|Title||Implantable (bio)sensors for in vivo monitoring of neurotransmitters: Design, characterization and applications|
This thesis reports on the design and development of a number of bio)sensors for the measurement of neurotransmitters, including nitric oxide NO), serotonin SR), dopamine DA), glutamate Gm) and glucose Glu). These chemicals are present in the central nervous system where they modulate a variety of physiological activities. SR is also present in the gastrointestinal tract where it regulates gastrointestinal motility. Glu is a well-known major source of energy in the physiological systems. The deficiency of which surfeit can be fatal. Monitoring these analytes in real-time is crucial for biomedical purposes including diagnosis and neurological mechanistic studies. However, their presence at very low concentrations and variable levels provides a challenge for their detection. Traditionally, neurotransmitters are monitored using microdialysis coupled with separation techniques such as chromatographic and capillary electrophoresis methods. Microdialysis is slow and cannot offer real-time analytical information. On the other hand, electrochemical sensors can provide real-time measurements in vivoï¼› they are small and are easily implantable. However, obtaining sensor stability and selectivity in the complex biological environment is a major challenge. The main objective of this work was to develop bio)sensors for NO, SR, DA and Gm with high selectivity, stability and sensitivity. These were designed to provide linear range and detection limits in the physiological relevant concentrations and be able to function in real-time implantable conditions. Towards this goal, we first engineered the electrode surface with biocompatible materials and enzymes and miniaturized the sensors. We then characterized the microelectrodes and determined their analytical performance in vitro in standard laboratory conditions. Finally, we demonstrated the use of three of the most successful configurations to monitor levels of neurotransmitters in biological tissues in vitro and in vivo. 1) The NO microelectrode was used to measure NO in brain slices. 2) The DA biosensor was implanted in the intact brain of an anesthetised rat to measure DA during high frequency stimulation. 3) The SR sensor was implanted in the intestine of live embryos to quantify SR levels at multiple locations throughout the gastrointestinal system, and monitor changes of this chemical as a result of pharmaceutical interventions. The analytical performance characteristics of all the sensor configurations were thoroughly investigated. After a general overview and introduction of bio)sensor technology Chapter 1), the research work and accomplishments are presented systematically in seven chapters. These include both fundamental and practical aspects in the fabrication of these devices. Chapter 2 focuses on the development and characterization of an NO sensor and its application on brain slices. Chapter 3 describes a sensor for dual detection of NO and Gm. Chapters 4 and 5 present optimization and in vivo implementation of an enzymatic biosensor for DA. Chapter 6 describes the fabrication of a carbon fiber microelectrode and its application for in vivo monitoring of SR in live zebrafish embryo. Chapters 7 and 8 describe synthesis and characterization of gold-polypyrrole composites for use in the immobilization of enzymes and biosensors fabrication. The research results of this work have been published in 10 peer-reviewed research articles six published, one in revision and one submitted), one topical review and one book chapter.
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