Investigating the role of blood perfusion of bone in mechanosensing and response to loading.

The clinical field of musculoskeletal rehabilitation would benefit from a deeper understanding of how to exploit bone's ability to sense changes in its physical environment and to adapt to them. Fractures in bone that has weakened as a result of disease (e.g. osteoporosis) and/or extended periods of disuse (ageing, paralysis, bedrest) cost the NHS £Billions annually. Diagnoses of osteoporosis and appropriate pharmacological treatments are typically given in response to fracture (according to NICE guidelines in England or SIGN guidelines in Scotland), but there would be considerable value (economic & quality of life) in preventing fractures by maintaining healthy bones through physical activity.

Musculoskeletal rehabilitation has the potential to reduce the negative consequences of muscle atrophy and associated bone loss by exploiting bone's adaptive response to loading. Relevant interventions are typically designed around the established concepts of Wolff's Law (1892), and the underlying feedback pathways outlined a century later in Frost's Mechanostat Theory (1997). These describe the close interactions between muscle and bone, with changes in the activity of the former affecting the response and adaptation of the latter. However, many of the detailed mechanisms through which the muscle-bone relationship is maintained remain to be elucidated. The musculoskeletal system does not function in isolation from other physiological systems, and external regulatory factors (e.g. hormones) play a role in maintaining healthy bone turnover and mediating repair. The proposition at the heart of this project is that blood flow is an additional key player involved in upholding the muscle-bone relationship: the hypothesis being that bone is only able to adapt to loading from muscles if there is adequate blood perfusion of the bone.

This hypothesis is based on the fact that bone has its own innervation and blood supply that are already known to be vital for bone formation and fracture repair, and there is a close coupling between blood vessel formation (angiogenesis) and bone formation (osteogenesis) (Kusumbe, 2014). According to the Fluid Shear Stress hypothesis (Piekarski & Munro, 1977), bone cells can mechanosense strain-generated potentials related to the shear stress of blood and other fluid flow in and around the bone. Specifically, local pressure gradients near vascular canals that perfuse the bone may cause these strain-generated potentials. Key factors that still require further investigation (Fritton & Weinbaum, 2009) for their role in mechanosensing include: (i) inhomogeneity of bone's microstructure, (ii) porosity of bones, (iii) permeability of the bone units (e.g. osteons) and (iv) pressure gradients/profiles.

Lab-based investigations will underpin the proposed project, in which state-of-the art imaging technology will be used to characterise the relationship between blood flow and bone's ability to mechanosense and adapt to changes in blood perfusion and blood flow. Objectives of the project are: (a) to develop a lab-based model of perfusion of bone, (b) to quantify the response of bone cells to different blood perfusion parameters of the bone, (c) to use the model to mimic the effects of a range of loading conditions of the bone (from disuse to overuse).