Manipulating Fluid Flow in Mechanoadaptation of Bone

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Bone is sensitive to mechanical loads, or “mechano-sensitive”. It responds to increased loading by making more bone and to decreased loading by taking away bone. This project will study how mechanical signals are translated into a biological response using analysis at the tissue, cellular, and molecular level. Investigations will reveal how to optimize the mechanical signal by adjusting the speed and magnitude of a load applied to the tibia bone of a living mouse. Evaluation of where new bone is made in response to the loading will be made by imaging methods. These include high resolution 3D x-ray tomography and fluorescent labeling that can indicate where new bone has formed. The in-flux of calcium signaling into bone cells in a mouse tibia will also be measured under different mechanical loading conditions. These measurements will indicate how the cell-level response changes with different loading protocols. A molecular imaging technique will be used to determine what proteins are being made by the bone cells in response to loading. Bones from old mice and younger mice will be compared to see how the response changes with age. This work will provide insight about how to optimize mechanical loading to cause bone formation, which can help to inform exercise and rehabilitation therapies to keep bone healthy.This project will use the in vivo murine tibial loading model to explore two potential fluid based stimuli: peak fluid velocity and fluid signal (integral of fluid velocity over time). By exploring the effects of loading profiles in a computational poroelastic finite element models, loading profiles will be designed to optimize each stimuli separately as well as both together in mature and aged bone. The effects of the loading profile on the tissue level will be observed by measuring the amount of bone formation. Cellular signaling during mechanical loading will be determined by using in vivo multi-photon imaging of calcium reporter osteocytes. This will indicate if cells are sensitive to peak fluid velocity or fluid signal (the amount of time there is fluid-induced shear stress). Fluorescence in situ hybridization (FISH) will be used to quantitatively assess intracellular signaling of genes involved in mechanoadaptation (mechano-RNA). This study will not only provide a mechanistic understanding of adaptation to load but will also advance imaging and assessment techniques for exploring mechanoadaptation at the cellular and molecular level. This work is co-funded by the Biomechanics & Mechanobiology and the Physiological Mechanisms & Biomechanics programs.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.