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

Review on carbon-derived, solid-state, micro and nano sensors for electrochemical sensing applications

The aim of this review is to summarize the most relevant contributions in the development of electrochemical sensors based on carbon materials in the recent years. There have been increasing numbers of reports on the first application of carbon derived materials for the preparation of an electrochemical sensor. These include carbon nanotubes, diamond like carbon films and diamond film-based sensors demonstrating that the particular structure of these carbon material and their unique properties make them a very attractive material for the design of electrochemical biosensors and gas sensors. Carbon nanotubes (CNT) have become one of the most extensively studied nanostructures because of their unique properties. CNT can enhance the electrochemical reactivity of important biomolecules and can promote the electron-transfer reactions of proteins (including those where the redox center is embedded deep within the glycoprotein shell). In addition to enhanced electrochemical reactivity, CNT-modified electrodes have been shown useful to be coated with biomolecules (e.g., nucleic acids) and to alleviate surface fouling effects (such as those involved in the NADH oxidation process). The remarkable sensitivity of CNT conductivity with the surface adsorbates permits the use of CNT as highly sensitive nanoscale sensors. These properties make CNT extremely attractive for a wide range of electrochemical sensors ranging from amperometric enzyme electrodes to DNA hybridization biosensors. Recently, a CNT sensor based fast diagnosis method using non-treated blood assay has been developed for specific detection of hepatitis B virus (HBV) (human liver diseases, such as chronic hepatitis, cirrhosis, and hepatocellular carcinoma caused by hepatitis B virus). The linear detection limits for HBV plasma is in the range 0.5–3.0 μL−1 and for anti- HBVs 0.035–0.242 mg/mL in a 0.1 M NH4H2PO4 electrolyte solution. These detection limits enables early detection of HBV infection in suspected serum samples. Therefore, non-treated blood serum can be directly applied for real-time sensitive detection in medical diagnosis as well as in direct in vivo monitoring. Synthetic diamond has been recognized as an extremely attractive material for both (bio-) chemical sensing and as an interface to biological systems. Synthetic diamond have outstanding electrochemical properties, superior chemical inertness and biocompatibility. Recent advances in the synthesis of highly conducting nanocrystalline-diamond thin films and nano wires have lead to an entirely new class of electrochemical biosensors and bio-inorganic interfaces. In addition, it also combines with development of new chemical approaches to covalently attach biomolecules on the diamond surface also contributed to the advancement of diamond-based biosensors. The feasibility of a capacitive field-effect EDIS (electrolyte-diamond-insulatorsemiconductor) platform for multi-parameter sensing is demonstrated with an O-terminated nanocrystalline-diamond (NCD) film as transducer material for the detection of pH and penicillin concentration. This has also been extended for the label-free electrical monitoring of adsorption and binding of charged macromolecules. One more recent study demonstrated a novel bio-sensing platform, which is introduced by combination of a) geometrically controlled DNA bonding using vertically aligned diamond nano-wires and b) the superior electrochemical sensing properties of diamond as transducer material. Diamond nanowires can be a new approach towards next generation electrochemical gene sensor platforms. This review highlights the advantages of these carbon materials to promote different electron transfer reactions specially those related to biomolecules. Different strategies have been applied for constructing carbon material-based electrochemical sensors, their analytical performance and future prospects are discussed

Micro- and nano-devices for electrochemical sensing

Electrode miniaturization has profoundly revolutionized the field of electrochemical sensing, opening up unprecedented opportunities for probing biological events with a high spatial and temporal resolution, integrating electrochemical systems with microfluidics, and designing arrays for multiplexed sensing. Several technological issues posed by the desire for downsizing have been addressed so far, leading to micrometric and nanometric sensing systems with different degrees of maturity. However, there is still an endless margin for researchers to improve current strategies and cope with demanding sensing fields, such as lab-on-a-chip devices and multi-array sensors, brain chemistry, and cell monitoring. In this review, we present current trends in the design of micro-/nano-electrochemical sensors and cutting-edge applications reported in the last 10 years. Micro- and nanosensors are divided into four categories depending on the transduction mechanism, e.g., amperometric, impedimetric, potentiometric, and transistor-based, to best guide the reader through the different detection strategies and highlight major advancements as well as still unaddressed demands in electrochemical sensing

Towards Single-Chip Nano-Systems

Important scientific discoveries are being propelled by the advent of nano-scale sensors that capture weak signals from their environment and pass them to complex instrumentation interface circuits for signal detection and processing. The highlight of this research is to investigate fabrication technologies to integrate such precision equipment with nano-sensors on a single complementary metal oxide semiconductor (CMOS) chip. In this context, several demonstration vehicles are proposed. First, an integration technology suitable for a fully integrated flexible microelectrode array has been proposed. A microelectrode array containing a single temperature sensor has been characterized and the versatility under dry/wet, and relaxed/strained conditions has been verified. On-chip instrumentation amplifier has been utilized to improve the temperature sensitivity of the device. While the flexibility of the array has been confirmed by laminating it on a fixed single cell, future experiments are necessary to confirm application of this device for live cell and tissue measurements. The proposed array can potentially attach itself to the pulsating surface of a single living cell or a network of cells to detect their vital signs

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

A 64-channel, 1.1-pA-accurate on-chip potentiostat for parallel electrochemical monitoring

Electrochemical monitoring is crucial for both industrial applications, such as microbial electrolysis and corrosion monitoring as well as consumer applications such as personal health monitoring. Yet, state-of-the-art integrated potentiostat monitoring devices have few parallel channels with limited flexibility due to their channel architecture. This work presents a novel, widely scalable channel architecture using a switch capacitor based Howland current pump and a digital potential controller. An integrated, 64-channel CMOS potentiostat array has been fabricated. Each individual channel has a dynamic current range of 120dB with 1.1pA precision with up to 100kHz bandwidth. The on-chip working electrodes are post-processed with gold to ensure (bio)electrochemical compatibility

Rapid and Sensitive Detection of Foodborne Pathogens Using Bio-Nanocomposites Functionalized Electrochemical Immunosensor with Dielectrophoretic Attraction.

Ph.D. Thesis. University of Hawaiʻi at Mānoa 2017

Towards a commerical microelectrode array based sensor for improved chlorine detection.

The commercial development of a disposable aqueous chlorine sensor based on a novel microelectrode array fabrication process is described. Non-conducting poly(o-phenylenediamine) films are firstly used to passivate conductive surfaces. Ultrasonic ablation of passivated electrode assemblies then results in the formation of a plurality of wells to expose the underlying conductive substrate, thereby forming a microelectrode array. Microelectrode arrays produced in this manner can be exploited within many electrochemical sensing applications; however, portable aqueous chlorine detection has been selected by Microarray Limited (the industrial sponsors of this project) as a primary vehicle for launching its generic production technology. The scale of microelectrode array production has been extended from that of individual gold sputtercoated glass slide electrodes - to the simultaneous production of hundreds of low-cost screen printed carbon-ink based sensors. A focus has been directed at all stages towards permitting the cost-effective large-scale mass production of sensors with a view to challenging existing portable aqueous chlorine measurement technologies both in terms of performance and unit cost. Based on volume batches of 250,000, it has been calculated that Microarray Limited sensors can be manufactured for a unit cost of approximately 2.5 pence, sufficiently low to provide scope for a competitive yet profitable sale price. The Microarray Limited aqueous chlorine detection system has improved the limit of detection from 0.01 ppm to 0.005 ppm total chlorine without sacrificing accuracy. Furthermore, this novel approach to aqueous chlorine detection offers numerous key benefits to the customer including reduced testing time, a more straightforward operation and the elimination of harmful reagents. Product development has been described from an initial concept through to a pre-production phase. The development of an innovative generic sensor packaging technology is also described

Towards Single Bacterium Detection: A Microelectronic/Microfluidic Hybrid System Based on a CMOS Technology

RÉSUMÉ Cette thèse porte sur le développement d'un biocapteur hybride CMOS microfluidique capable de détecter des bactéries pathogènes une à une en temps réel basé sur un principe de spectroscope impédimétrique. Le biocapteur proposé se compose d'une matrice de capteurs qui comportent une matrice de microélectrodes, desmultiplexeurs à commande numérique, et des circuits de détection intégrés sur une puce de silicium CMOS. Cette recherche propose une nouvelle structure de microélectrodes qui permet à une structure de microélectrodes face à face à haute densité intégrable par post-traitement d’une puce CMOS. Au lieu d’être créée par le dépôt et la gravure de couches métalliques supplémentaires, la structure de microélectrodes face à face est construite en exploitant un empilement de couches métalliques disponible avec la technologie CMOS adoptée. Les détecteurs sont obtenus en construisant des microcanaux qui traversent le substrat. Ces microcanaux passent entre les microélectrodes face à face. Lorsque les fluides où se trouvent les échantillons traversent le microcanal, le système détecte de façon continue les changements d'impédance entre les microélectrodes induits par le passage de chaque bactérie . Cette thèse étudie le processus de microfabrication qui permet de libérer la matrice de microélectrodes et de fabriquer les microcanaux traversant le substrat. Les techniques dites de FIB (pours Focused Ion Beam) et de DRIE (pour Deep Reactive Ion Etching) sont utilisées. Les forces et faiblesses de chaque technologie sont analysées et des recettes de processus optimisés sont étudiées. La matrice de microélectrodes a été réalisée avec succès par les deux technologies. Comme preuve de concept, plusieurs microcanaux traversant le substrat sont également formés en utilisant la technologie FIB. Cette thèse propose également un nouveau circuit de détection. Réalisé grâce à la micro-électronique, ce circuit est capable de détecter les changements d'impédance causés par le passage d’une seule bactérie dans un milieu conducteur. Sans conditionnement de signaux et de circuit de traitement complexes, tels que des amplificateurs de haute précision, des filtres ou des convertisseurs analogue à numérique ou numérique à analogique, les circuits de détection sont conçus pour offrir une bonne sensibilité et une configurabilité qui permet de l'adapter aux différentes conditions de détection. Une technique de mise en boîtier biocompatible est également mise en oeuvre pour encapsuler le capteur intégré tout en fournissant des interfaces fluidiques et électriques pour l'injection d'échantillons et de signaux électriques. Une nouvelle approche pour améliorer la sélectivité de détection basée sur l’utilisation de bactéries magnétotactiques est également proposée dans cette thèse. Sous le contrôle d’un champ magnétique extérieur, les bactéries magnétotactiques sont utilisées comme bio-transporteurs, qui peuvent chercher activement et capturer les bactéries pathogènes cibles afin de les amener à la zone de détection. Une puce microfluidique est fabriquée grâce à des techniques de prototypage rapide afin de valider les idées proposées et de fournir des guides de conception d'une puce plus avancés. Les résultats de microfabrication et les résultats des tests préliminaires montrent que l'intégration monolithique des technologies CMOS et microfluidique est possible et qu’elle permet la réalisation de microélectrodes face à face dans une plate-forme capable de détecter le passage d’une seule bactérie en isolation.----------ABSTRACT This thesis reports on the development of a CMOS Microfluidic hybrid biosensor technology that is proposed to detect single pathogenic bacterium in real time based on impedimetric spectroscopy. The proposed biosensor consists of a CMOS silicon die that incorporates a microelectrode array, digitally controlled multiplexers, and sensing circuits. This research proposes a novel microelectrode structure, which is obtained by first manufacturing high density face to face microelectrodes on a CMOS die, possible by a relatively simple CMOS post-processing. Instead of deposition and patterning of additional metal layers, the face to face microelectrode array is constructed by stacking metal and via layers of the adopted CMOS technology. By constructing through substrate microchannels in between pairs of face to face microelectrodes, when a fluid sample flows through the microchannel, the microelectrodes on the wall detect the impedance change induced by bacterium in the fluid in a continuous way. This thesis investigates the microfabrication process of releasing microelectrode arrays and constructing through substrate microchannels. FIB (Focused Ion Beam) and DRIE (Deep Reactive Ion Etching) technologies are utilized. The strength and weakness of each technology are analyzed and optimized process recipes are investigated. Microelectrode array were successfully released using both process technologies. As a proof of concept, several through substrate microchannels were also formed by using the FIB technology. This thesis also proposes a novel sensing microelectronic circuit, which is able to sense the impedance change caused by a single bacterium in a conductive medium. The system does not require complex signal conditioning and processing circuits, such as high precision amplifiers, filters or ADC/DAC. The proposed simple sensing structure offer high sensitivity, reliability and configurability. A dedicated biocompatible packaging is also implemented to encapsulate the CMOS die and provide a microchamber, fluidic and electrical interfaces for sample injection and signal interfaces. A new approach to achieve detection selectivity or specificity assisted by magnetotactic bacterium is also proposed in this thesis. Under the control of an external magnetic field, the viii magnetotactic bacteria are used as bio-carriers, which can actively search and capture some target pathogenic bacteria and bring them to the sensing area. A microfluidic chip is fabricated by rapid prototyping techniques to validate the proposed idea and to provide design guides for a more advanced and highly integrated CMOS chip. The achieved microfabrication results and preliminary testing results show that the monolithic integration of CMOS and microfluidic technology, especially the face to face microelectrode structure is a suitable platform for single bacterium detection and analysis