Skeletal muscle lysate derived macroporous hydrogel repairs spinal cord injury via immunoregulation and axon regeneration.

Secondary damage following spinal cord injury (SCI), mediated by excessive local inflammation, oxidative stress, and the limited regenerative capacity of the central nervous system, can lead to irreversible neurological dysfunction. Inspired by the role of exercise rehabilitation in promoting neural recovery post-SCI and the neuroregulatory functions of muscle-derived bioactive proteins in modulating inflammation and promoting regeneration, we developed a bioactive hydrogel (MTLH) using skeletal muscle lysate as the primary matrix cross-linked with sodium alginate. MTLH features a macroporous structure, an elastic modulus suitable for spinal cord regeneration, slow degradation kinetics, and low swelling ratio. Both in vitro microglial studies and murine SCI models demonstrated MTLH's superior efficacy in inflammation modulation via sustained release of bioactive proteins. It suppresses the IL-17/NF-κB pathway, promotes M2 polarization of microglia/macrophages, and enhances neuroprotection. In vitro, MTLH facilitates axonal growth of neuronal cells through the TrkB/PI3K-AKT pathway. In vivo, it induces early recruitment of endogenous neural progenitor cells (NPCs) into the scaffold, promotes neuronal and oligodendrocyte differentiation, inhibits glial scar formation, and facilitates axonal and myelin regeneration, ultimately improving functional recovery in mice. As an autologous skeletal muscle-derived biomaterial with significant therapeutic potential for SCI repair, MTLH represents a promising strategy for clinical translation in SCI treatment.