Methods for making injectable polymer hydrogels
Methods for preparing injectable hydrogels, particularly hydrogels containing hyaluronan, are described herein. Also described are hydrogel products made by the methods provided herein.
1 . A process for the preparation of an injectable hydrogel, the process comprising the steps of crosslinking one or more polymers to form a gel, washing the gel, purifying the gel, and homogenizing the gel to produce the hydrogel, wherein the process is carried out in a single reaction vessel as a continuous process.
2 . A process as claimed in claim 1 , wherein the polymer has one or more reactive groups selected from hydroxyl groups, carboxyl groups and amine groups.
3 . A process as claimed in claim 2 , wherein the polymer is a polysaccharide, a protein, or a synthetic polymer selected from the group consisting of poly(acrylic acid) and poly(vinyl alcohol).
4 . A process as claimed in claim 3 , wherein the polysaccharide is hyaluronic acid, chitosan, alginate acid, starch, dextran, or salts or water soluble derivatives thereof.
5 . A process as claimed in claim 1 , wherein the crosslinking reaction is carried out with a bi- or polyfunctional crosslinking agent.
6 . A process as claimed in claim 5 , wherein the crosslinking agent is an epoxide, aldehyde, polyaziridyl or divinyl sulphone.
7 . A process as claimed in claim 5 , wherein the crosslinking agent is 1,4-butanediol diglycidyl ether.
8 . A process as claimed in claim 1 , which is carried out at a pH of 11 or higher.
9 . A process as claimed in claim 1 , wherein the crosslinking reaction is carried out at a temperature of 37-60° C. for at least 4 hours.
10 . A process as claimed in claim 9 , wherein the crosslinking reaction is carried out at a temperature of 50° C.
11 . A process as claimed in claim 1 , wherein a solution of the one or more polymers in NaOH is first prepared, to which is added a crosslinking agent, with stirring.
12 . A process as claimed in claim 1 , wherein the formed gel is cut into pieces using one or more impellers. in the reaction vessel, and is washed and purified by means of one or more changes of PBS solution.
13 . A process as claimed in claim 12 , wherein the washing and purification process is carried out over 2 to 3 days with at least six changes of PBS solution.
14 . A process as claimed in claim 1 , wherein the polymer is hyaluronic acid.
15 . A process as claimed in claim 14 , wherein the process is carried out with a solution of hyaluronic acid in 0.25M NaOH, at a concentration up to 20% by weight.
16 . A process as claimed in claim 15 , wherein the initial concentration of hyaluronic acid is 11-14% by weight.
17 . A process as claimed in claim 1 , wherein the molar ratio of crosslinking agent to polymer is 0.5-2.4.
18 . An injectable hydrogel produced by the process as claimed in claim 1 .
19 . A biomaterial comprising an injectable hydrogel as claimed in claim 18 .
20 . A biomaterial as claimed in claim 19 in the form of a sheet, bead, sponge, or formed implant.