Floating Gate, Organic Field-Effect Transistor-Based Sensors towards Biomedical Applications Fabricated with Large-Area Processes over Flexible Substrates.

Organic Field-Effect Transistors (OFETs) are attracting a rising interest for the development of novel kinds of sensing platforms. In this paper, we report about a peculiar sensor device structure, namely Organic Charge-Modulated Field-Effect Transistor (OCMFET), capable of operating at low voltages and entirely fabricated with large-area techniques, i.e., inkjet printing and chemical vapor deposition, that can be easily upscaled to an industrial size. Device fabrication is described, and statistical characterization of the basic electronic parameters is reported. As an effective benchmark for the application of large-area fabricated OCMFET to the biomedical field, its combination with pyroelectric materials and compressible capacitors is discussed, in order to employ the proposed device as a temperature pressure sensor. The obtained sensors are capable to operate in conditions which are relevant in the biomedical field (temperature in the range of 18.5-50 °C, pressure in the range of 10²-10³ Pa) with reproducible and valuable performances, opening the way for the fabrication of low-cost, flexible sensing platforms.

Electronic Detection of DNA Hybridization by Coupling Organic Field-Effect Transistor-Based Sensors and Hairpin-Shaped Probes.

In this paper, the electronic transduction of DNA hybridization is presented by coupling organic charge-modulated field-effect transistors (OCMFETs) and hairpin-shaped probes. These probes have shown interesting properties in terms of sensitivity and selectivity in other kinds of assays, in the form of molecular beacons (MBs). Their integration with organic-transistor based sensors, never explored before, paves the way to a new class of low-cost, easy-to-use, and portable genetic sensors with enhanced performances. Thanks to the peculiar characteristics of the employed sensor, measurements can be performed at relatively high ionic strengths, thus optimizing the probes' functionality without affecting the detection ability of the device. A complete electrical characterization of the sensor is reported, including calibration with different target concentrations in the measurement environment and selectivity evaluation. In particular, DNA hybridization detection for target concentration as low as 100 pM is demonstrated.

Pressure Mapping Mat for Tele-Home Care Applications.

In this paper we present the development of a mat-like pressure mapping system based on a single layer textile sensor and intended to be used in home environments for monitoring the physical condition of persons with limited mobility. The sensor is fabricated by embroidering silver-coated yarns on a light cotton fabric and creating pressure-sensitive resistive elements by stamping the conductive polymer poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) ( PEDOT: PSS) at the crossing points of conductive stitches. A battery-operated mat prototype was developed and includes the scanning circuitry and a wireless communication module. A functional description of the system is presented together with a preliminary experimental evaluation of the mat prototype in the extraction of plantar pressure parameters.

Characterization of Screen-Printed Organic Electrochemical Transistors to Detect Cations of Different Sizes.

A novel screen-printing fabrication method was used to prepare organic electrochemical transistors (OECTs) based on poly(3,4-ethylenedioxythiophene) doped with polysterene sulfonate (PEDOT:PSS). Initially, three types of these screen-printed OECTs with a different channel and gate areas ratio were compared in terms of output characteristics, transfer characteristics, and current modulation in a phosphate buffered saline (PBS) solution. Results confirm that transistors with a gate electrode larger than the channel exhibit higher modulation. OECTs with this geometry were therefore chosen to investigate their ion-sensitive properties in aqueous solutions of cations of different sizes (sodium and rhodamine B). The effect of the gate electrode was additionally studied by comparing these all-PEDOT:PSS transistors with OECTs with the same geometry but with a non-polarizable metal gate (Ag). The operation of the all-PEDOT:PSS OECTs yields a response that is not dependent on a Na⁺ or rhodamine concentration. The weak modulation of these transistors can be explained assuming that PEDOT:PSS behaves like a supercapacitor. In contrast, the operation of Ag-Gate OECTs yields a response that is dependent on ion concentration due to the redox reaction taking place at the gate electrode with Cl- counter-ions. This indicates that, for cation detection, the response is maximized in OECTs with non-polarizable gate electrodes.

Turning an organic semiconductor into a low-resistance material by ion implantation.

We report on the effects of low energy ion implantation on thin films of pentacene, carried out to investigate the efficacy of this process in the fabrication of organic electronic devices. Two different ions, Ne and N, have been implanted and compared, to assess the effects of different reactivity within the hydrocarbon matrix. Strong modification of the electrical conductivity, stable in time, is observed following ion implantation. This effect is significantly larger for N implants (up to six orders of magnitude), which are shown to introduce stable charged species within the hydrocarbon matrix, not only damage as is the case for Ne implants. Fully operational pentacene thin film transistors have also been implanted and we show how a controlled N ion implantation process can induce stable modifications in the threshold voltage, without affecting the device performance.

Multimodal force and temperature tactile sensor based on a short-channel organic transistor with high sensitivity.

In this manuscript, we report on a novel architecture for the fabrication of highly sensitive multimodal tactile transducers, for the simultaneous detection of temperature and force. Such devices are based on a flexible Organic Charge Modulated Field Effect Transistor (OCMFET) coupled with a pyro/piezoelectric element, namely a commercial film of poly-vinylene difluoride (PVDF). The reduction of the channel length, obtained by employing a low-resolution vertical channel architecture, allowed to maximize the ratio between the sensing area and the transistor's channel area, a technological approach that allows to considerably enhance both temperature and force sensitivity, while at the same time minimize the sensor's dimensions. Thanks to the employment of a straightforward, up-scalable, and highly reproducible fabrication process, this solution represents an interesting alternative for all those applications requiring high-density, high-sensitivity sensors such as robotics and biomedical applications.

Simultaneous recording of electrical and metabolic activity of cardiac cells in vitro using an organic charge modulated field effect transistor array.

In vitro electrogenic cells monitoring is an important objective in several scientific and technological fields, such as electrophysiology, pharmacology and brain machine interfaces, and can represent an interesting opportunity in other translational medicine applications. One of the key aspects of cellular cultures is the complexity of their behavior, due to the different kinds of bio-related signals, both chemical and electrical, that characterize these systems. In order to fully understand and exploit this extraordinary complexity, specific devices and tools are needed. However, at the moment this important scientific field is characterized by the lack of easy-to-use, low-cost devices for the sensing of multiple cellular parameters. To the aim of providing a simple and integrated approach for the study of in vitro electrogenic cultures, we present here a new solution for the monitoring of both the electrical and the metabolic cellular activity. In particular, we show here how a particular device called Micro Organic Charge Modulated Array (MOA) can be conveniently engineered and then used to simultaneously record the complete cell activity using the same device architecture. The system has been tested using primary cardiac rat myocytes and allowed to detect the metabolic and electrical variations thar occur upon the administration of different drugs. This first example could lay the basis for the development of a new generation of multi-sensing tools that can help to efficiently probe the multifaceted in vitro environment.

Epidermal Electrodes with Ferrimagnetic/Conductive Properties for Biopotential Recordings.

Interfacing ultrathin functional films for epidermal applications with external recording instruments or readout electronics still represents one of the biggest challenges in the field of tattoo electronics. With the aim of providing a convenient solution to this ever-present limitation, in this work we propose an innovative free-standing electrode made of a composite thin film based on the combination of the conductive polymer PEDOT:PSS and ferrimagnetic powder. The proposed epidermal electrode can be directly transferred onto the skin and is structured in two parts, namely a conformal conductive part with a thickness of 3 µm and a ferrimagnetic-conductive part that can be conveniently connected using magnetic connections. The films were characterized for ECG recordings, revealing a performance comparable to that of commercial pre-gelled electrodes in terms of cross-spectral coherence, signal-to-noise ratio, and baseline wandering. These new, conductive, magnetically interfaceable, and free-standing conformal films introduce a novel concept in the domain of tattoo electronics and can set the basis for the development of a future family of epidermal devices and electrodes.

Parylene C-Based, Breathable Tattoo Electrodes for High-Quality Bio-Potential Measurements.

A breathable tattoo electrode for bio-potential recording based on a Parylene C nanofilm is presented in this study. The proposed approach allows for the fabrication of micro-perforated epidermal submicrometer-thick electrodes that conjugate the unobtrusiveness of Parylene C nanofilms and the very important feature of breathability. The electrodes were fully validated for electrocardiography (ECG) measurements showing performance comparable to that of conventional disposable gelled Ag/AgCl electrodes, with no visible negative effect on the skin even many hours after their application. This result introduces interesting perspectives in the field of epidermal electronics, particularly in applications where critical on-body measurements are involved.

In Vitro Multiparametric Cellular Analysis by Micro Organic Charge-modulated Field-effect Transistor Arrays.

Modern electrophysiology has been constantly fueled by the parallel development of increasingly sophisticated tools and materials. In turn, discoveries in this field have driven technological progress in a back-and-forth process that ultimately determined the impressive achievements of the past 50 years. However, the most employed devices used for cellular interfacing (namely, the microelectrode arrays and microelectronic devices based on transistors) still present several limitations such as high cost, the rigidity of the materials, and the presence of an external reference electrode. To partially overcome these issues, there have been developments in a new scientific field called organic bioelectronics, resulting in advantages such as lower cost, more convenient materials, and innovative fabrication techniques. Several interesting new organic devices have been proposed during the past decade to conveniently interface with cell cultures. This paper presents the protocol for the fabrication of devices for cellular interfacing based on the organic charge-modulated field-effect transistor (OCMFET). These devices, called micro OCMFET arrays (MOAs), combine the advantages of organic electronics and the peculiar features of the OCMFET to prepare transparent, flexible, and reference-less tools with which it is possible to monitor both the electrical and the metabolic activities of cardiomyocytes and neurons in vitro, thus allowing a multiparametric evaluation of electrogenic cell models.

Interfacing cells with organic transistors: a review of in vitro and in vivo applications.

Recently, organic bioelectronics has attracted considerable interest in the scientific community. The impressive growth that it has undergone in the last 10 years has allowed the rise of the completely new field of cellular organic bioelectronics, which has now the chance to compete with consolidated approaches based on devices such as micro-electrode arrays and ISFET-based transducers both in in vitro and in vivo experimental practice. This review focuses on cellular interfaces based on organic active devices and has the intent of highlighting the recent advances and the most innovative approaches to the ongoing and everlasting challenge of interfacing living matter to the "external world" in order to unveil the hidden mechanisms governing its behavior. Device-wise, three different organic structures will be considered in this work, namely the organic electrochemical transistor (OECT), the solution-gated organic transistor (SGOFET - which is presented here in two possible different versions according to the employed active material, namely: the electrolyte-gated organic transistor - EGOFET, and the solution gated graphene transistor - gSGFET), and the organic charge modulated field effect transistor (OCMFET). Application-wise, this work will mainly focus on cellular-based biosensors employed in in vitro and in vivo cellular interfaces, with the aim of offering the reader a comprehensive retrospective of the recent past, an overview of the latest innovations, and a glance at the future prospects of this challenging, yet exciting and still mostly unexplored scientific field.

Dynamic Surface Electromyography Using Stretchable Screen-Printed Textile Electrodes.

OBJECTIVE: Wearable devices have created new opportunities in healthcare and sport sciences by unobtrusively monitoring physiological signals. Textile polymer-based electrodes proved to be effective in detecting electrophysiological potentials but suffer mechanical fragility and low stretch resistance. The goal of this research is to develop and validate in dynamic conditions cost-effective and easily manufacturable electrodes characterized by adequate robustness and signal quality. METHODS: We here propose an optimized screen printing technique for the fabrication of PEDOT:PSS-based textile electrodes directly into finished stretchable garments for surface electromyography (sEMG) applications. A sensorised stretchable leg sleeve was developed, targeting five muscles of interest in rehabilitation and sport science. An experimental validation was performed to assess the accuracy of signal detection during dynamic exercises, including sit-to-stand, leg extension, calf raise, walking, and cycling. RESULTS: The electrodes can resist up to 500 stretch cycles. Tests on five subjects revealed excellent contact impedance, and cross-correlation between sEMG envelopes simultaneously detected from the leg muscles by the textile and Ag/AgCl electrodes was generally greater than 0.9, which proves that it is possible to obtain good quality signals with performance comparable with disposable electrodes. CONCLUSIONS: An effective technique to embed polymer-based electrodes in stretchable smart garments was presented, revealing good performance for dynamic sEMG detections. SIGNIFICANCE: The achieved results pave the way to the integration of unobtrusive electrodes, obtained by screen printing of conductive polymers, into technical fabrics for rehabilitation and sport monitoring, and in general where the detection of sEMG in dynamic conditions is necessary.

Electrolyte-gated transistors for enhanced performance bioelectronics.

Electrolyte-gated transistors (EGTs), capable of transducing biological and biochemical inputs into amplified electronic signals and stably operating in aqueous environments, have emerged as fundamental building blocks in bioelectronics. In this Primer, the different EGT architectures are described with the fundamental mechanisms underpinning their functional operation, providing insight into key experiments including necessary data analysis and validation. Several organic and inorganic materials used in the EGT structures and the different fabrication approaches for an optimal experimental design are presented and compared. The functional bio-layers and/or biosystems integrated into or interfaced to EGTs, including self-organization and self-assembly strategies, are reviewed. Relevant and promising applications are discussed, including two-dimensional and three-dimensional cell monitoring, ultra-sensitive biosensors, electrophysiology, synaptic and neuromorphic bio-interfaces, prosthetics and robotics. Advantages, limitations and possible optimizations are also surveyed. Finally, current issues and future directions for further developments and applications are discussed.

A three-dimensional micro-electrode array for in-vitro neuronal interfacing.

OBJECTIVE: In this paper, we report on the development of an easy-to-fabricate three-dimensional Micro-Electrode Array (3D-MEA) specifically designed for brain-on-a-dish applications. APPROACH: The proposed device consists of pillar-shaped gold microelectrodes realized by electroplating directly on top of a standard MEA, making this approach highly versatile and convenient for batch fabrication. Moreover, with this simple technique, it is possible to obtain electrodes with a height of more than 100 µm onto different kind of substrates, ranging from glass to flexible plastic ones. MAIN RESULTS: This novel 3D-MEA structure has been validated with acute brain slices, successfully recording both epileptiform-like discharges (upon the administration of 4-AP), and electrically-evoked neuronal activity. The preliminary validation showed a substantial improvement in the signals amplitude with respect to both commercial and custom planar electrodes thanks to a better coupling offered by the peculiar shape of the three-dimensional electrodes. SIGNIFICANCE: Beside the versatility of the fabrication approach, which allows to obtain 3D MEA devices onto both rigid and flexible substrates, the reported validation showed how the pillar approach can outperform standard planar MEA recordings in terms of signal amplitude. Moreover, thanks to the possibility of obtaining multi-level 3D structures within the same device, the proposed fabrication technique offers an interesting and flexible approach for the development of a new family of electrophysiological tools for 3D in vitro electrophysiology, in particular for acute brain slices and 3D neuronal cultures for brain-on-a-dish applications.

Electrophysiological Responses from the Human Tongue to the Six Taste Qualities and Their Relationships with PROP Taster Status.

Taste buds containing receptor cells that primarily detect one taste quality provide the basis for discrimination across taste qualities. The molecular receptor multiplicity and the interactions occurring between bud cells encode information about the chemical identity, nutritional value, and potential toxicity of stimuli before transmitting signals to the hindbrain. PROP (6-n-propylthiouracil) tasting is widely considered a marker for individual variations of taste perception, dietary preferences, and health. However, controversial data have been reported. We present measures of the peripheral gustatory system activation in response to taste qualities by electrophysiological recordings from the tongue of 39 subjects classified for PROP taster status. The waveform of the potential variation evoked depended on the taste quality of the stimulus. Direct relationships between PROP sensitivity and electrophysiological responses to taste qualities were found. The largest and fastest responses were recorded in PROP super-tasters, who had the highest papilla density, whilst smaller and slower responses were found in medium tasters and non-tasters with lower papilla densities. The intensities perceived by subjects of the three taster groups correspond to their electrophysiological responses for all stimuli except NaCl. Our results show that each taste quality can generate its own electrophysiological fingerprint on the tongue and provide direct evidence of the relationship between general taste perception and PROP phenotype.

From MEAs to MOAs: The Next Generation of Bioelectronic Interfaces for Neuronal Cultures.

Since their introduction in the early 1970s, microelectrode arrays (MEAs) have been dominating the electrophysiology market thanks to their reliability, extreme robustness, and usability. Over the past 40 years, silicon technology has also played a role in the advancement of the field, and CMOS-based in vitro and in vivo systems are now able to achieve unprecedented spatial resolutions, giving the possibility to unveil hidden behavior of cellular aggregates down to the subcellular level. However, both the MEAs and silicon-based electronic devices present unavoidable problems such as their expensiveness, the usual rigidity of the employed materials, and the need of an (usually bulky) external reference electrode. Possible interesting alternatives to these incredibly useful devices unexpectedly lie in the field of organic electronics, thanks to the fast-growing pace of improvement that this discipline has undergone in the last 10-15 years. In this chapter, a particular organic transistor called organic charge-modulated field-effect transistor (OCMFET) will be presented as a promising bio-electronic interface, and a complete description of its employment as a detector of cellular electrical activity and as an ultrasensitive pH sensor will be provided, together with the discussion about the possibility of using such a device as an innovative multisensing tool for both electrophysiology and (neuro)pharmacology.

Human Tongue Electrophysiological Response to Oleic Acid and Its Associations with PROP Taster Status and the CD36 Polymorphism (rs1761667).

The perception of fat varies among individuals and has also been associated with CD36 rs1761667 polymorphism and genetic ability to perceive oral marker 6-n-propylthiouracil (PROP). Nevertheless, data in the literature are controversial. We present direct measures for the activation of the peripheral taste system in response to oleic acid by electrophysiological recordings from the tongue of 35 volunteers classified for PROP taster status and genotyped for CD36. The waveform of biopotentials was analyzed and values of amplitude and rate of potential variation were measured. Oleic acid stimulations evoked positive monophasic potentials, which represent the summated voltage change consequent to the response of the stimulated taste cells. Bio-electrical measurements were fully consistent with the perceived intensity during stimulation, which was verbally reported by the volunteers. ANOVA revealed that the amplitude of signals was directly associated, mostly in the last part of the response, with the CD36 genotypes and PROP taster status (which was directly associated with the density of papillae). The rate of potential variation was associated only with CD36, primarily in the first part of the response. In conclusion, our results provide direct evidence of the relationship between fat perception and rs1761667 polymorphism of the CD36 gene and PROP phenotype.

Ultrathin, flexible and multimodal tactile sensors based on organic field-effect transistors.

In this study, a novel approach to the fabrication of a multimodal temperature and force sensor on ultrathin, conformable and flexible substrates is presented. This process involves coupling a charge-modulated organic field-effect transistor (OCMFET) with a pyro/piezoelectric element, namely a commercial film of poly-vinylene difluoride (PVDF). The proposed device is able to respond to both pressure stimuli and temperature variations, demonstrating the feasibility of the approach for the development of low-cost, highly sensitive and conformable multimodal sensors. The overall thickness of the device is 1.2 µm, being thus able to conform to any surface (including the human body), while keeping its electrical performance. Furthermore, it is possible to discriminate between simultaneously applied temperature and pressure stimuli by coupling sensing surfaces made of poled and unpoled spin-coated PVDF-trifluoroethylene (PVDF-TrFE, a PVDF copolymer) with OCMFETs. This demonstrates the possibility of creating multimodal sensors that can be employed for applications in several fields, ranging from robotics to wearable electronics.

Correction: An automated system for the objective evaluation of human gustatory sensitivity using tongue biopotential recordings.

[This corrects the article DOI: 10.1371/journal.pone.0177246.].

First objective evaluation of taste sensitivity to 6-n-propylthiouracil (PROP), a paradigm gustatory stimulus in humans.

Practical and reliable methods for the objective measure of taste function are critically important for studying eating behavior and taste function impairment. Here, we present direct measures of human gustatory response to a prototypical bitter compound, 6-n-propyltiouracil (PROP), obtained by electrophysiological recordings from the tongue of subjects who were classified for taster status and genotyped for the specific receptor gene (TAS2R38), and in which taste papilla density was determined. PROP stimulation evoked negative slow potentials that represent the summated depolarization of taste cells. Depolarization amplitude and rate were correlated with papilla density and perceived bitterness, and associated with taster status and TAS2R38. Our study provides a robust and generalizable research tool for the quantitative measure of peripheral taste function, which can greatly help to resolve controversial outcomes on the PROP phenotype role in taste perception and food preferences, and be potentially useful for evaluating nutritional status and health.