Accumulation of reactive oxygen species (ROS) following skin injury impairs tissue regeneration by inducing inflammation, oxidative damage, and cellular apoptosis. To address this challenge, we developed a multifunctional semi-interpenetrating polymer network hydrogel composed of silk fibroin methacrylate (SFMA) and Pluronic F127 (PF). The optimized SFMA9/PF1 hydrogel exhibits excellent mechanical compliance, electrical conductivity, antioxidant activity, and anti-freezing capacity. Incorporation of PF enhanced porosity, water retention, and ionic conductivity (∼0.42 S·cm−1), while preserving optical transparency and tunable viscoelasticity. Rheological and degradation analyses demonstrated outstanding elasticity, thermal stability, strain resistance, and sustained biodegradability under physiological conditions. Notably, the hydrogel maintains flexibility and structural integrity at subzero temperatures (−20°C and −80°C), indicating strong freeze resistance. In vitro assays confirmed superior cytocompatibility, with significant promotion of fibroblast adhesion, migration, and proliferation. The hydrogel also exhibited potent antioxidant capacity, effectively scavenging 1,1-diphenyl-2-picrylhydrazyl and H2O2 radicals and reducing intracellular ROS levels. In a full-thickness skin wound model in SD rats, SFMA9/PF1 hydrogel accelerated wound closure, enhanced re-epithelialization, and promoted organized collagen remodeling. Histological and immunofluorescence analyses revealed increased angiogenesis (CD31), reduced myofibroblast activation (α-SMA), and suppressed pro-inflammatory cytokine expression (IL-6), indicating the establishment of a regenerative and anti-inflammatory microenvironment. Overall, the SFMA9/PF1 hydrogel integrates mechanical adaptability, bioactivity, and oxidative stress modulation, representing a promising platform for advanced wound healing and skin tissue engineering.
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