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Innovative biochip for discovering drugs for treating neuronal conditions

Parkinson’s, Alzheimer’s and epilepsy are three prominent examples of neuronal conditions (disorders affecting the nerve cells) for which drugs for treatment are intensively sought. Paolo Cesare from the NMI in Reutlingen has developed an innovative 3D system for testing drugs that does not require animal testing. In 2015, the MEAFLUIT system was awarded first prize in BioRegio STERN Management GmbH's Science2Start idea competition.

In 1998, Dr. Paolo Cesare obtained his PhD from the University of London's renowned King’s College. His thesis dealt with the transformation of physical and chemical stimuli into electrical stimuli in the development of pain. After completing his PhD, Cesare worked for nine years at the La Sapienza University in Rome, before joining the NMI in 2011. © NMI Reutlingen

Alternatives to animal testing often fail because of their limited informative value. This is especially true in the case of substances that need to act in the central nervous system (CNS). Examples of such substances include drugs that provide relief to Alzheimer’s and Parkinson’s patients. The transmission and processing of neuronal signals are highly complex processes and cannot be reproduced with simple cell systems in the laboratory, which is why animals are needed. The search for alternatives to animal testing is not driven by ethical considerations alone. Animal testing is also time consuming, costly and the results cannot always be transferred to humans. Therefore, researchers around the world are working intensively on the development of realistic test scenarios and reliable laboratory methods for testing drugs.

The MEAFLUIT system developed by Dr. Paolo Cesare from the NMI in Reutlingen is a particularly promising system that has the potential to significantly reduce the need for animal testing in drug development. It can be used to analyse the molecular, cellular and functional mechanisms of neuronal conditions and test the efficiency of drugs against them. Cesare combines microelectrode arrays (MEAs) with microfluidic systems on a single biochip, a combination that is entirely new. Cesare explains the principle: “We have transferred the compartmentalisation of nerve cells to a biochip. Each chip contains an orderly arrangement of several cell culture chambers in which nerve cells grow. Microchannels five micrometres high and seven micrometres wide emanate from these chambers. Neurites, i. e. projections from the cell body of a neuron, fit through these channels while the much larger cell bodies do not. As a result, the two chip compartments are physically separated from each other. In a specific zone across the channels, hundreds of microelectrodes are embedded in the glass bottom of the biochip, and used to transfer the electrical signals of the neurites and stimulate the neurons .”

Analysing the transfer of synaptic signals without animal tests and under controlled conditions

Schematic representation of the functional principle of the MEAFLUIT system, which contains different microfluidic chambers (right, left, centre) connected with each other via microchannels, thus enabling the compartmentalisation of the neurons based on their function. The planar microelectrodes (black) are used for stimulating the neurons and measuring neural activities along a neuronal connection. © Paolo Cesare, NMI Reutlingen

Alzheimer’s, Parkinson’s and other neuronal conditions are characterised by the defective transmission of signals at the synaptic connections between two neurons. Now, with this new method, when neurons are placed in cell chambers on the right- and left-hand side of the chip, and when their neurites grow into the connecting microchannels, projections that come from the right and left will inevitably meet in a defined zone. And this is where the transmission of signals can be examined, either with or without the addition of pharmaceutical substances into the medium. “We can stimulate the neurons by applying a low electrical voltage to the microelectrodes. This enables us to assess the effect of substances that lead to the release of neurotransmitters into the synaptic cleft as well as the effect of substances that prevent post-synaptic signal transmission. We measure the specific effects on the synaptic level and can also measure the processing of signals of neuronal connections over an extended period,” says Cesare.

The neurons that Cesare uses for his test system can be obtained relatively easily from human stem cells. iPS (induced pluripotent stem cell) technology is used to turn these stem cells into neurons. At present, Cesare is further developing the MEAFLUIT system in cooperation with the industry, especially regarding its use for testing potential Alzheimer’s drugs. “Pharmaceutical companies require far better systems than those that currently exist for predicting the effect of such drugs,” says Cesare. A great advantage of his test system is its relatively high throughput. In the next development step, the biochip will contain as many chambers as needed to perform four separate experiments in parallel on one chip. And the team is already working on biochips with an even larger number of chambers.

Research also benefits from Cesare’s development. For example, signal processing in neurons of sick and healthy people can be compared with each other. This will help researchers to study and better understand neural functions. In an EU-funded project, Cesare plans to modify the chip to be able to measure and visualise neuron growth in 3D. Cesare also believes that the MEAFLUIT system can be successfully used in pain research. For example, it might be used for studying groups of patients with different types of pain in order to obtain new information on the phenomenon of pain. “We have already started the first experiments in which we are trying to reproduce neural pain circuits in order to explore the processing of pain,” says Cesare.

Overview of the entire chip. The central area within the black square is enlarged on the right-hand side, showing microfluidic channels and seeding areas. The MEA electrodes are not shown for reasons of clarity. The microfluidic channels are shown as grey lines. Cells and drugs can be applied to the biochip by way of the round seeding areas at the start and end of the culture chambers. © Paolo Cesare, NMI Reutlingen

Both drug development and research can benefit from the biochip 

The high potential of the biochip for commercial drug testing and research alike convinced the jury of the 2015 Science2Science idea competition. Cesare was awarded first prize for his MEAFLUIT system, which was presented to him at the traditional summer reception organised by BioRegio STERN Management GmbH in July 2015. Cesare continues to work on bringing the system to market maturity, while keeping a constant eye on research. He has just received funds from the BMBF’s “Alternatives to Animal Testing” programme for a research project, which, although it uses animal cells, is much better and has a greater predictive power than two-dimensional systems. “This brings us much closer to the natural physiology of humans and animals than traditional test methods,” says Cesare, referring to the benefits of the new system.

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/innovative-biochip-for-discovering-drugs-for-treating-neuronal-conditions