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

描述（由申请人提供）：异常血管生成-从现有血管中生长新血管-在70多种主要健康状况中起着核心作用，困扰着全球10亿多人。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，但由于缺乏可靠的血管生成研究和药物测试模型，从基础研究到临床的转化进展缓慢。现有的体外模型中没有一个包括在流动状态下从现有血管中生长出毛细血管芽，而毛细血管芽的生长，根据定义，是血管生成的标志。为了满足这一需求，我们公司开发了一种专有技术，用于在微流控芯片中创建人类微血管系统。在这些芯片中，我们从被细胞外基质凝胶包围的人内皮细胞中产生管腔灌注的“母体”血管。当暴露于血管生长因子时，载瘤血管表现出血管生成出芽并在周围基质中生长新的毛细血管。我们计划以PIVA（灌注体外血管生成）系统的名称将这项技术商业化。设想PIVA由以下组件组成：（1）一次性微流体芯片，（2）可堆叠在标准细胞培养箱内的便携式模块化灌注平台，（3）可支持多达六个微流体芯片的可扩展元模块，以及（4）图像分析软件。元模块的概念将允许用户运行100个或更多的分析同时每个孵化器的吞吐量能力，是足够的研究和药物发现的应用。在第一阶段， 项目，我们建立了制造技术的可行性，开发了一个原型的血管驱动灌注平台，并验证了我们的血管生成模型概括了体内微血管的特点。目前，芯片和灌注平台在美国各地的十多个研究实验室进行测试。第二阶段的目标是完成PIVA技术的开发，以实现向研究市场的快速商业过渡。目标一是完成微流控芯片、元模块灌注平台和图像分析软件的设计。目标2将侧重于定义检测参数，并建立图像分析的指标和下游分析的方法。目标3是测试PIVA对已知具有抗血管生成作用的药物的作用。一旦第二阶段完成，PIVA设计将在12个月内准备好进行生产转移。Nortis拥有丰富的专业知识 将原型技术推向市场。PIVA组件的商业发布将利用之前经过验证的制造工艺以及运营和业务基础设施来支持商业活动。第三阶段的资金是以天使的形式排队 投资及透过销售现有Nortis产品而获得的收入。我们相信PIVA将成为血管生成研究中的一个重要新工具，加速新型血管生成调节疗法的发现和临床转化。

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.