Multi-functional Small Molecule for Regenerative Healing of Avascular Meniscus Tears: Modulation of Inflammation, Differentiation, and Multi-Tissue Crosstalk

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 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.