Recent Advances in Cell Sheet-Based Tissue Engineering for Bone Regeneration

In conventional bone tissue engineering, cells are seeded onto scaffolds to create three-dimensional (3D) tissues, but the cells on the scaffolds are unable to effectively perform their physiological functions due to their low density and viability. Cell sheet (CS) engineering is expected to be free from this limitation. CS engineering uses the principles of self-assembly and self-organization of endothelial and mesenchymal stem cells to prepare CSs as building blocks for engineering bone grafts. This process recapitulates the native tissue development, thus attracting significant attention in the field of bone regeneration. However, the method is still in the prebasic experimental stage in bone defect repair. To make the method clinically applicable and valuable in personalized and precision medicine, current research is focused on the preparation of multifunctionalized building blocks using CS technologies, such as 3D layered CSs containing microvascular structures. Considering the great potential of CS engineering in repairing bone defects, in this review, the types of cell technologies are first outlined. We then summarize the various types of CSs as building blocks for engineering bone grafts. Furthermore, the specific applications of CSs in bone repair are discussed. Finally, we present specific suggestions for accelerating the application of CS engineering in the clinical treatment of bone defects. Impact statement Cell sheets (CSs) can be used independently for bone repair and act as a bionic periosteum with scaffolding materials to promote bone regeneration. CS engineering has shown distinct advantages in bone defect repair, especially in regard to the implantation of three-dimensional hierarchical CSs containing microvascular structures into bone defects, which can significantly improve bone regeneration. This has been well confirmed by microcomputed tomography and histological and immunohistochemical results. The shift of CS engineering to the clinic requires continuous research in the preparation of multifunctional and personalized CSs, as well as refinement of experimental design.