Developing organ-on-a-chip models of COVID-19

我们建议开发人体器官芯片模型来研究SARS-CoV-2感染。该病毒与其受体血管紧张素转换酶2 （ACE2）结合，该受体在上皮细胞和内皮细胞中大量表达。在早期阶段，先天免疫对SARS-CoV-2产生非特异性反应，并指导适应性免疫反应消除病毒，防止疾病发展到严重阶段。目前还无法预测谁会患上轻度和重度疾病。在这里，我们将开发肺和肾芯片设备，使冠状病毒感染的研究能够回答这些问题。独特的是，在器官芯片设备中，我们可以评估病毒感染后数小时内发生的最早的先天免疫反应。我们的目标是将这些设备迅速投放市场，以便其他学术和行业研究人员可以有效地使用它们。目前，所有的器官芯片设备都是由UofT的研究生和博士后手工制作的。合作组织uFluidix将开发一套设备放大程序和设备投放市场的渠道。Radisic博士在研究免疫细胞（如单核细胞和巨噬细胞）在仿生环境下的流动方面有着丰富的经验。在目标1中，我们将开发一个基于人类细胞的平台来研究上皮对SARC-CoV-2的反应。在aims 2中，我们将建立一个系统来研究巨噬细胞和中性粒细胞外渗对冠状病毒感染肺部的反应，该系统将基于血流系统，称为血管管。在第三部分中，我们将使用topmembrane平台建立SARS-CoV-2肾脏感染模型。所有模型都将首先使用拉迪西奇博士在实验室中可以使用的CL2冠状病毒229E和NL63进行开发。活的SARS-CoV-2感染将由张博士实验室的一名熟练的博士后在UofT CL3设施进行。项目成功的保证是加拿大领先的微流体设备制造商uFluidix的支持，uFluidix在过去10年中为1000多家客户制造了设备，使我们能够在极短的时间内将设备推向市场。

We propose the development of human organ-on-a-chip models to study SARS-CoV-2 infection. The virus binds to its receptor, angiotensin-converting enzyme 2 (ACE2), which is abundantly expressed in epithelial and endothelial cells. At the early stages, the innate immunity mounts a non-specific response to SARS-CoV-2 and directs the adaptive immune response to eliminate the virus and prevent disease progression to severe stages. It is currently impossible to predict who will experience a mild vs severe disease. Here, we will develop lung- and kidney-on-a-chip devices that enable studies of coronavirus infection to answer these questions. Uniquely, in organ-on-a-chip devices we can assess the earliest innate immunity responses that occur hours after the virus infection. Our goal is to place the devices on the market quickly so other academic and industry researchers can use them effectively. Currently, all organ-on-a-chip devices are produced by graduate students and post-docs manually at UofT. The partner organization, uFluidix, will develop a procedure for device scale-up and a conduit for device placement on the market. Dr. Radisic has a significant previous experience in studying immune cells such as monocytes and macrophages in a biomimetic environment under flow. In Aim 1, we will develop a human-cell based platform to study epithelial response to SARC-CoV-2. In Aim 2, a system to study macrophage and neutrophil extravasation in response to coronavirus infection of the lung will be established in our flow based systems, termed AngioTube. In Aim 3, model of SARS-CoV-2 infection of the kidney will be established using the Topomembrane platform. All models will first be developed with CL2 coronaviruses 229E and NL63 that Dr. Radisic has access to in her laboratory. Infection with a live SARS-CoV-2 will be performed by a skilled post-doc from the laboratory of Dr. Zhang in the CL3 facility at the UofT. Assurance of project success is the support of the leading Canadian microfluidic device manufacturer, uFluidix, who have manufactured devices for over 1000 customers over the past 10 years, enabling us to get the devices to the market in an extremely fast time frame.