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

描述（由申请人提供）：随着非侵入性诊断技术的发展，临床更准确地测量心血管疾病（cvd）的水平，一个重要的“平台科学”组成部分是对潜在物理的更好的机制理解，如动脉壁的结构-功能力学。这种基本的理解大部分来自生物力学模型的发展和研究，这将为发展诊断提供指导，而这些诊断在临床环境中的实施反过来又为完善物理模型提供数据。在这个项目中，我们试图从基础力学的角度，结合关键的生物物理输入，建立细胞外基质（ECM）力学的多尺度预测力学生物学模型，并提供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。该模型将使研究人员和临床医生能够探索心血管疾病的基本机制，并有助于合理设计心血管疾病的新疗法。具体目标1：建立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单纤维变形时的应变能变化。采用自由连接链（FJC）模型来描述纤维在拉伸过程中的可能构型，即熵。分子间交联密度是决定单根纤维延展性的材料参数。纤维组织层：通过引入纤维分布函数，并将纤维密度作为下一组材料参数，将纤维层模型推进到组织层模型。结合分子间交联、纤维分布和纤维密度的多尺度力学生物学模型将用于描述组织水平的功能。具体目标2：使用综合实验建模方法验证模型。组织水平的ECM力学：ECM网络的组织水平行为将通过双轴拉伸试验充分表征。将从主动脉组织中分离出弹性蛋白和胶原蛋白网络并分别进行测试。纤维分布函数：通过共聚焦显微镜获得弹性蛋白和胶原蛋白的纤维取向信息，并直接纳入模型。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化学方法测定。根据双轴拉伸试验数据拟合确定模型中相应的材料参数。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