A pH-responsive and self-healing CEC/PEG-(CHO)2 hydrogel for controlled neuropeptide S delivery and endogenous neural repair after spinal cord injury

Abstract

A pH-responsive CEC/PEG-(CHO)2 hydrogel scaffold was engineered for local delivery of neuropeptide S (NPS) to modulate the hostile microenvironment after spinal cord injury (SCI). The scaffold exhibited accelerated degradation under acidic conditions mimicking the injured site, enabling controlled release of NPS. Its porous microstructure (50−150 μm pore size) and compressive elastic modulus (0.081 MPa, slightly softer than that of a native spinal cord) provide a mechanical microenvironment conducive to neuronal survival and differentiation. In a T11 complete transection mouse model, the NPS-loaded scaffold significantly attenuated local inflammation (reduced MMP-9, TNF-α, CD68; increased IL-10), suppressed glial scar formation, recruited endogenous Nestin+ neural stem/progenitor cells (NSPCs), and promoted their differentiation into mature MAP2+ neurons with enhanced myelination (MBP+) and synaptic integration (SYP+/MAP2+). These effects were mediated through the NPS-NPSR axis and downstream Ca2 +/cAMP signaling pathways. This study demonstrates that a rationally designed pH-responsive hydrogel can effectively remodel the SCI microenvironment and activate endogenous neural repair mechanisms, offering a promising strategy for SCI treatment.