Bone Integrity for a Lifetime with Mechanical Loading

通过机械负荷实现骨的终身完整性全世界有超过5亿人受到肌肉骨骼疾病的影响，这些疾病大大降低了功能独立性。下一代骨骼完整性评估、干预和治疗技术将针对个人，旨在优化其结果。拟议研究计划的长期目标是通过提高对骨力学及其适应性反应的理解，为在人的一生中保持骨完整性提供科学依据。新兴技术、计算机模拟和组织生物学的整合提供了一种独特的方法来解锁负责骨适应的过程。骨完整性的关键特征是组成、矿物质密度和抗骨折性，这些特征通过形成和吸收的平衡过程来维持。微结构、刚度和强度响应于机械和生物化学刺激的变化有据可查。然而，将机械和生化刺激改变为生物反应的代谢途径尚不清楚。为了理解这种适应性反应，设计、测试和验证了一种独特的离体骨培养实验。在这种方法中，用培养基灌注的固定的骨小梁核心可维持存活组织长达7周。离体骨芯显示在负荷下骨矿物质沉积增加，并模拟体内人骨代谢。该系统提供了一个独特的机会来研究人类骨骼适应性，超越了更常见的2D细胞培养方法或更复杂的动物模型。短期目标是量化和模拟松质骨核心和骨植入物系统对应变率、载荷和激素的反应。一系列的3个实验和模拟与活的人骨小梁将量化的适应性生物和形态学的反应，以控制刺激。这个丰富的数据集将为预测骨骼和骨植入系统对刺激的反应的算法的开发提供支持。在5年的时间里，11.25名HQP将接受骨生物力学、骨培养和计算机模拟方面的培训。老年人群中的脆性骨折是一个主要的公共卫生问题。由于相关的死亡率（20-25%），丧失活动能力（40%）和依赖性（33%），预计到2050年，骨质疏松性髋部骨折的发病率将增加200%以上，这一点令人担忧。众所周知，循环载荷是骨形成的关键因素;因此，可以降低脆性骨折的发生率。然而，目前还不清楚什么形式的循环载荷，例如幅度和应变率，刺激骨形成。拟议的研究计划提供了科学基础和技术，可以导致新的选择，以促进骨完整性和创新的骨科治疗。

Bone Integrity for a Lifetime through Mechanical Loading Over half a billion people worldwide are affected by musculoskeletal disorders which dramatically diminish functional independence. The next generation of technologies for the assessment, intervention and treatment for skeletal integrity will be specific to the individual and designed to optimise their outcomes. The long-term goal of the proposed research program is to provide a scientific basis for the maintenance of bone integrity over a person's lifetime by improving the understanding of bone mechanics and its adaptive response. The integration of emerging technologies, computer simulation, and tissue biology provide a unique approach to unlock the processes responsible for bone adaptation. Key features of bone integrity are composition, mineral density and fracture resistance, which are maintained through a balanced process of formation and resorption. Changes in micro-architecture, stiffness and strength in response to mechanical and biochemical stimuli are well documented. However, the metabolic pathways that change the mechanical and biochemical stimuli into a biological response are unclear. To understand this adaptive response, a unique ex vivo bone culture experiment has been designed, tested and validated. In this approach, explanted trabecular bone cores, perfused with culture medium, maintain viable tissue for up to 7 weeks. Ex vivo bone cores demonstrate increased bone mineral apposition under load and mimic in vivo human bone metabolism. This system provides a unique opportunity to investigate human bone adaption beyond the more common approach of 2D cell culture or more complex animal models. The short-term objectives are to quantify and simulate the response of trabecular bone cores and bone-implant systems to strain rate, load and hormones. A series of 3 experiments and simulations with live human trabecular bone will quantify the adaptive biological and morphological responses to controlled stimuli. This rich dataset will feed the development of algorithms to predict the response of bone and bone-implant systems to stimuli. Over a 5y period 11.25 HQP will be trained in bone biomechanics, bone culture and computer simulations. Fragility fracture in the aging population is a major public health concern. Projected increases of more than 200% in rates of osteoporotic hip fracture by 2050 are of concern due to associated rates of mortality (20-25%), loss of mobility (40%) and dependency (33%). It is well known that cyclic loading is a critical factor in bone formation; and therefore, can reduce rates of fragility fracture. However, it is not well understood, what form of cyclic load, e.g. the magnitude and strain rate, stimulates bone formation. The proposed research program provides the scientific basis and technology that can lead to new options to promote bone integrity and innovations in orthopaedic treatment.