Chip based microelectrode array systems for modelling neurodegenerative diseases: A Multidisciplinary Approach to Model Neurodegenerative Disease

Parkinson’s disease (PD) is the second most common progressive degenerative disorder of the central nervous system. It is described as the degeneration of dopaminergic neurons in the substantia nigra, causing a decreased dopamine balance in the striatum, mainly affecting the motor system. There is currently no cure for PD. The available treatments only alleviate the symptoms and do not halt the progression. To understand the physiological and pathological mechanisms of PD, the disease models so far developed include in vitro cell models (2D and 3D systems), animal models, and clinical studies. Nevertheless, the disease models currently developed to understand the complex mechanism underlying the disease fail to reliably mimic the functional and structural complexity of PD found in vivo. Therefore, a novel disease model development is required to overcome the current challenges with the existing PD models.

The research conducted in this thesis presents the new strategies to establish an advanced disease model by integrating state-of-the-art technological advancements in microfabrication, moving from static cell culture platform to flow-based compartmentalized microfluidic cell culture systems, and the advanced design of microelectrode sensors for realtime detection of neurotransmitter release. The development of ultramicroelectrode arrays (UMEA) with 54 individually addressable recording sites on a small footprint (260 µm x 290 µm) enables recording single neuronal activity in a neuronal population to understand the intercellular network communication and detect electrochemically the release of neurotransmitter upon stimulation. The compartmentalized microfluidic chip (CMC) can model the various parts of the brain for constructing the disease model close to the in vivo environment to address PD. The designs include separate compartments connected through microchannels representing the brain's different parts in vivo in the CMC device. To establish more robust in vivo disease models, advanced microelectrode arrays were developed integrated with CMC devices to address individual compartments and manipulate the neuronal activity in one compartment and recording the activity in other compartments. Furthermore, a pyrolyzed 3D carbon scaffold (3D-CS) has been introduced for 3D sensing and characterized electrochemically. Disease modeling was further expanded by performing finite element simulations to evaluate the electric field behavior of an integrated 3D hydrogel scaffold that mimics brain tissue toward a combination of the 3D-CS and 3D hydrogel scaffold.