Magnesium-loaded PEGDA microspheres via microfluidics embedded in a sodium alginate/gelatin hydrogel for enhanced skin wound healing.

Magnesium ions (Mg2+) promote angiogenesis in wound healing, yet direct Mg salt incorporation causes burst release that limits efficacy. Herein, a composite delivery system SA/Gel@PM: Mg-loaded poly(ethylene glycol) diacrylate (PEGDA) microspheres embedded in a sodium alginate/gelatin (SA/Gel) hydrogel, that achieves dual-stage sustained Mg2+ release was reported. Food-grade peanut oil served as a biocompatible substitute for cytotoxic n-hexadecane in the continuous phase of a flow-focusing microfluidic device, enhancing PEGDA microsphere production throughput (droplet interval reduced from 260 ms to 232 ms). COMSOL-optimized flow rates (75:7.5 μL/min) yielded monodisperse PEGDA microspheres (140-170 μm). Magnesium salts were then loaded into the PEGDA microspheres by the immersion-precipitation method. SA/Gel@PM retained a 3D porous structure with ~2000% swelling and strong exudate uptake. In vitro, the SA/Gel matrix of SA/Gel@PM further retarded Mg2+ release compared to PM microspheres alone, thereby mitigating the initial burst effect (reducing the 4 h release of PM-10 from 39.1 to 13.9 μg/mL). CCK-8 assays with L929 fibroblasts showed >80% viability on day 1 and > 90% on day 3 for all SA/Gel@PM samples. In vivo, SA/Gel@PM-10 achieved 94.69% wound closure on day 10 with near-normal tissue remodeling. This microsphere-in-hydrogel dual-release platform offers a safe, tunable dressing strategy for Mg2+-enabled wound healing and related immunological regulation.