Bone healing mechanomics in a mouse model of accelerated aging.

Delayed bone healing or failed non-unions account for 5 – 10% of all bone fractures and present a challenging problem in regenerative medicine. Bone healing is a mechano-sensitive process; thus, mechanical stimuli can either enhance or impair fracture healing. The molecular mechanisms underlying this phenomenon are complex and poorly understood.

Consequently, clinical applications which harness this mechano-sensitivity to enhance healing are limited. It has also contributed to a lack of consensus on whether bone exhibits age-associated declines in mechano-sensitivity.

With this in mind, I present a multi-scale, multi-disciplinary approach to develop a molecular-based understanding of bone healing mechanobiology and to investigate how this mechano-sensitivity is compromised with age.

Using an established femur defect model in young and aged mice, my proposed approach will apply state-of-the-art techniques to spatially map: (i) the local mechanical environment, (ii) the molecular profiles of single cells, and (iii) the local tissue nanostructure within the fracture callus.

By combining single-cell “omics” technologies with established tissue-scale models of bone mechanobiology, MechanoHealing will quantify how mechanical stimuli are translated by individual cells and subcellular components to form bone.

MechanoHealing will also permit investigations into potential pathways by which mechanical stimuli influence formation of the nanostructure of bone – a key determinant of the overall fracture resistance of bone.

Identification of the molecular mechanisms of mechanically-driven bone formation will lead to new strategies and novel therapeutic targets to promote better and faster repair. Specifically, it will drive the development of safe, targeted and individualized mechanical intervention therapies.

Furthermore, insights into age-associated declines in mechano-sensitivity will better equip surgeons to optimize outcomes in compromised healing environments.