Multi‐Tissue Crosstalk Regulating Meniscus Healing Under Inflammation and Physiological Loading

The meniscus has been largely ignored in the emerging research interest in multi-tissue crosstalk in knee joints. This study discovers the novel roles of three-way crosstalk between meniscus, synovial membrane, and fat in the regulation of meniscus injury, degeneration, and healing. A novel meniscus-on-a-chip (MoC) model is developed, equipped with a bioprinted synovial membrane, engineered fat tissue, and a meniscus explant healing model, treated with bioactive glue and synovial mesenchymal stem cells (syMSCs). Our MoC integrated with a meniscus-specific bioreactor enables a comprehensive investigation into the combinational effects of inflammation and physiological/pathological loading on meniscus healing and degeneration. The MoC successfully replicates not only meniscus healing induced by bioactive glue but also the OA initiation and progression from meniscus injury. Comprehensive scRNA-seq with CellChat analysis suggests how communications between adipocytes, macrophages, fibrochondrocytes, and syMSCs regulate the fate of meniscus injury in response to exogenous stimulation. This study represents the first identification of cell-cell communication signals between meniscus, synovial membrane, fat, and syMSCs, which are potentially responsible for regulating meniscus healing under inflammation and mechanical loading. These novel findings may have significant implications for developing next-generation therapeutics for meniscus injury and prevention of joint degeneration through regulating multi-tissue crosstalk in the joint.