A 32-by-32 CMOS microelectrode array for capacitive biosensing and impedance spectroscopy

This paper presents the design of a 1024-channel dual-modality CMOS biosensor suitable for both capacitive sensing and impedance spectroscopy. The chip serves as a platform for detection, localization and monitoring of bacteria and can be adopted for affinity-based assays. The chip features a 32×32 array of unpassivated metal electrodes formed on the top metal of a 0.18μm CMOS process, with an overall sensing area of 2.06 mm2. The system design is based on a shared in-pixel integrator that can be used as a charge amplifier for capacitive sensing (CS) or as part of a transimpedance amplifier for electrical impedance spectroscopy (EIS). The CS mode is capable of a operation bandwidth of 50 MHz at a current consumption of 82 μA per pixel. The EIS channel operates over a bandwidth between 100 Hz and 1 MHz with a total input-referred current noise of 48 pArms and a current consumption of 210 μA per channel

A Label Free CMOS-Based Smart Petri Dish for Cellular Analysis

RÉSUMÉ Le dépistage de culture cellulaire à haut débit est le principal défi pour une variété d’applications des sciences de la vie, y compris la découverte de nouveaux médicaments et le suivi de la cytotoxicité. L’analyse classique de culture cellulaire est généralement réalisée à l’aide de techniques microscopiques non-intégrées avec le système de culture cellulaire. Celles-ci sont laborieuses spécialement dans le cas des données recueillies en temps réel ou à des fins de surveillance continue. Récemment, les micro-réseaux cellulaires in-vitro ont prouvé de nombreux avantages dans le domaine de surveillance des cellules en réduisant les coûts, le temps et la nécessité d’études sur des modèles animaux. Les microtechniques, y compris la microélectronique et la microfluidique,ont été récemment utilisé dans la biotechnologie pour la miniaturisation des systèmes biologiques et analytiques. Malgré les nombreux efforts consacrés au développement de dispositifs microfluidiques basés sur les techniques de microscopie optique, le développement de capteurs intégrés couplés à des micropuits pour le suivi des paramètres cellulaires tel que la viabilité, le taux de croissance et cytotoxicité a été limité. Parmi les différentes méthodes de détection disponibles, les techniques capacitives offrent une plateforme de faible complexité. Celles-ci ont été considérablement utilisées afin d’étudier l’interaction cellule-surface. Ce type d’interaction est le plus considéré dans la majorité des études biologiques. L’objectif de cette thèse est de trouver des nouvelles approches pour le suivi de la croissance cellulaire et la surveillance de la cytotoxicité à l’aide d’un réseau de capteurs capacitifs entièrement intégré. Une plateforme hybride combinant un circuit microélectronique et une structure microfluidique est proposée pour des applications de détection de cellules et de découverte de nouveaux médicaments. Les techniques biologiques et chimiques nécessaires au fonctionnement de cette plateforme sont aussi proposées. La technologie submicroniques Standard complementary metal-oxide-Semiconductor (CMOS) (TSMC 0.35 μm) est utilisée pour la conception du circuit microélectronique de cette plateforme. En outre, les électrodes sont fabriquées selon le processus CMOS standard sans la nécessité d’étapes de post-traitement supplémentaires. Ceci rend la plateforme proposée unique par rapport aux plateformes de dépistage de culture cellulaire à haut débit existantes. Plusieurs défis ont été identifiés durant le développement de cette plateforme comme la sensibilité, la bio-compatibilité et la stabilité et les solutions correspondantes sont fournies.----------ABSTRACT High throughput cell culture screening is a key challenge for a variety of life science applications, including drug discovery and cytotoxicity monitoring. Conventional cell culture analysis is widely performed using microscopic techniques that are not integrated into the target cell culture system. Additionally, these techniques are too laborious in particular to be used for real-time and continuous monitoring purposes. Recently, it has been proved that invitro cell microarrays offer great advantages for cell monitoring applications by reducing cost, time, and the need for animal model studies. Microtechnologies, including microelectronics and microfluidics, have been recently used in biotechnology for miniaturization of biological and analytical systems. Despite many efforts in developing microfluidic devices using optical microscopy techniques, less attention have been paid on developing fully integrated sensors for monitoring cell parameters such as viability, growth rate, and cytotoxicity. Among various available sensing methods, capacitive techniques offer low complexity platforms. This technique has significantly attracted attentions for the study of cell-surface interaction which is widely considered in biological studies. This thesis focuses on new approaches for cell growth and cytotoxicity monitoring using a fully integrated capacitive sensor array. A hybrid platform combining microelectronic circuitry and microfluidic structure is proposed along with other required biological and chemical techniques for single cell detection and drug discovery applications. Standard submicron complementary metal–oxide–semiconductor (CMOS) technology (TSMC 0.35 μm) is used to develop the microelectronic part of this platform. Also, the sensing electrodes are fabricated in standard CMOS process without the need for any additional post processing step, which makes the proposed platform unique compared to other state of the art high throughput cell assays. Several challenges in implementing this platform such as sensitivity, bio-compatibility, and stability are discussed and corresponding solutions are provided. Specifically, a new surface functionalization method based on polyelectrolyte multilayers deposition is proposed to enhance cell-electrode adherence and to increase sensing electrodes’ life time. In addition, a novel technique for microwell fabrication and its integration with the CMOS chip is proposed to allow parallel screening of cells. With the potential to perform inexpensive, fast, and real-time cell analyses, the proposed platform opens up the possibility to transform from passive traditional cell assays to a smart on-line monitoring system

Advances in High-Resolution Microscale Impedance Sensors

Sensors based on impedance transduction have been well consolidated in the industry for decades. Today, the downscaling of the size of sensing elements to micrometric and submicrometric dimensions is enabled by the diffusion of lithographic processes and fostered by the convergence of complementary disciplines such as microelectronics, photonics, biology, electrochemistry, and material science, all focusing on energy and information manipulation at the micro- and nanoscale. Although such a miniaturization trend is pivotal in supporting the pervasiveness of sensors (in the context of mass deployment paradigms such as smart city, home and body monitoring networks, and Internet of Things), it also presents new challenges for the detection electronics, reaching the zeptoFarad domain. In this tutorial review, a selection of examples is illustrated with the purpose of distilling key indications and guidelines for the design of high-resolution impedance readout circuits and sensors. The applications span from biological cells to inertial and ultrasonic MEMS sensors, environmental monitoring, and integrated photonics

Light-Addressing and Chemical Imaging Technologies for Electrochemical Sensing

Visualizing chemical components in a specimen is an essential technology in many branches of science and practical applications. This book deals with electrochemical imaging techniques based on semiconductor devices with capability of spatially resolved sensing. Two types of such sensing devices have been extensively studied and applied in various fields, i.e., arrayed sensors and light-addressed sensors. An ion-sensitive field-effect transistor (ISFET) array and a charge-coupled device (CCD) ion image sensor are examples of arrayed sensors. They take advantage of semiconductor microfabrication technology to integrate a large number of sensing elements on a single chip, each representing a pixel to form a chemical image. A light-addressable potentiometric sensor (LAPS), on the other hand, has no pixel structure. A chemical image is obtained by raster-scanning the sensor plate with a light beam, which can flexibly define the position and size of a pixel. This light-addressing approach is further applied in other LAPS-inspired methods. Scanning photo-induced impedance microscopy (SPIM) realized impedance mapping and light-addressable electrodes/light-activated electrochemistry (LAE) realized local activation of Faradaic processes. This book includes eight articles on state-of-the-art technologies of light-addressing/chemical imaging devices and their application to biology and materials science

Wideband Fully-Programmable Dual-Mode CMOS Analogue Front-End for Electrical Impedance Spectroscopy

This paper presents a multi-channel dual-mode CMOS analogue front-end (AFE) for electrochemical and bioimpedance analysis. Current-mode and voltage-mode readouts, integrated on the same chip, can provide an adaptable platform to correlate single-cell biosensor studies with large-scale tissue or organ analysis for real-time cancer detection, imaging and characterization. The chip, implemented in a 180-nm CMOS technology, combines two current-readout (CR) channels and four voltage-readout (VR) channels suitable for both bipolar and tetrapolar electrical impedance spectroscopy (EIS) analysis. Each VR channel occupies an area of 0.48 mm 2 , is capable of an operational bandwidth of 8 MHz and a linear gain in the range between -6 dB and 42 dB. The gain of the CR channel can be set to 10 kΩ, 50 kΩ or 100 kΩ and is capable of 80-dB dynamic range, with a very linear response for input currents between 10 nA and 100 μ A. Each CR channel occupies an area of 0.21 mm 2 . The chip consumes between 530 μ A and 690 μ A per channel and operates from a 1.8-V supply. The chip was used to measure the impedance of capacitive interdigitated electrodes in saline solution. Measurements show close matching with results obtained using a commercial impedance analyser. The chip will be part of a fully flexible and configurable fully-integrated dual-mode EIS system for impedance sensors and bioimpedance analysis

Integrated Electronics for Molecular Biosensing

This thesis, Integrated electronics for molecular biosensing, focuses on different approaches to sense the presence and activity of a specific analyte by using integrated electronic platforms. The aim of the first platform is to detect the enzyme telomerase. Telomerase causes the elongation of telomeres, which are part of the chromosomes, and determines the lifespan of cells. Telomerase expression is a marker of malignity in tumoral cells and its evaluation can be exploited for early diagnosis of many types of cancer cells. To detect the telomerase enzyme, a CMOS (complementary metal-oxide semiconductor) biosensor based on CMFET (Charge-Modulated Field Effect Transistor) able to measure kinetics of DNA replication and telomerase reaction was developed. The sensor can be functionalized by immobilizing single strands of DNA that contain the telomeric sequence, used as probes. If telomerase is present, the probes will be elongated by the enzyme and the charge on the sensing area will change, which reflects in a variation of the output current or voltage. The chip includes three different readout schemes (voltage, current- and time-based), each of which has different measuring ranges and operating conditions. The measured data is then digitized, stored, and can be sent off-chip through SPI (Serial Peripheral Interface) protocol. A total of 1024 biosensors have been integrated in a single chip with a size of 10x10 mm2. Each sensor can be independently addressed and functionalized by an electrochemical procedure using an integrated potentiostat, thus requiring no external equipment. Although the sensors have been tailored and optimized to perform telomerase detection, the sensing areas can be functionalized to be used with different analytes. This feature turns the chip into a complete bioassay platform. The second part of this work rises from the idea that bacteria, like Escherichia coli, can detect analytes in solution even at extremely low concentrations and change their movement through a process called chemotaxis, to move towards chemical gradients in the solution. E. coli moves by rotating its flagella either clockwise (for random tumbles) or counterclockwise (for straight runs, when it senses a chemical it is attracted to). Therefore, observing bacteria flagellar rotation can give enough information on the presence of a specific analyte in the solution. To electronically detect bacteria movement, an active surface covered in electrodes has been designed. By measuring the impedance between each pair of electrodes through an integrated LIA (lock-in amplifier), it is possible to know how a single bacterium is moving. By that, the presence or absence of the analyte can be deduced, thus effectively turning bacteria into chemical sensors

Lab-on-CMOS Sensors and Real-time Imaging for Biological Cell Monitoring

Monitoring biological cell growth and viability is essential for in vivo biomedical diagnosis and therapy, and in vitro studies of pharmaceutical efficacy and material toxicity. Conventional monitoring techniques involve the use of dyes and markers that can potentially introduce side effects into the cell culture and often function as end-point assays. This eliminates the opportunity to track fast changes and to determine temporal correlation between measurements. Particularly in drug screening applications, high-temporal resolution cell viability data could inform decisions on drug application protocols that could lead to better treatment outcomes. This work presents development of a lab-on-chip (LoC) sensor for real-time monitoring of biological cell viability and proliferation, to provide a comprehensive picture of the changes cells undergo during their lifecycle. The LoC sensor consists of a complementary metal-oxide-semiconductor (CMOS) chip that measures the cell-to-substrate coupling of adherent cells that are cultured directly on top. This technique is non-invasive, does not require biochemical labeling, and allows for automated and unsupervised cell monitoring. The CMOS capacitance sensor was designed to addresses the ubiquitous challenges of sensitivity, noise coupling, and dynamic range that affect existing sensors. The design includes on-chip digitization, serial data output, and programmable control logic in order to facilitate packaging requirements for biological experiments. Only a microcontroller is required for readout, making it suitable for applications outside the traditional laboratory setting. An imaging platform was developed to provide time-lapse images of the sensor surface, which allowed for concurrent visual and capacitance observation of the cells. Results showed the ability of the LoC sensor to detect single cell binding events and changes in cell morphology. The sensor was used in in vitro experiments to monitor chemotherapeutic agent potency on drug-resistant and drug-sensitive cancer cell lines. Concentrations higher than 5 μM elicited cytotoxic effects on both cell lines, while a dose of 1 μM allowed discrimination of the two cell types. The system demonstrates the use of real-time capacitance measurements as a proof-of-concept tool that has potential to hasten the drug development process

A Biosensor-CMOS Platform and Integrated Readout Circuit in 0.18-μm CMOS Technology for Cancer Biomarker Detection

This paper presents a biosensor-CMOS platform for measuring the capacitive coupling of biorecognition elements. The biosensor is designed, fabricated, and tested for the detection and quantification of a protein that reveals the presence of early-stage cancer. For the first time, the spermidine/spermine N1 acetyltransferase (SSAT) enzyme has been screened and quantified on the surface of a capacitive sensor. The sensor surface is treated to immobilize antibodies, and the baseline capacitance of the biosensor is reduced by connecting an array of capacitors in series for fixed exposure area to the analyte. A large sensing area with small baseline capacitance is implemented to achieve a high sensitivity to SSAT enzyme concentrations. The sensed capacitance value is digitized by using a 12-bit highly digital successive-approximation capacitance-to-digital converter that is implemented in a 0.18 μm CMOS technology. The readout circuit operates in the near-subthreshold regime and provides power and area efficient operation. The capacitance range is 16.137 pF with a 4.5 fF absolute resolution, which adequately covers the concentrations of 10 mg/L, 5 mg/L, 2.5 mg/L, and 1.25 mg/L of the SSAT enzyme. The concentrations were selected as a pilot study, and the platform was shown to demonstrate high sensitivity for SSAT enzymes on the surface of the capacitive sensor. The tested prototype demonstrated 42.5 μS of measurement time and a total power consumption of 2.1 μW

Towards CMOS Nuclear Magnetic Resonance Spectroscopy: Design, Implementation and Experimental Results

Nuclear Magnetic Resonance (NMR) Spectroscopy is used intensively along with other ancillary spectroscopic and characterization techniques. The design and implementation of High Throughput NMR Spectroscopy is a key challenge to accelerate the drug discovery process. On the other hand, the current conventional NMR technologies are expensive and bulky. The development of novel handheld NMR spectroscopy is a key challenge towards NMR spectroscopy for Point-of-Care (PoC) diagnostics applications. This thesis addresses the above-mentioned challenges of High Throughput NMR Spectroscopy and Handheld NMR spectroscopy by developing new integrated circuits dedicated to NMR spectroscopy using Complementary Metal Oxide Semiconductor (CMOS) technology. Simulation and characterization results were also used to prove the functionality and applicability of the proposed techniques. We have designed two CMOS chips using 0.13-m technology, first chip includes number of new vertical microcoils and LNA with 780 pV/Hz at 300 MHz and the second one is a new dual-path NMR receiver