Extracellular matrix-mimicking cryogels composed of methacrylated fucoidan enhance vascularized skeletal muscle regeneration following volumetric muscle loss

Volumetric muscle loss (VML) significantly impairs the inherent regenerative ability of skeletal muscle and results in chronic functional impairment. Polysaccharides in the muscle extracellular matrix are crucial for regulating cell proliferation and differentiation. Recent studies indicate that fucoidan has beneficial effects on musculoskeletal conditions. However, the impact of fucoidan on skeletal muscle regeneration remains poorly understood. In this study, methacrylated fucoidan (FuMA) was synthesized through chemical grafting of the methacryloyl group onto fucoidan. In vitro experiments demonstrated that treatment with FuMA significantly up-regulated the expression of myogenic markers and promoted the formation of myotubes in C2C12 myoblast cells. Importantly, FuMA treatment led to a significant enhancement in mitochondrial energy metabolism of myoblasts via activation of the NRF2 antioxidant signaling pathway. To further investigate the regenerative properties in repairing skeletal muscle defects, we fabricated a dual crosslinked cryogel consisting of FuMA and methacrylated gelatin (GelMA) with a porous and interconnected structure. In a rat tibialis anterior muscle VML model, implantation of the FuMA/GelMA cryogel effectively promoted the regeneration of muscle fibers, reduced collagen deposition, and facilitated the formation of new blood vessels. Hence, polysaccharide-based cryogels represent a promising implantable biomimetic scaffold for facilitating skeletal muscle regeneration following severe injuries.