Mechanical factors play a key role in regulation of tissue regeneration during skeletal healing, but the underlying mechanisms are not fully understood. The objective of the current study was to explore the role of mechanical factors on tissue differentiation during fracture healing, using a biphasic mechanoregulatory algorithm. The first specific objective was to investigate the effect of mechanical loading on a stem cell seeded collagenous scaffold in a one-dimensional confined compression configuration. Both empirical and computational data suggest that mechanical stimulation of the scaffold may be an effective way to initiate differentiation pathways prior to implantation for tissue engineering applications. The second objective was to predict the development of differentiated tissues in a tibia burr-hole fracture murine model with computational mechanoregulatory algorithms. The computational and experimental studies will be used simultaneously in future studies to further develop mechanoregulatory models with a more robust quantitative base.