Multi-Scale Integration of Extracellular Matrix Mechanics in Vascular Remodeling

项目总结： 随着目前非侵入性诊断技术的发展，更准确地测量 心血管疾病(CVD)临床上，一个重要的“平台科学”组成部分更好 对基础物理的机械理解，例如动脉的结构-功能力学 墙。这种基本的理解很大程度上来自于模型的开发和研究 生物力学，它将为开发诊断学提供指导，并实施这些 对临床环境的诊断反过来又为完善物理模型提供数据。在这个项目中， 我们试图建立细胞外基质(ECM)的多尺度预测性机械生物学模型。 从基础力学的角度结合关键的生物物理输入的力学，以及 提供生物力学完整性、生化成分之间的临床相关性 稳定性，以及ECM的微观结构。这种模式将使研究人员和临床医生能够探索 基本机制，并协助合理设计新的治疗心血管疾病的方法。 具体目标1：建立ECM力学的多尺度预测性机械生物学模型。 分子纤维水平：采用基于统计力学的方法来确定应变 单根纤维变形时的能量变化。自由连接链(FJC)模型 将被用来描述光纤的可能构型，从而在 伸展身体。分子间交联度是决定分子间交联度的材料参数 单根光纤的延伸性。 纤维-组织层：通过结合纤维，将纤维层模型提升为组织层模型 分布函数，并添加纤维密度作为下一组材料参数。一个 结合分子间交联、纤维的多尺度力学生物学模型 为了描述组织水平的功能，将获得分布和纤维密度。 具体目标2：使用综合实验-建模方法对模型进行验证。 组织级ECM机制：ECM网络的组织级行为将得到充分表征 采用双向拉伸试验。弹性蛋白和胶原网络将从主动脉组织中分离出来 单独测试。 纤维分布功能：获取弹性蛋白和胶原蛋白的纤维取向信息 使用共聚焦显微镜并直接结合到模型中。 纤维密度和交联度：弹性蛋白和胶原的含量和交联度将 通过生物化验进行生物化学测量。中对应的材料参数 模型将根据双轴拉伸试验数据进行拟合确定。 1

Project Summary: 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