Overcoming Barriers to Axonal Regeneration in Spinal Cord Injury: Mechanistic Insights and Therapeutic Frontiers

Spinal cord injury (SCI) is a devastating central nervous system disorder that often causes permanent neurological deficits, while effective disease-modifying therapies remain lacking. Functional recovery depends on axonal regeneration, which is limited by the inhibitory post-injury microenvironment and the reduced regenerative capacity of mature neurons.

This review summarizes the mechanisms underlying axonal regeneration failure after SCI and discusses recent advances in regenerative strategies and their translational progress.

Current evidence indicates that impaired axonal regeneration results from both extrinsic inhibitory factors and intrinsic neuronal growth limitations. Regenerative strategies, including modulation of glial scar dynamics, degradation of inhibitory extracellular matrix components, reconstruction of a permissive regenerative microenvironment, stem cell transplantation, biomaterial scaffolds, activation of intrinsic growth programs, and neuromodulation, have shown promising effects in preclinical studies. However, clinical translation remains limited by challenges related to therapeutic timing, delivery efficiency, biosafety, scalability, and insufficient clinical evidence.

Future SCI repair will likely require combinatorial strategies targeting multiple regenerative mechanisms while improving clinical feasibility. This review integrates current mechanistic and translational advances to support the development of more effective regenerative therapies for SCI.