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

描述（由申请人提供）：血管生成失调-从现有血管中生长出新血管-在70多种主要健康状况中起着核心作用，包括癌症、心血管疾病和黄斑变性。全球有超过十亿人患有血管生成依赖性疾病。靶向血管生长的治疗方法为治疗毁灭性疾病提供了新的可能性，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，从基础研究向临床转化的进展缓慢。目前，用于研究血管生成的现有体外模型中没有一个整合了代表体内血管生长的大多数关键要素，并且现有模型中没有一个包括在流动下从现有血管生长毛细血管芽-这根据定义是血管生成的标志。在此之前，我们已经开发了组织工程技术，用于在小型流体装置内创建微血管。在这些设备中，我们从内皮细胞生成管腔灌注的载瘤血管，这些内皮细胞随后在胶原蛋白中发芽并形成解剖毛细血管样网络。我们现在提出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）组织工程化的亲本血管模仿体内的结构和细胞组成，能够血管生成出芽到周围的三维基质中;（2）人源性细胞;（3）亲本血管和出芽的直接管腔灌注;（4）严格控制的物理和化学条件;（5）人源性细胞。和（5）可适用于现有高通量分析平台的批量生产的一次性流体装置。拟议项目的目标1将是完成流体装置的优化设计，并建立一个系统，允许严格控制装置内的灌注、温度、气体浓度和pH值。目标2将是实现建立的技术与血管生成的三个结构的关键组成部分：内皮细胞，周细胞和基底膜的微血管生成。一旦确定可行性，我们计划将我们的模型推进到一个标准化的，易于使用的产品，可以在开发一系列毁灭性疾病的疗法中具有重要价值。 公共卫生相关性：血管生长失调是癌症和其他重要疾病的核心因素。更可靠的分析和模型的研究血管生长和治疗药物的评价是必要的，以改善临床结果。我们提出了一个新的模型，更接近模仿天然血管的血管功能的研究。

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.