Angiogeneis and the Extracellular Matrix

描述(申请人提供)：这项生物工程研究基金的广泛目标是在微观水平上研究血管新生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。我们以前的工作提出了这样的假设，即血管新生微血管附近的ECM结构和机械载荷条件是血管新生萌发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，我们将评估基于胶原凝胶的三维微血管器官培养系统中的血管生成，其中存在改变的机械边界条件和扰动的胶原原纤维结构和凝胶特性。用材料点法(MPM)模拟和分析在该培养体系中形成的新生血管和新生血管与邻近的胶原基质之间的相互作用动力学以及组织的整体构建行为。微血管行为和胶原结构动力学的实验数据，通过先进的成像技术收集，将为建模工作提供框架和参数。由于微血管与ECM之间局部的、微观的、相互作用的重要性，该模型将强调这些方面。除了更好地了解血管新生血管、周围的ECM结构和经历血管生成的组织的力学之间的关系外，该项目还将为改进对天然组织(例如，修复缺血组织)和组织工程构建物中的组织血管形成的控制奠定基础。公共卫生相关性：拟议的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转移的一个重要环节。这项研究的结果将为血管新生微血管与细胞外基质的相互作用提供机制上的理解，并为血管化组织替代物的设计和开发提供指导。

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.