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US-12616773-B2 - Bioadhesive compositions and methods of making the same

US12616773B2US 12616773 B2US12616773 B2US 12616773B2US-12616773-B2

Abstract

Disclosed herein are citrate-based mussel-inspired bioadhesives and methods of making and using the same. Also disclosed herein are methods of treating wounds.

Inventors

  • Jian Yang
  • Jinshan Guo

Assignees

  • THE PENN STATE RESEARCH FOUNDATION

Dates

Publication Date
20260505
Application Date
20201218

Claims (19)

  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): wherein R 1 , R 2 , and R 3 are, independently, selected from hydrogen, —CH 3 , and CH 2 CH 3 ; R 4 is selected from hydrogen, a hydroxyl group, —NH 2 , —OCH 3 , —OCH 2 CH 3 , —CH 3 , —CH 2 CH 3 , a C 3 to C 22 alkyl or alkenyl group, —CH 2 CH 2 OH, and —CH 2 CH 2 NH 2 ; R 5 is selected from hydrogen, a hydroxyl group, —NH 2 , —CH 3 , —CH 2 CH 3 , a C 3 to C 22 alkyl or alkenyl group, —CH 2 CH 2 OH, and —CH 2 CH 2 NH 2 ; R 6 is selected from —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 OH, and —CH 2 CH 2 NH 2 ; R 8 , R 9 , R 10 , and R 11 are, independently, selected from hydrogen, —CH 2 (CH 2 ) x NH 2 , —CH 2 (CHR 13 ) NH 2 , and —CH 2 (CH 2 ) x COOH groups; wherein at least one of R 8 , R 9 , R 10 , and R 11 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; and a and b are independently chosen from n=1-20; wherein the polymerization product does not comprise metal cations; and b) a first crosslinking initiator having a formula A b′ O a′ , wherein A is a monovalent, divalent, or trivalent metallic cation and wherein a′ and b′ are dependent on the valency of A; wherein A is not a transition metal cation and wherein the first crosslinking initiator is configured to crosslink the polymerization product to form the crosslinked composition; and wherein the crosslinked composition is a polymer network having at least one crosslink comprising two catechol moieties directly and covalently coupled to each other; and wherein 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 dopamine or L-DOPA.
  3. 3 . The crosslinked composition of claim 1 , wherein the polymerization product comprises: wherein R″ is —N(H)R 15 , or —O(CO)(R 15 ), or —O(R 15 ); wherein R 15 is independently selected from C 1 -C 22 alkyl group, optionally substituted with 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 heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl groups; wherein R 6 is not hydrogen; wherein defines a bond to hydrogen, or optionally to a predetermined polymer chain if present; wherein a and b are independently chosen from n=1-20, and wherein z=1-100.
  4. 4 . The crosslinked composition of claim 1 , wherein the first crosslinking initiator simultaneously behaves as a first filler.
  5. 5 . The crosslinked composition of claim 4 , further comprising an additional filler that is different from the first filler.
  6. 6 . The crosslinked composition of claim 1 , further comprising a second crosslinking initiator that is different from the first crosslinking initiator.
  7. 7 . The crosslinked composition of claim 6 , wherein the second crosslinking initiator comprises sodium periodate, silver nitrate, or ferric chloride, or any combination thereof.
  8. 8 . The crosslinked 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. 9 . The crosslinked composition of claim 1 , wherein the compound of Formula (IV) is present in the polymerization product.
  10. 10 . The crosslinked composition of claim 1 , wherein the crosslinked composition comprises a sol content less than about 25%.
  11. 11 . The composition of claim 1 , further comprising at least one pharmaceutically active component.
  12. 12 . A method of treating disease, comprising disposing the composition of claim 11 , within the biological body, wherein the at least one pharmaceutically active component is active towards the disease and is configured to be released into the biological body at a predetermined time.
  13. 13 . The composition of claim 1 , wherein the composition is a wound closing composition.
  14. 14 . A method of making a composition of claim 1 , comprising: a) reacting a polycarboxylic acid of one or more monomers of Formula (I) with one or more units of a block copolymer of Formula (V) or Formula (V′), and with a compound of one or more monomers of Formula (III) and optionally with one or more compounds of Formula (IV) at conditions effective to form a prepolymer composition configured to be crosslinked; wherein R 1 , R 2 , and R 3 are, independently, selected from hydrogen, —CH 3 , and CH 2 CH 3 ; R 4 is selected from hydrogen, a hydroxyl group, —NH 2 , —OCH 3 , —OCH 2 CH 3 , —CH 3 , —CH 2 CH 3 , a C 3 to C 22 alkyl or alkenyl group, —CH 2 CH 2 OH, and —CH 2 CH 2 NH 2 ; R 5 is selected from hydrogen, a hydroxyl group, —NH 2 , —CH 3 , —CH 2 CH 3 , a C 3 to C 22 alkyl or alkenyl group, —CH 2 CH 2 OH, and —CH 2 CH 2 NH 2 ; R 6 is selected from —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 OH, and —CH 2 CH 2 NH 2 ; R 8 , R 9 , R 10 , and R 11 are, independently, selected from hydrogen, —CH 2 (CH 2 ) x NH 2 , —CH 2 (CHR 13 ) NH 2 , and —CH 2 (CH 2 ) x COOH groups; wherein at least one of R 8 , R 9 , R 10 , and R 11 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; and a and b are independently chosen from n=1-20; wherein the prepolymer composition does not comprise metal cations; b) adding a first crosslinking initiator to the prepolymer composition; wherein the first crosslinking initiator has a formula AbBa, wherein A is a monovalent, divalent, or trivalent metallic cation and B is an anion, and wherein a and b are defined by the valency of A and B; wherein 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 in the crosslinked polymer comprises two catechol moieties directly and covalently coupled to each other; and wherein the crosslinked composition is a hydrogel or organogel and is adhesive.
  15. 15 . The method of claim 14 , wherein a gel time needed to form the hydrogel or the organogel is from about 500 s to less than about 10 s.
  16. 16 . A method of adhering a biological tissue, comprising: a) disposing the crosslinked composition of claim 1 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.
  17. 17 . A method of delivering at least one pharmaceutically active component in an efficient amount wherein the method comprises: incorporating the at least one pharmaceutically active component into a crosslinked composition of claim 1 ; and b) releasing the at least one pharmaceutical agent into a biological body at a predetermined time.
  18. 18 . A method of promoting biological tissue growth comprising providing a scaffold comprising the composition of claim 1 and disposing the scaffold in a tissue growth media.
  19. 19 . A crosslinked composition formed by a) forming a polymerization product by reacting one or more monomers 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): wherein R 1 , R 2 , and R 3 are, independently, selected from hydrogen, —CH 3 , and —CH 2 CH 3 ; R 4 is selected from hydrogen, a hydroxyl group, —NH 2 , —OCH 3 , —OCH 2 CH 3 , —CH 3 , —CH 2 CH 3 , a C 3 to C 22 alkyl or alkenyl group, —CH 2 CH 2 OH, and —CH 2 CH 2 NH 2 ; R 5 is selected from hydrogen, a hydroxyl group, —NH 2 , —CH 3 , —CH 2 CH 3 , a C 3 to C 22 alkyl or alkenyl group, —CH 2 CH 2 OH, and —CH 2 CH 2 NH 2 ; R 6 is selected from —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 OH, and —CH 2 CH 2 NH 2 ; R 8 , R 9 , R 10 , and R 11 are, independently, selected from 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; and a and b are independently chosen from n=1-20; wherein the polymerization product does not comprise metal cations; b) crosslinking the polymerization product with a first crosslinking initiator having a formula A b′ O a′ , wherein A is a monovalent, divalent, or trivalent metallic cation and wherein a′ and b′ are defined by the valency of A; wherein A is not a transition metal cation; wherein the crosslinked composition is a polymer network having at least one crosslink comprising two catechol moieties directly and covalently coupled to each other; and wherein the crosslinked composition is a hydrogel or organogel and is an adhesive composition.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a national stage application filed under 35 U.S.C. § 371 of PCT/US2020/065951, filed Dec. 18, 2020, which claims the benefit of U.S. Provisional Application No. 62/953,401, filed Dec. 24, 2019, and U.S. Provisional Application No. 63/028,691, filed May 22, 2020, the contents of which are incorporated herein by reference in their entireties. TECHNICAL FIELD The present disclosure generally relates to bioadhesive compositions that can be used as wound closing or bone filling compositions and methods of making the same. BACKGROUND Tissue (bio)adhesives have attracted increased attention in recent years due to their wide applicability in the biomedical field, including wound closure, hemostat, tissue sealing, implant fixation, and drug delivery. Commercially available biologically-derived fibrin glue (Tisseel), which is mainly composed of concentrated fibrinogen, thrombin, and calcium chloride, thus duplicating the last stage of biological coagulation cascade, is the most widely used tissue adhesive due to its fast curing and biodegradability and often considered as the gold standard of tissue adhesives. However, there are also limitations, such as poor wet tissue adhesion, thus reducing its efficacy for applications where strong tissue adhesion is required. Other adhesives, for example, cyanoacrylate adhesives, offer advantages such as ease of use, strong adhesion to tissue. However, the applications of cyanoacrylates have also been mainly limited to topical uses due to concerns such as slow degradation, exothermic polymerization, and toxicity of degradation products. Additional adhesives, such as albumin-glutaraldehyde bioadhesives (BioGlue), are clinically used in cardiac and vascular repair and pulmonary repair, but it also brings concern on their toxicity due to the use of a toxic crosslinking component. Urethane-based (TissuGlu) tissue adhesives may offer strong tissue adhesion and fast curing, but they may suffer from vigorous exothermic chemical reactions and slow degradation. Poly(ethylene glycol) (PEG)-based bioadhesives, such as CoSeal and DuraSeal, have been used as tissue sealants for some applications, but concerns on their large swelling ratios and rapid degradation were believed to possibly trigger significant post-surgical complications such as rapid leakage, compression on the nearby nerve ends, and the formation of a hematoma. Accordingly, a need still exists for alternative bioadhesive compositions that have superior biocompatibility and strong wet tissue adhesion strength. Still further, a need exists for bioadhesives that are not toxic, have acceptable swelling ratios, and the desired degradation rate. Also, there are needs for methods of making such compositions. These needs and other needs are at least partially satisfied by the present disclosure. SUMMARY The present invention is directed to 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): wherein R1, R2, and R3 are, independently, selected from hydrogen, C1-C22 alkyl group; wherein each of R1, R2, and R3, are optionally substituted with C1-C22 alkyl, C1-C22 alkoxy, C2-C22 alkenyl, C2-C22 alkynyl, C6-C14 aryl, C1-C13 heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R4 is selected from hydrogen, a hydroxyl group, amine, alkoxyl group, C1-C22 alkyl group; R5 is selected from hydrogen, amine, a hydroxyl group, or a C1-C22 alkyl group; R6 is selected from hydrogen, a C1-C22 alkyl group, C2-C22 alkenyl group; R7 is selected from hydrogen, amine, a hydroxyl group, alkoxyl group, a C1-C22 alkyl group; wherein each of R4, R5, R6, and R7, are optionally substituted with C1-C22 alkyl, C1-C22 alkoxy, C2-C22 alkenyl, C2-C22 alkynyl, C6-C14 aryl, C1-C13 heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, phosphonyl; R8, R9, R10, and R11 are, independently, selected from hydrogen, hydroxyl, C1-C22 alkyl group, C1-C22 alkoxy group, amino group, halide, —SH— group, or a carboxyl group, wherein any of R8, R9, R10, and R11, are optionally substituted with C1-C22 alkyl, C1-C22 alkoxy, C2-C22 alkenyl, C2-C22 alkynyl, C6-C14 aryl, C1-C13 heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, cyano, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, thiol, or phosphonyl; and wherein at least one of R8, R9, R10, and R11 comprises at least one nucleophilic group selected from —N(H)—, —O—, —COO—, —Cl, —F; and —S(O)—, —S—; and wherein at least one of the nucleophilic groups is a terminal group;