Micro- and nano-devices for electrochemical sensing

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

Field effect transistor with integrated microfluidic channel as pH sensor

International audienceThis paper presents an original design of chemical sensors with an integrated microfluidic channel. Targeted applications are pH-meters devices. The integration of the microfluidic channel allows decreasing the volume required for each measurement. The sensing part of the device consists of a field effect transistor (FET) with a suspended gate directly performed above the fluidic channel. Chemicals under test are driven through the sensing area between the electrical channel of the FET and the suspended gate. By this way products that flow in the microfluidic channel directly module the concentration of charges inside the transistor's gap and thus induce changes in the transfer characteristic. This paper describes the fabrication process and the technological choices for materials. Electrical tests, performed in air and in liquid, have shown a good behavior of the transistor, linked to a good mechanical sustain of the fluidic channel. The system is able to detect transition between air and liquid media. Moreover, it has shown a high sensitivity (about 300 mV/pH) to pH measurements

Wearable, low-power CMOS ISFETs and compensation circuits for on-body sweat analysis

Complementary metal-oxide-semiconductor (CMOS) technology has been a key driver behind the trend of reduced power consumption and increased integration of electronics in consumer devices and sensors. In the late 1990s, the integration of ion-sensitive field-effect transistors (ISFETs) into unmodified CMOS helped to create advancements in lab-on-chip technology through highly parallelised and low-cost designs. Using CMOS techniques to reduce power and size in chemical sensing applications has already aided the realisation of portable, battery-powered analysis platforms, however the possibility of integrating these sensors into wearable devices has until recently remained unexplored. This thesis investigates the use of CMOS ISFETs as wearable electrochemical sensors, specifically for on-body sweat analysis. The investigation begins by evaluating the ISFET sensor for wearable applications, identifying the key advantages and challenges that arise in this pursuit. A key requirement for wearable devices is a low power consumption, to enable a suitable operational life and small form factor. From this perspective, ISFETs are investigated for low power operation, to determine the limitations when trying to push down the consumption of individual sensors. Batteryless ISFET operation is explored through the design and implementation of a 0.35 \si{\micro\metre} CMOS ISFET sensing array, operating in weak-inversion and consuming 6 \si{\micro\watt}. Using this application-specific integrated circuit (ASIC), the first ISFET array powered by body heat is demonstrated and the feasibility of using near-field communication (NFC) for wireless powering and data transfer is shown. The thesis also presents circuits and systems for combatting three key non-ideal effects experienced by CMOS ISFETs, namely temperature variation, threshold voltage offset and drift. An improvement in temperature sensitivity by a factor of three compared to an uncompensated design is shown through measured results, while adding less than 70 \si{\nano\watt} to the design. A method of automatically biasing the sensors is presented and an approach to using spatial separation of sensors in arrays in applications with flowing fluids is proposed for distinguishing between signal and sensor drift. A wearable device using the ISFET-based system is designed and tested with both artificial and natural sweat, identifying the remaining challenges that exist with both the sensors themselves and accompanying components such as microfluidics and reference electrode. A new ASIC is designed based on the discoveries of this work and aimed at detecting multiple analytes on a single chip. %Removed In the latter half of the thesis, Finally, the future directions of wearable electrochemical sensors is discussed with a look towards embedded machine learning to aid the interpretation of complex fluid with time-domain sensor arrays. The contributions of this thesis aim to form a foundation for the use of ISFETs in wearable devices to enable non-invasive physiological monitoring.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

Understanding silicon nanowire field-effect transistors for biochemical sensing

There is an ever increasing need for inexpensive chemical and biochemical sensors for medical diagnostics, drug screening as well as environmental monitoring. State-of-the-art methods require either expensive or time-consuming labeling and are not suitable for large-scale integration. Advances in biotechnology, microfluidics and micro- and nanotechnology have led to various approaches of micro-analytical systems. In particular systems based on silicon field-effect transistors (Si FETs) have a great potential for biochemical sensing due to their potentially cheap fabrication in a CMOS-compatible process and simple electronic readout. Thereby, the gate oxide material of the FET is in direct contact with the analyte solution, leading to the ion-sensitive field-effect transistor (ISFET). The detection principle of ISFETs is based on the change of the transistor current caused by charges adsorbed at the sensor surface. It has been suggested recently that by downscaling the devices to the nanoscale, increased sensitivities can be expected. In particular, ISFETs based on silicon nanowires (Si NWs) are therefore intensively studied. Despite the achievements obtained in the last years, commercial products based on ISFETs are using the device as a pH sensor only. The reason for this development lies in the incomplete understanding of the complex interface between the electrolyte and the solid-state sensor as well as the difficulties related to the design of surfaces which selectively bind a targeted analyte. In this PhD project, we address these points by studying arrays of ISFETs based on silicon nanowires (Si NWs) fabricated by a top-down lithography approach and investigate their potential as an integrable sensing platform. First we characterize the devices and analyze their pH response. We find a response to pH at the fundamental (Nernst) limit, due to the special properties of the gate oxide materials used for the devices. We further demonstrate that the sensor signal is not affected by the width of the NWs, i.e. enhanced sensing is not observed for nanoscale devices. However, we reveal that the low-frequency noise of the devices decreases for increasing NW width, an aspect which has to be considered when ultimate integration is targeted. For the specific detection of ionic species, the sensor surface needs to be modified with functional groups, which selectively bind the target analyte. Unfortunately, the high pH sensitivity of oxide surfaces greatly complicates the detection of any target analyte other than pH. To circumvent this problem, we propose the use of an additional coating with a material with minimal sensitivity to pH. We find that gold is a promising candidate easily applied for this purpose. The gold layer allows immobilizing ligands via the well-established thiol-based chemistry thereby providing a platform suitable for surface functionalization. Using the additional gold layer, we demonstrate the successful detection of different ions such as sodium, calcium and fluoride ions with a differential setup having both functionalized and control NWs on the same sample. Furthermore, we find that the residual pH response of the gold layer still influences the detection of the targeted species by affecting the effective binding constant via the surface potential. To take this effect into account, an extended site binding model is proposed. Finally, we show that SiNWs have the potential to even monitor binding kinetics of ligand-protein systems and we obtain concentration dependent signals for a clinically relevant protein

Metabolomic sensing system for personalised medicine using an integrated CMOS sensor array technology

Precision healthcare, also known as personalised medicine, is based on our understanding of the fundamental building blocks of biological systems, with the ultimate aim to clinically identify the best therapeutic strategy for each individual. Genomics and sequencing technologies have brought this to the foreground by enabling an individual’s entire genome to be mapped for less than a thousand dollar in just one day. Recently, metabolomics, the quantitative measurement of small molecules, has emerged as a field to understand an individual’s molecular profile in terms of both genetics and environmental factors. This is crucial because a genome could only indicate an individual’s susceptibility to a particular disease, whereas a metabolome provides an immediate measurement of body function, enabling a means of diagnosis. However, the current approach of measurements depends on large-scale and expensive equipment such as mass spectroscopy and NMR instrumentation, which does not offer a single analytical platform to detect the entire metabolome. This thesis describes the development of an integrated CMOS sensor array technology as a single platform to quantify different metabolites using specific enzymes. The key stages in the work were: to construct instrumentation systems to perform enzyme assays on the CMOS sensor array; to establish techniques to package the CMOS sensor array for an aqueous environment; to implement and develop a room temperature Ta2O5 sputtering process on CMOS sensor array for hydrogen ion detection; to collaborate with a chemist and investigate an inorganic layer on top of the CMOS ISFET sensor to show an improvement of sensitivity towards potassium ion; to test several different enzyme assays electrochemically and optically and show the functionalities of the sensors; to devise microfluidic channels for segregation of the sensor array into different compartments and perform enzyme immobilisation techniques on CMOS chips; and integrate the packaged chip with microfluidic channels and enzyme immobilisation using 2D inkjet printer into a complete system that has the potential to be used as a multi-enzyme platform for detection of different metabolites. Two CMOS sensor array chips (1) a 256×256-pixel ISFET array chip and (2) a 16×16-pixel Multi-Corder chip were fully understood. Therefore, a high-speed instrumentation system was constructed for the ISFET array chip with a maximum readout speed of 500 frames per second, with 2D and 3D imaging capability, as well as single pixel analysis. Follow by that, a miniaturised measurement platform was implemented for the Multi-Corder chip that has three different sensor arrays, which are ISFET, PD and SPAD. All the sensor arrays can be operated independently or together (ionic sensor and one of the optical sensors). Several post-processing steps were investigated to allow suitable fabrication process on small 4×4 mm2 CMOS chips. Post-processing of the CMOS chips was first established using room temperature sputtering process for Ta2O5 layer, achieving Ta:O ratio of 1:1.77 and a surface roughness of 0.42 nm. This Ta2O5 layer was then fabricated on top of CMOS ISFETs, which improves the ISFET pH sensitivity to 45 mV/pH, with an average drift of 6.5 ± 8.6 mV/hour from chip to chip and a working pH range of 2 to 12. Furthermore, a layer of POMs was drop casted on top of Ta2O5 ISFET to make ISFET sensitive to potassium ions. This was investigated in terms of potassium ions sensitivity, hydrogen ions sensitivity and sodium ions as interfering background ions. The POMs Ta2O5 ISFET was found to have a net potassium sensitivity of 75 mV/pK, with a linear range between pH 1.5 to 3. Moreover, the POMs ISFET has -5 mV/pH in pH sensitivity, showing that it is selectivity towards potassium ions and not hydrogen ions. However, sodium ions were found to produce a large interference towards the pK sensitivity of POMs ISFET and reduced the pK sensitivity of POMs ISFET. Hence, further work is still required to modify POMs layer for better selectivity and sensitivity. Besides that, microfluidic channels were fabricated on top of the CMOS chips that could provide segregation for multiple enzyme assays on a single chip. In addition, a PDMS and a manual dam and fill method were developed to encapsulate the CMOS chips for wet biochemistry measurements. The CMOS sensor array was found to have the ensemble averaging capability to reduce noise as a function of √N , where N is the number of sensors used for averaging. Several enzyme assays that include: hexokinase, lactate dehydrogenase, urease and lipase were tested on the ISFET sensor array. Moreover, using an optical sensor array, namely a PD on the Multi-Corder chip and using LED illumination, quantification of cholesterol levels in human blood serum was demonstrated. Enzyme kinetics calculations were performed for hexokinase and cholesterol oxidase assays and the results were comparable to that obtained from a bench top spectrophotometer. This shows the CMOS sensor array can be used as a low cost portable diagnostic device. Several enzyme immobilisation techniques were explored but were unsuccessful. Alginate enzyme gel immobilisation with a 2D inkjet printer was found to be the best candidate to bio-functionalise the CMOS sensor array. The packaged chip was integrated with microfluidic channels and alginate enzyme gel immobilisation into a complete system, in order to perform an enzyme assay with its control experiments simultaneously on a single chip. As a proof-of-concept, this complete system has the potential to be used as a multiple metabolite quantification platform

Biosensors and CMOS Interface Circuits

abstract: Analysing and measuring of biological or biochemical processes are of utmost importance for medical, biological and biotechnological applications. Point of care diagnostic system, composing of biosensors, have promising applications for providing cheap, accurate and portable diagnosis. Owing to these expanding medical applications and advances made by semiconductor industry biosensors have seen a tremendous growth in the past few decades. Also emergence of microfluidics and non-invasive biosensing applications are other marker propellers. Analyzing biological signals using transducers is difficult due to the challenges in interfacing an electronic system to the biological environment. Detection limit, detection time, dynamic range, specificity to the analyte, sensitivity and reliability of these devices are some of the challenges in developing and integrating these devices. Significant amount of research in the field of biosensors has been focused on improving the design, fabrication process and their integration with microfluidics to address these challenges. This work presents new techniques, design and systems to improve the interface between the electronic system and the biological environment. This dissertation uses CMOS circuit design to improve the reliability of these devices. Also this work addresses the challenges in designing the electronic system used for processing the output of the transducer, which converts biological signal into electronic signal.Dissertation/ThesisM.S. Electrical Engineering 201

Wearable System with Integrated Passive Microfluidics for Real-Time Electrolyte Sensing in Human Sweat

Wearable systems embodied as patches could offer noninvasive and real-time solutions for monitoring of biomarkers in human sweat as an alternative to blood testing, with applications in personalized and preventive healthcare. Sweat is considered to be a biofluid of foremost interest for analysis due the numerous biomarkers it contains. Recent studies have demonstrated that the concentration of some of these biomarkers in sweat, such as the electrolytes studied in this work, can be directly correlated to their concentrations in blood, making sweat a trusted biofluid candidate for non-invasive diagnostics. Until now, the biggest impediment to onâbody sweat monitoring was the lack of technology to analyze sweat composition in realâtime and mainly to continuously collect it. The goal of this work was to develop the building blocks of such wearable system for sweat electrolyte monitoring, with main emphasis on the passive microfluidics, the integrated miniaturized quasi-reference electrode and the functionalization of the sensing devices. The basic sensor technology is formed by Ion Sensitive Field Effect Transistors (ISFET) realized in FinFET and ultra-thin body Silicon on Insulator technology. This thesis shows the development of a state-of-the-art microsystem that allows multisensing of pH, Na+, K+ electrolyte concentrations in sweat, with high selectivity and high sensitivities (â50 mV/dec for all electrolytes), in a wearable fashion. The microsystem comprises a biocompatible skin interface that collects even infinitesimal quantities of sweat (of the order of hundreds of picoliters to tenths of nanoliters), which the body produces in periods of low physical effort. One of the main achievements of this work is the integration of Ion Sensing Fully Depleted FETs and zero power consumption microfluidics, enabling low power (less than 50 nWatts/sensor) wearable biosensing. The thesis presents the needed technological processes and optimizations, together with their characterization, in order to achieve a Lab-On-Skin system

Electrochemical Determination of PH using Paper-Based Devices

Indiana University-Purdue University Indianapolis (IUPUI)For the past decade, many microfluidic paper-based analytical devices have been developed and used in different research fields. These devices are low-cost, portable, flexible, sterilizable, disposable, and easy to manufacture. The microfluidic paper-based analytical devices offer good alternatives to measurements and assays commonly performed in laboratories for analytical and clinical purposes, especially in diagnostics. In this work, we developed an electrochemical paper-based pH sensor. The determination of pH is essential in applications in areas as diverse as in the food industry, agriculture, health care or water treatment. The method presented in this work is an electroanalytical method that involves quantification of pH using stencil-painted graphite electrodes. Preliminary tests showed that pH can be determined on paper-based devices, thus indicating the presence of electroactive elements sensitive to pH on the surface of our electrodes (Chapter 4). Chemical modification of the electrode by adsorption with sodium carbonate and modification of the surface of the electrode was accomplished via: oxygen (ambient air) plasma treatment and pure oxygen plasma treatment. These treatments were to attempt to improve the definition of redox peaks on the CVs (Chapter 5). The changes made to the design of the paper-based device and the addition of a conditioning step improved the definition of the redox peaks on the CVs and increased the pH-sensing ability of our method (Chapter 6). The pH-sensing ability of our method was evaluated by testing solutions over a wide pH range. Adding sodium chloride to samples adjust the solution for accurate pH determination. The pH was successfully measured for solutions with values ranging from 1 to 13 and for artificial saliva samples prepared with pH values in the cavity-prone range (Chapter 7). This work offers a method that uses electroactive elements sensitive to pH on the surface of the PBD electrodes for pH-sensing

Microfabricated Reference Electrodes and their Biosensing Applications

Over the past two decades, there has been an increasing trend towards miniaturization of both biological and chemical sensors and their integration with miniaturized sample pre-processing and analysis systems. These miniaturized lab-on-chip devices have several functional advantages including low cost, their ability to analyze smaller samples, faster analysis time, suitability for automation, and increased reliability and repeatability. Electrical based sensing methods that transduce biological or chemical signals into the electrical domain are a dominant part of the lab-on-chip devices. A vital part of any electrochemical sensing system is the reference electrode, which is a probe that is capable of measuring the potential on the solution side of an electrochemical interface. Research on miniaturization of this crucial component and analysis of the parameters that affect its performance, stability and lifetime, is sparse. In this paper, we present the basic electrochemistry and thermodynamics of these reference electrodes and illustrate the uses of reference electrodes in electrochemical and biological measurements. Different electrochemical systems that are used as reference electrodes will be presented, and an overview of some contemporary advances in electrode miniaturization and their performance will be provided