Development of an Advanced In-Vitro Model for Angiogenesis Research and Drug Test

描述(申请人提供)：失控的血管生成--从现有的血管系统生长出新的血管--在包括癌症、心血管疾病和黄斑变性在内的70多种主要健康疾病中起着核心作用。全球有10多亿人受到血管生成依赖型疾病的困扰。以血管生长为目标的治疗技术有望在治疗毁灭性疾病方面带来新的可能性，并具有巨大的经济潜力。然而，由于缺乏可靠的血管生成研究和药物测试模型，从基础研究到临床研究的进展缓慢。目前，现有的研究血管生成的体外模型中没有一个包含了代表体内血管生长的大多数关键因素，也没有一个现有的模型包括在流动下从现有血管中生长出的毛细血管芽--这是血管生成的定义。此前，我们已经开发了用于在小型流体设备中创建微血管的组织工程技术。在这些设备中，我们从内皮细胞产生发光灌流的母体血管，这些血管随后发芽，并在胶原中形成解剖的毛细血管样网络。我们现在建议将这种方法发展成具有以下属性的先进的体外血管生成模型：(1)模仿体内结构和细胞组成的组织工程亲本血管，能够在周围的三维基质中生成血管；(2)人类来源的细胞；(3)亲本血管和萌芽的直接管腔灌流；(4)严格控制的物理和化学条件；以及(5)批量生产的、一次性的流体设备，可以适应现有的高通量分析平台。拟议项目的目标1将是完成射流装置的优化设计，并建立一个系统，以便对装置内的灌流、温度、气体浓度和酸碱度进行严格控制。目标2将实现已建立的具有血管生成的三个结构关键成分：内皮细胞、周细胞和基底膜的微血管生成技术。一旦确定了可行性，我们计划将我们的模型推进到一种标准化的、易于使用的产品中，该产品在开发一系列毁灭性疾病的治疗方法方面具有重要价值。 与公共卫生相关：血管生长失控是癌症和其他重要疾病的核心因素。为了改善临床效果，需要更可靠的方法和模型来研究血管生长和评价治疗药物。我们提出了一个新的模型来研究更接近自然血管的血管功能。

DESCRIPTION (provided by applicant): Disregulated angiogenesis-the growth of new blood-vessels from existing vasculature-plays a central role in more than 70 major health conditions including cancer, cardiovascular disease, and macular degeneration. More than one billion people worldwide are afflicted by angiogenesis-dependent diseases. Therapeutics that target blood-vessel growth promise new possibilities in the treatment of devastating diseases and have vast economic potential. However, progress in translation from basic research into the clinic is slowed by the lack of dependable models for angiogenesis research and drug testing. Presently, none of the existing in-vitro models for the study of angiogenesis integrates most of the critical elements that typify vascular growth in vivo, and none of the existing models includes the growth of capillary sprouts from existing blood vessels under flow- which is by definition the hallmark of angiogenesis. Previously, we have developed tissue-engineering techniques for the creation of microvessels within small fluidic devices. Within these devices, we generate luminally-perfused parent vessels from endothelial cells that subsequently sprout and form anatomizing capillary-like networks in collagen. We now propose to develop this method into an advanced in-vitro angiogenesis model with the following attributes: (1) tissue-engineered parent vessels mimicking architecture and cell composition in vivo, capable of angiogenic sprouting into a surrounding three-dimensional matrix; (2) human-derived cells; (3) direct luminal perfusion of parent vessels and sprouts; (4) tightly-controlled physical and chemical conditions; and (5) a mass produced, disposable fluidic device that can be adapted for the use in existing high-throughput analysis platforms. Aim 1 of the proposed project will be the completion of an optimized design of the fluidic device and the establishment of a system that allows for the tight control of perfusion, temperature, gas concentration and pH within the device. Aim 2 will be to achieve established techniques for the generation of microvasculature with the three structural key components of angiogenesis: endothelial cells, pericytes, and basement membrane. Once feasibility is established, we plan to advance our model into a standardized, easy to use product that can be of significant value in the development of therapies for a range of devastating diseases. PUBLIC HEALTH RELEVANCE: Disregulated growth of blood vessels is a central element in cancer and other important diseases. More reliable assays and models for the study of vascular growth and the evaluation of therapeutic drugs are necessary to improve clinical results. We propose a new model for the study of vascular functions that closer mimics natural vessels.