Culturing cells in 3D scaffolds can help model a physiological process. The property of the substrate used for such scaffolds has been shown to modify and determine stem cell lineage. Using this knowledge, in-vitro 3D stem cell culture models with ex-vivo bone tissue investigations can offer insight and inspiration for the development of novel therapies for bone defects. Although many different scaffolds have been created for bone tissue repair, in situ cell level mechanics are not always given consideration as the main design target. Overall, the ideal tissue engineering solution to bone regeneration would incorporate cells of osteogenic potential into a synthetic bone scaffold in order to reduce the need for external factors added such as drugs or growth factors. Attention to the mechanical aspects of the bone to be studied as well as the cells to be placed within the scaffold is fundamental. In this chapter, we will explore studies investigating the role of cell communication in bone mechanosensing, including the roles of different bone cells in the process of bone adaptation and repair, and the use of this knowledge in creating a novel tissue engineering strategy for the repair of acute bone defects.