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Single-molecule detection at a nanometric interface in a femtomolar solution, can take weeks as the encounter rate between the diffusing molecule to be detected and the transducing nanodevice is negligibly small. On the other hand, several experiments prove that macroscopic label-free sensors based on field-effect-transistors, engaging micrometric or millimetric detecting interfaces are capable to assay a single-molecule in a large volume within few minutes. The present work demonstrates why at least a single molecule out of a few diffusing in a 100 µL volume has a high probability to hit a large capturing and detecting electronic interface. To this end, sensing data, measured with an electrolyte-gated FET whose gate is functionalized with 10 12 capturing anti-immunoglobulin G, are here provided along with a Brownian diffusion-based modeling. The EG-FET assays solutions down to some tens of zM in concentrations with volumes ranging from 25 µL to 1 mL in which the functionalized gates are incubated for times ranging from 30 s to 20 min. The high level of accordance between the experimental data and a model based on the Einstein's diffusion-theory proves how the single-molecule detection process at large-capturing interfaces is controlled by Brownian diffusion and yet is highly probable and fast., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Bioelectronic transducing surfaces that are nanometric in size have been the main route to detect single molecules. Though enabling the study of rarer events, such methodologies are not suited to assay at concentrations below the nanomolar level. Bioelectronic field-effect-transistors with a wide (μm 2 -mm 2 ) transducing interface are also assumed to be not suited, because the molecule to be detected is orders of magnitude smaller than the transducing surface. Indeed, it is like seeing changes on the surface of a one-kilometer-wide pond when a droplet of water falls on it. However, it is a fact that a number of large-area transistors have been shown to detect at a limit of detection lower than femtomolar; they are also fast and hence innately suitable for point-of-care applications. This review critically discusses key elements, such as sensing materials, FET-structures, and target molecules that can be selectively assayed. The amplification effects enabling extremely sensitive large-area bioelectronic sensing are also addressed.

The increasing interest in technologies capable of tracking a biomarker down to the physical limit points toward new opportunities in early diagnostics of progressive diseases. Indeed, single-molecule detection technologies are foreseen to enable clinicians to associate the tiniest increase in a biomarker with the progression of a disease, particularly at its early stage. Bioelectronic organic transistors represent an extremely powerful tool to achieve label-free and single-molecule detection of clinically relevant biomarkers. These electronic devices are millimetric in size and in the future could be mass-produced at low cost. The core of the single molecule with a large transistor (SiMoT) platform, based on an electrolyte-gated field-effect transistor, is a gold gate electrode biofunctionalized with a self-assembled monolayer, a densely packed layer of recognition elements. So far, only the SiMoT detection of proteins, using the corresponding antibodies as recognition elements, has been reported. In this study, the SiMoT sensing response toward genomic biomarkers is proposed. Herein, the gate is functionalized with a genomic biomarker for multiple sclerosis (miR-182). This is relevant, not only because a limit of detection of a single molecule is achieved but also because it proves that the SiMoT label-free, single-molecule detection principle is the only one of its kind that can detect, by means of the same platform, both protein and genomic markers.

Early diagnosis of the infection caused by human immunodeficiency virus type-1 (HIV-1) is vital to achieve efficient therapeutic treatment and limit the disease spreading when the viremia is at its highest level. To this end, a point-of-care HIV-1 detection carried out with label-free, low-cost, and ultra-sensitive screening technologies would be of great relevance. Herein, a label-free single molecule detection of HIV-1 p24 capsid protein with a large (wide-field) single-molecule transistor (SiMoT) sensor is proposed. The system is based on an electrolyte-gated field-effect transistor whose gate is bio-functionalized with the antibody against the HIV-1 p24 capsid protein. The device exhibits a limit of detection of a single protein and a limit of quantification in the 10 molecule range. This study paves the way for a low-cost technology that can quantify, with single-molecule precision, the transition of a biological organism from being "healthy" to being "diseased" by tracking a target biomarker. This can open to the possibility of performing the earliest possible diagnosis.

There is an increasing interest for low cost, ultrasensitive, time saving yet reliable, point-of-care bioelectronic sensors. Electrolyte gated organic field effect transistors (EGOFETs) are proven compelling transducers for various sensing applications, offering direct electronic, label-free transduction of bio-recognition events along with miniaturization, fast data handling and processing. Given that field effect transistors act as intrinsically signal amplifiers, even a small change of a chemical or biological quantity may significantly alter the output electronic signal. In EGOFETs selectivity can be guaranteed by the immobilization of bioreceptors able to bind specifically a target analyte. The layer of receptors can be linked to one of the electronic active interfaces of the transistor, and the interactions with a target molecule affect the electronic properties of the device. The present chapter discusses main aspects of EGOFETs transducers along with detailed examples of how to tailor the device interfaces with desired functionality. The development of an "electronic tongue" based on an EGOFET device coupled to odorant binding proteins (OBPs) for enantiomers differentiation is presented., (© 2020 Elsevier Inc. All rights reserved.)

In the last decade, saliva has been suggested as non-invasive diagnostic fluid, suitable for clinical use alternatively to blood serum and plasma. However, the clinical applicability of saliva has been hampered so far by the inadequate sensitivity of current methods to detect the lower salivary concentrations of many biomarkers monitored in blood products. Herein, a label-free biosensor based on electrolyte-gated organic thin-film transistor (EGOTFT) has been developed for the detection at the physical limit of C-reactive protein (CRP) in human saliva. CRP is a key relevant biomarker for inflammatory processes and is routinely monitored for many clinical purposes. Herein, an electrolyte-gated thin-film transistor (EGOTFT) has been proposed as a transducer of the biorecognition event taking place at the gate electrode, functionalized with a self-assembled monolayer (SAM) of highly densely packed capturing anti-CRP proteins. Thanks to the SAM, the biosensing platform herein proposed is endowed with ultra-high sensitivity, along with an extremely high selectivity, assessed by measuring the dose curves of CRP interacting with a bovine serum albumin-functionalized gate. Moreover, the biosensing platform is compatible with low-cost fabrication techniques and applicable to the ultra-sensitive detection of a plethora of clinically relevant biomarkers. Therefore, the EGOTFT device herein proposed, being able to operate in physiologically relevant fluids such as saliva, will set the ground to a major revolution in biosensing applications for early clinical detection.

Label-free single-molecule detection has been achieved so far by funnelling a large number of ligands into a sequence of single-binding events with few recognition elements host on nanometric transducers. Such approaches are inherently unable to sense a cue in a bulk milieu. Conceptualizing cells' ability to sense at the physical limit by means of highly-packed recognition elements, a millimetric sized field-effect-transistor is used to detect a single molecule. To this end, the gate is bio-functionalized with a self-assembled-monolayer of 10 12 capturing anti-Immunoglobulin-G and is endowed with a hydrogen-bonding network enabling cooperative interactions. The selective and label-free single molecule IgG detection is strikingly demonstrated in diluted saliva while 15 IgGs are assayed in whole serum. The suggested sensing mechanism, triggered by the affinity binding event, involves a work-function change that is assumed to propagate in the gating-field through the electrostatic hydrogen-bonding network. The proposed immunoassay platform is general and can revolutionize the current approach to protein detection.

This review aims to provide an update on the development involving dielectric/organic semiconductor (OSC) interfaces for the realization of biofunctional organic field-effect transistors (OFETs). Specific focus is given on biointerfaces and recent technological approaches where biological materials serve as interlayers in back-gated OFETs for biosensing applications. Initially, to better understand the effects produced by the presence of biomolecules deposited at the dielectric/OSC interfacial region, the tuning of the dielectric surface properties by means of self-assembled monolayers is discussed. Afterward, emphasis is given to the modification of solid-state dielectric surfaces, in particular inorganic dielectrics, with biological molecules such as peptides and proteins. Special attention is paid on how the presence of an interlayer of biomolecules and bioreceptors underneath the OSC impacts on the charge transport and sensing performance of the device. Moreover, naturally occurring materials, such as carbohydrates and DNA, used directly as bulk gating materials in OFETs are reviewed. The role of metal contact/OSC interface in the overall performance of OFET-based sensors is also discussed., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Thin-film transistors can be used as high-performance bioelectronic devices to accomplish tasks such as sensing or controlling the release of biological species as well as transducing the electrical activity of cells or even organs, such as the brain. Organic, graphene, or zinc oxide are used as convenient printable semiconducting layers and can lead to high-performance low-cost bioelectronic sensing devices that are potentially very useful for point-of-care applications. Among others, electrolyte-gated transistors are of interest as they can be operated as capacitance-modulated devices, because of the high capacitance of their charge double layers. Specifically, it is the capacitance of the biolayer, being lowest in a series of capacitors, which controls the output current of the device. Such an occurrence allows for extremely high sensitivity towards very weak interactions. All the aspects governing these processes are reviewed here., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Electrolyte-gated organic field-effect transistors are successfully used as biosensors to detect binding events occurring at distances from the transistor electronic channel that are much larger than the Debye length in highly concentrated solutions. The sensing mechanism is mainly capacitive and is due to the formation of Donnan's equilibria within the protein layer, leading to an extra capacitance (CDON) in series to the gating system., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Bottom- and top-contact organic thin film transistors (OTFTs) were fabricated, using poly(3-hexylthiophene-2,5-diyl) (P3HT) and poly[2,5-bis(3-tetradecylthiophen-2-yl)thieno[3,2-b]thiophene] (PBTTT-C16) as p-type channel semiconductors. Four different types of OTFTs were fabricated and investigated as gas sensors against three volatile organic compounds, with different associated dipole moments. The OTFT-based sensor responses were evaluated with static and transient current measurements. A comparison between the different architectures and the relative organic semiconductor was made.

An organic field-effect transistor (OFET) integrating bacteriorhodopsin (bR) nanoassembled lamellae is proposed for an in-depth study of the proton translocation processes occurring as the bioelectronic device is exposed either to light or to low concentrations of general anesthetic vapors. The study involves the morphological, structural, electrical, and spectroscopic characterizations necessary to assess the functional properties of the device as well as the bR biological activity once integrated into the functional biointerlayer (FBI)-OFET structure. The electronic transduction of the protons phototranslocation is shown as a current increase in the p-type channel only when the device is irradiated with photons known to trigger the bR photocycle, while Raman spectroscopy reveals an associated C═C isomer switch. Notably, higher energy photons bring the cis isomer back to its trans form, switching the proton pumping process off. The investigation is extended also to the study of a PM FBI-OFET exposed to volatile general anesthetics such as halothane. In this case an electronic current increase is seen upon exposure to low, clinically relevant, concentrations of anesthetics, while no evidence of isomer-switching is observed. The study of the direct electronic detection of the two different externally triggered proton translocation effects allows gathering insights into the underpinning of different bR molecular switching processes.

Among the metal oxide semiconductors, ZnO has been widely investigated as a channel material in thin-film transistors (TFTs) due to its excellent electrical properties, optical transparency and simple fabrication via solution-processed techniques. Herein, we report a solution-processable ZnO-based thin-film transistor gated through a liquid electrolyte with an ionic strength comparable to that of a physiological fluid. The surface morphology and chemical composition of the ZnO films upon exposure to water and phosphate-buffered saline (PBS) are discussed in terms of the operation stability and electrical performance of the ZnO TFT devices. The improved device characteristics upon exposure to PBS are associated with the enhancement of the oxygen vacancies in the ZnO lattice due to Na(+) doping. Moreover, the dissolution kinetics of the ZnO thin film in a liquid electrolyte opens the possible applicability of these devices as an active element in "transient" implantable systems.

Anchored, biotinylated phospholipids forming the capturing layers in an electrolyte-gated organic field-effect transistor (EGOFET) allow label-free electronic specific detection at a concentration level of 10 nM in a high ionic strength solution. The sensing mechanism is based on a clear capacitive effect across the PL layers involving the charges of the target molecules., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The detailed action mechanism of volatile general anesthetics is still unknown despite their effect has been clinically exploited for more than a century. Long ago it was also assessed that the potency of an anesthetic molecule well correlates with its lipophilicity and phospholipids were eventually identified as mediators. As yet, the direct effect of volatile anesthetics at physiological relevant concentrations on membranes is still under scrutiny. Organic field-effect transistors (OFETs) integrating a phospholipid (PL) functional bio inter-layer (FBI) are here proposed for the electronic detection of archetypal volatile anesthetic molecules such as diethyl ether and halothane. This technology allows to directly interface a PL layer to an electronic transistor channel, and directly probe subtle changes occurring in the bio-layer. Repeatable responses of PL FBI-OFET to anesthetics are produced in a concentration range that reaches few percent, namely the clinically relevant regime. The PL FBI-OFET is also shown to deliver a comparably weaker response to a non-anesthetic volatile molecule such as acetone., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Most of the success of electronic devices fabricated to actively interact with a biological environment relies on the proper choice of materials and efficient engineering of surfaces and interfaces. Organic materials have proved to be among the best candidates for this aim owing to many properties, such as the synthesis tunability, processing, softness and self-assembling ability, which allow them to form surfaces that are compatible with biological tissues. This review reports some research results obtained in the development of devices which exploit organic materials' properties in order to detect biologically significant molecules as well as to trigger/capture signals from the biological environment. Among the many investigated sensing devices, organic field-effect transistors (OFETs), organic electrochemical transistors (OECTs) and microcantilevers (MCLs) have been chosen. The main factors motivating this choice are their label-free detection approach, which is particularly important when addressing complex biological processes, as well as the possibility to integrate them in an electronic circuit. Particular attention is paid to the design and realization of biocompatible surfaces which can be employed in the recognition of pertinent molecules as well as to the research of new materials, both natural and inspired by nature, as a first approach to environmentally friendly electronics.

The effects of the exposure of organic thin-film transistors, comprising different organic semiconductors and gate dielectrics, to 1-pentanol are investigated. The transistor sensors exhibited an increase or a decrease of the transient source-drain current in the presence of the analyte, most likely as a result of a trapping or of a doping process of the organic active layer. The occurrence of these two effects, that can also coexist, depend on the gate-dielectric/organic semiconductor interface and on the applied gate field. Evidence of a systematic and sizable response enhancement for an OTFT sensor operated in the enhanced mode is also presented.