Injectable Hierarchical Microsphere-Hydrogel System for the Sustained Release of Bupivacaine and Celecoxib in Long-Acting Analgesia

Postoperative pain is a common issue after surgical procedures. While peripheral nerve blocks are an effective strategy for postoperative pain management, local anesthetics, although offering potent analgesia with minimal systemic side effects, are limited by their short half-life and rapid clearance. In this study, we developed an injectable microsphere/hydrogel (MS/Gel) composite designed to provide prolonged local anesthesia. The composite consists of poly(lactic-<i>co</i>-glycolic acid) (PLGA) microspheres coloaded with bupivacaine (Bup) and celecoxib (Cel) via electrostatic spraying and incorporated into a thermosensitive gel matrix composed of poloxamer 407 (P407) and hyaluronic acid (HA). The MS/Gel composite exhibited excellent injectability, uniform microsphere distribution, and a biphasic sustained-release profile, significantly reducing the burst release. In vitro evaluations demonstrated that drug release was extended to more than 10 days. Furthermore, in a rat sciatic nerve block model, the MS/Gel significantly prolonged both mechanical and thermal pain thresholds for up to 48 h. Biocompatibility assessments confirmed good cytocompatibility, biodegradability, lack of neurotoxicity, and only a mild, reversible inflammatory response. Overall, the MS/Gel composite presents a promising strategy for postoperative pain management, providing a safe and effective sustained-release system for long-acting local anesthesia.