Repair of spinal cord injury using a time-specific four-dimensional multifunctional hydrogel with anti-inflammatory and neuronal differentiated microenvironments.

Spinal cord injury (SCI) is a severe central nervous system (CNS) condition that often leads to permanent disability. The repair of SCI presents significant challenges globally, primarily due to serious inflammatory damage in the early stage and limited neural regeneration in the long-term stage. In response to these challenges, this study developed a novel time-specific four-dimensional multifunctional SilMA hydrogel (4DMSH) that releases Houttuynia cordata extract (HCT) in the early stage of post-implantation to combat inflammation and a sustained release of neurotrophin-3 (NT-3) in the long-term stage to promote neuronal differentiation of endogenous neural stem cells (eNSCs) for neuronal regeneration. As expected, the time-specific 4DMSH significantly mitigated inflammatory responses, leading to a shift from a pro-inflammatory to a neural regenerative environment, and enhanced the differentiation of eNSCs into neurons, thereby effectively improving the recovery of motor, sensory, and autonomic functions after SCI. Therefore, this study presents a novel time-specific 4DMSH that creates anti-inflammatory and neuroactive microenvironments, contributing to efficient neuronal regeneration and SCI repair.