Injectable glycol chitosan hydrogel system for sustained drug delivery to treat neuropathic pain

Spinal epidural injections remain a clinical challenge due to their limitations, including short drug durations and accidental drug flows to motor nerves. In this study, we developed and evaluated a CHA-DEX-MEPI hydrogel as a novel injectable drug delivery system to provide sustained pain relief and reduce temporary flow to motor nerves. Glycolic chitosan (gC) and oxidized hyaluronic acid (oHA) were used to form what is referred to as the gC/oHA (CHA) gel through self-crosslinking. Dexamethasone (DEX) and mepivacaine (MEPI) were embedded with the CHA gel to synthesize the CHA-DEX-MEPI gel. Bone marrow-derived macrophages (BMMs) were activated by lipopolysaccharide (LPS) to evaluate the anti-inflammatory effect for three days. The chronic constriction injury (CCI) model was employed in Sprague-Dawley (SD) rats to investigate the pain-relief effects for 14 days. The structure of the CHA gel indicated injectable viscosity and porosity. The CHA-DEX-MEPI gel sustainably released DEX and MEPI for more than 72 h. It prolonged the reduction of inflammatory cytokines genes for three days in the BMMs compared to that in a DEX-MEPI solution. Moreover, our results demonstrated that the CHA-DEX-MEPI gel significantly reduced both cold and mechanical allodynia after seven days post-injury (DPI). It also demonstrated sustained reductions in the expression levels of key nociceptive markers, including transient receptor potential vanilloid type-1 channel (Trpv1), transient receptor potential ankyrin 1 (Trpa1), and calcitonin-gene-related peptide (Cgrp), on 14 DPI. These findings suggest that the CHA-DEX-MEPI gel can serve as a promising approach for the treatment of neuropathic pain.