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.