Cross-linkable polymer, hydrogel, and method of preparation thereof

Patent metadata

Field	Value
Publication number	US-12138363-B2
Application number	US-201917282154-A
Country	US
Kind code	B2
Filing date	Oct 4, 2019
Priority date	Oct 4, 2018
Publication date	Nov 12, 2024
Grant date	Nov 12, 2024

Abstract

The invention relates to a cross-linkable polymer including a base polymer including functional groups at least some of which have been reacted with a first organic molecule including a cross-linkable unit and with a second organic molecule capable of bonding to organic and/or inorganic substrates. The invention further relates to a hydrogel including the cross-linkable polymer that includes cross-linkable polymer strands, wherein at least some of the cross-linkable units of different cross-linkable polymer strands have reacted to form a covalent bond thereby forming a covalently linked network. The invention further relates to a method for the preparation of the hydrogel and to the use of the hydrogel.

First claim

The invention claimed is:

1. A cross-linkable polymer comprising a base polymer comprising functional groups at least some of which have been reacted with a first organic molecule comprising a cross-linkable unit and with a second organic molecule capable of bonding to organic and/or inorganic substrates,
wherein the first organic molecule is selected from the group consisting of acrylic anhydride, acryloyl chloride, pent-4-enal, ethyl 2,3-epoxypropanoate, methacrylic anhydride, methacryloyl chloride, mercaptopropionic acid, and maleic anhydride.

2. The cross-linkable polymer according to claim 1 , wherein the functional groups of the base polymer comprise at least one of hydroxyl groups, amine groups, carboxylic acid groups, amide groups, and thiol groups.

3. The cross-linkable polymer according to claim 1 , wherein the base polymer is selected from the group consisting of hyaluronic acid, alginate, chitosan, pectine, poly(ethylene glycol), carboxymethyl cellulose, poly(vinyl alcohol), poly(2-hydroxyethyl methacrylate), poly(acrylamide), fibrin, silk, collagen, and mixtures thereof.

4. The cross-linkable polymer according to claim 1 , wherein the cross-linkable unit of the first organic molecule comprises at least one of a carbon-carbon double bond (—C═C—), a thiol group (—SH), an epoxide group, and an acid anhydride group.

5. The cross-linkable polymer according to claim 1 , wherein the first organic molecule comprises an attachment unit that allows the attachment of the first organic molecule to the functional groups of the base polymer.

6. The cross-linkable polymer according to claim 1 , wherein the second organic molecule comprises a bonding unit that comprises at least one of a catechol group; a quinone group; a group of the formula —SiX 1 X 2 X 3 , wherein X 1 , X 2 , and X 3 are independently selected from the group consisting of a halide, methoxy, ethoxy, isopropoxy, and acetoxy; a thiol group; a phosphono group or its derivatives; a phosphate group or its derivatives; and a dicarboxyl group.

7. The cross-linkable polymer according to claim 1 , wherein the second organic molecule comprises a connecting unit that allows the attachment of the second organic molecule to the functional groups of the base polymer.

8. The cross-linkable polymer according to claim 1 , wherein the second organic molecule is a molecule of the formula X′—R′—Y′, wherein X′ is an aldehyde group, an acid chloride group, an acid anhydride group, a carboxylic acid group, an amine group, or a hydroxyl group, R′ is an optionally substituted hydrocarbon moiety with 2 to 10 carbon atoms, and Y′ is a catechol group; a quinone group; a group of the formula —Six 1 X 2 X 3 , wherein X 1 , X 2 , and X 3 are independently selected from the group consisting of a halide, methoxy, ethoxy, isopropoxy, and acetoxy; a thiol group; a phosphono group or its derivatives; a phosphate group or its derivatives; or a dicarboxyl group and/or wherein the second organic molecule is selected from the group consisting of 3,4-dihydroxyphenethylamine and aminopropyltriethoxysilane.

9. The cross-linkable polymer according to claim 1 , wherein the cross-linkable polymer has a molecular weight less than 500 kDa and/or is water-soluble.

10. The cross-linkable polymer according to claim 1 , wherein from 0.1% to 99% of the functional groups of the base polymer have reacted with the first organic molecule.

11. The cross-linkable polymer according to claim 1 , wherein from 0.1% to 70% of the functional groups of the base polymer have reacted with the second organic molecule.

12. A hydrogel comprising the cross-linkable polymer according to claim 1 , further comprising cross-linkable polymer strands, wherein at least some of the cross-linkable units of different cross-linkable polymer strands have reacted to form a covalent bond thereby forming a covalently linked network.

13. The hydrogel according to claim 12 , wherein the hydrogel comprises at least one additive.

14. The hydrogel according to claim 12 , wherein the hydrogel comprises water, buffer, phosphate buffered saline (PBS), hepes buffer, or alcohol.

15. The hydrogel according to claim 12 , wherein the hydrogel has an elastic modulus from about 2 kPa to about 4 MPa.

16. The hydrogel according to claim 12 , wherein the hydrogel has a swelling ratio from −20% to 150%.

17. The hydrogel according to claim 12 , wherein the hydrogel adheres to different human or animal tissues.

18. A method for the preparation of a hydrogel, comprising the steps of
a. providing the cross-linkable polymer according to claim 1 ,
b. dissolving the cross-linkable polymer in a solvent to obtain a solution,
c. optionally, adding a cross-linking agent to the solution,
d. cross-linking of the cross-linkable polymer by an external stimulus to obtain a hydrogel.

19. The method according to claim 18 , wherein the cross-linking agent is biocompatible.

20. The method according to claim 18 , wherein the cross-linking agent is selected from the group consisting of a radical initiator, an oxidating agent, and a diamine.

21. The method according to claim 18 , wherein the solvent is selected from water, buffer, phosphate buffered saline (PBS), hepes buffer, and alcohol.

22. The method according to claim 18 , wherein the external stimulus is selected from the group consisting of UV irradiation, X-ray irradiation, infrared irradiation, and heating.

23. The method according to claim 18 , wherein the solution is degassed in a step prior to step d.

24. The method according to claim 18 , wherein an additive is added to the solution prior to step d.

25. The method according to claim 18 , wherein the concentration of the cross-linkable polymer is from 1 to 30 wt. %.

26. The hydrogel according to claim 12 for use in the treatment of cartilage damage, meniscus damage, corneal damage, nucleus pulposus or annulus fibrosus damage, cardiac tissue damage, bone tissue damage, dental tissue damage and/or as implant.

Assignees

• Ecole Polytechnique Fed Lausanne Epfl
• Ecole Polytechnique Fed Lausanne Epfl

Inventors

• Karami Peyman
• Pioletti Dominique
• Wyss Céline Samira
• Bourban Pierre-Etienne
• Moser Christophe

Classifications

• C08J2305/08

  Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof · CPC title

• C08J3/075

  Macromolecular gels · CPC title

• C08B37/0072

  Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates · CPC title

• A61L2430/06

  for cartilage reconstruction, e.g. meniscus · CPC title

• A61L2430/02

  for reconstruction of bones; weight-bearing implants · CPC title