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

健康、老年人和骨质疏松症患者骨折愈合的局部重塑和机械调节

基本信息

批准号：
323231527
负责人：
Professorin Dr. Anita Ignatius
金额：
--
依托单位：
Institut für Biomechanik (IfB)
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/323231527?language=en
关键词：
Local remodelling mechanoregulation bone fracture

项目摘要

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.

目前对骨折愈合的认识主要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骺端。关于骨小梁愈合的机械调节知之甚少，现有的知识是基于宏观组织水平上的组织学评价。因此，我们需要更好地了解愈合过程及其在健康，老年和骨质疏松的人骨的机械调节。然而，这是具有挑战性的，因为骨吸收和形成需要在患者骨折愈合期间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的力-这通常无法在患者中测量，并且其对愈合的影响尚未得到很好的理解。在拟议的研究中，我们的目的是（1）调查局部重塑和（2）全球负载条件对骨折愈合过程的影响，以及（3）健康，老年人和骨质疏松症患者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），以评估患者前臂远端的骨微结构，并开发图像分析方法，以量化延时图像之间的微结构差异。为了实现第二个目标，将在人类中研究骨折愈合的整体负荷效应，其中通过握力练习诱导额外的负荷。将开发一个计算肌肉模型，以根据测得的握力计算桡骨远端的力，并开发一个骨折愈合计算模型，以确定该过程中全局载荷的敏感性。将使用来自动物试验的数据对结果进行验证，其中通过实验控制整体载荷。为了实现第三个目标，将开发微观有限元（micro-FE）方法，以计算骨折HR-pQCT图像中的局部组织载荷，其中全局载荷通过目标2的肌肉模型量化。将目标1中确定的局部组织负荷和重塑部位相关联，最终将允许研究老年人骨和骨质疏松人骨愈合的机械调节。总体而言，该项目需要德国-奥地利-瑞士（DACH）合作提供的极其广泛的专业知识。因斯布鲁克大学和Inselspital伯尔尼在纵向临床研究方面的经验将负责目标1，乌尔姆大学在组织学和计算研究方面的专业知识将负责目标2，ETH苏黎世在骨成像和微观FE分析方面的专业知识将负责目标3。