Precise tailoring of tyramine-based hyaluronan hydrogel properties using DMTMM conjugation

Abstract

Injectable tyramine modified hyaluronic acid (HA-Tyr) hydrogels which are bio-orthogonally cross-linked with horseradish peroxidase (HRP) and hydrogen peroxide (H2O2) are excellent candidate biomaterials for drug delivery, regenerative medicine and tissue engineering. Ligation of tyramine to HA has been reported using the very well established N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) chemistry. Here we demonstrate the applicability of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) as an alternative coupling agent to synthesize HA-Tyr conjugates. The optimized derivatization process allows accurate control of the degree of substituted Tyr on hyaluronan (DSmol). Hence, viscoelastic properties, in vitro swelling and enzymatic digestion profiles of the crosslinked hydrogels can be precisely tuned via DSmol. Our study demonstrates the advantages of DMTMM conjugation as a powerful tool to synthesize HA-Tyr hydrogels with properties exactly tailored for biomedical applications.

Keywords: 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) (PubChem CID: 2734059); Hyaluronic acid; Hyaluronic acid sodium salt (PubChem CID: 23663392); Hydrogel; N-(3-dimethylaminopropyl)-N′′-ethylcarbodiimide hydrochloride (EDC) (PubChem CID: 2723939); N-hydroxysuccinimide (NHS) (PubChem CID: 80170); Tyramine; Tyramine hydrochloride (PubChem CID: 66449).