Hydrogels for skeletal muscle regeneration after volumetric muscle loss: from natural matrices to emerging peptide-based systems

Abstract – Volumetric muscle loss (VML) refers to the loss of skeletal muscle that exceeds intrinsic repair and heals with fibrosis, poor perfusion and denervation. Conventional treatments such as muscle grafts and decellularized matrices improve structure but rarely restore normal strength or limb use. Hydrogels have emerged as injectable scaffolds that fill irregular defects, deliver cells and cues and better match muscle-like mechanics. This review summarizes hydrogels for VML repair, including natural and semi-synthetic systems (gelatin, collagen, hyaluronan, fibrin, alginate, muscle-derived decellularized extracellular matrix (ECM)), synthetic networks and peptide-based hydrogels. Natural matrices provide tissue-derived signals but offer limited control over stiffness and degradation. Synthetic hydrogels allow precise tuning of mechanics and porosity but require additional ligands and growth factors to effectively support VML repair. Peptide hydrogels self-assemble into ECM-like nanofibres and can display multiple motifs for adhesion, immunomodulation, angiogenesis and neurotrophic support, although direct VML data remain sparse. Across these material classes, we highlight shared design principles: aligned architectures and hierarchical porosity, graded properties at muscle–tendon and muscle–nerve interfaces and degradation and cue delivery matched to overlapping healing phases, combined with appropriate cell strategies. Together, these concepts support a shift from passive defect filling towards reconstruction of a regenerative niche with hybrid hydrogel constructs for VML repair.