Mechanical forces are hypothesized to modulate periosteal bone generation during development, growth, healing and aging, in health and disease. A multi-scale understanding of periosteal osteochondroprogenitor cells and the periosteum tissue environment allows researchers and clinicians to develop surgical techniques, postsurgical physical therapies, and implants that harness the regenerative capacity of the periosteum and periosteal cells to repair tissue damage such as fractures or critical-sized defects. This research aims to bridge the gap between cellular, tissue, and organ levels using cellular and tissue studies as well as clinical models.

Using in vitro to ex vivo models, the following work identifies the mechanosensitivity of progenitor cells, the mechanical properties of the periosteum, and the prevailing loads that promote periosteal de novo bone generation in a critical-sized defect. Progenitor cells are incredibly sensitive to the mechanics of their environment (i.e. cell density and three-dimensionality of culture) and applied shear stress. In vitro experiments demonstrate that genes associated with the first stages of skeletogenesis are significantly up- and down-regulated in response to both factors. In fact, shear stresses two orders of magnitude less than those needed to stimulate differentiated osteogenic cells can alter genetic expression in progenitor cells in as little as 30 minutes. The tissue environment periosteal progenitor cells inhabit, the periosteum, is also remarkably responsive to different mechanical stimuli. Mechanical testing reveals that the periosteum is highly prestressed in situ and anisotropic. Upon removal from the underlying bone, periosteal samples will shrink to approximately half of their in situ area. Most of the shrinkage occurs in the axial direction. Likewise, when large strains are applied the periosteum is five fold stiffer in the axial direction than in the circumferential direction. Finally, ex vivo clinical model studies of de novo bone generation in a critical-sized defect help to establish the periosteal strain regimes needed for optimal healing and provide a basis to validate future computational models. This knowledge of the mechanobiology of the periosteum and its progenitor cells helps to bridge the gap between cellular and tissue levels. Also it is used to improve predictive models and to design implants for translational and clinical application.