Injectable Trimethyl Chitosan Hydrogel with Capsaicin Mitigates Functional Pain and Angio-Osteogenic Coupling in an Animal Model of Osteoarthritis
Abstract
Osteoarthritis (OA) remains a leading cause of disability worldwide, with current therapies limited to symptomatic relief. In this study, we developed and evaluated a thermoresponsive hydrogel system based on N,N,N-trimethyl chitosan (TMC) for the sustained intra-articular delivery of capsaicin, an established analgesic. This study focused on assessing the system’s biocompatibility, anti-inflammatory effects, and its impact on functional recovery in an animal model. A thermoresponsive hydrogel (1% TMC, 10% β-glycerophosphate) was formulated for stable gelation at 37 °C. Biocompatibility was assessed via cell count assays on rat articular chondrocytes and macrophages. Therapeutic impact was evaluated through rotarod performance and histological assessment of cartilage integrity in monoiodoacetate-induced OA in rats. Macrophage polarization was analyzed via immunofluorescence. In vitro, the TMC hydrogel successfully enhanced the biocompatibility of capsaicin while indicating a shift away from proinflammatory (M1) macrophage polarization, reflected in a 25% reduction of CD86+ cells while increasing CD206+ cells by 30%. Furthermore, this group exhibited consistent improvement in rotarod latency for up to 4 weeks post-treatment. Histopathological grading scores corroborated these functional improvements, with OA animal models treated with the TMC hydrogel loaded with capsaicin reaching only an average score of 2 compared to untreated control group’s 6. Immunofluorescence analysis revealed marked reduction in angiogenic and interleukin-6 inflammatory markers compared to control groups. The TMC–capsaicin hydrogel system shows promise as a biocompatible localized injectable treatment for OA. This system was associated with improved functional performance and joint protection, along with reduced inflammatory marker expression and preservation of cartilage tissue integrity.