A Flexible, Highly Integrated, Low Power pH Readout

Medical devices are widely employed in everyday life as wearable and implantable technologies make more and more technological breakthroughs. Implantable biosensors can be implanted into the human body for monitoring of relevant physiological parameters, such as pH value, glucose, lactate, CO2 [carbon dioxide], etc. For these applications the implantable unit needs a whole functional set of blocks such as micro- or nano-sensors, sensor signal processing and data generation units, wireless data transmitters etc., which require a well-designed implantable unit.Microelectronics technology with biosensors has caused more and more interest from both academic and industrial areas. With the advancement of microelectronics and microfabrication, it makes possible to fabricate a complete solution on an integrated chip with miniaturized size and low power consumption.This work presents a monolithic pH measurement system with power conditioning system for supply power derived from harvested energy. The proposed system includes a low-power, high linearity pH readout circuits with wide pH values (0-14) and a power conditioning unit based on low drop-out (LDO) voltage regulator. The readout circuit provides square-wave output with frequency being highly linear corresponding to the input pH values. To overcome the process variations, a simple calibration method is employed in the design which makes the output frequency stay constant over process, supply voltage and temperature variations. The prototype circuit is designed and fabricated in a standard 0.13-μm [micro-meter] CMOS process and shows good linearity to cover the entire pH value range from 0-14 while the voltage regulator provides a stable supply voltage for the system

Digital CMOS ISFET architectures and algorithmic methods for point-of-care diagnostics

Over the past decade, the surge of infectious diseases outbreaks across the globe is redefining how healthcare is provided and delivered to patients, with a clear trend towards distributed diagnosis at the Point-of-Care (PoC). In this context, Ion-Sensitive Field Effect Transistors (ISFETs) fabricated on standard CMOS technology have emerged as a promising solution to achieve a precise, deliverable and inexpensive platform that could be deployed worldwide to provide a rapid diagnosis of infectious diseases. This thesis presents advancements for the future of ISFET-based PoC diagnostic platforms, proposing and implementing a set of hardware and software methodologies to overcome its main challenges and enhance its sensing capabilities. The first part of this thesis focuses on novel hardware architectures that enable direct integration with computational capabilities while providing pixel programmability and adaptability required to overcome pressing challenges on ISFET-based PoC platforms. This section explores oscillator-based ISFET architectures, a set of sensing front-ends that encodes the chemical information on the duty cycle of a PWM signal. Two initial architectures are proposed and fabricated in AMS 0.35um, confirming multiple degrees of programmability and potential for multi-sensing. One of these architectures is optimised to create a dual-sensing pixel capable of sensing both temperature and chemical information on the same spatial point while modulating this information simultaneously on a single waveform. This dual-sensing capability, verified in silico using TSMC 0.18um process, is vital for DNA-based diagnosis where protocols such as LAMP or PCR require precise thermal control. The COVID-19 pandemic highlighted the need for a deliverable diagnosis that perform nucleic acid amplification tests at the PoC, requiring minimal footprint by integrating sensing and computational capabilities. In response to this challenge, a paradigm shift is proposed, advocating for integrating all elements of the portable diagnostic platform under a single piece of silicon, realising a ``Diagnosis-on-a-Chip". This approach is enabled by a novel Digital ISFET Pixel that integrates both ADC and memory with sensing elements on each pixel, enhancing its parallelism. Furthermore, this architecture removes the need for external instrumentation or memories and facilitates its integration with computational capabilities on-chip, such as the proposed ARM Cortex M3 system. These computational capabilities need to be complemented with software methods that enable sensing enhancement and new applications using ISFET arrays. The second part of this thesis is devoted to these methods. Leveraging the programmability capabilities available on oscillator-based architectures, various digital signal processing algorithms are implemented to overcome the most urgent ISFET non-idealities, such as trapped charge, drift and chemical noise. These methods enable fast trapped charge cancellation and enhanced dynamic range through real-time drift compensation, achieving over 36 hours of continuous monitoring without pixel saturation. Furthermore, the recent development of data-driven models and software methods open a wide range of opportunities for ISFET sensing and beyond. In the last section of this thesis, two examples of these opportunities are explored: the optimisation of image compression algorithms on chemical images generated by an ultra-high frame-rate ISFET array; and a proposed paradigm shift on surface Electromyography (sEMG) signals, moving from data-harvesting to information-focused sensing. These examples represent an initial step forward on a journey towards a new generation of miniaturised, precise and efficient sensors for PoC diagnostics.Open Acces

Field-Effect Sensors

This Special Issue focuses on fundamental and applied research on different types of field-effect chemical sensors and biosensors. The topics include device concepts for field-effect sensors, their modeling, and theory as well as fabrication strategies. Field-effect sensors for biomedical analysis, food control, environmental monitoring, and the recording of neuronal and cell-based signals are discussed, among other factors

Ultra-thin and flexible CMOS technology: ISFET-based microsystem for biomedical applications

A new paradigm of silicon technology is the ultra-thin chip (UTC) technology and the emerging applications. Very thin integrated circuits (ICs) with through-silicon vias (TSVs) will allow the stacking and interconnection of multiple dies in a compact format allowing a migration towards three-dimensional ICs (3D-ICs). Also, extremely thin and therefore mechanically bendable silicon chips in conjunction with the emerging thin-film and organic semiconductor technologies will enhance the performance and functionality of large-area flexible electronic systems. However, UTC technology requires special attention related to the circuit design, fabrication, dicing and handling of ultra-thin chips as they have different physical properties compared to their bulky counterparts. Also, transistors and other active devices on UTCs experiencing variable bending stresses will suffer from the piezoresistive effect of silicon substrate which results in a shift of their operating point and therefore, an additional aspect should be considered during circuit design. This thesis tries to address some of these challenges related to UTC technology by focusing initially on modelling of transistors on mechanically bendable Si-UTCs. The developed behavioural models are a combination of mathematical equations and extracted parameters from BSIM4 and BSIM6 modified by a set of equations describing the bending-induced stresses on silicon. The transistor models are written in Verilog-A and compiled in Cadence Virtuoso environment where they were simulated at different bending conditions. To complement this, the verification of these models through experimental results is also presented. Two chips were designed using a 180 nm CMOS technology. The first chip includes nMOS and pMOS transistors with fixed channel width and two different channel lengths and two different channel orientations (0° and 90°) with respect to the wafer crystal orientation. The second chip includes inverter logic gates with different transistor sizes and orientations, as in the previous chip. Both chips were thinned down to ∼20m using dicing-before-grinding (DBG) prior to electrical characterisation at different bending conditions. Furthermore, this thesis presents the first reported fully integrated CMOS-based ISFET microsystem on UTC technology. The design of the integrated CMOS-based ISFET chip with 512 integrated on-chip ISFET sensors along with their read-out and digitisation scheme is presented. The integrated circuits (ICs) are thinned down to ∼30m and the bulky, as well as thinned ICs, are electrically and electrochemically characterised. Also, the thesis presents the first reported mechanically bendable CMOS-based ISFET device demonstrating that mechanical deformation of the die can result in drift compensation through the exploitation of the piezoresistive nature of silicon. Finally, this thesis presents the studies towards the development of on-chip reference electrodes and biodegradable and ultra-thin biosensors for the detection of neurotransmitters such as dopamine and serotonin

Design and optimization of ultrathin silicon field effect transistor's for sensitive, electronic-based detection of biological analytes

Noncommunicable diseases (NCD) are currently the leading cause of death worldwide. Over 57 million deaths occur globally each year, with close to 36 million of them attributed to NCD’s, and 80% of those in low and middle income countries. Most of these were due to such chronic illnesses as cancer, cardiovascular disease, diabetes, and lung disease. Moreover, the prevalence of these diseases is rising fastest in low-income regions which have little resources to combat these large, yet avoidable costs. In particular, over 1.6 million cases of cancer are caused each year in the United States, with nearly 600,000 of these cases being fatal. Cancer is an uncontrolled growth and spread of abnormal cells in the body, and unfortunately, can exist in many different cell types. The complexity in the causes of cancer has made it tougher to diagnose since several factors may weight into its prevalence such as: genetic factors, lifestyle factors, certain types of infections, and different environmental exposures. As a result, the protocols for the most cost-effective intervention are available across four main approaches to cancer prevention and control: primary prevention, early detection, treatment, and palliative care. Early diagnosis based on awareness of early signs and symptoms and, if affordable, population-based screening improves survival, particularly for breast, cervical, colorectal, skin and oral cancers. If primary prevention of cancer fails, secondary prevention (early detection) may be the difference between irreversible spread of a malignant cancer, and the patient’s survival. Early detection commonly refers to the diagnosis of a disease before individuals show obvious signs or symptoms of illness. With cancer, RNA and protein biomarkers of cells are currently assayed to determine their serums level and if they have deviated from the normal ranges. However, these assays commonly require large centralized lab facilities, frequent monitoring during treatment, and expensive equipment and/or supplies. This has led to point-of-care diagnostics becoming a $16 billion global market, aimed at miniaturizing technology and making it cost-effective for individual patient testing and treatment without the use of centralized lab facilities. A main point-of-care testing platform being pursued utilizes Complementary Metal Oxide Semiconductor (CMOS) technology. CMOS-based products can enable clinical tests to be conducted in a fast, simple, safe, and reliable manner, with improved sensitivities. Moreover, CMOS products offer portability and low power consumption, in large part due to the explosion in the semiconductor and communications markets. Silicon nanowires are of great interest for point-of-care testing as they are a CMOS compatible structure, require the use of no labels, and are highly sensitive to the binding of molecules to their surfaces. This is due to the large surface area to volume ratio afforded to nanowires. Moreover, arrays of silicon nanowires have demonstrated multiplexed, label-free sensing of cancer markers from undiluted serum samples. However, the research going into CMOS for point-of-care is in its infancy compared to other optical (surface plasmon resonance, fluorescence) or electrochemical methods (glucose sensors), although the technology for CMOS has been around for decades. Thus, the protocols for optimization of the sensors and their bioconjugation have not matured to the point DNA microarrays and ELISA’s have. The protocols for creation of a dependable silicon nanowire biosensor revolve around three main aspects: semiconductor processing, device functionalization, and choice of analytes. In this dissertation, I discuss our efforts to create a stable, silicon nanowire based sensor using CMOS compatible techniques and optimization processes. Moreover, I talk about our efforts into creating a device functionalization protocol using monofunctional silanes which affords the best sensitivity and specify for an electronic based biosensor. Finally, I discuss our look towards the future in silicon nanowires by using high-k dielectrics in our fabrication process, as well as an alternative monolayer deposition method which utilizes sub-nanometer thickness poly-l-lysine monolayers, for sensing clinically relevant targets of microRNA. Using a special type of silane, called a monofunctional silane, and a vapor based deposition method, we were able to achieve sub-nanometer levels functional monolayers on thermally oxidized silicon surfaces. We employed a variety of characterization techniques (XPS, AFM, ellipsometry) to determine the densities of the monolayer, uniformity, topography, and their point of saturation. Furthermore, we demonstrate this method’s applicability to biosensors by using it to functionalize substrates for silicon nanowires, gold nanoparticles, and protein microarrays. In tandem with this work, we constructed a “top down” silicon nanowire processing protocol which yielded nanowires capable of long-term, stable measurements in aqueous solutions. The combination of anneals, dry etching, and final wet etching gave mV standard deviations in device threshold characteristics. This protocol combined with the monolayer protocol above allowed an in-depth characterization of the pH sensitivity of bare devices, ones with silanes, and ones conjugated with proteins to be determined. Similarly, different oxide thicknesses and their effect on device sensitivity for proteins were also explored. Using a bunch of different linker chemistries and characterizing their conjugation of antibodies through fluorescence and the device, allowed for a chemistry to be chosen which was used to sense mouse immunoglobulins in pg/mL levels with high specificity. Finally, we take the fabrication of nanowires to the next level by using high-k dielectrics (HfO2) as the gate insulator. We deposit HfO2 through ALD (atomic layer deposition) and optimize the anneals to provide nanowires with ~200mV subthreshold slopes, sub-mV threshold deviations, and sub nanoampere gate leakages. All these characteristics exceed the processes for thermal oxide gated silicon nanowires, some by an order of magnitude. Since HfO2 is a high-k material, reaction of silanes and its density were unknown, but high-k materials do form stable amide linkages. Thus, we optimized a wet deposition of small molecular weight poly-l-lysine to provide a sub-nm conjugation layer for proteins and nucleotides by using AFM, XPS, and ellipsometry to understand the process. Using these combined protocols, we were able to conjugate probe oligonucleotides to surfaces and detect target microRNA’s down to 100fM concentrations, with a dynamic range over 4 orders of magnitude. With these ranges well within the clinical levels (1pM-100pM), we believe silicon nanowires have the capability to become a well-established point-of-care diagnostic platform

Opportunities and challenges for biosensors and nanoscale analytical tools for pandemics: COVID-19

Biosensors and nanoscale analytical tools have shown a huge growth in literature in the past 20 years, with a large number of reports on the topic of ’ultra-sensitive’, ’costeffective’ and ’early-detection’ tools with a potential of ’mass-production’ cited on the web of science. Yet none of these tools are commercially available in the market or practically viable for mass production and use in pandemic diseases such as COVID-19. In this context, we review the technological challenges and opportunities of current bio/chemical sensors and analytical tools by critically analyzing the bottlenecks which have hindered the implementation of advanced sensing technologies in pandemic diseases. We also describe in brief COVID-19 by comparing it with other pandemic strains such as SARS and MERS for the identification of features that enable biosensing. Moreover, we discuss visualization and characterization tools that can potentially be used not only for sensing applications but also assist in speeding up the drug discovery and vaccine development process. Furthermore, we discuss the emerging monitoring mechanism, namely wastewater-based epidemiology, for early warning of the outbreak, focusing on sensors for rapid and on-site analysis of SARS-COV-2 in sewage. To conclude, we provide holistic insights into challenges associated with the quick translation of sensing technologies, policies, ethical issues, technology adoption, and an overall outlook of the role of the sensing technologies in pandemics

Modeling and Fundamental Design Considerations for Portable, Wearable and Implantable Electronic Biosensors

Chronic diseases such as cancer, diabetes, acquired immune deficiency syndrome (AIDS), etc. are leading causes of mortality all over the world. Portable, wearable and implantable biosensors can go a long way in preventing these premature deaths by frequent or continuous self-monitoring of vital health parameters

Isothermal-based DNA biosensors for application in pharmacogenetics

Tesis por compendio[EN] The determination of genetic biomarkers is progressively becoming more extended and popular, being commercialized even in kits for personalized medicine. Establishing specific genotype variations for each patient, such as single nucleotide polymorphisms (SNPs), could be a fundamental tool in the field of diagnosis, prognosis and therapy selection. However, the use of DNA testing is not fully implemented in general healthcare, mainly due to technical and economic barriers associated to the current technologies, which are limited only to specialized centers and large hospitals. In this thesis, the main goal was to overcome these obstacles by developing simpler, faster and more affordable point-of-care (POC) genotyping systems. Allele discrimination was achieved by employing isothermal enzymatic reactions, like recombinase polymerase amplification (RPA), ligation of oligonucleotides and loop-mediated isothermal amplification (LAMP). These processes were integrated to colorimetric indicators and immunoenzymatic assays, in a microarray format. Using compact discs and polycarbonate chips as platforms, the detection was achieved through widespread electronics, like disc-reader, flatbed scanner and smartphone. To demonstrate their capacities, the resulting systems were applied for identifying SNPs in human samples, associated to therapies for tobacco smoking cessation, major depression disorder and blood clotting-related diseases. After selecting the proper conditions, all studied strategies discriminated SNPs in samples containing as low as 100 copies of genomic DNA, with an error rate below 15%. Most importantly, the developed methods have reduced assays times varying between 70 and 140 minutes, at a cost similar to a conventional PCR-based analog, but maintaining or raising amplification efficiency and eliminating the need of specialized temperature cyclers and fluorescence scanners. In conclusion, the biosensors based in isothermal reactions and consumer electronics devices greatly improve the competitivity of POC DNA analysis. It was demonstrated that the technologies developed in this thesis could support genotyping assays in low-resource areas, such as primary healthcare centers and emerging countries. Through this democratization of genetic testing and by performing adequate association studies, molecular diagnostics and personalized medicine practices could have their application extended to the clinical routine.[ES] La determinación de biomarcadores genéticos es cada vez más extensa y popular, estando incluso comercializándose kits para medicina personalizada. Establecer las variaciones específicas en el genotipo de cada paciente, como los polimorfismos de un solo nucleótido (SNP) podría ser una herramienta fundamental en el campo del diagnóstico, pronóstico y selección de la terapia. Sin embargo, el uso de pruebas de ADN no se encuentra completamente implementado en la atención médica general, principalmente debido a las barreras técnicas y económicas asociadas a las tecnologías actuales, limitadas solamente a centros especializados y grandes hospitales. En esta tesis, el objetivo principal fue superar estos obstáculos mediante el desarrollo de sistemas de genotipado point-of-care (POC), más simples, rápidos y asequibles. La discriminación alélica se logró mediante el uso de reacciones enzimáticas isotermas, como la amplificación de la recombinasa polimerasa (RPA), la ligación de oligonucleótidos y la amplificación isotérmica mediada por bucle (LAMP). Estos procesos se integraron a indicadores colorimétricos y ensayos inmunoenzimáticos en formato de micromatriz. Utilizando discos compactos y chips de policarbonato como plataforma de ensayo, se ha logrado la detección mediante dispositivos electrónicos de consumo, como un lector de discos, escáner documental y teléfono móvil. Para demostrar sus capacidades, los sistemas resultantes se aplicaron a la identificación de SNPs en muestras humanas, asociados a terapias antitabaquismo, para depresión y enfermedades relacionadas con la coagulación de la sangre. Tras seleccionar las condiciones adecuadas, todas las estrategias estudiadas discriminaron SNPs en muestras conteniendo tan solo 100 copias de ADN genómico, con una tasa de error inferior al 15%. Más importante, los métodos desarrollados han reducido los tiempos de ensayo a valores entre 70 y 140 minutos, a un coste similar a un análogo convencional basado en la reacción en cadena de la polimerasa (PCR), pero manteniendo o aumentando la eficiencia de amplificación y eliminando la necesidad de termocicladores y escáneres de fluorescencia. En conclusión, los biosensores basados en reacciones isotérmicas y dispositivos de electrónica de consumo mejoran en gran medida la competitividad del análisis POC de ADN. Se ha demostrado que las tecnologías desarrolladas en esta tesis podrían apoyar los ensayos de genotipado en áreas de recursos escasos, como centros de atención primaria y países emergentes. A través de esta democratización de las pruebas genéticas y realización estudios de asociación adecuados, el diagnóstico molecular y las prácticas en medicina personalizada podrían extender su aplicación a la rutina clínica.[CA] La determinació de biomarcadors genètics és cada vegada més extensa i popular, estant fins i tot comercialitzant-se kits per a medicina personalitzada. Establir les variacions específiques en el genotip de cada pacient, com els polimorfismes d'un sol nucleòtid (SNP) podria ser una eina fonamental en el camp del diagnòstic, pronòstic i selecció de la teràpia. No obstant això, l'ús de proves d'ADN no es troba completament implementat en l'atenció mèdica general, principalment a causa de les barreres tècniques i econòmiques associades a les tecnologies actuals, limitades solament a centres especialitzats i grans hospitals. En aquesta tesi, l'objectiu principal va ser superar aquests obstacles mitjançant el desenvolupament de sistemes de genotipat point-of-care (POC), més simples, ràpids i assequibles. La discriminació al·lèlica es va aconseguir mitjançant l'ús de reaccions enzimàtiques isotermes, com l'amplificació de la recombinasa polimerasa (RPA), la lligació de oligonucleòtids i l'amplificació isotèrmica mediada per bucle (LAMP). Aquests processos es van integrar a indicadors colorimètrics i assajos inmunoenzimàtics en format de micromatriu. Utilitzant discos compactes i xips de policarbonat com a plataforma d'assaig, s'ha conseguit la detecció mitjançant dispositius electrònics de consum, com un lector de discos, escàner documental i telèfon mòbil. Per a demostrar les seues capacitats, els sistemes resultants es van aplicar a la identificació de polimorfismes en mostres humanes, associats a teràpies antitabaquisme, per a depressió i malalties relacionades amb la coagulació de la sang. Després de seleccionar les condicions adequades, totes les estratègies estudiades van ser capaces de discriminar SNPs en mostres contenint tan sols 100 còpies d'ADN genòmic, amb una taxa d'error inferior al 15%. Més important, els mètodes desenvolupats han reduït els temps d'assaig a valors entre 70 i 140 minuts, a un cost similar a un anàleg convencional basat en la reacció en cadena de la polimerasa (PCR), però mantenint o augmentant l'eficiència d'amplificació i eliminant la necessitat de termocicladors i escàners de fluorescència. En conclusió, els biosensors basats en reaccions isotèrmiques i dispositius d'electrònica de consum milloren en gran manera la competitivitat de l'anàlisi POC del ADN. S'ha demostrat que les tecnologies desenvolupades en aquesta tesi podrien donar suport als assajos de genotipat en àrees de recursos escassos, com a centres d'atenció primària i països emergents. A través d'aquesta democratització de les proves genètiques i realització estudis d'associació adequats, el diagnòstic molecular i les pràctiques en medicina personalitzada podrien estendre la seua aplicació a la rutina clínica.[PT] A determinação de biomarcadores genéticos está tornando-se cada vez mais extensa e popular, sendo comercializada até em kits para medicina personalizada. O estabelecimento de variações específicas de genotipo para cada paciente, tais como os polimorfismo de nucleotídeo único, pode ser uma ferramenta fundamental no campo do diagnóstico, prognóstico e seleção de terapias. No entanto, o uso de testes de DNA ainda não encontra-se totalmente implementado na área de saúde geral, principalmente devido às barreiras técnicas e econômicas associadas às tecnologias atuais, limitadas apenas a centros especializados e grandes hospitais. Nesta tese, o principal objetivo foi superar esses obstáculos desenvolvendo sistemas de genotipagem point-of-care (POC) de DNA, mais simples, rápidos e acessíveis. A discriminação de alelos foi alcançada empregando reações enzimáticas isotérmicas, como amplificação por recombinase polimerase (RPA), ligação de oligonucleotídeos e amplificação isotérmica mediada por loop (LAMP). Tais processos foram integrados a indicadores colorimétricos e ensaios imunoenzimáticos, em formato micromatriz. Usando discos compactos e chips de policarbonato como plataforma de ensaio, os analitos foram detectados através de dispositivos eletrônicos de consumo, como leitor de disco, scanner de mesa e smartphone. Para demonstrar suas capacidades, os sistemas resultantes foram aplicados para identificação de polimorfismos em amostras de DNA humano, associados a terapias antitabagismo, para depressão e doenças relacionadas à coagulação do sangue. Após a seleção das condições adequadas, todas as estratégias estudadas foram capazes de discriminar SNPs em amostras contendo até 100 cópias de DNA genômico, com uma taxa de erro inferior a 15%. Mais importante, os métodos desenvolvidos reduziram o tempo de ensaio a valores entre 70 e 140 minutos, com um custo similar a um método análogo baseado em reação em cadeia da polimerase (PCR), mas mantendo ou aumentando a eficiência da amplificação e eliminando a necessidade de cicladores de temperatura e scanners de fluorescência especializados. Em conclusão, os biosensores baseados em reações enzimáticas isotérmicas e dispositivos eletrônicos de consumo incrementam grandemente a competitividade da análise POC de DNA. Foi demonstrado que as tecnologias desenvolvidas nesta tese poderiam dar suporte a ensaios de genotipagem em lugares com poucos recursos, como centros de atenção primária e países emergentes. Através desta democratização dos testes genéticos e com a realização de estudos de associação adequados, o diagnóstico molecular e as práticas de medicina personalizada poderiam ter sua aplicação extendida à rotina clínica.The authors acknowledge the financial support received from the Generalitat Valenciana (GVA-PROMETEOII/2014/040 Project and GRISOLIA/2014/024 PhD grant) and the Spanish Ministry of Economy and Competitiveness (MINECO CTQ2013-45875-R project)Yamanaka, ES. (2020). Isothermal-based DNA biosensors for application in pharmacogenetics [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/148366TESISCompendi

A fully integrated CMOS microelectrode system for electrochemistry

Electroanalysis has proven to be one of the most widely used technologies for point-of-care devices. Owing to the direct recording of the intrinsic properties of biochemical functions, the field has been involved in the study of biology since electrochemistry’s conception in the 1800’s. With the advent of microelectronics, humanity has welcomed self-monitoring portable devices such as the glucose sensor in its everyday routine. The sensitivity of amperometry/ voltammetry has been enhanced by the use of microelectrodes. Their arrangement into microelectrode arrays (MEAs) took a step forward into sensing biomarkers, DNA and pathogens on a multitude of sites. Integrating these devices and their operating circuits on CMOS monolithically miniaturised these systems even more, improved the noise response and achieved parallel data collection. Including microfluidics on this type of devices has led to the birth of the Lab-on-a-Chip technology. Despite the technology’s inclusion in many bioanalytical instruments there is still room for enhancing its capabilities and application possibilities. Even though research has been conducted on the selective preparation of microelectrodes with different materials in a CMOS MEA to sense several biomarkers, limited effort has been demonstrated on improving the parallel electroanalytical capabilities of these devices. Living and chemical materials have a tendency to alter their composition over time. Therefore analysing a biochemical sample using as many electroanalytical methods as possible simultaneously could offer a more complete diagnostic snapshot. This thesis describes the development of a CMOS Lab-on-a-Chip device comprised of many electrochemical cells, capable of performing simultaneous amperometric/voltammetric measurements in the same fluidic chamber. The chip is named an electrochemical cell microarray (ECM) and it contains a MEA controlled by independent integrated potentiostats. The key stages in this work were: to investigate techniques for the electrochemical cell isolation through simulations; to design and implement a CMOS ECM ASIC; to prepare the CMOS chip for use in an electrochemical environment and encapsulate it to work with liquids; to test and characterise the CMOS chip housed in an experimental system; and to make parallel measurements by applying different simultaneous electroanalytical methods. It is envisaged that results from the system could be combined with multivariate analysis to describe a molecular profile rather than only concentration levels. Simulations to determine the microelectrode structure and the potentiostat design, capable of constructing isolated electrochemical cells, were made using the Cadence CAD software package. The electrochemical environment and the microelectrode structure were modelled using a netlist of resistors and capacitors. The netlist was introduced in Cadence and it was simulated with potentiostat designs to produce 3-D potential distribution and electric field intensity maps of the chemical volume. The combination of a coaxial microelectrode structure and a fully differential potentiostat was found to result in independent electrochemical cells isolated from each other. A 4 x 4 integrated ECM controlled by on-chip fully differential potentiostats and made up by a 16 × 16 working electrode MEA (laid out with the coaxial structure) was designed in an unmodified 0.35 μm CMOS process. The working electrodes were connected to a circuit capable of multiplexing them along a voltammetric measurement, maintaining their diffusion layers during stand-by time. Two readout methods were integrated, a simple resistor for an analogue readout and a discrete time digital current-to-frequency charge-sensitive amplifier. Working electrodes were designed with a 20 μm side length while the counter and reference electrodes had an 11 μm width. The microelectrodes were designed using the aluminium top metal layer of the CMOS process. The chips were received from the foundry unmodified and passivated, thus they were post-process fabricated with photolithographic processes. The passivation layer had to be thinned over the MEA and completely removed on top of the microelectrodes. The openings were made 25 % smaller than the top metal layer electrode size to ensure a full coverage of the easily corroded Al metal. Two batches of chips were prepared, one with biocompatible Au on all the microelectrodes and one altered with Pd on the counter and Ag on the reference electrode. The chips were packaged on ceramic pin grid array packages and encapsulated using chemically resistant materials. Electroplating was verified to deposit Au with increased roughness on the microelectrodes and a cleaning step was performed prior to electrochemical experiments. An experimental setup containing a PCB, a PXIe system by National Instruments, and software programs coded for use with the ECM was prepared. The programs were prepared to conduct various voltammetric and amperometric methods as well as to analyse the results. The first batch of post-processed encapsulated chips was used for characterisation and experimental measurements. The on-chip potentiostat was verified to perform alike a commercial potentiostat, tested with microelectrode samples prepared to mimic the coaxial structure of the ECM. The on-chip potentiostat’s fully differential design achieved a high 5.2 V potential window range for a CMOS device. An experiment was also devised and a 12.3 % cell-to-cell electrochemical cross-talk was found. The system was characterised with a 150 kHz bandwidth enabling fast-scan cyclic voltammetry(CV) experiments to be performed. A relatively high 1.39 nA limit-of-detection was recorded compared to other CMOS MEAs, which is however adequate for possible applications of the ECM. Due to lack of a current polarity output the digital current readout was only eligible for amperometric measurements, thus the analogue readout was used for the rest of the measurements. The capability of the ECM system to perform independent parallel electroanalytical measurements was demonstrated with 3 different experimental techniques. The first one was a new voltammetric technique made possible by the ECM’s unique characteristics. The technique was named multiplexed cyclic voltammetry and it increased the acquisition speed of a voltammogram by a parallel potential scan on all the electrochemical cells. The second technique measured a chemical solution with 5 mM of ferrocene with constant potential amperometry, staircase cyclic voltammetry, normal pulse voltammetry, and differential pulse voltammetry simultaneously on different electrochemical cells. Lastly, a chemical solution with 2 analytes (ferrocene and decamethylferrocene) was prepared and they were sensed separately with constant potential amperometry and staircase cyclic voltammetry on different cells. The potential settings of each electrochemical cell were adjusted to detect its respective analyte

BioMEMS

As technological advancements widen the scope of applications for biomicroelectromechanical systems (BioMEMS or biomicrosystems), the field continues to have an impact on many aspects of life science operations and functionalities. Because BioMEMS research and development require the input of experts who use different technical languages and come from varying disciplines and backgrounds, scientists and students can avoid potential difficulties in communication and understanding only if they possess a skill set and understanding that enables them to work at the interface of engineering and biosciences. Keeping this duality in mind throughout, BioMEMS: Science and Engineering Perspectives supports and expedites the multidisciplinary learning involved in the development of biomicrosystems. Divided into nine chapters, it starts with a balanced introduction of biological, engineering, application, and commercialization aspects of the field. With a focus on molecules of biological interest, the book explores the building blocks of cells and viruses, as well as molecules that form the self-assembled monolayers (SAMs), linkers, and hydrogels used for making different surfaces biocompatible through functionalization. The book also discusses: Different materials and platforms used to develop biomicrosystems Various biological entities and pathogens (in ascending order of complexity) The multidisciplinary aspects of engineering bioactive surfaces Engineering perspectives, including methods of manufacturing bioactive surfaces and devices Microfluidics modeling and experimentation Device level implementation of BioMEMS concepts for different applications. Because BioMEMS is an application-driven field, the book also highlights the concepts of lab-on-a-chip (LOC) and micro total analysis system (μTAS), along with their pertinence to the emerging point-of-care (POC) and point-of-need (PON) applications