Local remodelling and mechanoregulation of bone fracture healing in healthy, aged, and osteoporotic humans

目前关于骨折愈合的知识主要是基于骨干骨愈合的实验动物研究，尽管许多年龄和骨质疏松相关的骨折发生在骨干端。目前对骨小梁愈合的机制调控知之甚少，现有的认识都是基于宏观组织水平的组织学评价。因此，我们需要更好地了解健康、衰老和骨质疏松的人类骨骼的愈合过程及其机制调节。然而，这是具有挑战性的，因为在患者骨折愈合过程中，骨吸收和形成需要在体内和非侵入性地量化。研究机械调节还需要计算局部组织负荷，这反过来又需要定义全局负荷，即在器官水平上作用于骨骼的力，通常无法在患者中测量，其对愈合的影响也不是很清楚。在本研究中，我们的目标是(1)研究局部重塑，(2)整体加载条件对骨折愈合过程的影响，以及(3)健康、老年和骨质疏松人群干骺端骨折愈合的局部机械调节。为了实现第一个目标，我们提出了一项临床试验，使用高分辨率外周定量计算机断层扫描（HR-pQCT）来评估患者前臂远端骨微观结构，并开发图像分析方法来量化延时图像之间的微观结构差异。为了实现第二个目标，将研究人类骨折愈合的整体负荷效应，其中手部握力练习会引起额外的负荷。计算肌肉模型将根据测量的握力来计算桡骨远端受力，以及骨折愈合的计算模型来确定这一过程中全局载荷的敏感性。结果将通过动物试验的数据进行验证，其中全球负荷是通过实验控制的。为了实现第三个目标，将开发微有限元（micro-FE）方法来计算骨折HR-pQCT图像中的局部组织载荷，并使用目标2的肌肉模型量化全局载荷。将aim 1中确定的局部组织负荷和重构位点相关联，最终将有助于研究老年和骨质疏松症人类骨骼愈合的机制调节。总体而言，该项目需要极其广泛的专业知识，这些专业知识将在德国-奥地利-瑞士（DACH）合作中提供。拥有纵向临床研究经验的因斯布鲁克大学和伯尔尼因塞尔医院将负责目标1，乌尔姆大学将负责目标2，乌尔姆大学将负责目标2，苏黎世联邦理工学院将负责目标3，乌尔姆大学将负责组织和计算研究，苏黎世联邦理工学院将负责骨骼成像和微观有限元分析。

The current knowledge of fracture healing is mainly based on experimental animal studies of diaphyseal bone healing, even though many age and osteoporosis associated fractures occur in the bone metaphysis. Little is known about the mechanoregulation of trabecular bone healing and the existing knowledge is based on histological evaluations on the macroscopic tissue-level. We therefore need to better understand the healing process and its mechanoregulation in healthy, aged, and osteoporotic human bone. This is, however, challenging as bone resorption and formation needs to be quantified in vivo and non-invasively during fracture healing in patients. Investigating the mechanoregulation requires furthermore the calculation of local tissue loading, which in turn requires the definition of global loading - that are forces acting upon the bone on the organ-level - which usually cannot be measured in patients and its influence on the healing is not well understood. In the proposed study, we aim at (1) investigating local remodelling and (2) the effect of global loading conditions on the fracture healing process as well as (3) local mechanoregulation of metaphyseal bone fracture healing in healthy, aged, and osteoporotic humans. To achieve the first aim, we propose a clinical trial using high-resolution peripheral quantitative computed tomography (HR-pQCT) to assess bone microstructure at the distal forearm in patients, and to develop image analysis methods to quantify microstructural differences between time-lapse images. To achieve the second aim, global loading effects on fracture healing will be studied in humans where additional loading will be induced with hand grip exercises. A computational muscle model will be developed to calculate the forces at the distal radius from the measured hand grip strength as well as a computational model of fracture healing to determine the sensitivity of global loading on this process. Results will be validated with data from animal trials where global loading was controlled experimentally. To achieve the third aim, micro-finite element (micro-FE) methods will be developed to calculate local tissue loading in HR-pQCT images of fractures with global loading as quantified with the muscle model of aim 2. Correlating local tissue loading and remodelling sites as determined in aim 1 will finally allow to investigate the mechanoregulation of healing in aged and osteoporotic human bone. Overall, this project requires an extremely broad range of expertise that will be provided in a German-Austrian-Swiss (DACH) collaboration. Innsbruck University and Inselspital Bern with their experience in performing longitudinal clinical studies will be responsible for aim 1, Ulm University with its expertise in histological and computational studies for aim 2, and ETH Zurich with its expertise in bone imaging and micro-FE analysis for aim 3.