Intra-articular hexagonal boron nitride-hyaluronic acid composite hydrogels rebalance cytokine profiles and enhance extracellular matrix regeneration in a rabbit osteoarthritis model.

Abstract

OBJECTIVE: Osteoarthritis (OA) is a chronic, degenerative joint disease characterized by cartilage breakdown, inflammation, and progressive loss of joint function, leading to significant disability and reduced quality of life. Current treatment strategies, including pharmacological agents and intra-articular (IA) injections such as corticosteroids and hyaluronic acid (HA), provide symptomatic relief but fail to halt disease progression or promote cartilage regeneration. This study investigates the therapeutic potential of novel injectable hybrid hydrogels composed of hexagonal boron nitride (hBN) nanoparticles (NP) and nanosheets (NS) combined with HA. METHODS: A comprehensive in vivo evaluation was conducted using a rabbit OA model, incorporating biochemical, gene expression, histological, and Western blot analyses to assess the efficacy of these hybrid biomaterials. Cytotoxicity assays confirmed the biocompatibility of hBN-HA hybrid hydrogels at appropriate concentrations. RESULTS: Our results demonstrated that hybrid hydrogels significantly suppressed pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), while enhancing anti-inflammatory cytokine interleukin-10 (IL-10). Furthermore, key mediators involved in OA pathogenesis, such as vascular endothelial growth factor (VEGF) and semaphorin-3A (SEMA3A), were significantly downregulated in the treatment groups. Notably, NP hydrogels promoted collagen type II (COL2) synthesis and extracellular matrix restoration, while NS hydrogels exhibited superior anti-inflammatory effects. Histological analyses further confirmed improved cartilage integrity, with reduced fibrillation, inflammation, and vascular congestion in the NP and NS treatment groups compared to OA controls. CONCLUSION: The findings highlight the potential of hBN-HA hybrid hydrogels as a next-generation therapeutic strategy for OA, offering dual benefits of inflammation suppression and cartilage regeneration. Given their superior efficacy over HA alone, these biomaterials represent a promising translational approach that could be further explored for clinical applications in OA treatment.