Bone is regarded as a dynamic “mechanostat,” which constantly remodels its structure in accordance with mechanical demands. Our group has developed a segmental bone defect model to isolate the role of mechanical signals in skeletal regeneration. While it has been established that ambulatory load transfer supports successful bridging, the precise mechanisms dictating this process are unknown due to limitations in longitudinally assessing the local mechanical environment in vivo. We will leverage recent advances in biocompatible microelectromechanical systems (MEMS) technology to monitor mechanical loads on regenerating tissue in vivo with unprecedented spatiotemporal resolution. The insights offered by MEMS instrumentation will underpin the development of image-based finite element models which will serve as a parametric design space to address fundamental questions in bone mechanobiology, and to guide translational improvements of novel regenerative strategies through predictive computational simulations.