A Microfluidic Brain Interface for In Vivo Recording of Neurochemical Activity

Neurological disorders have a strong negative impact on the quality of life of affected patients, their close relatives as well as on the health economic system. Early diagnosis associated with better treatment outcomes remain difficult to reach. Similarly, misdiagnosis is frequent and can lead to the delivery of the wrong treatment to the patient. As a matter of fact, the therapeutic strategies developed to treat Alzheimer's Disease (AD) and Parkinson's Disease (PD), two major neurodegenerative diseases, are unfortunately only effective for reducing the symptoms. This illustrates the lack of complete understanding of the mechanisms underlining neurodegeneration. In this context, this thesis aims to contribute to a precise comprehension of the synaptic transmission, at the cellular level, by providing a biocompatible brain interface capable of collecting neurochemicals while establishing a tight electrical connection with the cerebral tissues. The first part of this thesis deals with the design and microfabrication of a novel neural probe which includes microelectrodes and a micro-scale droplet generator for the efficient collection of extracellular fluid. The design choices and the microfabrication approach are detailed while the behavior of the device is assessed using fluidic modeling. Experimental results regarding the neural probe's mechanical strength, electrical and fluidic functions are then presented. In particular, the electrode-tissue interface is assessed using impedance spectroscopy. The probe fluidic function and its ability to perform high frequency (6Hz) droplet segmented collection in a rapidly changing environment is experimentally demonstrated. In a second phase is reported the successful in vivo testing of the neural probe in the framework of a pilot animal trial performed on rats. A custom microfabricated analysis platform enabling to efficiently detect the content of the collected brain fluid samples is presented as well. In particular a microfabricated target plate for the distribution and handling of the segmented samples during analysis is reported. This unique approach allows to maintain the temporal history of the flow-segmented samples. Combined with Inductively Coupled (ICP) Mass Spectrometry (MS), the detection results show the presence in significant quantity of Na, Mg, K and Ca, reflecting the neurochemical state of the brain over time. Quantitative measurements are demonstrated, highlighting the power of this approach. Simultaneous cerebral tissues electrical modulation and neurochemical recording during periods of 15 min is demonstrated in a third phase. A significant neurochemical response is detected in correlation with the electrical stimulation periods (2 x 1 min). In particular, the extracellular K+ ion concentration appears to rise during these periods which is further confirmed on each of the 3 implanted subjects. It is stated that the electrical stimulation delivered to the tissues set the neurons in a permanent hyperpolarized state, forcing a strong K+ ions efflux towards the extracellular space. This work sets a basis for the development of novel approaches in the detection of malfunction in synaptic transmission. Future perspectives of this technology include new methods enabling earlier diagnosis of neurodegenerative diseases and more efficient treatments based on a closed-loop adjustment of electrical stimulation.