Rapamycin incorporating hydrogel improves the progression of osteoarthritis by inducing synovial macrophages polarization and reducing intra-articular inflammation

Abstract

In the macrophage-specific mTORC1 signaling activation model, the synovial macrophages polarized toward M1, thus aggravating synovitis and progression of OA. Therefore, intra-articular injection of rapamycin, a classical mTORC1 inhibitor, may show great potential for alleviating synovitis and delaying cartilage destruction in osteoarthritis (OA). However, the durable retention of drugs in the joint cavity is still a critical issue to be addressed. Herein, we crosslinked the Poloxamer 407 and hyaluronic acid (P-HA) to prepare an injectable and thermo-responsive drug delivery system to durably retain rapamycin and dramatically magnify their therapeutic effects in OA management. The prepared P-HA hydrogel showed excellent biocompatibility with chondrocytes and fibroblasts, as well as possessed sustained rapamycin release profiles for 14 days. Intra-articular injection of this rapamycin-incorporated P-HA hydrogel indicated a positively effect on inducing the polarization of synovial macrophages from M1 to M2 phenotype and reducing synovial inflammation in OA. This strategy significantly decreased the pro-inflammatory cytokines (e.g., TNF-α, IL-1β, and IL-6) and increased the anti-inflammatory cytokine (e.g., IL-10) expression in the synovial tissues and synovial fluid. As a result, intra-articular injection of rapamycin-incorporated P-HA hydrogel significantly prevented cartilage destruction by inducing cartilage matrix formation, which suggesting a great potential for the management of OA.