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

描述（由申请人提供）：血管生成异常——从新血管中生长出来的血管——在70多种主要健康状况中起着核心作用，困扰着全球超过10亿人。揭示控制血管生成的机制有望推动针对癌症、糖尿病、黄斑变性和其他疾病的新疗法的发现，但由于缺乏血管生成研究和药物测试的可靠模型，从基础研究到临床的进展缓慢。现有的体外模型都不包括现有血管在流动下的毛细血管芽的生长——这是血管生成的定义。为了满足这一需求，我们公司开发了一种专利技术，用于在微流控芯片中创建人体微血管。在这些芯片中，我们从被细胞外基质凝胶包围的人类内皮细胞中生成腔内灌注的“母体”血管。当暴露于血管生长因子时，母血管表现出血管新生芽，并在周围基质中生长新的毛细血管。我们计划以PIVA（体外灌注血管生成）系统的名义将这项技术商业化。PIVA预计由以下组件组成：(1)一次性微流控芯片，(2)可堆叠在标准细胞孵化器内的便携式模块化灌注平台，(3)可扩展的元模块，可支持多达6个微流控芯片，以及(4)图像分析软件。元模块概念将允许用户在每个培养箱同时运行100个或更多的检测，这一吞吐量足以用于研究和药物发现的应用。在第一阶段

DESCRIPTION (provided by applicant): Abnormal angiogenesis-the growth of new blood vessels from existing vasculature-plays a central role in more than seventy major health conditions, afflicting over one billion people worldwide. Uncovering the mechanisms that control angiogenesis promises to fuel the discovery of novel therapies targeting cancer, diabetes, macular degeneration and others-but the progress in translation from basic research into the clinic is slowed by the lack of dependable models for angiogenesis research and drug testing. None of the existing in-vitro models includes the growth of capillary sprouts from existing blood vessels under flow-which is, by definition, the hallmark of angiogenesis. To address this need, our company has developed a proprietary technology for the creation of human microvasculature within microfluidic chips. Within these chips, we generate lumenally perfused 'parent' vessels from human endothelial cells that are surrounded by an extracellular-matrix gel. When exposed to vascular growth factors the parent vessels exhibit angiogenic sprouting and grow new capillaries into the surrounding matrix. We plan to commercialize this technology under the name PIVA (Perfused In Vitro Angiogenesis) system. PIVA is envisioned to consist of the following components: (1) disposable microfluidic chips, (2) portable, modular perfusion platforms that can be stacked inside standard cell incubators, (3) scalable meta-modules that can support up to six microfluidic chips, and (4) image analysis software. The meta-module concept will allow users to run 100 or more assays simultaneously per incubator-a throughput capacity that is sufficient for applications in research and drug discovery. During Phase I of this project, we established feasibility of the manufacturing techniques, developed the prototype of a pneumatically driven perfusion platform and validated that our angiogenesis model recapitulates features of in vivo microvasculature. Currently, chips and perfusion platforms are tested in more than ten research laboratories throughout the U.S. The goal of Phase II is to finish the development of the PIVA technology to enable a rapid commercial transition into the research market. Aim 1 is to finalize the design of the microfluidic chip, meta-module perfusion platform, and the image analysis software. Aim 2 will focus on defining assay parameters and establishing the metrics for image analysis and methods for downstream analysis. Aim 3 will be to test PIVA on drugs with known anti-angiogenic effects. Once Phase II is completed, the PIVA design will be ready for production transfer within twelve months. Nortis has significant expertise in bringing prototype technologies to market. The commercial launch of the PIVA components will leverage previously validated manufacturing processes as well as operational and business infrastructure to support commercial activities. Phase III funding is lined up in the form of angel investments and revenue obtained through sales of existing Nortis products. We believe that PIVA will become an important new tool in angiogenesis research, accelerating the discovery and clinical translation of novel angiogenesis-modulating therapeutics.