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

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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.