ISFET Research Articles

Detection of HER-3 with an AlGaN/GaN-Based Ion-Sensitive Heterostructure Field Effect Transistor Biosensor.

Human epidermal growth factor receptor-3 (HER-3) plays a key role in the growth and metastasis of cancer cells. The detection of HER-3 is very important for early screening and treatment of cancer. The AlGaN/GaN-based ion-sensitive heterostructure field effect transistor (ISHFET) is sensitive to surface charges. This makes it a promising candidate for the detection of HER-3. In this paper, we developed a biosensor for the detection of HER-3 with AlGaN/GaN-based ISHFET. The AlGaN/GaN-based ISHFET biosensor exhibits a sensitivity of 0.53 ± 0.04 mA/dec in 0.01 M phosphate buffer saline (1× PBS) (pH = 7.4) solution with 4% bovine serum albumin (BSA) at a source and drain voltage of 2 V. The detection limit is 2 ng/mL. A higher sensitivity (2.20 ± 0.15 mA/dec) can be achieved in 1× PBS buffer solution at a source and drain voltage of 2 V. The AlGaN/GaN-based ISHFET biosensor can be used for micro-liter (5 μL) solution measurements and the measurement can be performed after incubation of 5 min.

Transparent and High-Performance Extended Gate Ion-Sensitive Field-Effect Transistors Using Electrospun Indium Tin Oxide Nanofibers

Herein, we propose a transparent high-performance extended-gate ion-sensitive field-effect transistor (EG-ISFET) using an electrospun indium-tin-oxide (ITO) nanofiber sensing membrane with a high specific surface area. Electrospinning is a simple and effective technique for forming nanofibers. Nevertheless, one-step calcination, such as conventional thermal annealing or microwave annealing, cannot sufficiently eliminate the inherent defects of nanofibers. In this study, we efficiently removed residual polymers and internal impurities from nanofibers via a two-step calcination process involving combustion and microwave annealing. Moreover, Ar plasma treatment was performed to improve the electrical characteristics of ITO nanofibers. Conformally coated thin-film sensing membranes were prepared as a comparative group and subjected to the same calcination conditions to verify the effect of the nanofiber sensing membrane. The characteristics of the ITO nanofiber and ITO thin-film sensing membranes were evaluated using scanning electron microscopy (SEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), optical transmittance, and conductivity. Moreover, the sensor operation of the EG-ISFETs is evaluated in terms of sensitivity and non-ideal behaviors. The optimized process improves the sensor characteristics and sensing membrane quality. Therefore, the ITO nanofiber sensing membrane improves the sensitivity and stability of the EG-ISFET, suggesting its applicability as a high-performance biochemical sensor.

ISFET Fabrication and Characterization for Hydrogen Peroxide sensing

This work presents the Ion-Sensitive Field Effect Transistor (ISFET) fabrication and electrical characterization for hydrogen peroxide sensing. Two configurations were set up to evaluate the devices sensitivity to the concentration of the solution. First, measurements with one electrode in the sample solution (contained over the gate area) were performed, but the results may not be directly related to the characteristics of the solution, due to the prevalence of secondary effects. The second method, using two electrodes in the sample solution, shows a higher sensitivity at increasing hydrogen peroxide concentrations, in smallest intervals when compared to measurements with one electrode.

Back Gate Bias Influence on BESOI ISFET Sensitivity

This paper presents, for the first time, the BESOI MOSFET working as Ion Sensitive Field Effect Transistor (ISFET): the BESOI ISFET. Experimental measurements were performed with standard pH solution replacing the gate electrode. The threshold voltage becomes lower when the pH decreases (changes from basic to acid) as expected. Furthermore, the back (substrate) bias influence was studied, showing an increase in the device sensitivity (mV/pH) as a function of the back voltage. The best sensitivity value was obtained for 30 V applied in the back bias, reaching 33 mV/pH. These results demonstrates that the BESOI ISFET has electrical behavior compatible with other ISFETs.

(Invited) ISFET-Based Sensors

This review presents the technological evolution of devices based on Ion Sensitive Field Effect Transistors (ISFETs), which try to go along with the Metal Oxide Semiconductor FET (MOSFET) technology. Furthermore, many examples of the applications as chemical or biological sensors with different structures (planar or 3D), conduction channels (Silicon or Graphene), and dielectric gate films (SiNx, TiOx, TaOx, and AlOx) will be discussed.

Design and analysis of high-performance double-gate ZnO nano-structured thin-film ISFET for pH sensing applications

This paper reports a high-performance double-gate zinc-oxide thin-film ion-sensitive field-effect transistor (DG-ZnO-ISFET) for pH sensing applications. The sensing mechanism of DG-ZnO-ISFET and a simulation model for pH sensing analysis are demonstrated herein. Various aspects of the device are elucidated through the study of channel conductance, electron density, energy band, and surface-potential profiles. The DG-ZnO-ISFETs enhance minor surface potential variations by capacitive coupling across the dielectrics of the top and bottom gates. Further, it operates by altering the bottom-gate voltage (VBG), obviating the need for a reference electrode system. The device depicts enhanced voltage sensitivity of 205.57 mV/pH, which is substantially 3.48 × greater than the Nernst limit sensitivity. In addition, the DG-ZnO-ISFET renders a maximum current sensitivity of 10.82 mA/mm.pH at VBG=5V. Furthermore, it exhibits high linearity in both voltage and current sensitivity, with the coefficient of determination (R2) values of 0.984 and 0.964, respectively. With their increased sensitivity and linearity, DG-ZnO-ISFETs have the potential device for next-generation biosensors.

Ion-Sensitive Stainless Steel Vessel for All-Solid- State pH Sensing System Incorporating pH-Insensitive Diamond Solution Gate Field-Effect Transistors

An all-solid-state pH sensing system utilizing a stainless steel vessel (SUS304) and a pH-insensitive diamond solution-gate field-effect transistor (SGFET) is presented here to explain the interaction between stainless steel vessel and field-effect transistor (FET) pH sensors for the first time. A pH sensitive ion-sensitive field-effect transistor (ISFET) was first used to show the change of the sensing behavior from 47.78 mV/pH to -4.73 mV/pH when using an Ag/AgCl electrode and stainless steel vessel as the gate, respectively. This intriguing sensing behavior was investigated by developing large and small-signal equivalent circuit models in a transistor circuit for both the Ag/AgCl and the stainless steel vessel gate. The result shows that the targeted ion change ΔQ <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">h</sub> corresponding to the pH sensitivity has been offset which explains the phenomenon observed when using the pH sensitive ISFET with the stainless steel vessel. We then hypothesize that combining a pH insensitive device with the stainless steel vessel gate should show a pH sensitivity close to the Nernst response. To validate this, a pH insensitive diamond SGFET was then fabricated and combined with the stainless steel vessel for pH measurements. The system demonstrates a high pH sensitivity at -54.18 mV/pH across a wide range of pH solutions (pH 2-12) and remains stable in elevated temperatures when measured with a potentiostat setup at 80 °C. The results also suggest that this all-solid-state sensing system has great potential to be used in the food and beverage industry where stainless steel is widely employed due to its excellent corrosion resistance, low cost, and high sensing capabilities.

Potentiometric Chloride Ion Biosensor for Cystic Fibrosis Diagnosis and Management: Modeling and Design

The ion-sensitive field-effect transistor is a well-established electronic device typically used for pH sensing. The usability of the device for detecting other biomarkers in easily accessible biologic fluids, with dynamic range and resolution compliant with high-impact medical applications, is still an open research topic. Here, we report on an ion-sensitive field-effect transistor that is able to detect the presence of chloride ions in sweat with a limit-of-detection of 0.004 mol/m3. The device is intended for supporting the diagnosis of cystic fibrosis, and it has been designed considering two adjacent domains, namely the semiconductor and the electrolyte containing the ions of interest, by using the finite element method, which models the experimental reality with great accuracy. According to the literature explaining the chemical reactions that take place between the gate oxide and the electrolytic solution, we have concluded that anions directly interact with the hydroxyl surface groups and replace protons previously adsorbed from the surface. The achieved results confirm that such a device can be used to replace the traditional sweat test in the diagnosis and management of cystic fibrosis. In fact, the reported technology is easy-to-use, cost-effective, and non-invasive, leading to earlier and more accurate diagnoses.

Wireless in vivo recording of cortical activity by an ion-sensitive field effect transistor

Wireless brain technologies are empowering basic neuroscience and clinical neurology by offering new platforms that minimize invasiveness and refine possibilities during electrophysiological recording and stimulation. Despite their advantages, most systems require on-board power supply and sizeable transmission circuitry, enforcing a lower bound for miniaturization. Designing new minimalistic architectures that can efficiently sense neurophysiological events will open the door to standalone microscale sensors and minimally invasive delivery of multiple sensors. Here we present a circuit for sensing ionic fluctuations in the brain by an ion-sensitive field effect transistor that detunes a single radiofrequency resonator in parallel. We establish sensitivity of the sensor by electromagnetic analysis and quantify response to ionic fluctuations in vitro. We validate this new architecture in vivo during hindpaw stimulation in rodents and verify correlation with local field potential recordings. This new approach can be implemented as an integrated circuit for wireless in situ recording of brain electrophysiology.

Self-sensitivity amplifiable dual-gate ion-sensitive field-effect transistor based on a high-k engineered dielectric layer

In this study, we propose a self-sensitivity amplifiable pH-sensor platform based on a dual-gate (DG) structure ion-sensitive-field-effect-transistor (ISFET) by applying a high-k engineered dielectric layer. We implement amplification according to the capacitance ratio of top and bottom gate dielectric layers through the capacitive coupling effect of DG structure, which exceeds the Nernst limit of the existing ISFET, and maximizes device sensitivity by extracting the change in current based on a reference voltage. In repeated and continuous pH sensitivity measurements and reliability evaluations under external noise conditions, the proposed sensor platform demonstrated excellent linearity and stability. Because the proposed sensor platform significantly exceeds the Nernst limit and has excellent reliability, it is expected to be a promising technology for use as a biosensor platform for detecting analytes with micro potentials.

Design-Oriented Physical Model of Ion-Sensitive Field Effect Transistor for pH Sensing

In this work, we present a circuit design-oriented physical model of the ion-sensitive field-effect transistor (ISFET) for pH-sensing applications. Particularly, this model considers the site-binding interactions at the interface of the electrolyte and the insulator and utilizes a charge-based approach to analyze the field-effect device. The light numerical solution based on the Newton–Raphson–Jacobian method is obtained and validated with experimental results. A semianalytical Verilog-A model is developed by proper selection of initial value and truncating the number of iterations in the numerical method. It follows the numerical results in all regions of operation with a relative error of 2% and a much faster simulation time. The model has a few calibration parameters extracted to fit two experimental devices, including a p-type silicon-on-insulator (SOI) nanowire and conventional n-type ISFET devices. These results suggest that the proposed model is a promising candidate for the circuit-level simulation of ISFET.

A 640 × 640 ISFET array for detecting cell metabolism

Ion sensitive field effect transistor (ISFET) devices are highly accurate, convenient, fast and low-cost in the detection of ions and biological macromolecules, such as DNA molecules, antibodies, enzymatic substrates and cellular metabolites. For high-throughput cell metabolism detection, we successfully designed a very large-scale biomedical sensing application specific integrated circuit (ASIC) with a 640 × 640 ISFET array. The circuit design is highly integrated by compressing the size of a pixel to 7.4 × 7.4 μm2 and arranging the layout of even and odd columns in an interdigital pattern to maximize the utilization of space. The chip can operate at a speed of 2.083M pixels/s and the dynamic process of the fluid flow on the surface of the array was monitored through ion imaging. The pH sensitivity is 33 ± 4 mV/pH and the drift rate is 0.06 mV/min after 5 h, indicating the stability and robustness of the chip. Moreover, the chip was applied to monitor pH changes in CaSki cells metabolism, with pH shifting from 8.04 to 7.40 on average. This platform has the potential for continuous and parallel monitoring of cell metabolism in single-cell culture arrays.

ISFET Pixel Array With Selectable Sensitivity and Bulk-Based Offset-Drift Nullification Capability for Reduction of Non-Ideality Effects

This article presents a monolithic, cost-effective, label free, low power, robust <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$3\times2$ </tex-math></inline-formula> fully differential ion-sensitive field-effect transistor (ISFET) pixel array aimed at pH sensing. Each pixel is based on a differential readout architecture which eliminates need for additional non-ideality compensation circuitry. Additionally, the design offers the capability to correct for residual drift and trapped charge offset through substrate-based voltage adjustment during calibration. The design also provides a unique ability for selecting pH sensitivity according to the desired mode of operation which has not been demonstrated previously. We present experimental results obtained from the pixel array fabricated in an unmodified AMS <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$0.35~\mu \text{m}$ </tex-math></inline-formula> CMOS process using a 3.3 V power supply. Each pixel demonstrates a differential sensitivity of 61 mV/pH when operated in high sensitivity mode and 25 mV/pH when operated in high non-ideality rejection mode over the entire pH range, with the ability to remove the already small drift of 0.3 mV/min and any offset mismatch by adjusting the substrate voltage.

Dual Ion-Selective Membrane Deposited Ion-Sensitive Field-Effect Transistor Integrating a Whole Blood Processing Microchamber for In Situ Blood Ion Testing.

Blood ion testing is one of the methods that is commonly used for monitoring the immune status and providing physiological information for disease diagnosis. However, traditional blood ion sensing methods often require well-trained operators to process the whole blood sample and perform the measurements using bulky instruments, making real-time and continuous blood ion sensing at the bedside difficult. To address the above issues, we proposed a dual ion-selective membrane deposited ion-sensitive field-effect transistor (DISM-ISFET) sensor integrating a microchamber to enable on-chip serum extraction and in situ Na+/K+ ion sensing. As a proof of concept, we sequentially dispensed NaCl and KCl solutions at various concentrations on the DISM-ISFET to find out the highest ion sensitivity and selectivity. Next, we also confirm the high red blood cell sedimentation and serum purity using a microchamber. Finally, we evaluated the system performance using nine clinical whole blood samples and compared their Na+/K+ ion-sensing results with a commercial pocket ion meter. To sum up, our results showed that a DISM-ISFET system can successfully extract 200 μL serum from 500 μL whole blood sample and simultaneously achieve Na+/K+ ion sensing. All the sample processes and measurements can be finished within 10 min in a single chip. We envision this compact and easy-to-use system can be potentially used for various medical environments requiring real-time and continuous blood ion monitoring, such as in a hemodialysis room, operation room, and intensive care unit.

Electrical biosensing system utilizing ion-producing enzymes conjugated with aptamers for the sensing of severe acute respiratory syndrome coronavirus 2

Viral outbreaks, which include the ongoing coronavirus disease 2019 (COVID-19) pandemic provoked by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are a major global crisis that enormously threaten human health and social activities worldwide. Consequently, the rapid and repeated treatment and isolation of these viruses to control their spread are crucial to address the COVID-19 pandemic and future epidemics of novel emerging viruses. The application of cost-efficient, rapid, and easy-to-operate detection devices with miniaturized footprints as a substitute for the conventional optic-based polymerase chain reaction (PCR) and immunoassay tests is critical. In this context, semiconductor-based electrical biosensors are attractive sensing platforms for signal readout. Therefore, this study aimed to examine the electrical sensing of patient-derived SARS-CoV-2 samples by harnessing the activity of DNA aptamers directed against spike proteins on viral surfaces. We obtained rapid and sensitive virus detection beyond the Debye length limitation by exploiting aptamers coupled with alkaline phosphatases, which catalytically generate free hydrogen ions which can readily be measured on pH meters or ion-sensitive field-effect transistors. Furthermore, we demonstrated the detection of the viruses of approximately 100 copies/μL in 10 min, surpassing the capability of typical immunochromatographic assays. Therefore, our newly developed technology has great potential for point-of-care testing not only for SARS-CoV-2, but also for other types of pathogens and biomolecules.

The Integration of Reference Electrode for ISFET Ion Sensors Using Fluorothiophenol-Treated rGO

Ion-sensitive field-effect transistors (ISFETs) detect specific ions in solutions that enable straightforward, fast, and inexpensive sensors compared to other benchtop equipment. However, a conventional reference electrode (RE) such as Ag/AgCl is limited on the miniaturization of the sensor. We introduce reduced graphene oxide (rGO), which serves as a new RE, when fluorinated (F-rGO) using fluorothiophenol through the π-π interaction. The circular RE is integrated between a fabricated microscale two-channel ISFET, which is capable of detecting two kinds of ions on an indium tin oxide (ITO) thin-film substrate, using the photolithography process. F-rGO bound to this circular region to function as an RE in the ISFETs sensor, which operated stably in solution and showed a relatively high transconductance (gm) value (1.27 mS), low drift characteristic (3.2 mV), and low hysteresis voltage (±0.05 mV). It detected proton (H+) ions in a buffer solution with high sensitivity (67.1 mV/pH). We successfully detected Na+ (62.1 mV/dec) and K+ (57.6 mV/dec) ions in human patient urine using a two-channel ISFET with the F-rGO RE. The F-rGO RE will be a suitable component in the fabrication of low-cost, mass-produced, and disposable ISFETs sensors.

Fabrication of high-performance dual-gate ISFET pH sensors using In2O3 nano-channel

Here, a high-performance dual-gate ionsensitive field-effect transistor (ISFET) was designed for pH detection based on the high carrier mobility and chemical stability of In2O3. To optimize the structural parameters of the ISFET, the ISFET model with a dual-gate structure was constructed using the Silvaco TCAD. The effects of the channel layer and gate dielectric layer parameters on the performance of the ISFET model were investigated in the dual-gate structure. Following the optimal parameters of the simulation, the dual-gate ISFET chip was fabricated by microfabrication techniques. The pH sensitivity of the fabricated chip was 321.54 mV/pH and exhibited good stability with low drift and hysteresis voltage. In addition, we also tested the pH change caused by the hydrogen peroxide oxidation reaction under catalysis by horseradish peroxidase. The sensitivity was up to 103.28 µA/mM, verifying this high-performance ISFET can be used to detect pH changes of trace substances in the biosensing field.

Exploring the methods of salivary analysis in the diagnosis of Alzheimer's disease: A scoping review

Alzheimer's disease is a common type of dementia. It is a progressive neurodegenerative disease that starts with mild memory loss and may progress to loss of ability to convey a conversation and respond to the surrounding. Early detection can help in the management of this disease. In this review, we attempted to find the most accurate method for salivary biomarkers detection, which can aid in the early diagnosis of Alzheimer's disease. For this scoping review; PubMed, Scopus, and Google Scholar online databases were searched to find studies and articles that test the salivary biomarkers for the diagnosis of Alzheimer's disease. Eleven studies were eligible for our research. Ten were case–control, and one was a cohort study. Seven of the studies used the enzyme-linked immunosorbent assay (ELISA) method, five of which showed diagnostic potential. Two studies used Luminex assay and photomultiplier tube, showing similar results to ELISA. AbsoluteIDQ®p150 Kit and faster ultra-performance liquid chromatography-mass spectrometry analysis and pattern recognition techniques tested different metabolites with potential diagnostic significance. Furthermore, another study using an extended gate ion sensitive field effect transistor sensor related salivary trehalose sugar to Alzheimer's disease. Different reliable biomarkers were detected using ELISA kit and appear to be effective in disease detection. Further studies and clinical trials on a large scale are required to determine the most accurate method of detecting Alzheimer's disease.

Efficient modeling approach for simulating multi-physics responses of an ion-sensitive field-effect transistor using artificial neural networks

Efficient modeling approach for simulating multi-physics responses of an ion-sensitive field-effect transistor using artificial neural networks

Top-down integration of suspended N+/P/N+ silicon-nanowire-based ion-sensitive field effect transistors for pH analysis at the submicronic scale

A technological process was proposed in order to integrate fully silicon-nanowire-based field-effect nanodevices on a silicon-on-insulator (SOI) substrate. Thanks to a double reactive ion etching process of the SOI silicon upper layer as well as to a "SiO2 thermal oxidation growth / Al2O3 atomic layer deposition" gate process, silicon-nanowire-based field-effect transistors (SiNW-FET) and silicon-nanowire-based ion-sensitive field-effect transistors (SiNW-ISFET) were fabricated. Focuses were brought on (i) the integration of a suspended N+/P/N+ double-junction structure (gate length: ∼ 0.75 μm and ∼ 3.75 μm), (ii) the fabrication of a SiO2/Al2O3 all-around surrounding gate structure, (iii) the achievement of low nanowire sections (width: ∼ 150 nm, height: ∼ 200 nm), and (iv) the final adaptation to the liquid phase analysis thanks to SU8-based wafer-level packaging. According to the proposed process, SiNW-FET and SiNW-ISFET devices showed excellent electrical characteristics in terms of leakage resistance ROFF, subthreshold current slope and ION/IOFF maximal ratio. SiNW-ISFET devices were finally studied for the pH analysis at the submicronic scale (analysed volumes: ∼ 10 pL), evidencing standard potentiometric detection sensitivity (∼ 56 mV/pH), as well as excellent amperometric detection sensitivity (∼ 0.4 current decade per pH) in subthreshold regime.