Micro-Macro Scale Investigations to Study Osteocyte Mechanobiology

骨质疏松症是一种低骨量和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”。 骨细胞彼此之间以及与骨表面上的其他细胞进行通信，以改变骨的大小以匹配骨上的负荷。这项工作的目标是确定如何检测骨骼变形和液体流动，并将其转化为细胞用于与其他细胞交流的化学信号。 使用先进的细胞生物学方法，机械负荷将与细胞的生物反应相关。这项研究的结果将确定固-流相互作用力学在骨形成激活中的作用，以帮助解释和减轻年龄相关的骨丢失。该项目将为当地高中生，特别是女学生提供为期一天的研究营，并鼓励他们接受工程和医学教育。本科生将参与该项目的各个方面，目的是更好地理解多尺度力学的作用-从宏观尺度的骨应变到微观尺度的应变（局部骨基质和腔隙应变以及细胞膜上相应的流体流动剪切应力），在骨细胞水平上的力学转导中。我们计划使用骨细胞中Wnt/β-连环蛋白信号通路的激活来研究这些效应，作为它们对负荷的反应的读数。已知该途径在介导负荷相关的骨形成中是重要的。这些方法包括使用小鼠整个前臂的轴向载荷实验的实验研究，使用MicroXCT-200（Carl Zeiss/Xradia）对小鼠尺骨切片进行新的微型轴向载荷实验以确定腔隙应变。新开发的多路复用三维共聚焦显微镜技术将用于三维建模的骨细胞和他们的腔隙流体空间的流体-结构相互作用有限元模型。

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.