Polysaccharide-inspired biomaterials for skeletal muscle regeneration: innovations for volumetric muscle loss treatment

Volumetric muscle loss (VML) is a severe condition caused by extensive damage to muscle tissue that exceeds the body's intrinsic regenerative capacity, resulting in significant functional deficits and long-term disability. Current clinical treatments, including autologous muscle grafts and physical therapy, often fall short due to donor site morbidity, limited functional recovery, and an inability to fully restore muscle structure and function. Polysaccharides as natural macromolecules are characterized by inherent biocompatibility, degradability, and tunable mechanical properties, making them highly suitable for tissue engineering applications. This comprehensive review examines the innovative application of polysaccharide-based biomaterials in VML repair, emphasizing their translational potential to regenerative treatment outcomes. Polysaccharide-based biomaterials can significantly enhance muscle regeneration by providing structural support, modulating immune responses to minimize fibrosis, and promoting new vascular and nerve formation, which are essential for functional muscle recovery. More importantly, these materials serve as effective carriers for cell therapy and the delivery of bioactive molecules, thereby enhancing regenerative efficacy. Despite challenges such as standardizing preparation protocols, ensuring consistent biocompatibility, and optimizing degradation rates, polysaccharide-based biomaterials hold great promise for advancing skeletal muscle regeneration and offer a potential breakthrough in treating VML. STATEMENT OF SIGNIFICANCE: Volumetric muscle loss (VML) is a severe clinical condition characterized by extensive muscle tissue damage that exceeds the body's natural regenerative capacity. Polysaccharide-based biomaterials have been extensively applied in tissue repair due to their favorable biological properties. They offer a promising therapeutic strategy for VML, for which currently available long-term treatments are limited in both safety and efficacy. However, a comprehensive review detailing the interaction mechanisms between polysaccharide-based biomaterials and muscle tissue regeneration remains lacking. This article focuses on the interactions and highlights recent evidence on the capacity of polysaccharide promoting myogenesis, modulating immune responses, restoring neural innervation, stimulating angiogenesis, and enhancing antioxidant activity. This review article provides insights into the future design and application of polysaccharide-based biomaterials for skeletal muscle regeneration after acute injuries.