Towards brain-on-a-chip : microfluidic and microelectrode array platforms for morphological and electrophysiological observations on the propagation of Alzheimer's disease

Since the first compartmentalized neuronal culture described by Robert B. Campenot in 1977, compartmentalized microfluidic devices have been widely used to engineer the cellular environment for cell culture. In previous research by Dr. Anja Kunze, a microfluidic device was able to build a "co-pathological" model with neuronal culture for neurodegenerative disease studies. In this model, two neuronal populations were cultured in independent compartments, while the axons of both populations were able to grow away from their own population and arrived in the same compartment, which was between the two compartments for the neuronal populations. When one neuronal population was exposed to a drug and expressed a specific disease state, different disease states were observed in the axon compartment towards the other unexposed cell population. This co-pathological pattern was achieved and early stage of disease propagation was observed in this compartmentalized microfluidic device. An example of this propagation pattern in the native brain is the well-known neurodegenerative disease Alzheimer's disease (AD), which still lacks effective treatments. In the AD brain, disease progression is observed from one brain region to another, eventually influencing the whole brain. This disease model can be mimicked in vitro within microdevices to assist neuroscientists in gaining a better understanding of the mechanisms of AD spreading in the native brain. In this thesis, we designed and fabricated compartmentalized microfluidic devices to build a co-pathological model to study the propagation of Tau pathology, which is one of the key pathological hallmarks of neurodegenerative disorders. Besides the morphological characteristics that we observe using our microfluidic device, microelectrode arrays (MEAs) technology, which is based on microtechnology and allows for recording extracellular neuronal activity, was integrated with the microfluidic device in this work. Together, the microfluidic and the integrated microfluidic-MEA devices provide us the possibility to monitor respectively time-variant morphological and electrophysiological alterations during disease spreading. We are therefore able to distinguish the contribution of neuron-to-neuron transmissions, observe different patterns of disease propagation with high and low drug-induced AD models, and observe the order in which the structural and functional alterations occur during AD progression. Based on the results that were achieved during our investigation of AD in this thesis, these microfluidic and integrated microdevices may potentially be used to study neurodegenerative diseases and perform pharmaceutical drug tests.