Innovations in skeletal muscle regeneration: from physiology to bioengineering approaches for repair and restoration

Skeletal muscle is a dynamic tissue essential for voluntary movement, metabolism, and thermoregulation. Yet, its intrinsic regenerative capacity is overwhelmed in volumetric muscle loss (VML), where damage exceeds the native repair threshold. Conventional treatments such as muscle flaps and grafts provide only partial structural and functional recovery, underscoring the need for regenerative strategies that more precisely recapitulate the molecular and cellular physiology of muscle healing. This review first outlines the physiology of injury and muscle regeneration, with emphasis on key molecular pathways that govern inflammation, fibrosis, and myogenesis in VML. Building on this biological framework, we then examine hydrogels as soft material platforms for skeletal muscle tissue engineering, including: (i) acellular hydrogels and nanoparticle-loaded hydrogels designed to modulate the biochemical and biophysical microenvironment; (ii) cell-loaded hydrogels that deliver myogenic or stem/progenitor cell populations; and (iii) drug-loaded hydrogels for localized, sustained release of growth factors, cytokines, nucleic acids, or small molecules. Finally, we discuss emerging directions, including nanoparticle-integrated systems, dynamically stiffening or softening hydrogels, and advanced biofabrication approaches, and consider how these cellularized and acellular drug-, cell-, or nanoparticle-loaded hydrogels can be strategically leveraged to treat complex skeletal muscle injuries.