Rationally Designed, Self‐Assembling, Multifunctional Hydrogel Depot Repairs Severe Spinal Cord Injury

Abstract Following severe spinal cord injury (SCI), dysregulated neuroinflammation causes neuronal and glial apoptosis, resulting in scar and cystic cavity formation during wound healing and ultimately the formation of an atrophic microenvironment that inhibits nerve regrowth. Because of this complex and dynamic pathophysiology, a systemic solution for scar‐ and cavity‐free wound healing with microenvironment remodeling to promote nerve regrowth has rarely been explored. A one‐step solution is proposed through a self‐assembling, multifunctional hydrogel depot that punctually releases the anti‐inflammatory drug methylprednisolone sodium succinate (MPSS) and growth factors (GFs) locally according to pathophysiology to repair severe SCI. Synergistically releasing the anti‐inflammatory drug MPSS and GFs in the hydrogel depot throughout SCI pathophysiology protects spared tissues/axons from secondary injury, promotes scar boundary‐ and cavity‐free wound healing, and results in permissive bridges for remarkable axonal regrowth. Behavioral and electrophysiological studies indicate that remnants of spared axons, not regenerating axons, mediate functional recovery, strongly suggesting that additional interventions are still required to render the rebuilt neuronal circuits functional. These findings pave the way for the development of a systemic solution to treat acute SCI.