O2 variant chip to simulate site-specific skeletogenesis from hypoxic bone marrow

Abstract

The stemness of bone marrow mesenchymal stem cells (BMSCs) is maintained by hypoxia. The oxygen level increases from vessel-free cartilage to hypoxic bone marrow and, furthermore, to vascularized bone, which might direct the chondrogenesis to osteogenesis and regenerate the skeletal system. Hence, oxygen was dif-fused from relatively low to high levels throughout a three-dimensional chip. When we cultured BMSCs in the chip and implanted them into the rabbit defect models of low-oxygen cartilage and high-oxygen calvaria bone, (i) the low oxygen level (base) promoted stemness and chondrogenesis of BMSCs with robust antioxidative po-tential; (ii) the middle level (two times >= low) pushed BMSCs to quiescence; and (iii) the high level (four times >= low) promoted osteogenesis by disturbing the redox balance and stemness. Last, endochondral or intramem-branous osteogenesis upon transition from low to high oxygen in vivo suggests a developmental mechanism- driven solution to promote chondrogenesis to osteogenesis in the skeletal system by regulating the oxygen environment.