Multi-Scale Integration of Extracellular Matrix Mechanics in Vascular Remodeling

项目摘要： 随着目前无创诊断的发展，可以更准确地测量 心血管疾病（CVD）临床上，一个显着的“平台科学”的组成部分是更好的 对基础物理学的机械理解，如动脉的结构-功能力学 墙这种基本的理解大部分来自于模型的开发和研究， 生物力学，这将为开发诊断提供指导，并实施这些 对临床环境的诊断又提供了用于精炼物理模型的数据。在这个项目中， 我们试图建立一个多尺度的预测细胞外基质（ECM）的机械生物学模型， 力学从基本力学的角度加上关键的生物物理输入，并 提供生物力学完整性、生化成分之间的临床相关关系 稳定性和ECM的微观结构。这种模型将使研究人员和临床医生能够探索 的基本机制，并协助合理设计新的治疗CVD。 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应变 能量变化伴随着单根纤维的变形。自由连接链（FJC）模型 将被采用来描述可能的配置，因此熵，纤维在 伸展分子间交联密度是决定聚合物的聚合度的材料参数。 单根纤维的延伸性。 纤维-组织水平：通过引入纤维，将纤维水平模型推进到组织水平模型 分布函数，并添加纤维密度作为下一组材料参数。一 多尺度机械生物学模型，包括分子间交联、纤维 分布和纤维密度将用于描述组织水平功能。 具体目标2：使用综合实验建模方法验证模型. 组织级ECM力学：ECM网络的组织级行为将得到充分表征 采用双向拉伸试验。将从主动脉组织中分离弹性蛋白和胶原蛋白网络， 单独测试。 纤维分布函数：将获得弹性蛋白和胶原的纤维取向信息 使用共聚焦显微镜并直接结合到模型中。 纤维密度和交联：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物化学测量。相应的材料参数 将根据双轴拉伸试验数据的拟合确定模型。 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