Hamburger-like biomimetic nutrient periosteum with osteoimmunomodulation, angio-/osteo-genesis capacity promoted critical-size bone defect repair

The periosteum is pivotal in bone repair, serving as a key facilitator for new bone formation through its osteoimmunomodulation and neovascularization. However, autologous periosteum sources are limited, and traditional periosteal tissue engineering makes it difficult to mimic these functions of periosteum through simple structural design. In this study, we present a biomimetic nutrient periosteum with a hamburger-like structure. The middle layer is a mixed cell sheet composed of million level of bone marrow stromal cells (BMSCs) and M2 macrophages. Silk protein based-hydrogel layer encapsulating porous PLLA microspheres and CaO2 nanoparticles was placed on the top and bottom layers of the cell sheets. The heterogeneous hydrogel enabled not only mechanical stability of the cell sheets, but also slow-releasement of oxygen from CaO2 up to 30 days, which further enhances the viability of the cell sheets. That is, it closely mimics the structure and functionality of natural periosteum, effectively replicating its regenerative microenvironment. This hamburger-like biomimetic nutrient periosteum not only facilitates the transition of macrophages to a pro-healing M2 phenotype but also enhances the osteogenic differentiation of BMSCs and angiogenesis of human umbilical vein endothelial cells (HUVECs). Importantly, these effects have been validated in vivo in a critical-size bone defect model, underlining the potential of this biomimetic nutrient periosteum as an effective approach for advanced bone repair.