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

Crexens™: an expandable general-purpose electrochemical analyzer

2019 Fall.Includes bibliographical references.Electrochemical analysis has gained a great deal of attention of late due to its low-cost, easy-to-perform, and easy-to-miniaturize, especially in personal health care where accuracy and mobility are key factors to bring diagnostics to patients. According to data from Centers for Medicare & Medicaid Services (CMS) in the US, the share of health expenditure in the US has been kept growing in the past 3 decades and reached 17.9% of its overall Gross Domestic Product till 2016, which is equivalent to $10,348 for every person in the US per year. On the other hand, health care resources are often limited not only in rural area but also appeared in well-developed countries. The urgent need and the lack of health resource brings to front the research interest of Point-of-Care (PoC) diagnosis devices. Electrochemical methods have been largely adopted by chemist and biologist for their research purposes. However, several issues exist within current commercial benchtop instruments for electrochemical measurement. First of all, the current commercial instruments are usually bulky and do not have handheld feature for point-of-care applications and the cost are easily near$5,000 each or above. Secondly, most of the instruments do not have good integration level that can perform different types of electrochemical measurements for different applications. The last but not the least, the existing generic benchtops instruments for electrochemical measurements have complex operational procedures that require users to have a sufficient biochemistry and electrochemistry background to operate them correctly. The proposed Crexens™ analyzer platform is aimed to present an affordable electrochemical analyzerwhile achieving comparable performance to the existing commercial instruments, thus, making general electrochemical measurement applications accessible to general public. In this dissertation, the overall Crexens™ electrochemical analyzer architecture and its evolution are presented. The foundation of the Crexens™ architecture was derived from two separate but related research in electrochemical sensing. One of them is a microelectrode sensor array using CMOS for neurotransmitter sensing; the other one is a DNA affinity-based capacitive sensor for infectious disease, such as ZIKA. The CMOS microelectrode sensor array achieved a 320uM sensitivity for norepinephrine, whereas the capacitive sensor achieved a dynamic range of detection from 1 /uL to 105 /uL target molecules (20 to 2 million targets), which makes it be within the detection range in a typical clinical application environment. This dissertation also covers the design details of the CMOS microelectrode array sensor and the capacitive sensor design as a prelude to the development of the Crexens™ analyzer architecture. Finally, an expandable integrated electrochemical analyzer architecture (Crexens™) has been designed for mobile point-of-care (POC) applications. Electrochemical methods have been explored in detecting various bio-molecules such as glucose, lactate, protein, DNA, neurotransmitter, steroid hormone, which resulted in good sensitivity and selectivity. The proposed system is capable of running electrochemical experiments including cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), electrochemical capacitive spectroscopy (ECS), amperometry, potentiometry, and other derived electrochemical based tests. This system consist of a front-end interface to sensor electrodes, a back-end user interface on smart phone and PC, a base unit as master module, a low-noise add-on module, a high-speed add-on module, and a multi-channel add-on module. The architecture allows LEGO™-like capability to stack add-on modules on to the base-unit for performance enhancements in noise, speed or parallelism. The analyzer is capable of performing up to 1900 V/s CV with 10 mV step, up to 12 kHz EIS scan range and a limit of detection at 637 pA for amperometric applications with the base module. With high performance module, the EIS scan range can be extended upto 5 MHz. The limit of detection can be further improved to be at 333 fA using the low-noise module. The form factor of the electrochemical analyzer is designed for its mobile/point-of-care applications, integrating its entire functionality on to a 70 cm² area of surface space. A glutamine enzymatic sensor was used to valid the capability of the proposed electrochemical analyzer and turned out to give good linearity and reached a limit of detection at 50 uM

Energy-Efficient PRBS Impedance Spectroscopy on a Digital Versatile Platform

partially_open6siThis research has been partially funded by the Italian Ministry of University and Research (MUR) through the program “Dipartimenti di Eccellenza” (2018-2022). The research has also received partial support from the Italian Ministry of University and Research (MUR) and the Eranet FLAG ERA initiative within CONVERGENCE project (CUP B84I16000030005) through the IUNET Consortium.This paper presents the digital design of a versatile and low-power broadband impedance spectroscopy (IS) system based on pseudo-random binary sequence (PRBS) excitation. The PRBS technique allows fast, and low-power estimation of the impedance spectrum over a wide bandwidth with adequate accuracy, proving to be a good candidate for portable medical devices, especially. This paper covers the low-power design of the firmware algorithms and implements them on a versatile and reconfigurable digital platform that can be easily adjusted to the specific application. It will analyze the digital platform with the aim of reducing power consumption while maintaining adequate accuracy of the estimated spectrum. The paper studies two main algorithms (time-domain and frequency-domain) used for PRBS-based IS and implements both of them on the ultra-low-power GAP-8 digital platform. They are compared in terms of accuracy, measurement time, and power budget, while general design trade-offs are drawn out. The time-domain algorithm demonstrated the best accuracy while the frequency-domain one contributes more to save power and energy. However, analysis of the energy-per-error FOM revealed that the time-domain algorithm outperforms the frequency-domain algorithm offering better accuracy for the same energy consumption. Numerical methods and microprocessor resources are exploited to optimize the implementation of both algorithms achieving 27 ms in processing time, power consumption as low as 1.4 mW and a minimum energy consumption per measurement of 0.5 mJ, for a dense impedance spectrum estimation of 214 points.embargoed_20210525Luciani G.; Crescentini M.; Romani A.; Chiani M.; Benini L.; Tartagni M.Luciani G.; Crescentini M.; Romani A.; Chiani M.; Benini L.; Tartagni M

New Architectures and Circuits for Pushing the Dynamic Range and Multiplexing Boundaries of CMOS-Integrated Sensors

Over the last decades, CMOS-integrated sensors have made impressive progress in performance, form-factor, and energy-efficiency for various applications such as imaging, physical/chemical sensing, bio/health monitoring. In the era of the artificial intelligence (AI) and the internet-of-things (IoT), such CMOS-integrated sensors are essential for massive and comprehensive data acquisition, where sensing range (or dynamic range), signal fidelity (or signal-to-noise ratio), and data throughput are key factors. Towards pushing the boundaries of such sensing capabilities, in this dissertation, novel sensing architectures are presented with energy/area-efficient circuit design techniques for multi-channel CMOS optical sensors and neural interfaces. The first topic is a fully-integrated, wide linear dynamic range optical sensor array combining linear and single-photon avalanche diode operation within each pixel. A pulse-counting readout scheme provides in-pixel digitization in an area-efficient manner for both operation modes, enabling fully parallel measurement across the array. The proposed dual-mode optical sensor array alternately requires high-voltage(10-20 V) and low-voltage supply (2-5 V) for reverse bias of the photodiodes, which is provided by a reconfigurable, closed-loop high-voltage charge pump in the same substrate. An 8 x 8 array architecture along with the dual-mode bias generator is fabricated in a general purpose 180 nm CMOS process and demonstrates 129 dB dynamic range while maintaining linear photoresponse operating with a dual-mode frame rate of 20 Hz. The second topic is a new approach for applying code-division multiplexing (CDM) to current-mode and voltage-mode sensor arrays with analog-domain orthogonal encoding directly in a shared, single analog-front-end circuit, which enables simultaneous readout for multiple sensors. The approach is applied to a 8 x 16 array of CMOS-integrated photodetectors and implemented in a general purpose 180 nm CMOS process, where the 16 channel CDM-based oversampling readout achieves an SNR improvement of more than 12 dB compared with time-division multiplexing at the same sampling rate. In addition, a CDM-based neural recording architecture is presented, which offers a significant tolerance to interference that can be injected through long cables

CMOS Transducers and Programmable Interface Circuits for Resource-Efficient Sensing Applications

Modern sensors are complex systems comprising multiple sub-systems such as transducers, analog and mixed-signal interface circuits, digital processing circuits, and packaging. Over the last few decades, innovations in these sub-systems combined with their increased integration in complementary metal-oxide semiconductor (CMOS) processes have led to the rapid growth in sensors for the Internet-of-Things (IoT), wearable devices, and fundamental scientific instrumentation. This thesis introduces novel ideas for various parts of a sensor signal chain. First, CMOS-based transducers (i.e. sensing elements) are introduced. Single-photon avalanche diodes (SPADs) fabricated in 0.18µm and 0.13µm standard CMOS processes are demonstrated and characterized for various optical sensing techniques. A resistor fabricated using standard CMOS-BEOL layers in a 0.18µm process is used to demonstrate a compact, fully-integrated single-element flow sensor occupying less than 0.065mm2. Second, front-end interface circuits for single-photon optical detectors are introduced. A fully-integrated SPAD-based ambient light sensor using mostly digital circuits and fabricated in a 0.13µm CMOS process is highlighted. It consumes 125μW and achieves one of the lowest reported areas (0.046mm2) in the literature. A custom analog front-end (AFE) chip is fabricated in a 0.18µm CMOS process for interfacing with a commercial silicon photomultiplier (SiPM) for gamma spectroscopy. It incorporates tunability of dynamic range and integration time, thus making it suitable for different detectors (i.e. SiPM and scintillator crystal combinations). Third, non-linear analog-to-digital converters (NL-ADCs) are explored as a viable alternative to linear ADCs for information-aware, non-uniform quantization and a widely reconfigurable piecewise-linear analog-to-digital converter (PWL-ADC) prototype chip (0.18µm CMOS) is used to validate this. With a 7-bit output word, it achieves 5.6-bit to 9.5-bit resolution in user-defined regions of the input full-scale range (FSR), while consuming 105µW at a sampling frequency of 42kHz. Measurements with recorded ECG waveforms are used to highlight the application-specific advantages of the PWL-ADC. Finally, some of the aforementioned ideas are used at the system level in a gamma spectrometer realized on a printed circuit board (PCB). The PCB design includes the AFE and PWL-ADC IC chips, a commercial SiPM and scintillator crystal, and a FPGA-based digital back-end (DBE). Several linear and non-linear isotope spectra with variable energy bin-widths (dE/bin) are recorded and analyzed to demonstrate the utility of the proposed concepts for peak enhancement and improved peak discrimination in radiation spectroscopy

New Techniques for Multi-Channel Biosignal Acquisition and Low-Power, Low-Resistance-Measurement Systems

Dense electrical recording of biosignals has been developed to provide spatial resolution and precise temporal information for health monitoring, diagnostics, and clinical research. However, more electrodes require more wires, and wiring density quickly becomes a limiting factor. To break this bottleneck, we proposed a frequency-division multiplexing (FDM) based architecture for multi-channel acquisition systems. In this final exam, I present two applications that make use of this FDM technique. The first is an FDM-based multi-channel electromyography (EMG) acquisition system, which demonstrates that the FDM system not only reduces wire count, but also mitigates the effect of low frequency motion artifacts and 50/60 Hz mains interference introduced in the wire. An FDM-based four-channel EMG recording is demonstrated, while carrying all channels over a 3-wire interface, and the system achieves an attenuation of low-frequency cable motion artifacts by 15X an! d 60Hz mains noise coupled in the cable by 62X. A second application that forms the basis of my current research effort is an FDM-based neural recording system with multiple graphene active electrodes. We demonstrated a two-channel system including graphene FET electrodes, a custom integrated circuit (IC) analog front-end (AFE), and digital demodulation. In related multi-channel sensor work, a growing need for ultra-low-power sensors has driven continuous advancement in read-out circuits for temperature, humidity, and pressure. IC-integrated Wheatstone bridges, commonly used, are efficient for large sensor resistance (5k-500kohm), but measuring small resistance (30,000x smaller nominal sensor resistance

Low-power Wearable Healthcare Sensors

Advances in technology have produced a range of on-body sensors and smartwatches that can be used to monitor a wearer’s health with the objective to keep the user healthy. However, the real potential of such devices not only lies in monitoring but also in interactive communication with expert-system-based cloud services to offer personalized and real-time healthcare advice that will enable the user to manage their health and, over time, to reduce expensive hospital admissions. To meet this goal, the research challenges for the next generation of wearable healthcare devices include the need to offer a wide range of sensing, computing, communication, and human–computer interaction methods, all within a tiny device with limited resources and electrical power. This Special Issue presents a collection of six papers on a wide range of research developments that highlight the specific challenges in creating the next generation of low-power wearable healthcare sensors