Toward an Integrated Strategy for Volumetric Muscle Loss Regeneration

Volumetric muscle loss (VML) constitutes a significant clinical challenge, defined by the irreversible loss of skeletal muscle tissue and resulting in persistent functional deficits due to fibrosis, chronic inflammation, and insufficient endogenous regeneration. Existing clinical interventions, such as autologous grafting and free functional muscle transfer, are constrained by donor-site morbidity including infection, pain, suboptimal vascularization, and limited functional integration. Although tissue engineering has advanced considerably, no FDA-approved regenerative therapies currently exist for VML, underscoring a substantial translational gap. This review provides a systems-level synthesis of skeletal muscle repair through integrating fundamental biological processes, such as inflammation, satellite-cell activation, myogenesis, angiogenesis, and neuromuscular junction formation, with recent advances in biomaterials, scaffold engineering, and biofabrication technologies. The analysis addresses how critical scaffold design parameters, including alignment, porosity, stiffness, degradation kinetics, and bioactivity, influence cellular responses and tissue integration. Additionally, emerging strategies such as 3D bioprinting, nanofiber-based architectures, stem cell and exosome therapies, and bio-functional stimulation are evaluated inside a unified mechanobiological framework. This analysis is further extended to the regulatory setting, with emphasis on how scaffold composition, mechanism of action, and degree of biological integration affect classification pathways governed by the U.S. Food and Drug Administration. Most advanced VML therapies are anticipated to be regulated as combination products, which will require rigorous preclinical validation, standardized manufacturing processes, and carefully designed clinical studies. By integrating biological principles, engineering design, and regulatory considerations, this review highlights key opportunities, remaining challenges, and future priorities for the clinical translation of next-generation regenerative strategies for VML.