Multi-functional Small Molecule for Regenerative Healing of Avascular Meniscus Tears: Modulation of Inflammation,...

Avascular meniscus tears are a major contributor to mechanical joint locking, compromised gait and function, and the initiation and progression of post-traumatic osteoarthritis. Unfortunately, the avascular meniscus tears hardly heal. Here, we report a novel small molecule, 4-PPBP, a sigma-1 receptor (σ1R) agonist, exhibiting significant potential to promote avascular meniscus healing by activating synovial mesenchymal stem cells (syMSCs) and modulating macrophage-regulated inflammation via multi-tissue crosstalk. In vitro, 4-PPBP promoted the proliferation and migration of meniscus cells and syMSCs, exhibited anti-inflammatory effects, and induced fibrochondrogenic differentiation. 4-PPBP significantly promoted the healing of avascular meniscus tears ex vivo. In vivo, a single injection of 4-PPBP-loaded bioglue minimized meniscal gapping, with improved meniscus healing and gait performance. In contrast to the degenerative changes in the untreated control, 4-PPBP/bioglue application resulted in integrated fibrocartilaginous tissues. scRNA-seq and CellChat analyses revealed 4-PPBP-activated cell-cell communications leading to inflammatory regulation and cell differentiation. Macrophages showed a robust reduction in pro-inflammatory genes, and fibroblasts, chondrocytes, and fibrochondrocytes increased genes associated with differentiation and matrix synthesis in response to 4-PPBP. Anti-inflammatory cell-cell communication signals were significantly elevated between adipocytes and macrophages. Together, this study demonstrates the notable potential of 4-PPBP as a multi-functional therapeutic for avascular meniscus tears.