Micro-Macro Scale Investigations to Study Osteocyte Mechanobiology

骨质疏松症是一种骨量低、骨折风险增加的疾病。运动可以增加骨骼大小，有助于防止骨折。该项目旨在提高对骨细胞如何检测骨负荷的理解。被认为是负荷检测器的骨细胞被称为“骨细胞”。骨细胞相互通信，并与骨骼表面的其他细胞通信，以改变骨骼大小，以适应骨骼上的负荷。这项工作的目标是确定骨骼变形和液体流动是如何被检测到的，并转化为细胞用来与其他细胞交流的化学信号。使用先进的细胞生物学方法，机械加载将与细胞的生物反应有关。这项研究的结果将确定固体-流体相互作用力学在激活骨形成中的作用，以帮助解释和减轻与年龄相关的骨丢失。该项目将为当地高中生，特别是女高中生提供有朝一日的研究夏令营，并鼓励他们继续接受工程和医学教育。本科生将从事该项目的各个方面的工作。目的是更好地了解多尺度力学-从宏观骨应变到微观应变(局部骨基质和腔隙应变以及相应的细胞膜上的流体流动剪应力)在骨细胞水平上的力学传递中的作用。我们计划利用骨细胞中Wnt/β-catenin信号通路的激活来研究这些效应，以此作为它们对负荷反应的读数。已知这一途径在调节负荷相关的骨形成中起重要作用。这些方法包括对小鼠整个前臂进行轴向加载的实验研究，在小鼠尺骨切片上使用MicroXCT-200(Carl Zeiss/XRadia)进行新的微型轴向加载实验来确定腔隙应变。新开发的多路三维共聚焦显微镜技术将用于骨细胞及其腔隙流体空间的三维建模，以实现流固耦合有限元模型。

Osteoporosis is a disease of low bone mass and increased risk of fracture. Exercise can increase bone size and help protect against fractures. This project aims to improve understanding of how bone cells detect bone loading. The bone cell thought to be the load detector is called the "osteocyte". Osteocytes communicate with each other and to other cells on the surface of the bone to change bone size to match the loads on the bone. The goal of the work is to determine how bone deformation and fluid flow are detected and changed into a chemical signal that the cell uses to communicate to other cells. Mechanical loading will be related to the biological response of the cell using advanced cell biological methods. The outcomes of this research will determine the role of solid-fluid interaction mechanics in the activation of bone formation to help explain and mitigate age related bone loss. The project will offer local high school students, especially female students, one day research camps and encourage them to pursue engineering and medical education. Undergraduate students will work on various aspects of the project.The objective is to gain a better understanding of the role of multiscale mechanics - from macro-scale bone strains to micro-scale strains (local bone matrix and lacunar strain and the corresponding fluid flow shear stress on the cell membrane) in mechanotransduction at the osteocyte cellular level. We plan to study these effects using the activation of the Wnt/beta-catenin signaling pathway in osteocytes as a readout for their response to loading. This pathway is known to be important in mediating load related bone formation. The methods include experimental studies using axial loading experiments on mouse whole forearm, novel microscale axial loading experiments on murine ulna sections using the MicroXCT-200 (Carl Zeiss/Xradia) to determine lacunar strains. Newly developed multiplexed 3D confocal microscopy techniques will be used for 3D modelling of osteocytes and their lacunar fluid space for fluid-structure interaction FE models.