An injectable self-healing hydrogel with pH-responsiveness for local analgesia and ROS scavenging in wound healing

A Ce 3+ -crosslinked injectable self-healing hydrogel with pH responsiveness is developed for wound analgesia and ROS removal. • Hydrogel enables rapid drug and cerium release in acidic wounds, while achieving sustained release with minimal leakage at physiological pH. • Acid-triggered cerium release achieves ≥78% ROS clearance, with the hydrogel maintaining excellent cytocompatibility (viability ≥95%) at neutral pH. • A single perilesional injection achieves 36-hour analgesia in the mouse plantar incision model, significantly surpassing free ropivacaine. • Analgesia is achieved by inhibiting TRPV1+ neuron activation in DRG and spinal dorsal horn, with reliable biosafety and intact wound healing. Since tissue acidification in wounds is tightly linked to pain and inflammation, pH-responsive hydrogels are promising candidates for local analgesia and ROS scavenging in wound management. Herein, an injectable, self-healing and pH-responsive hydrogel crosslinked by coordination bonds between cerium ions and carboxylate moieties of carboxymethyl cellulose (CMC) is developed to encapsulate ropivacaine (Rop). The hydrogel features rapid matrix dissolution accompanied by fast release of both Rop and cerium ions under acidic conditions (pH 6.2), while providing sustained Rop release and extremely limited cerium ion release at physiological pH of 7.4. These features contribute to prominent antioxidant activity (ROS clearance rate ≥78%) under acidic conditions, and excellent cytocompatibility (cell viability ≥95%) at pH 7.4. Injecting the hydrogels into mouse plantar incisions resulted in prolonged analgesia (36 h) matching their Rop release feature, alongside excellent biosafety without impairing wound repair. Immunofluorescent assays demonstrate that such analgesic effects are realized by inhibiting the activation of TRPV1 + neurons in the DRG and neurons in the spinal dorsal horn. These findings provide an injectable, self-healing and pH-responsive hydrogel crosslinked by cerium ion coordination for local anesthetic loading and antioxidation in wound healing. Download: Download high-res image (104KB) Download: Download full-size image