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

肌肉骨骼康复的临床领域将受益于更深入地了解如何利用骨骼的能力，以感知其物理环境的变化，并适应他们。由于疾病（如骨质疏松症）和/或长期废用（衰老、瘫痪、卧床）而导致的骨折每年花费NHS数十亿英镑。骨质疏松症的诊断和适当的药物治疗通常是对骨折的反应（根据英格兰的NICE指南或苏格兰的SIGN指南），但通过体育活动保持健康的骨骼来预防骨折会有相当大的价值（经济和生活质量）。肌肉骨骼康复有可能通过利用骨骼对负荷的适应性反应来减少肌肉萎缩和相关骨丢失的负面后果。相关的干预措施通常是围绕沃尔夫定律（1892年）的既定概念设计的，以及世纪后弗罗斯特的恒力理论（1997年）中概述的潜在反馈途径。这些描述了肌肉和骨骼之间的密切相互作用，前者活动的变化影响后者的反应和适应。然而，维持肌肉-骨骼关系的许多详细机制仍有待阐明。肌肉骨骼系统不能与其他生理系统隔离，外部调节因子（如激素）在维持健康的骨转换和介导修复中发挥作用。该项目的核心命题是，血流是维持肌肉-骨骼关系的另一个关键因素：假设骨骼只有在有足够的血液灌注的情况下才能适应肌肉的负荷。该假设基于骨具有其自身的神经支配和血液供应这一事实，已知这对骨形成和骨折修复至关重要，并且血管形成（血管生成）和骨形成（骨生成）之间存在密切耦合（Kusumbe，2014）。根据流体剪切应力假说（Piekarski & Munro，1977），骨细胞可以机械感测与骨中和骨周围的血液和其他流体流动的剪切应力相关的应变产生的电位。具体而言，灌注骨的血管通道附近的局部压力梯度可能导致这些应变生成电位。仍需进一步调查的关键因素（Fritton & Weinbaum，2009）在机械传感中的作用包括：（i）骨的微观结构的不均匀性，（ii）骨的多孔性，（iii）骨单位的渗透性（如骨单位）和（iv）压力梯度/分布。基于实验室的研究将支持拟议的项目，其中最先进的成像技术将被用于验证血流与骨骼机械感知能力之间的关系，并适应血液灌注和血流的变化。该项目的目标是：（a）开发基于实验室的骨灌注模型，（B）量化骨细胞对骨的不同血液灌注参数的响应，（c）使用该模型来模拟骨的一系列负荷条件（从废用到过度使用）的影响。

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).