Restoring joint homeostasis: In vitro and in vivo efficacy of a sodium hyaluronate-lipoate-formate therapy for osteoarthritis.

Osteoarthritis (OA) is a multifactorial joint disorder characterized by inflammation, cartilage homeostasis disruption, and extracellular matrix degradation. Although hyaluronic acid (HA) viscosupplementation is widely used, available formulations mainly provide symptomatic relief without targeting underlying inflammatory and catabolic processes. Here, two innovative HA derivatives covalently functionalized with lipoic acid and formate (SHLF0.5% and SHLF1%) were developed to enhance viscoelastic properties and modulate the oxidative joint microenvironment. Biological performance was evaluated in human chondrocyte-synoviocyte co-cultures under healthy and OA conditions by assessing cell viability and markers of cartilage metabolism, extracellular matrix turnover, and inflammation. The most promising formulation, SHLF0.5%, was further investigated in vivo in a rat destabilization of the medial meniscus (DMM) model, evaluating pain-related behaviour, cartilage integrity, synovial morphology, and extracellular matrix features. In vitro, SHLF0.5% supported cell viability and modulated markers associated with cartilage homeostasis and matrix turnover (increased expression of PRG4 and TIMP1, and decreased expression of MMP1, MMP3, MMP13, ADAMTS-5, IL6, and PTGS2). SHLF1% also showed a favourable biological profile, supporting the functional potential of the SHLF platform. In vivo, SHLF0.5% improved pain-related outcomes and preserved cartilage structure, with lower OARSI scores, maintained proteoglycan content and Type II collagen/aggrecan expression, and preserved synovial features compared with NaCl and a clinically used HA formulation. Overall, SHLF0.5% showed favourable biological performance and preservation of joint tissue integrity, supporting its potential as a next-generation viscosupplement combining enhanced viscoelastic properties with features resembling physiological synovial fluid.