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.

人的骨骼在骨重建过程中不断更新，在这个过程中，成熟的骨组织被破骨细胞移除(这个过程称为骨吸收)，新的骨组织由成骨细胞形成(这个过程称为骨形成)。在健康的成人骨骼中，基于改建的骨形成(RBF)占主导地位，骨形成与先前的骨吸收激活紧密耦合，导致骨量没有净变化。最近的研究提出了一种更有效的骨组织形成途径，它刺激了基于建模的骨形成(MBF)，即在成人骨骼中，无需事先激活破骨细胞的吸收即可形成骨。虽然基于靶向建模的骨形成可以最大限度地增加净骨体积的能力，但通过这种细胞机制产生的新骨组织的质量尚不清楚。关键是要了解(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，将建立一个集先进成像、力学测试和计算建模于一体的新型研究平台。该项目的目标是填补两个基本但不同的细胞过程--MBF和RBF--在决定多个长度尺度的骨小梁力学特性方面的关键知识空白。教育和推广计划包括设计课程计划，让本科生参与肌肉骨骼工程和科学的长期学习、教学和研究。该研究计划重点关注MBF的机械方面，MBF是一种高效但经常被忽视的再生机制。以前在骨方面的工作很少涉及来自MBF的骨组织的特性，部分原因是可靠地将其与RBF区分开来的挑战。将开发一种新型的显微成像平台，将亮场成像、荧光成像和二次谐波成像结合在一起，用于在厚骨切片上可视化新骨形成和潜在的胶原结构。这种成像方法将克服基于薄层切片的传统成像方法的局限性，允许在同一骨样本上进行进一步的力学测试。此外，骨组织的纳米和微观力学研究大多集中在皮质骨。这项研究计划将填补有关MBF对松质骨组织结构-功能关系的贡献的关键知识空白。我们期望这项研究计划的结果将为未来调节MBF的治疗策略的研究提供基础知识和创新的研究工具。