Bioadhesive composition and method for producing same

Abstract

Mussel-inspired citrate-based bioadhesives, and methods of making and using same, are disclosed herein. Methods of treating wounds are also disclosed herein.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 953,401, filed December 24, 2019, and U.S. Provisional Application No. 63 / 028,691, filed May 22, 2020, the contents of each of which are incorporated herein by reference in their entirety.

[0002] FIELD OF THE DISCLOSURE The present disclosure generally relates to bioadhesive compositions, which can be used as wound closure compositions or bone filler compositions, and methods for making the same. [Background technology]

[0003] Tissue (bio) adhesives have attracted increasing attention in recent years due to their wide range of applications in the biomedical field, including wound closure, hemostasis, tissue sealing, implant fixation, and drug delivery. Commercially available bio-derived fibrin glue (Tisseel), which primarily consists of concentrated fibrinogen, thrombin, and calcium chloride and thus mimics the final step of the biological coagulation cascade, is the most widely used tissue adhesive due to its fast-setting and biodegradable properties and is often considered the gold standard for tissue adhesives. However, it has limitations, such as poor adhesion to wet tissue, making it less effective for applications requiring strong tissue adhesion. Other adhesives, such as cyanoacrylate adhesives, offer advantages such as ease of application and strong adhesion to tissue. However, cyanoacrylates have been limited to primarily topical use due to concerns about slow decomposition, exothermic polymerization, and the toxicity of their degradation products. Other adhesives, such as albumin-glutaraldehyde bioadhesive (BioGlue), have been clinically used for cardiac and vascular repair and lung repair, but their toxicity is also a concern due to the use of toxic crosslinking components. Urethane-based (TissuGlu) tissue adhesives have strong adhesion to tissue and cure quickly, but they generate a lot of heat during the chemical reaction and take a long time to decompose. Polyethylene glycol (PEG)-based bioadhesives, such as CoSeal and DuraSeal, are used in some applications as tissue sealants, but their high swelling rate and rapid degradation are thought to potentially cause serious postoperative complications, such as rapid leakage, compression of nearby nerve endings, and hematoma formation.

[0004] Therefore, there is a need for bioadhesive compositions that are highly biocompatible and have strong adhesive strength to wet tissue. Furthermore, there is a need for bioadhesives that are non-toxic, have acceptable swelling ratios, and have desirable degradation rates. There is also a need for methods of making such compositions. These and other needs are met, at least in part, by the present disclosure. Summary of the Invention

[0005] The present invention relates to a) a polymerization product of one or more monomers of formula (I) and one or more units of a block copolymer comprising one or more monomers of formula (II) and / or formula (II'), one or more monomers of formula (III), and / or optionally one or more compounds of formula (IV), [ka] R1, R2, and R3 are each independently hydrogen, C1-C 22 alkyl groups; each of R, R, and R is selected from C-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R is hydrogen, hydroxyl, amine, alkoxyl, C-C 22 alkyl group; R5 is selected from hydrogen, amine, hydroxyl group, or C1-C 22 alkyl group; R6 is selected from hydrogen, C1-C 22 Alkyl groups, C2-C 22 alkenyl groups; R7 is selected from hydrogen, amine, hydroxyl groups, alkoxyl groups, C1-C 22 each of R, R, R, and R is selected from C-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13Optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R, R, R 10 , and R 11 are each independently hydrogen, hydroxyl, C1-C 22 Alkyl groups, C1-C 22 R8, R9, R are selected from an alkoxy group, an amino group, a halide, an -SH- group, or a carboxyl group; 10 , and R 11 All of the above are C1-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl; R, R, R 10 , and R 11 at least one of the nucleophilic groups comprises at least one nucleophilic group selected from -N(H)-, -O-, -COO-, -Cl, -F, -S(O)-, and -S-; at least one of the nucleophilic groups is a terminal group; n and m are each independently an integer of 1 to 20; R 12 is the amino acid side chain; R 14 is —OH or —NH2; the polymerization product does not contain a metal cation; and b) a compound of formula A b’ O a’wherein A is a monovalent, divalent, or trivalent metal cation; a' and b' depend on the valence of A; and A is not a transition metal cation; and a first crosslinking initiator configured to crosslink a reaction product to form a crosslinked composition; the crosslinked composition is a polymer network having at least one crosslink comprising two catechol moieties directly and covalently bonded to each other; the crosslinked composition is a hydrogel or an organogel, and is an adhesive composition.

[0006] In still further aspects, the compositions disclosed herein include embodiments, wherein R1, R2, and R3 are each independently selected from hydrogen, a -CH3 group, or a -CH2CH3 group; R4 is hydrogen, a hydroxyl group, -NH2, -OCH3, -OCH2CH3, -CH3, -CH2CH3 group, C3-C 22 R5 is selected from an alkyl or alkenyl group, —CH2CH2OH, or —CH2CH2NH2; R5 is hydrogen, a hydroxyl group, —NH2, —CH3, or —CH2CH3 group, C3-C 22 R6 is selected from hydrogen, a -CH3 group, or a -CH2CH3 group, -CH2CH2OH, or -CH2CH2NH2; R7 is selected from hydrogen or a -CH3 group; R8, R9, R 10 , and R 11 are each independently hydrogen, -CH2(CH2) x NH2, -CH2(CHR 13 )NH2, or -CH2(CH2) x COOH group; R, R, R 10 , and R 11 At least one of R is not hydrogen; 13 is -COOH or -(CH2) y is a COOH group; n and m are each independently an integer of 1 to 20; x is an integer of 0 to 20; and y is an integer of 1 to 20.

[0007] In yet further embodiments, the first cross-linking initiator simultaneously acts as a first filler. Also disclosed herein are embodiments in which the composition further comprises a second cross-linking initiator different from the first cross-linking initiator. In still further embodiments, the second cross-linking initiator can comprise sodium periodate, silver nitrate, or ferric chloride, or any combination thereof. The present invention provides a method for producing a polymeric product by a) reacting one or more monomeric polycarboxylic acids of formula (I) with a block copolymer comprising one or more monomers of formula (II) and / or formula (II'), one or more monomers of formula (III), and / or optionally one or more compounds of formula (IV), [ka] R1, R2, and R3 are each independently hydrogen, C1-C 22 alkyl groups; each of R, R, and R is selected from C-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halogen, hydroxy, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R is hydrogen, hydroxyl, amine, alkoxyl, C-C 22 alkyl group; R5 is selected from hydrogen, amine, hydroxyl group, or C1-C 22 alkyl group; R6 is selected from hydrogen, C1-C 22 Alkyl groups, C2-C 22 alkenyl groups; R7 is selected from hydrogen, amine, hydroxyl groups, alkoxyl groups, C1-C 22 each of R, R, R, and R is selected from C-C 22 Alkyl, C1-C 22 Alkoxy, C2-C22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 Optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R, R, R 10 , and R 11 are each independently hydrogen, hydroxyl, C1-C 22 Alkyl groups, C1-C 22 R8, R9, R are selected from an alkoxy group, an amino group, a halide, an -SH- group, or a carboxyl group; 10 , and R 11 All of the above are C1-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl; R, R, R 10 , and R 11 at least one of the nucleophilic groups comprises at least one nucleophilic group selected from -N(H)-, -O-, -COO-, -Cl, -F, -S(O)-, and -S-; at least one of the nucleophilic groups is a terminal group; n and m are each independently an integer of 1 to 20; R 12 is the amino acid side chain; R 14 is —OH or —NH2; the polymerization product does not contain a metal cation; forming a polymerization product; and b) forming a compound of formula A b’ O a’wherein A is a monovalent, divalent, or trivalent metal cation; a' and b' depend on the valence of A; and A is not a transition metal cation; and crosslinking the polymerization product with a first crosslinking initiator, wherein the crosslinked composition is a polymer network having at least one crosslink comprising two catechol moieties directly and covalently bonded to each other; and the crosslinked composition is a hydrogel or an organogel, and is an adhesive composition.

[0008] Also disclosed herein are methods of making the disclosed compositions. In certain embodiments, the method comprises: a) reacting one or more monomeric polycarboxylic acids of formula (I) with: [ka] one or more units of a block copolymer comprising one or more monomers of formula (II) and (II'); [ka] and one or more monomeric compounds of formula (III) [ka] and Optionally, one or more compounds of formula (IV) [ka] reacting under conditions effective to form a prepolymer composition configured to be crosslinked, wherein R1, R2, and R3 are each hydrogen, C1-C 22 alkyl groups; each of R, R, and R is selected from C-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C22 Alkynyl, C6-C 14 Aryl, C1-C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R is hydrogen, hydroxyl, amine, alkoxyl, C-C 22 alkyl group; R5 is selected from hydrogen, amine, hydroxyl group, or C1-C 22 alkyl group; R6 is selected from hydrogen, C1-C 22 Alkyl groups, C2-C 22 alkenyl groups; R7 is selected from hydrogen, amine, hydroxyl groups, alkoxyl groups, C1-C 22 each of R, R, R, and R is selected from C-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 Optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R, R, R 10 , and R 11 are each independently hydrogen, hydroxyl, C1-C 22 Alkyl groups, C1-C 22 R8, R9, R are selected from an alkoxy group, an amino group, a halide, an -SH- group, or a carboxyl group; 10 , and R 11 All of the above are C1-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl; R, R, R 10 , and R 11 at least one of the nucleophilic groups comprises at least one nucleophilic group selected from -N(H)-, -O-, -COO-, -Cl, -F, -S(O)-, and -S-; at least one of the nucleophilic groups is a terminal group; n and m are each independently an integer of 1 to 20; R 12 is the amino acid side chain; R 14 is —OH or —NH2; the polymerization product is free of metal cations; and b) adding a first crosslinking initiator to the prepolymer composition, wherein the first crosslinking composition has the formula A b B a wherein A is a monovalent, divalent, or trivalent metal cation and B is an anion; a and b are defined by the valences of A and B; and A is not a transition metal cation; and c) crosslinking the prepolymer composition to form a crosslinked composition comprising a polymer network, wherein at least one crosslink of the crosslinked polymer comprises two catechol moieties directly and covalently bonded to each other; the crosslinked composition is a hydrogel or an organogel and is an adhesive composition; disclosed herein is a method of making the composition.

[0009] Also disclosed herein are embodiments that describe methods of adhering biological tissues, including: a) placing a composition described herein between a first portion of the biological tissue and a second portion of the biological tissue; and b) contacting the first portion of the biological tissue with the second portion of the biological tissue.

[0010] Additionally, in certain aspects, methods of treating a disease are disclosed that include placing a composition described herein in vivo, wherein at least one pharmaceutically active ingredient is active against the disease and configured to be released in vivo at a predetermined time.

[0011] Also disclosed are methods of promoting the growth of biological tissue, comprising providing a scaffold comprising a composition described herein and placing the scaffold in a tissue growth medium.

[0012] Also disclosed herein are kits for adhering biological tissues that include any of the crosslinking compositions disclosed herein.

[0013] Also disclosed herein is a method for delivering an effective amount of at least one pharmaceutically active ingredient, the method comprising: a) preparing a polymerizable copolymer comprising: i) one or more monomers of formula (I) and one or more units of a block copolymer comprising one or more monomers of formula (II) and / or formula (II'), one or more monomers of formula (III), and / or optionally one or more compounds of formula (IV), [ka] R1, R2, and R3 are each hydrogen, C1-C 22 alkyl groups; each of R, R, and R is selected from C-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R is hydrogen, hydroxyl, amine, alkoxyl, C-C 22 alkyl group; R5 is selected from hydrogen, amine, hydroxyl group, or C1-C 22 alkyl group; R6 is selected from hydrogen, C1-C 22 Alkyl groups, C2-C 22alkenyl groups; R7 is selected from hydrogen, amine, hydroxyl groups, alkoxyl groups, C1-C 22 each of R, R, R, and R is selected from C-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 Optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R, R, R 10 , and R 11 are each independently hydrogen, hydroxyl, C1-C 22 Alkyl groups, C1-C 22 R8, R9, R are selected from an alkoxy group, an amino group, a halide, an -SH- group, or a carboxyl group; 10 , and R 11 All of the above are C1-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl; R, R, R 10 , and R 11 at least one of the nucleophilic groups comprises at least one nucleophilic group selected from -N(H)-, -O-, -COO-, -Cl, -F, -S(O)-, and -S-; at least one of the nucleophilic groups is a terminal group; n and m are each independently an integer of 1 to 20; R 12 is the amino acid side chain; R 14 is —OH or —NH2; the polymerization product does not contain a metal cation; and ii) a compound of formula Ab’ O a’ wherein A is a monovalent, divalent, or trivalent metal cation; a' and b' depend on the valence of A; and A is not a transition metal cation; the first crosslinking initiator is configured to crosslink the reaction product to form a crosslinked composition; the crosslinked composition is a polymer network having at least one crosslink comprising two catechol moieties directly and covalently bonded to each other; the crosslinked composition is a hydrogel or organogel, and is an adhesive composition; and b) incorporating at least one pharmaceutically active ingredient into the composition; and a) releasing the at least one agent in vivo at a predetermined time.

[0014]

[0013] Further aspects of the disclosure are set forth in part in the following detailed description, drawings, or claims, and in part will be derived from the detailed description or may be learned by practice of the specification. It should be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are not restrictive of the invention as disclosed. [Brief explanation of the drawings]

[0015] [Figure 1A] We demonstrate the synthesis of iC-EPE (mussel-inspired injectable citric acid-based bioadhesive (iCMBA, iC)) prepolymer made of PEG-PPG-PEG(EPE) diol. [Figure 1B] Magnesium oxide (MgO) functions as a crosslinker and composite filler, allowing for wide tunability in terms of crosslinking time and adhesive strength of the resulting iC-EPE / MgO hydrogel, which has great potential for myriad surgical applications such as wound closure and healing. [Figure 2]Characterization of the prepolymers is shown. (A) FTIR of 0.4 mg / mL iC-EPE and iC-P400 (iCMBA consisting of citric acid, polyethylene glycol (PEG400) with a molecular weight of 400 Da, and dopamine) in an ethanol / water mixture (w / w = 40 / 60). (B) H-NMR. (C) UV-visible absorption spectrum. The inset panel in C is a standard curve of dopamine in an ethanol / water mixture (w / w = 40 / 60). [Figure 3] The multifaceted crosslinking mechanism of iC-EPE by MgO is shown. [Figure 4] Figure 1 shows the results of gelation (gel) time measurements. A shows the gel time (obtained by gradient test) of iC-EPE crosslinked with MgO at different MgO concentrations. B shows the gel time at different temperatures. C shows the gel time at different MgO / PI concentrations in water. D shows representative rheological test results for iC-EPE crosslinked with 10 wt% MgO dispersion in different solvents (ethanol or water). E shows test results at different temperatures (MgO was dispersed in water). F shows test results crosslinked with a mixed solution of MgO and 8 wt% PI. The gel time was determined from the intersection (red circle) of the storage modulus (G') and loss modulus (G"). [Figure 5] Characterization of crosslinked hydrogels. Mechanical, swelling, and degradation properties, including tensile strength (A), initial modulus (B), elongation at break (C), sol content (D), swelling ratio (E), and degradation profile (F) of iC-EPE bioadhesives crosslinked with MgO, MgO + PI, or PI. [Figure 6] The adhesive strength of iC-EPE cross-linked with MgO, PI (sodium periodate), or MgO + PI and fibrin glue to moist porcine small intestinal mucosa is shown, as measured by tensile shear strength testing (*p<0.05, **p<0.01). [Figure 7]Cytotoxicity evaluation of iC-EPE composite hydrogels. Cytotoxicity against human mesenchymal stem cells (hMSCs) by MTT assay is shown for exudates (sol content) (A) and degradation products (B). Cell proliferation was evaluated by Live / Dead assay of hMSCs seeded on MgO (10 wt%) cross-linked iC-EPE casts on glass slides on days 1, 3, and 7 after cell seeding (C). #p>0.05, **p<0.01. [Figure 8] Antibacterial effect. (A) Bacterial inhibition rate of iC-EPE-MgO hydrogel (0.5 g hydrogel in 5 mL bacteria-containing broth) against Staphylococcus aureus and Escherichia coli, and (B) growth images of Staphylococcus aureus and Escherichia coli on agar gels with different MgO concentrations after 24 hours of incubation (MgO concentration (mg / mL) dispersed in a 6-well plate is indicated by black numbers). *p<0.05, **p<0.01. [Figure 9] In vivo evaluation of the biocompatibility and wound closure ability of iC-EPE-MgO(W10). (A) Macroscopic observations of skin wounds treated with sutures and W10 at different time points (5 min, 7 days, and 28 days; an image of the back of a skin sample taken near the treated wound on day 28 is also shown on the right). (B) H&E staining images of the suture and W10 groups. (C) Infiltrating cell density at the incision site. (D) CD11b immunohistochemical staining images of the suture and W10 groups. (E) Number of CD11b-positive cells around the wound site. (F) Masson's Trichrome staining images of the suture and W10 groups. (G) Collagen density. #p>0.05, *p<0.05, **p<0.01. DETAILED DESCRIPTION OF THE INVENTION

[0016] The present invention may be more readily understood by reference to the following detailed description, examples, figures, and claims, as well as their foregoing and following descriptions. However, before the present articles, systems, and / or methods are disclosed and described, it is to be understood that, unless otherwise specified, the present invention is not limited to the particular or exemplary embodiments of the disclosed articles, systems, and / or methods, which may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0017] The following description of the present invention is provided as an enabling teaching of the present invention in its best currently known mode. To this end, those skilled in the relevant art will recognize and appreciate that many changes can be made to the various aspects of the present invention described herein while still obtaining the beneficial results of the present invention. It will also be apparent that some of the desired benefits of the present invention can be obtained by selecting some of the features of the present invention without utilizing other features. Accordingly, those skilled in the relevant art will recognize that many modifications and adaptations to the present invention are possible and may even be desirable in certain circumstances and are a part of the present invention. Accordingly, the following description is further provided as an illustration of the principles of the present invention, and not as a limitation thereof.

[0018] definition As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description encompasses instances in which the event or circumstance occurs and instances in which it does not occur.

[0019] It will be appreciated that certain features of the present disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the present disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0020] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "functional group" includes two or more such functional groups, reference to a "composition" includes two or more such compositions, and so forth.

[0021] It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. As used in this specification and the appended claims, the term "comprising" can include embodiments such as "consisting of" and "consisting essentially of." Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In this specification and the appended claims, reference is made to several terms defined herein.

[0022] The terms "for example" and "such as," as well as their grammatical equivalents, are understood to be followed by the phrase "including but not limited to," unless expressly stated otherwise.

[0023] As used herein, the term "substituted" means that a hydrogen atom has been removed and replaced with a substituent. It is intended to include all permissible substituents of organic compounds. As used herein, the phrase "optionally substituted" means unsubstituted or substituted. It is understood that substitution of any atom is limited by valence. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituent of organic compounds, described herein, that satisfy the valence of the heteroatom. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. The terms "substituted" or "substituted with" also include the implicit proviso that such substitution is made in accordance with the allowed valences of the substituted atom and substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo change by rearrangement, cyclization, elimination, etc. In still a further aspect, when the present disclosure describes a group being substituted, it is understood to mean that the group is substituted with one or more (i.e., 1, 2, 3, 4, or 5) groups, as allowed by valence, selected from alkyl, alkyl halide, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol, as described below.

[0024] As used herein, the expressions "ambient temperature" and "room temperature" are understood in the art and generally refer to a temperature about the temperature of the room in which the reaction is carried out, e.g., a temperature of about 20°C to about 30°C, e.g., the reaction temperature.

[0025] The term "aliphatic" as used herein means a non-aromatic hydrocarbon group, including branched and unbranched alkyl, alkenyl, or alkynyl groups. As used herein, "C" when used alone or in combination with other terms means a non-aromatic hydrocarbon group. n -C m The term "alkyl" refers to a saturated hydrocarbon group having n to m carbons, which may be straight-chained or branched. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. Alkyl groups may also be substituted or unsubstituted. Throughout this specification, the term "alkyl" is used generally to refer to both unsubstituted and substituted alkyl groups, although substituted alkyl groups are also specifically referred to herein by identifying particular substituents on the alkyl group. Alkyl groups can be substituted with one or more groups including, but not limited to, alkyl, alkyl halide, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol, as described below.

[0026] For example, the term "halogenated alkyl" specifically refers to an alkyl group substituted with one or more halogens, such as fluorine, chlorine, bromine, or iodine. The term "alkoxyalkyl" specifically refers to an alkyl group substituted with one or more alkoxy groups, as described below. The term "alkylamino" specifically refers to an alkyl group substituted with one or more amino groups, as described below. If "alkyl" is used in one example and a specific term such as "alkylalcohol" is used in another example, this does not mean that the term "alkyl" does not also refer to the specific term such as "alkylalcohol."

[0027] As used herein, "C n -C m "Alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds and having n to m carbons. Examples of alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, theobutenyl, and the like. In various embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Alkenyl groups can be substituted with one or more groups, including, but not limited to, alkyl, alkyl halide, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl, as described below.

[0028] As used herein, "C n -C m"Alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds and having n to m carbons. Exemplary alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In various embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Alkynyl groups can be substituted with one or more groups, including, but not limited to, alkyl, alkyl halide, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl, as described below.

[0029] As used herein, "C" when used alone or in combination with other terms n -C m The term "alkylene" refers to a divalent alkyl-linked group having n to m carbons. Examples of alkylene groups include, but are not limited to, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, 2-methylpropane-1,3-diyl, and the like. In various embodiments, the alkylene moiety contains 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or 1 to 2 carbon atoms.

[0030] As used herein, "C" when used alone or in combination with other terms n -C m The term "alkoxy" refers to a group of formula -O-alkyl, where the alkyl group has n to m carbons. Examples of alkoxy groups include methoxy, ethoxy, propoxy (e.g., w-propoxy and isopropoxy), tert-butoxy, and the like. In various aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0031] As used herein, the term "amine" or "amino" refers to a group of the formula -NR1 R 2 and R 1 and R 2 may each be a substituent as described herein, for example, hydrogen, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group as described above. An "amide" is -C(O)NR 1 R 2 is.

[0032] The term "aldehyde" as used herein is represented by the formula -C(O)H. Throughout this specification, the terms "C(O)" or "CO" are shorthand notations for C=O, also referred to herein as "carbonyl."

[0033] As used herein, the term "carboxylic acid" is represented by the formula -C(O)OH. As used herein, a "carboxylate" or "carboxyl" group is represented by the formula -C(O)O - It is expressed as:

[0034] As used herein, the term "ester" refers to an ester of the formula -OC(O)R 1 , or -C(O)OR 1 and R 1 can be an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group as described above.

[0035] As used herein, the term "ether" refers to a group of the formula R 1 OR 2 and R 1 and R 2 may each independently be an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group as described above.

[0036] As used herein, the term "ketone" refers to a compound of formula R 1 C(O)R 2 and R 1 and R 2 may each independently be an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group as described above.

[0037] As used herein, the term "thio" refers to a group of formula --SH.

[0038] As used herein, "C n -C m The term "alkylthio" refers to a group of formula -S-alkyl, where the alkyl group has n to m carbon atoms. In various embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0039] As used herein, "C n -C m The term "alkylsulfomyl" refers to a group of formula -S(O)-alkyl, where the alkyl group has n to m carbon atoms. In various embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0040] As used herein, "C n -C m The term "alkylsulfonyl" refers to a group of formula -S(O)-alkyl, where the alkyl group has n to m carbon atoms. In various embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0041] As used herein, the term "carbamyl" refers to a group of formula -C(O)NH2.

[0042] As used herein, the term "carbonyl," employed alone or in combination with other terms, refers to a -C(=O)- group, which can also be written as C(O).

[0043] As used herein, the term "carboxy" refers to a group of formula -C(O)OH.

[0044] As used herein, "halogen" refers to F, Cl, Br, or I. The term "hydroxyl" as used herein is represented by the formula --OH.

[0045] The term "cyano" as used herein is represented by the formula -CN. The term "nitro" as used herein is represented by the formula -NO.

[0046] The term "phosphonyl" refers to a group of the formula -P(O)(OR 1 As used herein, R refers to a phospho-oxo group represented by 1 can be absent, hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or cycloalkenyl.

[0047] As used herein, the term "silyl" refers to a group of the formula -SiR 1 R 2 R 3 and R 1 , R 2 , and R 3 may each independently be hydrogen, an alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group as described above.

[0048] The term "sulfonyl" refers to a group of the formula -S(O)R 1 As used herein, R refers to a sulfo-oxo group represented by 1 can be hydrogen, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group as described above.

[0049] The term "sulfonylamino" or "sulfonamide" as used herein is represented by the formula -S(O)2NH-.

[0050] As used herein, the term "cycloalkyl" refers to a non-aromatic cyclic hydrocarbon, including cyclized alkyl and / or alkenyl groups. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups, and spirocyclic rings. Cycloalkyl groups can include 3, 4, 5, 6, 7, 8, 9, or 10 ring carbons (C3- 10 ) The ring-forming carbon atoms of a cycloalkyl group can be optionally substituted with oxo or sulfido (e.g., C(O) or C(S)). Cycloalkyl groups also include cycloalkylidenes. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, and the like. In various embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, or adamantyl.

[0051] As used herein, "heterocycloalkyl" refers to a non-aromatic monocyclic or polycyclic heterocycle having one or more ring-forming heteroatoms selected from O, N, or S. Heterocycloalkyl includes monocyclic 4-, 5-, 6-, and 7-membered heterocycloalkyl groups. Heterocycloalkyl groups also include spirocycles. Examples of heterocycloalkyl groups include pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydrofuran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, and the like. The ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted with oxo or sulfido (e.g., C(O), S(O), C(S), or S(O)). The heterocycloalkyl group can be bonded through a ring-forming carbon atom or a ring-forming heteroatom. In various embodiments, a heterocycloalkyl group contains 0 to 3 double bonds.

[0052] As used herein, the term "cycloalkenyl" refers to a non-aromatic carbon-based ring consisting of at least three carbon atoms and containing at least one double bond, i.e., C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like. The term "heterocycloalkenyl" is a type of cycloalkenyl group defined above and is included within the meaning of the term "cycloalkenyl," in which at least one of the ring carbon atoms is replaced with a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. Cycloalkenyl and heterocycloalkenyl groups can be substituted or unsubstituted. The cycloalkenyl and heterocycloalkenyl groups can be substituted with one or more groups including, but not limited to, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halogen, hydroxy, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl, as described herein.

[0053] As used herein, the term "aryl," used alone or in combination with other terms, refers to an aromatic hydrocarbon group that can be monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings). n-m The term "aryl" refers to an aryl group having n to m ring carbon atoms. Examples of aryl groups include phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In various embodiments, the aryl group has from 6 to about 20 carbon atoms, from 6 to about 15 carbon atoms, or from 6 to about 10 carbon atoms. In various embodiments, the aryl group is substituted or unsubstituted phenyl.

[0054] As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, phosphorus, and nitrogen. In various embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In various embodiments, any ring-forming N in the heteroaryl moiety can be an N-oxide. In various embodiments, the heteroaryl has 5 to 10 ring atoms and 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In various embodiments, the heteroaryl has 5 to 6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In various embodiments, the heteroaryl is a 5- or 6-membered heteroaryl ring. A 5-membered heteroaryl ring is a heteroaryl having a ring with 5 ring atoms, wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary 5-membered heteroaryls include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl. A 6-membered heteroaryl ring is a heteroaryl having a ring with 6 ring atoms, wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary 6-membered heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

[0055] The aryl or heteroaryl group can be substituted with one or more groups, including, but not limited to, alkyl, alkyl halide, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl, as described herein. The term "biaryl" is a special type of aryl group and is included in the definition of aryl. Biaryl refers to two aryl groups bonded through a fused ring structure, as in naphthalene, or through one or more carbon-carbon bonds, as in biphenyl.

[0056] As used herein, "R 1 "," "R 2 "," "R 3 "," "R n " etc. can each independently have one or more of the groups described above. For example, R 1 When is a straight-chain alkyl group, one of the hydrogen atoms of the alkyl group may optionally be replaced with a hydroxyl group, an alkoxy group, an amine group, an alkyl group, a halide, or the like. Depending on the group selected, the first group can be incorporated into the second group, or the first group can be pendant (i.e., attached) to the second group. For example, in the phrase "an alkyl group comprising an amino group," the amino group can be incorporated within the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group. The nature of the group(s) selected will determine whether the first group is embedded in or attached to the second group.

[0057] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the present disclosure are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Further, while various ranges of values ​​are set forth herein, it is contemplated that any combination of these values, inclusive of the recited values, may be used. Furthermore, ranges may be expressed herein as from "about" one particular value and / or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value.

[0058] Similarly, when values ​​are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. Unless otherwise specified, the term "about" means within 5% (e.g., within 2% or 1%) of the particular value modified by the term "about."

[0059] Also, all ranges disclosed herein should be understood to encompass any and all subranges subsumed therein. For example, a range stated as "1.0 to 10.0" should be considered to include any and all subranges beginning with a minimum value equal to or greater than 1.0 and ending with a maximum value equal to or less than 10.0, such as 1.0 to 5.3, or 4.7 to 10.0, or 3.6 to 7.9.

[0060] All ranges disclosed herein are also considered to include the endpoints of the range, unless otherwise specified. For example, the ranges "between 5 and 10," "from 5 to 10," and "5-10" should generally be considered to include the endpoints of 5 and 10. Furthermore, when the term "up to" is used in connection with an amount, it should be understood that the amount is at least a detectable amount. For example, a substance present "up to" a specified amount can be present from a detectable amount up to and including the specified amount.

[0061] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product resulting directly or indirectly from combining the specified ingredients in the specified amounts.

[0062] The polymeric or oligomeric compositions of the present invention may be self-curing. As used herein, the term "self-curing" refers to the ability of a composition to form a crosslinked polymer network. In some embodiments, a self-curing composition may be a liquid composition that can polymerize into a rigid polymer network. The crosslinking (curing) reaction can proceed at room temperature and physiological temperatures without the need for reagent changes or the addition of catalysts. Thus, in some embodiments, a crosslinked polymer network can spontaneously form, for example, at room temperature or body temperature, i.e., about 37°C. In some embodiments, a crosslinked polymer network can be formed within a subject, for example, a human subject, after injection of the polymeric or oligomeric composition of the present invention into the subject.

[0063] In this specification and the concluding claims, reference to parts by weight of a particular element or component in a composition refers to the weight relationship between the element or component and any other element or component in the composition or article to which the parts by weight are expressed. Thus, in a mixture containing 2 parts by weight of component X and 5 parts by weight of component Y, X and Y are present in a weight ratio of 2:5, regardless of whether additional components are included in the mixture.

[0064] Weight percent (wt%) of an ingredient is based on the total weight of the formulation or composition in which the ingredient is included, unless specifically stated to the contrary.

[0065] When an element is referred to as being "connected" or "coupled" to another element, it will be understood that the element may be directly connected or coupled to the other element, or that intervening elements may be present. Conversely, when an element is referred to as being "directly connected" or "directly coupled" to another element, there are no intervening elements present. Other words used to describe the relationship between elements or layers should be interpreted similarly (e.g., "between" vs. "directly between," "adjacent" vs. "directly adjacent," "on" vs. "directly on"). As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items.

[0066] As used herein, the terms or phrases "effective," "effective amount," or "conditions effective for" refer to an amount or conditions that allow the effective amount or effective condition to perform the function or property being expressed. As noted below, the exact amount or specific conditions required will vary from one aspect to another, depending on recognized variables such as the materials utilized and the process conditions observed. Thus, it is not always possible to specify an exact "effective amount" or "effective condition." However, it should be understood that an appropriate effective amount can be readily determined by one of ordinary skill in the art using only routine experimentation.

[0067] It will be understood that terms such as "first" and "second" may be used herein to describe various elements, components, regions, layers, and / or sections. These elements, components, regions, layers, and / or sections are not limited by these terms. These terms are only used to distinguish one element, component, region, layer, or section from another element, component, region, layer, or section. Thus, a first element, component, region, layer, or section described below could be referred to as a second element, component, region, layer, or section without departing from the teachings of the exemplary embodiments.

[0068] As used herein, the term "substantially" means that the subsequently described events or circumstances occur exactly, or that the subsequently described events or circumstances occur typically, typically, or approximately.

[0069] Additionally, the term "substantially" can, in some embodiments, refer to at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% of a stated property, ingredient, composition, or other condition used to characterize or quantify the amount.

[0070] In other aspects, as used herein, when used in the context of a composition or component of a composition that is substantially free, the term "substantially free" is intended to refer to an amount of less than about 1% by weight, e.g., less than about 0.5% by weight, less than about 0.1% by weight, less than about 0.05% by weight, or less than about 0.01% by weight of the described material, based on the total weight of the composition.

[0071] As used herein, the term "substantially," for example, in the context of "substantially identical" or "substantially similar," refers to a method or system, or component that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% similar to the method, system, or component being compared.

[0072] As used herein, the terms "substantially identical reference composition" or "substantially identical reference article" refer to a reference composition or article that contains substantially the same components in the absence of the inventive components. In another exemplary embodiment, the term "substantially," for example, in the context of "substantially identical reference component," refers to a reference component that contains substantially the same components, where the inventive components are substituted with components common in the art.

[0073] Although aspects of the present invention may be described and claimed in particular statutory classes, such as system statutory classes, this is merely for convenience, and one of ordinary skill in the art will recognize that each aspect of the present invention may be described and claimed in any statutory class. Unless expressly stated otherwise, no method or aspect set forth herein is intended to be construed as requiring its steps to be performed in a particular order. Thus, unless a method claim specifically states in the claim or description that the steps are to be limited to a particular order, no order is intended to be implied in any way. This is true regardless of any potentially imprecise criteria for interpretation, including questions of logic regarding the arrangement of steps or operational flow, the plain meaning of grammatical construction or punctuation, or the number or type of aspects described in the specification.

[0074] The present invention may be understood more readily by reference to the following detailed description of various aspects of the invention and the examples contained therein, as well as by reference to the drawings and their preceding and following descriptions.

[0075] The present invention may be understood more readily by reference to the following detailed description of various aspects of the invention and the examples contained therein, as well as by reference to the drawings and their preceding and following descriptions. composition

[0076] This disclosure relates to novel bioadhesives with excellent biocompatibility and strong wet tissue adhesive strength. Inspired by the strong adhesion of marine mussels to multiple heterogeneous surfaces in water, mussel-derived bioadhesives have been developed by incorporating L-DOPA (L-3,4-dihydroxyphenylalanine) or dopamine into polymers to enhance wet tissue adhesive strength and biocompatibility. Mussel-inspired injectable citric acid-based adhesives (iCMBA, or iC) have been developed to date, exhibiting strong tissue adhesive strength in the range of 30–215 kPa (tensile shear strength), 2.5–13.0 times stronger than the gold standard fibrin glue (approximately 15 kPa). However, the harsh oxidizing agents used to crosslink these materials, such as sodium periodate (PI), silver nitrite (SN), and iron(III) chloride (FeCl), have raised significant toxicity concerns. Furthermore, because they are composed of hydrophilic PEG, crosslinked iCMBA exhibits a high swelling ratio (over 1000 wt%).

[0077] In this disclosure, a more hydrophobic iCMBA prepolymer (iC-EPE) was synthesized, providing a composition with a lower swelling ratio, high compatibility, and adhesive properties.

[0078] The present invention relates to a polymerisation product of a) one or more monomers of formula (I), one or more monomers of formula (II) and / or formula (II'), one or more monomers of formula (III), and / or optionally one or more compounds of formula (IV), [ka] R1, R2, and R3 are each independently hydrogen, C1-C 22 alkyl groups; each of R, R, and R is selected from C-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13R4 may be optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R4 may be hydrogen, hydroxyl group, amine, alkoxyl group, C1-C 22 Alkyl groups, C2-C 22 alkenyl groups; R5 is selected from hydrogen, amine, hydroxyl groups, alkoxyl groups, or C1-C 22 Alkyl groups, C2-C 22 alkenyl groups; R6 is selected from hydrogen, C1-C 22 Alkyl groups, C2-C 22 alkenyl groups; R7 is selected from hydrogen, amine, hydroxyl group, alkoxyl group, C1-C22 alkyl group, or C2-C 22 alkenyl groups; each of R, R, R, and R is selected from C-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 R, R, R may be optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; 10 , and R 11 are each independently hydrogen, C1-C 22 R8, R9, R are selected from alkyl groups, amines, or carboxylic acids; 10 , and R 11 Each of the C1-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl; n and m are each independently an integer from 1 to 2,000; R 12 is the amino acid side chain; R 14 is —OH or —NH; the polymerization product of said polymer composition, wherein the formed polymer composition is free of metal cations; and b) adding a first crosslinker to the formed polymer composition; and c) crosslinking the formed polymer composition to form a composition comprising a crosslinked polymer composition that forms a polymer network, wherein at least one crosslink in the crosslinked polymer comprises two catechol moieties directly and covalently bonded to each other, and wherein said composition is an adhesive composition.

[0079] In a still further aspect, the present disclosure provides a polymerizable composition comprising: a) one or more monomers of formula (I) and one or more units of a block copolymer comprising one or more monomers of formula (II) and / or formula (II'), one or more monomers of formula (III), and / or optionally one or more compounds of formula (IV), [ka] R1, R2, and R3 are each independently hydrogen, C1-C 22 alkyl groups; each of R, R, and R is selected from C-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R is hydrogen, hydroxyl, amine, alkoxyl, C-C 22 alkyl group; R5 is selected from hydrogen, amine, hydroxyl group, or C1-C 22 alkyl group; R6 is selected from hydrogen, C1-C 22 Alkyl groups, C2-C 22 alkenyl groups; R7 is selected from hydrogen, amine, hydroxyl groups, alkoxyl groups, C1-C 22 each of R, R, R, and R is selected from C-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 Optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R, R, R 10 , and R 11 are each independently hydrogen, hydroxyl, C1-C 22 Alkyl groups, C1-C 22 R8, R9, R are selected from an alkoxy group, an amino group, a halide, an -SH- group, or a carboxyl group; 10 , and R 11 All of the above are C1-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl; R, R, R 10 , and R 11 at least one of the nucleophilic groups comprises at least one nucleophilic group selected from -N(H)-, -O-, -COO-, -Cl, -F, -S(O)-, and -S-; at least one of the nucleophilic groups is a terminal group; n and m are each independently an integer of 1 to 20; R 12 is the amino acid side chain; R 14 is —OH or —NH2; the polymerization product does not contain a metal cation; and b) a compound of formula A b’ O a’ wherein A is a monovalent, divalent, or trivalent metal cation; a' and b' depend on the valence of A; and A is not a transition metal cation; and a first crosslinking initiator configured to crosslink a reaction product to form a crosslinked composition; the crosslinked composition is a polymer network having at least one crosslink comprising two catechol moieties directly and covalently bonded to each other; the crosslinked composition is a hydrogel or an organogel, and is an adhesive composition.

[0080] It is understood that n and m can be integers from 1 to 2,000, with exemplary values ​​of 1 to 100, or 1 to 250, or 1 to 500, or 1 to 750, or 1 to 1,000, or 1 to 1,250, or 1 to 1,500, or 1 to 1,750.

[0081] In still other embodiments, n and m can be any integer between 1 and 20, including exemplary values ​​of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and 19.

[0082] In still further aspects, the compositions disclosed herein, including embodiments, include those in which R1, R2, and R3 are each independently selected from hydrogen, a -CH3 group, or a -CH2CH3 group; R4 is selected from hydrogen, a hydroxyl group, -NH2, -OCH3, -OCH2CH3, -CH3, -CH2CH3 group, a C3-C22 alkyl or alkenyl group, -CH2CH2OH, or -CH2CH2NH2; and R5 is , hydrogen, a hydroxyl group, —NH2, —OCH3, —OCH2CH3, —CH3, or —CH2CH3 group, a C3-C22 alkyl or alkenyl group, —CH2CH2OH, or —CH2CH2NH2; R6 is selected from hydrogen, a —CH3 group, or a —CH2CH3 group, —CH2CH2OH, or —CH2CH2NH2; R7 is selected from hydrogen or a —CH3 group; R8, R9, R 10 , and R 11 are each independently hydrogen, -CH2(CH2) x NH2, -CH2(CHR 13 )NH2, or -CH2(CH2) x COOH group; R 13 is -COOH or -(CH2) y is a COOH group; n and m are each independently an integer of 1 to 2,000; x is an integer of 0 to 20; and y is an integer of 1 to 20.

[0083] In further embodiments, the crosslinked compositions disclosed herein include embodiments, wherein R1, R2, and R3 are each independently selected from hydrogen, a -CH3 group, or a -CH2CH3 group; and R4 is selected from hydrogen, a hydroxyl group, -NH2, -OCH3, -OCH2CH3, -CH3, -CH2CH3 group, C3-C 22 R5 is selected from an alkyl or alkenyl group, —CH2CH2OH, or —CH2CH2NH2; R5 is hydrogen, a hydroxyl group, —NH2, —CH3, or —CH2CH3 group, C3-C 22R6 is selected from hydrogen, a -CH3 group, or a -CH2CH3 group, -CH2CH2OH, or -CH2CH2NH2; R7 is selected from hydrogen or a -CH3 group; R8, R9, R 10 , and R 11 are each independently hydrogen, -CH2(CH2) x NH2, -CH2(CHR 13 )NH2, or -CH2(CH2) x COOH group; R, R, R 10 , and R 11 At least one of R is not hydrogen; 13 is -COOH or -(CH2) y is a COOH group; n and m are each independently an integer of 1 to 20; x is an integer of 0 to 20; and y is an integer of 1 to 20.

[0084] It is understood that in certain embodiments, n and m can be any integer as described above. Further, in other embodiments, x can be any integer between 0 and 20, including exemplary values ​​of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and 19, while in other embodiments, y can be any integer between 0 and 20, including exemplary values ​​of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and 19.

[0085] In still further embodiments, formula (I) can include alkoxylated, alkenoxylated, or non-alkoxylated and non-alkenoxylated citric acid or esters / amides of citric acid.

[0086] In still further embodiments, Formula (II) can include polyethylene glycol, polypropylene glycol, or any combination thereof. In yet other embodiments, block polymers including polyethylene glycol, polypropylene glycol, and polyethylene glycol sequences can be formed. In still further exemplary embodiments, Formula (II) can include poly(ethylene glycol) (PEG) or poly(propylene glycol) (PPG) having terminal hydroxyl or amine groups. In some embodiments, for example, the PEG or PPG has a weight average molecular weight between about 100 and about 5000 Da, or between about 200 and about 1000 Da, or between 200 and about 100,000 Da.

[0087] In some embodiments, a block copolymer as disclosed herein can include repeat units of two or more monomers of formula (II): [ka] R4 is selected from hydrogen, a hydroxyl group, -NH2, -CH2CH2OH, or -CH2CH2NH2; R5 is hydrogen, a hydroxyl group, -NH2, -CH2CH2OH, or -CH2CH2NH2; and R6 is selected from hydrogen, a -CH3 group, or a -CH2CH3 group, -CH2CH2OH, or -CH2CH2NH2.

[0088] For example, but not limited to, the block copolymer can have the formula (V) or the formula (V'): [ka] a and b are each independently selected from n=1 to 20, and R6 is not hydrogen.

[0089] In still further embodiments, the monomer of formula (II') can comprise any polyol known in the art. In certain embodiments, the monomer of formula (II') can comprise a diol, while in other embodiments, the monomer of formula (II') can also comprise a polyamine. In such exemplary embodiments, the monomer of formula (II') can also comprise a diamine. Non-limiting examples of polyols / polyamines suitable for use in some embodiments described herein include C2-C3 polyols / polyamines, including α,ω-η-alkanediols / diamines, or α,ω-alkenediols / diamines. 20 , C2-C 12 or C2-C6 aliphatic alkanediols / diamines. For example, in some embodiments, the polyol or polyamine can include 1,4-butanediol or 1,4-butanediol or 1,4-butanediamine, 1,6-hexanediol or 1,6-hexanediamine, 1,8-octanediol or 1,8-octanediamine, 1,10-decanediol or 1,12-dodecanediol or 1,16-hexadecanediol or 1,16-hexadecanediamine, or 1,20-eicosanediol or 1,20-eicosanediamine. Branched α,ω-alkanediols / diamines or α,ω-alkenediols / diamines can also be used. Furthermore, the polyol / polyamine can be an aromatic diol / diamine.

[0090] Furthermore, the amine, if present, can include one or more primary amines having 2 to 10 carbon atoms in some embodiments. In other cases, the amine can include one or more secondary or tertiary amines having 2 to 15 carbon atoms. The isocyanate, in some embodiments, includes a monoisocyanate. In other cases, the isocyanate includes a diisocyanate, such as an alkane diisocyanate having 4 to 20 carbon atoms. The isocyanates described herein can also include a monocarboxylic acid moiety. Some additional examples of various isocyanates can be found in U.S. Patent Application Publication No. 2020 / 0140607 and International Patent Application Publication No. WO2018 / 227151, the contents of each of which are incorporated herein in their entirety.

[0091] In still further embodiments, the nucleophilic group of one or more monomers of Formula (III) is configured to react with at least one of RCOO-, RCOO-, or RCOO- of one or more monomers of Formula (I) to form a covalent bond. In still further embodiments, Formula (III) can include any catechol-containing species. In certain embodiments, the catechol-containing species can include at least one moiety capable of forming an ester or amide bond with another chemical species used to form a polymer in the manner in which the monomers are reacted. For example, in some cases, the catechol-containing species includes an alcohol moiety, an amine moiety, a carboxylic acid moiety, or a combination thereof. Furthermore, in some cases, the catechol-containing species includes a hydroxyl moiety that is not part of the catechol moiety. In some embodiments, the catechol-containing species includes dopamine. In other embodiments, the catechol-containing species includes L-3,4-dihydroxyphenylalanine (L-DOPA) or D-3,4-dihydroxyphenylalanine (D-DOPA). In yet other embodiments, the catechol-containing species includes gallic acid or caffeic acid.

[0092] In some cases, the catechol-containing species includes 3,4-dihydroxyhydrocinnamic acid. Furthermore, the catechol-containing species can also include naturally occurring species such as tannic acid or tannin, or derivatives thereof. Furthermore, in some embodiments, the catechol-containing species is attached to the backbone of the polymer via an amide bond. In other embodiments, the catechol-containing species is attached to the backbone of the polymer formed by the monomer via an ester bond. Some additional examples can be found in U.S. Patent Application Publication No. 2020 / 0140607 and International Patent Application Publication No. WO2018 / 227151, the contents of each of which are incorporated herein in their entirety.

[0093] In still further embodiments, formula (III) can include dopamine, L-DOPA, D-DOPA, and 3,4-dihydroxyhydrocinnamic acid. In still further embodiments, the monomer of formula (III) includes dopamine L-DOPA. In some embodiments, the composition includes one or more monomers selected from maleic acid, maleic anhydride, and fumaric acid.

[0094] In certain exemplary, non-limiting aspects, the polymerization product comprises: [ka] and R'' is -N(H)R 15 , or -O(CO)(R 15 ), or -O(R 15 ) and R 15 are independently C1-C 22 alkyl groups, C1-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl groups; R6 is not hydrogen; [ka] defines a bond to hydrogen, or optionally a bond to a given polymer chain, if present; a and b are each independently selected from n=1-20, and z=1-100.

[0095] In yet a further aspect, the polymer composition can include one or more monomers of formula (II) and (II').

[0096] In still further embodiments, when a composition of Formula (IV) is present, the composition can comprise an α-amino acid. In still further embodiments, the α-amino acid can comprise an L-amino acid, a D-amino acid, or a D,L-amino acid. In some cases, the α-amino acid can comprise alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, praline, phenylalanine, serine, threonine, tyrosine, tryptophan, valine, or a combination thereof. Furthermore, in some cases, the α-amino acid comprises an alkyl-substituted α-amino acid, such as a methyl-substituted amino acid derived from any of the 22 "standard" or proteinogenic amino acids, such as methylserine. In some embodiments, it is understood that the polymerization product described herein can be the polymerization product of one or more monomers of Formula (I) and a compound of Formula (IV), with or without one or more monomers of Formula (II) and / or Formula (II') or Formula (III). In still further embodiments where a compound of formula (IV) is present in the polymerization product, the composition may exhibit fluorescent, phosphorescent, or luminescent properties.

[0097] Additional examples of monomers, and ratios thereof, used to form polymer compositions can be found in U.S. Patent Application Publication No. 2020 / 0140607 and International Patent Application No. WO2018 / 227151, the contents of each of which are incorporated herein in their entirety.

[0098] In yet further embodiments, the polymerization products described herein can also be formed from the monomers described herein of formula (I), (II), and / or (II'), and (III) with a polycarboxylic acid, such as a dicarboxylic acid, or a functional equivalent thereof, such as an acid anhydride or acid chloride of the polycarboxylic acid. In such cases, the polyol / polyamine can include any of the polyols / polyamines described above, and the citric acid ester can include any of the citric acid esters / amides described above. Furthermore, the polycarboxylic acid or functional equivalent thereof can be saturated or unsaturated. For example, in some cases, the polycarboxylic acid or functional equivalent thereof includes maleic acid, maleic anhydride, fumaric acid, or fumaryl chloride. Vinyl-containing polycarboxylic acids or functional equivalents thereof, such as allylmalonic acid, allylmalonic acid chloride, itaconic acid, and itaconic acid chloride, can also be used.

[0099] Furthermore, in some cases, the polycarboxylic acid or its functional equivalent can be at least partially replaced with an olefin-containing monomer, which may or may not be a polycarboxylic acid. In such embodiments, for example, the olefin-containing monomer comprises an unsaturated polyol, such as a vinyl-containing diol. Additional examples can be found in U.S. Patent Application Publication No. 2020 / 0140607 and International Patent Application Publication No. WO2018 / 227151, the contents of each of which are incorporated herein in their entirety.

[0100] In still further embodiments, the polymer composition is a polymerization product, which is the product of a condensation polymerization reaction of any of the monomers disclosed herein and combinations thereof. In some embodiments, at least two of the identified species or monomers are polymerized to form a copolymer. In still further embodiments, and as disclosed herein, at least two of the identified species or monomers form a block copolymer. In still further embodiments, the block copolymers described herein can be formed prior to forming the polymerization products disclosed herein. For example, and without limitation, a block copolymer can be first formed from two or more monomers of formula (II) and then reacted with monomers of formula (I) and / or formula (III). In some such embodiments, the monomers react to form an alternating copolymer of the reacted monomers, or a statistical copolymer. Furthermore, the species or monomers described herein can also react to form pendant groups or side chains of a copolymer, or to form cyclic structures that can form part of the backbone of a polymer or oligomer.

[0101] In still further embodiments, the polymerization products described herein can also be formed from monomers described herein of formula (I), (II), and / or (II'), (III), and / or optionally compounds of formula (IV), and one or more monomers comprising one or more alkyne moieties or one or more azide moieties, while in other embodiments, the diols described herein can comprise diazido-diols or alkynediols. Additional examples of alkyne or azide moieties can be found in U.S. Patent Application Publication No. 2020 / 0140607 and International Patent Application Publication No. WO2018 / 227151, the contents of each of which are incorporated herein in their entirety.

[0102] Furthermore, in some embodiments, the monomers used to form the polymer compositions can be functionalized with a biologically active species. Furthermore, additional monomers can include one or more alkyne and / or azide moieties. For example, in some cases, the polymer compositions described herein are formed from one or more monomers comprising a peptide, polypeptide, nucleic acid, or polysaccharide, where the peptide, polypeptide, nucleic acid, or polysaccharide is functionalized with one or more alkyne and / or azide moieties. In some cases, the biologically active species of the polymer compositions described herein is a growth factor or signaling molecule. Furthermore, the peptide can include a dipeptide, tripeptide, tetrapeptide, or longer peptide. As further described herein below, forming the polymer compositions from such monomers can, in some embodiments, provide additional biological functionality to the compositions described herein.

[0103] In yet another embodiment, the composition comprises a compound of formula A b B a where A is a monovalent, divalent, or trivalent metal cation, B is an anion, and a and b are defined by the valences of A and B. Compound A b B a It is understood that A can include any salt or oxide known in the art. For example, in some cases, A is a monovalent, divalent, or trivalent cationic metal, and B is a simple or complex anion. The monovalent, divalent, or trivalent cations described herein are not particularly limited and include, for example, Mg 2+ , Ca 2+ , Zn 2+ , Cu 2+ , Co 2+ , Fe 2+ , Fe 3+ , Cr 2+ , Mn 2+ , Co 3+ , Sr 2+ , V 2+ , V 3+ , Ti 2+ , Ti 3+ , Sr 2+ , Ni2+ , Al 3+ , Al 2+ , Cr 3+ , Ba 2+ , Na + , K. + , and Li + The anion B is not particularly limited, and may be an anion that forms a neutral salt or an oxide with a monovalent, divalent, or trivalent metal cation. For example, but not limited to, B may be O 2- , Cl - , Citrate, Br - , CO3 2- , PO4 3- , or NO3 - Other anions can also be used.

[0104] Additionally, in other aspects, the compositions described herein comprise a compound of formula A b’ O a’ wherein A is a monovalent, divalent, or trivalent metal cation, a' and b' depend on the valence of A, and A is not a transition metal cation. For example, in some cases, A is a monovalent, divalent, or trivalent metal cation. The monovalent, divalent, or trivalent cations described herein include, but are not limited to, Mg 2+ , Ca 2+ , Zn 2+ , Cu 2+ , Co 2+ , Fe 2+ , Fe 3+ , Cr 2+ , Mn 2+ , Co 3+ , Sr 2+ , V 2+ , V 3+ , Ti 2+ , Ti 3+ , Sr 2+ , Ni 2+ , Al 3+ , Al 2+ , Cr 3+ , Ba 2+ , Na + , K. + , and Li +In yet another embodiment, the compound may comprise at least one of the following: b’ O a’ The first cross-linking initiator having the formula (I) can include magnesium oxide, calcium oxide, zinc oxide, barium oxide, cesium oxide, or any combination thereof.

[0105] In still further embodiments, a compound of formula A b B a The compound having the formula A behaves as a first cross-linking initiator. It is understood that when the polymerization product as described herein is mixed with a first cross-linking initiator, a cross-linked polymer composition as claimed is formed. Such compositions further comprise a compound having the formula A b B a In yet a further embodiment, the compound of formula A b B a The compound of formula (I) comprises a metal oxide. In such exemplary embodiments, the metal oxide is an oxide of Zn, Mg, Cu, Fe, Ba, Ca, or a combination thereof.

[0106] In yet another aspect, the compositions described herein comprise a compound of formula A b’ O a’ In such an embodiment, as in any embodiment described above, the polymerization product comprises a first cross-linking initiator having the formula A b’ O a’ When mixed with a first cross-linking initiator having the formula A, a cross-linked polymer composition as claimed is formed. b’ B a’ It is further understood that the compound further includes an amount of a compound having the formula: Additionally, it is understood that any of the disclosed metal oxides can be used.

[0107] In still further embodiments, the first cross-linking initiator can act as a filler. In such embodiments, the first cross-linking initiator can simultaneously act as both a cross-linking initiator and a filler. In such exemplary embodiments, substantially no additional fillers need be added. However, in still further embodiments, for example, in embodiments where the composition is self-hardening, additional fillers such as hydroxyapatite, B-tricalcium phosphate, pearl powder, octacalcium phosphate, or any combination thereof can be added.

[0108] As shown herein, metal oxides can, in the first case, act as both crosslinking initiators (biocompatible oxidants) and composite fillers, simultaneously enhancing the cohesive and adhesive strength of these bioadhesives, and acting as bioactive components that promote antibacterial properties and modulate cellular activity over the lifetime of the composite.

[0109] In still further embodiments, a compound of formula A b B a or formula A b’ O a’ can be present in an amount of from greater than 0 wt% to less than 100 wt%, based on the weight percent of the dry polymer or dry polymerization product. In some exemplary embodiments, the first crosslinking initiator, or compound of formula A b B a or more specifically, for example, but not limited to, compounds of b’ O a’ can be present in an amount of about 0.1 wt%, about 0.5 wt%, about 1 wt%, about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt%, about 55 wt%, about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, about 80 wt%, about 85 wt%, about 90 wt%, and about 95 wt%. b B a or formula A b’ O a’can be present in an amount of greater than 0 wt% to about 40 wt%, including exemplary values ​​of about 1 wt%, about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, and about 35 wt%, based on weight percent of the dry polymer (or dry polymerization product).

[0110] In still further embodiments, the polymer compositions or crosslinked polymer compositions described herein comprise a majority of the composition. In still further embodiments, the polymer compositions described herein are present in an amount of 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, 99% or more, or about 99% or more of the total weight of the composition. Furthermore, in other embodiments, the polymer compositions described herein can be present in any amount from greater than 0 wt% to less than 100 wt%. For example, the polymer compositions described herein can be present in an amount of about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95% of the total weight of the composition.

[0111] In yet a further aspect, a polymer composition and a compound of formula A b B a or formula A b’ O a’ can be present in any ratio between 1:10 and 10:1. For example, they can be present in a ratio of 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1.

[0112] In yet a further embodiment, the first cross-linking initiator, or a compound of formula A b B a Or formula A b’ O a’ can be added to form the composition as a solid or dispersion. In certain embodiments, the first cross-linking initiator, or a compound of formula A b B a Or formula A b’ O a’can be present at a concentration of about 0.001 M or greater, e.g., about 0.005 M or greater, about 0.01 M or greater, about 0.05 M or greater, about 0.1 M or greater, about 0.5 M or greater, or about 1 M or greater. In still further embodiments, the first cross-linking initiator, or compound of formula A b B a can be present at a concentration of about 0.001 M or greater, e.g., about 0.005 M or greater, about 0.01 M or greater, about 0.05 M or greater, about 0.1 M or greater, about 0.5 M or greater, or about 1 M or greater.

[0113] In some embodiments, the polymer or oligomer compositions of the invention can comprise a salt, e.g., an associated or dissociated salt comprising a monovalent, divalent, or trivalent metal cation or metal oxide, at a concentration of about 0.001 M to about 2 M, about 0.001 M to about 0.01 M, about 0.005 M to about 0.01 M, about 0.005 M to about 0.05 M, about 0.01 M to about 0.1 M, about 0.05 M to about 0.1 M, about 0.1 M to 1 M, or about 0.5 M to about 2 M.

[0114] In still further embodiments, the composition is a hydrogel or organogel. In still further embodiments, the composition can include an amount of solvent. In certain embodiments, the solvent can include water or a mixture of water and an organic solvent. In further embodiments, the mixture is primarily water, e.g., the solvent includes at least 95% water by volume. An aqueous solvent can include a large amount (50% or more) of water, such as 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, or 99% or more, but not 100% water. In some embodiments, the aqueous solvent also includes an organic co-solvent, including an amount greater than 0% but less than or equal to 50% of a polar or non-polar organic solvent (e.g., acetone or ethanol). In still further embodiments, the organic solvent can be any biocompatible solvent. In still further embodiments, the organic solvent includes ethanol. In such exemplary embodiments, the solvent can be water, ethanol, or a combination thereof.

[0115] In some embodiments, the first cross-linking initiator, or a compound of Formula A b B a Or formula Ab’ O a’ The compound of formula A may have a solubility of at least 50 g / 100 mL in water at 25° C. In some embodiments, the first cross-linking initiator, or compound of formula A b B a Or formula A b’ O a’ The compound of formula A may have a solubility of 5.0 g / L or less in water at 25° C. In some embodiments, the first cross-linking initiator, or compound of formula A b B a Or formula A b’ O a’ The compound of formula A may have a solubility of 1.0 g / L or less in water at 25° C. In some embodiments, the first cross-linking initiator, or compound of formula A b B a Or formula A b’ O a’ are described herein, which may be soluble, partially soluble, or insoluble in water or an aqueous solvent as described herein. In yet a further aspect, a first crosslinking initiator, or compound of formula A b B a Or formula A b’ O a’ In some cases, the first crosslinking initiator, or compound of formula A, can be added as a dispersion. b B a Or formula A b’ O a’ The solubility of the compound of formula A in water at 25° C. may be at least 30 g / 100 mL, at least 50 g / 100 mL, or at least 75 g / 100 mL. b B a or formula A b’ O a’ The solubility of the compound in water at 25°C may be less than 30 g / L, less than 20 g / L, less than 10 g / L, less than 5 g / L, or less than 1 g / L.

[0116] In still further embodiments, a compound of formula A b’ O a’ and formula A in which B is not oxygen b B aThe ratio of these two compounds, A, may also be present in the compositions described herein. b’ O a’ :A b B a can be anywhere between 10:1 and 1:10, including exemplary values ​​of about 9:1, about 8:1, about 7:1, about 6:1, 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 1:6, about 1:7, about 1:8, and about 1:9. It is understood that any ratio between any two of the foregoing values ​​can also be used.

[0117] In still further embodiments, the composition can further include a second crosslinking initiator. In such embodiments, the second crosslinking initiator can be different from the first crosslinking initiator. It is understood that any additional crosslinking initiator known in the art can be added. In certain embodiments, the crosslinking initiator can include sodium periodate, silver nitrate, or ferric chloride, or any combination thereof. In still further embodiments, the second crosslinking initiator can be present in an amount of greater than 0 wt% to about 40 wt%, with exemplary values ​​of about 1 wt%, about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, and about 35 wt%, based on a weight percent of the dry polymer or dry polymerization product. In still further embodiments, the second crosslinking initiator is present in an amount of greater than 0 wt% to about 8 wt%, based on the weight percent of the dry polymerized material, with exemplary values ​​of about 0.01 wt%, about 0.05 wt%, about 0.1 wt%, about 0.5 wt%, about 1 wt%, about 1.5 wt%, about 2 wt%, about 2.5 wt%, about 3 wt%, about 3.5 wt%, about 4 wt%, about 4.5 wt%, about 5 wt%, about 5.5 wt%, about 6 wt%, about 6.5 wt%, about 7 wt%, and about 7.5 wt%.

[0118] In such embodiments, the second crosslinking initiator can be added to the composition in any form similar to the first crosslinking initiator. In yet further embodiments, the second crosslinking initiator and the first crosslinking initiator have a synergistic effect on the composition.

[0119] In still further embodiments, the composition can comprise less than about 25%, less than about 20%, less than about 15%, less than about 10%, or less than about 5% sol content.

[0120] In still further embodiments, the compositions exhibit a swelling ratio of less than about 200%, less than about 190%, less than about 180%, less than about 170%, less than about 160%, less than about 150%, less than about 140%, less than about 130%, less than about 120%, less than about 110%, less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 60%, or less than about 50%.

[0121] In yet further embodiments, the compositions described herein may also be self-hardening compositions. The self-hardening formulations described herein can, in some embodiments, act as void-filling agents with significant mechanical strength, elasticity, and self-repairing capabilities. The self-hardening formulations described herein can also be modified by the addition of ceramic or other additives. The metal oxide-derived crosslinks described herein can incorporate ions including calcium, magnesium, and zinc, which have osteogenic differentiation potential, and ions including copper and zinc, which have antibacterial potential. Thus, the self-hardening citrate-based materials described herein have potential in orthopedic applications as void-filling and fixative agents for surgical implants and scaffolds, and, when combined with porogens and other additives, as anatomically accurate scaffolds based on patient-specific anatomy. In some embodiments, the self-hardening compositions of the present invention have a hardening time of less than 120 minutes at room temperature (25° C.), e.g., less than 80 minutes at room temperature (25° C.), or less than 60 minutes at room temperature (25° C.). In some embodiments, the self-curing compositions of the present invention have a cure time of less than 40 minutes at a physiological temperature of 37° C., such as less than 20 minutes at a physiological temperature of 37° C. In some embodiments, the composition does not contain a catalyst that affects the cure time.

[0122] In still further aspects, the compositions described herein are not self-curing.

[0123] In still further embodiments, the composition may exhibit a tensile strength in the dry state of about 1 to about 10 MPa, as measured according to ASTM D412A, with exemplary values ​​including about 2 MPa, about 3 MPa, about 4 MPa, about 5 MPa, about 6 MPa, about 7 MPa, about 8 MPa, and about 9 MPa.

[0124] In still further embodiments, the composition comprises about 18%, about 20%, about 22%, about 25%, about 27%, about 30%, about 32%, about 35%, about 37%, about 40%, about 42%, about 45%, about 47%, about 50%, about 52%, about 55%, about 57%, about 60%, about 62%, about 65%, about 67%, about 70%, about 72%, about 75%, about 77%, about 80%, about 82%, about 85%, about 87%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 108%, about 109%, about 110%, about 111%, about 112%, about 113%, about 114%, about 115%, about 116%, about 117%, about 118%, about 119%, about 120%, about 121%, about 122%, about 123%, about 124%, about 125%, about 126%, about 127%, about 128%, about 129%, about 130%, about 131%, about 132%, about 133%, about 134%, about 135%, about 136%, about 137%, about 138%, about 139%, about 140%, about 142%, about 143%, about 144%, about 145%, about 146%, about 147%, about 148%, about 149%, about 150%, about 1 The elongation at break may be from about 15% to about 150% in the dry state as measured in accordance with ASTM D412A, including exemplary values ​​of about 7%, about 90%, about 92%, about 95%, about 97%, about 100%, about 102%, about 105%, about 107%, about 110%, about 112%, about 115%, about 117%, about 120%, about 122%, about 125%, about 127%, about 130%, about 132%, about 135%, about 137%, about 140%, about 142%, about 145%, and about 147%.

[0125] In still further embodiments, the composition may exhibit a modulus of elasticity in the dry state of about 1 to about 10 MPa, measured according to ASTM D412A, with exemplary values ​​including about 2 MPa, about 3 MPa, about 4 MPa, about 5 MPa, about 6 MPa, about 7 MPa, about 8 MPa, and about 9 MPa.

[0126] In still further embodiments, the composition may exhibit a lap shear strength of greater than about 30 kPa, greater than about 35 kPa, greater than about 40 kPa, greater than about 45 kPa, greater than about 50 kPa, greater than about 55 kPa, or greater than about 60 kPa, as measured according to a modified ASTM D1002-05 method.

[0127] In yet a further aspect, the composition may exhibit increased cytocompatibility as measured against human mesenchymal stem cells when compared to a substantially identical reference composition without metal oxides, hi yet a further aspect, the composition exhibits increased inhibition against Staphylococcus aureus and Escherichia coli when compared to a substantially identical reference composition in the absence of metal oxides.

[0128] In still further embodiments, the composition can include at least one pharmaceutically active ingredient, which can include any agent capable of assisting in a particular treatment, such as, but not limited to, an antibiotic, an anti-inflammatory compound, a steroid, etc.

[0129] In yet a further aspect, the composition is injectable. In yet a further aspect, the composition is configured to fill a void, which can be physiological. In yet a further aspect, the composition is a wound closure composition.

[0130] In yet further aspects, the compositions of the present invention may have multiple potential applications in tissue engineering, including in situ curing, the formation of anatomically correct scaffolds when combined with molding, and 3D printing of scaffolds, taking advantage of the rapid setting potential of the system. Additionally, the compositions of the present invention have potential in orthopedics as void fillers and fixatives in surgical implants and scaffolds, and when combined with porogens and other additives, as anatomically accurate scaffolds based on patient-specific anatomy.

[0131] In still further aspects, uses of the compositions disclosed herein include, but are not limited to, orthopedic tissue engineering materials, including composites and porous scaffolds for critical-sized segmental defect repair and fixation and spinal fixation, and membranes for periosteal repair and barrier function; antibacterial-capable materials for preventing and controlling infection; hemostatic-capable materials for controlling bleeding in wounds and surgical implant procedures; self-hardening materials for void filling and fracture fixation; and self-hardening materials for the generation of molded or 3D printed scaffolds.

[0132] Any of the compositions described herein can also be prepared by forming a polymerization product by reacting a polycarboxylic acid of one or more monomers of formula (I) with a block copolymer comprising one or more monomers of formula (II) and / or formula (II'), and one or more monomers of formula (III), and / or optionally one or more compounds of formula (IV), [ka] R1, R2, and R3 are each hydrogen, C1-C 22 alkyl groups; each of R, R, and R is selected from C-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R is hydrogen, hydroxyl, amine, alkoxyl, C-C 22 alkyl group; R5 is selected from hydrogen, amine, hydroxyl group, or C1-C 22 alkyl group; R6 is selected from hydrogen, C1-C 22 Alkyl groups, C2-C 22 alkenyl groups; R7 is selected from hydrogen, amine, hydroxyl groups, alkoxyl groups, C1-C 22 each of R, R, R, and R is selected from C-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R, R, R 10 , and R 11 are each independently hydrogen, hydroxyl, C1-C 22 Alkyl groups, C1-C 22 R8, R9, R are selected from an alkoxy group, an amino group, a halide, an -SH- group, or a carboxyl group; 10 , and R 11 All of the above are C1-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl; R, R, R 10 , and R 11 at least one of the nucleophilic groups comprises at least one nucleophilic group selected from -N(H)-, -O-, -COO-, -Cl, -F, -S(O)-, and -S-; at least one of the nucleophilic groups is a terminal group; n and m are each independently an integer of 1 to 20; R 12 is the amino acid side chain; R 14 is —OH or —NH2; the polymerization product is free of metal cations; forming said polymerization product; and b) forming a compound of formula A b’ O a’wherein A is a monovalent, divalent, or trivalent metal cation; a' and b' depend on the valence of A; and A is not a transition metal cation; the crosslinked composition is a polymer network having at least one crosslink comprising two catechol moieties directly and covalently bonded to each other; the crosslinked composition is a hydrogel or an organogel, and is an adhesive composition.

[0133] It is understood that any of the above disclosed compounds, monomers, solvents, reactants can be utilized to form the compositions disclosed herein.

[0134] method Also disclosed herein are methods of making the above-described compositions. In such embodiments, the method of making a composition comprises: a) reacting one or more monomeric polycarboxylic acids of formula (I) with: [ka] a compound comprising one or more monomers of formula (II) and / or formula (II'); [ka] and one or more monomeric compounds of formula (III) [ka] and Optionally, one or more compounds of formula (IV) [ka] and mixing under conditions effective to form a polymer composition configured to be crosslinked, wherein R1, R2, and R3 are each independently hydrogen, C1-C 22alkyl groups; each of R, R, and R is selected from C-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 R4 may be optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R4 may be hydrogen, hydroxyl group, amine, alkoxyl group, C1-C 22 Alkyl groups, C2-C 22 alkenyl groups; R5 is selected from hydrogen, amine, hydroxyl groups, alkoxyl groups, or C1-C 22 Alkyl groups, C2-C 22 alkenyl groups; R6 is selected from hydrogen, C1-C 22 Alkyl groups, C2-C 22 alkenyl groups; R7 is selected from hydrogen, amine, hydroxyl groups, alkoxyl groups, C1-C 22 Alkyl groups, or C2-C 22 alkenyl groups; each of R, R, R, and R is selected from C-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 R, R, R may be optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; 10 , and R 11 are each independently hydrogen, C1-C 22 R8, R9, R are selected from alkyl groups, amines, or carboxylic acids; 10 , and R 11 Each of the C1-C 22 Alkyl, C1-C22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl; n and m are each independently an integer from 1 to 2,000; R 12 is the amino acid side chain; R 14 is —OH or —NH; and the formed polymer composition is free of metal cations; b) mixing; and c) crosslinking the formed polymer composition to form a composition comprising a crosslinked polymer composition that forms a polymer network, wherein at least one crosslink in the crosslinked polymer comprises two catechol moieties directly and covalently bonded to each other, and wherein the composition is an adhesive composition.

[0135] In yet a further aspect, there is provided a method of making a composition, comprising the steps of: a) reacting one or more monomeric polycarboxylic acids of formula (I) with [ka] one or more units of a block copolymer comprising one or more monomers of formula (II) and formula (II'); [ka] and one or more monomeric compounds of formula (III) [ka] and Optionally, one or more compounds of formula (IV) [ka] reacting under conditions effective to form a prepolymer composition configured to be crosslinked, wherein R1, R2, and R3 are each hydrogen, C1-C 22 alkyl groups; each of R, R, and R is selected from C-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R is hydrogen, hydroxyl, amine, alkoxyl, C-C 22 alkyl group; R5 is selected from hydrogen, amine, hydroxyl group, or C1-C 22 alkyl group; R6 is selected from hydrogen, C1-C 22 Alkyl groups, C2-C 22 alkenyl groups; R7 is selected from hydrogen, amine, hydroxyl groups, alkoxyl groups, C1-C 22 each of R, R, R, and R is selected from C-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 Optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R, R, R 10 , and R 11 are each independently hydrogen, hydroxyl, C1-C 22 Alkyl groups, C1-C 22R8, R9, R are selected from an alkoxy group, an amino group, a halide, an -SH- group, or a carboxyl group; 10 , and R 11 All of the above are C1-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl; R, R, R 10 , and R 11 at least one of the nucleophilic groups comprises at least one nucleophilic group selected from -N(H)-, -O-, -COO-, -Cl, -F, -S(O)-, and -S-; at least one of the nucleophilic groups is a terminal group; n and m are each independently an integer of 1 to 20; R 12 is the amino acid side chain; R 14 is —OH or —NH2; the polymerization product is free of metal cations; and b) adding a first crosslinking initiator to the prepolymer composition, wherein the first crosslinking composition has the formula A b B a wherein A is a monovalent, divalent, or trivalent metal cation and B is an anion; a and b are defined by the valences of A and B; and A is not a transition metal cation; and c) crosslinking the prepolymer composition to form a crosslinked composition comprising a polymer network, wherein at least one crosslink of the crosslinked polymer comprises two catechol moieties directly and covalently bonded to each other; the crosslinked composition is a hydrogel or an organogel and is an adhesive composition; disclosed herein is a method of making the composition.

[0136] In still further embodiments, R1, R2, and R3 are each independently selected from hydrogen, a -CH3 group, or a -CH2CH3 group; and R4 is selected from hydrogen, a hydroxyl group, -NH2, -OCH3, -OCH2CH3, -CH3, -CH2CH3 group, C3-C 22 R5 is selected from an alkyl or alkenyl group, —CH2CH2OH, or —CH2CH2NH2; R5 is selected from hydrogen, a hydroxyl group, —NH2, —OCH3, —OCH2CH3, —CH3 or —CH2CH3 group, C3-C 22 R6 is selected from a hydrogen, a -CH3 group or a -CH2CH3 group, -CH2CH2OH, or -CH2CH2NH2; R7 is selected from a hydrogen or a -CH3 group; R8, R9, R 10 , and R 11 are each independently hydrogen, -CH2(CH2) x NH2, -CH2(CHR 13 )NH2, or -CH2(CH2) x COOH group; R 13 is -COOH or -(CH2) y is a COOH group; n and m are each independently an integer of 1 to 2,000; x is an integer of 0 to 20; and y is an integer of 1 to 20.

[0137] While in still further embodiments, R1, R2, and R3 are each independently selected from hydrogen, a -CH3 group, or a -CH2CH3 group; R4 is hydrogen, a hydroxyl group, -NH2, -OCH3, -OCH2CH3, -CH3, -CH2CH3 group, C3-C 22 R5 is selected from an alkyl or alkenyl group, —CH2CH2OH, or —CH2CH2NH2; R5 is hydrogen, a hydroxyl group, —NH2, —CH3, or —CH2CH3 group, C3-C 22 R6 is selected from hydrogen, a -CH3 group, or a -CH2CH3 group, -CH2CH2OH, or -CH2CH2NH2; R7 is selected from hydrogen or a -CH3 group; R8, R9, R10 , and R 11 are each independently hydrogen, -CH2(CH2) x NH2, -CH2(CHR 13 )NH2, or -CH2(CH2) x COOH group; R, R, R 10 , and R 11 At least one of R is not hydrogen; 13 is -COOH or -(CH2) y is a COOH group; n and m are each independently an integer of 1 to 20; x is an integer of 0 to 20; and y is an integer of 1 to 20.

[0138] In still further embodiments, a nucleophilic group of one or more monomers of formula (III) reacts with at least one of R1COO-, R2COO-, or R3COO- of one or more monomers of formula (I) to form a covalent bond.

[0139] In still further aspects, any of the disclosed monomers of formula (I), (II), (II'), or (III) can be used in the disclosed methods.

[0140] In still further embodiments, the block copolymer may be formed prior to the reacting of step a) above.

[0141] Also disclosed herein is a method wherein a block copolymer is formed prior to the reacting of step a) and comprises repeat units of two or more monomers of formula (II): [ka] R4 is selected from hydrogen, a hydroxyl group, -NH2, -CH2CH2OH, or -CH2CH2NH2; R5 is hydrogen, a hydroxyl group, -NH2, -CH2CH2OH, or -CH2CH2NH2; and R6 is selected from hydrogen, a -CH3 group, or a -CH2CH3 group, -CH2CH2OH, or -CH2CH2NH2.

[0142] In some exemplary and non-limiting embodiments, the block copolymer can have formula (V) or formula (V'): [ka] a and b are each independently selected from n=1 to 20, and R6 is not hydrogen.

[0143] Any of the above disclosed monomers of formula (III) can be reacted with the block polymers and monomers of formula (I) disclosed herein.

[0144] In some exemplary and non-limiting embodiments, the polymerization product formed by the methods disclosed herein comprises: [ka] and R'' is -N(H)R 15 , or -O(CO)(R 15 ), or -O(R 15 ) and R 15 are independently C1-C 22 alkyl groups, C1-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl groups; R6 is not hydrogen; [ka] defines a bond to hydrogen, or optionally a bond to a given polymer chain, if present; a and b are each independently selected from n=1-20, and z=1-100.

[0145] In yet further embodiments, the first cross-linking initiator can be any compound in any amount, as described above. It is understood that these compounds can be added as solids or solutions, and the compositions disclosed herein can be formed by simple mixing. In yet further embodiments, where the first cross-linking initiator is provided as a solution, it can be a dispersion of the first cross-linking initiator in a solvent. Any of the solvents disclosed above can be used.

[0146] In such embodiments, the first crosslinking initiator can simultaneously act as the first filler. In certain exemplary and non-limiting embodiments, no other filler is added to the composition. Furthermore, in some additional embodiments, an additional filler different from the first crosslinking initiator can also be added.

[0147] In still further embodiments, the methods disclosed herein include the addition of a second crosslinking initiator. Any known crosslinking initiator can be utilized. In certain embodiments, the second crosslinking initiator includes sodium periodate, silver nitrate, or ferric chloride, or any combination thereof. In still further embodiments, the second crosslinking initiator is added to a solvent dispersion of the first crosslinking initiator, while in other embodiments, the second crosslinking initiator can be added as a separate solvent dispersion of the second crosslinking initiator. Any amount of the first crosslinking initiator and / or second crosslinking initiator disclosed herein can be used in the methods described above.

[0148] In still further embodiments, the formed compositions disclosed herein are hydrogels or organogels. In such embodiments, the gelation time required to form the hydrogel or organogel is from about 500 seconds to less than about 10 seconds, with exemplary values ​​of about 450 seconds, about 400 seconds, about 350 seconds, about 300 seconds, about 250 seconds, about 200 seconds, about 150 seconds, about 100 seconds, about 50 seconds, about 40 seconds, about 30 seconds, about 20 seconds, about 10 seconds, about 5 seconds, or about 1 second.

[0149] In yet a further aspect, the first cross-linking initiator and the second cross-linking initiator have a synergistic effect on the process of forming the desired composition.

[0150] In certain aspects, the methods described herein involve substantially faster crosslinking rates when compared to a substantially identical reference method in the absence of metal oxide.

[0151] Also disclosed are methods in which the compound of formula (IV) is present.

[0152] In still further aspects, the crosslinking step comprises crosslinking with a metal oxide via coupling of catechol groups of the polymer composition, forming a metal complex with the catechol groups of the polymer composition, binding of the metal oxide to carboxyl or catechol groups of the polymer composition via hydrogen bonding or surface bonding, or any combination thereof.

[0153] In still further embodiments, the formed composition exhibits a sol content and swelling ratio as described above. For example, in some embodiments, the formed composition can include a sol content of less than about 25%, less than about 20%, less than about 15%, less than about 10%, or less than about 5%. While in other embodiments, the formed composition can exhibit a swelling ratio of less than about 200%, less than about 190%, less than about 180%, less than about 170%, less than about 160%, less than about 150%, less than about 140%, less than about 130%, less than about 120%, less than about 110%, less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 60%, or less than about 50%.

[0154] In still further embodiments, the compositions formed by the methods disclosed herein may exhibit a tensile strength in the dry state of about 1 to about 10 MPa, as measured according to ASTM D412A, with exemplary values ​​including about 2 MPa, about 3 MPa, about 4 MPa, about 5 MPa, about 6 MPa, about 7 MPa, about 8 MPa, and about 9 MPa.

[0155] In still further embodiments, the compositions formed by the methods disclosed herein have a solubility of about 18%, about 20%, about 22%, about 25%, about 27%, about 30%, about 32%, about 35%, about 37%, about 40%, about 42%, about 45%, about 47%, about 50%, about 52%, about 55%, about 57%, about 60%, about 62%, about 65%, about 67%, about 70%, about 72%, about 75%, about 77%, about 80%, about 82%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 108%, about 109%, about 110%, about 111%, about 112%, about 113%, about 114%, about 115%, about 116%, about 117%, about 118%, about 119%, about 120%, about 121%, about 122%, about 123%, about 124%, about 125%, about 126%, about 127%, about 128%, about 129%, about 130%, about 131%, about 132%, about 133%, about 134%, about 135%, about 136%, about 137%, about 138%, about 139%, about 140%, about 142%, about 143%, about 144%, about 145%, about 146%, The elongation at break may be from about 15% to about 150% in the dry state as measured in accordance with ASTM D412A, including exemplary values ​​of about 2%, about 85%, about 87%, about 90%, about 92%, about 95%, about 97%, about 100%, 102%, 105%, about 107%, about 110%, about 112%, about 115%, about 117%, about 120%, about 122%, about 125%, about 127%, about 130%, about 132%, about 135%, about 137%, about 140%, about 142%, about 145%, and about 147%.

[0156] In still further embodiments, the compositions formed by the methods disclosed herein may exhibit a modulus of elasticity in the dry state of about 1 to about 10 MPa, as measured according to ASTM D412A, with exemplary values ​​including about 2 MPa, about 3 MPa, about 4 MPa, about 5 MPa, about 6 MPa, about 7 MPa, about 8 MPa, and about 9 MPa.

[0157] In still further embodiments, the compositions formed by the methods disclosed herein may exhibit a tensile shear strength of greater than about 30 kPa, greater than about 35 kPa, greater than about 40 kPa, greater than about 45 kPa, greater than about 50 kPa, greater than about 55 kPa, or greater than about 60 kPa, as measured according to a modified ASTM D1002-05 method.

[0158] In yet further aspects, the compositions formed by the methods disclosed herein may exhibit increased cytocompatibility as measured against human mesenchymal stem cells when compared to a substantially identical reference composition without metal oxides, hi yet further aspects, the compositions exhibit increased inhibition of Staphylococcus aureus and Escherichia coli when compared to a substantially identical reference composition in the absence of metal oxides.

[0159] In still further aspects, when the composition is a self-curing composition, the composition is cured for the time period disclosed above. In aspects where the method includes forming a self-curing composition, the method further includes adding any of the additional fillers disclosed above.

[0160] In yet a further embodiment, the method includes adding at least one pharmaceutically active ingredient to the formed composition.

[0161] In still further embodiments, the method can include adding a porogen to the metal oxide / polymer mixture. In some embodiments, the method can include forming a film or mold from the metal oxide / polymer mixture. In some embodiments, the method can further include injecting the metal oxide / polymer mixture into a cavity, such as an orthopedic cavity. In some embodiments, the method can further include evaporating a liquid or solvent from the metal oxide / polymer mixture. In some embodiments, the method can further include thermally crosslinking the metal oxide / polymer mixture, for example, after the liquid or solvent from the metal oxide / polymer mixture has evaporated.

[0162] In some aspects, the present disclosure also provides additional methods of manufacturing, including forming multiple layers of a three-dimensional object from any of the disclosed compositions.

[0163] In some aspects, methods of filling a void are also provided, comprising injecting any of the disclosed compositions into the void, e.g., an orthopedic void such as a bone fracture.

[0164] In some aspects, the present disclosure also provides a method of adhering biological tissue, comprising: a) placing any of the compositions disclosed herein between a first portion of biological tissue and a second portion of biological tissue; and b) contacting the first portion of biological tissue and the second portion of biological tissue.

[0165] In yet a further aspect, disclosed herein is a method of treating a disease comprising placing in a living body a composition comprising at least one pharmaceutically active agent, wherein the at least one pharmaceutically active agent is active against the disease and configured to be released in the living body at a predetermined time.

[0166] Also disclosed herein is a method of promoting growth of biological tissue, comprising providing a scaffold comprising any of the disclosed compositions and placing the scaffold in a tissue growth medium.

[0167] Also disclosed is a method for delivering an effective amount of at least one pharmaceutically active ingredient, said method comprising: a) preparing a polymerizable copolymer comprising: i) one or more monomers of formula (I) and one or more units of a block copolymer comprising one or more monomers of formula (II) and / or formula (II'), one or more monomers of formula (III), and / or optionally one or more compounds of formula (IV), [ka] R1, R2, and R3 are each hydrogen, C1-C 22 alkyl groups; each of R, R, and R is selected from C-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R is hydrogen, hydroxyl, amine, alkoxyl, C-C 22 alkyl group; R5 is selected from hydrogen, amine, hydroxyl group, or C1-C 22 alkyl group; R6 is selected from hydrogen, C1-C 22 Alkyl groups, C2-C 22alkenyl groups; R7 is selected from hydrogen, amine, hydroxyl groups, alkoxyl groups, C1-C 22 each of R, R, R, and R is selected from C-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R, R, R 10 , and R 11 are each independently hydrogen, hydroxyl, C1-C 22 Alkyl groups, C1-C 22 R8, R9, R are selected from an alkoxy group, an amino group, a halide, an -SH- group, or a carboxyl group; 10 , and R 11 All of the above are C1-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl; R, R, R 10 , and R 11 at least one of the nucleophilic groups comprises at least one nucleophilic group selected from -N(H)-, -O-, -COO-, -Cl, -F, -S(O)-, and -S-; at least one of the nucleophilic groups is a terminal group; n and m are each independently an integer of 1 to 20; R 12 is the amino acid side chain; R 14 is —OH or —NH2; the polymerization product does not contain a metal cation; and ii) a compound of formula Ab’ O a’ wherein A is a monovalent, divalent, or trivalent metal cation; a' and b' depend on the valence of A; and A is not a transition metal cation; wherein the first crosslinking initiator is configured to crosslink the reaction product to form the crosslinked composition; the crosslinked composition is a polymer network having at least one crosslink comprising two catechol moieties directly and covalently bonded to each other; the crosslinked composition is a hydrogel or organogel, and is an adhesive composition; and the method comprises b) incorporating at least one pharmaceutically active ingredient into the composition; and c) releasing the at least one agent in vivo at a predetermined time.

[0168] In such embodiments, any of the disclosed compositions and monomers described above can be utilized.

[0169] Also disclosed herein are kits for adhering biological tissues that include any of the crosslinking compositions disclosed herein. [Example]

[0170] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and evaluate the compounds, compositions, articles, devices, and / or methods claimed herein, and are intended to be purely illustrative and are not intended to limit the present disclosure. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperatures, etc.), but some errors and deviations should be expected.

[0171] material All reagents and solvents, including magnesium oxide (MgO, Lot#MKBS7178V, approximately 325 mesh), poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) (PEG-PPG-PEG, Pluronic® L-31, average molecular weight 1100 Da), and dopamine, were purchased from Sigma-Aldrich and used without further purification unless otherwise noted.

[0172] Synthesis and characterization of IC-EPE prepolymer iC-EPE prepolymer was synthesized by polycondensation of citric acid (CA), PEG-PPG-PEG, and dopamine (DP) as previously reported (Figure 1A). Briefly, CA, PEG-PPG-PEG, and DP (molar ratio = 1.2:1.0:0.3) were placed in a one-neck round-bottom flask equipped with a vacuum stopper, and the mixture was heated to 160 °C under stirring until completely melted. The temperature was then lowered to 140 °C, and the reaction was continued under vacuum until the stirring rod stopped rotating at 60 rpm. The reaction mixture was dissolved in ethanol, precipitated in a large amount of deionized (DI) water, and then lyophilized to obtain purified iC-EPE prepolymer.

[0173] iC-EPE and regular iC-P 400 (iCMBA-P 400 D 0.3Fourier transform infrared (FTIR) spectra of the prepolymers (synthesized as known in the art according to, e.g., M. Mehdizadeh, et al., "Injectable citrate-based mussel-inspired tissue bioadhesives with high wet strength for sutureless wound closure," Biomaterials 33(32)(2012)7972-7983; J. Guo et al., "Click chemistry improved wet adhesion strength of mussel-inspired citrate-based antimicrobial bioadhesives," Biomaterials 112(2017)275-286) were obtained on a Nicolet 6700 FTIR spectrometer to characterize the functional groups of the prepolymers. A solution of the prepolymer in acetone was cast onto a KBr plate, the solvent was evaporated, and a blank KBr plate was used as the background. A solution of the prepolymer in DMSO-d6 was cast onto a KBr plate, the solvent was evaporated, and a blank KBr plate was used as the background. 1 H-NMR spectra were recorded on a 300 MHz Bruker DPX-300 FT-NMR spectrometer. The dopamine content in the prepolymer was measured by UV-vis spectra using a Shimadzu UV-2450 spectrophotometer with a minimum wavelength resolution of 0.2 nm.

[0174] Preparation of IC-EPE / MGO composite hydrogels and gelation time test iC-EPE prepolymer was dissolved in a mixed solution (ethanol:pure water = 80:20, w / w) to form a 40 wt% polymer solution. 5, 10, 15, or 20 wt% MgO powder (wt% relative to the dry polymer) was dispersed in DI water, ethanol, or sodium periodate (PI) solution (dissolved in DI water) as a crosslinking initiator. The polymer solution and MgO dispersion were mixed in a 2:1 volume ratio to fabricate iC-EPE / MgO composite hydrogels. Unless otherwise noted, all hydrogels were cured for 24 h and then freeze-dried for at least 2 days for further characterization. The gelation time of different samples was measured by tilt test. For each sample, the test was performed three times and the average value was calculated.

[0175] The names of the iC-EPE prepolymer samples crosslinked with different amounts of MgO, different solvents / solutions used to disperse MgO, and with or without PI are shown in Table 1. Table 1 also shows the nomenclature of different iC-EPE composite hydrogels crosslinked with different MgO contents, different MgO dispersion solvents / solutions, and with or without sodium (meta)periodate (PI). All of these composite hydrogels were crosslinked at room temperature. [Table 1]

[0176] Rheological test of IC-EPE / MGO composite hydrogel Rheological tests were performed using a Discovery Series Hybrid Rheometer (DHR-1, TA Instruments, USA) in a parallel-plate configuration using sand-polished 40 mm diameter stainless steel plates throughout and a Peltier plate for temperature control. Two milliliters of iC-EPE prepolymer solution (40 wt%) was mixed with 1 ml of crosslinking initiator dispersion (10 wt% MgO in pure water, ethanol, or 8 wt% PI solution), and the mixture was immediately attached to the lower plate of the rheometer. The upper plate was immediately lowered to a gap distance of 40 μm, and both the storage modulus (G') and loss modulus (G') values ​​were measured as a function of time at a frequency of 1 Hz and a strain of 1%. Each measurement was performed in triplicate. The gelation time was approximated by the G' / G" crossover time.

[0177] Characterization of IC-EPE / MGO composite hydrogel The mechanical properties of dried iC-EPE composite hydrogel membranes were determined according to ASTM D412A using an Instron 5966 machine equipped with a 1 kN (for dry membranes) or 10 N (for swollen membranes) load cell (Instron, Norwood, MA). Dumbbell-shaped specimens (25 mm × 6 mm × 1.5 mm, length × width × thickness) were stretched to failure at a strain rate of 500 mm / min. The modulus, tensile stress, and elongation at break were recorded for various membranes as average values ​​of eight replicates. To evaluate the effect of hydration on the mechanical properties of iC-EPE composite hydrogels, mechanical testing was also performed on specimens after 48 h of hydration in the wet state.

[0178] The sol content and swelling ratio of the crosslinked iC-EPE / MgO composite hydrogels were measured according to procedures known in the art and then calculated using equations (1) and (2), respectively.

number

[0179] In the formula, W i represents the initial mass of the dried iC-EPE hydrogel sample, and W drepresents the mass of the lyophilized sample after leaching the uncrosslinked portion with 1,4-dioxane for 48 hours, and W s represents the mass of the network sample that was suspended in water for 24 hours, then wiped dry with filter paper.

[0180] The degradation profile was evaluated by in vitro degradation in phosphate-buffered saline (PBS, pH 7.4, 0.1M) at 37°C. Disc-shaped specimens (7 mm diameter, 1 mm thickness) were accurately weighed (W0), immersed in 10 mL of PBS, and incubated at 37°C. The PBS solution was changed every other day. At the designated time points, the samples were thoroughly washed with DI water, lyophilized, and the residual mass was measured (W0). t ) The mass loss was calculated using equation (3).

number

[0181] Adhesion strength of IC-EPE / MGO composite hydrogel The adhesive strength of iC-EPE composite hydrogels was measured using a tensile shear strength test according to a modified ASTM D1002-05 method. Porcine-derived acellular small intestinal submucosa (SIS) material (OASIS®, HealthPoint Ltd., Fort Worth, TX) was cut into 40 mm x 4 mm strips and hydrated in PBS for at least 1 hour before testing. After mixing the iC-EPE polymer solution with a predetermined amount of cross-linking initiator, 10 μL of the mixture was added and spread over one end of the strip. Subsequently, a second wet strip was brought into contact with the first, forming an overlapping area of ​​6 mm x 4 mm. The bonded strips were compressed with a 100 g weight for 20 minutes and placed in a humid chamber for 2 hours before testing. The tensile shear strength of the bonded strips was then measured at a rate of 1.3 mm / min using an Instron 5966 equipped with a 10 N load cell. For comparison, the tensile shear strength of fibrin glue (Tisseel, Baxter Healthcare Corp.) was used.

[0182] In vitro biocompatibility testing The in vitro biocompatibility of the crosslinked iC-EPE / MgO composite hydrogel was evaluated by testing the sol content (or elutable fraction) and cytotoxicity of the degradation products. Human mesenchymal stem cells (hMSCs, ATCC® PCS-500-012™, ATCC, passages 5–10) were used.

[0183] The cytotoxicity of the sol content of the crosslinked iC-EPE / MgO composite hydrogels against hMSCs was also investigated using the MTT (methylthiazolyl-diphenyl-tetrazolium bromide) assay. A 0.5 g sample of dried hydrogel was incubated in 5 mL of PBS (pH 7.4) at 37°C for 24 hours to obtain a hydrogel leachate (sol content) solution. Three dilutions were then prepared: 1×, 10×, and 100× (1× is the undiluted leachate solution, while 10× and 100× are the 1× solution diluted 10- and 100-fold with PBS, respectively). The hMSC solution in MgO medium was added to each well of a 96-well cell culture plate at a concentration of 5 × 10 4 200 μL of the sol-containing solution was added at a density of 100 cells / mL and incubated for 24 hours. After that, 20 μL of the sol-containing solution at various concentrations was added, and the cells were further incubated for 24 hours, after which an MTT assay was performed.

[0184] We also evaluated the cytotoxicity of the hydrogel degradation products. Equal weights (1 g) of dried iC-EPE / MgO hydrogel samples and FDA-approved polylactic-co-glycolic acid (PLGA, used as a control; LA / GA = 50 / 50, Mw approximately 60 kDa, purchased from Polyscitech) were completely degraded in 10 mL of 0.2 M NaOH solution. After adjusting the pH to 7.4, the resulting solution was diluted to three concentrations (1x, 10x, and 100x) with PBS (pH 7.4) and used for cell culture (the process was the same as that used in the sol-containing cell cytotoxicity test described above) and subsequent MTT analysis.

[0185] We also investigated cell adhesion and proliferation on iC-EPE composite hydrogel membranes using hMSC cells. Cell morphology was observed by a Live / Dead staining assay using W10 as an example. Briefly, 20 μL of iC-EPE prepolymer solution was mixed with 10 μL of MgO DI aqueous solution (0.088 g / mL). This mixture was evenly spread on the surface of a glass slide to form a 15 mm diameter thin film of W10 before crosslinking was complete. The samples were then sterilized by incubating in 70% ethanol for 24 hours and then irradiating with UV light for 3 hours. The samples were then placed in a 24-well plate and 500 μL of hMSC solution was added at 5,000 cells / cm. 2 The cells were seeded at a density of 1000 x g and the MG medium was replaced the next day. At the designated time points (cells were cultured for 1, 3, and 7 days), the medium was removed from the well plates, and the cells were washed with PBS. They were then stained with a Live / Dead Viability / Cytotoxicity Kit (Invitrogen, molecular probes, Eugene, OR). Cell morphology was observed using an inverted optical microscope (Nikon Eclipse Ti-U) equipped with an ANDOR DL-604M-#VP camera and Prior Lumen 200.

[0186] In vitro antibacterial properties of IC-EPE bioadhesive The antibacterial properties of the iC-EPE composite hydrogel were tested against Staphylococcus aureus (S. aureus) as a positive bacterial model and Escherichia coli (E. coli) as a negative bacterial model. Staphylococcus aureus (ATCC® 6538™) and E. coli (ATCC® 25922™) were purchased from the American Type Culture Collection (ATCC) and used according to established safety protocols. Tryptic soy broth (Cat. #: C7141) and tryptic soy agar (Cat. #: C7121) used for culturing Staphylococcus aureus were purchased from Criterion (via VWR). Luria broth base (LB broth, Cat. #: 12795-027) and Select agar (Cat. #: 30391-023) used for culturing E. coli were purchased from Invitrogen. Monocolonies of S. aureus and E. coli were incubated overnight in sterile tryptic soy broth and LB broth, respectively, on an orbital shaker at 37°C, and the resulting bacterial suspensions were diluted to the desired concentration before use.

[0187] W10, E10, W10 + 8PI, and 8PI were selected as representative experimental samples, and PEGDA / HEMA (w / w = 1 / 1) was used as a positive control. A bacterial cell suspension with an optical density (OD) at 600 nm of 0.07 was first prepared. The bacterial suspension was then diluted 100-fold with broth medium to obtain the desired concentration. Colony counts were performed to determine the bacterial cell concentration in terms of CFU (colony-forming units) / ml. 0.2 g of lyophilized sample (without removing the eluted components) was immersed in 20 ml of the above bacterial suspension and incubated at 37°C on an orbital shaker for 24 hours. The diluted medium was then cast onto an agar plate and colony counts were performed. Bacterial growth broth was also tested as a negative control. The bacterial inhibition rate of the sample was calculated using Equation (4).

number

[0188] In the formula, N0 represents the bacterial concentration in the broth medium before cultivation in units of CFUs / mL. t and Ncon is the bacterial concentration in the broth containing the hydrogel and in the pure broth (control) after 24 hours of incubation, also in CFUs / mL.

[0189] IN VIVO experiments Skin incisions were made in Sprague-Dawley rats (female, 260 ± 50 g, n = 5) to evaluate the in vivo biocompatibility and wound healing ability of iC-EPE crosslinked with MgO (10 wt% in water, W10). All in vivo experiments were performed with the approval of Third Military Medical University (China). Briefly, rats were anesthetized with 40 mg / kg ketamine, and the dorsal hair was shaved. After sterilizing the dorsal skin surgical site with 75% ethanol, a full-thickness surgical skin wound (2 cm long x 0.5 cm deep) was created. Sterilized iC-EPE was mixed with MgO (W10), and the adhesive was applied dropwise to the wound, which was then clamped with fingers for 5 minutes. Conventional sutures were used as a positive control. Treated skin wounds were harvested 7 and 28 days after application, fixed in 4% paraformaldehyde, and histologically examined. Hematoxylin and eosin (H&E) staining and Masson's trichrome staining were performed to evaluate morphology and collagen production, respectively. To assess inflammation, immunohistochemistry for CD11b expression was also performed. CD11b-positive cells in the tissue were detected using rabbit anti-rat integrin aM (H-61, Santa) and peroxidase-conjugated goat anti-rabbit secondary antibody (Santa). Stained tissue sections were observed under a light microscope (Nikon, Tokyo, Japan). At different time points after treatment, the number of cells infiltrating the incision and the number of CD11b-positive cells were calculated in random fields using Image J. Collagen density (%) was measured using Image J by calculating the ratio of the blue-stained area to the total area of ​​the Masson's trichrome-stained image. At least five fields were randomly selected, and the results were averaged.

[0190] statistical analysis All data are expressed as mean ± standard deviation, and the number of test samples was at least 5. The significance of differences between results was evaluated by one-way analysis of variance. A p value of <0.05 (*) was considered statistically significant.

[0191] Example 1 Synthesis and characterization of iC-EPE prepolymer The original iCMBA used a hydrophilic PEG diol to impart water solubility. Therefore, as is known, such crosslinked hydrogels have very high water swelling ratios, exceeding 1000 wt% in extreme cases. To reduce the swelling ratio, the more hydrophobic PEG-PPG-PEG (EPE) was used, and CA was reacted with dopamine in a simple one-pot polycondensation to produce the iC-EPE prepolymer (Figure 1A). iC-EPE and iC-P 400 (For comparison, PEG 400 The FTIR spectrum of the prepolymer (synthesized using ) is shown in Figure 2A. -1 The peak between 1540 cm and 1540 cm was that of the carbonyl group (C=O) of the ester group. -1 The peak at 2932 cm was that of the amide group (-C(=O)-NH-), confirming the formation of an amide bond between the -COOH group of CA and the -NH2 group of dopamine. -1 and 2870cm -1 The peaks around 3364 cm were due to the methyl group (-CH3) and methylene group (-CH2-) derived from PEG-PPG-PEG, respectively. -1 The relatively broad peaks of iC-EPE and iC-P are thought to be due to the presence of hydroxyl groups. 400 of 1 The H-NMR spectrum is shown in Figure 2B. 400 of 1 The peak at 1.02 ppm in the iC-EPE spectrum, which was not present in the H-NMR spectrum, was due to the proton of -CH3 derived from EPE, which is the most characteristic peak of iC-EPE. The multiple peaks between 2.55 and 2.90 ppm were due to the protons of the methylene groups of citric acid and dopamine.400 The chemical shifts between 6.40 and 6.70 ppm observed in the spectra of both prepolymers were those of the phenyl protons characteristic of the catechol group. 1 H-NMR data further confirmed the esterification reaction between CA and EPE and the formation of an amide bond between the -COOH group of CA and the -NH group of dopamine. UV-vis spectra further confirmed the availability of catechol hydroxyl groups in the iC-EPE prepolymer via a UV absorption peak at 280 nm (Figure 2C). The dopamine content in the iC-EPE prepolymer was determined to be 0.308 mmol / g according to the dopamine standard curve shown in the inset panel of Figure 2C.

[0192] Example 2 Preparation of iC-EPE / MgO composite hydrogels and gelation time measurements Crosslinking of polymers with catechol often involves the use of harsh and hazardous aqueous oxidizing agents, such as sodium periodate (PI), silver nitrate (SN), or FeCl3. Enzymes such as horseradish peroxidase (HRP) and mushroom tyrosinase (MT) are effective when used to crosslink tyramine- or tyrosine-containing polymers, but they often exhibit long crosslinking times of several hours and require large amounts of enzyme, making such systems both practical and cost-effective. Currently, there are few reports of effective crosslinking of catechol-containing polymers without the use of hazardous oxidizing agents.

[0193] Here, we found that MgO particles could crosslink iC-EPE or other iCMBAs simply by mixing them with MgO dispersions in water or ethanol (Figure 1B). The effect of MgO content on the gelation time of iC-EPE / MgO composite hydrogels is shown in Figure 4A and Table 1. The gelation time decreased with increasing MgO content. Furthermore, at the same MgO content, MgO dispersed in water crosslinked the iC-EPE prepolymer faster than the same amount of MgO dispersed in ethanol. The effect of temperature on gelation time is shown in Figure 4B. At comparable MgO contents, increasing the temperature significantly shortened the gelation time. For example, with 10 wt% MgO, the gelation time was reduced from 324 seconds at 25°C (room temperature) to 176 seconds at 37°C (human body temperature). The gelation times of iC-EPE crosslinked with MgO ranged from 200 to 1300 seconds (Figure 4A-4B). Most gelation times were reduced compared to the gelation time of iC-EPE crosslinked with pure 8 wt% PI (1568 ± 47 seconds, Table 1). When MgO and PI were mixed in water, the gelation times were comparable to those of known iCMBA crosslinked with PI. The gelation times were significantly reduced to less than 60 seconds for all tested samples (Figure 4C and Table 1). At the same MgO content, 2 wt% PI crosslinked the fastest, and increasing the PI concentration did not result in faster crosslinking. Without being bound by theory, we hypothesize that this effect may be due to mutual inhibition between MgO and PI. Furthermore, we speculate that a PI concentration of 2 wt% promoted crosslinking of iC-EPE prepolymer, but that the mutual inhibition effect between MgO and PI became more pronounced when the PI concentration was increased to 4 wt%. When the PI concentration increased to 8 wt%, compared to 4 wt% PI, except for the case of W15 + 8PI (W15 is defined as 15 wt% MgO / composite using water as the dispersion medium for MgO particles. The nomenclature of the different iC-EPE composite hydrogels is listed in Table 1), the gelation time decreased again, which, without being bound by any theory, was attributed to the relatively increased cross-linking by PI compared to cross-linking by MgO (Figure 4C).

[0194] Rheological tests were performed using representative samples, and the intersection of the curves of storage modulus (G') and loss modulus (G") was determined as the gelation time (red circle in Figure 4D-F). The gelation time measured by the rheological test was equivalent to that measured by the tilt test, proving that the tilt test is more reliable, convenient, and easier to perform. Figure 4D shows that when the amount of MgO used was the same (10 wt% MgO), changing the MgO dispersion solvent from ethanol to water reduced the gelation time from 558 seconds to 3 seconds. It can be seen that the gel time was reduced to 86 seconds, consistent with the results of the tilt test (Figure 4A). Figure 4E further confirmed the same trend shown in Figure 4B, where increasing the temperature from RT (25 °C) to 37 °C led to a reduction in gel time. The synergistic effect between MgO and PI was also further confirmed by Figure 4F, where the gel time was significantly reduced from 386 seconds (W10, using 10 wt% MgO in water) to less than 10 seconds for W10 + 8PI (using 10 wt% MgO dispersed in an 8 wt% PI solution).

[0195] Experimental Example 3 Multifaceted cross-linking mechanism of MgO A possible cross-linking mechanism for MgO is shown in Figure 3. Without being bound by any theory, we speculate that the creation of a moderate alkaline condition through a slow reaction between MgO and water is the key step (Figure 3). This can be inferred from the fact that iC-EPE / MgO cannot be cross-linked in a formulation that does not use any water (iC-EPE dissolved in ethanol and MgO dispersed in ethanol), whereas cross-linking occurs more quickly in formulations that use a large amount of water (see Table 2 and Figures 4A to 4F). [Table 2]

[0196] Without wishing to be bound by any theory, it was speculated that the crosslinking mechanism of the iC-EPE / MgO adhesive may be multifaceted.

[0197] The surface of MgO particles is oxidized by the strong superoxide anion (O2 -Reactive oxygen species (ROS) such as ) induce the oxidation of catechol groups under alkaline conditions, followed by the generation of free radicals and cross-linking by coupling (Route 1 in Figure 3). The crystal defects of MgO particles are caused by the oxidation of O2 on the surface of MgO. - Furthermore, the formation of O2 on the surface of the MgO particles can be further promoted. - Without being bound by any theory, we believe that the strong oxidizing power of MgO in alkaline conditions may also be the reason for its antibacterial activity. Excessive production of ROS at inflammatory sites is thought to delay or hinder the wound healing process, and the inclusion of catechol-containing iC-EPE may function as an ROS scavenger, reducing the adverse effects of ROS on wound healing.

[0198] Without being bound by any theory, it is believed that magnesium ions (Mg 2+ It was speculated that the formation of metal complexes between the catechol groups and the hydroxyl groups also contributed to the cross-linking (Route 2 in Figure 3).

[0199] Furthermore, without being bound by any theory, it is believed that the iC-EPE prepolymer also contains free carboxyl (-COOH) groups, and therefore the reaction between Mg(OH)2 (or, in some cases, MgO) and the -COOH groups and the Mg2 + and -COO - We speculated that the formation of electrostatic interactions between Mg and Mg could contribute to the cross-linking (Route 4 in Figure 3). 2+ and -COO - The formation of ionic bonds between these molecules must be very slow. This assumption was supported by the fact that poly(poly(ethylene glycol)citrate) (PEGC, a catechol-free prepolymer of citric acid containing -COOH, synthesized by reacting CA with PEG), could not be crosslinked with MgO (data not shown).

[0200] Again, without being bound by any theory, it was speculated that surface or hydrogen bonding interactions between catechol or carboxyl groups and MgO particles (Routes 3 and 5 in Figure 3) served as an additional method of cross-linking.

[0201] In addition to triggering intermolecular cross-linking, the oxidized catechol group (ortho-quinone group) can also contribute to strong adhesion to biological surfaces by forming covalent bonds with nucleophilic groups (e.g., -NH, -SH, -OH, and -COOH groups) on tissue surfaces.

[0202] Example 4 Preparation of cross-linked iC-EPE To investigate the mechanical properties of the crosslinked iC-EPE composite hydrogels, tensile tests were performed in both dry and wet states (Figures 5A–5F and Table 2). The tensile strength of the dried iC-EPE / MgO composite hydrogels, with and without PI, ranged from 2 to 5 MPa, comparable to the tensile strength of conventional iCMBA crosslinked with PI (1–7.5 MPa). Overall, increasing the MgO content increased the tensile strength of the tested formulations (Figure 5A). The Young's modulus of the crosslinked iC-EPE / MgO hydrogels gradually increased with increasing MgO content, while the elongation at break decreased (Figures 5B–C). The tensile strength and modulus of iC-EPE crosslinked with MgO or MgO + PI were much higher than those of hydrogels crosslinked with PI alone, indicating that MgO functions not only as a crosslinker but also as a composite filler. The combination of MgO and PI not only improved the modulus and tensile strength, but also the elongation at break. The stress-strain curve of the crosslinked iC-EPE / MgO hydrogel was characteristic of an elastomer, which is particularly important for soft tissue applications because it allows mechanical adaptation and stress transfer between the hydrogel and flexible, dynamic soft tissue (Figure 5D). The mechanical properties of the crosslinked iC-EPE hydrogel in the wet state are shown in Table 3. It can be seen that the tensile strength decreased as the sample hydrated and swelled. These results suggest that the crosslinked iC-EPE hydrogel has tailorable mechanical properties suitable for a variety of clinical applications. [Table 3]

[0203] The sol content of iC-EPE hydrogels crosslinked with MgO, MgO + PI, or PI is shown in Figure 5D. The sol content of all tested formulations was below 25%. Hydrogels crosslinked with MgO dispersions in ethanol had the lowest sol content, much lower than hydrogels crosslinked with MgO dispersions in water or MgO + PI solutions. Without being bound by any theory, this is attributed to the alkalinity of MgO, which partially destroys the hydrogel network. As shown in Figure 5E, the swelling ratios of iC-EPE hydrogels crosslinked with either MgO (dispersed in water or ethanol), MgO + PI, or PI were all below 200 wt%, with the lowest being below 10 wt% (E5). The swelling ratios of all EPE-based iC formulations were much lower than those of the PEG-based iCMBA (some exceeding 1000 wt%), confirming the benefit of replacing the hydrophilic PEG with the more hydrophobic EPE.

[0204] Degradation of crosslinked iC-EPE composite hydrogels was performed in PBS at 37 °C, and mass loss at preset time points was recorded (Figure 5F). iC-EPE hydrogels crosslinked with PI exhibited the slowest degradation rate, with a mass loss of less than 40 wt% after 28 days. Hydrogels crosslinked with a 5 wt% MgO dispersion in water exhibited the fastest degradation, with complete degradation in 7 days. For hydrogels crosslinked solely with MgO, such as W5, W10, W15, and E10, the degradation rate decreased with increasing MgO content, suggesting that higher MgO content resulted in higher crosslink density. Interestingly, iC-EPE crosslinked with 10 wt% MgO and 8 wt% PI (W10+8PI) degraded faster than iC-EPE crosslinked with 8 wt% PI (8PI) or 10 wt% MgO (W10) alone, suggesting that MgO and PI inhibit each other's crosslinking of the iC-EPE prepolymer. Again, without being bound by any theory, the alkalinity of MgO in aqueous solution may also be a factor in promoting degradation.

[0205] Example 5 Adhesive strength A preliminary evaluation of the tissue adhesive strength of the iC-EPE / MgO bioadhesive was performed by tensile shear strength tests under wet conditions. The wet tensile shear strengths of iC-EPE crosslinked with different crosslinkers are shown in Figure 6. The adhesive strengths of all tested formulations were higher than that of commercially available fibrin glue (15.4 ± 2.8 kPa). iC-EPE hydrogels crosslinked with PI (8PI) or MgO / ethanol dispersion (E10) exhibited the lowest adhesive strength, but this value was twice that of fibrin glue. iC-EPE hydrogels crosslinked with MgO and 8 wt% PI (W10 + 8PI) exhibited the highest adhesive strength (127.0 ± 14.0 kPa). The tensile shear strength not only reflects the adhesive strength to the substrate but also closely relates to the cohesive strength of the bioadhesive matrix. Therefore, the tensile shear strength test results further demonstrated that the incorporation of MgO simultaneously improved the adhesive and cohesive strength of the iC-EPE bioadhesive. The adhesive strength of the iC-EPE / MgO system was superior to that of commercially available fibrin glue and could be adjusted by changing the cross-linking agent.

[0206] Example 6 In vitro cell viability and proliferation The biocompatibility of iC-EPE hydrogels crosslinked with different crosslinkers was evaluated by testing the soluble (dissolvable) content of various crosslinked iC-EPE hydrogels and the cytotoxicity of their degradation products using the MTT assay on human mesenchymal stem cells (hMSCs) (Figures 7A-7C). The sol content of the 1× iC-EPE hydrogels, except for 8PI, resulted in hMSC viability of over 80%, confirming minor cytotoxicity. The cell viability of all tested samples increased with dilution, approaching or exceeding 100% at 100x dilution (Figure 7A). The 1× degradation products showed significantly lower cell viability (<20%) compared to PLGA (approximately 50%). However, the cell viability of 10× and 100× diluted solutions of the degradation products was much higher and comparable to that of blank medium and PLGA (Figure 7B). The cytotoxicity of crosslinked iC-EPE hydrogels is thought to be due to the release of MgO particles, residual PI, and its reduced components from the hydrogel. The proliferation of hMSCs on crosslinked iC-EPE membranes was investigated by live / dead assay at three time points (days 1, 3, and 7) using W10 as a representative sample (Figure 7D). hMSCs proliferated well and exhibited elongated / stretched morphology, confirming good cell adhesion and proliferation on the crosslinked iC-EPE membranes. These studies clearly demonstrated that iC-EPE hydrogels crosslinked with MgO or MgO + PI are cytocompatible with hMSCs.

[0207] Example 7 in vitro antibacterial performance The antibacterial performance of crosslinked iC-EPE hydrogels was evaluated using PEGDA / HEMA as a positive control, Staphylococcus aureus (a Gram-positive bacterium commonly used in medicine), and Escherichia coli (a Gram-negative bacterium). Figure 8A shows the bacterial inhibition rates of crosslinked iC-EPE against S. aureus and E. coli. The iC-EPE hydrogel crosslinked with a combination of MgO and PI (W10 + 8PI, >95%) exhibited the highest inhibition rates against both S. aureus and E. coli among the tested formulations. The inhibition rate was lower for hydrogels crosslinked with PI alone (8PI, approximately 80%), and the hydrogel crosslinked with MgO alone (W10, E10) exhibited the lowest bacterial inhibition rate at approximately 60%. Without being bound by any theory, these results may be due to the following: 1) PI is a water-soluble small molecule, whereas MgO particles (micron-sized) can only be dispersed in water, so PI was released much faster than MgO particles; and 2) PI itself has a much stronger antibacterial effect than MgO particles, as evidenced by previous studies on the antibacterial performance of PI and the antibacterial test of MgO particles described in the following experiment (Figure 8B).

[0208] To further demonstrate the antibacterial properties of MgO particles, their antibacterial activity against Staphylococcus aureus and Escherichia coli was evaluated by the agar plate dilution method. Figure 8B shows representative images of the bactericidal activity of agar samples at different MgO concentrations. Clearly, higher MgO concentrations exhibited superior antibacterial activity. Only a few bacterial colonies were observed on plates with MgO concentrations exceeding 1 mg / mL for Staphylococcus aureus and 2 mg / mL for Escherichia coli. Without being bound by any theory, these results suggest that MgO has considerable antibacterial activity and that its bactericidal activity against Staphylococcus aureus is greater than that against E. coli.

[0209] Based on the experimental data, it was suggested that the antibacterial activity of iC-EPE / MgO bioadhesive could be beneficial for biomedical applications where microbial infection is a major challenge to overcome.

[0210] Example 8 In vivo testing To further evaluate the biocompatibility and wound closure efficacy of iC-EPE crosslinked with MgO, in vivo studies were performed (Figures 9A–9G). Application of iC-EPE / MgO (W10) immediately stopped incision bleeding in Sprague-Dawley rats, achieving effective wound closure within 5 min (Figure 9A). Application of W10 to the wound, using a mussel-inspired strategy (15), produced a bulk adhesive that chemically crosslinked and adhered to the wound tissue, providing a physical and mechanical barrier against bleeding. Without being bound by any theory, we speculate that the abundant carboxyl groups present in iC-EPE contribute to its hemostatic effect. Previously, Mg 2+ ions have been reported to be involved in the blood coagulation cascade. Without being bound by any theory, Mg 2+ These results suggest that the inclusion of MgO particles that release hydroxybenzoates also promotes hemostasis, another benefit of the iC-EPE / MgO adhesive. Ethanol, the solvent in iC-EPE, functions as another hemostatic component, also helping to control bleeding. Visual observation and comparison of W10-treated and sutured wounds at different time points demonstrated the high wound healing efficiency of iC-EPE. W10-treated wounds showed reduced scarring compared with sutured wounds at both 7 and 28 days (Figure 9A). Histological evaluation (H&E staining) revealed only slight acute inflammation on day 7 after W10 application (Figure 9B). The total cell density at the incision of the W10-treated wounds (4691.7 ± 187.6 # / mm) was significantly higher than that of the sutured wounds (Figure 9B). 2 ) was the mean value of the sutured wound on the 7th day (4975.0±125.0# / mm 2 ) and the total cell density of the W10-treated wound (2241.7 ± 142.2 # / mm ) was not significantly different from that of the W10-treated wound (Figure 9C). 2 ) in wounds treated with sutures on day 28 (3691.7±112.7# / mm 2 ) (Figure 9C). Similarly, the density of CD11b-positive cells in the incision on day 7 was significantly lower in the W10-treated wounds (975.0 ± 90.1 # / mm 2 ) and sutured wound (1125.0±114.6# / mm 2) was not significantly different from the control group (Figures 9D-9E). On the other hand, on day 28, the number of CD11b-positive cells in the W10-treated wounds (291.7 ± 38.2 # / mm 2 ) was observed in the sutured wound (383.3±38.1# / mm 2 The inflammatory response of rats to W10 was significantly lower than that of the wounds treated with sutures (Figure 9E), indicating minimal inflammatory response in rats to W10. Furthermore, the W10-treated wounds (day 7: 41.7%, day 28: 70.3%) showed higher collagen expression levels, especially on day 28, than the wounds treated with sutures (day 7: 34.7%, day 28: 60.3%) (Figure 9F-G). These results suggest that iC-EPE crosslinked with MgO exhibits excellent in vivo biocompatibility. Application of iC-EPE / MgO improved and accelerated wound healing compared with sutures.

[0211] The claims are not intended to, and should not be construed to, include means-plus-function or step-plus-function limitations unless such limitations are expressly recited in a given claim using the phrase(s) "means for" or "step for," respectively.

[0212] In view of the processes and compositions described, certain more particularly described aspects of the invention are set forth below, although these specific stated aspects should not be construed as having any limiting effect on any different claims that incorporate different or more general teachings set forth herein, nor should the "specific" aspects be construed as being limited in any way other than by the inherent meaning of the words and phrases literally used herein. The present invention includes the following aspects. [Section 1] 1. A crosslinked composition comprising: a) a polymerization product of one or more monomers of formula (I) and one or more units of a block copolymer comprising one or more monomers of formula (II) and / or formula (II'), one or more monomers of formula (III), and / or optionally one or more compounds of formula (IV), [C1] TIFF0007811173000034.tif110164 R 1、R 2 , and R 3 are each independently hydrogen, C 1 -C 22 alkyl groups; R 1 、R 2 , and R 3 Each of the 1 -C 22 Alkyl, C 1 -C 22 Alkoxy, C 2 -C 22 Alkenyl, C 2 -C 22 Alkynyl, C 6 -C 14 Aryl, C 1 -C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R 4 is hydrogen, hydroxyl group, amine, alkoxyl group, C 1 -C 22 alkyl groups; R 5 is a hydrogen, amine, hydroxyl group, or C 1 -C 22 alkyl groups; R 6 is hydrogen, C 1 -C 22 Alkyl group, C 2 -C 22 alkenyl groups; R 7 is hydrogen, amine, hydroxyl group, alkoxyl group, C 1 -C 22 alkyl groups; R 4 、R 5 、R 6 , and R 7 Each of the 1 -C 22 Alkyl, C 1 -C 22 Alkoxy, C 2 -C 22 Alkenyl, C 2 -C 22 Alkynyl, C 6 -C 14 Aryl, C1 -C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R 8 、R 9 、R 10 , and R 11 are each independently hydrogen, hydroxyl, or C 1 -C 22 Alkyl group, C 1 -C 22 R is selected from an alkoxy group, an amino group, a halide, an -SH- group, or a carboxyl group; 8 、R 9 、R 10 , and R 11 Both of these are C 1 -C 22 Alkyl, C 1 -C 22 Alkoxy, C 2 -C 22 Alkenyl, C 2 -C 22 Alkynyl, C 6 -C 14 Aryl, C 1 -C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl; R 8 、R 9 、R 10 , and R 11 at least one of the nucleophilic groups is selected from -N(H)-, -O-, -COO-, -Cl, -F, and -S(O)-, -S-; and at least one of the nucleophilic groups is a terminal group; n and m each independently represent an integer of 1 to 20; R 12 is an amino acid side chain; R 14 is -OH or -NH 2 the polymerization product, the polymerization product does not contain any metal cations; b) Formula A b’ O a’ wherein A is a monovalent, divalent, or trivalent metal cation, a' and b' depend on the valence of A, and A is not a transition metal cation, wherein the first crosslinking initiator crosslinks the reaction product to form the crosslinked composition; The crosslinked composition is a polymer network having at least one crosslink comprising two catechol moieties directly and covalently bonded to each other; The crosslinked composition is a hydrogel or an organogel and is an adhesive composition. [Section 2] R 1 、R 2 , and R 3 are each independently hydrogen, -CH 3 group, or -CH 2 CH 3 selected from the group R 4 represents hydrogen, a hydroxyl group, -NH 2 , -OCH 3 , -OCH 2 CH 3 , -CH 3 , -CH 2 CH 3 group, C 3 -C 22 Alkyl or alkenyl group, -CH 2 CH 2 OH, or -CH 2 CH 2 NH 2 Selected from; R 5 represents hydrogen, a hydroxyl group, -NH 2 , -CH 3 , or -CH 2 CH 3 group, C 3 -C 22 Alkyl or alkenyl group, -CH 2 CH 2 OH, or -CH 2 CH 2 NH 2 and; R 6 is hydrogen, -CH 3 group, or -CH 2 CH 3 group, -CH 2 CH 2 OH, or -CH 2 CH 2 NH 2 Selected from; R 7 is hydrogen or -CH 3 selected from the group R 8 、R 9 、R 10 , and R 11 are each independently hydrogen, -CH 2 (CH 2 ) x NH 2 , -CH 2 (CHR 13 )NH 2 , or -CH 2 (CH 2 ) x COOH group; R 8 、R 9 、R 10 , and R 11 At least one of the is not hydrogen; R 13 is -COOH or -(CH 2 ) y COOH group; n and m each independently represent an integer of 1 to 20; x is an integer from 0 to 20; Item 2. The crosslinked composition according to item 1, wherein y is an integer of 1 to 20. [Section 3] The nucleophilic group of the one or more monomers of formula (III) is R of the one or more monomers of formula (I). 1 COO-, R 2 COO-, or R 3 Item 3. The crosslinking composition according to item 1 or 2, which is configured to react with at least one of the COO- to form a covalent bond. [Section 4] The block copolymer comprises repeat units of two or more monomers of formula (II): [Case 2] TIFF0007811173000035.tif38164 R 4 represents hydrogen, a hydroxyl group, -NH 2 , -CH 2 CH 2 OH, or -CH 2 CH 2 NH 2 Selected from; R 5 represents hydrogen, a hydroxyl group, -NH 2 , -CH 2 CH 2 OH, or -CH 2 CH 2 NH 2 and; R 6 is hydrogen, -CH 3 group, or -CH 2 CH 3 group, -CH 2 CH 2 OH, or -CH 2 CH 2 NH 2 Item 4. The crosslinked composition according to any one of items 1 to 3, selected from the group consisting of: [Section 5] The block copolymer has formula (V) or formula (V'): [C3] TIFF0007811173000036.tif69164 a and b are each independently selected from n=1 to 20; R 6 Item 5. The crosslinked composition according to item 4, wherein is not hydrogen. [Section 6] Item 6. The crosslinked composition according to any one of items 1 to 5, wherein the monomer of formula (III) comprises dopamine L-DOPA. [Section 7] The polymerization product is [C4] TIFF0007811173000037.tif58164 Including, R'' is -N(H)R 15 , or -O(CO)(R 15 ), or -O(R 15 ) and; R 15 are each independently 1 -C 22 alkyl groups, C 1 -C 22 Alkyl, C 1 -C 22 Alkoxy, C 2 -C 22 Alkenyl, C 2 -C 22 Alkynyl, C 6 -C 14 Aryl, C 1 -C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl groups; R 6 is not hydrogen; [5] TIFF0007811173000038.tif18164 defines a bond to a hydrogen, or optionally, if present, to a given polymer chain; Item 7. The crosslinked composition according to any one of items 1 to 6, wherein a and b are each independently selected from n=1 to 20, and z=1 to 100. [Section 8] Item 8. The crosslinked composition according to any one of items 1 to 7, wherein the first crosslinking initiator simultaneously acts as a first filler. [Section 9] Item 9. The crosslinking composition according to any one of items 1 to 8, further comprising a second crosslinking initiator different from the first crosslinking initiator. [Section 10] Item 10. The cross-linking composition according to item 9, wherein the second cross-linking initiator comprises sodium periodate, silver nitrate, or ferric chloride, or any combination thereof. [Section 11] Item 11. The crosslinked composition according to any one of items 8 to 10, further comprising an additional filler different from the first filler. [Section 12] Item 12. The crosslinked composition according to any one of items 1 to 11, wherein the metal oxide is magnesium oxide, calcium oxide, zinc oxide, barium oxide, cesium oxide, or any combination thereof. [Section 13] Item 13. The crosslinked composition according to any one of items 1 to 12, wherein the compound of formula (IV) is present in the polymerization product. [Section 14] Item 14. The crosslinking composition according to any one of items 1 to 13, wherein the first crosslinking initiator is present in an amount of more than 0 wt% to less than 100 wt%, based on the weight percent of the dry polymerization product. [Section 15] Item 15. The crosslinking composition according to any one of items 10 to 14, wherein the second crosslinking initiator is present in an amount of more than 0 wt% to 8 wt%, based on the weight percent of the dry polymerization product. [Section 16] Item 16. The crosslinking composition according to any one of items 1 to 15, further comprising a solvent. [Section 17] Item 17. The crosslinking composition according to item 16, wherein the solvent is water, ethanol, or a combination thereof. [Section 18] Item 18. The crosslinked composition according to any one of items 1 to 17, wherein the crosslinked composition comprises a sol content of less than about 25%. [Section 19] Item 19. The crosslinked composition according to any one of items 1 to 18, wherein the crosslinked composition exhibits a swelling ratio of less than about 200%. [Section 20] 20. The crosslinked composition according to any one of items 1 to 19, wherein the crosslinked composition exhibits a tensile strength in a dry state of about 1 to about 10 MPa as measured according to ASTM D412A. [Section 21] 21. The crosslinked composition according to any one of items 1 to 20, wherein the crosslinked composition exhibits an elongation at break of about 15% to about 150% in a dry state as measured according to ASTM D412A. [Section 22] 22. The composition according to any one of items 1 to 21, wherein the crosslinked composition exhibits a modulus of elasticity in a dry state of about 1 to about 10 MPa as measured according to ASTM D412A. [Section 23] 23. The composition of any one of items 1 to 22, wherein the crosslinked composition exhibits a tensile shear strength of greater than 30 kPa as measured according to a modified ASTM D1002-05 method. [Section 24] Item 26. The composition according to any one of items 1 to 25, wherein the crosslinked composition exhibits high cytocompatibility as measured with human mesenchymal stem cells when compared to a substantially identical reference composition that does not contain the metal oxide. [Section 25] 25. The composition of any one of items 10 to 24, wherein the crosslinked composition exhibits increased inhibition of Staphylococcus aureus and Escherichia coli when compared to a substantially identical reference composition in the absence of the metal oxide. [Section 26] Item 26. The composition according to any one of items 1 to 25, further comprising at least one pharmaceutically active ingredient. [Section 27] Item 27. The composition according to any one of items 1 to 26, wherein the composition is a wound closure composition. [Section 28] 1. A crosslinked composition comprising: a) forming a polymerization product by reacting one or more monomeric polycarboxylic acids of formula (I) with a block copolymer comprising one or more monomers of formula (II) and / or formula (II'), one or more monomers of formula (III), and / or optionally one or more compounds of formula (IV), [6] TIFF0007811173000039.tif110164 R 1 、R 2 , and R 3 are each independently hydrogen, C 1 -C 22 alkyl groups; R 1 、R 2 , and R 3 Each of the 1 -C 22 Alkyl, C 1 -C 22 Alkoxy, C 2 -C 22 Alkenyl, C 2 -C 22 Alkynyl, C 6 -C 14 Aryl, C 1 -C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R 4 is hydrogen, hydroxyl group, amine, alkoxyl group, C 1 -C 22 alkyl groups; R 5 is a hydrogen, amine, hydroxyl group, or C 1 -C 22 alkyl groups; R 6 is hydrogen, C 1 -C 22 Alkyl group, C 2 -C 22 alkenyl groups; R 7 is hydrogen, amine, hydroxyl group, alkoxyl group, C 1 -C 22 alkyl groups; R 4 、R 5 、R 6 , and R 7 Each of the 1 -C 22 Alkyl, C 1 -C 22 Alkoxy, C 2 -C 22 Alkenyl, C 2 -C22 Alkynyl, C 6 -C 14 Aryl, C 1 -C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R 8 、R 9 、R 10 , and R 11 are each independently hydrogen, hydroxyl, or C 1 -C 22 Alkyl group, C 1 -C 22 is selected from an alkoxy group, an amino group, a halide, an -SH- group, or a carboxyl group; R 8 、R 9 、R 10 , and R 11 Both of these are C 1 -C 22 Alkyl, C 1 -C 22 Alkoxy, C 2 -C 22 Alkenyl, C 2 -C 22 Alkynyl, C 6 -C 14 Aryl, C 1 -C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl; R 8 、R 9 、R 10 , and R 11 at least one of the nucleophilic groups comprises at least one nucleophilic group selected from -N(H)-, -O-, -COO-, -Cl, -F, and -S(O)-, -S-; and at least one of the nucleophilic groups is a terminal group; n and m each independently represent an integer of 1 to 20; R 12 is an amino acid side chain; R 14 is -OH or -NH 2 the polymerization product, forming a polymerization product, the polymerization product being free of metal cations; b) Formula A b’ O a’ wherein A is a monovalent, divalent, or trivalent metal cation, a' and b' are defined by the valence of A, and A is not a transition metal cation; and The crosslinked composition is a polymer network having at least one crosslink comprising two catechol moieties directly and covalently bonded to each other; The crosslinked composition is a hydrogel or an organogel and is an adhesive composition. [Section 29] R 1 、R 2 , and R 3 are each independently hydrogen, -CH 3 group, or -CH 2 CH 3 selected from the group R 4 represents hydrogen, a hydroxyl group, -NH 2 , -OCH 3 , -OCH 2 CH 3 , -CH 3 , -CH 2 CH 3 group, C 3 -C 22 Alkyl or alkenyl group, -CH 2 CH 2 OH, or -CH 2 CH 2 NH 2 Selected from; R 5 represents hydrogen, a hydroxyl group, -NH 2 , -CH 3 , or -CH 2 CH 3 group, C 3 -C 22 Alkyl or alkenyl group, -CH 2 CH 2 OH, or -CH 2 CH 2 NH 2 and; R 6 is hydrogen, -CH 3 group, or -CH 2 CH 3 group, -CH 2 CH 2 OH, or -CH 2 CH 2 NH 2 Selected from; R 7 is hydrogen or -CH 3 selected from the group R 8 、R 9 、R 10 , and R 11 are each independently hydrogen, -CH 2 (CH 2 ) x NH 2 ,-CH 2 (CHR 13 )NH 2 , or -CH 2 (CH 2 ) x COOH group; R 8 、R 9 、R 10 , and R 11 At least one of the is not hydrogen; R 13 is -COOH or -(CH 2 ) y COOH group; n and m each independently represent an integer of 1 to 20; x is an integer from 0 to 20; Item 29. The crosslinked composition according to item 28, wherein y is an integer of 1 to 20. [Section 30] The nucleophilic group of the one or more monomers of formula (III) is R of the one or more monomers of formula (I). 1 COO-, R 2 COO-, or R 3 30. The crosslinked composition according to item 28 or 29, wherein the crosslinked composition reacts with at least one of the COO- groups to form a covalent bond. [Section 31] The block copolymer comprises repeat units of two or more monomers of formula (II): [7] TIFF0007811173000040.tif38164 R 4 represents hydrogen, a hydroxyl group, -NH 2 , -CH 2 CH 2 OH, or -CH 2 CH 2 NH 2 Selected from; R 5 represents hydrogen, a hydroxyl group, -NH 2 , -CH 2 CH 2 OH, or -CH 2 CH 2 NH 2 and; R 6 is hydrogen, -CH 3 group, or -CH 2 CH 3 group, -CH 2 CH 2 OH, or -CH 2 CH 2 NH 2 Item 31. The crosslinked composition according to any one of items 28 to 30, selected from: [Section 32] The block copolymer has formula (V) or formula (V'): [8] TIFF0007811173000041.tif69164 a and b are each independently selected from n=1 to 20; R 6 Item 32. The crosslinked composition according to item 31, wherein is not hydrogen. [Section 33] Item 33. The crosslinked composition according to any one of Items 28 to 32, wherein the monomer of formula (III) comprises dopamine L-DOPA. [Section 34] The polymerization product is [9] TIFF0007811173000042.tif58164 Including, R'' is -N(H)R 15 , or -O(CO)(R 15 ), or -O(R 15 ) and; R 15 are each independently 1 -C 22 alkyl groups, C 1 -C 22 Alkyl, C 1 -C 22 Alkoxy, C 2 -C 22 Alkenyl, C 2 -C 22 Alkynyl, C 6 -C 14 Aryl, C 1 -C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl groups; R 6 is not hydrogen; [C10] TIFF0007811173000043.tif12164 defines a bond to a hydrogen, or optionally, if present, to a given polymer chain; Item 34. The crosslinked composition according to any one of Items 28 to 33, wherein a and b are each independently selected from n=1 to 20, and z=1 to 100. [Section 35] 1. A method of making a composition, comprising: a) one or more monomeric polycarboxylic acids of formula (I), [C11] TIFF0007811173000044.tif38164 one or more units of a block copolymer comprising one or more monomers of formula (II) and (II′); [C12] TIFF0007811173000045.tif38164 and one or more monomeric compounds of formula (III) [C13] TIFF0007811173000046.tif53164 and Optionally, one or more compounds of formula (IV) [C14] TIFF0007811173000047.tif38164 reacting under conditions effective to form a prepolymer composition configured to be crosslinked, R 1 、R 2 , and R 3 are each independently hydrogen, C 1 -C 22 alkyl groups; R 1 、R 2 , and R 3 Each of the 1 -C 22 Alkyl, C 1 -C 22 Alkoxy, C 2 -C 22 Alkenyl, C 2 -C 22 Alkynyl, C 6 -C 14 Aryl, C 1 -C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R 4 is hydrogen, hydroxyl group, amine, alkoxyl group, C 1 -C 22 alkyl groups; R 5 is a hydrogen, amine, hydroxyl group, or C 1 -C 22 alkyl groups; R 6 is hydrogen, C 1 -C 22 Alkyl group, C 2 -C 22 alkenyl groups; R 7 is hydrogen, amine, hydroxyl group, alkoxyl group, C 1 -C 22 alkyl groups; R 4 、R 5 、R 6 , and R 7 Each of the 1 -C 22 Alkyl, C 1 -C 22 Alkoxy, C 2 -C 22 Alkenyl, C 2 -C 22 Alkynyl, C 6 -C 14 Aryl, C 1 -C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R 8 、R 9 、R 10 , and R 11 are each independently hydrogen, hydroxyl, or C 1 -C 22 Alkyl group, C 1 -C 22 is selected from an alkoxy group, an amino group, a halide, an -SH- group, or a carboxyl group; R 8 、R 9 、R 10 , and R 11 Both of these are C 1 -C 22 Alkyl, C 1 -C 22 Alkoxy, C 2 -C 22 Alkenyl, C 2 -C 22 Alkynyl, C 6 -C 14 Aryl, C 1 -C13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl; R 8 、R 9 、R 10 , and R 11 at least one of the nucleophilic groups comprises at least one nucleophilic group selected from -N(H)-, -O-, -COO-, -Cl, -F, and -S(O)-, -S-; and at least one of the nucleophilic groups is a terminal group; n and m each independently represent an integer of 1 to 20; R 12 is an amino acid side chain; R 14 is -OH or -NH 2 and; the polymerization product is free of metal cations; b) adding a first crosslinking initiator to the prepolymer composition, wherein the first crosslinking initiator is represented by the formula A b B a wherein A is a monovalent, divalent, or trivalent metal cation, B is an anion, a and b are defined by the valences of A and B, and A is not a transition metal cation; c) crosslinking the prepolymer composition to form a crosslinked composition comprising a polymer network, wherein at least one crosslink in the crosslinked polymer comprises two catechol moieties directly and covalently bonded to each other; The crosslinked composition is a hydrogel or an organogel and is an adhesive composition. [Section 36] R 1 、R 2 , and R 3 are each independently hydrogen, -CH 3 group, or -CH 2 CH 3 selected from the group R 4 represents hydrogen, a hydroxyl group, -NH 2 , -OCH 3 , -OCH 2 CH 3 , -CH 3 , -CH 2 CH 3 group, C 3 -C 22 Alkyl or alkenyl group, -CH 2 CH 2 OH, or -CH 2 CH 2 NH 2 Selected from; R 5 represents hydrogen, a hydroxyl group, -NH 2 , -CH 3 , or -CH 2 CH 3 group, C 3 -C 22 Alkyl or alkenyl group, -CH 2 CH 2 OH, or -CH 2 CH 2 NH 2 and; R 6 is hydrogen, -CH 3 group, or -CH 2 CH 3 group, -CH 2 CH 2 OH, or -CH 2 CH 2 NH 2 Selected from; R 7 is hydrogen or -CH 3 selected from the group R 8 、R 9 、R 10 , and R 11 are each independently hydrogen, -CH 2 (CH 2 ) x NH 2 , -CH 2 (CHR 13 )NH 2 , or -CH 2 (CH 2 ) x COOH group; R 8 、R 9 、R 10 , and R 11 At least one of the is not hydrogen; R 13 is -COOH or -(CH 2 ) y COOH group; n and m each independently represent an integer of 1 to 20; x is an integer from 0 to 20; Item 36. The method according to Item 35, wherein y is an integer of 1 to 20. [Section 37] Item 37. The method of item 35 or 36, wherein the block copolymer is formed prior to reacting in step a). [Section 38] The block copolymer is formed prior to reacting in step a) and comprises repeat units of two or more monomers of formula (II): [C15] TIFF0007811173000048.tif38164 R 4 represents hydrogen, a hydroxyl group, -NH 2 , -CH 2 CH 2 OH, or -CH 2 CH 2 NH 2 Selected from; R 5 represents hydrogen, a hydroxyl group, -NH 2 , -CH 2 CH 2 OH, or -CH 2 CH 2 NH 2 and; R 6 is hydrogen, -CH 3 group, or -CH 2 CH 3 group, -CH 2 CH 2 OH, or -CH 2 CH 2 NH 2 Item 38. The method according to any one of items 35 to 37, wherein the method is selected from the group consisting of: [Section 39] The block copolymer has formula (V) or formula (V'): [C16] TIFF0007811173000049.tif75164 a and b are each independently selected from n=1 to 20; R 6 39. The method of claim 38, wherein is not hydrogen. [Section 40] Item 40. The method according to any one of Items 35 to 39, wherein the monomer of formula (III) comprises dopamine L-DOPA. [Section 41] The polymerization product is [C17] TIFF0007811173000050.tif58164 Including, R'' is -N(H)R 15 , or -O(CO)(R 15 ), or -O(R 15 ) and; R 15 are each independently 1 -C 22 alkyl groups, C 1 -C 22 Alkyl, C 1 -C 22 Alkoxy, C 2 -C 22 Alkenyl, C 2 -C22 Alkynyl, C 6 -C 14 Aryl, C 1 -C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl groups; R 6 is not hydrogen; [C18] TIFF0007811173000051.tif18164 defines a bond to a hydrogen, or optionally, if present, to a given polymer chain; 41. The method according to any one of items 35 to 40, wherein a and b are each independently selected from n=1 to 20, and z=1 to 100. [Section 42] Item 42. The method according to any one of Items 35 to 41, wherein the first crosslinking initiator simultaneously acts as a first filler. [Section 43] Item 43. The method according to any one of Items 35 to 42, further comprising adding a second crosslinking initiator different from the first crosslinking initiator. [Section 44] Item 44. The method of item 43, wherein the second cross-linking initiator comprises sodium periodate, silver nitrate, or ferric chloride, or any combination thereof. [Section 45] Item 45. The method according to any one of items 42 to 44, further comprising an additional filler different from the first filler. [Section 46] Item 46. The method according to any one of Items 35 to 45, wherein the metal oxide is magnesium oxide, calcium oxide, zinc oxide, barium oxide, cesium oxide, or any combination thereof. [Section 47] 47. The method according to any one of items 35 to 46, wherein the compound of formula (IV) is present. [Section 48] Item 48. The method according to any one of items 35 to 47, wherein the first cross-linking initiator is added in an amount of more than 0 wt% and less than 100 wt%, based on the weight percent of the dry polymerization product. [Section 49] Item 49. The method according to any one of Items 35 to 48, wherein the first crosslinking initiator is a solvent dispersion of the first crosslinking initiator. [Section 50] 50. The method of claim 49, wherein the solvent dispersion comprises water, ethanol, or a combination thereof. [Section 51] Item 51. The method of any one of items 43 to 50, wherein the second cross-linking initiator is added in an amount of from greater than 0 wt% to about 8 wt%, based on the weight percent of the dry polymerization product. [Section 52] Item 43 to 51, wherein the second crosslinking initiator is added together with the first crosslinking initiator, or added before the first crosslinking initiator is added, or added after the first crosslinking initiator is added. [Section 53] Item 53. The method according to any one of Items 49 to 52, wherein the second crosslinking initiator is added to a solvent dispersion of the first crosslinking initiator. [Section 54] Item 54. The method according to any one of Items 43 to 53, wherein the second crosslinking initiator is added as a separate solvent dispersion of the second crosslinking initiator. [Section 55] 56. The method of claim 55, wherein the separate solvent dispersion comprises water, ethanol, or a combination thereof. [Section 56] Item 56. The method according to any one of Items 43 to 55, wherein the first cross-linking initiator and the second cross-linking initiator have a synergistic effect. [Section 57] Item 57. The method according to any one of Items 35 to 56, wherein the gelation time required to form the hydrogel or organogel is from about 500 seconds to less than about 10 seconds. [Section 58] Item 58. The method of any one of items 43 to 57, wherein the crosslinking rate is substantially faster when compared to a substantially identical reference method in the absence of said metal oxide. [Section 59] Item 43 to 58, the crosslinking step includes crosslinking with a metal oxide via coupling of a catechol group of the polymer composition, forming a metal complex with the catechol group of the polymer composition, binding of the metal oxide to a carboxyl group or a catechol group of the polymer composition via a hydrogen bond or a surface bond, or any combination thereof. [Section 60] 60. The method of any one of paragraphs 35 to 59, wherein the formed crosslinked composition comprises less than about 25% sol content. [Section 61] Item 61. The method according to any one of Items 35 to 60, wherein the formed crosslinked composition exhibits a swelling ratio of less than about 200%. [Section 62] Item 62. The method of any one of Items 35 to 61, wherein the formed crosslinked composition exhibits a tensile strength in the dry state of about 1 to about 10 MPa as measured according to ASTM D412A. [Section 63] Item 63. The method according to any one of Items 35 to 62, wherein the formed crosslinked composition exhibits an elongation at break of about 18% to about 150% in a dry state as measured according to ASTM D412A. [Section 64] Item 64. The method according to any one of Items 35 to 63, wherein the formed crosslinked composition exhibits a modulus of elasticity in a dry state of about 1 to about 10 MPa as measured according to ASTM D412A. [Section 65] 65. The method of any one of paragraphs 35 to 64, wherein the formed crosslinked composition exhibits a tensile shear strength of greater than 30 kPa as measured according to a modified ASTM D1002-05 method. [Section 66] Item 66. The method of any one of Items 35 to 65, wherein the formed crosslinked composition exhibits increased cytocompatibility as measured with human mesenchymal stem cells when compared to a substantially identical reference composition that does not contain the metal oxide. [Section 67] 67. The method of any one of paragraphs 43 to 66, wherein the formed crosslinked composition exhibits increased inhibition of Staphylococcus aureus and Escherichia coli when compared to a substantially identical reference composition in the absence of the metal oxide. [Section 68] 68. The method of any one of paragraphs 35 to 67, further comprising adding at least one pharmaceutically active ingredient to the formed crosslinked composition. [Section 69] Item 69. The method of any one of items 35 to 68, wherein the formed crosslinked composition is a wound closure composition. [Section 70] A method for adhering biological tissue, comprising: a) placing the crosslinking composition according to any one of items 1 to 34 between a first portion of biological tissue and a second portion of biological tissue; b) contacting the first portion of the biological tissue with the second portion of the biological tissue. [Section 71] Item 27. A method for treating a disease, comprising placing the composition according to item 26 in a living body, wherein the at least one pharmaceutically active ingredient is active against the disease and is configured to be released in the living body at a predetermined time. [Section 72] Item 35. A method for promoting the growth of biological tissue, comprising providing a scaffold comprising the composition according to any one of items 1 to 34, and placing the scaffold in a tissue growth medium. [Section 73] Item 35. A kit for adhering biological tissues, comprising the crosslinking composition according to any one of Items 1 to 34. [Section 74] 1. A method for delivering an effective amount of at least one pharmaceutically active ingredient, comprising: a) i) a polymerization product of one or more monomers of formula (I) and one or more units of a block copolymer comprising one or more monomers of formula (II) and / or formula (II'), one or more monomers of formula (III), and / or optionally one or more compounds of formula (IV), [C19] TIFF0007811173000052.tif110164 R 1 、R 2 , and R 3 are each independently hydrogen, C 1 -C 22 alkyl groups; R 1 、R 2 , and R 3 Each of the 1 -C 22 Alkyl, C 1 -C 22 Alkoxy, C 2 -C 22 Alkenyl, C 2 -C 22 Alkynyl, C 6 -C 14 Aryl, C 1 -C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R 4 is hydrogen, hydroxyl group, amine, alkoxyl group, C 1 -C 22 alkyl groups; R 5 is a hydrogen, amine, hydroxyl group, or C 1 -C 22 alkyl groups; R 6 is hydrogen, C 1 -C 22 Alkyl group, C 2 -C 22 alkenyl groups; R 7 is hydrogen, amine, hydroxyl group, alkoxyl group, C 1 -C 22 alkyl groups; R 4 、R 5 、R 6 , and R 7 Each of the 1-C 22 Alkyl, C 1 -C 22 Alkoxy, C 2 -C 22 Alkenyl, C 2 -C 22 Alkynyl, C 6 -C 14 Aryl, C 1 -C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R 8 、R 9 、R 10 , and R 11 are each independently hydrogen, hydroxyl, or C 1 -C 22 Alkyl group, C 1 -C 22 is selected from an alkoxy group, an amino group, a halide, an -SH- group, or a carboxyl group; R 8 、R 9 、R 10 , and R 11 Both of these are C 1 -C 22 Alkyl, C 1 -C 22 Alkoxy, C 2 -C 22 Alkenyl, C 2 -C 22 Alkynyl, C 6 -C 14 Aryl, C 1 -C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl; R 8 、R 9 、R 10 , and R 11 at least one of the nucleophilic groups comprises at least one nucleophilic group selected from -N(H)-, -O-, -COO-, -Cl, -F, and -S(O)-, -S-; and at least one of the nucleophilic groups is a terminal group; n and m each independently represent an integer of 1 to 20; R 12 is an amino acid side chain; R 14 is -OH or -NH 2 the polymerization product, the polymerization product does not contain any metal cations; ii) Formula A b’ O a’ wherein A is a monovalent, divalent, or trivalent metal cation, a' and b' depend on the valence of A, and A is not a transition metal cation, wherein the first crosslinking initiator crosslinks the reaction product to form the crosslinked composition; The crosslinked composition is a polymer network having at least one crosslink comprising two catechol moieties directly and covalently bonded to each other; The crosslinked composition is a hydrogel or organogel and is an adhesive composition; incorporating the at least one pharmaceutically active ingredient into the composition; b) releasing said at least one agent in vivo at a predetermined time. [Section 75] R 1 、R 2 , and R 3 are each independently hydrogen, -CH 3 group, or -CH 2 CH 3 selected from the group R 4 represents hydrogen, a hydroxyl group, -NH 2 , -OCH 3 , -OCH 2 CH 3 , -CH 3 , -CH 2 CH 3 group, C 3 -C 22 Alkyl or alkenyl group, -CH 2 CH 2 OH, or -CH 2 CH 2 NH 2 Selected from; R 5 represents hydrogen, a hydroxyl group, -NH 2 , -CH 3 , or -CH 2 CH 3 group, C 3 -C 22 Alkyl or alkenyl group, -CH 2 CH 2 OH, or -CH 2 CH 2 NH 2 and; R 6 is hydrogen, -CH 3 group, or -CH 2 CH 3 group, -CH 2 CH 2 OH, or -CH 2 CH 2 NH 2 Selected from; R 7 is hydrogen or -CH 3 selected from the group R 8 、R 9、R 10 , and R 11 are each independently hydrogen, -CH 2 (CH 2 ) x NH 2 , -CH 2 (CHR 13 )NH 2 , or -CH 2 (CH 2 ) x COOH group; R 8 、R 9 、R 10 , and R 11 At least one of the is not hydrogen; R 13 is -COOH or -(CH 2 ) y COOH group; n and m each independently represent an integer of 1 to 20; x is an integer from 0 to 20; Item 75. The method according to Item 74, wherein y is an integer of 1 to 20. [Section 76] The block copolymer comprises repeat units of two or more monomers of formula (II):

[20] TIFF0007811173000053.tif38164 R 4 represents hydrogen, a hydroxyl group, -NH 2 , -CH 2 CH 2 OH, or -CH 2 CH 2 NH 2 Selected from; R 5 represents hydrogen, a hydroxyl group, -NH 2 , -CH 2 CH 2 OH, or -CH 2 CH 2 NH 2 and; R 6 is hydrogen, -CH 3 group, or -CH 2 CH 3 group, -CH 2 CH 2 OH, or -CH 2 CH 2 NH 2 Item 74 to 75, the method according to any one of items 74 to 75, selected from: [Section 77] The block copolymer has formula (V) or formula (V'):

[21] TIFF0007811173000054.tif69164 a and b are each independently selected from n=1 to 20; R 6 77. The method of claim 76, wherein is not hydrogen. [Section 78] Item 78. The method according to any one of items 74 to 77, wherein the monomer of formula (III) comprises dopamine L-DOPA. [Section 79] The polymerization product is [C22] TIFF0007811173000055.tif58164 Including, R'' is -N(H)R 15 , or -O(CO)(R 15 ), or -O(R 15 ) and; R 15 are each independently 1 -C 22 alkyl groups, C 1 -C 22 Alkyl, C 1 -C 22 Alkoxy, C 2 -C 22 Alkenyl, C 2 -C 22 Alkynyl, C 6 -C 14 Aryl, C 1 -C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl groups; R 6 is not hydrogen;

[23] TIFF0007811173000056.tif12164 defines a bond to a hydrogen, or optionally, if present, to a given polymer chain; 79. The method according to any one of items 74 to 78, wherein a and b are each independently selected from n=1 to 20, and z=1 to 100. Aspects

[0213] Aspect 1: A polymer composition that is the polymerization product of one or more monomers of formula (I), one or more monomers of formula (II) and / or formula (II'), one or more monomers of formula (III), and / or optionally one or more compounds of formula (IV), [ka] R1, R2, and R3 are each independently hydrogen, C1-C 22 alkyl groups; each of R, R, and R is selected from C-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 R4 may be optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R4 may be hydrogen, hydroxyl, amine, alkoxyl, C1-C 22 Alkyl groups, C2-C 22 alkenyl groups; R5 is selected from hydrogen, amine, hydroxyl groups, alkoxyl groups, or C1-C 22 Alkyl groups, C2-C 22 alkenyl groups; R6 is selected from hydrogen, C1-C 22 R7 is selected from the group consisting of hydrogen, amine, hydroxyl, alkoxyl, C1-C 22 Alkyl groups, or C2-C 22 alkenyl groups; each of R, R, R, and R is selected from C-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13R, R, R may be optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; 10 , and R 11 are each independently hydrogen, C1-C 22 R8, R9, R are selected from alkyl groups, amines, or carboxylic acids; 10 , and R 11 Each of the C1-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl; n and m are each independently an integer from 1 to 2,000; R 12 is the amino acid side chain; R 14 is —OH or —NH2; said polymer composition is crosslinked to form a polymer network; at least one crosslink of the crosslinkable polymer comprises two catechol moieties directly and covalently bonded to each other; said polymer composition is free of metal cations; said polymer composition and a) a compound of formula A b B a wherein A is a monovalent, divalent, or trivalent metal cation, B is an anion, and a and b are defined by the valences of A and B; said compound behaves as a first crosslinking initiator; and a composition comprising said compound, said composition being an adhesive composition.

[0214] Aspect 2: R1, R2, and R3 are each independently selected from hydrogen, a -CH3 group, or a -CH2CH3 group; R4 is hydrogen, a hydroxyl group, -NH2, -OCH3, -OCH2CH3, -CH3, -CH2CH3 group, C3-C22 R5 is selected from a hydrogen, a hydroxyl group, -NH2, -OCH3, -OCH2CH3, -CH3, or -CH2CH3 group, a C3-C22 alkyl or alkenyl group, -CH2CH2OH, or -CH2CH2NH2; R6 is selected from a hydrogen, a -CH3 group or a -CH2CH3 group, -CH2CH2OH, or -CH2CH2NH2; R7 is selected from a hydrogen or a -CH3 group; R8, R9, R 10 , and R 11 are each independently hydrogen, -CH2(CH2) x NH2, -CH2(CHR 13 )NH2, or -CH2(CH2) x COOH group; R 13 is -COOH or -(CH2) y 2. The composition of embodiment 1, wherein n is a COOH group; n and m are each independently an integer from 1 to 2,000; x is an integer from 0 to 20; and y is an integer from 1 to 20.

[0215] Embodiment 3: The composition of embodiment 1 or 2, wherein said monomer of formula (III) comprises dopamine, L-DOPA.

[0216] Embodiment 4: The composition of embodiment 1 or 2, wherein the first cross-linking initiator behaves as a filler.

[0217] Aspect 5: The composition of any one of Aspects 1-3, wherein the first cross-linking initiator comprises a metal oxide.

[0218] Aspect 6: The composition of aspect 5, wherein the metal oxide is magnesium oxide, calcium oxide, zinc oxide, copper oxide, barium oxide, iron oxide, or any combination thereof.

[0219] Aspect 7: The composition of any one of Aspects 1-6, wherein the polymer composition comprises the one or more monomers of Formula (II) and Formula (II').

[0220] Aspect 8: The composition of Aspect 6, wherein the polymerization product comprises a block polymer in which the one or more monomers of Formula (II) and Formula (II') are polymerized with the one or more monomers of Formula (I) and Formula (III).

[0221] Aspect 9: The composition of any one of Aspects 1-8, wherein the compound of Formula (IV) is present in the polymerization product.

[0222] Embodiment 10: The composition of any one of embodiments 1 to 9, wherein the composition is a hydrogel.

[0223] Aspect 11: The composition of any one of Aspects 1-10, wherein the first cross-linking initiator is present in an amount greater than 0 wt% and less than 100 wt%, based on the weight percent of the dry polymerization product.

[0224] Aspect 12: The composition of any one of Aspects 1 to 11, wherein the composition further comprises a second cross-linking initiator comprising sodium periodate.

[0225] Aspect 13: The composition of any one of Aspects 1 to 12, wherein the composition further comprises a solvent.

[0226] Embodiment 14: The composition of embodiment 13, wherein the solvent is water, ethanol, or a combination thereof.

[0227] Embodiment 15: The composition of any one of embodiments 1 to 14, wherein the composition comprises less than about 25% sol content.

[0228] Embodiment 16: The composition of any one of embodiments 1 to 15, wherein the composition exhibits a swelling ratio of less than about 200%.

[0229] Aspect 17: The composition of any one of Aspects 1 to 16, wherein the composition exhibits a tensile strength in the dry state of about 1 to about 10 MPa as measured according to ASTM D412A.

[0230] Aspect 18: The composition of any one of aspects 1 to 17, wherein the composition exhibits an elongation at break in the dry state of about 15% to about 150%, as measured according to ASTM D412A.

[0231] Aspect 19: The composition of any one of aspects 1 to 18, wherein the composition exhibits a modulus of elasticity in the dry state of about 1 to about 10 MPa as measured according to ASTM D412A.

[0232] Aspect 20: The composition of any one of Aspects 1-19, wherein the composition exhibits a tensile shear strength of greater than 30 kPa as measured according to a modified ASTM D1002-05 method.

[0233] Aspect 21: The composition of any one of aspects 5 to 20, wherein the composition exhibits increased cytocompatibility as measured against human mesenchymal stem cells when compared to a substantially identical reference composition that does not contain the metal oxide.

[0234] Aspect 22: The composition of any one of aspects 12 to 21, wherein the composition exhibits increased inhibition against Staphylococcus aureus and Escherichia coli when compared to a substantially identical reference composition in the absence of the metal oxide.

[0235] Embodiment 23: The composition of any one of embodiments 1 to 22, further comprising at least one pharmaceutically active ingredient.

[0236] Aspect 24: The composition of any one of Aspects 1 to 23, wherein the composition is a wound closure composition.

[0237] Embodiment 25: A method of making a composition, comprising: a) reacting one or more monomeric polycarboxylic acids of formula (I) with: [ka] a compound comprising one or more monomers of formula (II) and / or formula (II'); [ka] and one or more monomeric compounds of formula (III) [ka] and Optionally, one or more compounds of formula (IV) [ka] and mixing under conditions effective to form a polymer composition configured to be crosslinked, wherein R1, R2, and R3 are each independently hydrogen, C1-C 22 alkyl groups; each of R, R, and R is selected from C-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 R4 may be optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R4 may be hydrogen, hydroxyl group, amine, alkoxyl group, C1-C 22 Alkyl groups, C2-C 22 alkenyl groups; R5 is selected from hydrogen, amine, hydroxyl groups, alkoxyl groups, or C1-C 22 Alkyl groups, C2-C 22 alkenyl groups; R6 is selected from hydrogen, C1-C 22 Alkyl groups, C2-C 22 alkenyl groups; R7 is selected from hydrogen, amine, hydroxyl group, alkoxyl group, C1-C22 alkyl group, or C2-C 22 alkenyl groups; each of R, R, R, and R is selected from C-C 22 Alkyl, C1-C 22 Alkoxy, C2-C22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 R, R, R may be optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; 10 , and R 11 are each independently hydrogen, C1-C 22 R8, R9, R are selected from alkyl groups, amines, or carboxylic acids; 10 , and R 11 Each of the C1-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl; n and m are each independently an integer from 1 to 2,000; R 12 is the amino acid side chain; R 14 is -OH or -NH2; the formed polymer composition is free of metal cations; and b) mixing; and c) crosslinking the formed polymer composition to form a composition comprising a crosslinked polymer composition that forms a polymer network, wherein at least one crosslink in the crosslinked polymer comprises two catechol moieties directly and covalently bonded to each other, and the composition is an adhesive composition.

[0238] Embodiment 26: R1, R2, and R3 are each independently selected from hydrogen, a -CH3 group, or a -CH2CH3 group; R4 is hydrogen, a hydroxyl group, -NH2, -OCH3, -OCH2CH3, -CH3, -CH2CH3 group, C3-C 22 R5 is selected from an alkyl or alkenyl group, —CH2CH2OH, or —CH2CH2NH2; R5 is selected from hydrogen, a hydroxyl group, —NH2, —OCH3, —OCH2CH3, —CH3, or —CH2CH3 group, C3-C 22 R6 is selected from hydrogen, a -CH3 group or a -CH2CH3 group, -CH2CH2OH, or -CH2CH2NH2; R7 is selected from hydrogen or a -CH3 group; R8, R9, R 10 , and R 11 are each independently hydrogen, -CH2(CH2) x NH2, -CH2(CHR 13 )NH2, or -CH2(CH2) x COOH group; R 13 is -COOH or -(CH2) y A method according to aspect 25, wherein n is a COOH group; n and m are each independently an integer of 1 to 2,000; x is an integer of 0 to 20; and y is an integer of 1 to 20.

[0239] Embodiment 27 The method of embodiment 25 or 26, wherein said monomer of formula (III) comprises dopamine, L-DOPA.

[0240] Embodiment 28: The method of any one of embodiments 25 to 27, wherein the first cross-linking initiator behaves as a filler.

[0241] Embodiment 29: The method of any one of embodiments 25 to 28, wherein the first cross-linking initiator comprises a metal oxide.

[0242] Aspect 30: The method of aspect 29, wherein the metal oxide is magnesium oxide, calcium oxide, zinc oxide, copper oxide, barium oxide, iron oxide, or any combination thereof.

[0243] Aspect 31: The method of any one of Aspects 25 to 30, wherein the polymer composition comprises the one or more monomers of Formula (II) and Formula (II').

[0244] Aspect 32: The method of aspect 33, wherein the one or more monomers of Formula (II) and Formula (II') form a block polymer comprising repeating units of Formula (II) and Formula (II') before combining with the polycarboxylic acid.

[0245] Aspect 33: The method of any one of Aspects 25 to 32, wherein said compound of Formula (IV) is present.

[0246] Embodiment 34: The method of any one of embodiments 25 to 33, wherein the composition is a hydrogel.

[0247] Aspect 35: The method of any one of aspects 25 to 34, wherein the first cross-linking initiator is added in an amount greater than 0 wt% and less than 100 wt%, based on the weight percent of the dry polymerization product.

[0248] Aspect 36: The method of any one of Aspects 25 to 35, wherein the first cross-linking initiator is a solvent dispersion of the first cross-linking initiator.

[0249] Aspect 37: The method of aspect 36, wherein the solvent dispersion comprises water, ethanol, or a combination thereof.

[0250] Embodiment 38: The method of any one of embodiments 25 to 37, further comprising a second cross-linking initiator comprising sodium periodate.

[0251] Aspect 39: The method of aspect 38, wherein the second crosslinker is added to the solvent dispersion of the first crosslinker initiator.

[0252] Aspect 40: The method of aspect 39, wherein the second cross-linking initiator is added as a separate solvent dispersion of the second cross-linking initiator.

[0253] Aspect 41: The method of aspect 40, wherein the separate solvent dispersion comprises water, ethanol, or a combination thereof.

[0254] Aspect 42: The method of aspect 34, wherein the gelation time required to form the hydrogel is from about 500 seconds to less than about 10 seconds.

[0255] Aspect 43: The method of aspect 42, wherein the first cross-linking initiator and the second cross-linking initiator have a synergistic effect.

[0256] Aspect 44: The method of any one of Aspects 30 to 43, wherein the rate of crosslinking is substantially faster when compared to a substantially identical reference method in the absence of said metal oxide.

[0257] Aspect 45: The method of any one of aspects 30 to 44, wherein the crosslinking step includes crosslinking with a metal oxide via coupling of catechol groups of the polymer composition, forming a metal complex with the catechol groups of the polymer composition, bonding of the metal oxide with carboxyl groups or catechol groups of the polymer composition via hydrogen bonds or surface bonds, or any combination thereof.

[0258] Embodiment 46: The method of any one of embodiments 25 to 45, wherein the formed composition comprises less than about 25% sol content.

[0259] Embodiment 47: The method of any one of embodiments 25-46, wherein the formed composition exhibits a swelling ratio of less than about 200%.

[0260] Aspect 48: The method of any one of aspects 25 to 47, wherein the formed composition exhibits a tensile strength in the dry state of about 1 to about 10 MPa as measured according to ASTM D412A.

[0261] Aspect 49: The method of any one of aspects 25 to 28, wherein the formed composition exhibits an elongation at break in the dry state of about 15% to about 150% as measured according to ASTM D412A.

[0262] Aspect 50: The method of any one of aspects 25 to 49, wherein the formed composition exhibits a modulus of elasticity in the dry state of about 1 to about 10 MPa as measured according to ASTM D412A.

[0263] Aspect 51: The method of any one of Aspects 25-50, wherein the formed composition exhibits a tensile shear strength of greater than 30 kPa as measured according to a modified ASTM D1002-05 method.

[0264] Aspect 52: The method of any one of Aspects 30-51, wherein the formed composition exhibits increased cytocompatibility as measured against human mesenchymal stem cells when compared to a substantially identical reference composition that does not contain the metal oxide.

[0265] Aspect 53: The method of any one of Aspects 30 to 52, wherein the formed composition exhibits increased inhibition of Staphylococcus aureus and Escherichia coli when compared to a substantially identical reference composition in the absence of the metal oxide.

[0266] Embodiment 54: The method of any one of embodiments 25 to 53, further comprising adding at least one pharmaceutically active ingredient to said formed composition.

[0267] Aspect 55: The method of any one of Aspects 25 to 54, wherein the formed composition is a wound closure composition.

[0268] Aspect 56: A method for adhering biological tissues, comprising: a) placing a composition described in any one of aspects 1 to 24 between a first portion of the biological tissue and a second portion of the biological tissue; and b) contacting the first portion of the biological tissue with the second portion of the biological tissue.

[0269] Aspect 57: A method of treating a disease, comprising placing the composition of aspect 23 in the living body, wherein the at least one pharmaceutically active ingredient is active against the disease and is configured to be released in the living body at a predetermined time.

[0270] Embodiment 58: A method of promoting growth of biological tissue, comprising: providing a scaffold comprising the composition of any one of embodiments 1 to 24; and placing the scaffold in a tissue growth medium.

[0271] Aspect 59: a) A polymerization product of one or more monomers of formula (I) and one or more units of a block copolymer comprising one or more monomers of formula (II) and / or formula (II'), one or more monomers of formula (III), and / or optionally one or more compounds of formula (IV), [ka] R1, R2, and R3 are each independently hydrogen, C1-C 22 alkyl groups; each of R, R, and R is selected from C-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R is hydrogen, hydroxyl, amine, alkoxyl, C-C 22 alkyl group; R5 is selected from hydrogen, amine, hydroxyl group, or C1-C 22 alkyl group; R6 is selected from hydrogen, C1-C 22 Alkyl groups, C2-C 22 alkenyl groups; R7 is selected from hydrogen, amine, hydroxyl groups, alkoxyl groups, C1-C22 each of R, R, R, and R is selected from C-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 Optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R, R, R 10 , and R 11 are each independently hydrogen, hydroxyl, C1-C 22 Alkyl groups, C1-C 22 R8, R9, R are selected from an alkoxy group, an amino group, a halide, an -SH- group, or a carboxyl group; 10 , and R 11 All of the above are C1-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl; R, R, R 10 , and R 11 at least one of the nucleophilic groups comprises at least one nucleophilic group selected from -N(H)-, -O-, -COO-, -Cl, -F, -S(O)-, and -S-; at least one of the nucleophilic groups is a terminal group; n and m are each independently an integer of 1 to 20; R 12 is the amino acid side chain; R 14 is —OH or —NH2; the polymerization product does not contain a metal cation; the polymerization product and b) a compound of formula A b’ O a’wherein A is a monovalent, divalent, or trivalent metal cation; a' and b' depend on the valence of A; and A is not a transition metal cation; and a first crosslinking initiator configured to crosslink the reaction product to form the crosslinked composition; the crosslinked composition is a polymer network having at least one crosslink comprising two catechol moieties directly and covalently bonded to each other; the crosslinked composition is a hydrogel or an organogel, and is an adhesive composition.

[0272] Embodiment 60: R1, R2, and R3 are each independently selected from hydrogen, a -CH3 group, or a -CH2CH3 group; R4 is hydrogen, a hydroxyl group, -NH2, -OCH3, -OCH2CH3, -CH3, -CH2CH3 group, C3-C 22 R5 is selected from an alkyl or alkenyl group, —CH2CH2OH, or —CH2CH2NH2; R5 is hydrogen, a hydroxyl group, —NH2, —CH3, or —CH2CH3 group, C3-C 22 R6 is selected from hydrogen, a -CH3 group, or a -CH2CH3 group, -CH2CH2OH, or -CH2CH2NH2; R7 is selected from hydrogen or a -CH3 group; R8, R9, R 10 , and R 11 are each independently hydrogen, -CH2(CH2) x NH2, -CH2(CHR 13 )NH2, or -CH2(CH2) x COOH group; R, R, R 10 , and R 11 At least one of R is not hydrogen; 13 is -COOH or -(CH2) y 60. The crosslinked composition of embodiment 59, wherein n is a COOH group; n and m are each independently an integer from 1 to 20; x is an integer from 0 to 20; and y is an integer from 1 to 20.

[0273] Aspect 61: The crosslinked composition of aspect 59 or 60, wherein the nucleophilic group of the one or more monomers of Formula (III) is configured to react with at least one of R1COO-, R2COO-, or R3COO- of the one or more monomers of Formula (I) to form a covalent bond.

[0274] Embodiment 62: The block copolymer comprises repeat units of two or more monomers of Formula (II): [ka] A crosslinked composition according to any one of aspects 59 to 61, wherein R4 is selected from hydrogen, a hydroxyl group, -NH2, -CH2CH2OH, or -CH2CH2NH2; R5 is hydrogen, a hydroxyl group, -NH2, -CH2CH2OH, or -CH2CH2NH2; and R6 is selected from hydrogen, a -CH3 group, or a -CH2CH3 group, -CH2CH2OH, or -CH2CH2NH2.

[0275] Embodiment 63: The block copolymer has Formula (V) or Formula (V'): [ka] 63. The crosslinked composition of embodiment 62, wherein a and b are each independently selected from n=1 to 20, and R6 is not hydrogen.

[0276] Aspect 64: The crosslinked composition of any one of aspects 59 to 63, wherein said monomer of formula (III) comprises dopamine, L-DOPA.

[0277] Aspect 65: The polymerization product comprises: [ka] Including, R'' is -N(H)R 15 , or -O(CO)(R 15 ), or -O(R 15 ) and R15 are independently C1-C 22 alkyl groups, C1-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl groups; R6 is not hydrogen; [ka]

[0049] 65. The crosslinked composition of any one of aspects 59-64, wherein a defines a bond to hydrogen, or, if present, optionally a bond to a given polymer chain; a and b are each independently selected from n=1-20, and z=1-100.

[0278] Aspect 66: The crosslinked composition of any one of aspects 59 to 65, wherein the first crosslinking initiator simultaneously behaves as a filler.

[0279] Embodiment 67: The crosslinked composition of any one of embodiments 59 to 66, further comprising a second crosslinking initiator different from the first crosslinking initiator.

[0280] Embodiment 68: The cross-linking composition of embodiment 67, wherein the second cross-linking initiator comprises sodium periodate, silver nitrate, or ferric chloride, or any combination thereof.

[0281] Embodiment 69: The crosslinked composition of any one of embodiments 66 to 68, further comprising an additional filler different from the first filler.

[0282] Aspect 70: The crosslinked composition of any one of aspects 59 to 69, wherein the metal oxide is magnesium oxide, calcium oxide, zinc oxide, barium oxide, cesium oxide, or any combination thereof.

[0283] Aspect 71: The crosslinked composition of any one of Aspects 59 to 70, wherein the compound of Formula (IV) is present in the polymerization product.

[0284] Aspect 72: The crosslinked composition of any one of aspects 59 to 71, wherein the first crosslinking initiator is present in an amount greater than 0 wt% and less than 100 wt%, based on the weight percent of the dry polymerization product.

[0285] Aspect 73: The crosslinked composition of any one of aspects 69 to 72, wherein the second crosslinking initiator is present in an amount of greater than 0 wt% to about 8 wt%, based on the weight percent of the dry polymerization product.

[0286] Embodiment 74: The crosslinked composition of any one of embodiments 59 to 73, wherein the crosslinked composition further comprises a solvent.

[0287] Embodiment 75: The crosslinked composition of embodiment 74, wherein the solvent is water, ethanol, or a combination thereof.

[0288] Embodiment 76: The crosslinked composition of any one of embodiments 59 to 75, wherein the crosslinked composition comprises less than about 25% sol content.

[0289] Embodiment 77: The crosslinked composition of any one of embodiments 59 to 76, wherein the crosslinked composition exhibits a swelling ratio of less than about 200%.

[0290] Aspect 78: The crosslinked composition of any one of aspects 59 to 77, wherein the crosslinked composition exhibits a tensile strength in the dry state of about 1 to about 10 MPa as measured according to ASTM D412A.

[0291] Aspect 79: The crosslinked composition of any one of aspects 59 to 78, wherein the crosslinked composition exhibits an elongation at break in the dry state of about 15% to about 150%, as measured according to ASTM D412A.

[0292] Aspect 80: The composition of any one of aspects 59 to 79, wherein the crosslinked composition exhibits a modulus of elasticity in the dry state of about 1 to about 10 MPa as measured according to ASTM D412A.

[0293] Aspect 81: The composition of any one of aspects 59 to 80, wherein the crosslinked composition exhibits a tensile shear strength of greater than 30 kPa as measured according to a modified ASTM D1002-05 method.

[0294] Aspect 82: The composition of any one of aspects 59 to 81, wherein the crosslinked composition exhibits increased cytocompatibility as measured against human mesenchymal stem cells when compared to a substantially identical reference composition that does not contain the metal oxide.

[0295] Aspect 83: The composition of any one of aspects 69 to 82, wherein the crosslinked composition exhibits increased inhibition against Staphylococcus aureus and Escherichia coli when compared to a substantially identical reference composition in the absence of the metal oxide.

[0296] Embodiment 84: The composition according to any one of embodiments 59 to 83, further comprising at least one pharmaceutically active ingredient.

[0297] Aspect 85: The composition of any one of aspects 59 to 84, wherein the composition is a wound closure composition.

[0298] Aspect 86: a) forming a polymerization product by reacting one or more monomeric polycarboxylic acids of formula (I) with a block copolymer comprising one or more monomers of formula (II) and / or formula (II'), one or more monomers of formula (III), and / or optionally one or more compounds of formula (IV), [ka] R1, R2, and R3 are each hydrogen, C1-C 22 alkyl groups; each of R, R, and R is selected from C-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R is hydrogen, hydroxyl, amine, alkoxyl, C-C 22 alkyl group; R5 is selected from hydrogen, amine, hydroxyl group, or C1-C 22 alkyl group; R6 is selected from hydrogen, C1-C 22 Alkyl groups, C2-C 22 alkenyl groups; R7 is selected from hydrogen, amine, hydroxyl groups, alkoxyl groups, C1-C 22 each of R, R, R, and R is selected from C-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R, R, R 10 , and R 11 are each independently hydrogen, hydroxyl, C1-C 22 Alkyl groups, C1-C 22 R8, R9, R are selected from an alkoxy group, an amino group, a halide, an -SH- group, or a carboxyl group; 10 , and R 11 All of the above are C1-C22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl; R, R, R 10 , and R 11 at least one of the nucleophilic groups comprises at least one nucleophilic group selected from -N(H)-, -O-, -COO-, -Cl, -F, -S(O)-, and -S-; at least one of the nucleophilic groups is a terminal group; n and m are each independently an integer of 1 to 20; R 12 is the amino acid side chain; R 14 is —OH or —NH2; said polymerization product is free of metal cations; forming said polymerization product; and b) forming a compound of formula A b’ O a’ wherein A is a monovalent, divalent, or trivalent metal cation; a' and b' are defined by the valence of A; and A is not a transition metal cation; the crosslinked composition is a polymer network having at least one crosslink comprising two catechol moieties directly and covalently bonded to each other; the crosslinked composition is a hydrogel or an organogel and is an adhesive composition; and

[0299] Embodiment 87: R1, R2, and R3 are each independently selected from hydrogen, a -CH3 group, or a -CH2CH3 group; R4 is hydrogen, a hydroxyl group, -NH2, -OCH3, -OCH2CH3, -CH3, -CH2CH3 group, C3-C 22 R5 is selected from an alkyl or alkenyl group, —CH2CH2OH, or —CH2CH2NH2; R5 is hydrogen, a hydroxyl group, —NH2, —CH3, or —CH2CH3 group, C3-C 22R6 is selected from hydrogen, a -CH3 group, or a -CH2CH3 group, -CH2CH2OH, or -CH2CH2NH2; R7 is selected from hydrogen or a -CH3 group; R8, R9, R 10 , and R 11 are each independently hydrogen, -CH2(CH2) x NH2, -CH2(CHR 13 )NH2, or -CH2(CH2) x COOH group; R, R, R 10 , and R 11 At least one of R is not hydrogen; 13 is -COOH or -(CH2) y 87. The crosslinked composition of embodiment 86, wherein n is a COOH group; n and m are each independently an integer from 1 to 20; x is an integer from 0 to 20; and y is an integer from 1 to 20.

[0300] Aspect 88: A crosslinked composition according to aspect 86 or 87, wherein a nucleophilic group of the one or more monomers of Formula (III) reacts with at least one of R1COO-, R2COO-, or R3COO- of the one or more monomers of Formula (I) to form a covalent bond.

[0301] Embodiment 89: The block copolymer comprises repeat units of two or more monomers of Formula (II): [ka] A crosslinked composition according to any one of aspects 86 to 88, wherein R4 is selected from hydrogen, a hydroxyl group, -NH2, -CH2CH2OH, or -CH2CH2NH2; R5 is hydrogen, a hydroxyl group, -NH2, -CH2CH2OH, or -CH2CH2NH2; and R6 is selected from hydrogen, a -CH3 group, or a -CH2CH3 group, -CH2CH2OH, or -CH2CH2NH2.

[0302] Embodiment 90: The block copolymer has Formula (V) or Formula (V'): [ka] 90. The crosslinked composition of embodiment 89, wherein a and b are each independently selected from n=1 to 20, and R6 is not hydrogen.

[0303] Aspect 91: The crosslinked composition of any one of aspects 86 to 90, wherein said monomer of formula (III) comprises dopamine, L-DOPA.

[0304] Aspect 92: The polymerization product comprises: [ka] Including, R'' is -N(H)R 15 , or -O(CO)(R 15 ), or -O(R 15 ) and R 15 are independently C1-C 22 alkyl groups, C1-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl groups; R6 is not hydrogen; [ka]

[0049] Aspect 92. The crosslinked composition of any one of aspects 86-91, wherein a defines a bond to hydrogen, or, if present, optionally a bond to a given polymer chain; a and b are each independently selected from n=1-20, and z=1-100.

[0305] Embodiment 93: A method of making a composition, comprising: a) reacting one or more monomeric polycarboxylic acids of Formula (I): [ka] one or more units of a block copolymer comprising one or more monomers of formula (II) and (II'); [ka] and one or more monomeric compounds of formula (III) [ka] and Optionally, one or more compounds of formula (IV) [ka] reacting under conditions effective to form a prepolymer composition configured to be crosslinked, wherein R1, R2, and R3 are independently hydrogen, C1-C 22 alkyl groups; each of R, R, and R is selected from C-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R is hydrogen, hydroxyl, amine, alkoxyl, C-C 22 alkyl group; R5 is selected from hydrogen, amine, hydroxyl group, or C1-C 22 alkyl group; R6 is selected from hydrogen, C1-C 22 Alkyl groups, C2-C22 alkenyl groups; R7 is selected from hydrogen, amine, hydroxyl groups, alkoxyl groups, C1-C 22 each of R, R, R, and R is selected from C-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 Optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R, R, R 10 , and R 11 are each independently hydrogen, hydroxyl, C1-C 22 Alkyl groups, C1-C 22 R8, R9, R are selected from an alkoxy group, an amino group, a halide, an -SH- group, or a carboxyl group; 10 , and R 11 All of the above are C1-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl; R, R, R 10 , and R 11 at least one of the nucleophilic groups comprises at least one nucleophilic group selected from -N(H)-, -O-, -COO-, -Cl, -F, -S(O)-, and -S-; at least one of the nucleophilic groups is a terminal group; n and m are each independently an integer of 1 to 20; R 12 is the amino acid side chain; R 14is —OH or —NH2; the polymerization product is free of metal cations; and b) adding a first crosslinking initiator to the prepolymer composition, wherein the first crosslinking composition has the formula A b B a wherein A is a monovalent, divalent, or trivalent metal cation and B is an anion; a and b are defined by the valences of A and B; and A is not a transition metal cation; and c) crosslinking the prepolymer composition to form a crosslinked composition comprising a polymer network, wherein at least one crosslink of the crosslinked polymer comprises two catechol moieties directly and covalently bonded to each other; the crosslinked composition is a hydrogel or an organogel and is an adhesive composition; a method of making the composition comprising:

[0306] Embodiment 94: R1, R2, and R3 are each independently selected from hydrogen, a -CH3 group, or a -CH2CH3 group; R4 is hydrogen, a hydroxyl group, -NH2, -OCH3, -OCH2CH3, -CH3, -CH2CH3 group, C3-C 22 R5 is selected from an alkyl or alkenyl group, —CH2CH2OH, or —CH2CH2NH2; R5 is hydrogen, a hydroxyl group, —NH2, —CH3, or —CH2CH3 group, C3-C 22 R6 is selected from hydrogen, a -CH3 group, or a -CH2CH3 group, -CH2CH2OH, or -CH2CH2NH2; R7 is selected from hydrogen or a -CH3 group; R8, R9, R 10 , and R 11 are each independently hydrogen, -CH2(CH2) x NH2, -CH2(CHR 13 )NH2, or -CH2(CH2) x COOH group; R, R, R 10 , and R 11 At least one of R is not hydrogen; 13 is -COOH or -(CH2) y94. The method of claim 93, wherein n is a COOH group; n and m are each independently an integer from 1 to 20; x is an integer from 0 to 20; and y is an integer from 1 to 20.

[0307] Embodiment 95: The method of embodiment 93 or 94, wherein the block copolymer is formed prior to the reacting of step a).

[0308] Embodiment 96: The block copolymer is formed prior to the reacting of step a) and comprises repeat units of two or more monomers of Formula (II): [ka] A method according to any one of aspects 93 to 95, wherein R4 is selected from hydrogen, a hydroxyl group, -NH2, -CH2CH2OH, or -CH2CH2NH2; R5 is hydrogen, a hydroxyl group, -NH2, -CH2CH2OH, or -CH2CH2NH2; and R6 is selected from hydrogen, a -CH3 group, or a -CH2CH3 group, -CH2CH2OH, or -CH2CH2NH2.

[0309] Embodiment 97: The block copolymer has Formula (V) or Formula (V'): [ka] 97. The method of embodiment 96, wherein a and b are each independently selected from n=1 to 20, and R6 is not hydrogen.

[0310] Embodiment 98: The method of any one of embodiments 93 to 97, wherein said monomer of formula (III) comprises dopamine, L-DOPA.

[0311] Aspect 99: The polymerization product is [ka] Including, R'' is -N(H)R 15, or -O(CO)(R 15 ), or -O(R 15 ) and R 15 are independently C1-C 22 alkyl groups, C1-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl groups; R6 is not hydrogen; [ka] defines a bond to hydrogen, or, if present, optionally a bond to a given polymer chain; a and b are each independently selected from n=1 to 20, and z=1 to 100.

[0312] Embodiment 100: The method of any one of embodiments 93 to 99, wherein the first cross-linking initiator simultaneously behaves as a filler.

[0313] Embodiment 101: The method of any one of embodiments 93 to 100, further comprising adding a second cross-linking initiator different from the first cross-linking initiator.

[0314] Embodiment 102: The method of embodiment 101, wherein the second cross-linking initiator comprises sodium periodate, silver nitrate, or ferric chloride, or any combination thereof.

[0315] Embodiment 103: The method of any one of embodiments 100 to 102, further comprising an additional filler different from the first filler.

[0316] Aspect 104: The method of any one of aspects 100 to 103, wherein the metal oxide is magnesium oxide, calcium oxide, zinc oxide, barium oxide, cesium oxide, or any combination thereof.

[0317] Embodiment 105: The method of any one of embodiments 100 to 104, wherein said compound of Formula (IV) is present.

[0318] Aspect 106: The method of any one of aspects 100 to 105, wherein the first cross-linking initiator is added in an amount greater than 0 wt% and less than 100 wt%, based on the weight percent of the dry polymerization product.

[0319] Embodiment 107: The method of any one of embodiments 100 to 106, wherein the first cross-linking initiator is a solvent dispersion of the first cross-linking initiator.

[0320] Aspect 108: The method of aspect 107, wherein the solvent dispersion comprises water, ethanol, or a combination thereof.

[0321] Aspect 109: The method of any one of aspects 100 to 108, wherein the second cross-linking initiator is added in an amount of greater than 0 wt% to about 8 wt%, based on the weight percent of the dry polymerization product.

[0322] Embodiment 110: The method of any one of embodiments 101 to 109, wherein the second cross-linking initiator is added together with the first cross-linking initiator, or added before adding the first cross-linking initiator, or added after adding the first cross-linking initiator.

[0323] Embodiment 111: The method of any one of embodiments 107 to 110, wherein the second cross-linking initiator is added to a solvent dispersion of the first cross-linking initiator.

[0324] Embodiment 112: The method of any one of embodiments 101 to 111, wherein the second cross-linking initiator is added as a separate solvent dispersion of the second cross-linking initiator.

[0325] Embodiment 113: The method of embodiment 112, wherein the separate solvent dispersion comprises water, ethanol, or a combination thereof.

[0326] Embodiment 114: The method of any one of embodiments 101 to 113, wherein the first cross-linking initiator and the second cross-linking initiator have a synergistic effect.

[0327] Embodiment 115: A method described in any one of embodiments 93 to 114, wherein the gelation time required to form the hydrogel or organogel is from about 500 seconds to less than about 10 seconds.

[0328] Embodiment 116: The method of any one of embodiments 101 to 115, wherein the rate of crosslinking is substantially faster when compared to a substantially identical reference method in the absence of said metal oxide.

[0329] Aspect 117: A method described in any one of aspects 101 to 116, wherein the crosslinking step includes crosslinking with a metal oxide via coupling of catechol groups of the polymer composition, forming a metal complex with the catechol groups of the polymer composition, bonding of the metal oxide with carboxyl groups or catechol groups of the polymer composition via hydrogen bonds or surface bonds, or any combination thereof.

[0330] Embodiment 118: The method of any one of embodiments 93 to 117, wherein the formed crosslinked composition comprises less than about 25% sol content.

[0331] Embodiment 119: The method of any one of embodiments 93 to 118, wherein the formed crosslinked composition exhibits a swelling ratio of less than about 200%.

[0332] Embodiment 120: The method of any one of embodiments 93 to 119, wherein the formed crosslinked composition exhibits a tensile strength in the dry state of about 1 to about 10 MPa as measured according to ASTM D412A.

[0333] Aspect 121: The method of any one of aspects 93 to 120, wherein the formed crosslinked composition exhibits an elongation at break in the dry state of about 18% to about 150%, as measured according to ASTM D412A.

[0334] Aspect 122: The method of any one of aspects 93 to 121, wherein the formed crosslinked composition exhibits a dry modulus of elasticity of about 1 to about 10 MPa as measured according to ASTM D412A.

[0335] Example 123: The method of any one of Examples 93 to 122, wherein the formed crosslinked composition exhibits a lap shear strength of greater than 30 kPa as measured according to a modified ASTM D1002-05 method.

[0336] Embodiment 124: The method of any one of embodiments 93 to 123, wherein the formed crosslinked composition exhibits increased cytocompatibility as measured against human mesenchymal stem cells when compared to a substantially identical reference composition that does not contain the metal oxide.

[0337] Aspect 125: The method of any one of aspects 101 to 124, wherein the formed crosslinked composition exhibits increased inhibition against Staphylococcus aureus and Escherichia coli when compared to a substantially identical reference composition in the absence of the metal oxide.

[0338] Embodiment 126: The method of any one of embodiments 93 to 125, further comprising adding at least one pharmaceutically active ingredient to the formed crosslinked composition.

[0339] Embodiment 127: The method of any one of embodiments 93 to 126, wherein the formed crosslinked composition is a wound closure composition.

[0340] Aspect 128: A method for adhering biological tissues, comprising: a) placing the crosslinking composition described in any one of aspects 59 to 92 between a first portion of biological tissue and a second portion of biological tissue; and b) contacting the first portion of biological tissue with the second portion of biological tissue.

[0341] Embodiment 129: A method for treating a disease, comprising placing the composition described in embodiment 84 in the living body, wherein the at least one pharmaceutically active ingredient is active against the disease and is configured to be released in the living body at a predetermined time.

[0342] Embodiment 130: A method of promoting growth of biological tissue, comprising: providing a scaffold comprising the composition of any one of embodiments 59 to 92; and placing the scaffold in a tissue growth medium.

[0343] Embodiment 131: A kit for adhering biological tissues, comprising the crosslinking composition according to any one of embodiments 59 to 92.

[0344] Aspect 132: A method for delivering at least one pharmaceutically active ingredient in an effective amount, said method comprising: a) a polymerization product of i) one or more monomers of Formula (I) and one or more units of a block copolymer comprising one or more monomers of Formula (II) and / or Formula (II'), one or more monomers of Formula (III), and / or optionally one or more compounds of Formula (IV), [ka] R1, R2, and R3 are independently hydrogen, C1-C 22 alkyl groups; each of R, R, and R is selected from C-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R is hydrogen, hydroxyl, amine, alkoxyl, C-C 22alkyl group; R5 is selected from hydrogen, amine, hydroxyl group, or C1-C 22 alkyl group; R6 is selected from hydrogen, C1-C 22 Alkyl groups, C2-C 22 alkenyl groups; R7 is selected from hydrogen, amine, hydroxyl groups, alkoxyl groups, C1-C 22 each of R, R, R, and R is selected from C-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R, R, R 10 , and R 11 are each independently hydrogen, hydroxyl, C1-C 22 Alkyl groups, C1-C 22 R8, R9, R are selected from an alkoxy group, an amino group, a halide, an -SH- group, or a carboxyl group; 10 , and R 11 All of the above are C1-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl; R, R, R 10 , and R 11at least one of the nucleophilic groups comprises at least one nucleophilic group selected from -N(H)-, -O-, -COO-, -Cl, -F, -S(O)-, and -S-; at least one of the nucleophilic groups is a terminal group; n and m are each independently an integer of 1 to 20; R 12 is the amino acid side chain; R 14 is —OH or —NH2; the polymerization product does not contain a metal cation; and ii) a compound of formula A b’ O a’ wherein A is a monovalent, divalent, or trivalent metal cation; a' and b' depend on the valence of A; and A is not a transition metal cation; wherein the first crosslinking initiator is configured to crosslink the reaction product to form the crosslinked composition; the crosslinked composition is a polymer network having at least one crosslink comprising two catechol moieties directly and covalently bonded to each other; the crosslinked composition is a hydrogel or organogel and is an adhesive composition; and b) incorporating at least one pharmaceutically active ingredient into the composition; and a) releasing the at least one agent in vivo at a predetermined time.

[0345] Embodiment 133: R1, R2, and R3 are each independently selected from hydrogen, a -CH3 group, or a -CH2CH3 group; R4 is hydrogen, a hydroxyl group, -NH2, -OCH3, -OCH2CH3, -CH3, -CH2CH3 group, C3-C 22 R5 is selected from an alkyl or alkenyl group, —CH2CH2OH, or —CH2CH2NH2; R5 is hydrogen, a hydroxyl group, —NH2, —CH3, or —CH2CH3 group, C3-C 22 R6 is selected from hydrogen, a -CH3 group, or a -CH2CH3 group, -CH2CH2OH, or -CH2CH2NH2; R7 is selected from hydrogen or a -CH3 group; R8, R9, R 10 , and R 11 are each independently hydrogen, -CH2(CH2) xNH2, -CH2(CHR 13 )NH2, or -CH2(CH2) x COOH group; R, R, R 10 , and R 11 At least one of R is not hydrogen; 13 is -COOH or -(CH2) y 133. The method of claim 132, wherein n is a COOH group; n and m are each independently an integer from 1 to 20; x is an integer from 0 to 20; and y is an integer from 1 to 20.

[0346] Embodiment 134: The block copolymer comprises repeat units of two or more monomers of formula (II): [ka] A method according to any one of aspects 132 to 133, wherein R4 is selected from hydrogen, a hydroxyl group, -NH2, -CH2CH2OH, or -CH2CH2NH2; R5 is hydrogen, a hydroxyl group, -NH2, -CH2CH2OH, or -CH2CH2NH2; and R6 is selected from hydrogen, a -CH3 group, or a -CH2CH3 group, -CH2CH2OH, or -CH2CH2NH2.

[0347] Embodiment 135: The block copolymer has Formula (V) or Formula (V'): [ka] The method of embodiment 134, wherein a and b are each independently selected from n=1 to 20, and R6 is not hydrogen.

[0348] Embodiment 136: The method of any one of embodiments 132 to 135, wherein the monomer of formula (III) comprises dopamine, L-DOPA.

[0349] Aspect 137: The polymerization product is [ka] Including, R'' is -N(H)R 15 , or -O(CO)(R 15 ), or -O(R 15 ) and R 15 are independently C1-C 22 alkyl groups, C1-C 22 Alkyl, C1-C 22 Alkoxy, C2-C 22 Alkenyl, C2-C 22 Alkynyl, C6-C 14 Aryl, C1-C 13 optionally substituted with heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxide, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl groups; R6 is not hydrogen; [ka] defines a bond to hydrogen, or, if present, optionally to a given polymer chain; a and b are each independently selected from n=1 to 20, and z=1 to 100.

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Claims

1. 1. A crosslinked composition comprising: a) a polymerization product of one or more monomers of formula (I), one or more units of a block copolymer of formula (V) or formula (V'), one or more monomers of formula (III), and optionally one or more compounds of formula (IV), 【Chemistry 1】 R １ , R ２ , and R ３ are each independently hydrogen, —CH ３ , and -CH ２ CH ３ Selected from: R ４ represents hydrogen, a hydroxyl group, -NH ２ , -OCH ３ , -OCH ２ CH ３ , -CH ３ , -CH ２ CH ３ , C ３ -C ２２ Alkyl or alkenyl group, —CH ２ CH ２ OH, and -CH ２ CH ２ NH ２ Selected from: R ５ represents hydrogen, a hydroxyl group, -NH ２ , -CH ３ , -CH ２ CH ３ , C ３ -C ２２ Alkyl or alkenyl group, —CH ２ CH ２ OH, and -CH ２ CH ２ NH ２ Selected from: R ６ is -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ OH, and -CH ２ CH ２ NH ２ Selected from: R ８ , R ９ , R １０ , and R １１ are each independently hydrogen, —CH ２ (CH ２ ) ｘ NH ２ , -CH ２ (CHR １３ ) NH ２ , and -CH ２ (CH ２ ) ｘ COOH group; R ８ , R ９ , R １０ , and R １１ at least one of which is not hydrogen; R １２ is an amino acid side chain; R １３ is -COOH or -(CH ２ ) ｙ COOH; x is an integer from 0 to 20; y is an integer from 1 to 20; a and b are each independently selected from n=1 to 20; the polymerization product the polymerization product does not contain any metal cations; b) Formula A ｂ’ O ａ’ wherein A is a monovalent, divalent, or trivalent metal cation, a' and b' depend on the valence of A, and A is not a transition metal cation, wherein the first crosslinking initiator crosslinks the polymerization product to form the crosslinked composition; the crosslinked composition is a polymer network having at least one crosslink comprising two catechol moieties directly and covalently bonded to each other; The crosslinked composition is a hydrogel or an organogel and is an adhesive composition.

2. 2. The crosslinked composition of claim 1, wherein the monomer of formula (III) comprises L-DOPA or dopamine.

3. The polymerization product is 【Chemistry 2】 Including, R″ is —N(H)R １５ , or —O(CO)(R １５ ), or -O(R １５ ) and R １５ are each independently C １ -C ２２ alkyl groups; 【Transformation 3】 defines a bond to a hydrogen, or optionally, if present, to a given polymer chain; 3. The crosslinked composition according to claim 1, wherein z=1 to 100.

4. The crosslinked composition according to any one of claims 1 to 3, wherein the first crosslinking initiator simultaneously behaves as a first filler.

5. The crosslinking composition according to any one of claims 1 to 4, further comprising a second crosslinking initiator different from the first crosslinking initiator.

6. 6. The crosslinking composition of claim 5, wherein the second crosslinking initiator comprises sodium periodate, silver nitrate, or ferric chloride, or any combination thereof.

7. The crosslinked composition of any one of claims 4 to 6, further comprising an additional filler different from the first filler.

8. 8. The crosslinking composition of claim 1, wherein the first crosslinking initiator is a metal oxide selected from magnesium oxide, calcium oxide, zinc oxide, barium oxide, cesium oxide, or any combination thereof.

9. The crosslinked composition according to any one of claims 1 to 8, wherein said compound of formula (IV) is present in said polymerization product.

10. 10. The crosslinking composition of any one of claims 1 to 9, wherein the first crosslinking initiator is present in an amount of greater than 0 wt% to less than 100 wt%, based on the weight percent of the dry polymerization product.

11. 11. The crosslinking composition of any one of claims 6 to 10, wherein the second crosslinking initiator is present in an amount of greater than 0 wt% to 8 wt%, based on the weight percent of the dry polymerization product.

12. The crosslinking composition according to any one of claims 1 to 11, further comprising a solvent.

13. The crosslinking composition of claim 12 , wherein the solvent is water, ethanol, or a combination thereof.

14. The crosslinked composition of any one of claims 1 to 13, wherein the crosslinked composition exhibits a swelling ratio of less than about 200%.

15. The crosslinked composition of any one of claims 1 to 14, wherein the crosslinked composition exhibits a tensile strength in the dry state of about 1 to about 10 MPa measured according to ASTM D412A.

16. 16. The crosslinked composition of any one of claims 1 to 15, wherein the crosslinked composition exhibits an elongation at break in the dry state of from about 15% to about 150% as measured according to ASTM D412A.

17. 17. The composition of any one of claims 1 to 16, wherein the crosslinked composition exhibits a modulus of elasticity in the dry state of about 1 to about 10 MPa, measured according to ASTM D412A.

18. 18. The composition of any one of claims 1 to 17, wherein the crosslinked composition exhibits a lap shear strength of greater than 30 kPa measured according to modified ASTM D1002-05 method.

19. 19. The composition of any one of claims 1 to 18, wherein the crosslinked composition exhibits increased cytocompatibility as measured with human mesenchymal stem cells when compared to a substantially identical reference composition that does not contain the metal oxide.

20. 20. The composition of any one of claims 1 to 19, wherein the crosslinked composition exhibits increased inhibition of Staphylococcus aureus and Escherichia coli when compared to a substantially identical reference composition in the absence of the metal oxide.

21. The composition of any one of claims 1 to 20, further comprising at least one pharmaceutically active ingredient.

22. The composition of any one of claims 1 to 21, wherein the composition is a wound closure composition.

23. 1. A crosslinked composition comprising: a) forming a polymerization product by reacting one or more monomeric polycarboxylic acids of formula (I) with a block copolymer of formula (V) or formula (V'), one or more monomers of formula (III) and, optionally, one or more compounds of formula (IV), 【Chemistry 4】 R １ , R ２ , and R ３ are each independently hydrogen, —CH ３ , and -CH ２ CH ３ Selected from: R ４ represents hydrogen, a hydroxyl group, -NH ２ , -OCH ３ , -OCH ２ CH ３ , -CH ３ , -CH ２ CH ３ , C ３ -C ２２ Alkyl or alkenyl group, —CH ２ CH ２ OH, and -CH ２ CH ２ NH ２ Selected from: R ５ represents hydrogen, a hydroxyl group, -NH ２ , -CH ３ , -CH ２ CH ３ , C ３ -C ２２ Alkyl or alkenyl group, —CH ２ CH ２ OH, and -CH ２ CH ２ NH ２ Selected from: R ６ is -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ OH, and -CH ２ CH ２ NH ２ Selected from: R ８ , R ９ , R １０ , and R １１ are each independently hydrogen, —CH ２ (CH ２ ) ｘ NH ２ , -CH ２ (CHR １３ ) NH ２ , and -CH ２ (CH ２ ) ｘ COOH group; R ８ , R ９ , R １０ , and R １１ at least one of which is not hydrogen; R １２ is an amino acid side chain; R １３ is -COOH or -(CH ２ ) ｙ COOH; x is an integer from 0 to 20; y is an integer from 1 to 20; a and b are each independently selected from n=1 to 20; forming a polymerization product, the polymerization product being free of metal cations; b) Formula A ｂ’ O ａ’ wherein A is a monovalent, divalent, or trivalent metal cation, a' and b' are defined by the valence of A, and A is not a transition metal cation; and the crosslinked composition is a polymer network having at least one crosslink comprising two catechol moieties directly and covalently bonded to each other; The crosslinked composition is a hydrogel or an organogel and is an adhesive composition.

24. 24. The crosslinked composition of claim 23, wherein the monomer of formula (III) comprises L-DOPA or dopamine.

25. The polymerization product is 【Transformation 5】 Including, R″ is —N(H)R １５ , or —O(CO)(R １５ ), or -O(R １５ ) and R １５ are each independently C １ -C ２２ alkyl groups; 【Transformation 6】 defines a bond to a hydrogen, or optionally, if present, to a given polymer chain; 25. The crosslinked composition of claim 23 or 24, wherein z=1 to 100.

26. 1. A method of making a composition, comprising: a) reacting one or more monomeric polycarboxylic acids of formula (I) with 【Transformation 7】 one or more units of a block copolymer comprising one or more monomers of formula (V) and (V'); 【Transformation 8】 and one or more monomeric compounds of formula (III) 【Chemistry 9】 and Optionally, one or more compounds of formula (IV) 【Chemistry 10】 R １ , R ２ , and R ３ are each independently hydrogen, —CH ３ , and -CH ２ CH ３ Selected from: R ４ represents hydrogen, a hydroxyl group, -NH ２ , -OCH ３ , -OCH ２ CH ３ , -CH ３ , -CH ２ CH ３ , C ３ -C ２２ Alkyl or alkenyl group, —CH ２ CH ２ OH, and -CH ２ CH ２ NH ２ Selected from: R ５ represents hydrogen, a hydroxyl group, -NH ２ , -CH ３ , -CH ２ CH ３ , C ３ -C ２２ Alkyl or alkenyl group, —CH ２ CH ２ OH, and -CH ２ CH ２ NH ２ Selected from: R ６ is -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ OH, and -CH ２ CH ２ NH ２ Selected from: R ８ , R ９ , R １０ , and R １１ are each independently hydrogen, —CH ２ (CH ２ ) ｘ NH ２ , -CH ２ (CHR １３ ) NH ２ , and -CH ２ (CH ２ ) ｘ COOH group; R ８ , R ９ , R １０ , and R １１ at least one of which is not hydrogen; R １２ is an amino acid side chain; R １３ is -COOH or -(CH ２ ) ｙ COOH; x is an integer from 0 to 20; y is an integer from 1 to 20; a and b are each independently selected from n=1 to 20; reacting to form a polymerization product, reacting to form the polymerization product, wherein the polymerization product does not include metal cations; b) adding a first cross-linking initiator to the polymerization product, wherein the first cross-linking initiator is represented by the formula A ｂ B ａ wherein A is a monovalent, divalent, or trivalent metal cation, B is an anion, a and b are defined by the valences of A and B, and A is not a transition metal cation; c) crosslinking the polymerization product to form a crosslinked composition comprising a polymer network, wherein at least one crosslink in the crosslinked polymer comprises two catechol moieties directly and covalently bonded to each other; The crosslinked composition is a hydrogel or an organogel and is an adhesive composition.

27. 27. The method of claim 26, wherein the block copolymer is formed prior to the reacting of step a).

28. 28. The method of claim 26 or 27, wherein the monomer of formula (III) comprises L-DOPA or dopamine.

29. The polymerization product is 【Chemistry 11】 Including, R″ is —N(H)R １５ , or —O(CO)(R １５ ), or -O(R １５ ) and R １５ are each independently C １ -C ２２ alkyl groups; 【Chemistry 12】 defines a bond to a hydrogen, or optionally, if present, to a given polymer chain; 29. The method of any one of claims 26 to 28, wherein z=1 to 100.

30. 30. The method according to any one of claims 26 to 29, wherein the first cross-linking initiator simultaneously behaves as a first filler.

31. 31. The method of any one of claims 26 to 30, further comprising adding a second cross-linking initiator different from the first cross-linking initiator.

32. 32. The method of claim 31 , wherein the second cross-linking initiator comprises sodium periodate, silver nitrate, or ferric chloride, or any combination thereof.

33. 31. The method of claim 30, further comprising an additional filler different from the first filler.

34. 34. The method of any one of claims 26 to 33, wherein the first cross-linking initiator is a metal oxide selected from magnesium oxide, calcium oxide, zinc oxide, barium oxide, cesium oxide, or any combination thereof.

35. 35. The method of any one of claims 26 to 34, wherein the compound of formula (IV) is present.

36. 36. The method of any one of claims 26 to 35, wherein the first cross-linking initiator is added in an amount of greater than 0 wt% to less than 100 wt%, based on the weight percent of the dry polymerization product.

37. The method of any one of claims 26 to 36, wherein the first cross-linking initiator is a solvent dispersion of the first cross-linking initiator.

38. 38. The method of claim 37, wherein the solvent dispersion comprises water, ethanol, or a combination thereof.

39. 39. The method of any one of claims 31 to 38, wherein the second crosslinking initiator is added in an amount of from greater than 0 wt% to about 8 wt%, based on the weight percent of the dry polymerization product.

40. 40. The method of any one of claims 31 to 39, wherein the second crosslinking initiator is added together with the first crosslinking initiator, or is added before adding the first crosslinking initiator, or is added after adding the first crosslinking initiator.

41. The method according to any one of claims 31 to 40, wherein the second cross-linking initiator is added to a solvent dispersion of the first cross-linking initiator.

42. 41. The method of any one of claims 31 to 40, wherein the second crosslinking initiator is added as a solvent dispersion of the second crosslinking initiator that is separate from the solvent dispersion of the first crosslinking initiator.

43. 43. The method of claim 42, wherein the separate solvent dispersion comprises water, ethanol, or a combination thereof.

44. 44. The method of any one of claims 26 to 43, wherein the gelation time required to form the hydrogel or organogel is from about 500 seconds to less than about 10 seconds.

45. 45. A method according to any one of claims 26 to 44, wherein the rate of crosslinking is substantially faster when compared to a substantially identical reference method in the absence of said metal oxide.

46. 46. ​​The method of any one of claims 26 to 45, wherein the crosslinking step comprises crosslinking with a metal oxide via coupling of a catechol group of the polymerization product, forming a metal complex with the catechol group of the polymerization product, binding of the metal oxide to a carboxyl group or a catechol group of the polymerization product via hydrogen bonding or surface bonding, or any combination thereof.

47. 47. The method of any one of claims 26 to 46, wherein the formed crosslinked composition exhibits a swelling ratio of less than about 200%.

48. 48. The method of any one of claims 26 to 47, wherein the formed crosslinked composition exhibits a tensile strength in the dry state of about 1 to about 10 MPa as measured according to ASTM D412A.

49. 49. The method of any one of claims 26 to 48, wherein the formed crosslinked composition exhibits an elongation at break in the dry state of from about 18% to about 150% as measured according to ASTM D412A.

50. 50. The method of any one of claims 26 to 49, wherein the formed crosslinked composition exhibits a dry modulus of elasticity of about 1 to about 10 MPa measured according to ASTM D412A.

51. 51. The method of any one of claims 26 to 50, wherein the formed crosslinked composition exhibits a lap shear strength of greater than 30 kPa measured according to modified ASTM D1002-05 method.

52. 52. The method of any one of claims 26-51, wherein the formed crosslinked composition exhibits increased cytocompatibility as measured with human mesenchymal stem cells when compared to a substantially identical reference composition that does not contain the metal oxide.

53. 53. The method of any one of claims 26-52, wherein the formed cross-linked composition exhibits increased inhibition of Staphylococcus aureus and Escherichia coli when compared to a substantially identical reference composition in the absence of the metal oxide.

54. 54. The method of any one of claims 26 to 53, further comprising adding at least one pharmaceutically active ingredient to the formed crosslinked composition.

55. The method of any one of claims 26 to 54, wherein the formed crosslinked composition is a wound closure composition.

56. A method for adhering biological tissue, comprising: a) placing a crosslinking composition according to any one of claims 1 to 25 between a first portion of biological tissue and a second portion of biological tissue; b) contacting the first portion of the biological tissue with a second portion of the biological tissue.

57. 22. A method of treating a disease comprising placing the composition of claim 21 in a living body, wherein the at least one pharmaceutically active ingredient is active against the disease and is configured to be released in the living body at a predetermined time.

58. 26. A method of promoting growth of biological tissue, comprising: providing a scaffold comprising the composition of any one of claims 1-25; and placing the scaffold in a tissue growth medium.

59. A kit for adhering biological tissues, comprising the crosslinking composition according to any one of claims 1 to 25.

60. 1. A method for delivering an effective amount of at least one pharmaceutically active ingredient, comprising: a) i) a polymerization product of one or more monomers of formula (I), one or more units of a block copolymer of formula (V) or formula (V'), one or more monomers of formula (III), and optionally one or more compounds of formula (IV), 【Chemistry 13】 R １ , R ２ , and R ３ are each independently hydrogen, —CH ３ , and -CH ２ CH ３ Selected from: R ４ represents hydrogen, a hydroxyl group, -NH ２ , -OCH ３ , -OCH ２ CH ３ , -CH ３ , -CH ２ CH ３ , C ３ -C ２２ Alkyl or alkenyl group, —CH ２ CH ２ OH, and -CH ２ CH ２ NH ２ Selected from: R ５ represents hydrogen, a hydroxyl group, -NH ２ , -CH ３ , -CH ２ CH ３ , C ３ -C ２２ Alkyl or alkenyl group, —CH ２ CH ２ OH, and -CH ２ CH ２ NH ２ Selected from: R ６ is -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ OH, and -CH ２ CH ２ NH ２ Selected from: R ８ , R ９ , R １０ , and R １１ are each independently hydrogen, —CH ２ (CH ２ ) ｘ NH ２ , -CH ２ (CHR １３ ) NH ２ , and -CH ２ (CH ２ ) ｘ COOH group; R ８ , R ９ , R １０ , and R １１ at least one of which is not hydrogen; R １２ is an amino acid side chain; R １３ is -COOH or -(CH ２ ) ｙ COOH; x is an integer from 0 to 20; y is an integer from 1 to 20; a and b are each independently selected from n=1 to 20; the polymerization product the polymerization product does not contain any metal cations; ii) Formula A ｂ’ O ａ’ wherein A is a monovalent, divalent, or trivalent metal cation, a' and b' depend on the valence of A, and A is not a transition metal cation, wherein the first crosslinking initiator crosslinks the polymerization product to form the crosslinked composition; the crosslinked composition is a polymer network having at least one crosslink comprising two catechol moieties directly and covalently bonded to each other; The crosslinked composition is a hydrogel or organogel and is an adhesive composition; incorporating the at least one pharmaceutically active ingredient into the composition; b) releasing said at least one pharmaceutically active ingredient in vivo at a predetermined time.

61. 61. The method of claim 60, wherein the monomer of formula (III) comprises L-DOPA or dopamine.

62. The polymerization product is 【Chemistry 14】 Including, R″ is —N(H)R １５ , or —O(CO)(R １５ ), or -O(R １５ ) and R １５ are each independently C １ -C ２２ alkyl groups; 【Chemistry 15】 defines a bond to a hydrogen, or optionally, if present, to a given polymer chain; 62. The method of claim 60 or 61, wherein z=1 to 100.

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