An Integrative Multi-Scale Model of Extracellular Matrix Mechanics in Vascular Re

描述（由申请人提供）：随着目前无创诊断的发展，临床上可以更准确地测量心血管疾病（CVD）的水平，一个重要的“平台科学”组成部分是对基础物理学（如动脉壁的结构-功能力学）的更好的机械理解。这种基本的理解大部分来自生物力学模型的开发和研究，这将为开发诊断提供指导，而这些诊断在临床环境中的实施反过来又为改进物理模型提供了数据。在这个项目中，我们寻求开发一个多尺度的预测力学模型的细胞外基质（ECM）力学从一个基本的力学角度加上关键的生物物理输入，并提供一个临床相关的生物力学的完整性，生化成分的稳定性和微观结构的ECM之间的关系。该模型将使研究人员和临床医生能够探索基本机制，并有助于合理设计CVD的新疗法。具体目标1：创建ECM力学的多尺度预测力学生物学模型。分子纤维水平：采用基于统计力学的方法来确定伴随单根纤维变形的应变能变化。一个自由连接链（FJC）模型将被采用来描述可能的配置，从而熵，在拉伸过程中的纤维。分子间交联密度是决定单根纤维延展性的材料参数。纤维组织水平：通过结合纤维分布函数并添加纤维密度作为下一组材料参数，将纤维级模型推进到组织级模型。一个多尺度的力学生物学模型，结合分子间的交联，纤维分布和纤维密度将实现组织水平的功能的描述。具体目标2：使用综合实验建模方法验证模型.组织水平ECM力学：ECM网络的组织水平行为将使用双轴拉伸试验进行充分表征。将从主动脉组织中分离弹性蛋白和胶原蛋白网络，并单独进行试验。光纤分布功能：弹性蛋白和胶原的纤维取向信息将使用共聚焦显微镜获得并直接结合到模型中。纤维密度和交联：弹性蛋白和胶原蛋白的含量和交联密度将通过生物测定进行生化测定。模型中的相应材料参数将根据双轴拉伸试验数据拟合确定。1 公共卫生相关性：在这个项目中，我们寻求开发一个多尺度的预测力学模型的细胞外基质力学的研究，从基本力学的角度加上关键的生物物理输入。拟议的工作将通过两个具体的目标，耦合建模和实验工作，一个完整的模型开发和验证。本研究的结果将提供ECM的生物力学完整性、生化成分稳定性和微观结构之间的临床相关关系。1

DESCRIPTION (provided by applicant): With the current development of non-invasive diagnostics to more accurately measure the level of cardiovascular diseases (CVDs) clinically, a significant "platform science" component is better mechanistic understanding of underlying physics, such as structure-function mechanics of the arterial wall. Much of this fundamental understanding comes from the development and study of models for biomechanics, which will provide guidance for developing diagnostics, and implementation of these diagnostics to the clinical setting in turn provides data for refining the physics models. In this project, we seek to develop a multiscale predictive mechanobiology model of extracellular matrix (ECM) mechanics from a fundamental mechanics perspective coupled with critical biophysical input, and to provide a clinical relevant relationship between biomechanical integrity, biochemical composition stability, and microstructure of the ECM. Such model will enable researchers and clinicians to probe basic mechanisms, and to assist in rational design of new therapies for CVD. Specific Aim 1: Create a multiscale predictive mechanobiology model of ECM mechanics. Molecular - fiber level: a statistical mechanics based approach is adopted to determine the strain energy change accompanying deformation of a single fiber. A freely joined chain (FJC) model will be adopted to describe the possible configurations, thus entropy, of a fiber during stretching. Inter-molecular cross-linking density is a material parameter that determines the extensibility of a single fiber. Fiber - tissue level: advance the fiber-level model into a tissue-level model by incorporating fiber distribution function and adding fiber density as the next set of material parameter. A multiscale mechanobiological model that incorporates inter-molecular cross-linking, fiber distribution and fiber density will be achieved for the description of tissue-level function. Specific Aim 2: Validation of the model using an integrated experimental - modeling approach. Tissue-level ECM mechanics: the tissue-level behavior of ECM network will be fully characterized using biaxial-tensile test. Elastin and collagen network will be isolated from aortic tissue and tested individually. Fiber distribution function: the fiber orientation information of elastin and collagen will be obtained using confocal microscopy and directly incorporated into the model. Fiber density and cross-linking: the content and crosslinking density of elastin and collagen will be measured biochemically through biological assay. Corresponding material parameters in the model will be determined from fits to the biaxial-tensile testing data. 1 PUBLIC HEALTH RELEVANCE: In this project, we seek to develop a multiscale predictive mechanobiology model for the study of extracellular matrix mechanics from a fundamental mechanics perspective coupled with critical biophysical input. The proposed work will be accomplished through two specific aims that couple modeling and experimental work for a complete model development and validation. Results from this research will provide clinical relevant relationship between biomechanical integrity, biochemical composition stability, and microstructure of the ECM. 1