As direct effector cells for osteogenesis, osteoblastic cells are commonly used for evaluating the in vitro osteogenic capacity of bone biomaterials, and the traditional biological principle for developing bone biomaterials is to directly stimulate osteogenic differentiation. With this principle, most efforts are currently spent on optimizing the bio-mechanical and physicochemical properties to induce osteogenic differentiation of mesenchymal stem cells. This strategy has achieved certain success in the development of bone biomaterials; however, inconsistencies between in vitro and in vivo studies are not uncommon, implying the mechanisms that govern the material's capacity to mediate osteogenesis is not well-understood. Osteoimmunology has revealed the vital role of immune cells in regulating bone dynamics. Neglecting the importance of the immune response is a major shortcoming of the traditional strategy, and may explain inconsistencies between in vitro and in vivo conditions. Here, we proposed osteoimmunomodulation (OIM) in recognition of the importance of the immune response during biomaterial-mediated osteogenesis. Accordingly, we proposed the paradigm shift of bone biomaterials to an osteoimmunomodulatory material and discussed the evaluation strategy for the osteoimmunomodulation property of bone biomaterials. It is the ambition of authors that this review will change traditional methods for bone biomaterials assessment and assist in developing new bone biomaterials with the osteoimmunomodulatory property for orthopedic and dental applications

Mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into various cell types and have been widely used in tissue engineering application. In tissue engineering, a scaffold, MSCs and growth factors are used as essential components and their interactions have been regarded to be important for regeneration of tissues. A critical problem for MSCs in tissue engineering is their low survival ability and functionality. Most MSCs are going to be apoptotic after transplantation. Therefore, increasing MSC survival ability and functionalities is the key for potential applications of MSCs. Several approaches have been studied to increase MSC tissue forming capacity including application of growth factors, overexpression of stem cell regulatory genes, and improvement of biomaterials for scaffolds. The effects of these approaches on MSCs have been associated with activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. The pathway plays central regulatory roles in MSC survival, proliferation, migration, angiogenesis, cytokine production, and differentiation. In this review, we summarize and discuss the literatures related to the roles of the PI3K/Akt pathway in the functionalities of MSCs and the involvement of the pathway in biomaterials-increased MSC functionalities. Biomaterials have been modified in their properties and surface structure and loaded with growth factors to increase MSC functionalities. Several studies demonstrated that the biomaterials-increased MSC functionalities are mediated by the activation of the PI3K/Akt pathway.