In situ osteogenic activation of mesenchymal stem cells by the blood clot biomimetic mechanical microenvironment.

Blood clots (BCs) play a crucial biomechanical role in promoting osteogenesis and regulating mesenchymal stem cell (MSC) function and fate. This study shows that BC formation enhances MSC osteogenesis by activating Itgb1/Fak-mediated focal adhesion and subsequent Runx2-mediated bone regeneration. Notably, BC viscoelasticity regulates this effect by modulating Runx2 nuclear translocation. To mimic this property, a viscoelastic peptide bionic hydrogel named BCgel was developed, featuring a nanofiber network, Itgb1 binding affinity, BC-like viscoelasticity, and biosafety. The anticipated efficacy of BCgel is demonstrated by its ability to induce nuclear translocation of Runx2 and promote bone regeneration in both in vitro experiments and in vivo bone defect models with blood clot defect, conducted on rats as well as beagles. This study offers insights into the mechano-transduction mechanisms of MSCs during osteogenesis and presents potential guidelines for the design of viscoelastic hydrogels in bone regenerative medicine.