A 3D Multiscale Computational Model for Fluid Flow Over Osteocyte in Loaded Bone

骨调节在几种骨相关疾病（如骨质疏松症）和病症（如骨折）中起着重要作用。 了解如何改善这种情况需要更多地了解骨骼成分，包括骨细胞，重要的骨细胞，当感知力或应力时，发出信号，使其他细胞产生或破坏骨骼。 尽管有实验证据表明骨细胞确实显著影响骨调节，但早期观察显示，启动骨调节活动所需的骨细胞应力远大于日常活动中骨骼经历的应力。 为了激发骨细胞的骨调节能力，当力通过骨向下传递到骨细胞内和附近的微尺度区域时，似乎必须以某种方式放大力。 虽然已经提出了各种合理的解释如何产生这种力放大，但尚未达成共识，主要是因为骨骼的复杂性使得难以在任何单一的现有研究中考虑所有可能的因素。 为了解决这个问题，这项研究将开发一个综合模型，将骨细胞的多个组成部分及其周围环境在多个尺度上结合起来，以更好地了解日常力量如何在它们到达骨细胞时被放大。 该模型将用于识别细胞的哪些组件最有可能负责感知力。 该模型还可用于未来的研究，以考虑如何改善骨质疏松症，骨关节炎，白血病，骨折和其他骨相关疾病患者的力感知和骨调节。该项目的目标是通过计算建模和实验室实验更好地了解骨细胞如何在体内感知力（机械感知）以及骨细胞及其微环境如何将应力和应变放大到骨细胞在体内可检测的水平。这一目标将通过引入一个多尺度的骨细胞-流体陷窝-小管系统和机械载荷下的包裹骨基质的三维计算模型来实现。综合模型包括三个部分：一个交联的粘弹性纤维网络为基础的“细胞固体模型”的细胞中的受力组件;一个格子玻尔兹曼方程为基础的“流体模型”（细胞内和细胞外）的剩余的细胞和间质物质;和一个连续的“多孔弹性模型”的骨基质。这三个子模型将通过相互的流体-结构-相互作用（FSI）使用浸没边界（IB）框架集成。模型参数将从文献中的现有数据和合作者的体外实验中获得。在组装前，将通过单独的实验数据对三个子模型进行验证，并使用离体实验对集成模型进行确认。在大规模CPU-GPU计算机集群上的集成计算模型的预测将用于表征应力和应变场，并研究应力和应变放大机制，产生对骨细胞机械感觉和应力/应变放大的新见解，并引入新的实验设计来研究疾病-该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的智力价值和更广泛的影响进行评估来支持审查标准。

Bone regulation plays a major role in several bone-related diseases (e.g. osteoporosis) and conditions (e.g. broken bone). Understanding how to improve such scenarios requires increased understanding of bone components including osteocytes, important bone cells that, when sensing force or stress, send out signals that make other cells create or destroy bone. Despite experimental evidence that osteocytes do significantly affect bone regulation, early observations revealed that the stress on the osteocyte needed to initiate bone regulating activities was much greater than the stress bones experience during daily activities. For osteocytes’ bone regulating abilities to be triggered, it appears force must somehow be amplified as it is transferred through the bone down into the microscale regions in and near the osteocytes. While various reasonable explanations for how such force amplification can arise have been suggested, a consensus has not been reached primarily because the complexity of bone has made it difficult to consider all possible factors in any single existing study. Addressing this issue, this study will develop an integrative model to combine multiple components of the osteocyte and its surrounding environment across multiple scales to better understand how everyday forces can be amplified as they travel to the osteocyte. The model will be used to identify which components of the cell are most likely responsible for sensing force. The model can also be used in future studies to consider how to improve force sensing and resulting bone regulation in individuals with osteoporosis, osteoarthritis, leukemia, broken bones, and other bone-related conditions. The goal of this project is to better understand how osteocytes sense forces in vivo (mechanosensation) and how the osteocyte and its microenvironment amplifies stress and strain to levels detectable by osteocytes in vivo by computational modeling and laboratory experiments. This goal will be achieved by introducing a multiscale 3D computational model for the osteocyte-fluid lacuna-canaliculi system and the encasing bone matrix under mechanical loading. The integrative model comprises three parts: a cross-linked viscoelastic fiber-network based “cytosolid model” for force-bearing components in the cell; a lattice-Boltzmann-equation based “fluid model” (intracellular and extracellular) for the remaining cellular and interstitial substances; and a continuum “poroelastic model” for the bone matrix. These three submodels will be integrated through the mutual fluid-structure-interaction (FSI) using the immersed boundary (IB) framework. Model parameters will be obtained from both existing data in literature and collaborators’ in vitro experiments. The three submodels will be verified prior to assembly by separate experimental data and the integrated model will be validated using the ex-vivo experiments. Predictions of the integrated computational model on large-scale CPU-GPU computer clusters will be used to characterize the stress and strain fields, and investigate the stress and strain magnification mechanism, generate new insights into osteocyte mechanosensation and stress/strain amplification, and introduce novel experimental designs to study how disease-related changes may regulate osteocyte mechanotransduction.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.