ISFET Research Articles

Self-oscillating chemoelectrical interface of solution-gated ion-sensitive field-effect transistor based on Belousov\u2013Zhabotinsky reaction

The Belousov–Zhabotinsky (BZ) self-oscillation reaction is an important chemical model to elucidate nonequilibrium chemistry in an open system. However, there are only a few studies on the electrical behavior of pH oscillation induced by the BZ reaction, although numerous studies have been carried out to investigate the mechanisms by which the BZ reaction interacts with redox reactions, which results in potential changes. Needless to say, the electrical characteristic of a self-oscillating polymer gel driven by the BZ reaction has not been clarified. On the other hand, a solution-gated ion-sensitive field-effect transistor (ISFET) has a superior ability to detect ionic charges and includes capacitive membranes on the gate electrode. In this study, we carried out the electrical monitoring of self-oscillation behaviors at the chemoelectrical interface based on the BZ reaction using ISFET sensors, focusing on the pH oscillation and the electrical dynamics of the self-oscillating polymer brush. The pH oscillation induced by the BZ reaction is not only electrically observed using the ISFET sensor, the electrical signals of which results from the interfacial potential between the solution and the gate insulator, but also visualized using a large-scale and high-density ISFET sensor. Moreover, the N-isopropylacrylamide (NIPAAm)-based self-oscillating polymer brush with Ru(bpy)3 as a catalyst clearly shows a periodic electrical response based on the swelling–deswelling behavior caused by the BZ reaction on the gate insulator of the ISFET sensor. Thus, the elucidation of the electrical self-oscillation behaviors induced by the BZ reaction using the ISFET sensor provides a solution to the problems of nonequilibrium chemistry.

Recent advances in ion‐sensitive field‐effect transistors for biosensing applications

AbstractOver the past decades, considerable development and improvement can be observed in the area of the ion‐sensitive field‐effect transistor (ISFET) for biosensing applications. The mature semiconductor industry provides a solid foundation for the commercialization of the ISFET‐based sensors and extensive research has been conducted to improve the performance of ISFET, with a special research focus on the materials, device structures, and readout topologies. In this review, the basic theories and mechanisms of ISFET are first introduced. Research on ISFET gate materials is reviewed, followed by a summary of typical gate structures and signal readout methods for the ISFET sensing system. After that, a variety of biosensing applications including ions, deoxyribonucleic acid, proteins, and microbes are presented. Finally, the prospects and challenges of the ISFET‐based biosensors are discussed.

A proton-selective membrane (PSM)-deposited dual-gate ion-sensitive field-effect transistor (DG-ISFET) integrating a microchamber-embedded filter membrane for bacterial enrichment and antimicrobial susceptibility test

The antimicrobial susceptibility test (AST) is one of the most common methods to evaluate bloodstream infections (BSI). Currently, AST methods usually required prolonged sample preparation processes and bulky systems, making it difficult to provide timely information for clinical decisions. In this paper, we integrated a proton-selective membrane (PSM)-deposited dual-gate ion-sensitive field-effect transistor (DG-ISFET) with a microchamber-embedded filter membrane to perform bacterial enrichment and incubation followed by on-chip AST. The DG-ISFET sensor consists of a high-k dielectric hafnium oxide (HfO2) sensing surface and dual gate, enabling high ion sensitivity, and low drifting and hysteresis issues. By depositing a PSM on DG-ISFET, the sensor has higher proton sensitivity and selectivity, preventing interference from other ion signals in the bacterial culture medium. To further shorten the bacterial culture time, we integrated a microchamber-embedded filter membrane on top of the DG-ISFET sensor to enrich the amount of bacteria and place seeded bacteria close to DG-ISFET’s sensing surface. As a proof of concept, we first evaluated the proton sensitivity and selectivity of DG-ISFET under various PSM deposition thicknesses. Then, we demonstrated that the PSM-deposited DG-ISFET system can successfully distinguish kanamycin-susceptible and resistant Escherichia coli strains treated with various kanamycin concentrations in 30 min based on the continuous drain-source current (Ids) pattern. We envision that this fully integrated system can perform rapid, real-time, continuous AST, which can potentially be applied in resource-limited environments or point-of-care settings.

Polycrystalline-silicon-based double-gate ion-sensitive field-effect transistors using APTES/SiO2 stack-sensing membrane

Abstract This study demonstrated a polycrystalline-silicon (poly-Si)-based double-gate (DG) ion-sensitive field-effect transistors (DG-ISFETs) using APTES/SiO2 stack-sensing membrane. The APTES/SiO2 stack-sensing membrane enhanced the single-gate (SG) sensitivity, and suppressed the hysteresis. The DG structure was preferred to have a capacitive coupling effect and to amplify the sensitivity of ISFETs. The sensitivities of SG- and DG-ISFETs were approximately 56.8 and 294 mV/pH, respectively. In addition, the corresponding amplifying factor was approximately 5.2. With this approach, the poly-Si DG-ISFETs can be a candidate for future high-performance biochemical sensing applications.

Analysis of static behavior of ion sensitive field effect Transistor for pH measurements

The Ion-Sensitive Field-Effect Transistor (ISFET) is one of the most popular pH sensors traditionally using to measure hydrogen ion concentration (pH) of the electrolytic solutions. It is developed from Metal Oxide Semiconductor Field-Effect Transistor (MOSFET) by replacing gate electrode with an electrolytic solution to be tested, and a reference metal electrode immersed in that solution. Basic principle of ISFET operation is based on that of standard NMOS structure in conjunction with the insulator-electrolyte capacitor as described in this paper. The site-binding theory (generalized to two kinds of binding sites), together with the Gouy-Chapman-Stern model for the potential profile in the electrolyte, is coupled to the MOS physics. As a result, an approximate analytical model which completely describes static behavior of the ISFET is obtained. The developed description can serve as useful tool for understanding many contemporary biosensors based on original ISFET structure which has broad application in bio-medicine, biological, chemistry and environmental areas.

Zinc Oxide Nanowire Field Effect Transistor Used as a pH Sensor

An ion sensitive field effect transistor can outperform conventional ion-selective electrodes. Thus, a zinc oxide (ZnO) nanowire field effect transistor (NWFET) pH sensor was fabricated and measured. The sensor contained a channel with 1.7×1018 cm-3 donor concentration and 100 ZnO nanowires in parallel, each with the following dimensions: 10 μm×120 nm×20 nm. The active channel is passivated with an 18 nm Al2O3 layer. The device was measured under a controlled environment with and without pH solutions. The pH range was 3–9 with a sensitivity of 2.48 mV to 10.3 mV. The voltage sensitivity translates to a percentage value of 15%. The measurements obtained before and after the pH solution treatment demonstrate the possibility of re-use of the device by rinsing and brushing the sensing layer.

Detection of cell membrane proteins using ion-sensitive field effect transistors combined with chemical signal amplification

Detection concept of HER2 via an enzyme reaction using an ISFET pH sensor.

Ultra‐thin ISFET‐based sensing systems

AbstractThe ion‐sensitive field effect transistors (ISFETs), proposed little over 50 years ago, today make the most promising devices for lab‐on‐a‐chip, implantable, and point‐of‐care (POC) diagnostics. Their compatibility with CMOS (Complementary Metal Oxide Semiconductor) technology and the low cost through mass production have been the driving factors so far. Nowadays, they are also being developed in flexible form factors for new applications such as wearables and to improve the effective usage in existing applications such as implantable systems. In this regard, the CMOS ultra‐thin chip (UTC) technology and the bonding by printing are the noteworthy advances. This paper comprehensively reviews such new developments in the CMOS‐compatible ISFETs, along with their theory, readout circuitries, circuit‐based techniques for compensation of the ISFET's instabilities, such as the offset, flicker noise, and drift. The sensing mechanisms and the properties of interface between the electrolyte under test and the metal‐oxide based ion‐sensitive electrodes have been discussed along with a brief overview of the metal‐oxide based pH sensors. An overview of the reported mechanically flexible pH sensors, including ISFETs, is provided and the history of ISFET applications are also covered. Finally, established models that can be used to design flexible circuits are presented, and possible opportunities to use circuit techniques to compensate for mechanical deformation are discussed.

Super-Nernstian ion sensitive field-effect transistor exploiting charge screening in WSe2/MoS2 heterostructure

Ion-sensitive field-effect transistors (ISFETs) have gained a lot of attention in recent times as compact, low-cost biosensors with fast response time and label-free detection. Dual gate ISFETs have been shown to enhance detection sensitivity beyond the Nernst limit of 59 mV pH−1 when the back gate dielectric is much thicker than the top dielectric. However, the thicker back-dielectric limits its application for ultrascaled point-of-care devices. In this work, we introduce and demonstrate a pH sensor, with WSe2(top)/MoS2(bottom) heterostructure based double gated ISFET. The proposed device is capable of surpassing the Nernst detection limit and uses thin high-k hafnium oxide as the gate oxide. The 2D atomic layered structure, combined with nanometer-thick top and bottom oxides, offers excellent scalability and linear response with a maximum sensitivity of 362 mV pH−1. We have also used technology computer-aided (TCAD) simulations to elucidate the underlying physics, namely back gate electric field screening through channel and interface charges due to the heterointerface. The proposed mechanism is independent of the dielectric thickness that makes miniaturization of these devices easier. We also demonstrate super-Nernstian behavior with the flipped MoS2(top)/WSe2(bottom) heterostructure ISFET. The results open up a new pathway of 2D heterostructure engineering as an excellent option for enhancing ISFET sensitivity beyond the Nernst limit, for the next-generation of label-free biosensors for single-molecular detection and point-of-care diagnostics.

Cross-compensation of FET sensor drift and matrix effects in the industrial continuous monitoring of ion concentrations

Field-effect transistor (FET) sensors are attractive potentiometric (bio)chemical measurement devices because of their fast response, low output impedance, and potential for miniaturization in standard integrated circuit manufacturing technologies. Yet the wide adoption of these sensors for real-world applications is still limited, mainly due to temporal drift and cross-sensitivities that introduce considerable error in the measurements. In this paper, we demonstrate that such non-idealities can be corrected by joint use of an array of FET sensors – selective to target and major interfering ions – with machine learning (ML) methods in order to accurately predict ion concentrations continuously and in the field. We studied the predictive performance of linear regression (LR), support vector regression (SVR), and state-of-art deep neural networks (DNNs) when monitoring pH from combinatorial H+, Na+, and K+ ion-sensitive FET (ISFET) sequences of readings collected over a period of 90 consecutive days in real water quality assessment conditions. The proposed ML algorithms were trained against reference online measurements obtained from a commercial pH sensor. Results show a greater capability of DNNs to provide precise pH monitoring for longer than a week, achieving a relative root-mean-square error reduction of 73% over standard two-point sensor calibration methods.

Fabrication of a Mesoporous Multimetallic Oxide-based Ion-Sensitive Field Effect Transistor for pH Sensing.

Sensitive and reliable noninvasive sensors are in demand to cope with an increasing need for robust working conditions and fast results. One of the leading potential technologies is field-effect transistor (FET)-based sensors to improve response time, sensitivity, and stability. Here, a sol–gel method fabricates an ion-sensitive field-effect transistor with a high current and output sensitivity for electrochemical sensing, solving binary device design, component regulating, and long-term stability, while maintaining the promoted sensitivity. Metal oxide-based devices with single and binary contents are fabricated and characterized for monitoring pH changes, with performance fitted to a Nernst–Poisson model. After detecting the performance, the result was compared with devices in different components and ratios to obtain excellent performance and high stability. In addition, these extended gate FETs with multimetallic oxide promise efficiency and stability optimization in terms of a flexible component design, demonstrating the feasibility of the novel sol–gel fabrication method to achieve efficient and reliable FET sensors.

Ion-Selective Membrane-Coated Graphene-Hexagonal Boron Nitride Heterostructures for Field-Effect Ion Sensing.

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.

Chemically Induced pH Perturbations for Analyzing Biological Barriers Using Ion-Sensitive Field-Effect Transistors.

Potentiometric pH measurements have long been used for the bioanalysis of biofluids, tissues, and cells. A glass pH electrode and ion-sensitive field-effect transistor (ISFET) can measure the time course of pH changes in a microenvironment as a result of physiological and biological activities. However, the signal interpretation of passive pH sensing is difficult because many biological activities influence the spatiotemporal distribution of pH in the microenvironment. Moreover, time course measurement suffers from stability because of gradual drifts in signaling. To address these issues, an active method of pH sensing was developed for the analysis of the cell barrier in vitro. The microenvironmental pH is temporarily perturbed by introducing a low concentration of weak acid (NH4+) or base (CH3COO−) to cells cultured on the gate insulator of ISFET using a superfusion system. Considering the pH perturbation originates from the semi-permeability of lipid bilayer plasma membranes, induced proton dynamics are used for analyzing the biomembrane barriers against ions and hydrated species following interaction with exogenous reagents. The unique feature of the method is the sensitivity to the formation of transmembrane pores as small as a proton (H+), enabling the analysis of cell–nanomaterial interactions at the molecular level. The new modality of cell analysis using ISFET is expected to be applied to nanomedicine, drug screening, and tissue engineering.

Machine Learning on FPGA for Robust ${\rm {Si}}_{3}{\rm {N}}_{4}$-Gate ISFET pH Sensor in Industrial IoT Applications

This article presents performance enhancement of <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"><tex-math notation="LaTeX">${\rm {Si}}_{3}{\rm {N}}_{4}$</tex-math></inline-formula> -gate ion-sensitive field-effect transistor based pH sensor using machine learning (ML) techniques. A robust SPICE macromodel is developed using experimental data, which incorporates intrinsic temperature and temporal characteristics of the device, which is further used in sensor readout circuit (ROIC), which shows a nonideal temperature and time dependence in the voltage output. To make the device robust to the critical drifts, we exploit six state-of-the-art ML models, which are trained using the data generated from ROIC for a wide range of pH, temperature, and temporal conditions. Thorough comparison between ML models shows random forest outperforms other models for drift compensation task. This work also shows a preliminary time series classification task. The ML models are implemented on a Xilinx PYNQ-Z1 field-programmable gate array (FPGA) board to validate the performance in power and memory-restricted environment, crucial for IoT applications. A parameter, implementation factor is defined to evaluate best ML model for IoT deployment using FPGA/MCU hardware implementation. The significantly lower power consumption of FPGA board as compared to CPU with no noticeable performance drop is a pointer to the future of robust pH sensors used in industrial and remote IoT applications.

ISFET‐based ion sensors with photopolymerizable membranes

AbstractThis minireview summarizes the information on the development and application of ion‐sensitive field‐effect transistors (ISFETs) with UV‐cured polyurethane ion‐selective membranes. Among the advantages of photopolymerizable polymer membranes in comparison with traditional poly(vinyl chloride) are excellent adhesion to a solid sensor surface and very fast curing time. Moreover, processes of membrane deposition and curing are compatible with ISFETs fabrication technology which is important for sensors mass production. The paper presents specific features of photopolymerizable membranes and discusses required precautions in their preparation and treatment. Examples of various analytical applications of this kind of sensors are provided. Finally, the outlook and perspectives of further development in the field of miniature solid‐state ion sensors are given.

Fabrication, Characterization, and Modeling of an Aluminum Oxide-Gate Ion-Sensitive Field-Effect Transistor-Based pH Sensor.

The ion-sensitive field-effect transistor (ISFET) is a popular technology utilized for pH sensing applications. In this work, we have presented the fabrication, characterization, and electrochemical modeling of an aluminum oxide (Al2O3)-gate ISFET-based pH sensor. The sensor is fabricated using well-established metal–oxide–semiconductor (MOS) unit processes with five steps of photolithography, and the sensing film is patterned using the lift-off process. The Al2O3 sensing film is deposited over the gate area using pulsed-DC magnetron-assisted reactive sputtering technique in order to improve the sensor performance. The material characterization of sensing film has been done using x-ray diffraction, field-emission scanning electron microscopy, energy-dispersive spectroscopy, and x-ray photoelectron spectroscopy techniques. The sensor has been packaged using thick-film technology and encapsulated by a dam-and-fill approach. The packaged device has been tested in various pH buffer solutions, and a sensitivity of nearly 42.1 mV/pH has been achieved. A simulation program with integrated circuit emphasis (SPICE) macromodel of the Al2O3-gate ISFET is empirically derived from the experimental results, and the extracted electrochemical parameters have been reported. The drift and hysteresis characteristics of the Al2O3-gate ISFET were also studied, and the obtained drift rates for different pH buffer solutions of 4, 7, and 10 are 0.136 μA/min, 0.124 μA/min, and 0.108 μA/min, respectively. A hysteresis of nearly 5.806 μA has been obtained. The developed sensor has high sensitivity along with low drift and hysteresis.

Electrical Characterization and Study of Current Drift Phenomena and Hysteresis Mechanism in Junctionless Ion-Sensitive Field-Effect Transistor

A comprehensive study of the drain current drift mechanism and hysteresis phenomena in fabricated p-channel junctionless ion-sensitive field-effect transistor (JL-ISFET) has been investigated for the first time. The current drift measurements have been performed through transient analysis of drain current, under different pH and liquid-gate bias (Vlg). Further, time-dependent gate-capacitance (CG) has also been analyzed to see the effect of hydroxyl ions (OH−) in the sensing film (Al2O3). The hysteresis has also been investigated for different pH loop (7 → 3 → 7 → 11 → 7 and 7 → 11 → 7 → 3 → 7) and times (960s, 1500s, and 1920s). It has been observed that the drift of JL-ISFET occurs because of chemical modification of the sensing film, due to OH−. The proposed device exhibits a threshold voltage sensitivity of 58.2 mV/pH that is near the Nernstian limit. Further, the hysteresis width and maximum drain current drift are measured as \(\sim \) 1.3 mV and 2.4 μ A (\(\sim \) 75%), respectively.

Sensitivity optimization of a Double-Gated ISFET pH-sensor with HfO2/SiO2 gate dielectric stack

This paper investigates the sensitivity enhancement of Ion-Sensitive Field Effect Transistor (ISFET) pH-sensor using double-gate operation and illustrates how different structure modifications between the top and back oxides give different sensitivity gain factors. The gain factor is controlled through top and back oxide thickness, channel thickness and SiGe channel material. The sensitivity at the back gate is 59.52 mV/pH (27 °C) and the amplified sensitivity at the front gate reaches 476.54 ±33 mV/pH (27 °C). Furthermore, the issues related to high sensitivity-amplification such as sensitivity variation and dielectric breakdown are discussed, followed by optimization of the device structure in the linear regime to overcome them. Stacking a thin HfO2 layer over the top SiO2 layer helps in preventing dielectric breakdown at high sensitivity analysis. Synopsys TCAD is utilized for this proposed work with the electrolyte material and site-binding reactions being modeled through user-defined features of TCAD with explicit references from experimental data.

CMOS ISFET Arrays for Integrated Electrochemical Sensing and Imaging Applications: A Tutorial

The ion-sensitive field-effect transistor (ISFET) is a type of electrochemical sensor with a wide range of applications. They offer advantages of being compatible with standard CMOS technology, a miniaturised form-factor, robustness, scalability and low power requirements to name a few. There are now many architectures and design strategies to construct ISFET-based systems in CMOS, and the appropriate choice of these depends heavily on the specifications of the intended application. This tutorial aims to give a designer the knowledge needed to make the best decisions for the required specifications by providing a background in theory and an overview of design trade-offs and existing approaches. Example designs which maximise performance in particular applications are discussed and practical considerations for simulation, layout and implementation are presented.

A comprehensive review of FET‐based pH sensors: materials, fabrication technologies, and modeling

AbstractThe demand for miniaturized point‐of‐care chemical/biochemical sensors has driven the development of field‐effect transistors (FETs) based pH sensors over the last 50 years. This paper aims to review the fabrication technologies, device structures, sensing film materials, and modeling techniques utilized for FET‐based pH sensors. We present the governing principles of potentiometric sensors, with major focus on the working principles of ion‐sensitive FETs (ISFETs). We extensively review different sensing film materials deposited by various techniques, which is critical to the sensing performance of ISFETs. The popular fabrication technologies have been presented, with special emphasis on state‐of‐the‐art silicon‐on‐insulator based technology, which can achieve high sensitivity by utilizing the dual‐gate effect. Furthermore, recent advancements in nano‐ISFETs has been elucidated. We also discuss the adoption of unmodified complementary metal‐oxide semiconductor (CMOS) ISFETs using standard CMOS processes, which has enabled the fabrication of integrated ISFET arrays, which are especially suited for ion‐imaging applications. Moreover, recent developments in extended‐gate FETs has been discussed, which have gained lot of attention due to their design flexibility and ease of fabrication, which is desirable for wearable sensing applications. In addition, recently there have been efforts to utilize nonsilicon channel materials for pH‐sensing application to obtain superior performance and various channel materials have been reviewed. Finally, we have extensively reviewed the ISFET device modeling and simulation techniques using various computer‐aided design tools, which aid in sensor design and characterization.