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

职业：了解小长度尺度下骨组织的动态机械适应

• 批准号: 2339836
• 负责人: Ottman Tertuliano
• 金额: $ 71.95万
• 依托单位: University of Pennsylvania
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-05-01 至 2029-04-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2339836&HistoricalAwards=false
• 关键词: CAREER; Understanding; Dynamic; Mechanical; Adaptations

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.

该学院早期职业发展（职业）奖支持将力学和高分辨率成像相结合的研究，以揭示人体骨骼如何在动态负载下适应以防止骨折。在运动、受伤和修复过程中，纳米长度的骨组织暴露在不断变化的载荷下。然而，目前理解骨折的框架主要基于骨骼健康的静态和宏观评估。定量评估和减轻骨折风险并制定治疗方案的能力需要对纳米长度尺度骨组织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体骨骼的纳米级成分在受到模拟从行走到创伤等生理条件的动态负载时如何重新排列和变形。该项目将研究这种适应在健康和骨质疏松的人体组织中如何变化，以了解骨折风险增加的根本原因。未来，希望这种方法将有助于加速对组织进化和骨折方面的疗法的评估。这项工作与当地博物馆和高中教育工作者合作整合了教育活动，开发互动模块，向历史上服务不足和代表性不足的高中生教授生物系统的力学和成像。该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纤维在人骨中的适应性。将分析纳米级骨骼的动态和非仿射变形，以通过实验回答：1）骨骼的纳米结构在循环负载下如何变化2）哪些机制决定骨骼的动态断裂以及3）微观组织层次结构的组成部分如何贡献损害健康和骨质疏松骨骼的耐受性。为了回答 1) 和 2)，该项目将在扫描电子和同步加速器 X 射线显微镜中以 30 nm 和 20 ms 时空分辨率对微米级骨样本进行疲劳和动态断裂实验。小型实验长度尺度将独特地允许使用小型人体骨活检来回答问题 3)。在现有宏观骨力学的背景下，该研究将提供并开发本构模型，以不断演变的动态内聚区的形式描述相对于裂纹速度的强度和韧性。实验数据将托管在一个开源存储库中，有助于加深对细胞外基质如何​​在时间尺度上适应的理解太快，以至于细胞无法做出反应和重塑，并通过后续研究来了解这如何影响细胞命运。该方法将建立一个可推广的框架，用于跨长度和时间尺度的组织骨折调查。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。