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Piet Bergveld-40 years of ISFET technology: From neuronal sensing to DNA sequencing
Electronics Letters
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.
... 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. ...
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.
... Traditional methods that have been used for BSA detection, such as the Bradford protein assay, have drawbacks such as extended detection times and the requirement for specialized equipment [14][15][16]. To address these challenges, the ion-sensitive fieldeffect transistor (ISFET) has emerged as an effective solution that offers rapid detection, affordability, and portability [17][18][19][20][21]. Developed by Bergveld in the early 1970s, the ISFET is a type of biosensor that analyzes the electrical characteristics of the detection material based on the interaction between the sensing membrane and ions. ...
Bovine serum albumin (BSA) is commonly incorporated in vaccines to improve stability. However, owing to potential allergic reactions in humans, the World Health Organization (WHO) mandates strict adherence to a BSA limit (≤50 ng/vaccine). BSA detection with conventional techniques is time-consuming and requires specialized equipment. Efficient alternatives such as the ion-sensitive field-effect transistor (ISFET), despite rapid detection, affordability, and portability, do not detect BSA at low concentrations because of inherent sensitivity limitations. This study proposes a silicon-on-insulator (SOI) substrate-based dual-gate (DG) ISFET platform to overcome these limitations. The capacitive coupling DG structure significantly enhances sensitivity without requiring external circuits, owing to its inherent amplification effect. The extended-gate (EG) structure separates the transducer unit for electrical signal processing from the sensing unit for biological detection, preventing chemical damage to the transducer, accommodating a variety of biological analytes, and affording easy replaceability. Vapor-phase surface treatment with (3-Aminopropyl) triethoxysilane (APTES) and the incorporation of a SnO2 sensing membrane ensure high BSA detection efficiency and sensitivity (144.19 mV/log [BSA]). This DG-FET-based biosensor possesses a simple structure and detects BSA at low concentrations rapidly. Envisioned as an effective on-site diagnostic tool for various analytes including BSA, this platform addresses prior limitations in biosensing and shows promise for practical applications.
... (A) A roadmap describing the progress in the development of field-effect transistor-based biosensors[54][55][56][57][58]; (B) Architecture of the representative FET biosensor[59]. ...
Alzheimer’s disease (AD) is closely related to neurodegeneration, leading to dementia and cognitive impairment, especially in people aged > 65 years old. The detection of biomarkers plays a pivotal role in the diagnosis and treatment of AD, particularly at the onset stage. Field-effect transistor (FET)-based sensors are emerging devices that have drawn considerable attention due to their crucial ability to recognize various biomarkers at ultra-low concentrations. Thus, FET is broadly manipulated for AD biomarker detection. In this review, an overview of typical FET features and their operational mechanisms is described in detail. In addition, a summary of AD biomarker detection and the applicability of FET biosensors in this research field are outlined and discussed. Furthermore, the trends and future prospects of FET devices in AD diagnostic applications are also discussed.
... Therefore, there is a need for a multiplexed setup with controlled immobilization of these peptide sequences on devices that enable highly sensitive and label-free sensing of the target analytes. Field-effect transistor (FET)-based immunosensors are good candidates for multiplexed label-free sensing due to their high scalability, compatibility with current CMOS technology, fast response time, and label-free sensitivity [10][11][12][13]. When functionalized with short sequences of peptides, a FET gate can detect the binding of proteins in close proximity to the sensitive region within the Debye screening length of the protein solution [14]. ...
Label-free field-effect transistor-based immunosensors are promising candidates for proteomics and peptidomics-based diagnostics and therapeutics due to their high multiplexing capability, fast response time, and ability to increase the sensor sensitivity due to the short length of peptides. In this work, planar junctionless field-effect transistor sensors (FETs) were fabricated and characterized for pH sensing. The device with SiO2 gate oxide has shown voltage sensitivity of 41.8 ± 1.4, 39.9 ± 1.4, 39.0 ± 1.1, and 37.6 ± 1.0 mV/pH for constant drain currents of 5, 10, 20, and 50 nA, respectively, with a drain to source voltage of 0.05 V. The drift analysis shows a stability over time of −18 nA/h (pH 7.75), −3.5 nA/h (pH 6.84), −0.5 nA/h (pH 4.91), 0.5 nA/h (pH 3.43), corresponding to a pH drift of −0.45, −0.09, −0.01, and 0.01 per h. Theoretical modeling and simulation resulted in a mean value of the surface states of 3.8 × 1015/cm2 with a standard deviation of 3.6 × 1015/cm2. We have experimentally verified the number of surface sites due to APTES, peptide, and protein immobilization, which is in line with the theoretical calculations for FETs to be used for detecting peptide-protein interactions for future applications.
... 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. ...
An intrinsic ion sensitivity exceeding the Nernst–Boltzmann limit and an sp²-hybridized carbon structure make graphene a promising channel material for realizing ion-sensitive field-effect transistors with a stable solid–liquid interface under biased conditions in buffered salt solutions. Here, we examine the performance of graphene field-effect transistors coated with ion-selective membranes as a tool to selectively detect changes in concentrations of Ca²⁺, K⁺, and Na⁺ in individual salt solutions as well as in buffered Locke’s solution. Both the shift in the Dirac point and transconductance could be measured as a function of ion concentration with repeatability exceeding 99.5% and reproducibility exceeding 98% over 60 days. However, an enhancement of selectivity, by about an order magnitude or more, was observed using transconductance as the indicator when compared to Dirac voltage, which is the only factor reported to date. Fabricating a hexagonal boron nitride multilayer between graphene and oxide further increased the ion sensitivity and selectivity of transconductance. These findings incite investigating ion sensitivity of transconductance in alternative architectures as well as urge the exploration of graphene transistor arrays for biomedical applications.
... Today biosensors are usually based on some forms of the metal-oxide-semiconductor field-effect transistor (MOSFET), which was invented by Mohamed M. Atalla and Dawon Kahng in 1959 (Bassett, 2002). The first bio-field-effect transistor (BioFET), which was an ion-sensitive field-effect transistor (ISFET) and invented by Piet Bergveld in 1970(Toumazou & Georgiou, 2011, is a special type of MOSFET, where the metal gate is replaced by an ionsensitive membrane, electrolyte solution and reference electrode. It is widely used in biomedical applications such as detection of DNA hybridization, biomarker detection from blood, antibody detection, glucose measurement, and pH sensing (Schöning & Poghossian, 2002). ...
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.
... 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. ...
Printed electrolyte-gated transistors (EGTs) are an emerging biosensor platform that leverage the facile fabrication engendered by printed electronics with the low voltage operation enabled by ion gel dielectrics. The resulting label-free, nonoptical sensors have high gain and provide sensing operations that can be challenging for conventional chemical field effect transistor architectures. After providing an overview of EGT device fabrication and operation, we highlight opportunities for microfluidic enhancement of EGT sensor performance via multiplexing, sample preconcentration, and improved transport to the sensor surface.
... 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]. ...
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.
... 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. ...
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.
... 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]. ...
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.
... 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]. ...
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.
... 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. ...
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.
... 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]. ...
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 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. ...
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.
... 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. ...
Low cost, portable sensors can transform health care by bringing easily available diagnostic devices to low and middle income population, particularly in developing countries. Sample preparation, analyte handling and labeling are primary cost concerns for traditional lab-based diagnostic systems. Lab-on-a-chip (LoC) platforms based on droplet-based microfluidics promise to integrate and automate these complex and expensive laboratory procedures onto a single chip; the cost will be further reduced if label-free biosensors could be integrated onto the LoC platforms. Here, we review some recent developments of label-free, droplet-based biosensors, compatible with "open" digital microfluidic systems. These low-cost droplet-based biosensors overcome some of the fundamental limitations of the classical sensors, enabling timely diagnosis. We identify the key challenges that must be addressed to make these sensors commercially viable and summarize a number of promising research directions.
... 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]. ...
... 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]. ...
This study presents the effect of source-drain metal shield in FET structure on drain leakage current. The FET structure was fabricated on the wafer by using MIMOS's standard fabrication process. Aluminum (Al) was sputtered with thickness of 400 nm as metal shield layer at the source and drain area of FET structure. There are four different layout designs of source-drain metal shield that were tested by Keithley 236 current-voltage sourcing under light and dark conditions. The measurements were carried out in a dark box with controllable light intensity. Besides the drain leakage current investigation, this study also investigates the light effect of various layout designs with source-drain metal shield on FET structure. It was found that the layout design with source-drain metal shield has lower drain leakage current compared to the layout design without source-drain metal shield. However, the various layout design of source-drain metal shield cannot eliminate the light effect.
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.
Among the various types of transducers applied in Bioelectronics (i.e., the combination of biological materials and electronic components), Bergveld introduced the concept of field-effect transistor (FET) for neurophysiological measurements presenting to the scientific community the ion-sensitive field-effect transistor (ISFET) [1, 2]. An ISFET is a device very similar to a MOSFET (metal–oxide–semiconductor field-effect transistor). The difference between them is the non-existence of the metallic gate electrode in the ISFET, replaced by a reference electrode in a solution [3].
Biosensors are analyzers used to detect chemicals in combination with physicochemical detectors. Sensitive biological element fabrics, microorganisms, organelles, cell receptors, enzymes, antibodies, nucleic acids, etc. are biologically derived materials that cooperate or recognize test analytes or biomimetic ingredient. Biologically sensitive elements can also be produced by biological engineering. Transducer or detector element that converts transducers or signals into another action is optically, piezoelectric, electrochemical, electrochemical minethimensens, etc. Create and quantify. The biosensor reader device connects to the relevant electronic processor or signal processor. This is mainly responsible for displaying results in a user-friendly way. When this is sometimes creating the most expensive part of the sensor device, it is possible to create a user-friendly display that contains transducers and sensitive elements (holographic sensors). Readers are usually custom designed and manufactured in different operating principles of biosensors. In the field of plant biology, biosensor applications are frequently used to identify missing connections in metabolic pathways. Defense, the clinical sector, and marine applications are among the other applications.
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.
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.
This review provides a critical overview of current developments on nanoelectronic biochemical sensors based on graphene. Composed of a single layer of conjugated carbon atoms, graphene has outstanding high carrier mobility and low intrinsic electrical noise, but a chemically inert surface. Surface functionalization is therefore crucial to unravel graphene sensitivity and selectivity for the detection of targeted analytes. To achieve optimal performance of graphene transistors for biochemical sensing, the tuning of the graphene surface properties via surface functionalization and passivation is highlighted, as well as the tuning of its electrical operation by utilizing multifrequency ambipolar configuration and a high frequency measurement scheme to overcome the Debye screening to achieve low noise and highly sensitive detection. Potential applications and prospectives of ultrasensitive graphene electronic biochemical sensors ranging from environmental monitoring and food safety, healthcare and medical diagnosis, to life science research, are presented as well.
It has been known that the slow response of ion-sensitive field-effect-transistors (ISFETs), with tremendous challenges on meeting the requirements of the accuracy and long-term stability, handicaps extensive application of ISFET sensors. In this paper, dual-mechanism slow site-response (DSSR) model, combining enriched buried sites theory and the mechanism of specific adsorption activity (SAA) of effective sites, is proposed to systematically understand the slow response characteristics of ISFETs during a test of pH variation. The SAA variation occurs during the whole slow response process, while the effects of buried sites dominate only at the short-term slow response stage. Experiments based on extended-gate ion-sensitive field-effect-transistors using both aluminum oxide and silicon nitride as sensing layer were carried out. It is found that the DSSR model can excellently explain the slow response characteristics of the measured ISFETs. Furthermore, the slow response characteristics of ISFETs with silicon nitride are revealed to be superior to that of ISFETs with aluminum oxide in the slow response performance.
For conventional open-loop hydrogel-based pH sensors, the sensor performance is often limited by the slow cooperative diffusion process of hydrogels. To overcome this drawback, a pH sensor with force compensation is developed. This new sensor concept capitalizes on the fact that a compensation pressure arising from an actuator can suppress the hydrogel's swelling, accelerate the diffusion process within the hydrogel and, eventually, improve the sensor's dynamic behaviour. To further miniaturize this force-compensated sensor, a microactuator with a high energy density is applied to replace the previous macroscopic actuator. It is the first time to present miniaturized force-compensated sensors, where both sensor elements and actuators are manufactured by microfabrication technologies. Following tests reveal that this sensor offers a wide operating pH range 4...10, a maximum sensitivity of -4.4. K/pH, and an average response time of 44. min, which is 5.8%...27.4% shorter than that of conventional open-loop sensors. Those experimental results clearly demonstrate that the sensor performance of hydrogel-based sensors can be improved by means of the force compensation approach.
Understanding the dynamics of hydrogen ion reactivity at the solid/liquid interface is of paramount importance for applications involving ion sensing in electrolytes. However, the correlation of this interfacial process to noise generation is poorly characterized. Here, the relationship is unveiled by characterizing the interfacial process with impedance spectroscopy assisted by a dedicated electrochemical impedance model. The model incorporates both thermodynamic and kinetic properties of the amphoteric hydrogen ion site-binding reactions with the surface OH groups. It further takes into consideration the distributed nature of the characteristic energy of the binding sites. The simulated impedance matches the experimental data better with an energy distribution of the kinetic parameters than with that of the thermodynamic ones. Since the potentiometric low-frequency noise (LFN) originating from the solid/liquid interface correlates excellently with the real part of its electrochemical impedance spectrum, this work establishes a method for evaluating sensing surface quality aimed at mitigating LFN.
Recent research trends now offer new opportunities for developing the next generations of label-free biochemical sensors using graphene and other two-dimensional materials. While the physics of graphene transistors operated in electrolyte is well grounded, important chemical challenges still remain to be addressed, namely the impact of the chemical functionalizations of graphene on the key electrical parameters and the sensing performances. In fact, graphene - at least ideal graphene - is highly chemically inert. The functionalizations and chemical alterations of the graphene surface - both covalently and non-covalently - are crucial steps that define the sensitivity of graphene. The presence, reactivity, adsorption of gas and ions, proteins, DNA, cells and tissues on graphene have been successfully monitored with graphene. This review aims to unify most of the work done so far on biochemical sensing at the surface of a (chemically functionalized) graphene field-effect transistor and the challenges that lie ahead. The authors are convinced that graphene biochemical sensors hold great promise to meet the ever-increasing demand for sensitivity, especially looking at the recent progresses suggesting that the obstacle of Debye screening can be overcome.
This paper describes the design and implementation of a low-power current-mode logarithmic analog-to-digital converter (ADC) for an ISFET-based \(p\!H\) digital readout system. The system comprises a front-end ISFET-based \(p\!H\) readout circuit and a succeeding logarithmic ADC to produce a digital output signal which is linearly related to the input \(p\!H\) variation. The front-end \(p\!H\) readout circuit is realized using a subthreshold ISFET/REFET differential pair with a current-mode translinear multiplier/divider circuit. The logarithmic ADC is realized using the cyclic architecture and current-mode circuit techniques to achieve low power dissipation. High-accuracy current sample-and-hold circuit based on the regulated-cascode switched-current memory cell and low-power high-resolution current comparator are proposed for the ADC realization. All circuits were designed to operate with a single 1-V power supply voltage, and were simulated with process parameters from a 0.18- \(\mu \) m CMOS technology. The power dissipation of the front-end \(p\!H\) readout circuit and the logarithmic ADC is 20 and 330 nW, respectively. The front-end \(p\!H\) readout circuit can produce an output current range of 0.1-300 nA which is logarithmically corresponded to the input \(p\!H\) range of 4-10. The logarithmic ADC operates with 1-kS/s sampling rate and achieves the integral nonlinearity error of \(\pm 0.8\) LSB, the effective number of bits of 5.95, and 37.6-dB of signal-to-noise-distortion ratio with 100-nA full-scale input range.
The advent of semiconductors in health care has enabled significant advancements in the development of point-of-care biomedical devices. Miniaturized portable systems are replacing bulky instruments. Telemedicine and remote care are being practiced in diagnostics. However, their communication with the biology is mainly in digital, whereas biology is analog. On the other hand, the potential in semiconductors is much more. With a bioinspired vision, it is possible to develop systems on a microchip that can mimic biological processes. In addition, interfacing with the biochemistry of body functions allows for the providing of therapy at the same point as diagnosis and at the same time. In this article, examples of bio-inspired inventions are provided. Stepping beyond, we will see how semiconductor microchips can provide prediction and early detection for personalized care, which will reshape the future of health care.
This paper presents a novel scalable readout-converter operating in weak inversion with a least significant bit resolution of 0.015pH change. The readout-converter eliminates the effect of temperature on measurements and suppresses the influence of sensing membrane buffer capacity as well as the transistor slope factor variation when in weak inversion. With the ISFET floating-gate resetting, there is no limit on dynamic range while maintaining its linearity. The system is scalable for higher resolutions and ranges without any compromise on performance. While the readout-converter can be used separately, a reference pixel is used here to eliminate the effect of any possible common mode signals in measurements with a common mode rejection ratio of 83.5dB. The system operates in continuous time and does not require any clock signal.
The adaptation of semiconductor technologies for biological applications may lead to a new era of inexpensive, sensitive, and portable diagnostics. At the core of these developing technologies is the ion-sensitive field-effect transistor (ISFET), a biochemical to electrical transducer with seamless integration to electronic systems. We present a novel structure for a true dual-gated ISFET that is fabricated with a silicon-on-insulator (SOI) complementary metal-oxide-semiconductor process by Taiwan Semiconductor Manufacturing Company (TSMC). In contrast to conventional SOI ISFETs, each transistor has an individually addressable back-gate and a gate oxide that is directly exposed to the solution. The elimination of the commonly used floating gate architecture reduces the chance of electrostatic discharge and increases the potential achievable transistor density. We show that when operated in a "dual-gate" mode, the transistor response can exhibit sensitivities to pH changes beyond the Nernst limit. This enhancement in sensitivity was shown to increase the sensor's signal-to-noise ratio, allowing the device to resolve smaller pH changes. An improved resolution can be used to enhance small signals and increase the sensor accuracy when monitoring small pH dynamics in biological reactions. As a proof of concept, we demonstrate that the amplified sensitivity and improved resolution result in a shorter detection time and a larger output signal of a loop-mediated isothermal DNA amplification reaction (LAMP) targeting a pathogenic bacteria gene, showing benefits of the new structure for biosensing applications.
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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