Developmental Extracellular Matrix as a Bioactive Niche for Spinal Cord Organoid Maturation and SCI Repair.

Spinal cord injury (SCI) causes permanent sensorimotor deficits due to the inhibitory extracellular microenvironment that forms post-injury, hindering regeneration. The extracellular matrix (ECM) plays a critical role in neural development and repair, with the developmental spinal cord ECM being enriched in pro-regenerative molecules and containing relatively low levels of inhibitory components. In contrast, the ECM of the adult injured spinal cord is characterized by an abundance of growth-inhibitory molecules. Human pluripotent stem cell-derived spinal cord organoids have emerged as promising in vitro models for studying spinal cord development and disease; however, their application is limited by incomplete structural and functional maturation. The incorporation of developmental ECM components into organoid cultures has been shown to promote maturation, neuronal connectivity, and functional integration. This review provides a comprehensive overview of the regenerative properties of developmental spinal cord ECM and discusses its applications in organoid engineering and SCI repair, including decellularized ECM biomaterials, hydrogels, synthetic analogs, and combinatorial approaches. Collectively, developmental ECM-based strategies represent a promising platform for the development of precision regenerative therapies aimed at enhancing functional recovery after SCI.