Available online 5 November 2025

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 (<one thousandth) of adjuvant dexmedetomidine (29.1 h) was evidently longer than those of the free Rop HCl (4.2 h) and the commercial EXPAREL® injection (4–6 h) groups in the rat sciatic nerve model. Such a ropivacaine/dexmedetomidine-loaded micelles/hydrogel composite via a solvent-free process could be a promising strategy for long-term postoperative pain management.

Local anesthetics are preferred for use in postoperative pain management to avoid using opioids, but their short duration limits their clinical use. Nowadays, many attempts have been reported to load local anesthetics into the nano/microparticles in the hydrophobic free base form for prolonged analgesia, which inevitably involved the use of organic solvents. In this study, we develop the ropivacaine-loaded pH-sensitive micelles/hydrogel composite via a solvent-free process based on pH-sensitive and biodegradable polymeric micelles and thermosensitive and injectable hydroxypropyl chitin for postoperative pain management. The drug-loaded micelles/hydrogel composite exhibited sustained drug release in vitro and in vivo, displaying a much longer effective analgesic time than those of the free ropivacaine injection and the commercial EXPAREL® injection in the rat sciatic nerve blockade model.

Long-term analgesia

pH-sensitive micelles

Injectable thermosensitive hydrogel

Ropivacaine

Hydroxypropyl chitin

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