Biophysical signal-driven scaffold design for stem cell-guided osteochondral regeneration

Osteochondral tissue comprises two structurally and functionally distinct regions: An avascular, low-cellularity cartilage layer with poor self-healing capacity, and a vascularized, mineralized subchondral bone. This pronounced heterogeneity complicates the repair of defects that span both regions. Conventional clinical treatments, such as microfracture and autologous chondrocyte implantation, often fail to restore the native biphasic architecture, leading to disorganized fibrocartilage and poor tissue integration. Tissue engineering has emerged as a promising strategy by integrating mesenchymal stem cells (MSCs) with engineered biomaterial scaffolds. However, spatially directing MSCs toward chondrogenic and osteogenic lineages remains challenging. Beyond biochemical cues, biophysical cues play pivotal roles in modulating MSC fate <i>via</i> integrin-mediated mechanotransduction, cytoskeletal remodeling, and mechanosignaling pathways, including TRPV4, Piezo1, and YAP/TAZ. When appropriately encoded within scaffolds, these biophysical cues provide sustained, spatially defined guidance to MSCs. This review summarizes recent advances in scaffold design that leverage mechanobiology to construct biomimetic microenvironments, thereby manipulating lineage-specific MSC differentiation and facilitating layered, stratified osteochondral regeneration.