Draper Achieves First SARS-CoV-2 Virus Replication in a Lung-on-a-Chip Platform

For the first time in an organ-on-a-chip model, the live SARS-CoV-2 virus has successfully infected and replicated in human tissue.

This finding paves the way toward development of COVID-19 disease models and screening of potential treatments for the infection using tissues that accurately replicate human organs, thus overcoming the inherent limitations to currently-used tissue models to study the virus.

This study, led by Draper and using its PREDICT96-ALI (air liquid interface) tissue culture technology, recently was published as a preprint in bioRxiv. The work was conducted with researchers from Massachusetts General Hospital.

Using the PREDICT96-ALI organ-on-a-chip model, the research team investigated the viral infection kinetics of the SARS-CoV-2 virus in the PREDICT96-ALI platform human lung tissue in a BSL-3, high-containment laboratory environment.

When measuring viral RNA levels of infected airway tissue in the organ-on-a-chip, they found the viral copy number of the SARS-CoV-2 virus increased as much as 600-fold in six days, exhibiting a dependence on time and initial virus concentration relevant for human infections. They also detected strong expression of the virus’s nucleocapsid and spike proteins in large, multi-cell clusters, which confirmed viral replication and that it spread to nearby cells.

The model has been shown to mimic the human body’s response to pathogens such as influenza, enabling rapid repurposing of this platform for COVID-19.

Unlike many organ-on-a-chip platforms that are designed for basic research, this one is designed with the biopharmaceutical industry in mind. Consequently, it integrates into standard industry workflows and infrastructure, such as liquid handling robotics and high content confocal imaging systems.

“This platform provides the scientific community a preclinical technology solution that has been specifically designed with industry and high-throughput workflows in mind,” Draper researcher Ashley Gard said. “The PREDICT96-ALI platform allows us to mimic human tissue biology and arrive at suitable therapeutic solutions for diseases like COVID-19 rapidly and efficiently.”

Specifically, it features integrated, real-time sensing and dynamic fluid control, so researchers can monitor the health status of human tissues and recreate the physiological environment of the human body.

It also permits studying the effects of different biophysical stimuli like exposure to an air-liquid interface or fluid flow by moving media nutrients around the platform. Additionally, she said, “In situ imaging lets researchers visualize the tissue during the experiment, so they can study what specific cells in the tissue engage with or are affected by a virus following exposure. Since the system supports confocal imaging, researchers can monitor the infection over time and watch how important events play out in.”

Currently, “There has been a lack of suitable pre-clinical models for studying COVID-19 and for screening and identifying potential therapeutic solutions,” she explained. “The tools that have been used to evaluate candidate therapies to date have some notable benefits but are limited in what they can do to model human biology.”

For example, she continued, “Researchers have used immortalized cells grown in culture plates or animal models to study infectious pathogens and screen possible therapies. The immortalized cells provide a quick way to gather information, but they don’t capture the specific features of the human lung and thereby fail to paint a complete picture of lung tissue physiology and response to pathogens.”

In the paper, the researchers cited the lack of ciliary differentiation and mucociliary clearance, which may be critical in understanding viral pathogenesis and predicting therapeutic efficacy.

Animal models often are used to study human infections and screen therapeutic candidates since they have complete immune systems, but may be limited in their immune responses, or may not be available or applicable.

Pseudoviruses also have been employed, but are functionally limited research tools for infection studies since they lack critical features necessary for recapitulating viral infections in humans.

Recently, reports describe membrane insert-based human primary airway epithelial cell systems grown at an air-liquid interface as a tool for assaying for SARS-CoV-2 infection. As the authors wrote, “Such membrane insert-based systems are quite limited relative to organ-on-chip models in several key respects.”

They cited difficulties in terms of high-resolution imaging, large media volume, the lack of dynamic media circulation, and real-time sensing.

Draper’s model is derived from epithelial cells of living donors.

Because it replicates the entire organ, it can better support studies involving a variety of pathogen affecting human airways, including toxic agents that pose threats when inhaled. This organ-on-a-chip model also can be used to conduct studies involving lung health or conditions such as fibrosis and chronic obstructive pulmonary disease.

This study is expected to help organ-on-a-chip technology to increase its foothold in the pharmaceutical industry.

“The field of organ-on-a-chip has been slow to gain traction in the pharmaceutical industry because the field has struggled to provide high throughput screening,” Jeff Borenstein of Draper explained.

Most organ-on-a-chip systems are configured as lab research tools, but operation in a BSL-3 environment requires an instrumented well-plate that fits standard tools in the pharmaceutical industry.

“The need for features like onboard sensing and imaging, as well as the need to move to a higher level of lab containment, worked against many other organ-on-a-chip technologies,” Borenstein said.

Looking to pharmaceutical research – and the next pandemic – Gard predicted organ-on-a chip technology will enable faster, more targeted responses.

“A high-throughput platform technology and robust preclinical airway tissue model gives Draper the ability to rapidly pivot and respond to high-threat and newly emerging pathogens. With this platform, we can quickly implement our model and execute in the lab to investigate pathogenesis and collaborate with industry to evaluate therapeutic candidates quickly.”

She noted the ability to use the high throughput capabilities and versatile features of this model to assess primary human tissue samples from a wide range of demographics and comorbidities.

That work, she said, is in the early stages at Massachusetts General Hospital. There, Benjamin Medoff, M.D., and his lab are showing they can acquire airway cells from living patients and provide them to Draper to interrogate a wide range of patients and conditions in relation to SARS-CoV-2 infection or infection with other respiratory pathogens.

“That allows us to evaluate a broad and inclusive patient demographic and gives us the ability to return to specific patients for re-evaluation or for more cell samples to enhance our work and acquire more information. It’s definitively a big advantage and a unique feature.”

“To date, no group has shown viral replication in a lung-on-a-chip model. We’re the only group to demonstrate that,” she reiterated.

This finding, therefore, introduces a potentially powerful new tool for both disease modelling and therapeutic screening.