH that is substantially similar to a physiological pH value ranging from about 7 to about 8, from about 7.1 to about 7.9, from about 7.2 to about 7.8, from about 7.3 to about 7.7, from about 7.4 to about 7.6, or from about 7.5. In various embodiments, advantageously, the functionalized thermogelling polymer can exhibit pH-responsive drug release. For example, functionalized thermogelling polymers functionalized with anionic carboxylate, anionic sulfonate, cationic amine, zwitterionic amino acid (e.g., cysteine) can exhibit pH-dependent sustained drug release and antifouling properties.

[0113] In various embodiments, advantageously, the functionalized thermogelling polymer can still be useful for medical and / or non-medical applications when the pH of the functionalized thermogelling polymer exceeds the physiological range. For example, the functionalized thermogelling polymer can be used in acidic environments such as the stomach and / or cancer sites, or for managing chronic wounds that exhibit alkaline pH levels.

[0114] In various embodiments, the functionalized thermogelling polymer has a critical gelation temperature / thermoreversible sol-gel transition temperature / transforms from a liquid / flowable state to a non-flowable / gel-like state at a temperature range of about 4°C to about 60°C, about 5°C to about 50°C, about 6°C to about 45°C, about 7°C to about 40°C, about 7.5°C to about 39°C, about 8°C to about 38°C, about 8.5°C to about 37°C, about 9°C to about 36°C, about 9.5°C to about 35°C, about 10°C to about 34°C, about 15°C to about 33°C, about 20°C to about 32°C, about 21°C to about 31°C, about 22°C to about 30°C, about 23°C to about 29°C, about 24°C to about 28°C, about 25°C to about 27°C, or about 26°C, or at a temperature substantially similar to a living human body temperature in the range of about 36°C to about 37°C, or at about 37°C. For example, the functionalized thermogelling polymer can be in a liquid / flowable state at ambient room temperature (e.g., about 20°C to about 30°C) and / or in a non-flowable / gel-like state at a living human body temperature (e.g., about 36°C to about 40°C). Thus, in some embodiments, the functionalized thermogelling polymer is in a flowable state at a temperature in the range of 20°C to 30°C, and in a non-flowable gel-like state at a temperature in the range of 30°C to 37°C. Advantageously, in various embodiments, the functionalized thermogelling polymer is deliverable / injectable / sprayable or capable of encapsulating a thermosensitive therapeutic agent, drug, protein, or cell, as it is liquid at 25°C and a gel (with a viscosity in the range of about 10 Pa.s to about 200 Pa.s) at about 37°C. Even more advantageously, the functionalized thermogelling polymer can self-assemble into a supramolecular gel when warmed (i.e., upon contact with a human). In various embodiments, the thermogelling polymer remains inert after functionalization. In various embodiments, functionalizing the thermogelling polymer does not substantially affect its original gelation properties. For example, highly charged cationic and anionic polymers retain the ability to form a gel at 37°C. For example, while hydrophobic aromatic phenyl groups increase the storage modulus of the thermogel at 37°C, they remain soluble at low temperatures. In various embodiments, when the functionalized thermogelling polymer has a critical gelation temperature / thermoreversible sol-gel transition temperature / transforms from a liquid / flowable state to a non-flowable / gel-like state at a temperature beyond a temperature range substantially similar to a living human body temperature, the functionalized thermogelling polymer can be used for non-biological applications.

[0115] In various embodiments, the cross modulus of the functionalized thermogelling polymer can range from about 5 Pa to about 1000 Pa, about 5 Pa to about 900 Pa, about 5 Pa to about 800 Pa, about 5 Pa to about 700 Pa, about 5 Pa to about 600 Pa, about 5 Pa to about 500 Pa, about 5 Pa to about 400 Pa, about 5 Pa to about 300 Pa, about 5 Pa to about 200 Pa, about 5 Pa to about 150 Pa, about 6 Pa to about 140 Pa, about 7 Pa to about 130 Pa, about 8 Pa to about 120 Pa, about 9 Pa to about 115 Pa, about 10 Pa to about 110 Pa, about 20 Pa to about 100 Pa, about 30 Pa to about 90 Pa, about 40 Pa to about 80 Pa, about 50 Pa to about 70 Pa, about 11 Pa, about 11.1 Pa, about 11.2 Pa, about 11.3 Pa, about 11.4 Pa, about 11.5 Pa, about 11.6 Pa, about 11.7 Pa, about 11.8 Pa, about 11.9 Pa, about 12 Pa, about 102 Pa, about 101.9 Pa, about 101.8 Pa, about 101.7 Pa, about 101.6 Pa, about 101.5 Pa, about 101.4 Pa, about 101.3 Pa, about 101.2 Pa, about 101.1 Pa, or about 101 Pa. It will be understood that the cross modulus of the thermogelling polymer depends on its functional groups, catalyst, and polymer concentration.

[0116] In various embodiments, the storage modulus (G') of the functionalized thermogelling polymer at 37°C can range from about 1 Pa to about 5000 Pa, about 1 Pa to about 4000 Pa, about 1 Pa to about 3000 Pa, about 1 Pa to about 2000 Pa, about 1 Pa to about 1000 Pa, about 2 Pa to about 900 Pa, about 3 Pa to about 800 Pa, about 4 Pa to about 700 Pa, about 50 Pa to about 650 Pa, about 100 Pa to about 600 Pa, about 150 Pa to about 550 Pa, about 200 Pa to about 500 Pa, about 250 Pa to about 450 Pa, about 300 Pa to about 400 Pa, about 4.1 Pa, about 4.2 Pa, about 4.3 Pa, about 4.4 Pa, about 4.5 Pa, about 4.6 Pa, about 4.7 Pa, about 4.8 Pa, about 690 Pa, about 689 Pa, or about 688 Pa, or about 350 Pa. It will be understood that the storage modulus of the thermogelling polymer depends on its functional groups, catalyst, and polymer concentration. In various embodiments, the functionalized thermogelling polymer with one or more hydrophobic aromatic phenyl groups can have an increased storage modulus at 37°C while remaining soluble at low temperatures.

[0117] In various embodiments, the functionalized thermogelling polymer can have a complex viscosity at 37°C in the range of about 1 Pa.s to about 1000 Pa.s, about 1 Pa.s to about 900 Pa.s, about 1 Pa.s to about 800 Pa.s, about 1 Pa.s to about 700 Pa.s, about 1 Pa.s to about 600 Pa.s, about 1 Pa.s to about 500 Pa.s, about 1 Pa.s to about 400 Pa.s, about 1 Pa.s to about 300 Pa.s, about 1 Pa.s to about 200 Pa.s, about 5 Pa.s to about 200 Pa.s, about 10 Pa.s to about 200 Pa.s, about 20 Pa.s to about 190 Pa.s, about 20 Pa.s to about 180 Pa.s, about 30 Pa.s to about 170 Pa.s, about 40 Pa.s to about 160 Pa.s, about 50 Pa.s to about 150 Pa.s, about 60 Pa.s to about 140 Pa.s, about 70 Pa.s to about 130 Pa.s, about 80 Pa.s to about 120 Pa.s, about 90 Pa.s to about 110 Pa.s, about 100 Pa.s, about 1.5 Pa.s, about 1.6 Pa.s, about 1.7 Pa.s, about 1.8 Pa.s, about 119 Pa.s, about 118 Pa.s, about 117 Pa.s, about 116 Pa.s, about 115 Pa.s, or about 114 Pa.s. It will be understood that the complex viscosity of the thermogelling polymer depends on its functional groups, catalyst, and polymer concentration.

[0118] In various embodiments, X 1 and / or X 2about 0.01 mmol / g to about 7 mmol / g, about 0.01 mmol / g to about 6 mmol / g, about 0.01 mmol / g to about 5 mmol / g, about 0.01 mmol / g to about 4 mmol / g, about 0.01 mmol / g to about 3 mmol / g, about 0.01 mmol / g to about 2 mmol / g, about 0.02 mmol / g to about 1.50 mmol / g, about 0.03 mmol / g to about 1.40 mmol / g, about 0.05 mmol / g to about 1.35 mmol / g, about 0.10 mmol / g to about 1.30 mmol / g, about 0.15 mmol / g to about 1.25 mmol / g, about 0.20 mmol / g to about 1.20 mmol / g, about 0.25 mmol / g to about 1.15 mmol / g, about 0.30 mmol / g to about 1.10 mmol / g, about 0.35 mmol / g to about 1.05 mmol / g, about 0.40 mmol / g to about 1.00 mmol / g, about 0.45 mmol / g to about 0.95 mmol / g, about 0.50 mmol / g to about 0.90 mmol / g, about 0.55 mmol / g to about 0.85 mmol / g, about 0.60 mmol / g to about 0.80 mmol / g, about 0.65 mmol / g to about 0.75 mmol / g, about 0.70 mmol / g, about 0.031 mmol / g, about 0.032 mmol / g, about 0.033 mmol / g, about 0.034 mmol / g, about 0.035 mmol / g, about 0.036 mmol / g, about 0.037 mmol / g, about 0.038 mmol / g, about 0.039 mmol / g, about 1.350 mmol / g, about 1.349 mmol / g, about 1.348 mmol / g, about 1.347 mmol / g, or about 1.348 mmol / g. Advantageously, the high functional group density achieved by providing mid-chain functionalizable vinyl groups is higher than the functional group density of existing strategies of introducing functional groups through terminal domains. It will be understood that the functional group density can be adjusted by varying the number of vinyl groups introduced into the thermogelling polymer. In different embodiments, the functional group density can vary according to the functionalization of the vinyl-containing glycol monomer (e.g., HDDO) with different hydrophobic / hydrophilic groups. In different embodiments, the functional group density can vary according to the ratio of hydrophilic polymer to thermally responsive / thermosensitive polymer in the functionalized thermogelling polymer.

[0119] In various embodiments, a method of making the thermogelling polymer disclosed herein is also provided, the method comprising coupling one or more hydrophilic polymers, one or more thermally responsive / thermosensitive polymers, and one or more vinyl-containing diol monomers in the presence of a coupling agent to obtain the thermogelling polymer.

[0120] In various embodiments, the one or more hydrophilic polymers are represented by Formula (6), the one or more thermally responsive / thermosensitive polymers are represented by Formula (7), and the one or more vinyl-containing diol monomers are represented by Formula (8) together with Formula (5). The coupling step can be performed in the presence of a coupling agent to chemically couple / ligate the one or more hydrophilic polymers represented by Formula (6), the one or more thermally responsive / thermosensitive polymers represented by Formula (7), and the one or more vinyl-containing diol monomers represented by Formula (8) together via at least one of a carbamate / carbamate bond, a carbonate bond, an ester bond, or a combination thereof to form the thermogelling polymer:

[0121]

[0122] wherein R 1 -R 10 , m and n are as defined above.

[0123] In various embodiments, the at least one of a carbamate / carbamate bond, a carbonate bond, an ester bond, or a combination thereof is represented by Formula (5)

[0124]

[0125] wherein R 11 is as defined above.

[0126] In various embodiments, Formula (6) is different from Formula (7) in the thermogelling polymer. For example, Formula (6) can comprise PEG, while Formula (7) can comprise PPG. In various embodiments, Formula (5) comprises a carbamate / carbamate. Thus, in various embodiments, Formula (6) comprises poly(ethylene glycol) (PEG), Formula (7) comprises poly(propylene glycol) (PPG), and Formula (8) comprises 1,5-hexadiene-3,4-diol (HDDO).

[0127] In various embodiments, the one or more hydrophilic polymers of Formula (6), the one or more thermally responsive / sensitive polymers of Formula (7), and the one or more vinyl-containing diol monomers of Formula (8) are mixed in a mass ratio of about 1-20: 1-10: 0.01-3. For example, the mass ratio of the one or more hydrophilic polymers of Formula (6), the one or more thermally responsive / sensitive polymers of Formula (7), and the one or more vinyl-containing diol monomers of Formula (8) can be about 3: 1: 0.01, about 3: 1: 0.10, about 3: 1: 0.20, about 3: 1: 0.30, about 3: 1: 0.40, about 3: 1: 0.50, about 3: 1: 0.51, about 3: 1: 0.52, about 3: 1: 0.53, about 3: 1: 0.54, about 3: 1: 0.55, about 3: 1: 0.56, about 3: 1: 0.57, about 3: 1: 0.58, about 3: 1: 1, about 3: 1: 2, about 3: 1: 3, about 3: 1: 4, or about 3: 1: 5. In various embodiments, the mass ratio of the one or more hydrophilic polymers of Formula (6) to the one or more thermally responsive / sensitive polymers of Formula (7) is about 3: 1, about 3: 2, about 3: 3, about 3: 4, about 3: 5, about 15: 1, about 15: 2, about 15: 3, or about 15: 4. It will be appreciated that functionalizing the vinyl-containing diol monomer (e.g., HDDO) with different mass ratios of hydrophobic and hydrophilic groups can affect the hydrophilic / hydrophobic balance and thermal gelation capacity of the functionalized thermal gelation polymer. For example, adjusting the ratio of PEG:PPG can allow for obtaining a functionalized thermal gelation polymer with a high HDDO content.

[0128] In various embodiments, the coupling and / or mixing step is performed at an elevated temperature of about 60 °C to about 150 °C, about 70 °C to about 150 °C, about 80 °C to about 150 °C, about 90 °C to about 150 °C, about 100 °C to about 150 °C, about 102 °C to about 148 °C, 104 °C to about 146 °C, about 106 °C to about 144 °C, about 108 °C to about 142 °C, about 110 °C to about 140 °C, about 112 °C to about 138 °C, about 114 °C to about 136 °C, about 116 °C to about 134 °C, about 118 °C to about 132 °C, about 120 °C to about 130 °C, about 122 °C to about 128 °C, about 124 °C to about 126 °C, or about 123 °C. It will be appreciated that the temperature can vary depending on the reaction time and catalyst used.

[0129] In various embodiments, the coupling and / or mixing step is performed for up to about 36 hours, up to about 35 hours, up to about 30 hours, up to about 24 hours, up to about 20 hours, up to about 15 hours, up to about 10 hours, at least about 2 hours, at least about 3 hours, at least about 4 hours, or at least about 5 hours.

[0130] In various embodiments, the coupling and / or mixing steps are performed in the absence of air and / or water / moisture and / or in the presence of a drying agent, such as molecular sieves. Thus, in various embodiments, the absence of air and / or water / moisture can reduce or prevent the occurrence of undesirable side reactions. For example, the absence of air and / or water / moisture can reduce or prevent the occurrence of premature termination of polymerization and allow for the attainment of a thermal gelling polymer of sufficient molecular weight.

[0131] In various embodiments, the coupling agent comprises a urethane / urethane-forming agent, a carbonate-forming agent, an ester-forming agent, or a combination thereof. In various embodiments, the coupling agent comprises an isocyanate monomer that contains at least 2 (e.g., 2 or more) isocyanate functional groups. The coupling agent can be selected from the group consisting of hexamethylene diisocyanate (HMDI), tetramethylene diisocyanate, cyclohexane diisocyanate, tetramethylxylylene diisocyanate, dodecane diisocyanate, toluene 2,4-diisocyanate, toluene 2,6-diisocyanate, and the like, and combinations thereof. In various embodiments, the coupling agent can be a compound comprising a diisocyanate that is proprietary / synthesized in-house or commercially available. In various embodiments, the coupling agent can not contain an isocyanate, such as for precursors of non-isocyanate polyurethanes.

[0132] In various embodiments, the coupling agent is added in a ratio of about 1-2: about 1-2, about 1 : 1, about 1 : 1.01, about 1 : 1.02, about 1 : 1.03, about 1 : 1.04, about 1 : 1.05, about 1 : 1.06, about 1 : 1.07, about 1 : 1.08, about 1 : 1.09, about 1 : 1.10, about 1 : 1.2, about 1 : 1.3, about 1 : 1.4, about 1 : 1.5, about 1 : 1.6, about 1 : 1.7, about 1 : 1.8, about 1 : 1.9, about 1 : 2, about 1.10: 1, about 1.2: 1, about 1.3: 1, about 1.4: 1, about 1.5: 1, about 1.6: 1, about 1.7: 1, about 1.8: 1, about 1.9: 1, about 2: 1, relative to one or more monomers of Formula (6), (7), and / or (8).

[0133] In various embodiments, the coupling and / or mixing steps are performed in the presence of a solvent. The solvent can comprise anhydrous solvent selected from the group consisting of toluene, benzene, xylene, and the like, and combinations thereof.

[0134] In various embodiments, the coupling and / or mixing steps are performed in the presence of a metal-containing or non-metal-containing catalyst capable of catalyzing, for example, the formation of a urethane / urethane bond, a carbonate bond, an ester bond, or combinations thereof from an alcohol and a suitable isocyanate precursor or derivative thereof. Metal-containing catalysts can include Lewis acid metals such as Bi 3+ , Fe 3+ , Zn 2+ , Sc 3+ , La 3+ , Ti 4+ , and Sn 4+ . In various embodiments, it is preferred that the metal-containing catalysts include Sn(IV) complexes. In various embodiments, the Lewis acid metals can be in any oxidation state. In various embodiments, the metal-containing catalysts can include tin-based or zinc-based catalysts selected from the group consisting of alkyl tin compounds, aryl tin compounds, and dialkyl tin diesters such as dibutyl tin dilaurate (DBTL), dibutyl tin diacetate, dibutyl tin dioctoate, dibutyl tin distearate, zinc diethyl dithiocarbamate, and the like, and combinations thereof. In various embodiments, the non-metal-containing catalysts can be organic catalysts.

[0135] In various embodiments, the method includes functionalizing the thermogelling polymer with one or more thiols to obtain a functionalized thermogelling polymer having thiol- containing functional groups X 1 -S and X 2 -S, wherein X 1 and X 2 each independently include a functional group.

[0136] In various embodiments, X 1 and X 2 may each independently be a moiety including one or more functional groups. The functional groups can be carboxylic acids, amino acids, sulfonate esters / salts, alkyl sulfonate esters / salts, amine hydrochlorides, alcohols, diols, benzene, alkyl benzenes, and the like, or derivatives thereof. In various embodiments, X 1 and X 2 may each independently be selected from the following structures, or derivatives thereof:

[0137]

[0138] In various embodiments, derivatives of the above structures include their ionized forms, which can also be used. It will be understood that other commercially available thiols such as mercaptoethanol, aromatic thiols (e.g., thiophenol), and the like, or derivatives thereof, can also be used to obtain functional groups X 1 -S and X 2 -S.

[0139] It will be appreciated that in different embodiments, the thermogelling polymer can be functionalized with different or the same plurality of functional groups. For example, the vinyl groups of the thermogelling polymer can be functionalized with two or more of the structures of X 1 and X 2 .

[0140] In different embodiments, after the functionalization step, the total weight % of the thermogelling polymer that has been functionalized (e.g., click efficiency) is in the range of about 1 wt% to about 100 wt%, at least about 5 wt%, at least about 10 wt%, at least about 15 wt%, at least about 20 wt%, at least about 25 wt%, at least about 30 wt%, at least about 35 wt%, at least about 40 wt%, about at least 45 wt%, at least about 50 wt%, at least about 55 wt%, at least about 60 wt%, at least about 65 wt%, at least about 70 wt%, at least about 75 wt%, at least about 80 wt%, at least about 85 wt%, at least about 90 wt%, or at least about 95 wt%.

[0141] In different embodiments, the step of functionalizing the thermogelling polymer is performed in the presence of a free radical initiator, a photo-initiator, and / or a source of radiation, such as ultraviolet (UV) light, and the like. In different embodiments, the functionalization step is performed for at least about 30 minutes, at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, or at least about 12 hours, optionally in the presence of a free radical initiator, a photo-initiator, and / or a source of radiation, such as ultraviolet (UV) light, and the like.

[0142] In different embodiments, the step of functionalizing the thermogelling polymer with one or more thiols is performed in the presence of an anhydrous solvent. In different embodiments, the anhydrous solvent can be selected from the group consisting of anhydrous tetrahydrofuran (THF), anhydrous methanol, and the like, and combinations thereof. It will be appreciated that the choice of the anhydrous solvent depends on the solubility of the one or more thiols used. For example, thiols such as 2-mercaptoethanesulfonic acid sodium salt, 2-aminoethanethiol hydrochloride, cysteine hydrochloride, and histamine-1-thiol (His-SH) can be soluble in anhydrous methanol, while thiols such as mercaptoacetic acid, thioglycerol, and 2-phenylethanethiol can be soluble in anhydrous THF.

[0143] In various embodiments, the one or more thiols are added in a molar ratio of 20-1 : 1-20 relative to the vinyl groups in the thermogelling polymer. For example, the molar ratio of the one or more thiols added to the vinyl groups in the thermogelling polymer can be about 20: 1, about 15: 1, about 10: 1, about 5: 1, about 4: 1, about 3: 1, about 2: 1, about 1: 1, about 1:2, about 1:3, about 1:4, about 1:5, about 1: 10, about 1: 15, or about 1:20. Advantageously, in some embodiments, it is found that when the one or more thiols are added in a 20-fold excess, the functionalization step can reach completion, which achieves a 100% functionalization efficiency. In embodiments where the ratio of the thiols to vinyl groups is low, the partially completed thiol-alkene click reaction can be utilized to produce a thermogelling polymer containing both vinyl groups and both X1and X2in ionized form (e.g., cations).

[0144] In various embodiments, the free radical initiator and / or photoinitiator is added in a molar ratio of at least 1-3:3-1 relative to the vinyl groups in the functionalized thermogelling polymer. For example, the molar ratio of the free radical initiator and / or photoinitiator to the vinyl groups in the thermogelling polymer can be about 3: 1, about 2: 1, about 1: 1, about 1:2, or about 1:3.

[0145] In various embodiments, the free radical initiator comprises a photoinitiator, 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone.

[0146] In various embodiments, the functionalization efficiency (e.g., click efficiency) of the step of functionalizing the thermogelling polymer with one or more thiols is in the range of about 5% to about 100%, about 10% to about 95%, about 15% to about 90%, about 20% to about 85%, about 25% to about 80%, about 30% to about 75%, about 35% to about 70%, about 40% to about 65%, about 45% to about 60%, about 50% to about 55%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, or at least about 28%. It will be understood that in various embodiments, quantitative functionalization can be improved by using thiols in greater excess.

[0147] In various embodiments, the method further comprises the step of quenching the coupling reaction using a quenching agent (e.g., an alcohol and derivatives thereof). In various embodiments, the quenching agent comprises ethanol. In various embodiments, the quenching step can be performed for at least about 10 minutes, at least about 20 minutes, at least about 30 minutes, at least about 40 minutes, at least about 50 minutes, or at least about 1 hour. In various embodiments, the quenching step can be performed at an elevated temperature of no less than about 80 °C, no less than about 85 °C, no less than about 90 °C, no less than about 95 °C, from about 100 °C to about 150 °C, from about 102 °C to about 148 °C, from 104 °C to about 146 °C, from about 106 °C to about 144 °C, from about 108 °C to about 142 °C, from about 110 °C to about 140 °C, from about 112 °C to about 138 °C, from about 114 °C to about 136 °C, from about 116 °C to about 134 °C, from about 118 °C to about 132 °C, from about 120 °C to about 130 °C, from about 122 °C to about 128 °C, from about 124 °C to about 126 °C, or about 125 °C.

[0148] In various embodiments, the method further comprises removing / purifying contaminants of the synthesized thermogelling polymer and / or the synthesized functionalized thermogelling polymer via precipitation, filtration using a metal sieve, and / or drying overnight in the absence of air and / or water / moisture and / or in the presence of an inert gas, e.g., nitrogen, to remove unreacted reactants, solvents, and catalysts. In various embodiments, dialysis can be performed at least about 3 times, at least about 4 times, or at least about 5 times at intervals of at least about 4 hours, at least about 5 hours, or at least about 6 hours prior to each change of dialysis buffer.

[0149] In various embodiments, the thermogelling polymer and / or the functionalized thermogelling polymer disclosed herein can have a high water content of greater than about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% by weight. Thus, the thermogelling polymer can be a water-based polymer. BRIEF DESCRIPTION OF DRAWINGS

[0150] Figure 1is a schematic illustration to illustrate the use of hydrogels in drug delivery, tissue engineering, wound healing, and consumer cosmetics. Due to the high water content in hydrogels, hydrogels tend to be biocompatible, while the polymeric scaffold can impart desirable properties such as mechanical integrity and bioactivity. This allows their use in drug delivery, wound healing, tissue engineering, and consumer cosmetics. However, the limitation of traditional hydrogels is their non-injectable and non-conformal properties. There is a need to develop a general synthetic route to form multifunctional thermogels with chemically modifiable functional handles. To address this problem, thermoresponsive hydrogels have been developed according to the different embodiments disclosed herein (whereby the solution remains liquid at room temperature, but solidifies at 37°C or upon body contact, making it injectable). In the different embodiments disclosed herein, the thermogelating polymer comprises hydrophilic PEG, hydrophobic PPG segments, functionalizable HDDO present as a single unit or as a segment, which is connected / coupled via a HMDI linker.

[0151] Figure 2 shows the1H NMR spectrum of EP(7.7)V thermogelating polymer with 7.7 wt% vinyl groups according to the embodiments disclosed herein. 1 The peaks and■indicate the presence of PPG segments; the peaks ● indicate the presence of PEG segments; the peaks, and★indicate the presence of HMDI moieties; and the peaks a, b, and c indicate the presence of reactive vinyl handles derived from the integration of HDDO into the polymer backbone. The spectrum shows that the EP(7.7)V thermogelating polymer was successfully synthesized, comprising PEG, PPG, and HDDO connected via HMDI. Additional peaks generated by H2O impurities and HMDI moieties (i.e. OCON H andC H2 OCONH) can also be observed.

[0152] Figure 3 shows the1H NMR spectrum of EP(7.7)V-COOH thermogelating polymer. 1 The peaks and■indicate the presence of PPG segments; the peaks ● indicate the presence of PEG segments; the peaks, and★indicate the presence of HMDI moieties; the peaks a indicate the presence of functional groups -COOH. Figure 4The absence of peak b in the spectrum indicates a successful thiol-ene click reaction between the vinyl groups and the thiolated substituents. The spectrum shows a successful functionalization of the EP (7.7) V thermogelling polymer with -COOH according to one exemplary embodiment disclosed herein.

[0153] Figure 4 The spectrum shows the EP (7.7) V-SO3Na thermogelling polymer according to one exemplary embodiment disclosed herein. 1 The H NMR spectrum (in MeOD at 25°C) initially contains 7.7 wt% of vinyl groups which are subsequently functionalized with -SO3Na according to the embodiments disclosed herein. Peaks and ■ indicate the presence of PPG segments; peak ● indicates the presence of PEG segments; peaks ▲, ♦ and ★ indicate the presence of HMDI moieties; peaks a and b indicate the presence of functional groups -SO3Na. Figure 4 The absence of peak b in the spectrum indicates a successful thiol-ene click reaction between the vinyl groups and the thiolated substituents. The spectrum shows a successful functionalization of the EP (7.7) V thermogelling polymer with -SO3Na according to one exemplary embodiment disclosed herein.

[0154] Figure 5 The spectrum shows the EP (7.7) V-NH3Cl thermogelling polymer according to one exemplary embodiment disclosed herein. 1 The H NMR spectrum (in MeOD at 25°C) initially contains 7.7 wt% of vinyl groups which are subsequently functionalized with -NH3Cl according to the embodiments disclosed herein. Peaks and ■ indicate the presence of PPG segments; peak ● indicates the presence of PEG segments; peaks ▲, ♦ and ★ indicate the presence of HMDI moieties; peak a indicates the presence of functional groups -NH3Cl. Figure 4 The absence of peak b in the spectrum indicates a successful thiol-ene click reaction between the vinyl groups and the thiolated substituents. The spectrum shows a successful functionalization of the EP (7.7) V thermogelling polymer with -NH3Cl according to one exemplary embodiment disclosed herein.

[0155] Figure 6 The spectrum shows the EP (7.7) V-Cys thermogelling polymer according to one exemplary embodiment disclosed herein. 1 The H NMR spectrum (in MeOD at 25°C) initially contains 7.7 wt% of vinyl groups which are subsequently functionalized with -Cys according to the embodiments disclosed herein. Peaks and ■ indicate the presence of PPG segments; peak ● indicates the presence of PEG segments; peaks ▲, ♦ and ★ indicate the presence of HMDI moieties; peaks a and b indicate the presence of functional groups -Cys. Figure 4The absence of peak b in the spectrum indicates a successful thiol-ene click reaction between the vinyl groups and the thiolated substituents. The spectrum shows that the EP(7.7) V thermogelling polymer was successfully functionalized with -Cys according to one exemplary embodiment disclosed herein.

[0156] Figure 7 The spectrum shows that the EP(7.7) V thermogelling polymer was successfully functionalized with -Cys according to one exemplary embodiment disclosed herein. 1 The spectrum shows that the EP(7.7) V thermogelling polymer was successfully functionalized with -Cys according to one exemplary embodiment disclosed herein. and The presence of PPG segments is indicated by peaks and the presence of PEG segments is indicated by peaks. The presence of HMDI moieties is indicated by peaks, and the presence of functional groups -Cys is indicated by peak a. Figure 4 The absence of peak b in the spectrum indicates a successful thiol-ene click reaction between the vinyl groups and the thiolated substituents. The spectrum shows that the EP(7.7) V thermogelling polymer was successfully functionalized with -Cys according to one exemplary embodiment disclosed herein.

[0157] Figure 8 The spectrum shows that the EP(7.7) V thermogelling polymer was successfully functionalized with -Cys according to one exemplary embodiment disclosed herein. 1 The spectrum shows that the EP(7.7) V thermogelling polymer was successfully functionalized with -Cys according to one exemplary embodiment disclosed herein. and ■ indicate the presence of PPG segments; peak • indicates the presence of PEG segments; peaks,, and indicate the presence of HMDI moieties; and peaks a-e indicate the presence of functional groups -His. Figure 4 The absence of peak b in the spectrum indicates a successful thiol-ene click reaction between the vinyl groups and the thiolated substituents. The spectrum shows that the EP(7.7) V thermogelling polymer was successfully functionalized with -Cys according to one exemplary embodiment disclosed herein.

[0158] Figure 9 The spectrum shows that the EP(7.7) V thermogelling polymer was successfully functionalized with -Cys according to one exemplary embodiment disclosed herein. 1 The spectrum shows that the EP(7.7) V thermogelling polymer was successfully functionalized with -Cys according to one exemplary embodiment disclosed herein. and The presence of PPG segments is indicated by peaks and the presence of PEG segments is indicated by peaks. The presence of HMDI moieties is indicated by peaks, and the presence of functional groups -Cys is indicated by peak a. Figure 4The absence of peak b in the middle indicates a successful thiol-ene click reaction between the vinyl group and the thiolated substituent. This spectrum shows that the EP (7.7) V thermogelling polymer was successfully functionalized with -phenyl according to one exemplary embodiment disclosed herein.

[0159] Figure 10 is an Ashby plot showing the change in storage modulus (G') of exemplary functionalized thermogelling polymers at 37°C and their corresponding gelation temperatures. The Y-axis represents the storage modulus, which is an indication of how hard the gel is, and the X-axis is the temperature at which the functionalized thermogel becomes a gel. EPV represents the PEG / PPG / vinyl-containing HDDO triblock thermogelling polymer before functionalization, where the numbers in the brackets represent the weight percent of the vinyl-containing monomer. Such EPV thermogelling polymer backbones were used, which contained 0.4 wt%, 0.9 wt%, 4 wt%, and 7.7 wt% HDDO, and were subsequently functionalized with -COOH, -SO3Na, NH3Cl, Cys-HCl, phenyl, histamine, or diol. All functionalized thermogelling polymers retained their thermogelling ability. The storage modulus and gelation temperature were measured on a rheometer with a temperature sweep from 10°C to 50°C at 1 Hz. Examples

[0160] Exemplary embodiments of the present disclosure will be better understood and readily apparent to one of ordinary skill in the art from the examples, tables, and, if applicable, the drawings, that follow. It should be understood that other modifications might be made without departing from the scope of the application. The exemplary embodiments are not necessarily mutually exclusive, as some might be combined with one or more embodiments to form a new exemplary embodiment. The exemplary embodiments should not be construed as limiting the scope of the present disclosure.

[0161] In the following examples, an unprecedented general method for the synthesis of multifunctional thermoresponsive random block polyurethane copolymer libraries is described. The polymers used in the examples contain urethane-linked segments of poly(ethylene glycol), poly(propylene glycol), and vinyl-containing 1,5-hexadiene-3,4-diol (EPV). By introducing vinyl groups, it was sought to dramatically expand the functional diversity of these thermoresponsive polymers. These vinyl groups serve as reactive handles to enable the introduction of chemical moieties that impart additional functional properties or mechanical enhancements. By exploiting the versatility of thiol-ene click chemistry, the inventors have now been able to functionalize these thermogels with a wide range of commercially available thiol-containing functional groups (TcFGs) in one step. These functional groups inherently alter the chemical and mechanical properties of the hydrogel while allowing it to retain its thermogelation properties - this allows unprecedented ease in the bottom-up engineering of a large number of different thermogels that impact its functional properties and expand its potential applications.

[0162] The following examples demonstrate (1) the synthesis of vinyl-containing thermogels, (2) the ease of post-polymerization functionalization using thiol-ene click chemistry, and (3) the thermogelation ability of the functionalized polyurethane copolymers.

[0163] Example 1: Synthesis and characterization of thermogelating polymers

[0164]

[0165] Scheme 1. Chemical structures and polymerization procedures of exemplary EPV thermogelating polymers.

[0166] The general procedure for preparing the thermogelating polymers according to the various embodiments disclosed herein includes coupling one or more polymers of general formula (6) (PEG was used in the following examples), one or more polymers of general formula (7) (PPG was used in the following examples), and one or more monomers of general formula (8) (HDDO was used in the following examples) as shown in Scheme 1 in the presence of a coupling agent (HMDI was used in the following examples), a suitable catalyst (DBTL was used in the following examples), and a suitable solvent (anhydrous toluene was used in the following examples) to obtain the thermogelating polymers.

[0167]

[0168] The following examples detail the preparation of thermogelating polymers designed according to the various embodiments disclosed herein.

[0169] Materials

[0170] anhydrous acetonitrile, anhydrous tetrahydrofuran, anhydrous methanol, Molecular sieves (8-12 mesh), polyethylene glycol (Mn-2050), polypropylene glycol (Mn-2000), hexamethylene diisocyanate, dibutyltin dilaurate, and histamine were purchased from Sigma-Aldrich. 1,5-hexadien-3,4-diol, mercaptoacetic acid, sodium mercaptoethane sulfonate, aminoethane hydrochloride, phenylethanethiol, thioglycerol, and g-thiobutyrolactone were purchased from Tokyo Chemical Industry. Anhydrous toluene was purchased from Tedia, and diethyl ether was purchased from Fisher.

[0171] Methods

[0172] First, The molecular sieve was washed three times in excess acetone, air-dried, and further activated under vacuum at 130°C for over 15 hours. Subsequently, a 1000 mL two-necked round-bottom flask was filled with approximately 90 g of the molecular sieve and approximately 500 mL of commercially available anhydrous toluene, and the mixture was dried for over 24 hours. In parallel, macromonomers PEG (Mn = 2050 Da) and PPG (Mn = 2000 Da) were weighed into a two-necked round-bottom flask equipped with a stir bar, and the side arms were sealed with a rubber diaphragm. Then, approximately 20 mL of anhydrous toluene was introduced into the flask, and azeotropic distillation was performed at 60°C under reduced pressure (less than 55 MPa) using a rotary evaporator for 15 minutes. This process was repeated twice. The macromonomers were then further dried under high vacuum at 110°C for 1 hour. Next, in the same round-bottom flask, 100 mL of anhydrous toluene and a catalytic amount of dibutyltin dilaurate were added. Subsequently, HDDO (Mn = 114.14 Da) was added to the solution at a reactant mass ratio of 3 PEG: 1 PPG: 0-0.58 HDDO. HMDI (Mn = 168.2 Da) was then introduced at a ratio of 1 glycol: 1.01 HMDI to initiate addition polymerization. The polymerization was carried out at 110 °C for 2 hours. To terminate the polymerization, 5 ml of ethanol was added, and the mixture was maintained at 110 °C for 30 minutes. The resulting EPV thermogel polymer was precipitated in diethyl ether at a ratio of 1:15, further filtered using a metal sieve, and dried overnight under nitrogen.

[0173] It will be understood that, optionally, anhydrous toluene, DBTL, and HDDO can be added simultaneously. It will also be understood that anhydrous toluene, DBTL, and HDDO can be added in any other order, and the order in which these reagents are added will have little impact on the results, provided that HMDI is not added to initiate the polymerization.

[0174] The composition and the amount of vinyl groups (mol / g) per gram of the thermogelling polymer were determined using nuclear magnetic resonance (NMR) spectroscopy. The composition was then used to determine the stoichiometric ratio of the vinyl functionalization. Table 1 shows the reaction and NMR composition of each EPV thermogelling polymer with different weight percentages of vinyl groups. Table 2 shows the characterization of the molecular weight and composition of the EPVs described in Table 1.

[0175] Table 1. Reaction composition of the EPV synthesis and composition of the formed polymer verified by NMR. The EPV samples are named with the weight percentage of HDDO in brackets. EP(0)V was used as a control.

[0176]

[0177]

[0178]

[0179] This general platform for the synthesis of multifunctional thermogels combines a vinyl-containing diol with an amphiphilic dihydroxyl-terminated macromonomer via addition polymerization in the presence of a diisocyanate. Thus, this enabling strategy results in polymers that can be easily functionalized using thiol-ene click chemistry.

[0180] Example 2: Synthesis and characterization of functionalized thermogelling polymers

[0181]

[0182] Scheme 2. Chemical structure and functionalization procedure of exemplary EPV thermogelling polymers with different TcFG synthesized via thiol-ene click.

[0183] The general procedure for functionalizing thermogelling polymers according to the different embodiments disclosed herein comprises functionalizing the thermogelling polymer (EP(0.9)V was used in the following examples) with one or more thiols in the presence of a photoinitiator (2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone was used in the following examples) and / or ultraviolet (UV) light (UV light with a wavelength of 365 nm was used in the following examples) to obtain a functionalized thermogelling polymer, wherein the functional moiety (mercaptoacetic acid (anionic), 2-mercaptoethanesulfonic acid sodium salt (anionic) (acid and acidic salt with a pKa of about 5 to about -7), 2-aminoethanethiol hydrochloride (cationic), cysteine hydrochloride (zwitterionic), 2-phenylethanethiol (aromatic), His-SH (imidazole, metal binding), and thioglycerol (dihydroxy, hydrogen bonding) were used in the following examples) is X 1 -S and X 2— S, wherein X 1 and X 2 each independently is a moiety comprising a carboxylic acid, an amino acid, a sulfonate, an alkyl sulfonate, an amine hydrochloride, an alcohol, a diol, benzene, an alkyl benzene, or a derivative thereof, and X 1 and X 2 corresponds to R in Scheme 2.

[0184] The following detailed examples illustrate the functionalization of thermogelling polymers designed according to the different embodiments disclosed herein.

[0185] First, 1 g of EP(0.9) V was introduced into a 20 mL vial with a septum and a stir bar. Thereafter, the photoinitiator 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone was added in a 2:1 vinyl: photoinitiator molar ratio, while the TcFG was added in a 1 :3 vinyl: TcFG molar ratio. Depending on the solubility of the TcFG, 10 mL of anhydrous methanol or THF was added to the vial to obtain a solution with a concentration of 100 mg / mL. For example, methanol-soluble TcFGs include 2-mercaptoethanesulfonic acid sodium salt, 2-aminoethanethiol hydrochloride, cysteine hydrochloride, and His-SH, while THF-soluble TcFGs include mercaptoacetic acid, thioglycerol, and 2-phenylethanethiol. The reactants were dissolved under continuous stirring on a magnetic stirrer. Next, the solution was sparged with argon for 10 minutes, and then exposed to an 8 W UV lamp (λ = 365 nm, UVP, UVLS-28) for 3 hours under stirring. Subsequently, the formed functionalized polymer was precipitated in diethyl ether in a 1 : 10 ratio, filtered using a metal sieve, and dried under nitrogen overnight. The formed polymer was redissolved in MilliQ water (or methanol for His-SH) and dialyzed against MilliQ water (or methanol for His-SH) for a total of three times, with a minimum of 4 hours before changing the dialysis buffer. Finally, the dialyzed sample was freeze-dried to obtain the functionalized thermogelling polymer.

[0186] EP(7.7) V was functionalized with TcFG as described above for the functionalization of EP(0.9) V, with the difference that it was done at different concentrations due to the limited solubility of the TcFG. Figures 2-10 The NMR spectra of the successfully synthesized functionalized EP(7.7) V are shown. Table 3 shows the concentrations of the solvents used for the functionalization of EP(7.7) V with different TcFGs.

[0187] Table 3. Amount of polymer (EP(7.7) V) and corresponding solvent volume and type used in the thiol-ene click reaction with different TcFGs.

[0188] TcFG Amount of functionalized EP (7.7) V (g) Solvent for thiol-ene click reaction -COOH 1g Methanol - 10 mL -SO3Na 0.5g Methanol - 10 mL -NH3Cl 1g Methanol - 10 mL -Cys 0.5g Methanol - 10 mL -Diol 0.5g THF - 5 mL -His 0.5g Methanol - 10 mL -Phenyl 0.5g THF - 5 mL

[0189] The functionalized thermogelling polymers were further characterized. Table 4 shows the thiol-ene click reaction efficiency and corresponding gel rheological properties for each synthesized functionalized thermogelling polymer.

[0190]

[0191] The results show that the efficiency of the thiol-ene click reaction varied from 28% to 100%. Nonetheless, quantitative functionalization can be achieved with more excess of thiol. The results also indicate that the nature of the functional group appended to the polymer and its composition greatly affect its mechanical and gelation properties, as shown in Figure 10 Thus, it is important to be able to tune its composition and is a unique feature of the present disclosure. In addition to functional versatility and compositional versatility, different molecular weights can be achieved by tuning the polymerization time and poly(caprolactone) can be co-polymerized to provide biodegradability, thus expanding the adaptability of this synthetic strategy for developing multifunctional thermogels.

[0192] Example 3: Synthesis of His-SH TcFG

[0193] According to different embodiments disclosed herein, the general steps for functionalizing a thermogelling polymer can further comprise, prior to the functionalization step, synthesizing a compound comprising one or more TcFG (for the following example, His-SH was synthesized).

[0194] The following details an example of synthesizing a compound comprising one or more TcFG according to different embodiments disclosed herein.

[0195] First, the synthesis of His-SH started by weighing 500 mg of histamine into a 50 mL round bottom flask. Subsequently, 7.5 ml of anhydrous acetonitrile and 505.4 mg of γ-thiobutyrolactone were introduced to the flask. The reaction was then allowed to proceed at a temperature of 95 °C for a duration of 16 hours. After the reaction was complete, the formed precipitate was filtered and washed three times with 10 mL of acetonitrile each time. The formed product was then dried under vacuum at 60 °C for 16 hours to obtain His-SH.

[0196] Discussion of Examples

[0197] In Example 1, a highly streamlined and general strategy for generating a library of functionalized polyurethane-based thermoresponsive polymers using polyaddition and thiol-ene click chemistry is shown. To synthesize the vinyl-containing thermogel, poly(ethylene glycol) (PEG, Mn ~2050), poly(propylene glycol) (PPG, Mn ~2000), and 1,5-hexadiene-3,4-diol (HDDO) were polymerized in the presence of hexamethylene diisocyanate (HMDI) (where the molar ratio of diol:HMDI = 1 : 1.01) at 110 °C in anhydrous toluene and a catalytic amount of dibutyltin dilaurate (DBTL). The weight percentage of vinyl groups incorporated into the polymer can be tuned by controlling the initial amount of HDDO in the reaction. The resulting vinyl-containing polymer was then reacted with the desired TcFG in the presence of 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone) and UV light (365 nm). By incorporating these vinyl groups along the chain, a wide range of functional groups can be easily attached at high density compared to existing strategies such as chain-end modification.

[0198] Scheme 3 below provides an illustration of EPV, indicating PEG and PPG block copolymers containing reactive vinyl handles, which are derived from the incorporation of HDDO into the polymer backbone. The EPVs can then be subsequently functionalized by thiol-containing functional groups via thiol-ene click reactions. A non-exhaustive list of functional groups is shown in the present disclosure.

[0199]

[0200] Examples have shown the generality of this functionalization strategy using mercaptoacetic acid (anion) and sodium 2-mercaptoethanesulfonate (anion) (one acid and one acidic salt, pKas are ~5 and ~-7). Thus, the latter will be pH insensitive and remain negatively charged in the physiological pH range. Functionalization of 2-aminoethanethiol hydrochloride (cation), cysteine hydrochloride (zwitterion), 2-phenylethanethiol (aromatic), His-SH (imidazole, metal binding), and thioglycerol (dihydroxy, hydrogen bonding) was also demonstrated.

[0201] In summary, the examples detail a streamlined two-stage synthetic approach that allows for the facile and efficient production of thermogelling multi-block polymers with multiple functional groups and control over their composition. The versatility of this approach is demonstrated in the examples by the synthesis of thermogels containing carboxylic acids, sulfonate esters / salts, amines, cysteines (zwitterions), benzene rings, diols, and histamines (imidazoles). With the embodiments of the disclosed method, it is contemplated that multi-functional thermogels can also be achieved by mixing and matching thiol-containing moieties (e.g., carboxylic acids for sustained release of cationic drugs and histamines for metal coordination crosslinking), creating a truly versatile platform for thermogels with unique and diverse functionalities.

[0202] Applications

[0203] Embodiments of the present disclosure provide a versatile synthetic platform for multi-functional polyurethane thermogels via thiol-ene click chemistry. Advantageously, embodiments of the present disclosure provide a new functionalizable polymer backbone design for thermogels.

[0204] Embodiments of the present disclosure also provide methods for post-polymerization functionalization of EPVs with thiol-ene click chemistry. Thus, a library of thermogels with unprecedented diversity and functionality of functional groups, including charged, pH-responsive, zwitterionic, aromatic rings capable of cation-π interactions, hydrogen bonding, and metal binding groups, can be obtained in an easy manner.

[0205] Advantageously, the number of functional groups in the disclosed embodiments of thermogels can be varied. For example, this has been demonstrated in the synthesis of different compositions of vinyl-containing thermogelling polyurethanes consisting of PEG, PPG, and vinyl-containing 1,5-hexadiene-3,4-diol (EPV). These thermogels can be modified post-polymerization (e.g., EP(0)V, EP(0.4)V, EP(0.9)V, EP(4)V, EP(7.7)V), which in turn results in a variation in the number of functional groups per polymer chain (e.g., EP(0.4)V-COOH, EP(0.9)V-COOH, EP(4)V-COOH, EP(7.7)V-COOH). Thus, embodiments of the methods disclosed herein also provide the synthesis and purification of EPV with a versatile backbone of tunable functional group types and densities as multi-functional thermogelling polymers.

[0206] Advantageously, embodiments of the presently disclosed methods provide a synthetic platform for the preparation of thermogelling polyurethanes that facilitate easy post-polymerization functionalization of these polymers with a library of functional groups to impart a range of functional properties. This easy and versatile modification of the thermogel allows for tunability of the functional group density and provides an inert thermogelling backbone after functionalization. These easily tunable gel properties and applications include pH responsiveness, mechanical elasticity, bioadhesion, etc. Such tunability can be achieved by simply changing the type and ratio of functionalization. In various embodiments, this is first achieved by the incorporation of a vinyl-containing diol monomer (which will provide a reactive handle for subsequent functionalization) into the amphiphilic thermogelling backbone. This allows for easy functionalization of a wide range of thiol-containing functional groups using thiol-ene click chemistry. Thereafter, the functional group density can be conveniently tuned by varying the vinyl content and degree of functionalization. In other words, the unique approach of incorporating vinyl-containing monomers into the backbone of a polyurethane thermogel can be subsequently used for post-synthetic functionalization. This can result in thermogels with a broadened range of properties when compared to traditional PEG-based thermogels, which allow for customizable multifunctionality and temperature responsiveness for an expanded range of applications that are not typically suitable for PEG-based thermogels. Examples (non-exhaustive list) of successful incorporation of functional groups and their applications include:

[0207] • Anionic carboxylate and sulfonate salts for pH-dependent and pH-independent sustained drug release;

[0208] • Cationic amines for pH-dependent sustained drug release;

[0209] • Zwitterions (cysteine) for pH-dependent sustained drug release and antifouling applications;

[0210] • Benzene rings for π-cationic interactions and dual crosslinking gels;

[0211] • Imidazoles (histamine) for metal binding and dual crosslinking gels; and

[0212] • Diols for hydrogen bonding and dual crosslinking gels.

[0213] Advantageously, the functionalized polymer libraries obtained from embodiments of the methods disclosed herein add another dimension of functionality to thermoresponsive gels in terms of their aqueous solubility at lower temperatures and thermal gelation behavior at higher temperatures, and cannot be easily predicted a priori. For example, the highly charged cationic and anionic polymers obtained by embodiments of the methods disclosed herein retain the ability to form gels at 37°C, while the hydrophobic aromatic phenyl groups increase the storage modulus of the thermal gels at 37°C, while remaining soluble at low temperatures. The large number of new and unexpected thermal gel properties that can be obtained using embodiments of the methods disclosed herein have the potential to be developed in a number of advantageous new biomedical applications that are traditionally not suitable for thermal gels.

[0214] Those skilled in the art will appreciate that other variations and / or modifications can be made to the embodiments disclosed herein without departing from the spirit or scope of the broad disclosure. For example, in the description herein, features of different example embodiments can be mixed, combined, interchanged, incorporated, adapted, modified, included, etc. in different example embodiments. Accordingly, the embodiments of the present application are to be considered as illustrative and not restrictive, in all respects.

Claims

1. A thermal-gelling polymer comprising one or more repeating units derived from a hydrophilic polymer, one or more repeating units derived from a thermally-responsive polymer, and one or more repeating units derived from a vinyl-containing diol monomer, wherein the one or more repeating units derived from a hydrophilic polymer, the one or more repeating units derived from a thermally-responsive polymer, and the one or more repeating units derived from a vinyl-containing diol monomer are chemically coupled together by at least one of a urethane / urea linkage, a carbonate linkage, an ester linkage, or a combination thereof.

2. The thermal-gelling polymer of claim 1, wherein the one or more repeating units derived from a hydrophilic polymer are represented by general formula (1); the one or more repeating units derived from a thermally-responsive polymer are represented by general formula (2); the one or more repeating units derived from a vinyl-containing diol monomer are represented by general formula (3); and the at least one of a urethane / urea linkage, a carbonate linkage, an ester linkage, or a combination thereof is represented by general formula (5): wherein R 1 -R 10 each independently selected from H, alkyl or optionally substituted alkyl; m≥1； n≥1； R 11 is alkyl or optionally substituted alkyl.

3. The thermal-gelling polymer of claim 2, wherein general formula (1) comprises poly(ethylene glycol) (PEG), general formula (2) comprises poly(propylene glycol) (PPG), general formula (3) comprises 1,5-hexadiene-3,4-diol (HDDO), and general formula (5) comprises hexamethylene diisocyanate (HMDI).

4. The thermal-gelling polymer of any one of claims 2-3, wherein general formula (1) is present in an amount of 0 mass % - 90 mass % of the thermal-gelling polymer, general formula (2) is present in an amount of 0 mass % - 90 mass % of the thermal-gelling polymer, general formula (3) is present in an amount of 0.1 mass % - 40 mass % of the thermal-gelling polymer, and general formula (5) is present in an amount of 10 mass % - 60 mass % of the thermal-gelling polymer.

5. The thermal-gelling polymer of any one of the preceding claims, wherein the thermal-gelling polymer comprises 0.01 mmol / g - 7 mmol / g of vinyl groups (e.g., -CH=CH2).

6. The thermal-gelling polymer of any one of the preceding claims, wherein the thermal-gelling polymer has a polydispersity index (PDI) in the range of 1 - 2.

7. The thermal-gelling polymer of any one of the preceding claims, wherein one or more vinyl groups of the thermal-gelling polymer are further functionalized.

8. A functionalized thermal-gelling polymer comprising one or more repeating units derived from a hydrophilic polymer, one or more repeating units derived from a thermally-responsive polymer, and one or more repeating units derived from a functionalized vinyl-containing diol monomer, wherein the one or more repeating units derived from a hydrophilic polymer, the one or more repeating units derived from a thermoresponsive polymer, and the one or more repeating units derived from a functionalized vinyl-containing diol monomer are chemically coupled together by at least one of a urethane / urethane linkage, a carbonate linkage, an ester linkage, or a combination thereof.

9. The functionalized thermal gelation polymer of claim 8, wherein the one or more repeating units derived from a hydrophilic polymer is represented by general formula (1); the one or more repeating units derived from a thermoresponsive polymer is represented by general formula (2); the one or more repeating units derived from a functionalized vinyl-containing diol monomer is represented by general formula (4); and the at least one of a urethane / urethane linkage, a carbonate linkage, an ester linkage, or a combination thereof is represented by general formula (5): wherein R 1 -R 10 , m and n are as defined above; X 1 -S and X 2 -S each independently comprises a thiol-containing functional group; R 11 is alkyl or optionally substituted alkyl.

10. The functionalized thermal gelation polymer of claim 9, wherein general formula (1) comprises poly(ethylene glycol) (PEG), general formula (2) comprises poly(propylene glycol) (PPG), general formula (3) comprises 1,5-hexadiene-3,4-diol (HDDO), and general formula (5) comprises hexamethylene diisocyanate (HMDI).

11. The functionalized thermal gelation polymer of any one of claims 9-10, wherein X 1 and X 2 each independently is a moiety comprising one or more of a carboxylic acid, an amino acid, a sulfonate, an alkyl sulfonate, an amine hydrochloride, an alcohol, a glycol, benzene, an alkyl benzene, or a derivative thereof.

12. The functionalized thermal gelation polymer of any one of claims 9-11, wherein X 1 and X 2 each is independently selected from the following structures or a derivative thereof:

13. The functionalized thermal gelation polymer of any one of claims 8-12, wherein the functionalized thermal gelation polymer has one or more of a pH value in a range of 1-10; a gelation temperature in a range of 4 °C-60 °C; a cross modulus in a range of 5 Pa-1000 Pa; a storage modulus (G’) in a range of 4 Pa-5000 Pa at about 37 °C; or a complex viscosity in a range of 1 Pa.s-500 Pa.s at about 37 °C.

14. The functionalized thermal-gelling polymer according to any one of claims 9-13, wherein the functionalized thermal-gelling polymer has a functional group density of X 1 and / or X 2 in the range of 0.01 mmol / g to 7 mmol / g.

15. A method of making the thermal gelation polymer of any one of claims 1-7, the method comprising: coupling one or more hydrophilic polymers, one or more thermoresponsive polymers, and one or more vinyl-containing diol monomers in the presence of a coupling agent to obtain a thermal gelation polymer, wherein the coupling agent comprises a urethane / urethane-forming agent, a carbonate-forming agent, an ester-forming agent, or a combination thereof.

16. The method of claim 15, wherein the one or more hydrophilic polymers is represented by general formula (6); the one or more thermoresponsive polymers is represented by general formula (7); and the one or more vinyl-containing diol monomers is represented by general formula (8), wherein R 1 -R 10 , m and n are as defined above.

17. The method of claim 16, wherein general formula (6) comprises poly(ethylene glycol) (PEG), general formula (7) comprises poly(propylene glycol) (PPG), and general formula (8) comprises 1,5-hexadiene-3,4-diol (HDDO).

18. The method of any one of claims 16-17, wherein one or more hydrophilic polymers of general formula (6), one or more thermoresponsive polymers of general formula (7), and one or more vinyl-containing diol monomers of general formula (8) are mixed in a mass ratio of 1-20: 1-10: 0.01-3.

19. The method of any one of claims 15-18, wherein the coupling step is performed at an elevated temperature in the range of 60 °C-150 °C.

20. The method of any one of claims 15-19, wherein the coupling step is performed for at least 2 hours.

21. The method of any one of claims 15-16, wherein the coupling agent is a diisocyanate selected from the group consisting of hexamethylene diisocyanate (HMDI), tetramethylene diisocyanate, cyclohexane diisocyanate, tetramethylxylylene diisocyanate, dodecane diisocyanate, toluene 2,4-diisocyanate, and toluene 2,6-diisocyanate.

22. The method of claim 21, wherein the coupling agent is added in a ratio of 1-2: 1-2 relative to the one or more vinyl-containing diol monomers of general formula (8).

23. The method of any one of claims 15-22, wherein the coupling step is performed in the presence of a water-free solvent selected from the group consisting of toluene, benzene, and xylene.

24. The method of any one of claims 15-23, wherein the coupling step is performed in the presence of a metal-containing or metal-free catalyst capable of catalyzing the formation of urethane / urethane bonds, carbonate bonds, ester bonds, or combinations thereof from an alcohol and a suitable isocyanate precursor or derivative thereof.

25. The method of claim 24, wherein the metal-containing catalyst comprises a tin-based catalyst and / or a zinc-based catalyst.

26. The method according to any one of claims 15-25, wherein the method further comprises functionalizing the thermogelling polymer with one or more mercaptans to obtain a functionalized thermogelling polymer having mercaptan-containing functional groups X 1 — S and X 2 — S. The functionalized thermogelling polymer wherein X 1 and X 2 each independently comprises a functional group.

27. The method of claim 26, wherein X 1 and X 2 each independently is a moiety comprising one or more of a carboxylic acid, an amino acid, a sulfonate, an alkyl sulfonate, an amine hydrochloride, an alcohol, a glycol, benzene, an alkyl benzene, or a derivative thereof.

28. The method of any one of claims 26-27, wherein X 1 and X 2 each is independently selected from the following structures or derivatives thereof:

29. The method of any one of claims 26-28, wherein functionalizing the thermogelling polymer is performed in the presence of a free radical initiator, a photoinitiator, and / or ultraviolet (UV) light.

30. The method of any one of claims 26-29, wherein functionalizing the thermogelling polymer is performed in the presence of UV light for at least 30 minutes.

31. The method of any one of claims 26-30, wherein functionalizing the thermogelling polymer is performed in the presence of a water-free solvent, optionally wherein the water-free solvent is selected from the group consisting of water-free tetrahydrofuran (THF) and water-free methanol.

32. The method of any one of claims 26-31, wherein the one or more thiols are added in a molar ratio of 20-1: 1-20, optionally 3: 1, relative to the vinyl groups in the thermogelling polymer.

33. The method of claim 29, wherein the photoinitiator is added in a molar ratio of at least 3-1: 1-3, optionally 2: 1, relative to the vinyl groups in the functionalized thermogelling polymer.

34. The method of claim 33, wherein the photoinitiator comprises 2-hydroxy-4'-(2- hydroxyethoxy)-2-methylpropiophenone.

35. The method of any one of claims 26-34, wherein the functionalization efficiency of functionalizing the thermogelling polymer with one or more mercaptans is in the range of 5% - 100%.

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