Angiogeneis and the Extracellular Matrix

描述（由申请人提供）：该生物工程研究资助的主要目标是在微观水平上研究血管生成微血管与细胞外基质（ECM）的生物力学相互作用，以开发血管生成的计算模型。我们以前的工作已经导致了这样的假设，即邻近血管生成微血管的ECM结构和机械负荷条件是血管生成萌芽和新生血管生长和引导的潜在决定因素。为了验证这一假设，我们将评估血管生成的胶原凝胶为基础的，三维器官培养系统的微血管的存在下，改变机械边界条件和扰动的胶原纤维结构和凝胶特性。将使用材料点法（MPM）对在该培养系统中形成的血管生成芽和新血管与相邻胶原基质之间的相互作用动力学以及整体组织构建行为进行建模和分析。通过先进的成像技术收集的微血管行为和胶原结构动力学的实验数据将为建模工作提供框架和参数。由于微血管和ECM之间的局部、微尺度相互作用的重要性，该模型将强调这些方面。除了更好地理解血管生成血管、周围ECM结构和经历血管生成的组织力学之间的关系外，该项目还将为改善天然组织（例如，修复缺血组织）和组织工程构建体。公共卫生相关性：这项研究将阐明机械力和细胞外基质结构在血管生成中的作用的基本方面。血管生成过程是伤口愈合和肿瘤坏死的一个重要特征。这项研究的结果将提供一个机制的理解与细胞外基质的血管生成微血管的相互作用，并提供指导方针的设计和开发血管化组织替代。

DESCRIPTION (provided by applicant): The broad objective of this Bioengineering Research Grant is to study biomechanical interactions of angiogenic microvessels with the extracellular matrix (ECM) on the microscale level to develop a computational model of angiogenesis. Our previous work has lead to the hypothesis that the ECM structure adjacent to angiogenic microvessels and the mechanical loading conditions are potential determinants of angiogenic sprouting and neovessel growth and guidance. To test this hypothesis, we will evaluate angiogenesis in a collagen gel-based, 3- dimensional organ culture system of microvessels in the presence of altered mechanical boundary conditions and perturbed collagen fibril structure and gel properties. The interaction dynamics between the angiogenic sprouts and neovessels that form in this culture system with the adjacent collagen matrix and the overall tissue construct behavior will be modeled and analyzed using material point method (MPM). Experimental data of both microvessel behavior and collagen structure dynamics, gathered with advanced imaging techniques, will provide the framework and parameters for the modeling effort. Because of the importance of the local, microscale, interactions between the microvessel and the ECM, the model will emphasize these aspects. In addition to establishing a better understanding of the relationship between angiogenic vessels, the surrounding ECM structure, and the mechanics of the tissue undergoing angiogenesis, the project will provide the basis for improved control of tissue vascularization in both native tissues (e.g., repairing ischemic tissue) and tissue engineered constructs. PUBLIC HEALTH RELEVANCE: The proposed research will elucidate fundamental aspects of the roles of mechanical forces and extracellular matrix structure in angiogenesis. The process of angiogenesis is an integral feature of wound healing and tumor metastastis. The results of this research will provide a mechanistic understanding of the interaction of angiogenic microvessels with the extracellular matrix, and provide guidelines for the design and development of vascularized tissue replacements.