Integrating physicomechanical and biological strategies for BTE: biomaterials-induced osteogenic differentiation of MSCs.

Large bone defects are a major global health concern. Bone tissue engineering (BTE) is the most promising alternative to avoid the drawbacks of autograft and allograft bone. Nevertheless, how to precisely control stem cell osteogenic differentiation has been a long-standing puzzle. Compared with biochemical cues, physicomechanical stimuli have been widely studied for their biosafety and stability. The mechanical properties of various biomaterials (polymers, bioceramics, metal and alloys) become the main source of physicomechanical stimuli. By altering the stiffness, viscoelasticity, and topography of materials, mechanical stimuli with different strengths transmit into precise signals that mediate osteogenic differentiation. In addition, externally mechanical forces also play a critical role in promoting osteogenesis, such as compression stress, tensile stress, fluid shear stress and vibration, etc. When exposed to mechanical forces, mesenchymal stem cells (MSCs) differentiate into osteogenic lineages by sensing mechanical stimuli through mechanical sensors, including integrin and focal adhesions (FAs), cytoskeleton, primary cilium, ions channels, gap junction, and activating osteogenic-related mechanotransduction pathways, such as yes associated proteins (YAP)/TAZ, MAPK, Rho-GTPases, Wnt/ß-catenin, TGFß superfamily, Notch signaling. This review summarizes various biomaterials that transmit mechanical signals, physicomechanical stimuli that directly regulate MSCs differentiation, and the mechanical transduction mechanisms of MSCs. This review provides a deep and broad understanding of mechanical transduction mechanisms and discusses the challenges that remained in clinical translocation as well as the outlook for the future improvements.

3D printed Ti-5Cu alloy accelerates osteogenic differentiation of MC3T3-E1 cells by stimulating the M2 phenotype polarization of macrophages.

Ti-5Cu alloy has been proved to have excellent mechanical properties and cell compatibility and has certain antibacterial properties due to the addition of Cu. However, there are few studies on the effects of Ti-5Cu alloy on macrophage polarization and immune-related bone formation. In this study, we prepared Ti-5Cu alloy by three-dimensional printing technology and found that Ti-5Cu alloy presented a much smoother surface compared with Ti. In addition, the CCK-8 results indicated the Ti-5Cu alloy had no cytotoxicity to RAW264.7 cells by co-culture. The results of inductively coupled plasma mass spectrometry showed that the concentration of Cu2+ was 0.133 mg/L after 7 days of co-culture, and the CCK-8 results proved that Cu2+ had no cytotoxicity to RAW264.7 at this concentration. Then, we studied the effects of Ti-5Cu alloy on macrophage polarization; it was shown that the Ti-5Cu alloy is more prone to modulate the RAW264.7 polarization towards the M2 phenotype and the conditioned medium derived from Ti-5Cu alloy significantly promoted the proliferation and osteogenic differentiation of MC3T3-E1 cells. However, when the expression of Oncostatin M (OSM) gene of RAW264.7 was knocked down, the osteogenic differentiation of MC3T3-E1 cells was decreased. This suggests that the OSM secreted by RAW264.7 co-cultured with Ti-5Cu alloy could accelerate the osteogenic differentiation of MC3T3-E1 cells by acting on OSMR/gp130 receptors.