CAREER: Understanding the Dynamic Mechanical Adaptations of Bone Tissue at Small Length Scales

该学院早期职业发展（Career）奖支持将力学和高分辨率成像相结合的研究，以揭示人类骨骼如何适应动态负载以防止骨折。在运动、损伤和修复过程中，纳米尺度的骨组织暴露在不断变化的负荷下。然而，目前理解骨折的框架很大程度上是基于对骨骼健康的静态和宏观评估。定量评估和减轻骨折风险以及制定治疗方案的能力需要对骨组织在纳米长度尺度上的时间依赖性特性有基本的了解。这项研究将致力于实时解决人类骨骼的纳米级成分是如何重新排列和变形的，当受到模拟生理条件的动态负荷时，从行走到创伤。该项目将调查这种适应在健康和骨质疏松的人体组织中是如何变化的，以了解骨折风险增加的根本原因。在未来，希望这种方法将有助于加快对组织进化和骨折治疗的评估。这项工作将教育活动与当地博物馆和高中教育工作者合作，开发互动模块，向历史上缺乏服务和代表性不足的高中学生教授生物系统的力学和成像。本研究计划将在生理相关的快速时间尺度上研究纳米级矿化胶原原纤维在人骨中的适应性。在纳米尺度下，骨骼的动态和非仿射变形将被分析，以实验回答：1)在循环载荷下骨骼的纳米结构如何变化；2)什么机制决定了骨骼的动态骨折；3)微尺度组织层次的组成部分如何促进健康和骨质疏松骨骼的损伤耐受性。为了回答1)和2)，该项目将在30 nm和20 ms时空分辨率的扫描电子和同步加速器x射线显微镜下对微米尺寸的骨样品进行疲劳和动态断裂实验。小的实验长度尺度将独特地允许使用小型人类骨活检来回答问题3)。在已有的宏观骨力学背景下，该研究将告知和开发本构模型，以一个不断发展的动态内聚区的形式描述与裂纹速度相关的强度和韧性。实验数据将托管在一个开源存储库中，并有助于推进对细胞外基质如何在时间尺度上适应太快而使细胞无法响应和重塑的理解，并进行后续研究以了解这如何影响细胞命运。该方法将为跨越长度和时间尺度调查组织骨折建立一个可推广的框架。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

This Faculty Early Career Development (CAREER) award supports research that will combine mechanics and high-resolution imaging to uncover how human bones adapt under dynamic loads to prevent fracture. During exercise, injury, and repair, bone tissue at nanometer length scales is exposed to constantly changing loads. However, the current framework for understanding fracture is largely based on static and macroscale assessments of bone health. The ability to quantitatively assess and mitigate fracture risk and prescribe treatment requires a fundamental understanding of time-dependent properties of bone tissue at nanometer length scales. This research will work to resolve in real time how the nanoscale constituents of human bones rearrange and deform, when subjected to dynamic loads that mimic physiological conditions ranging from walking to trauma. The project will investigate how this adaptation varies in healthy and osteoporotic human tissue to understand the fundamental causes of increased fracture risk. In the future, it is hoped that this approach will help accelerate assessment of therapies with respect to tissue evolution and fracture. This work integrates educational activities in partnership with local museums and high school educators, to develop interactive modules that teach mechanics and imaging of biological systems to historically underserved and underrepresented high school students. This research program will investigate the adaptation of nanoscale mineralized collagen fibrils in human bone at physiologically relevant, fast time scales. The dynamic and non-affine deformations of bone at the nanoscale will be analyzed to experimentally answer: 1) how the nanostructure of bone changes under cycling loading 2) what mechanisms dictate dynamic fracture in bone and 3) how the components of microscale tissue hierarchy contribute to damage tolerance in healthy and osteoporotic bone. To answer 1) and 2), the program will develop fatigue and dynamic fracture experiments on micron-sized bone samples in scanning electron and synchrotron X-ray microscopes with 30 nm and 20 ms spatio-temporal resolution. The small experimental length scales will uniquely allow the use of small human bone biopsies to answer question 3). In the context of pre-existing macroscale bone mechanics, the research will inform and develop constitutive models to describe strength and toughness with respect to crack velocity in the form of an evolving dynamic cohesive zone. The experimental data will be hosted in an open-source repository and help advance the understanding of how the extracellular matrix adapts at timescales too fast for cells to respond and remodel, with follow-up studies to understand how this impacts cell fate. The approach will establish a generalizable framework for investigating tissue fracture across length and time scales.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.