Let's practice on chips

How the Russian microbioreactor "Homunculus" helps in testing new drugs

Roman Fishman, N+1

New drugs can be tested on experimental animals, it is possible on human volunteers, but it is much more convenient – and humane – to use cellular models for this. However, not everything is simple with them either: you can take cells of a certain human organ, or you can assemble cells of several organs into a single system similar to a living organism – with such a system, the test result will be the most accurate. To achieve it, the microbioreactor "Homunculus" was developed, created jointly by German and Russian scientists. We turned to the dean of the Faculty of Chemical Technology and Biotechnology of Moscow Polytechnic University Natalia Pulkova to find out more about the operation of this device.

Before the benefits and safety of a new drug are proven, the drug undergoes a long series of tests, and several phases of clinical trials on volunteers are only the last acts of the process, which usually takes more than one year. Before human testing begins, experimental animals come into play: more than 115 million mice, rats and representatives of other species are used in laboratories every year. At the same time, animals act only as approximate models of the human body, allowing to study the course of the disease or the effect of a new drug without taking into account species specificity.

General view of the "Homunculus": the microchip fits in the palm of your hand
(photo here and below – Konstantin Titov)

We are arranged very similarly, but sometimes the effect on people of a substance that seems to be well studied in animals turns out to be completely unexpected. The experimental immunomodulator TGN1412, which was considered a promising remedy for rheumatoid arthritis and other diseases of the immune system, demonstrated itself well in mice, but already at the first human trials caused an acute autoimmune reaction in them and led to the death of several volunteers. Today, when isolated cultures of human cells can be grown in the laboratory, one of the stages of testing new substances has become preclinical tests "in vitro", in vitro. To evaluate the effect of the drug on the cells of the heart muscle or the danger of air pollution for the lungs, to check the reaction of neurons to changes in temperature or hormonal profile – all this is possible without animals and without people.

In culture media in which human cell lines are grown,
a special dye is added, by the shade of which the pH of the medium can be controlled

The next step was the methods of growing cellular models of human organs and tissues in the laboratory in the same environment in which they function in the whole organism. At the same time, it is not too important how many cells there are in the real liver or heart – for tests, as a rule, only a microscopic analogue is enough. Using miniature cells of microbioreactors, precisely controlling the composition of solutions that come to them through microchannels, and other external factors, it is already possible to study with a high degree of reliability all changes occurring at the cellular level.

Having learned how to obtain cellular models of organs, it is worth taking the next step and trying to assemble from them – no, not yet a model of a whole person, but at least a set of individual systems whose work we want to investigate. "The pioneers in the development of human-on-a–chip technologies were researchers from Germany, who have been developing them for more than ten years, at the Technical University of Berlin and at the Fraunhofer Institute in Dresden," Natalia Pulkova, Dean of the Faculty of Chemical Technology and Biotechnology at Moscow Polytechnic University, told N+1. – Quite quickly, in 2009, the team of the Russian company STC "BioClinicum" joined the work of German scientists. Their strong engineering team has engaged in the creation of a control unit that is able to control the movement of the nutrient medium." The Moscow Polytechnic University, a partner of this material, closely cooperates with the scientific and technical center "BioClinicum".

Our interlocutor, Dean of the Faculty of Chemical Technology and Biotechnology of the Moscow Polytechnic University, Candidate of Biological Sciences Natalia Pulkova, formerly a senior researcher at the Bioclinicum, where the biotechnological platform Homunculus was developed with the possibility of obtaining simplified cellular models of organs and tissues in a single man-on-a-chip system

The main result of the partnership of biologists from Germany and Russian engineers was the microbioreactor "Homunculus", which allows modeling the operation of a system of six, and in the future – ten different cellular models of tissues and organs. This is a system of two equally important components, a control unit and a "biochip" in which cells are cultured. "A biochip is no bigger than a matchbox," Natalia Pulkova continues, "and, like a sandwich, it is composed of several layers: on the slide there is a layer of silicone in which microchannels and cells for cell culture are located. Finally, the top layer is a plexiglass panel that gives rigidity to the system."

The cells are connected by a system of microchannels, like blood vessels, the flow of fluid in them is controlled by the jewelry work of pumps and valves. There can be a different number of cells, from two to six, depending on the specific task and, accordingly, different cells that need to be used. Such a microbioreactor allows you to assemble a cellular "homunculus" from individual components, as from the parts of a designer, simulating the interactions of not only different organs, but also different ways of administering the drug.

"If, for example, a substance is administered orally, then it is absorbed into the blood through the intestinal walls, after which it is metabolized in the liver, and then it spreads throughout the body and affects the target organ," explains Pulkova. "We are learning to simulate the operation of this entire system, and in Homunculus, unlike similar developments, it is possible to control the pressure and frequency of changing the fluid entering the biochip, simulating the circulation of blood flow."

Nutrient media for bacteria are being prepared for sterilization

Immortal lines are dedicated to this pH indicator:
"The alkali makes me yellow like a fever
I'm turning pink from acids, as if from shame
And I throw myself into the water without looking back
I'm orange almost always here."

The latest generations of the Homunculus can be equipped with various sensors, individual for different cells, the system can be controlled via a convenient remote interface, and the researcher can even receive SMS messages about all important events. In parallel, German biologists under the leadership of Uwe Marx are developing methods of cultivation of cells of different tissues – intestines, liver, skin, heart, brain, kidneys and lungs - on a chip. "For example, intestinal cells are cultured on a special porous membrane, which leads to their polarization similar to in vivo," says Pulkova. – Of course, a biochip is far from a whole organism, but it is already close enough to it."

Such installations work both in Germany, and in the Novosibirsk Scientific Center of Clinical and Experimental Medicine of the Siberian Branch of the Russian Academy of Medical Sciences, and in Moscow State University, where fundamental research is conducted on them. "Homunculus" is now installed in our Moscow Polytechnic University," Pulkova continues. – We have received a joint grant with the "Bioclinicum", our students are trained on the master's program "Engineering of biopharmaceuticals" on the system. There is something to work on, and the work continues. For example, to ensure the joint cultivation of different cell types in a multipath chip for a long time. The design of the biochip is also being finalized, engineers are achieving greater automation of the system, working on ten-hole chips."

It is unlikely that a more complex platform will be needed in the future: according to Natalia Pulkova, there is no need to assemble a "whole" "man-on-a-chip". It is enough to more or less fully simulate the work of individual body systems that are important for specific tasks of medicine, pharmacology, biology and ecology. And if animal rights activists are seriously changing research plans on mice and primates, then the fate of microscopic "homunculi" on biocips is unlikely to bother anyone. After all, it's just a model.

Portal "Eternal youth" http://vechnayamolodost.ru  21.10.2016