New Models for Studying Diseases: From Petri Dishes to Organs-on-a-Chip

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Biologists from HSE University, in collaboration with researchers from the Kulakov National Medical Research Centre for Obstetrics, Gynecology, and Perinatology, have used advanced microfluidic technologies to study preeclampsia—one of the most dangerous pregnancy complications, posing serious risks to the life and health of both mother and child. In a paper published in BioChip Journal, the researchers review modern cellular models—including advanced placenta-on-a-chip technologies—that offer deeper insights into the mechanisms of the disorder and support the development of effective treatments.

The traditional approach to testing medical products involves first assessing their safety and effectiveness on animals, followed by trials on human volunteers. Clinical trials are a lengthy, costly, and strictly regulated process. However, despite all precautions, accidents can still happen.

One of the most well-known incidents occurred in the UK in 2006 during the testing of TGN1412, a drug developed to treat leukaemia and autoimmune diseases. According to the trial protocol, two volunteers received a placebo, while six were given one five-hundredth of the dose that had previously been successfully tested on animals. Within an hour, the participants began to feel unwell, experiencing shortness of breath, vomiting, fever, headaches, and muscle pain. Some lost consciousness, and two fell into a coma. The participants developed severe oedema, and one patient's face and body became so swollen that journalists referred to him as the 'Elephant Man.' Fortunately, all participants survived the experiment, but their health was severely affected.  

It was later discovered that the cause of the tragedy was a subpopulation of immune cells in humans with specific receptors not found in animals. These receptors triggered a cytokine storm rather than regulating the immune response and reducing inflammation—a reaction that was impossible to predict during the clinical trial phase. Still, the scientists conducting the trial made a critical error: they administered the drug to all participants simultaneously instead of giving it sequentially at two-hour intervals. Had they done so, only one subject might have been affected by the tragedy.

However, even when testing is successful, clinical trials often face a challenge: they typically recruit adults who have no serious health issues aside from the condition being studied. But in reality, the medication will be taken by a diverse range of patients, including children, pregnant women, older adults, and individuals with various chronic conditions. Different dosage levels are appropriate for different groups of people, and these dosages must be carefully calculated. Additionally, individual reactions such as allergies and other side effects can occur. Even with a low side effect probability of 0.1%, there would be one affected person for every thousand.

Today, an alternative to animal testing exists. Scientists have developed models of human organs—and even organ systems—on small plates about the size of a coin. This technology is known as organ-on-a-chip. Visually, the lungs, liver, or intestines grown on a chip bear little resemblance to real organs. The chip itself is made of plastic, glass, or silicon and contains microchannels of varying lengths and sizes that direct or mix fluid flows. This approach models the environment and processes occurring in human tissues and organs, such as blood circulation. Another advantage is the potential for personalised treatment, as organs-on-a-chip can be created using a patient’s own cells. 

How Scientists Study Diseases and Test Drugs

Petri Dish

A traditional and well-known method for growing cell cultures in the laboratory. Cells grow as a monolayer on the Petri dish, interacting only with their own kind and not with other cell types. The drawback of this method is that cell life in a Petri dish only loosely resembles the natural environment and fails to accurately reflect the processes occurring within the body. 

Cell Lines in 3D

Three-dimensional cell cultures are compact clusters that, unlike traditional flat cultures, grow in all directions, forming 3D structures. A key component of 3D cultures is the extracellular matrix—a three-dimensional network of natural or synthetic molecules that provides mechanical support to cells and regulates their behaviour. The advantage of this method is that it allows the study of cells in a 3D environment, which more closely mimics their natural conditions in the body. However, these models have limitations: they lack blood vessels with circulating blood, immune cells, and the ability to replicate interactions between different tissues and organs. As a result, a molecule that performs well in cell culture may not produce the desired effect in a whole organ, let alone in a person.

Animal Testing

Rodents, pigs, and other animals are whole organisms that share many similarities with humans, making them common subjects for research and experiments. However, this method also has drawbacks: animal bodies differ from humans’, so test results are not always predictive—the tragedy during TGN1412 drug testing is a vivid example. Additionally, ethical concerns arise. 

Chips (Microfluidic Technology)

This technology has been developing since the 2010s. An organ-on-a-chip is a three-dimensional structure where multiple processes occur simultaneously, closely mimicking those in a real organism. Chips enable the modelling of fluid movement (such as blood flow) and the simulation of physical forces (such as heart contractions). Additionally, multiple layers of different cell types can be cultured on chips, and the use of a porous structure allows signals to be transmitted between them. Currently, organs such as the lungs, liver, kidneys, intestines, heart, as well as skin and bones, are successfully modelled and studied on chips.

Biologists from HSE University, in collaboration with researchers from the Kulakov National Medical Research Centre for Obstetrics, Gynecology, and Perinatology, have been using microfluidic technology to study preeclampsia. This dangerous complication affects approximately 8% of pregnancies worldwide. Preeclampsia typically manifests in late pregnancy, most often presenting with high blood pressure, protein in the urine, and impaired organ function. Despite decades of research, the exact causes of the disease remain poorly understood. However, scientists believe its origins lie in the early stages of placenta formation. 

At the start of pregnancy, the embryo implants into the uterine wall, and the placenta begins to form. To ensure the embryo receives a consistent supply of nutrients regardless of the mother’s condition, the blood vessels must maintain a stable diameter to provide steady blood flow. To achieve this, specialised cells from the embryo—the trophoblast—invade the uterine wall and locate these vessels.

Evgeny Knyazev

'Technically, this process closely resembles tumour invasion. Specialised embryonic cells, similar to metastases, penetrate the uterine tissues and line the blood vessels from the inside. Since these cells originate differently from vascular cells, they do not respond to changes occurring in the mother,' explains the first author of the study, Evgeny Knyazev, Head of the Laboratory of Molecular Physiology of the HSE Faculty of Biology and Biotechnology. If this process is incomplete for any reason, the vessels start responding to various signals by changing their diameter, and the placenta releases substances that adversely affect the health of both the mother and foetus.

Despite many years of research, there is no universal treatment for preeclampsia; therapy primarily focuses on managing symptoms, such as lowering blood pressure and supporting organ function. One of the main obstacles in developing therapies is the difficulty of studying the pathogenesis, ie the mechanism of disease development. The placenta is a unique and temporary organ, and conducting experiments on pregnant women is ethically impossible. Animal models, particularly rodents—which are the closest to humans—do not replicate the key features of human placentation. Therefore, researchers are turning to cellular models.

Placenta-on-a-chip technology enables the simulation of blood flow and metabolism between mother and foetus under conditions that closely mimic reality. Technological advancements have enabled scientists to replicate key processes of the disease, including the initial formation of the placenta. 'Models that simulate key features of preeclampsia, such as insufficient trophoblast invasion and vascular dysfunction, are especially valuable,' says Knyazev. 'They enable us not only to observe the pathological process but also to explore potential ways to correct it.'

In the initial stage of studying preeclampsia, it is essential to develop a model for assessing permeability, which is crucial, for example, in drug selection. This helps determine whether a drug can be safely used during pregnancy. The second stage involves creating a model using human cells to assess disease progression and individual risk factors. This is particularly important for women at high risk of complications, such as those undergoing IVF or with a family history of related conditions. These approaches will pave the way for screening potential drugs, predicting pregnancy outcomes, and developing individualised intervention strategies.

The authors emphasise that modelling preeclampsia, like other diseases, is not merely an academic exercise. It is a crucial part of translational medicine, which aims to rapidly translate laboratory findings into clinical practice. In the future, chip technologies may be integrated with big data analysis, artificial intelligence, and automated drug testing platforms.

The study was conducted with support from HSE University's Basic Research Programme within the framework of the Centres of Excellence project, and with support from the Russian Science Foundation (grant 24-14-00382).