Hierarchically engineered injectable hydrogels loaded with polyphenol for enhanced wound healing and tissue regeneration

Abstract

The healing of deep wounds is severely impeded by the converging pathophysiology of persistent inflammation, oxidative stress, bacterial infection, and many other factors that necessitate an ideal solution that simultaneously targets multiple barriers to accelerate the healing of wounds. Here, we report SCLP, a multifunctional, dynamically cross-linked hierarchical hydrogel network synthesised through the strategic integration of a lab-synthesised spermine–gellan gum conjugate (S), chondroitin sulfate (C), LAPONITE®–polyethyleneimine (L–PEI) nanohybrids, and the plant-derived polyphenol protocatechualdehyde (P). The materials chemistry of SCLP relies on stable amide conjugation, polyelectrolyte complexation, and reversible Schiff-base bridging to mimic the extracellular matrix (ECM) while providing superior tissue adhesiveness and shear-thinning injectability. Physicochemical evaluations indicate robust cross-linking, an interconnected porous framework, improved mechanical reliability, and controlled biodegradation. Furthermore, the hydrogel exhibits synergistic antioxidant, anti-inflammatory, and potent antibacterial properties through the rational assembly of bioactive moieties. In vitro studies show steady exudate absorption, hemocompatibility, enhanced fibroblast viability, and the inhibition of bacterial biofilms. In vivo full-thickness wound models display accelerated wound closure and significant granulation tissue formation, without organ toxicity or adverse skin reactions. Collectively, SCLP offers a next-generation bioactive platform that simultaneously addresses the multifaceted barriers to wound healing while outperforming conventional dressings and monofunctional materials, thereby setting a new standard in effective wound care.