Like from a villi: Gut-mimicking membrane will speed up drug testing

Russian scientists have created a membrane that reproduces the permeability of the human small intestine about 100 times more accurately. The development will make it possible to more reliably assess the absorption of medicinal substances at the preclinical stage, reduce the number of unsuccessful studies and reduce the cost of creating new drugs. In the future, the technology can make testing faster, cheaper and much more reliable, experts told Izvestia. However, according to them, for the widespread implementation of the model, there are still a number of tasks to be solved and its effectiveness to be further confirmed.

Penetration of drugs through the intestinal barrier

The Institute of Biomedical Engineering of NUST MISIS has created a prototype of a porous polymer membrane with a microrelief that mimics the folded surface of the small intestine. Based on it, an experimental sample of the intestinal barrier has been developed, the permeability of which is almost 100 times closer to that of real tissue than that of a standard laboratory model. In the future, this will improve the accuracy of preclinical drug testing.

Every year, up to 90% of drugs that have shown high results in vitro (in the laboratory) and in animal experiments turn out to be ineffective for humans in further research, scientists told Izvestia. One of the reasons for this discrepancy is species differences and the imperfection of existing preclinical models that do not reliably predict the body's response. The insufficient accuracy of such models leads to a loss of up to 75% of all costs for the development of a new drug.

Permeability is the ability of a biological barrier to pass various substances through itself. For the intestine, this indicator determines how effectively medicines and nutrients pass from its lumen into the blood. To assess the permeability, a marker substance is passed through the membrane and it is measured how much of it passes to the opposite side over a certain period of time. The closer the value obtained is to the real tissue, the more reliable the model is considered.

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— Caco-2 cells specially grown in a specific system remain the standard for studying the intestinal barrier in vitro. This system is a flat monolayer without the characteristic intestinal relief of the "villi — crypt" mucosa (the villi absorbs useful substances from food, and the crypt, that is, the pit at its base, gives birth to new cells to replace the old ones), and the forming barrier is three times denser than human tissue, which is why permeability For soluble substances, it is significantly reduced," said Elizaveta Kudan, professor at the Institute of Biomedical Engineering at NUST MISIS.

To solve this problem, NUST MISIS has proposed a method for producing membranes from polycaprolactone, a biocompatible polymer that is already used in medicine. Scientists have proved that the permeability of the created membrane is two orders of magnitude closer to that of real tissue than that of a standard laboratory model.

— We have managed to form a membrane with a stable microrelief that does not smooth out. It is thanks to the combination of shape and properly selected porosity that we can grow intestinal epithelial cells on the surface. They form a living barrier capable of mimicking both a healthy mucosa and its pathologies. To create conditions for an even distribution of cells over a complex surface, we additionally treated it with chitosan and polyglutamic acid," said Valentina Kostenko, co—author of the study and graduate of the university's iPhD Biomaterial Science program.

New generation drug testing platforms

According to Alevtina Chernikova, Rector of NUST MISIS, within the framework of the strategic technological project "Biomedical Engineering and Biomaterials", implemented at the university under the state program "Priority 2030", scientists have been conducting research for a number of years, and their developments can significantly improve the quality of people's lives. A patent application has already been filed for a new method for producing a biomimetic membrane.

—The development can serve as the basis for a more advanced model, which in the future will speed up and reduce the cost of drug testing at the stage of choosing the optimal dosage form, replacing some stages of pharmacokinetic tests on animals," Arkady Zinchenko, head of the analytical research department at the R-Pharm Medical Directorate, told Izvestia.

The creation of a porous polycaprolactone membrane with a three—dimensional "villi—crypt" microrelief is an important step from outdated flat systems to full-fledged reproduction of living tissue, said Evgenia Krylova, gastroenterologist, acting director of the NSU Medical Center.

— The main achievement is to create a stable relief that perfectly mimics the inner surface of the small intestine and does not smooth out over time. In classical experimental models based on standard cell lines, there is a serious problem: cells secrete an excessive amount of proteins of dense contacts, which causes the barrier to become over-sealed, and its permeability turns out to be significantly lower than the real one. The new development eliminates this excess density," the specialist said.

According to her, this will reduce the risk of erroneous screening of promising water-soluble molecules and accelerate the transition from laboratory research to the first phases of clinical trials of drugs.

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At the same time, development is only the first stage of creating a universal platform. To turn the model into a full-fledged system for drug testing, there are still several difficult tasks to be solved, the expert noted. In particular, it is necessary to simulate the mechanical deformation of the membrane under the influence of intestinal motility, both in normal and pathological conditions, such as diarrhea or constipation. Nevertheless, this work is already setting a high standard in the field of biomedical engineering and laying the foundation for the creation of new generation drug testing platforms.