Oxidized pullulan/carboxymethyl chitosan hydrogel with salidroside for enhanced wound healing

Polysaccharide-based hydrogels with integrated bioactive functionality are highly desirable for wound dressing applications. Here, we report an injectable, self-healing hydrogel (OPC@Sal) fabricated via dynamic Schiff-base crosslinking between oxidized pullulan (OPL) and carboxymethyl chitosan (CMCS), with simultaneous incorporation of salidroside as a therapeutic agent. The gelation kinetics, mechanical properties, and microstructure were finely tuned by varying the OPL concentration at a fixed oxidation degree. The optimized OPC@Sal hydrogel exhibited rapid self-healing, excellent injectability, favorable biocompatibility, moisture retention, exudate absorption, and sustained salidroside release, along with pronounced antibacterial activity against E. coli and S. aureus . In vitro, the hydrogel effectively scavenged intracellular reactive oxygen species and suppressed the expression of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) in LPS-stimulated macrophages. Based on the established in vitro effects, network pharmacology analysis was performed as a mechanistic interpretation tool, identifying key targets (TNF-α, IL-6, CASP3, IL-1β) through which salidroside exerts its multi-target regulation of wound healing. In a mouse full-thickness skin defect model, OPC@Sal significantly accelerated wound closure, promoted collagen deposition, and enhanced re-epithelialization. Collectively, this work establishes a fully polysaccharide-derived hydrogel platform that synergistically integrates structural functionality with intrinsic bioactivity. The molecular engineering of oxidized pullulan and carboxymethyl chitosan, combined with network pharmacology-guided active compound selection, offers a sustainable and scalable strategy for developing advanced wound dressings.