Tremendous efforts are currently made to develop bioceramics and other biomaterials for bone tissue engineering. Even if biomaterials capacity to induce osteogenesis has been observed in vivo (Martin & Bettencourt, Mater. Sci. Eng., 2018), bone formation in vitro or ex vivo still remains a real scientific and societal challenge. In vitro bone engineering is often addressed through drug delivery, by sending suitable biochemical mediators toward bone cells through a functionalized scaffold. However, bone is well known to be a mechanobiological material: bone integrity relies on how the biomechanical stimuli are transmitted to bone cells through bone architecture. In that context, a new generation of biomaterials, with complex architecture, are being developed in order to match bone biomechanical properties. While the biomechanical properties of the structure play a major role in the transmission of mechanical stimuli to the cells, the deformation experienced by bone matrix during walking is around 0.05 %. According to Frost’s mechanostat theory, such low deformation is too small to initiate bone remodeling. This suggests that other biomechanical features are involved in bone mechanobiology and might probably be considered as additional biomechanical boundary conditions for a successful in vitro bone engineering.
Bone cells mechanosensitivity has to be considered regarding the complex bone architecture. For example, during loading, the multiscale bone porous network is deformed. The induced pressure gradients influence the physiological fluid dynamics flowing across bone porous network. Bone cells are known to be sensitive to fluid flow. These shift in fluid dynamics then represent a way to transmit the mechanical loading towards cells. In that context, investigating flow patterns within bone scaffold during loading is growing in interest (Mainardi et al., Acta Biomater., 2022). However, within bone complex porous architecture, the fluid behavior is complex, and has to be accurately understood to better understand bone mechanobiology. Additionally, cells differentiation is another determinant step during bone formation. After having synthetized the osteoid, osteoblasts migrate within this collagenous matrix before differentiating into osteocytes, cells that orchestrate bone remodeling, together with matrix mineralization. The capacity for osteoblasts to migrate and differentiate into osteocytes depends on the substrate stiffness.  While bioceramics are very stiff, a softer surface substrate might have a relevant role in promoting this essential osteocyte differentiation step.
Through these two examples of in vivo biomechanical features, it is clear that it is necessary to better understand how biomechanical stimuli are transmitted through bone architecture to develop efficient bone regenerative bioceramics and more generally biomaterials. Furthermore, while current bone in vitro engineering strategies are mostly focused on drug delivery, applying such suitable biomechanical boundary conditions might be of great interest to promote bone mechanobiological formation. This review work is a state of the art regarding bone mechanobiological remodeling and provide some clues for what should be considered for the future of bone in vitro mechanobiological engineering (Gauthier et al., Biocell, 2022).