Organ-on-a-chip – Organs in miniature format

In vitro processes and animal tests are used to develop new medications and novel therapeutic approaches. However, animal testing raises important ethical concerns. Organ-on-a-chip models promise to be a feasible alternative. In a system the size of a smartphone, organs are connected using artificial circulation.

Animal testing is still required before therapies and medications can be approved for treatment and use on patients. These tests are designed to predict the activity and toxicity of drugs and their effects on human organs. They also enable researchers to determine the causes of diseases and to develop new therapeutic approaches. The medical industry benefits from animal experiments by contributing a cost-effective option that ensures the health of humans. Yet despite the advantages that animal experiments offer the medical industry, it is not only in the best interest of most people, but also of research companies to replace animal testing or to reduce these tests as much as possible. But how can this become a viable option?

As an alternative to animal experiments, scientist have relied on the Petri dish to grow or culture cells. The cells are embedded in a two-dimensional environment, which is not even remotely comparable to the natural physiological environment of organs. This makes it nearly impossible to accurately predict the effects of medication. Advances in medicine – among them stem cell research – have made organ-on-a-chip systems possible. These three-dimensional cell and tissue models enable continuous real-time in vitro monitoring of cell populations. The key advantage of organ-on-a-chip models is that they replicate the natural environment found in human cells in specific organs and tissues at microscale. So far, the "2-Organ-Chip" model (2-OC) and the "4-Organ-Chip" model (4-OC) have proven successful in the medical market. The former monitors drug efficacy and effectiveness and diseases based on two organs and the causes of diseases, while the latter studies four organoids. However, both models only allow studies of the cells of either two or four organs and are unable to rule out adverse effects on other types of cells.

3D printing technology makes the fabrication of the "organ-on-a-chip" models or chips possible. Scientists must also have the cells of the organs they aim to research at their disposal. These cells are obtained from tissue that was either medical waste from surgeries or a donation. The cells, which are the smallest functional unit of the organs, are then applied in layers onto the chip. The cells or organoids are grown on this three-dimensional scaffold and connected using artificial circulation. The circulation is made up of microchannels of the chip, which are perfused by a nutrient solution. A pump simulates the heart’s function and rhythm and transports the nutrient solution through the channels of the chip. The latter operate like human blood vessels. Cells can grow in three dimensions on the organ-on-a-chip the same way they do inside the human body.

When researchers want to monitor the effects of drugs and toxins on organs, they inject the respective substance into the tissue and study its impact. To do this, organ chips must be completely dissected, so that the cell function can be monitored. Researchers at the University of Cambridge have now developed an organ-on-a-chip model that attaches electrodes to cells. These are not made from metal but of conductive polymer sponge. This allows the cells to communicate with each other by electrical signals, ensuring continuous real-time monitoring of the miniature organ models. Unlike other organ-on-a-chip systems, the Cambridge model facilitates longer-term experiments.

The three-dimensional organ-on-a-chip models are a substantial advancement in medical technology and represent the next generation following two-dimensional cell culture. 3D technology and cell-based assays make it possible to not only more closely examine the physiology of human organs and tissues -  as they are affected by pharmaceutical substances and pathogens for instance – but to also give researchers a clear indication of the types of therapies that should be either embraced or avoided. Another advantage is that, depending on the organs in question, you can combine two or more organ tissues to conduct effective research on the target organs. Meanwhile, the drawback is that the 4-OC models don’t function properly yet because it is very difficult to mimic blood flow. Even though organ chips speed up the development of new drugs thanks to real-time monitoring of cell function, this is not a technically mature process at this point. Professor Thomas Korff, Director of the Institute of Physiology and Pathophysiology at the Medical Faculty of the Heidelberg University cautions that "the danger here is to generalize things. When I test a substance in an organ-on-a-chip system that combines lung, liver, kidney and intestinal cells, and I do not detect any adverse effects, I can only conclude that it has no harmful effects in this particular system and these cells. A false conclusion would be to infer that there would be no side effects on other types of cells." Having said that, one important aspect to remember is that organ chips address the ethical issues of animal experimentation. And although they are still not able to completely replace animal testing, they can at least significantly reduce it. What’s more, these systems considerably advance personalized medicine.

The human-on-a-chip or body-on-a-chip is a challenge in organ chip development. This is a patient-specific chip that is virtually a stand-in and duplicate of the human body. The chip combines all of a person’s organs, allowing researchers to check whether a medication helps and how it affects the particular patient. "Our assumption is that future ’chip patients’ can generate meaningful data for the majority of disease patterns and subsequently replace the respective animal experiments," says Uwe Marx, Head of the  "Multi-Organ-Chip" program at the Technical University of Berlin and founder of TissUse GmbH.
Another challenge is that liver and brain cells cannot be cultivated. Liver cells die within a few short days, rendering long-term experiments nearly impossible. Brain cells, which reproduce every day take up to a day before they pass information via new junctions called synapses. That’s why it is impossible to accurately depict central functions such as systemic blood pressure and cardiac and basal ganglia function, thus making continued animal testing necessary. Having said that, research aims to spare animals from being used in medical experiments in the future and apply human-on-a-chip systems as an alternative.