The sequential injection of hyaluronic acid-tyramine conjugates and enzymes forms biodegradable hydrogels in vivo by enzyme-induced oxidative coupling, offering high potential as a promising biomaterial for drug delivery and tissue engineering.

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.

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