Dual-functionalized GelFuMA hydrogel with sequential crosslinking for tunable mechanics and controlled drug release.

Abstract

Articular cartilage repair is constrained by the tissue's low regenerative capacity, prompting the development of biomaterials that can integrate mechanical support with bioactive cues to modulate stem cell behavior. We report a dual-functionalized gelatin-based hydrogel platform (GelFuMA), in which furan and methacryloyl functionalities are integrated within a single gelatin backbone to enable sequential network formation, mechanical reinforcement, and controlled delivery of bioactive cues. Dual-crosslinkable hydrogels were formed via aqueous Diels-Alder (DA) 'click' chemistry using a poly(ethylene glycol) bismaleimide crosslinker, followed by photoinitiated methacrylate polymerization. Varying the GelFuMA-to-crosslinker ratio yielded an energy-dissipative hybrid network with tunable mechanical properties, exhibiting a 4-fold increase in compressive modulus relative to single-network counterparts. Dexamethasone release followed diffusion-dominated Korsmeyer-Peppas kinetics (n ≤ 0.45) across all formulations. When seeded with Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs), this hydrogel system supported increased expression of early chondrogenic markers, including significant upregulation of the cartilage-associated gene COL2A1 (P < 0.001) in the absence of exogenous chondrogenic supplements. These findings establish GelFuMA as a tunable gelatin-based hydrogel platform that combines mechanical reinforcement and controlled drug release, highlighting its potential for regenerative biomaterial design.