Neuromuscular-Junction-on-a-Chip to study medication for Parkinson

Project Information

NMJ

Grant agreement ID: 840984

DOI

10.3030/840984

Project closed

EC signature date 27 March 2019

Start date 1 July 2019

End date 30 June 2021

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 184 707,84

EU contribution

€ 184 707,84

Coordinated by

ELVESYS
France

Periodic Reporting for period 1 - NMJ (Neuromuscular-Junction-on-a-Chip to study medication for Parkinson)

Reporting period: 2019-07-01 to 2021-06-30

Summary of the context and overall objectives of the project

Parkinson’s disease is a neurodegenerative disorder that affects 1-2 people out of 1000 overall, increasing to an incidence of 1% over 60 years old. There is currently no cure but medications can substantially reduce the symptoms of tremors and associated difficulties with movement and balance. However, the condition is progressive in severity and research into improved treatments and preventions is critically needed.

Brain research faces many limitations due to the complexity of control and accessibility of the area. Investing in models of brain diseases will fill an urgent unmet need for accessible and reliable predictive models, notably, for nervous system diseases.

The aim of this project was to develop a small medical device in the form of a miniature chamber to grow brain-derived cells that can be perfused with liquid and that mimics as closely as possible some key features of the brain environment. Creating these kinds of devices are the milestone of tomorrow’s diseases research.
Here the long-term goal is to use this “brain-on-chip” to study Parkinson’s disease. Dopamine is a potent chemical messenger molecule (neurotransmitter) made by nerve cells in the brain and used to transmit signals to other cells. Dopamine deficiency is associated with some neurodegenerative conditions, including Parkinson’s disease. Current therapies include a dopamine precursor that can cross into the brain from the blood stream. Once validated, this micro brain-on-chip technology will have the potential to test therapies for Parkinson’s disease and other nervous system disorders.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

During this project, the ER investigated different designs for a microfluidic brain-on-chip model. A suitable model was realised with multiple compartments connected by microchannels, intended to host different cell types and enable cross-talk in a controlled microenvironment.
A key function of the brain is to send and receive electrical and chemical signals. Neurons are brain cells that generate these signals and use them to communicate. Therefore, one important component of a miniature brain-on-chip device is to integrate electrodes to enable the researcher to measure electrical signals. In this project, collaborations were pursued to successfully achieve electrode surface patterning on the base layer of the microfluidic brain chip.

Another important feature of the brain is a highly selective membrane that acts as a barrier between the brain and blood vessels (the “blood-brain-barrier”). In this project, a membrane was employed as a barrier between compartments in order to better mimic tissue interfaces that are found in the body. Fabrication of the upper layers of the device focussed on testing different materials for their suitability for use as a thin membrane in the organ chip. The polymer FlexDym is transparent, gas permeable, flexible and easy to shape into thin sheets. It is also biocompatible, making it a good alternative to the commonly used thermo-polymer PDMS, which absorbs certain types of molecules. These polymers and commercially available polycarbonate membranes were tested for integration efficiency and bonding stability in the chip. Consideration was simultaneously given to user-friendly chip-to-world connections and ease of device handling.

Assembled chips were tested for leak performance by perfusing with model liquids using microfluidic flow control instruments. Candidate device prototypes were tested for compatibility with cell growth and device feedback in collaboration with external partners.

The project was presented to diverse and global scientific audiences at numerous European conferences and symposia, as well as through collaborative discussions and networking with the neuroscience and organ on chip communities, key technology stakeholders.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The brain-on-chip technology developed in this project will have the potential to be adapted to investigate the underlying biology and mechanism of disease progression of a range of different neurodegenerative pathologies, and for testing candidate drugs, including dosage and drug combinations. Importantly, this will require further rounds of validation and benchmarking of the device against existing technology to prove reliability and superior predictive capability.

Future applications include the possibility to test a patient’s own cells for a highly advanced “personalised medicine” approach to treatment.

Indeed, organ-on-chip devices are an emerging technology that is showing potential to advance the current state of the art in disease models that are used by scientists to validate new therapies. Currently, disease models are based on cells grown in static liquid in plastic flasks. Microfluidic cell culture offers physical stimuli to cells arising from the controlled flow of cell nutrients through the device, mimicking the constant flow of blood in the body, and the option to modulate the cell growth environment to be closer to real-life conditions. Thus, this technology is leading the way towards creating more advanced models of human diseases that can be used to test pre-clinical drug candidates and improve selection of target compounds. This will reduce the costs associated with developing new drugs and bring them to the market quicker for the benefit of society.

Moreover, organ-on-chip models with improved predictive ability will be strong alternatives to using animals for drug testing. Reducing the use of laboratory animals for screening drugs for human diseases is a key component of the global roadmap for animal protection. This project is fully aligned with these global legislative directives.

Ilustration of brain-on-chip system with perfusion setup.