Model inside
Scientists have created an artificial intestine to study COVID-19
Maria Nedyuk, Izvestia
Scientists from China have developed a device that will allow in the future to create an effective cure for the intestinal form of coronavirus. The device is a miniature intestine on a chip. The device cultivates human cells on a special substrate, due to which it is possible to simulate the work of the organs of the gastrointestinal tract. Testing coronavirus drugs on such models may be more effective than standard preclinical studies on laboratory animals, according to Russian experts. Specialists will be able to track the process of coronavirus infection and the effect of therapy in real time in as close to real conditions as possible.
It gets to the guts
Scientists already know that in addition to respiratory infection, the new coronavirus is able to take an intestinal form. But it has not yet been possible to understand what exactly happens in the human gastrointestinal tract during infection. Lack of knowledge causes difficulties in terms of treatment and diagnosis of this form of COVID-19.
Scientists of the Department of Biotechnology of the Dalian Institute of Chemical Physics of the Chinese Academy of Sciences studied the processes of infection of the gastrointestinal tract with coronavirus using a constructed intestine on a chip (in this case, a chip is called a special microfluidic substrate).
Article by Guo et al. SARS-CoV-2 induced intestinal responses with a biomimetic human gut-on-chip is published in the journal Science Bulletin.
"We have created a model of the intestine on a chip that allows us to recreate the relevant pathophysiology of intestinal infection caused by SARS-CoV-2," the article says.
The human intestine contains complex multicellular components. But now SARS-CoV-2 is being studied on the basis of monolayer cultures of intestinal epithelial cells. Such models have limitations: they are overly simplified and cannot reproduce what is actually happening inside the human body. Moreover, they lack a specific microenvironment, that is, constantly circulating physiological fluids.
In the mini-intestine developed by Chinese specialists, all the key features of the human epithelium and vascular endothelium are recreated. These structures are formed from human stem cells that are cultured on a chip.
The microchips themselves are pieces of plastic the size of a slide (25 by 75 mm), Dmitry Khushpulyan, head of the Laboratory of Microphysiological Systems at the FEFU School of Biomedicine, told Izvestia.
– They are equipped with a system of microchannels separated by a membrane. Thus, the upper and lower chambers of the channel are formed," the expert explained. – It is possible to cultivate human vascular cells (at the bottom) and epithelial cells (at the top) on both sides of the membrane. Thus, it is possible to simulate various barrier tissues, including the intestine, placenta, lungs, and so on.
The main potential of the new model is that it can be used to investigate the mechanisms of infection of SARS-CoV-2 on human cells in laboratory conditions in real time and to search for drugs, Dmitry Khushpulyan noted.
Chip COVID
Chinese scientists cultured intestinal epithelial cells and vascular endothelial cells on a special membrane in the chip. Then the mini-intestine was infected with SARS-CoV-2. The clinical isolate of the virus was obtained from the Center for Disease Control and Prevention of Guangdong Province, the article says.
As a result of the experiment, the intestinal epithelium demonstrated permeability to coronavirus infection and obvious morphological changes. This indicates the destruction of the integrity of the intestinal barrier caused by the virus. Moreover, the vascular endothelium also demonstrated an abnormal cell structure. In addition, scientists have recorded changes in the mucous layer, which may explain symptoms such as diarrhea and hemorrhagic colitis in patients with COVID-19.
The data obtained are important for understanding exactly how the coronavirus damages the intestine and which cells need to be affected during therapy. According to scientists, research using microchips will allow the development of the most effective drugs for COVID-19. Since the chips are usually made of transparent plastic, scientists have the opportunity to observe the tissue in real time through a microscope. Such devices well simulate the real conditions of the existence of cells in the body, Dmitry Khushpulyan said.
Don't catch mice
The technology of creating such chips has been known for a long time. One of the most well-known devices of this type were microfluidic chips ("lung on a chip" and "intestine on a chip"), introduced in 2012 by Harvard University staff led by Donald Ingber. As indicated on the project's website, a feature of American chips is the presence of additional vacuum channels inside the device, which allow you to shrink the membrane, simulating peristalsis for better correlation with real conditions in the intestine.
Several institutes in Russia are conducting similar research. One of the leaders of the direction is the Faculty of Biology and Biotechnology of the Higher School of Economics, which is headed by Corresponding Member of the Russian Academy of Sciences Alexander Tonevitsky. Together with the Institute of Bioorganic Chemistry of the Russian Academy of Sciences, the HSE has opened a laboratory of microfluidic technologies for biomedicine, in which work is underway to create and study models of the intestine on a chip, liver on a chip, placenta on a chip, brain on a chip and a number of other organs.
– When you study something on mice, it is obvious: you are treating mice, - Pavel Volchkov, head of the laboratory of genomic engineering at MIPT, told Izvestia. – However, the effects observed in animals are not always repeated in humans. Therefore, now they have begun to make chimeric systems, that is, to introduce human genes to mice. But it is long and costly to create such animals. Therefore, such artificial systems can be used as an alternative.
The results obtained on chips really correlate more accurately with real data compared to the results of animal experiments. And in the case of SARS-CoV-2, animal studies are practically impossible, since the virus is adapted specifically to human, not animal cells, Stepan Nersisyan, a junior researcher at the International Laboratory of Microphysiological Systems of the Faculty of Biology and Biotechnology of the Higher School of Economics, told Izvestia.
According to him, genetically modified rodents have already been obtained, whose cells express human receptors for coronavirus, which makes them susceptible to COVID-19. But the whole animal's body still remains only vaguely similar to a human one. There are differences both at the level of genes and proteins, and at the level of anatomy and physiology.
"Models of organs on a chip allow us to study the mechanisms of viral infection development and evaluate the effectiveness of certain treatment methods, including COVID–19, before proceeding to clinical trials involving humans," the expert noted.
As scientists explain, in a pandemic, when a drug needs to be created as quickly as possible, this can become a life-saving strategy. As for the developers from China, they are confident that the intestine on a chip will accelerate the research of the virus and the development of new therapeutic agents.
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