Brain-on-a-chip toward neurological diseases' drug discovery
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Neurological diseases are a leading cause of global disability, yet no effective treatments have been developed to reverse neurological diseases. Drugs which ameliorate their effects are expensive and/or have been reported to present high risk of adverse side effects. The drug discovery process for neurological diseases uses animal models, but use of these models is under increasing scrutiny because data from animal models is suspected to come with knowledge gaps due to genetic, size, and neural plasticity differences between animals and humans, which may translate to high failure rate of drugs. One of the strategies to develop cheap and effective drugs in a short time lies in utilizing highly physiologically relevant human cell-based models to determine drugs which have high success potential early in the drug development process. In this work, we developed a microsystem which uses human neural stem cells to form 3D neuronal networks which recapitulate functional connectivity between specific human brain regions, in vitro. In the first part of this study, we motivate the development of a 3D cell culture microsystem, rather than a 2D cell culture platform, with a mathematical model for calcium signaling mechanisms which make 3D cell cultures a more physiologically relevant model for nerve tissue in comparison to 2D cultures. The second part presents a microfluidic device (brain-on-a-chip) for patterning neurospheres and directing neural stem cells’ fate toward networks of multiple neuronal phenotypes. We validated our design by specification of human neural stem cells, in different compartments of the device, to form dopaminergic and GABAergic circuits. Such a device may provide basis for formation of multi neurotransmission circuits to model complex diseases such as schizophrenia. Lastly, to facilitate rapid analysis of data in our device, we illustrate an automated morphology independent procedure for cell recognition, segmentation and calcium spike detection technique for high throughput analysis of calcium data in neurospheroids.