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

人类骨骼通过骨重建过程不断更新，其中成熟的骨组织被破骨细胞去除（称为骨吸收的过程），新的骨组织由成骨细胞形成（称为骨形成的过程）。基于重塑的骨形成（RBF）在健康成人骨骼中占主导地位，其中骨形成与骨吸收的先前激活紧密耦合，导致骨量没有净变化。最近的研究提出了更有效的骨组织形成途径，其刺激基于建模的骨形成（MBF），即，在成年骨骼中没有破骨细胞再吸收的预先激活的骨形成。虽然基于靶向建模的骨形成可以最大化净骨体积增加的能力，但通过这种细胞机制产生的新骨组织的质量尚不清楚。理解（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不同是至关重要的。为了回答这些问题，将建立一个新的研究平台，集成先进的成像，机械测试和计算建模。该项目的目标是填补两个基本的，但不同的细胞过程，MBF和RBF，在确定多个长度尺度的骨小梁的机械性能的作用的关键知识空白。 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。该研究计划侧重于MBF的机械方面，这是一种高效但经常被忽视的再生机制。先前在骨方面的工作最低限度地解决了来自MBF的骨组织的性质，部分原因是可靠地将其与RBF区分开来的挑战。将开发一种新的显微成像平台，以结合明场成像，荧光成像和二次谐波成像，用于可视化厚骨切片上的新骨形成和底层胶原结构。这种成像方法将克服基于薄切片的传统成像方法的局限性，以允许对同一骨样本进行进一步的机械测试。此外，大多数关于骨组织的纳米和微观力学的研究都集中在皮质骨上。这项研究计划将填补关键的知识空白，关于MBF的贡献，骨小梁组织的结构-功能关系。我们希望这项研究计划的结果将为未来研究调节MBF的治疗策略提供基础知识和创新的研究工具。

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.