Thermosensitive injectable graphene oxide/chitosan-based nanocomposite hydrogels for controlling the in vivo release of bupivacaine hydrochloride

Local anesthetics are commonly used for the management of intraoperative and postoperative acute and chronic pain caused by small invasive procedures. However, their short half-life and duration of action limit their clinical benefits. In this study, we proposed the incorporation of graphene oxide (GO) nanosheets to chitosan (CS)/β-glycerophosphate (GP) thermosensitive hydrogel system to form an injectable nanocomposite hydrogel (NCH) with improved mechanical properties and better control over the release of bupivacaine hydrochloride (BH). The prepared NCHs were characterized for their gelation time, porosity, swelling ratio, injectability, mechanical strength and in vitro drug release. In vivo, the efficacy of the prepared NCH containing 0.5 % w/v BH was evaluated using a thermal nociceptive assay in a rat model. The incorporation of GO significantly enhanced the physicochemical and mechanical properties of the hydrogel scaffolds in a concentration-dependent manner. Inclusion of 0.1% w/v GO resulted in 84% reduction in gelation time and 16% and 40% decrease in the porosity and swelling ratio of the NCHs, respectively. The mechanical strength of the CS/GP hydrogel scaffolds was also significantly improved in presence of GO. BH was slowly released from the NCHs containing 0.1% w/v GO and resulted in a 55% and 86.43% drug release after 6 and 24 h, respectively. In vivo studies showed that BH-loaded NCH significantly prolonged the local anesthetic effect and resulted in a 6.5-fold increase in blocking the pain sensory reflex compared to BH solution. These results indicate that the incorporation of GO significantly improved the physical and mechanical properties of CS/GP thermosensitive hydrogels and successfully sustained the effect of local anesthesia for more effective pain management.