Orchestrating Scarless Spinal Cord Repair: Dynamic Glial‐Immune Interplay and Biomaterial Support

ABSTRACT Glial scar formation stands as a defining pathological hallmark and a primary barrier to functional recovery following traumatic spinal cord injury (SCI). This review highlights the intricate and dynamic interplay among glial cells (astrocytes, oligodendrocytes, microglia) and infiltrating peripheral immune cells, recognizing them as critical orchestrators whose activities profoundly influence scar formation and “scarless repair” strategies. We explore mechanisms by which these cellular populations contribute to the scar and inhibitory milieu, while also possessing potential roles in promoting regeneration. “Scarless repair” is aimed at precisely orchestrating this complex glial‐immune interaction network to minimize detrimental scar formation, promoting axonal regeneration and functional recovery. Achieving this precise spatiotemporal modulation requires sophisticated tools, among which advanced biomaterial platforms have emerged as key enablers for engineering the injury microenvironment, guiding cell behaviors, and enabling controlled delivery of therapeutic factors. While experimental approaches, including glial cell‐based therapies, show promise, significant challenges persist, including model limitations, clinical translation barriers, and long‐term safety. Future research should harness advanced technologies to dissect glial interaction networks, develop multi‐target combination therapies, and identify biomarkers indicative of effective scar remodeling and functional neural repair. The ultimate goal is effective SCI repair and providing insights for other neurological disorders.