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