A bioadhesive antioxidant dual-crosslinked hydrogel mitigates endothelial pyroptosis to enhance ischemic flap...

Multiterritory perforator flaps are widely used in reconstructive surgery; however, distal regions, particularly the choke zone, remain highly susceptible to necrosis due to sustained ischemia, oxidative stress, and endothelial inflammatory injury that impair microcirculatory remodeling. Although stem cell-derived exosomes are promising cell-free therapeutics, their efficacy in ischemic flaps is often limited by poor local retention and rapid loss of bioactivity. Here, we develop a bioadhesive antioxidant hydrogel composed of oxidized hyaluronic acid-dopamine and sericin methacrylate (SerMA) to enable stable wet-tissue adhesion and sustained local delivery of hypoxia-preconditioned adipose-derived stem cell exosomes. This strategy attenuates oxidative stress, suppresses NLRP3 inflammasome activation and endothelial pyroptosis, and preserves mitochondrial and angiogenic function under ischemic conditions. In a rat multiterritory perforator flap model, local application of the exosome-loaded hydrogel significantly enhanced flap perfusion and survival, promoted vascular remodeling within the choke zone, and reduced inflammatory responses. Transcriptomic analysis further revealed suppression of inflammasome-associated pathways and enrichment of vascular remodeling programs. Collectively, this work presents a bioadhesive hydrogel-based exosome delivery strategy that stabilizes the ischemic microenvironment and improves outcomes in complex perforator flap reconstruction.