In a recently published review article in the journal Drug Discovery Today, scientists have described the utility of human-based microphysiological systems (MPSs) in understanding the pathophysiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and developing effective therapeutic interventions. Moreover, they have described the establishment of a global working group to synchronize recent developments around MPSs and coronavirus disease 2019 (COVID-19) research.
Background
Soon after its emergence in December 2019 in China, the deadly SARS-CoV-2 of the human betacoronavirus family experienced a rapid transmission trajectory and quickly became a public health emergency of international concern. Given the sharp rise in COVID-19 cases and mortality worldwide, the World Health Organization (WHO) has declared the condition a pandemic on March 11, 2020. As of August 3, 2021, globally, there have been 198 million confirmed COVID-19 cases, including 4.2 million deaths, registered to the WHO.
To develop effective therapeutics, prophylactics, and diagnostics, it is important to thoroughly understand the life-cycle and transmission dynamics of SARS-CoV-2. A collaborative approach at the global level has made it possible to rapidly identify vital viral features, including host cell entry receptor (angiotensin-converting enzyme 2; ACE2), spike glycoprotein on viral envelop, and dynamics of SARS-CoV-2 replication.
Although various animal models, including mice, hamsters, ferrets, and non-human primates, contribute significantly toward understanding the pathophysiology of SARS-CoV-2 infection, they often have limitations. One such limitation is major differences in disease pathophysiology and outcomes between animals and humans.
Recent advancement in the bioengineering field has made it possible to develop human-based MPSs that can substantially overcome the shortcomings of animal models. MPSs are in vitro platforms of complex cellular networks in a microenvironment that recapitulates biochemical, electrical, and mechanical responses to display organ-level functions. Some prevailing examples of MPSs are organ-on-a-chip, organoid, and bioreactor models, wherein various types of human cells interact with each other to form complex structures under the influence of physical forces, such as fluid flow. These structures replicate various biological activities, including barrier function, membrane transport, metabolic system, and neuronal network.
Organoids
Organoids are three-dimensional tissue constructs typically composed of adult or pluripotent stem cells that mimic the characteristic features of an organ. The development of organoids mostly depends on the intrinsic self-organization of multiple cells to form organotypic structures.
Although organoids have extensive utility in biomedical research because of their simplicity, these in vitro platforms have a disadvantage of random configuration, which leads to structural and functional variation between manufacturing batches, between multiple organoids within a culture, and even between different regions of a single organoid. Moreover, the absence of vasculature, representative microenvironment, and immune cells further limits the utility of organoids in certain biomedical areas.
Despite these disadvantages, organoids are widely used to study basic biological processes and to determine the safety and efficacy profiles of drugs because of their ability to mimic functional aspects of native organs.
Organ-on-a-chip
Organs on chips are microfabricated cell culture tools that mimic the functional units of organs. Within the organ chips, hollow microfluidic channels are lined with organ-specific cells on one surface and vascular endothelial cells on the other surface. The physical microenvironment of the organ of concern is recapitulated by controlling fluid flow rate and mechanical forces inside microfluidic channels.
The main advantage of organ-on-a-chip models is low variability between chips. Its fabrication process permits precise controlling of cellular and tissue networks. Moreover, tissue function sensors can be incorporated into chips for real-time measurement of various biological aspects.
Microphysiological systems in COVID-19 research
Various novel MPSs have been developed and utilized to study the impact of SARS-CoV-2 infection on lungs and other affected organs, such as the brain, kidney, and gut. Lung organoids composed of primary human alveolar epithelial cells have been used to study the viral entry process, viral replication, interferon response, and pro-inflammatory microenvironment. Similarly, lung-on-a-chip models with active vasculatures have been developed to induce SARS-CoV-2 infection at the air-liquid interface. The interplay between viral life-cycle and host immune responses can also be investigated in these models by incorporating immune cells into the vascular network.
Furthermore, brain, kidney, blood vessel, and gut organoids have been developed to study pathological consequences of SARS-CoV-2 infection in respective organs, as well as to examine the efficacy of soluble human recombinant ACE2 in inhibiting infection of blood vessels and kidneys.
To put together all efforts related to the development and application of MPSs, the MPS COVID-19 research working group has been established under the leadership of the UK National Centre for the Replacement, Refinement and Reduction of Animals in Research and the US National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods. The primary aim of the group is to connect researchers, method developers, drug and vaccine manufacturers, and regulatory bodies across the world to maximize the scientific benefits of MPSs and to reduce the use of animals.
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