A solvent-free ropivacaine-loaded composite hydrogel assembled from pH-sensitive micelles and a thermosensitive injectable hydrogel for prolonged local anesthesia

Postoperative pain is a major clinic challenge and local anesthetics are preferred for use in postoperative pain management, but their short duration of analgesia limits their clinical use. Various drug carriers such as liposomes or nano/microparticles have been developed for prolonging the analgesic duration, yet how to achieve effective drug loading without using organic solvents and sustained-release local anesthetics remains a big challenge. Herein, we synthesized a pH-sensitive and biodegradable polymer to efficiently load ropivacaine (Rop-micelles) by pH-induced micellization method without using any organic solvent, avoiding the aggregation and precipitation of Rop under neutral conditions within 7 days. Subsequently, an injectable dispersion of Rop-micelles in hydroxypropyl chitin (Rop-micelles@HPCH) was developed for long-term local anesthesia. This system was prepared via a simple and solvent-free process that combined pH-sensitive micelles with thermosensitive HPCH, demonstrating proven biocompatibility and biodegradability. Importantly, the obtained Rop-micelles@HPCH composite hydrogel exhibited a much more sustained Rop release than that of drug loaded in micelles or hydrogel alone in vitro. The effective analgesic time of Rop-micelles@HPCH (20.3 h) or Rop-micelles@HPCH-Dex with only a small fraction (