Accelerated wound healing via ERK1/2 activation using tracheloside loaded multifunctional photocrosslinked ECM hybrid hydrogel

Chronic wounds remain a significant clinical challenge as prolonged inflammation, oxidative stress, infection, and insufficient structural support in the microenvironment prevent effective tissue regeneration. A multifunctional photocrosslinkable hybrid hydrogel, Tr-maCSE, was developed through methacrylation of extracellular matrix (maECM) and chitosan (maCS), incorporating tracheloside (Tr), a lignan glycoside with keratinocyte-proliferative, antioxidant, and anti-inflammatory properties. Photocrosslinking enabled in situ gelation under cytocompatible conditions to produce a flexible hydrogel with tunable mechanics. In particular, this system integrates structural reinforcement, ECM-derived bioactivity, and localized therapeutic modulation to actively promote wound regeneration. 1 H-NMR, FTIR, and SEM confirmed the modification and conjugation of materials, while physicochemical analysis demonstrated stability, flexibility, and controlled degradation with sustained drug release. In-vitro, Tr-maCSE promoted cell proliferation, migration, oxidative stress resistance, antimicrobial activity, and reduced inflammatory response. In a rat full-thickness wound model, the hydrogel evidenced accelerated wound closure, enhanced granulation tissue formation, organized collagen deposition, and promoted adnexal regeneration. Biological response investigations confirmed elevated expression of angiogenic, macrophage-polarization, and reparative markers in the hybrid hydrogel, as well as increased ERK1/2 expression. Altogether, these observations demonstrate the potential of multifunctional, bioinspired Tr-maCSE hydrogel as a promising platform for orchestrating enhanced skin wound repair and restoring functional epidermal regeneration.