An injectable enzymatically crosslinked hyaluronic acid–tyramine hydrogel system with independent tuning of mechanical strength and gelation rate

Abstract

In this study, we propose an enzymatically crosslinked hyaluronic acid (HA) hydrogel with tunable mechanical strength and gelation rate as a novel injectable system. The hydrogel composed of HA--tyramine conjugate (HA--Tyr) was formed using the oxidative coupling of tyramine moieties catalyzed by hydrogen peroxide (H 2 O 2 ) and horseradish peroxidase (HRP). The mechanical strength of the HA--Tyr hydrogel was tuned solely by the H 2 O 2 amount without affecting the gelation rate. The hydrogels formed more rapidly with increasing HRP concentration and the gelation time ranged from 1 s to 20 min. A faster gelling system yielded more localized gel formation than a slower gelling one at the site where it was administered through subcutaneous injection. Studies on the swelling ratio and scanning electron microscopy images of the hydrogel structure further demonstrated that the crosslinking density was controlled by the concentration of H 2 O 2 used. The mechanical strength of HA--Tyr hydrogels strongly affected the degradation rate in the presence of hyaluronidase in vitro; hydrogels degraded more slowly with increasing mechanical strength of the hydrogel. The independently tunable mechanical strength and gelation rate achieved by this enzymatically formed HA--Tyr hydrogel system will provide great advantages to a wide range of applications of injectable hydrogels, such as drug delivery and tissue regeneration.

Enzyme Initiated Radical Polymerizations

“…However, even if no phenolic side chain is present in the polymer, it may be introduced chemically. In that respect, tyramine has gained some popularity e.g., for the crosslinking of carboxymethyl cellulose [154], alginate [155], hyaluronic acid [156], dextran [157] or artificial polymers such as Tetronic [158].…”

Low Viscosity Poly(trimethylene carbonate) for Localized Drug Delivery: Rheological Properties and in vivo Degradation

“…For this purpose, injectable, fluid polymers that either gel in situ or possess high viscosity are being investigated as alternative approaches to the use of more conventional formulations such as microspheres, emulsions, and liposomes. [1][2][3][4][5][6][7][8][9][10] This interest is a result of advantages that include a relatively facile formulation approach coupled with retention at the injection site.…”

Mechanical and Swelling Properties of Poly (vinyl alcohol) and Hyaluronic Acid Gels used in Biomaterial Systems - a Comparative Study

“…The storage modulus is an indication of gel strength during the frequency sweep 25 . Also, the modulus becomes independent of frequency over a range, which is the rheological signature of gel [26][27][28] .…”