Spatial Mechanomics of Bone Regeneration and Adaptation

For over a century, the remarkable ability of bone to adapt to its mechanical environment has been a source of scientific fascination. Each cell within a skeletal site exists within diverse local micro-environments with each environment characterized by different levels of mechanical strain. The challenge within the field of bone mechanobiology has been the need for more integrative approaches to investigate the response of individual cells to their local in vivo mechanical environment. Insights into this critical knowledge gap have the potential to be transformative within the field by greatly improving our ability to anticipate cellular responses to different magnitudes or modes of mechanical stimuli.

Multiple cell types are recognized to be mechanosensitive and respond to mechanical stimuli through the activation of specific molecular signalling pathways. Despite the fundamental importance of the mechanical environment in influencing bone regeneration and adaptation, the molecular mechanisms underlying this phenomenon are complex and poorly understood. This has prevented wider-scale harnessing of the mechano-sensitivity of bone in clinical applications.

The use of mechanical intervention therapies to augment the regenerative response is of particular relevance in recalcitrant fractures. Delayed bone healing or failed non-unions account for 5 – 10% of all bone fractures, presenting a significant challenge in regenerative medicine. Moreover, the prevalence of these recalcitrant fractures is significantly greater in elderly populations. However, the field has yet to achieve consensus on whether bone exhibits age-associated declines in mechano-sensitivity.

To investigate the effects of mechanical loading on bone, we have established models of bone adaptation and regeneration. Using these in vivo models, our objectives are to: (i) to develop a molecular-based understanding of bone mechanobiology and (ii) to investigate how this mechano-sensitivity is compromised with age. To achieve our objectives, we have established “spatial mechanomics” – an approach which integrates (i) in vivo imaging (time-lapsed micro-computed tomography, micro-CT), (ii) in silico modelling (micro-finite element analysis, micro-FE) and (iii) spatially-resolved single-cell transcriptomics to quantify how mechanical stimuli are translated by individual cells and subcellular components to form bone (external page Mathavan et al. Sci. Adv. 2025).