Mechanical Remodeling and Mechanosensing after Spinal Cord Injury: From Molecular to Translational Approaches

Spinal cord injury triggers a profound, spatiotemporally dynamic remodeling of the local mechanical microenvironment. Acute tissue softening and extracellular matrix degradation give way progressively to chronic fibrotic stiffening and dense matrix cross-linking. This pathological transformation establishes a formidable physical barrier to axonal regeneration while simultaneously disrupting the biomechanical signals that normally guide cellular behavior and maintain tissue homeostasis. Within this evolving niche, diverse cell populations decode altered stiffness and matrix composition through an array of specialized mechanosensitive receptors. The resulting intracellular signaling cascades orchestrate lineage-specific transcriptional and cytoskeletal programs that ultimately govern the delicate equilibrium between endogenous repair and irreversible fibrotic scar consolidation. This review examines the temporal progression and spatial heterogeneity of postinjury mechanical alterations across the spinal parenchyma, delineates the principal mechanotransduction pathways engaged, and critically evaluates emerging therapeutic strategies designed to modulate this aberrant physical landscape and restore a permissive regenerative milieu. We highlight translational advances spanning surgical decompression, mechanically responsive biomaterials engineered for dynamic niche reprogramming, and mechanoprimed cellular therapies. By framing spinal cord injury as a disorder of aberrant mechanobiology, this work advances a conceptual foundation for precision interventions aimed at overcoming regenerative failure through active remodeling of the tissue microenvironment.