Physically crosslinked agarose-hyaluronic acid hydrogel for injectable treatment of photoaged skin.

Prolonged ultraviolet (UV) exposure leads to photoaging characterized by collagen degradation, oxidative stress, and impaired skin barrier function. Injectable hydrogels offer a minimally invasive strategy for dermal repair, but conventional materials often rely on chemical crosslinkers, raising concerns over biosafety and long-term biocompatibility. Herein, we develop a physically crosslinked agarose-hyaluronic acid (Aga-HA) composite hydrogel derived from marine-sourced Gelidium agarose and optimized with 0.5% HA. The resulting Aga-0.5% HA hydrogel exhibits shear-thinning behavior, enhanced injectability, low swelling, and improved acid resistance without chemical modification. Spectroscopic and thermal analyses reveal that HA incorporation disrupts agarose double-helix packing via hydrogen bonding, forming a flexible and porous network. In vitro, the hydrogel promotes human dermal fibroblast proliferation and displays excellent cytocompatibility. In vivo, it demonstrates non-pyrogenic and non-hemolytic behavior, enhances tissue hydration, and accelerates regeneration in zebrafish and murine photoaging models. Importantly, Aga-0.5% HA restores dermal density, improves collagen deposition, reduces inflammation, and attenuates oxidative stress. This biocompatible, chemically crosslinker-free hydrogel offers a safe and effective injectable platform for treating photoaged skin and regenerating soft tissue.