pH responsive self-healing hydrogels formed by boronate-catechol complexation

Patent metadata

Field	Value
Publication number	US-9572910-B2
Application number	US-201213476422-A
Country	US
Kind code	B2
Filing date	May 21, 2012
Priority date	May 19, 2011
Publication date	Feb 21, 2017
Grant date	Feb 21, 2017

Abstract

Biocompatible hydrogels made from cross-linked catechol-borate ester polymers are disclosed, along with methods of synthesizing and using such hydrogels. The hydrogels of the present invention are prepared by boronic acid-catechol complexation between catechol-containing macromonomers and boronic acid-containing cross-linkers. The resulting hydrogels are pH-responsive and self-healing, and can be used in a number of different biomedical applications, including in surgical implants, in surgical adhesives, and in drug delivery systems is data provides further evidence of the viability of using the disclosed hydrogels for in vivo in biomedical applications.

First claim

We claim:

1. A biocompatible pH-responsive self-healing hydrogel comprising a cross-linked polymer comprising:
(a) a plurality of macromonomers each comprising at least four terminal catechol moieties and having a molecular weight of 1,000 to 20,000 Daltons; and
(b) one or more cross-linkers each comprising two or more terminal boronic acid moieties;
wherein the catechol moieties of the macromonomers are covalently bonded to the boronic acid moieties of the cross linker to form a tetrahedral borate ester, wherein the macromonomers are cross-linked into the polymer when the macromonomers are at physiological pH or above and the polymer dissociates into the macromonmers at pH 3.0.

2. The hydrogel of claim 1 , wherein the macromonomers have a molecular weight of 5,000 to 15,000 Daltons.

3. The hydrogel of claim 1 , wherein the macromonomers are polyethylene glycols or (dihydroxyphenyl)ethyl methacrylamide copolymers.

4. The hydrogel of claim 3 , wherein the polyethylene glycols are 4-arm polyethylene glycols wherein each arm is terminated with a catechol moiety.

5. The hydrogel of claim 4 , wherein the 4-arm polyethylene glycols have the structure:

wherein each n is independently selected to be from 1 to 200.

6. The hydrogel of claim 3 , wherein the (dihydroxyphenyl)ethyl methacrylamide copolymers are comprised of (dihydroxyphenyl)ethyl methacrylamide monomers wherein the phenyl group is nitro substituted.

7. The hydrogel of claim 3 , wherein the (dihydroxyphenyl)ethyl methacrylamide copolymers have the structure:

wherein each of m, n and a are independently selected to be from 1 to 200.

8. The hydrogel of claim 1 , wherein two terminal boronic acid moieties on the cross-linkers are attached to an aromatic ring.

9. The hydrogel of claim 8 , wherein the two terminal boronic acid moieties on the cross linkers are either attached to the same aromatic ring or to two different aromatic rings on opposite ends of the cross-linkers.

10. The hydrogel of claim 8 , wherein the cross-linkers have the structure:

wherein n is from 1 to 100.

11. The hydrogel of claim 1 , wherein the tetrahedral borate ester group covalently bonding the macromonomers to the cross-linkers has the structure:

Assignees

• Messersmith Phillip B
• He Lihong
• Fullenkamp Dominic E
• Univ Northwestern

Inventors

• Messersmith Phillip B
• He Lihong
• Fullenkamp Dominic E

Classifications

• C08G65/337 Primary

  containing other elements (organic compounds containing halogens only as halides of a carboxyl group C08G65/332) · CPC title

• C08G65/328

  containing other elements · CPC title

• A61K9/06

  Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)} · CPC title

• A61L15/26

  Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds; Derivatives thereof {(A61L15/225 takes precedence)} · CPC title

• A61L27/52

  Hydrogels or hydrocolloids · CPC title