Signal transduction interfaces for field-effect transistor-based biosensors.

Biosensors based on field-effect transistors (FETs) are suitable for use in miniaturized and cost-effective healthcare devices. Various semiconductive materials can be applied as FET channels for biosensing, including one- and two-dimensional materials. The signal transduction interface between the biosample and the channel of FETs plays a key role in translating electrochemical reactions into output signals, thereby capturing target ions or biomolecules. In this Review, distinctive signal transduction interfaces for FET biosensors are introduced, categorized as chemically synthesized, physically structured, and biologically induced interfaces. The Review highlights that these signal transduction interfaces are key in controlling biosensing parameters, such as specificity, selectivity, binding constant, limit of detection, signal-to-noise ratio, and biocompatibility.

Estimation of the Depletion Layer Thickness in Silicon Nanowire-Based Biosensors from Attomolar-Level Biomolecular Detection.

Silicon nanowire (SiNW) biosensors have attracted a lot of attention due to their superior sensitivity. Recently, the dependence of biomolecule detection sensitivity on the nanowire (NW) width, number, and doping density has been partially investigated. However, the primary reason for achieving ultrahigh sensitivity has not been elucidated thus far. In this study, we designed and fabricated SiNW biosensors with different widths (10.8-155 nm) by integrating a complementary metal-oxide-semiconductor process and electron beam lithography. We aimed to investigate the detection limit of SiNW biosensors and reveal the critical effect of the 10-nm-scaled SiNW width on the detection sensitivity. The sensing performance was evaluated by detecting antiovalbumin immunoglobulin G (IgG) with various concentrations (from 6 aM to 600 nM). The initial thickness of the depletion region of the SiNW and the changes in the depletion region due to biomolecule binding were calculated. The basis of this calculation are the resistance change ratios as functions of IgG concentrations using SiNWs with different widths. The calculation results reveal that the proportion of the depletion region over the entire SiNW channel is the essential reason for high-sensitivity detection. Therefore, this study is crucial for an indepth understanding on how to maximize the sensitivity of SiNW biosensors.

Effect of Surface Modification on the Fundamental Electrical Characteristics of Solution-Gated Indium Tin Oxide-Based Thin-Film Transistor Fabricated by One-Step Sputtering.

Our solution-gated indium tin oxide (ITO)-based thin-film transistor (TFT) produced by single-step sputtering has great future potential in bioelectronics. In particular, chemical modifications of the ITO channel surface are expected to contribute to biomolecular recognition with ultrahigh sensitivity owing to a remarkably steep subthreshold slope (SS). In this study, we investigate the effect of a chemical modification of an aptamer as a receptor molecule at the ITO channel surface on the electrical characteristics of the solution-gated TFT. In this case, a SARS-CoV-2 aptamer is immobilized using a spacer molecule on an aryl diazonium monolayer that is electrochemically deposited with a radical scavenger. The monolayer is expected to not only passivate the ITO channel surface but also change the electron density in the ITO channel owing to the reduction reaction of aryl diazonium salts. Indeed, the electrochemical deposition of aryl diazonium salts decreases the leakage current through the ITO channel surface and provides a steep SS, which is near the thermal limit at 300 K, owing to the decrease in depletion layer capacitance. After the aptamer immobilization, the leakage current and SS unexpectedly return close to their original values before the surface modifications. This finding indicates that aptamer molecules should be carefully used because their negative charges would attract cations around the detection interface. Eventually, the solution-gated ITO-based TFT with the SARS-CoV-2 aptamer clearly responds to inactivated SARS-CoV-2 particles owing to the successful surface modification.

Evaluation of glycated albumin levels in tears and saliva as a marker in patients with diabetes mellitus.

AIMS: Glycated albumin (GA) is a biomarker, whose level reflects glycemic control status over the previous 2 weeks. To develop a non-invasive method for evaluating glycemic control in people with diabetes mellitus, we investigated the measurement of GA levels in tears and saliva, which could be collected noninvasively. METHODS: Tear and saliva samples were collected from 48 participants with diabetes mellitus. The GA levels in the tear and saliva specimens were measured by Liquid Chromatography-Mass Spectrometry (LC-MS/MS). RESULTS: GA levels in both tear and saliva samples were significantly correlated with the GA levels in the blood (P < 0.001). Multiple regression analysis revealed that these correlations were maintained even after adjustments for the BMI, age, and nephropathy stage (P < 0.001). CONCLUSION: GA levels in tear and saliva specimens, as diabetes-related biomarkers, can be measured non-invasively. Since this measurement can be performed noninvasively and not as frequently as compared with the more invasive finger prick method, it is expected to reduce the burden on people with diabetes in terms of both the invasiveness and cost-effectiveness. In the future, we would like to verify the effect of regular GA measurement on the glycemic control while considering the clinical cost-effectiveness.

Aptamer-Based Glycated Albumin Sensor for Capacitive Spectroscopy.

Glycated albumin (GA) is a candidate for glycemic indicator to control prediabetes, the half-life of which is about 2 weeks, which is neither too long nor too short, considering that there is no longer any need for daily fingerstick sampling but glucose levels can be controlled in a relatively short term. Its usefulness as a glycemic indicator must be widely recognized by developing a simple and miniaturized GA sensor for point-of-care testing (POCT) devices. In this study, we propose an aptamer-based capacitive electrode for electrochemical capacitance spectroscopy (ECS) to specifically detect GA in an enzyme-/antibody-free manner. As a component of the bioelectrical interface between the sample solution and the electrode, a densely packed capacitive polyaryl film coated on a gold electrode contributes to the detection of GA by the ECS method. In addition, the GA aptamer tethered onto the polyaryl-film-coated gold electrode is useful for not only specifically capturing GA but also inducing changes in the concentration of cations released from the cation/GA aptamer complexes by GA/GA aptamer binding. Also, hydrophilic poly(ethylene glycol) (PEG) coated on the polyaryl film electrode in parallel with the GA aptamer prevents interfering proteins such as human serum albumin (HSA) and immunoglobulin G (IgG) from nonspecifically absorbing on the polyaryl film electrode. Such a GA aptamer-based capacitive electrode produces significant signals of GA against HSA and IgG with the change in GA concentration (0.1, 1, and 10 mg/mL) detected by the ECS method. This indicates that the ECS method contributes to the evaluation of the GA level, which is based on the rate of glycation of albumin. Thus, a platform based on ECS measurement using the aptamer-based capacitive electrode is useful for protein analysis in an enzyme-/antibody-free manner.

Development of a Redox-Label-Doped Molecularly Imprinted Polymer on ß-Cyclodextrin/Reduced Graphene Oxide for Electrochemical Detection of a Stress Biomarker.

Cortisol is a major stress biomarker involved in the regulation of metabolic and immune responses. Readily accessible assays with sufficient quantitative and temporal resolution can assist in prevention, early diagnosis, and management of chronic diseases. Whereas conventional assays are costly in terms of time, labor, and capital, an electrochemical approach offers the possibility of miniaturization and detection at the point-of-care. Here, we investigate the biosensor application of molecularly imprinted polypyrrole (PPy) doped with hexacyanoferrate (HCF) and coupled to reduced graphene oxide functionalized with ß-cyclodextrin (ß-CD). ß-CD provides an inclusion site for lipophilic cortisol and was electrochemically grafted simultaneous with reduction of GO. Next, PPy was electrochemically deposited in presence of cortisol template with HCF dopant ions serving as intrinsic redox probe. Thus, the sensor response was evaluated via changes of redox peak current in cyclic voltammetry and demonstrated a broad logarithmic detection range (5 pg/mL to 5000 ng/mL, R 2 = 0.995), with a sensitivity of 8.809 µA log-1 (ng/mL) cm-2 and LOD of 19.3 pM. The sensor was shown to be specific toward cortisol in reference to salivary cortisol concentration in saliva over structural analogues. The sensor was exhibited to determine cortisol in artificial saliva at normal and elevated levels. The good performance and facile electrochemical fabrication of this antibody- and external label-free interface are promising for the development of affordable point-of-care biosensors.

Surface Characteristics and Formation of Polyserotonin Thin Films for Bioelectrical and Biocompatible Interfaces.

In this study, we examined the fundamental surface characteristics of a polyserotonin (pST) film, which is attractive as a bioelectrical and biocompatible interface of biosensors. The pST film can easily be modified on electrode materials such as Au by self-polymerization and electropolymerization. By a simple cytotoxicity test using nonadhesive living cells, we found that the pST film is biocompatible for culturing cells on it. This finding is also supported by the fact that the surface tension of the pST film is moderate for protein adsorptions. The pST film is thinner and smoother than a poly-dopamine film, the chemical structure of which is similar to that of the pST film, depending on the polymerization time, cycle, and temperature; thus, ST as the main monomer can facilitate the precise control of the thickness and roughness of functional polymer membranes on the nanometer order. In addition, the pST film is useful as a relatively insulative interface for preventing interfering species from approaching electrode surfaces without their nonspecific adsorption, depending on the surface charges of the pST film in solutions of different pHs. The formation of the pST film self-polymerized on electrode materials is derived from the adsorption of pST nanoparticles formed by oxidative polymerization under basic conditions; therefore, the process of pST film formation should be considered in the functionalization of the pST film as a bioelectrical interface that allows biomolecular recognition (e.g., molecularly imprinted polymer membrane) for its application to wearable and biocompatible biosensors.

Technical Perspectives on Applications of Biologically Coupled Gate Field-Effect Transistors.

Biosensing technologies are required for point-of-care testing (POCT). We determine some physical parameters such as molecular charge and mass, redox potential, and reflective index for measuring biological phenomena. Among such technologies, biologically coupled gate field-effect transistor (Bio-FET) sensors are a promising candidate as a type of potentiometric biosensor for the POCT because they enable the direct detection of ionic and biomolecular charges in a miniaturized device. However, we need to reconsider some technical issues of Bio-FET sensors to expand their possible use for biosensing in the future. In this perspective, the technical issues of Bio-FET sensors are pointed out, focusing on the shielding effect, pH signals, and unique parameters of FETs for biosensing. Moreover, other attractive features of Bio-FET sensors are described in this perspective, such as the integration and the semiconductive materials used for the Bio-FET sensors.

Direct Electrochemical Signaling in Organic Electrochemical Transistors Comprising High-Conductivity Double-Network Hydrogels.

In composite hydrogels, the high electrical performance of poly(3,4-ethylenedioxythiophene) complexed with poly(styrenesulfonate) (PEDOT:PSS) is integrated with complementary structural and electrochemical functions via a rationally designed poly(acrylamide) second network incorporating phenylboronic acid (PBA). Free-standing double-network hydrogels prepared by a simple one-pot radical polymerization exhibit state-of-the-art electrical conductivity (∼20 S cm-1 in phosphate buffered saline) while retaining a degree of hydration similar to that of biological soft tissues. Low resistance contacts to Au electrodes are formed via facile thermo-mechanical annealing and demonstrate stability over a month of continuous immersion, thus enabling hydrogels to serve as channels of organic electrochemical transistors (OECTs). Despite thicknesses of ∼100 µm, gating of hydrogel OECTs is efficient with transconductances gm ∼ 40 mS and on/off ratios of 103 in saturation mode operation, whereas sufficiently high conductivity enables linear mode operation (gm ∼ 1 mS at -10 mV drain bias). This drives a shift of sensing strategy toward detection of electrochemical signals originating within the bulky channel. A kinetic basis for glucose detection via diol esterification on PBA is identified as the coupling of PBA equilibrium to electrocatalyzed O2 reduction occurring on PEDOT in cathodic potentials. Hydrogel OECTs inherently amplify this direct electrochemical signal, demonstrating the viability of a new class of soft, structural biosensors.

Free-standing conductive hydrogel electrode for potentiometric glucose sensing.

Flexible conductive polymer hydrogels are attracting attention as an electrode material. Electrochemical biosensors with conductive polymer hydrogels have been developed because they have some advantages such as biocompatibility, high conductivity, 3D nanostructure, solvated surface, and enlarged interface. Conductive polymer hydrogels bearing receptor molecules such as enzymes in its 3D nanostructure enable the detection of target analytes with high sensitivity. However, because such hydrogels are fragile, they cannot stand on their own and a supporting substrate is required to fabricate them. This means that the loss of mechanical toughness is detrimental for their application to flexible biosensors. In this study, we have proposed a free-standing conductive hydrogel electrode with no coating on a substrate, which is composed of polyaniline with phenyl boronic acid including polyvinyl alcohol, for potentiometric glucose sensing. In addition, its electrical responsivity to glucose has been confirmed by investigating its mechanical properties at various glucose concentrations, considering the hydrogel compositions.

Hydrogel-Coated Gate Field-Effect Transistor for Real-Time and Label-Free Monitoring of ß-Amyloid Aggregation and Its Inhibition.

In this paper, we propose a hydrogel-coated gate field-effect transistor (FET) for the real-time and label-free monitoring of ß-amyloid (Aß) aggregation and its inhibition. The hydrogel used in this study is composed of poly tetramethoxysilane (TMOS), in which Aß monomers are entrapped and then aggregate, and coated on the gate insulator; that is, Aß aggregation is induced in the vicinity of the sensing surface. With the Aß hydrogel-coated gate FET, the steplike decrease in the surface potential of the Aß hydrogel-coated gate electrode is electrically monitored in real time, according to the stepwise aggregation of Aß monomers to form into fibrils through oligomers and so forth in stages. This is because the capacitance of the Aß-hydrogel membrane decreases depending on the stage of aggregation; that is, the hydrophobicity of the Aß-hydrogel membrane increases stepwise depending on the amount of Aß aggregates. The formation of Aß fibrils is also confirmed in the measurement solution using a fluorescent dye, thioflavin T, which selectively binds to the Aß fibrils. Moreover, the addition of daunomycin, an inhibitor of Aß aggregation, to the measurement solution suppresses the stepwise electrical response of the Aß hydrogel-coated gate FET. Thus, a platform based on the Aß hydrogel-coated gate FET is suitable for a simple screening system for inhibitors of Aß aggregation, which may lead the identification of potential therapeutic agents for Alzheimer's disease.

Self-oscillating chemoelectrical interface of solution-gated ion-sensitive field-effect transistor based on Belousov-Zhabotinsky 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.

In Situ Electrical Monitoring of Methylated DNA Based on Its Conformational Change to G-Quadruplex Using a Solution-Gated Field-Effect Transistor.

Methylated DNA is not only a diagnostic but also a prognostic biomarker for early-stage cancer. However, sodium bisulfite sequencing as a "gold standard" method for detection of methylation markers has some drawbacks such as its time-consuming and labor-intensive procedures. Therefore, simple and reliable methods are required to analyze DNA sequences with or without methylated residues. Herein, we propose a simple and direct method for detecting DNA methylation through its conformation transition to G-quadruplex using a solution-gated field-effect transistor (SG-FET) without using labeled materials. The BCL-2 gene, which is involved in the development of various human tumors, contains G-rich segments and undergoes a conformational change to G-quadruplex depending on the K+ concentration. Stacked G-quadruplex strands move close to the SG-FET sensor surface, resulting in large electrical signals based on intrinsic molecular charges. In addition, a dense hydrophilic polymer brush is grafted using surface-initiated atom transfer radical polymerization onto the SG-FET sensor surface to reduce electrical noise based on nonspecific adsorption of interfering species. In particular, control of the polymer brush thickness induces electrical signals based on DNA molecular charges in the diffusion layer, according to the Debye length limit. A platform based on the SG-FET sensor with a well-defined polymer brush is suitable for in situ monitoring of methylated DNA and realizes a point-of-care device with a high signal-to-noise ratio and without the requirement for additional processes such as bisulfite conversion and polymerase chain reaction.

Densification of Diazonium-Based Organic Thin Film as Bioelectrical Interface.

Aryl diazonium chemistry generates a covalently attached thin film on various materials. This chemistry has diverse applications owing to the stability, ease of functionalization, and versatility of the film. However, the uncontrolled growth into a polyaryl film has limited the controllability of the film's beneficial properties. In this study, we developed a multistep grafting protocol to densify the film while maintaining a thickness on the order of nanometers. This simple protocol enabled the full passivation of a nitrophenyl polyaryl film, completely eliminating the electrochemical reactions at the surface. We then applied this protocol to the grafting of phenylphosphorylcholine films, with which the densification significantly enhanced the antifouling property of the film. Together with its potential to precisely control the density of functionalized surfaces, we believe this grafting procedure will have applications in the development of bioelectrical interfaces.

Solution-Gated Ultrathin Channel Indium Tin Oxide-Based Field-Effect Transistor Fabricated by a One-Step Procedure that Enables High-Performance Ion Sensing and Biosensing.

In this paper, we propose a one-step procedure for fabricating a solution-gated ultrathin channel indium tin oxide (ITO)-based field-effect transistor (FET) biosensor, thus providing an ″all-by-ITO″ technology. A thin-film sheet was placed on both ends of a metal shadow mask, which were contacted with a glass substrate. That is, the bottom of the metal shadow mask corresponding to the channel was slightly raised from the substrate, resulting in the creeping of some particles into the gap during sputtering. Owing to this modified metal shadow mask, a thin ITO channel (<30-40 nm) and thick ITO source/drain electrodes (ca. 100 nm) were simultaneously fabricated during the one-step sputtering. The thickness of ITO films was critical for them to be semiconductive, depending on the maximum depletion width (∼30-40 nm for the ITO channel), similarly to 2D materials. The ultrathin ITO channel worked as an ion-sensitive membrane as well owing to the intrinsic oxidated surface directly contacting with an electrolyte solution. The solution-gated 20-nm-thick channel ITO-based FET, with a steep subthreshold slope (SS) of 55 mV/dec (pH 7.41) attributable to the electric double-layer capacitance at the electrolyte solution/channel interface and the absence of interfacial traps among electrodes formed in one step, demonstrated an ideal pH responsivity (∼56 mV/pH), resulting in the real-time monitoring of cellular respiration and the long-term stability of electrical properties for 1 month. Moreover, the chemical modification of the ITO channel surface is expected to contribute to biomolecular recognition with ultrahigh sensitivity owing to the remarkably steep SS, which provided the exponential pH sensitivity in the subthreshold regime. Our new device produced in this one-step manner has a great future potential in bioelectronics.

Cell Adhesion Characteristics on Tantalum Pentoxide Gate Insulator for Cultured-Cell-Gate Field-Effect Transistor.

Understanding the interaction between living cells and a tantalum pentoxide (Ta2O5) gate electrode is important for controlling cell adhesion and functions when developing a cultured-cell-gate field-effect transistor biosensor. In this study, we evaluate the cell adhesion characteristics of the Ta2O5 membrane without or with a polydopamine (pDA) coating for chondrocytes, which is expected as a treatment for improving biocompatibility. As a result, the native and pDA-modified Ta2O5 membranes are shown to have the appropriate surface tension (35-40 dyn/cm) for the adhesion of chondrocytes owing to the contribution of surface tension to not only the nonspecific adsorption of serum proteins as the scaffold of chondrocytes but also the maintenance of the conformation of serum proteins. In particular, the serum proteins adhere more efficiently to the native Ta2O5 membrane than to the pDA-modified ones owing to the relatively smaller surface tension of the native Ta2O5 membrane; as a result, the proliferation and production of extracellular matrix (ECM) proteins such as collagen and proteoglycans by chondrocytes are clearly enhanced on the native Ta2O5 membrane. Thus, the native Ta2O5 membrane shows superior performance for the chondrocyte culture on it compared with the pDA-modified ones.

Association between tear and blood glucose concentrations: Random intercept model adjusted with confounders in tear samples negative for occult blood.

AIMS/INTRODUCTION: To prevent diabetic complications, strict glucose control and frequent monitoring of blood glucose levels with invasive methods are necessary. We considered the monitoring of tear glucose levels might be a possible method for non-invasive glucose monitoring. To develop tear glucose monitoring for clinical application, we investigated the precise correlation between the blood and tear glucose concentrations. MATERIALS AND METHODS: A total of 10 participants and 20 participants with diabetes were admitted, and blood and tear samples were collected. Before statistical analysis, we eliminated tear samples contaminated with blood. We observed the daily blood and tear glucose dynamics, and carried out a random intercept model analysis to examine the association between the blood and tear glucose concentrations. RESULTS: Tear occult blood tests showed that the tear glucose concentrations and their variation increased in both participants with and without diabetes as contamination of blood increased. In both participants with and without diabetes, fluctuations of the plasma glucose concentrations were observed depending on the timing of collection of the samples, and the dynamics of the tear glucose concentrations paralleled those of the plasma glucose concentrations. The random intercept model analysis showed a significant association between the plasma and tear glucose concentrations in participants with diabetes (P < 0.001). This association still existed even after adjusting for the glycated hemoglobin levels and the prandial state (P < 0.001). CONCLUSIONS: It is important to eliminate the tear samples contaminated with blood. Tear glucose monitoring might be a reliable and non-invasive substitute method for monitoring the blood glucose concentrations for diabetes patients, irrespective of glycated hemoglobin levels and timing of sample collection.

Design and Fabrication of Silicon Nanowire-Based Biosensors with Integration of Critical Factors: Toward Ultrasensitive Specific Detection of Biomolecules.

As critical factors affecting the sensing performance of silicon nanowire (SiNW) biosensors, the structure, functional interface, and detection target were analyzed and designed to improve sensing performance. For an improved understanding of the dependence of sensor structure on sensitivity, a simple theoretical analysis was proposed to predict the sensitivity of biosensors with different SiNW types, widths, and doping concentrations. Based on the theoretical analysis, a biosensor integrating optimized critical factors was designed and fabricated. Optimizations focusing on the following aspects are considered: (1) employing n-type SiNW and controlling the impurity doping concentration of SiNW at approximately 2 × 1016-6 × 1016 atoms/cm3 to obtain a suitable charge density, (2) minimizing the SiNW width to 16.0 nm to increase the surface area-to-volume ratio, (3) using a native oxide layer on SiNW as a gate insulator to transport the captured charge molecules closer to the SiNW surface, (4) modifying the SiNW surface by 2-aminoethylphosphonic acid coupling to form a high-density self-assembled monolayer for enhancing the stability bound molecules, and (5) functionalizing the SiNW with ovalbumin molecules for specifically capturing the target immunoglobulin G (IgG) molecules. The sensing performance was evaluated by detecting IgG with concentrations ranging from 6 aM to 600 nM and control experiments. The SiNW biosensor revealed ultrahigh sensitivity and specific detection of target IgG with a measured limit of detection of 6 aM. The integration of the critical SiNW biosensor factors provides a significant possibility of a rapid and ultrasensitive diagnosis of diseases at their early stages.

Biocompatible and flexible paper-based metal electrode for potentiometric wearable wireless biosensing.

A paper-based electrode is a very attractive component for a disposable, nontoxic, and flexible biosensor. In particular, wearable biosensors, which have recently been attracting interest, not only require these characteristics of paper-based electrodes but must also be able to detect various ions and biomolecules in biological fluids. In this paper, we demonstrate the detection ability of paper-based metal electrodes for wearable biosensors as part of a wireless potentiometric measurement system, focusing on the detection of pH and sodium ions. The paper-based metal electrodes were obtained by simply coating a silicone-rubber-coated paper sheet with a Au (/Cr) thin film by sputtering then modifying it with different functional membranes such as an oxide membrane (Ta2O5) and a fluoropolysilicone (FPS)-based Na+-sensitive membrane, corresponding to the targeted ions. Satisfactory and stable detection sensitivities of the modified paper-based Au electrodes were obtained over several weeks even when they were bent to a radius of curvature in the range of 6.5 to 25 mm, assuming use in a flexible body patch biosensor. Moreover, the Na+ concentration in a sweat sample was evaluated using the paper-based Au electrode with the FPS-based Na+-sensitive membrane in a wireless and real-time manner while the electrode was bent. Thus, owing to their complex mesh structure, flexible paper sheets should be suitable for use as potentiometric electrodes for wearable wireless biosensors.

Enhancement of Signal-to-Noise Ratio for Serotonin Detection with Well-Designed Nanofilter-Coated Potentiometric Electrochemical Biosensor.

In this paper, we proposed to enhance a signal-to-noise (S/N) ratio for detecting a primary stress marker, serotonin, using a potentiometric biosensor modified by a well-designed nanofilter film. An extended-Au-gate field-effect transistor (EG-Au-gate FET) biosensor exhibits highly sensitive electrochemical detection toward various small biomolecules, including serotonin. Therefore, to enhance the S/N ratio for the serotonin detection, we designed an appropriate nanofilter film on the Au electrode by combining the aryldiazonium salt reduction strategy and boronate affinity. That is, only serotonin can approach the Au sensing surface to generate an electrical signal; interfering biomolecules are prevented from penetrating through the nanofilter, either because large interfering biomolecules cannot permeate through the highly dense, nanoporous multilayer film, or because phenylboronic acids included in the nanofilter captures small interfering biomolecules (e.g., catecholamines). The potentiometric biosensor modified by such a nanofilter film detected serotonin in a model sample solution containing catecholamines, cortisol, and human serum albumin with a high S/N ratio for the serotonin levels in the blood. Furthermore, we found that the effect of the nanofilter directly reflects the binding affinity of the receptors such as phenylboronic acids included in the nanofilter; thus, the selectivity and dynamic range of small target biomolecules can be tuned freely by designing the appropriate receptors for the nanofilter. The results show that a well-designed nanofilter biointerface can be a versatile biosensing platform for point-of-care testing, particularly for a simple stress check.