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Alternative to animal experiments

Drug tests using miniature organs

At present, potential new drugs have to be tested on animals before they can be used on humans. However, results obtained from animals are not always transferrable to the situation in humans, which is why researchers around the world have long been seeking alternatives. Miniature human organs that can be used to test the efficacy of potential human drugs might provide a solution. Researchers from a Karlsruhe Institute of Technology start-up called vasQlab have developed such a test system.

Around three million animal experiments are carried out in Germany every year. The majority of animals are used in basic medical research and drug testing. However, animal experiments are not only ethically controversial, they are also expensive and time-consuming. In addition, the results gained from animal experiments are only of limited significance because the metabolisms of different animal species respond differently to active pharmaceutical substances. For example, cats and dogs tolerate the Frontline flea medication well, while rabbits do not. Accordingly, four out of five potential drugs found to be effective and safe in animal studies fail clinical trials on humans either because they produce side effects or do not work at all.

Glossary

  • Embryonic stem cells are cells, which were developed from early blastocyst stage of embryos generated by in vitro fertilisation, or from primordial germ cells of five to nine-week old aborted foetuses. It is possible to proliferate embryonic stem cells in virtually unlimited numbers without showing signs of cell ageing. In addition, these cells are pluripotent, i.e. they possess the ability to differentiate into many, possibly all of the approximately 200 different cell types of the body.
  • Pluripotent cells are able to differentiate into all cell types of the organism. Contrary to totipotent cells they cannot generate a new organism.
  • Stem cells are cells from the embryo, fetus or adult that that have the ability to divide for indefinite periods in culture and give rise to specialized cells. In Germany it is illegal to extract the stem cells from embryos.
  • A cell culture is a pool of uniform cells which were isolated from multicellular organisms and are cultivated on an artificial nutrition medium (in vitro) for experimental research.
  • The differentiation of cells describes their specialisation in their function and structure. Different cell types like myocardial, neural or liver cells with totally different appearance and functions develop from undifferentiated stem cells in this way.
  • Plasticity is the attribute of organisms to change their characteristic values under the influence of environmental factors. Therefore, neuroplasticity is the characteristic of neurons to change their response behaviour dependent from their activity. In most cases, the strength of the synaptic transmission is influenced (synaptic plasticity). The neuroplasticity or synaptic plasticity, respectively, is considered to be the basic mechanism in learning processes and in the formation of memories.
  • Aggregation is the forming of a functional cluster of cells or molecules.
  • The term metabolism includes the uptake, transport, biochemical conversion and excretion of substances within an organism. These processes are necessary to build up the body mass and to meet the energy demand of the body. The opposed processes of metabolism are called anabolism and catabolism. Effectiveness of several enzymes could be catabol and anabol. Within one biochemical pathway they cannot work in both directions at the same time.
  • Hepatocytes are liver cells. Metabolically they are very active and responsible for many physiological processes in the liver.

Organ chips to replace animal experiments

Schematic of a vasQchip © Ute Schepers / vasQlab

So-called organ-on-a-chip systems are seen as a technology with huge potential as an alternative to animal experiments. At the very least, they could reduce the number of animals used, help make the identification of potential drugs faster, cheaper and more efficient, and be used for assessing drug compatibility. Organ-on-a-chip systems simulate entire human organs in miniaturised form. At the Karlsruhe Institute of Technology, a group of researchers led by Professor Ute Schepers has developed an organ-on-a-chip system called 1-organ vasQchip, which is already being tested in academic research and is expected to be ready for market by April 2018.

But what does a miniaturised organ look like? The actual vasQchip represents an artificial blood vessel system. The chip consists of narrow, parallel circular channels made of a thin plastic film, which serve as artificial blood vessels. “The plastic blood vessels have small pores a few micrometres in diameter through which nutrients and drugs are able to enter the miniaturised organs,” says Schepers.

The team of researchers introduces vascular cells into these channels, which then attach to the inner surface of the channels and grow until they completely line the channels. The miniaturised organs are subsequently printed on the back of the artificial blood vessels as follows: a 3D printer prints a mixture of human cells (e.g. hepatocytes), extracellular matrix cells and growth factors layer by layer on the blood vessels. “This does not look like a real liver of course. It looks more like a cube-shaped piece of pressed ham,” says Schepers. “But in terms of function, the model comes very close to the real organ.”

The art of cultivating organs

This may sound simple, but there is an art to it: the scientists have to give the organ cells a living space in which they feel comfortable enough to grow and unfold in a self-organised manner in all three dimensions, form cell colonies and end up behaving like a real organ. This means that the carrier medium must be produced in such a way that the cells adhere to and grow on it, and the nutrient solution – artificial blood – must have the correct composition and circulate in the system at the correct speed.

Hepatocytes are particularly sensitive. If hepatocytes are unable to form three-dimensional aggregates, they are unable to form bile channels, and quickly lose their shape and function, with the result that a hepatocyte is no longer a hepatocyte,” explains Schepers. Many other cell types also lose their cell-specific properties when kept in standard two-dimensional Petri dish cultures. This is the reason why two-dimensional cell cultures cannot replace animal experiments.

Cultured cells have to able to grow in all three dimensions in order to make them behave like cells in the human body. If the researchers manage to create the right living conditions for the cells, the miniature organs will fulfil their metabolic and tissue functions for several weeks or months, thus creating the prerequisite conditions for simulating a real organ.

Miniature organs as test systems

The long-term expectation is to be able to several organs on a single chip. © Ute Schepers / vasQlab

The drugs to be tested enter the miniaturised organ models via the artificial blood vessels. The researchers can deduce from blood and liver values as well as from certain enzyme activities how the organ cells are reacting to the drugs to which they are exposed. This enables the researchers to make statements about the efficacy and compatibility of a drug, even before it has been tested on animals or humans.

Miniaturisation also makes it possible to carry out several series of experiments automatically and in parallel. "We offer a plug-and-play system with integrated analytics that improves the statistical evaluation of the results; the results become comparable and can easily be repeated on a large scale,” says Schepers.

The team is currently working on the development of perfused liver, colon and tumour models as well as a blood-brain barrier model. In the medium term, a range of different organs will be combined on a single chip, thus enabling the interactions between different organs to be evaluated. “Our dream is a body-on-a-chip, a chip that contains all the major human organs,” says Schepers. “We even believe that in the long term we will be able to produce personalised organ chips.”

Due to the enormous progress that has been made in stem cell research, it is now possible to obtain inducible pluripotent stem cells from a patient’s cells. This enables human tissue to be cultivated and differentiated without having to use ethically controversial embryonic stem cells. For example, the following scenario would be conceivable: a doctor who wishes to prescribe a third drug to a patient would first order an appropriate organ chip in order to laboratory test and rule out possible interactions and side effects of the drugs.

Personalised organ chips such as these are still a pipe dream. However, the first organ models are close to being placed on the market where they will be able to demonstrate in practice how well they keep up with their living role models.

References:

https://www.bmel.de/DE/Tier/Tierschutz/_texte/TierschutzTierforschung.html?docId=7027766 (20th February 2018)

https://www.aerzte-gegen-tierversuche.de/de/infos/allgemein/248-warum-tierversuche-nicht-noetig-sind
(20th February 2018)

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/drug-tests-using-miniature-organs/