A microenvironment-responsive chitosan based injectable hydrogel with synergistic anti-inflammatory effects of triptolide and copper ions for spinal cord injury repair.

The inflammatory microenvironment and irregular lesion cavities following spinal cord injury (SCI) severely hinder neural regeneration. This study developed a copper-based supramolecular hydrogel (COCu/TP-g-COS) loaded with triptolide-grafted chitosan oligosaccharide (TP-g-COS) via a dynamic covalent crosslinking strategy for synergistic anti-inflammatory effects and SCI repair. The hydrogel, based on dynamic schiff base bonds between carboxymethyl chitosan (CMCS) and aldehyde-chitosan (OCS), as well as Cu2+ coordination crosslinking, exhibits injectability, self-healing capability, and microenvironment responsiveness, enabling precise filling of irregular lesion cavities and sustained drug release. In vitro experiments demonstrated that COCu/TP-g-COS achieves pH-dependent staged release of TP, accompanied by continuous Cu2+ release, which significantly suppresses inflammatory responses and promotes neural differentiation. In vivo experiments confirmed that COCu/TP-g-COS synergistically inhibits inflammation through TP and Cu2+, elevating the BBB score to 11 (0) in rats (vs. 3 (0.75) in the SCI group). Histological analysis revealed that the hydrogel significantly promoted axon regeneration and inhibited glial scar formation. Overall, this study provides a multifunctional therapeutic strategy integrating anti-inflammatory regulation and neural regeneration for SCI repair.