Roles of Modeling- and Remodeling-based Bone Formation in Determining Trabecular Bone Mechanics at Multiple Length Scales

基于建模和重塑的骨形成在确定多个长度尺度的小梁骨力学中的作用

• 批准号: 1661858
• 负责人: Xiaowei Sherry Liu
• 金额: $ 36.69万
• 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: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1661858&HistoricalAwards=false
• 关键词: Roles; Modeling; Remodeling; based; Bone

The human skeleton is continuously renewed through the bone remodeling process where mature bone tissue is removed by osteoclasts (a process called bone resorption) and new bone tissue is formed by osteoblasts (a process called bone formation). Remodeling-based bone formation (RBF) dominates in the healthy adult skeleton, where bone formation is tightly coupled with prior activation of bone resorption, resulting in no net changes in bone mass. Recent studies suggest a more efficient bone tissue formation pathway, which stimulates modeling-based bone formation (MBF), i.e., bone formation without prior activation of osteoclast resorption in the adult skeleton. While targeting modeling-based bone formation could maximize the capacity of net bone volume increase, the quality of the new bone tissue generated through this cellular mechanism is unknown. It is critical to understand (1) how MBF influences the structural organization and mechanics of bone tissue, and (2) whether this is different from more naturally occurring RBF. To answer these questions, a novel research platform integrating advanced imaging, mechanical testing, and computational modeling will be established. The goal of the project is to fill the critical knowledge gap on the roles of two fundamental, but distinct cellular processes, MBF and RBF, in determining the mechanical properties of trabecular bone at multiple length scales. The education and outreach program includes designing lesson plans to engage undergraduate students in long-term learning, teaching, and research in musculoskeletal engineering and science.This research program focuses on the mechanical aspects of MBF, a highly efficient but often overlooked regenerative mechanism. Prior work in bone has minimally addressed the properties of bone tissue derived from MBF, partially due to the challenge of reliably differentiating it from RBF. A novel microscopic imaging platform will be developed to incorporate bright field imaging, fluorescence imaging, and second harmonic generation imaging for visualizing the new bone formation and underlying collagen structure on a thick bone section. This imaging method will overcome limitations of traditional imaging methods based on thin sections, to allow further mechanical testing on the same bone sample. Moreover, most studies on nano- and micro-mechanics of bone tissue have focused on the cortical bone. This research program will fill the critical knowledge gap regarding the contribution of MBF to structure-function relationships of trabecular bone tissue. We expect that the outcomes of this research program will provide fundamental knowledge and innovative research tools for future investigations of therapeutic strategies that modulate MBF.

通过骨骼重塑过程不断更新人类的骨骼，其中通过破骨细胞去除成熟的骨组织（一种称为骨吸收的过程），并由成骨细胞（称为骨形成）形成新的骨组织。基于重塑的骨形成（RBF）在健康的成年骨骼中占主导地位，在健康的成年骨骼中，骨形成与先前激活骨吸收紧密结合，导致骨骼质量没有净变化。最近的研究表明，更有效的骨组织形成途径，该途径刺激基于建模的骨形成（MBF），即，骨形成，而没有事先激活成人骨骼中破骨细胞吸收的情况。虽然靶向基于建模的骨形成可以最大化净骨骼体积的能力增加，但通过这种细胞机制产生的新骨组织的质量尚不清楚。了解（1）MBF如何影响骨组织的结构组织和力学，以及（2）这是否与更自然发生的RBF不同。为了回答这些问题，将建立一个新的研究平台，集成了高级成像，机械测试和计算建模。该项目的目的是填补两个基本但不同的细胞过程MBF和RBF的角色的关键知识差距，在确定小梁骨在多个长度尺度下的机械性能中的机械性能。 教育和外展计划包括设计课程计划，使本科生在肌肉骨骼工程和科学领域进行长期学习，教学和研究。该研究计划着重于MBF的机械方面，MBF是一种高效但经常被忽视的再生机制。骨骼中的先前工作最小化了源自MBF的骨组织的特性，部分原因是将其可靠地与RBF区分开的挑战。将开发一个新型的微观成像平台，以结合明亮的田间成像，荧光成像和第二次谐波产生成像，以可视化新的骨形成和厚骨部分的潜在胶原蛋白结构。这种成像方法将克服基于薄部分的传统成像方法的局限性，以便对同一骨样品进行进一步的机械测试。此外，大多数关于骨组织纳米和微力学的研究都集中在皮质骨上。该研究计划将填补有关MBF对小梁骨组织结构 - 功能关系的贡献的关键知识差距。我们预计该研究计划的结果将为未来调查MBF的治疗策略提供基本知识和创新研究工具。