Injectable thermosensitive hydrogel based on hyaluronic acid and poloxamer for sustained bupivacaine release and prolonged analgesia

Local anesthetics are commonly used for postoperative pain relief but have limited effectiveness due to their short half-life and low molecular weight. Various sustained-release systems have been explored but face challenges such as low encapsulation efficiency in liposomes, rapid degradation and limited release durations of hydrogel, and difficulties with injectability in combined microsphere/hydrogel. This study presents a double cross-linked hydrogel (Bup/PO) made from aminated poloxamer 407 (P407) and oxidized hyaluronic acid (OHA), cross-linked via oxime bonds and hydrophobic interactions. Rheological analysis showed that the hydrogel exhibited temperature sensitivity, with a storage modulus of up to 10,000 Pa at 37 °C, significantly higher than pure P407. In vitro, the hydrogel provided sustained bupivacaine release for up to 8 days. In vivo, a rat sciatic nerve block model demonstrated that the Bup/PO hydrogel significantly extended the mechanical pain threshold for 32 h and thermal pain threshold for 48 h. The hydrogel was fully biodegradable within 21 days, with mild reversible inflammation and no neurotoxicity. This study introduces a double-cross-linking mechanism that improves hydrogel stability, mechanical properties, and drug release, offering a promising solution for long-term postoperative pain management and regional anesthesia.