Micelle-to-Gel: Thermosensitive intra-articular hydrogels for osteoarthritis management

Abstract

Osteoarthritis (OA) is a chronic and degenerative joint disease with a rising incidence worldwide. Current therapeutic approaches primarily focus on symptom relief through systemic administration, which raises safety concerns related to side effects and long-term use. In this context, the local administration of natural compounds with anti-inflammatory and anti-arthritic properties, such as β-Lapachone constitutes an interesting alternative. In this work, we prepared and characterized injectable thermosensitive hybrid hydrogels loaded with β-Lapachone. A comprehensive characterization of the hydrogel systems was performed, including micellar diameter, mechanical properties at different temperatures, the ability to control drug release and microstructure. The anti-inflammatory activity of the free drug, as well as that of the blank or loaded hydrogels was then evaluated ex vivo, using OA cartilage explants. Additionally, in vivo studies were carried out in a rabbit model of OA to assess their clinical potential. The results suggest that the hydrogel systems possess a composite microstructure integrating micelles, together with a temperature-responsive stiffness and the ability to modulate drug release. In addition, β-Lapachone-loaded hydrogels display an interesting immunomodulatory potential ex vivo, as they were able to efficiently reduce the secretion of several proinflammatory mediators, such as IL-6, MMP9, MMP13 and CXCL8. Furthermore, the drug-loaded hydrogels were found to improve in vivo cartilage and bone histomorphometric markers, such as subchondral bone thickness, as well as early signs of cartilage damage, such as the fibrillation index. Therefore, the developed β-Lapachone-loaded thermosensitive hydrogels constitute a promising alternative for OA management.

Keywords: Anti-inflammatory activity; Hyaluronic acid; Osteoarthritis; Thermosensitive hydrogels; β-Lapachone.