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Piet Bergveld-40 years of ISFET technology: From neuronal sensing to DNA sequencing

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Abstract

This article presents a personal account of the life and scientifi c journey of Professor Piet Bergveld, the inventor and founding father of the Ion-Sensitive Field Effect Transistor (ISFET). The interview gives a unique overview of how ISFET technology has evolved over the years, and the challenges faced during the development from its initial use in neuronal sensing to the technology we see today, which has huge potential in the current era of genetic technology.

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... The BioFET is a label-free electrochemical biosensor that has been studied as a sensitive and low-cost portable proposal for a variety of biological agents' detection [7][8][9][10][11][12] . The electrolyte gated FET is one of several FET sensor structures in which electrochemical gating is achieved through a reference electrode immersed into the solution [13][14][15][16] . ...
... In parallel, several channel materials have been explored in BioFETs, with graphene gaining significant attention recently. Graphene, a sheet of sp 2 -bonded carbon atoms arranged into a honeycomb structure 15,17 has been exploited as the sensing element in BioFETs owing to its unique electronic and chemical properties 13 . Graphene BioFETs display improved performance (i.e. ...
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Lab-on-Chip is a technology that aims to transform the Point-of-Care (PoC) diagnostics field; nonetheless a commercial production compatible technology is yet to be established. Lab-on-Printed Circuit Board (Lab-on-PCB) is currently considered as a promising candidate technology for cost-aware but simultaneously high specification applications, requiring multi-component microsystem implementations, due to its inherent compatibility with electronics and the long-standing industrial manufacturing basis. In this work, we demonstrate the first electrolyte gated field-effect transistor (FET) DNA biosensor implemented on commercially fabricated PCB in a planar layout. Graphene ink was drop-casted to form the transistor channel and PNA probes were immobilized on the graphene channel, enabling label-free DNA detection. It is shown that the sensor can selectively detect the complementary DNA sequence, following a fully inkjet-printing compatible manufacturing process. The results demonstrate the potential for the effortless integration of FET sensors into Lab-on-PCB diagnostic platforms, paving the way for even higher sensitivity quantification than the current Lab-on-PCB state-of-the-art of passive electrode electrochemical sensing. The substitution of such biosensors with our presented FET structures, promises further reduction of the time-to-result in microsystems combining sequential DNA amplification and detection modules to few minutes, since much fewer amplification cycles are required even for low-abundance nucleic acid targets.
... The extended gate is a chemically-sensitive membrane, deposited on the signal line extended from the FET gate electrode [5]. EGFET have been applied in many applications, especially as pH sensor [6][7][8]. While ISFET and EGFET have the same surface ion adsorption mechanism for the pH sensing [9], compared with the ISFET, EGFET has many advantages, such as temperature and light insensitivity, low-cost, simpler to passivate and package, and better long-term stability [10]. ...
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This study presents an investigation on zinc oxide (ZnO) and titanium dioxide (TiO2) bilayer film applied as the sensing membrane for extended-gate field effect transistor (EGFET) for pH sensing application. The influences of the drying temperatures on the pH sensing capability of ZnO/TiO2 were investigated. The sensing performance of the thin films were measured by connecting the thin film to a commercial MOSFET to form the extended gates. By varying the drying temperature, we found that the ZnO/TiO2 thin film dried at 150°C gave the highest sensitivity compared to other drying conditions, with the sensitivity value of 48.80 mV/pH.
... Since invented by Piet Bergveld in 1970 [1,2], ISFET sensors exhibit a number of advantages in comparison to conventional pH-glass electrodes [3,4]. Due to small size and fast response, ISFET devices show advantages, in comparison to conventional ion selective electrodes, of implementation in integrated circuits based on complementary metal-oxide semiconductor (CMOS) technology, especially in biomedical applications, such as detection of DNA-hybridization [5,6], biomarker detection from blood [7], antibody detection [8], glucose measurement [9] and pH sensing [10]. ...
Article
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Pt electrode used as reference electrode (RE) of Ion Sensitive Field-Effect Transistor (ISFET) is controversial with respect to its redox reactions with the electrolyte so that its potential can be easily perturbed by compositional changes or the flow of electrolyte. The microfluidic-controlled Pt-KCl RE system (PtRE) has been previously proposed to potentially replace the conventional RE for specific applications. This paper presents our further study on the stability of Pt electrode as ISFET's RE using the PtRE system. It is found that the potential of Pt electrode preserved in air is not stable in the beginning and drifts slowly for quite a few minutes. However, by immersing the Pt electrode in KCl reference electrolyte for a certain time prior to test, the reference characteristics of the Pt electrode can be greatly improved and exhibit as almost good stability performance as conventional Ag/AgCl electrode. Hence, Pt electrode in the PtRE system can be used as a viable alternative to conventional RE for ISFETs and other biochemical sensors.
... The extended gate is a chemically-sensitive membrane, deposited on the signal line extended from the FET gate electrode. According to the previous researches, EGFET had been applied in many applications, especially as pH sensor [2]. Even though EGFET is still a new finding in fabrication and nanotechnology field, many studies and investigations are undergoing to prove its advantages compared with the ISFET. ...
Conference Paper
The effect of annealing temperature on the surface morphology and electrical properties of composite bilayer, TiO 2 /ZnO were studied in this investigation. The composite thin films were applied as the sensing membrane of an Extended Gate Field-Effect Transistor (EGFET) based pH sensor. TiO 2 and ZnO were deposited on Indium Tin Oxide (ITO) by using sol-gel spin-coating process. The effects of the varied parameter on the sensor sensitivity and linearity were also investigated. The sensitivity of the TiO 2 thin film towards pH buffer solution was measured by dipping the sensing membrane in pH4, pH7 and pH10 buffer solution. In addition, these thin films were characterized by using Field Emission Scanning Electron Microscope (FESEM) to obtain the surface morphology of the composite thin films. Meanwhile, I–V measurement was done in order to determine the electrical properties of the thin films. According to the result obtained in this experiment, thin film that annealed at highest temperature, which is 500°C produced highest sensitivity, 53.3 mV/pH. Relating the I–V characteristic of the thin films and sensitivity, the sensing membrane with higher conductivity gave better sensitivity.
... It is often stated that a reference electrode (with corresponding liquidgate voltage, V g ) is required for a reproducible and stable signal from FET-sensors. 48,53,55,56 Nonetheless, it is not uncommon for devices to be fabricated without any reference electrode in the liquid 25,28,36,37,57 which can reduce the possibility of dielectric breakdown of the device under applied gate voltage (e.g. as described in the ESI of Stern et al. 36 ). Such devices often have a gate connected to the substrate (backgate) which is either (a) at a constant gate voltage, usually chosen to optimise the transconductance of the device at that gate voltage, or (b) swept across a range of gate voltages in a similar way to which a liquid-gate might be operated. ...
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Field-Effect Transistor sensors (FET-sensors) have been receiving increasing attention for biomolecular sensing over the last two decades due to their potential for ultra-high sensitivity sensing, label-free operation, cost reduction and miniaturisation. Whilst the commercial application of FET-sensors in pH sensing has been realised, their commercial application in biomolecular sensing (termed BioFETs) is hindered by poor understanding of how to optimise device design for highly reproducible operation and high sensitivity. In part, these problems stem from the highly interdisciplinary nature of the problems encountered in this field, in which knowledge of biomolecular-binding kinetics, surface chemistry, electrical double layer physics and electrical engineering is required. In this work, a quantitative analysis and critical review has been performed comparing literature FET-sensor data for pH-sensing with data for sensing of biomolecular streptavidin binding to surface-bound biotin systems. The aim is to provide the first systematic, quantitative comparison of BioFET results for a single biomolecular analyte, specifically Streptavidin, which is the most commonly used model protein in biosensing experiments, and often used as an initial proof-of-concept for new biosensor designs. This novel quantitative and comparative analysis of the surface potential behaviour of a range of devices demonstrated a strong contrast between the trends observed in pH-sensing and those in biomolecule-sensing. Potential explanations are discussed in detail and surface-chemistry optimisation is shown to be a vital component in sensitivity-enhancement. Factors which can influence the response, yet which have not always been fully appreciated, are explored and practical suggestions are provided on how to improve experimental design.
... Potentiometric biosensors, which detect the analyte charge directly, allow label-free detection and are easily miniaturized [36][37][38][39][40]. Since the target molecules conjugate with the probe molecules (usually immobilized on the sensor surface as shown in Figure 1(c4), left) only in salt-based electrolyte solutions, screening by these ions fundamentally limits the sensitivity of charge-based (potentiometric) biosensors. ...
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... However, inclusion of the bulky reference electrode poses challenges towards commercialization of ISFETs due to its dimension and CMOS incompatibility. Attempts to miniaturize the reference electrode were not successful due to the resulting drift and instability [16], [17]. ...
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This paper reports ultrahigh-sensitive and ultralow-power CMOS compatible pH sensors that are developed in the back-end-of-line (BEOL) of industrial 28 nm ultrathin body and buried oxide (UTBB) fully-depleted silicon-on-insulator (FDSOI) transistors. Fabricating the sensing gate and the control gate of the sensors in a capacitive divider circuit, CMOS compatible pH sensors are demonstrated where the front gate bias is applied through a control gate rather than a bulky reference electrode. On the other hand, the strong electrostatic coupling between the front gate and the back gate of FDSOI devices provide an intrinsic signal amplification feature for sensing applications. Utilizing an ALD deposited aluminum oxide (Al2O3) as a pH sensing film, pH sensors having a sensitivity of 475 mV/pH and 730 mV/pH in the extended gate and BEOL configuration respectively are reported. Sensitivities of both configurations are superior to state-of-the-art low power ISFETs. The small sensing area and the FDSOI based low power technology of the device make the sensors ideal for the IoT market. The proposed approach has been validated by TCAD simulation, and demonstrated through experimental measurements on proof-of-concept extended gate pH sensors and on sensors that are developed in the BEOL of industrial UTBB FDSOI devices.
... En cuanto a las aplicaciones del ISFET, éstas han sido variadas desde el momento de su concepción. Bergveld [32] inicialmente lo construyó para realizar mediciones neurofisiológicas, en las cuales se necesitaba identificar las causas del potencial eléctrico producidos en las neuronas, empleando el ISFET para medir su actividad iónica [53]. Otras aplicaciones, también presentadas por Bergveld [54], comprenden su empleo como sensores en la punta de catéteres para medición de parámetros fisiológicos de sistemas vivos, tal como la medición de la presión en la sangre a partir del valor del pH. ...
Thesis
The aim of the thesis "Modeling and implementation of a low-power pH monitoring system applied to control the rivers water quality", is the development of a low-power pH monitoring system which would be incorporated to a wireless sensor network. The pH is one of the most important operational measurements whose variations are indicators of water composition changes and, therefore, dangerous effects to the ecosystem which use them and live there, employing remote monitoring systems to detect those variations. However, systems based on conventional sensors and techniques, usually have higher levels of energy consumption, implying short autonomy periods. Hence, in this thesis, a selection of a low-power sensor technology is performed, as well as, the implementation of readout and processing systems in the same device through a mixed-signal microcontroller. In addition to this, for the communication with Internet, another microcontroller is used to implement a low-power wireless protocol. The system is tested in a laboratory environment, measuring the power levels at each stage. Results show a lower consumption, in its analogue component, than other commercial alternatives, as well as, an appropriate sensibility and a continuous communication with the Internet platform. The presented solution constitutes an adequate alternative for the pH sensing applied to the water quality control, which could be extended to other applications such as agriculture and biomedicine.
... As a result, the CMOS ISFET can lead to on-chip integration with high-speed and low-noise CMOS readout circuit for large chemical sensor array. These advantages enable the ISFET applications to evolve over years from neuronal sensing to personalized biomedical diagnosis such as DNA sequencing34567, where the features of high-throughput, low-cost, and miniaturization are required [8, 9]. DNA sequencing has profound impact on life technologies such as personal genome study, health care, drug development [10]. ...
... The great success of this platform consists of the integration of a chip that has millions of CMOS sensors in its matrix, so that the compilation of all the data can be performed in an inexpensive and simple way [39]. The second major innovation of this platform was the introduction of an electro-chemical ISFET (ion field sensitive transistor) sensor at the bottom of each well [40], which act as a pH meter that is sensitive to changes in H + concentration ( Figure 10). To perform sequencing on the Ion Torrent platform, the DNA template is presented on the surface of a sphere (or bead) obtained by a PCR emulsion [41]. ...
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The first sequencing of a complete genome was published forty years ago by the double Nobel Prize in Chemistry winner Frederick Sanger. That corresponded to the small sized genome of a bacteriophage, but since then there have been many complex organisms whose DNA have been sequenced. This was possible thanks to continuous advances in the fields of biochemistry and molecular genetics, but also in other areas such as nanotechnology and computing. Nowadays, sequencing sensors based on genetic material have little to do with those used by Sanger. The emergence of mass sequencing sensors, or new generation sequencing (NGS) meant a quantitative leap both in the volume of genetic material that was able to be sequenced in each trial, as well as in the time per run and its cost. One can envisage that incoming technologies, already known as fourth generation sequencing, will continue to cheapen the trials by increasing DNA reading lengths in each run. All of this would be impossible without sensors and detection systems becoming smaller and more precise. This article provides a comprehensive overview on sensors for DNA sequencing developed within the last 40 years.
... The principle of detecting a chemical in solution via transduction by a FET, known as a ChemFET, was introduced in the 1970s, with the earliest work pioneered by Bergveld [46][47][48] and Janata. 49,50 Figure 1 illustrates the basic principle behind different variants of a ChemFET. ...
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... 7 The need for ISFETs with outstanding sensitivity, selectivity, repeatability, response time, and stability in biological fluids remains unaddressed to electronically interface with cells and tissues during the in vitro and in vivo experiments essential to understand the disordered physiological processes associated with diseases or injury and its rapid diagnosis on the bedside. 8 Work to date has explored tailoring the semiconductor− oxide−electrolyte interface using proteins and nucleic acid sequences to selectively detect a wide range of biomolecules, 9,10 increasing the intrinsic sensitivity using various gate dielectric, 11−13 nanoscale channel materials such as silicon nanowires, 14,15 carbon nanotubes, 16,17 organic semiconductors, 18−20 and graphene 21, 22 and in situ amplification of the intrinsic sensitivity using strategies involving dual (solution/ bottom) gating 23 and parallel channels of different areas. 24 Graphene and organic semiconductor ISFETs allow overcoming two limiting aspects of silicon analogues. ...
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... ISFET is the acronym of ion sensitive field effect transistor. Professor Piet Bergveld has developed ISFET since about 40 years ago that is in 1970 on the basis of MOSFET (metal oxide field effect transistor) [1,2]. Bergveld has developed ISFET based on a bulk transistor design for neurophysiological measurement application since 4 decades ago [3]. ...
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Chapter
As a new type of sensing platform, graphene field-effect transistor biosensor has unique advantages for sensing applications such as magnetism, pressure, chemistry, and biology. Using graphene as a sensing channel, because any local graphene conductance changes caused by magnetic force, pressure, chemical, and biological, and other complex factors coupling will affect the conductance of the entire graphene channel, thus this new type of sensing platform theoretically has a high sensitivity. For the graphene field-effect transistor biosensor, the surface of the graphene sensing channel directly contacts the test liquid, and then the electric signal (current Ids signal is usually used) is used to quickly and quantitatively detect the concentration of specific molecules in the test liquid. This chapter first introduces the unique electric double layer structure formed at the interface between graphene and the liquid to be measured. After that, the basic structure and sensing principle of graphene field-effect transistors are introduced, and then the relationship between the adsorption of specific molecules and the change of current is proposed. Finally, the main applications of current biosensors based on graphene field-effect transistors are briefly introduced. This chapter first introduces the unique electric double layer structure formed at the interface between graphene and the test liquid. After that, the basic structure and sensing principle of graphene field-effect transistors are demonstrated. Then the relationship between the adsorption of specific molecules and the variation of current Ids (the variation of current Ids and the concentration of specific molecules) is proposed. Finally, the main applications of graphene field-effect transistor biosensors are briefly introduced.
Chapter
Biotechnology utilizes biological systems or living organisms to create, develop, or make products. This chapter reviews the current state of biotechnology and examines its future trends. Currently, biotechnology plays key roles in medicine, agriculture, and industry. In medicine, vaccines which still rely on biological systems for their production, are the best tools to prevent infectious diseases; antibodies and RNA/DNA probes have been crucial in detecting and treating diseases; and genetic editing and gene therapy is making it possible to treat hereditary diseases. In agriculture, biotechnology is generating crops that produce high yields and need fewer inputs, crops that need fewer applications of pesticides, and crops with enhanced nutrition profiles. In industry, biotechnology is being utilized in food processing, metal ore processing, the production of chemicals, and reducing energy consumption and pollution.
Chapter
This chapter details the various transistor architectures that are applied to biosensors, and particularly for the detection and quantification of biomarkers. After a general introduction on the application of transistors for the detection of biomarkers, a list of potentially pertinent biomarkers is drawn up, then details are given on the operation principles of transistors, in particular field-effect ones. It is first explained why these devices rely on charged interfaces, which define the sensitive surfaces. Then, several architectures are detailed such as single-gate and dual-gate ion sensitive field-effect transistors (ISFETs) that allow to place transistors around their best functioning point, leading to better gain and sensitivity. ISFETs and their derivatives, the electric double-layer field-effect transistors (FETs), may present some drawbacks such as high operating potentials. Electrolyte-gated FETs, by suppressing the intermediate dielectric layer, allow to lower this potential down to a few tens or hundreds of millivolt, for low power consumption and better functioning without any risk of water splitting. Organic semiconductors give excellent results in this configuration, but graphene and its derivatives, even of being not semiconductors, also give very promising results because they allow for high currents so high sensitivities, along with excellent stability. Most of these transistors are still at the research stage, however. Conversely, extended-gate FETs are very promising devices which take advantage of the existing CMOS technology, just adding an extension to the gate contact of a commercial FET, which serves as sensing electrode. Extreme miniaturization can be achieved with these transistors and commercial applications are expected shortly.
Conference Paper
This paper presents a novel readout circuit for ionic concentration change measurement overcoming the non-linear effects of the Ion-sensitive Field-effect Transistor. The readout periodically resets the ISFET biasing and integrates its signal change around a certain operating point utilising a switched current integrator. This enables a linear approximation of the signal change over time which suppresses non-linear effects such as the sensing membrane buffer capacity change, and transistor slope factor variation in weak inversion. We show how the exponential relation of the current with pH change in weak inversion may be linearised, which allows further current mode processing and proton counting for DNA sequencing applications.
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