Multimodal integrated sensor platform for rapid biomarker detection

Precision metabolomics and quantification for cost-effective, rapid diagnosis of disease are key goals in personalized medicine and point-of-care testing. Presently, patients are subjected to multiple test procedures requiring large laboratory equipment. Microelectronics has already made modern computing and communications possible by integration of complex functions within a single chip. As More than Moore technology increases in importance, integrated circuits for densely patterned sensor chips have grown in significance. Here, we present a versatile single CMOS chip forming a platform to address personalized needs through on-chip multimodal optical and electrochemical detection that will reduce the number of tests that patients must take. The chip integrates interleaved sensing subsystems for quadruple-mode colorimetric, chemiluminescent, surface plasmon resonance and hydrogen ion measurements. These subsystems include a photodiode array and a single photon avalanche diode array, with some elements functionalized to introduce a surface plasmon resonance mode. The chip also includes an array of ion sensitive field effect transistors. The sensor arrays are distributed uniformly over an active area on the chip surface in a scalable and modular design. Bio-functionalization of the physical sensors yields a highly selective simultaneous multiple-assay platform in a disposable format. We demonstrate its versatile capabilities through quantified bioassays performed on-chip for glucose, cholesterol, urea and urate, each within their naturally occurring physiological range

CMOS MULTI-MODAL INTEGRATED SYSTEMS FOR FUTURE BIOELECTRONICS AND BIOSENSORS

Cells are the basic structural biological units of all known living organisms. They are highly sophisticated system with thousands of molecules operating in hundreds of pathways to maintain their proper functions, phenotypes, and physiological behaviors. With this scale of complexity, cells often exhibit multi-physiological properties as their cellular fingerprints from external stimulations. In order to further advance the frontiers in bioscience and biotechnologies such as stem cell manufacturing, synthetic biology, and regenerative medicine, it is required to comprehend complex cell physiology of living cells. Therefore, a comprehensive set of technologies is needed to harvest quantitative biological data from given cell samples. Such demands have stimulated extensive research on new bioelectronics and biosensors to characterize their functional information by converting their biological activities to electrical signals. As a result, various bioelectronics and biosensors are reported and employed in many in vivo and in vitro applications. Since sensing electrodes of the devices are physically in touch with biological/chemical samples and record their signals, long-term biocompatibility and chemical/mechanical stability is of paramount importance in numerous biological applications. Furthermore, the devices should achieve high sensitivity/resolution/linearity, large field-of-view (FoV), multi-modal sensing, and real-time monitoring, while maintaining small feature size of devices to use small volume of biological/chemical samples and reduce cost. As a result, My Ph.D research aims to study interfacial electrochemical impedance spectroscopy (EIS) of electrodes with different combination of materials/sizes and to design novel multi-modal sensing/actuation array architectures with CMOS compatible in-house post-processing to address the design challenges of the bioelectronics and biosensors.Ph.D

The potential of microelectrode arrays and microelectronics for biomedical research and diagnostics

Planar microelectrode arrays (MEAs) are devices that can be used in biomedical and basic in vitro research to provide extracellular electrophysiological information about biological systems at high spatial and temporal resolution. Complementary metal oxide semiconductor (CMOS) is a technology with which MEAs can be produced on a microscale featuring high spatial resolution and excellent signal-to-noise characteristics. CMOS MEAs are specialized for the analysis of complete electrogenic cellular networks at the cellular or subcellular level in dissociated cultures, organotypic cultures, and acute tissue slices; they can also function as biosensors to detect biochemical events. Models of disease or the response of cellular networks to pharmacological compounds can be studied in vitro, allowing one to investigate pathologies, such as cardiac arrhythmias, memory impairment due to Alzheimer's disease, or vision impairment caused by ganglion cell degeneration in the retin

A dual-sensing thermo-chemical ISFET array for DNA-based diagnostics.

This paper presents a 32x32 ISFET array with in-pixel dual-sensing and programmability targeted for on-chip DNA amplification detection. The pixel architecture provides thermal and chemical sensing by encoding temperature and ion activity in a single output PWM, modulating its frequency and its duty cycle respectively. Each pixel is composed of an ISFET-based differential linear OTA and a 2-stage sawtooth oscillator. The operating point and characteristic response of the pixel can be programmed, enabling trapped charge compensation and enhancing the versatility and adaptability of the architecture. Fabricated in 0.18 μm standard CMOS process, the system demonstrates a quadratic thermal response and a highly linear pH sensitivity, with a trapped charge compensation scheme able to calibrate 99.5% of the pixels in the target range, achieving a homogeneous response across the array. Furthermore, the sensing scheme is robust against process variations and can operate under various supply conditions. Finally, the architecture suitability for on-chip DNA amplification detection is proven by performing Loop-mediated Isothermal Amplification (LAMP) of phage lambda DNA, obtaining a time-to-positive of 7.71 minutes with results comparable to commercial qPCR instruments. This architecture represents the first in-pixel dual thermo-chemical sensing in ISFET arrays for Lab-on-a-Chip diagnostics

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

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 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

A Multimodal Neural Activity Readout Integrated Circuit for Recording Fluorescence and Electrical Signals

Monitoring the electrical neural signals is an important method for understanding the neuronal mechanism. In particular, in order to perform a cell-type-specific study, it is necessary to observe the concentration of calcium ions using fluorescent indicators in addition to measuring the electrical neural signal. This paper presents a multimodal multichannel neural activity readout integrated circuit that can perform not only electrical neural recording but also fluorescence recording of neural activity for the cell-type-specific study of heterogeneous neuronal cell populations. For monitoring the calcium ions, the photodiode generates the current according to the fluorescence expressed by the reaction between the genetically encoded calcium indicators and calcium ions. The time-based fluorescence recording circuit then records the photodiode current. The electrical neural signal captured by the microelectrode is recorded through the low-noise amplifier, variable gain amplifier, and analog-to-digital converter. The proposed integrated circuit is fabricated in a 1-poly 6-metal (1P6M) 0.18- ??m CMOS process. The fluorescence recording circuit achieves a recording range of 81 dB (75 pA to 860 nA) and consumes a power of 724 nW/channel. The electrical recording circuit achieves an input-referred noise of 2.7 ??Vrms over the bandwidth of 10 kHz, while consuming the power of 4.9 ??W /channel. The functionality of the proposed circuits is verified through the in vivo and in vitro experiments. Compared to the conventional neuroscience tools, which consist of bulky off-chip components, this neural interface is implemented in a compact size to perform multimodal neural recording while consuming low power

Design and implementation of a multi-modal sensor with on-chip security

With the advancement of technology, wearable devices for fitness tracking, patient monitoring, diagnosis, and disease prevention are finding ways to be woven into modern world reality. CMOS sensors are known to be compact, with low power consumption, making them an inseparable part of wireless medical applications and Internet of Things (IoT). Digital/semi-digital output, by the translation of transmitting data into the frequency domain, takes advantages of both the analog and digital world. However, one of the most critical measures of communication, security, is ignored and not considered for fabrication of an integrated chip. With the advancement of Moore\u27s law and the possibility of having a higher number of transistors and more complex circuits, the feasibility of having on-chip security measures is drawing more attention. One of the fundamental means of secure communication is real-time encryption. Encryption/ciphering occurs when we encode a signal or data, and prevents unauthorized parties from reading or understanding this information. Encryption is the process of transmitting sensitive data securely and with privacy. This measure of security is essential since in biomedical devices, the attacker/hacker can endanger users of IoT or wearable sensors (e.g. attacks at implanted biosensors can cause fatal harm to the user). This work develops 1) A low power and compact multi-modal sensor that can measure temperature and impedance with a quasi-digital output and 2) a low power on-chip signal cipher for real-time data transfer