Design and Implementation of an Integrated Biosensor Platform for Lab-on-a-Chip Diabetic Care Systems

Recent advances in semiconductor processing and microfabrication techniques allow the implementation of complex microstructures in a single platform or lab on chip. These devices require fewer samples, allow lightweight implementation, and offer high sensitivities. However, the use of these microstructures place stringent performance constraints on sensor readout architecture. In glucose sensing for diabetic patients, portable handheld devices are common, and have demonstrated significant performance improvement over the last decade. Fluctuations in glucose levels with patient physiological conditions are highly unpredictable and glucose monitors often require complex control algorithms along with dynamic physiological data. Recent research has focused on long term implantation of the sensor system. Glucose sensors combined with sensor readout, insulin bolus control algorithm, and insulin infusion devices can function as an artificial pancreas. However, challenges remain in integrated glucose sensing which include degradation of electrode sensitivity at the microscale, integration of the electrodes with low power low noise readout electronics, and correlation of fluctuations in glucose levels with other physiological data. This work develops 1) a low power and compact glucose monitoring system and 2) a low power single chip solution for real time physiological feedback in an artificial pancreas system. First, glucose sensor sensitivity and robustness is improved using robust vertically aligned carbon nanofiber (VACNF) microelectrodes. Electrode architectures have been optimized, modeled and verified with physiologically relevant glucose levels. Second, novel potentiostat topologies based on a difference-differential common gate input pair transimpedance amplifier and low-power voltage controlled oscillators have been proposed, mathematically modeled and implemented in a 0.18μm [micrometer] complementary metal oxide semiconductor (CMOS) process. Potentiostat circuits are widely used as the readout electronics in enzymatic electrochemical sensors. The integrated potentiostat with VACNF microelectrodes achieves competitive performance at low power and requires reduced chip space. Third, a low power instrumentation solution consisting of a programmable charge amplifier, an analog feature extractor and a control algorithm has been proposed and implemented to enable continuous physiological data extraction of bowel sounds using a single chip. Abdominal sounds can aid correlation of meal events to glucose levels. The developed integrated sensing systems represent a significant advancement in artificial pancreas systems

Conception et fabrication d'un biocapteur à haute sensibilité pour la détection des neurotransmetteurs

Dans ce mémoire, nous présentons de nouvelles architectures de différents biocapteurs électrochimiques discrets et intégrés appelés potentiostats. Tous les potentiostats développés sont basés sur une structure entièrement différentielle pour une meilleure sensibilité et une meilleure précision. Deux conceptions discrètes à un et quatre canaux ont été proposées. La conception discrète à un canal détecte la molécule de dopamine avec un courant de l’ordre du nA et une consommation électrique de 120 mW. Cette architecture a été développée sur une carte de circuit imprimé (PCB) de 20 mm x 35 mm. L’architecture discrète à quatre canaux est la version améliorée de la précédente en termes de superficie, de sensibilité et de consommation électrique. Une autre version du potentiostat, implémentée sur un PCB de 15 mm x 15 mm, peut mesurer les courants d’oxydoréduction dans la plage du pA avec une consommation de puissance de 60 mW. L’avantage de la structure à multicanaux est qu’elle offre des sensibilités différentes allant du pA au mA pour chaque canal. Une chambre microfluidique de 7,5 mm x 5 mm avec deux entrées et une sortie a été déposée sur le PCB. Une solution saline tampon au phosphate (PBS) avec une solution de ferrocyanure a été utilisée pour tester la fonctionnalité du système réalisé. La voltampérométrie cyclique a été utilisée comme technique de détection. Un comportement linéaire a été observé lorsque la concentration des neurotransmetteurs change. De plus, un potentiostat intégré a été proposé et fabriqué en technologie CMOS 180 nm, basé sur une structure entièrement « différentiel de différence » (Fully Differential Diffrence Amplifier FDDA) pour une faible consommation de puissance et un système à haute sensibilité. Cette nouvelle configuration a été conçue pour la détection des neurotransmetteurs en très faible concentration avec un faible bruit et une plage dynamique élevée. Cette architecture intégrée peut détecter les courants dans une plage inférieure au pA avec un bruit d’entrée faible de 6,9 μVrms tout en consommant seulement 53,9 μW. Le potentiostat proposé est dédié aux dispositifs implantables à faible consommation de puissance et à sensibilité et linéarité élevées.In this thesis, we present different discrete and integrated electrochemical biosensors. All these designed potentiostats are based on fully-differential architecture to enhance sensitivity and accuracy. Two complete single channel and four-channel discrete designs were fabricated. The single channel discrete design imaged the dopamine neurotransmitter with the sensed current of approximately low nano-ampere and power consumption of 120 mW implemented on a 20 x 35 mm PCB. The four-channel discrete design was the improved version of previous one in terms of area, sensitivity and power consumption. The 15 x 15 mm PCB was able to measure the reduction-oxydation currents in the range of high pico-ampere while consuming 60 mW. The advantage of the multichannel architecture is to provide a system with different sensitivity going from pA to mA for each channel. A microfluidic 7.5 x 5 mm chamber with two inlets and one outlet was bonded to the PCB. A phosphate buffered saline (PBS) with ferrocyanide solution was used to test the functionality of the implemented system. Cyclic voltammetry has been used as a detection technique. A linear behavior had been observed when the neurotransmitter concentration changed. An integrated CMOS potentiostat was designed and fabricated in 180 nm technology based on a fully-differential-difference architecture for a low power consumption and also high sensitivity system. This new architecture was designed in order to sense ultra-low concentration of neurotransmitters with low noise and high dynamic range. This integrated design was able to image currents in the range of sub-pA with low input-referred noise of 6.9 µVrms while consuming only 53.9 µW. The proposed potentiostat is dedicated for implantable devices with low power consumption and high sensitivity and linearity

Development Of Carbon Based Neural Interface For Neural Stimulation/recording And Neurotransmitter Detection

Electrical stimulation and recording of neural cells have been widely used in basic neuroscience studies, neural prostheses, and clinical therapies. Stable neural interfaces that effectively communicate with the nervous system via electrodes are of great significance. Recently, flexible neural interfaces that combine carbon nanotubes (CNTs) and soft polymer substrates have generated tremendous interests. CNT based microelectrode arrays (MEAs) have shown enhanced electrochemical properties compared to commonly used electrode materials such as tungsten, platinum or titanium nitride. On the other hand, the soft polymer substrate can overcome the mechanical mismatch between the traditional rigid electrodes (or silicon shank) and the soft tissues for chronic use. However, most fabrication techniques suffer from low CNT yield, bad adhesion, and limited controllability. In addition, the electrodes were covered by randomly distributed CNTs in most cases. In this study, a novel fabrication method combining XeF2 etching and parylene deposition was presented to integrate the high quality vertical CNTs grown at high temperature with the heat sensitive parylene substrate in a highly controllable manner. Lower stimulation threshold voltage and higher signal to noise ratio have been demonstrated using vertical CNTs bundles compared to a Pt electrode and other randomly distributed CNT films. Adhesion has also been greatly improved. The work has also been extended to develop cuff shaped electrode for peripheral nerve stimulation. Fast scan cyclic voltammetry is an electrochemical detection technique suitable for in-vivo neurotransmitter detection because of the miniaturization, fast time response, good sensitivity and selectivity. Traditional single carbon fiber microelectrode has been limited to single detection for in-vivo application. Alternatively, pyrolyzed photoresist film (PPF) is a good candidate for this application as they are readily compatible with the microfabrication process for precise fabrication of microelectrode arrays. By the oxygen plasma treatment of photoresist prior to pyrolysis, we obtained carbon fiber arrays. Good sensitivity in dopamine detection by this carbon fiber arrays and improved adhesion have been demonstrated

45-nm SOI CMOS Bluetooth Electrochemical Sensor for Continuous Glucose Monitoring

Due to increasing rates of diabetes, non-invasive glucose monitoring systems will become critical to improving health outcomes for an increasing patient population. Bluetooth integration for such a system has been previously unattainable due to the prohibitive energy consumption. However, enabling Bluetooth allows for widespread adoption due to the ubiquity of Bluetooth-enabled mobile devices. The objective of this thesis is to demonstrate the feasibility of a Bluetooth-based energy-harvesting glucose sensor for contact-lens integration using 45~nm silicon-on-insulator (SOI) complementary metal-oxide-semiconductor (CMOS) technology. The proposed glucose monitoring system includes a Bluetooth transmitter implemented as a two-point closed loop PLL modulator, a sensor potentiostat, and a 1st-order incremental delta-sigma analog-to-digital converter (IADC). This work details the complete system design including derivation of top-level specifications such as glucose sensing range, Bluetooth protocol timing, energy consumption, and circuit specifications such as carrier frequency range, output power, phase-noise performance, stability, resolution, signal-to-noise ratio, and power consumption. Three test chips were designed to prototype the system, and two of these were experimentally verified. Chip 1 includes a partial implementation of a phase-locked-loop (PLL) which includes a voltage-controlled-oscillator (VCO), frequency divider, and phase-frequency detector (PFD). Chip 2 includes the design of the sensor potentiostat and IADC. Finally, Chip 3 combines the circuitry of Chip 1 and Chip 2, along with a charge-pump, loop-filter and power amplifier to complete the system. Chip 1 DC power consumption was measured to be 204.8~$\mu$W, while oscillating at 2.441 GHz with an output power $P_{out}$ of -35.8 dBm, phase noise at 1 MHz offset $L(1\text{ MHz})$ of -108.5 dBc/Hz, and an oscillator figure of merit (FOM) of 183.44dB. Chip 2 achieves a total DC power consumption of 5.75~$\mu$W. The system has a dynamic range of 0.15~nA -- 100~nA at 10-bit resolution. The integral non-linearity (INL) and differential non-linearity (DNL) of the IADC were measured to be -6~LSB/$\pm$0.3~LSB respectively with a conversion time of 65.56~ms. This work achieves the best duty-cycled DC power consumption compared to similar glucose monitoring systems, while providing sufficient performance and range using Bluetooth