A microenvironment-responsive chitosan based injectable hydrogel with synergistic anti-inflammatory effects of...

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.