Enhancing Electrochemical Sensing through Molecular Engineering of Reduced Graphene Oxide-Solution Interfaces and Remote Floating-Gate FET Analysis.

Two-dimensional nanomaterials such as reduced graphene oxide (rGO) have captured significant attention in the realm of field-effect transistor (FET) sensors due to their inherent high sensitivity and cost-effective manufacturing. Despite their attraction, a comprehensive understanding of rGO-solution interfaces (specifically, electrochemical interfacial properties influenced by linker molecules and surface chemistry) remains challenging, given the limited capability of analytical tools to directly measure intricate solution interface properties. In this study, we introduce an analytical tool designed to directly measure the surface charge density of the rGO-solution interface leveraging the remote floating-gate FET (RFGFET) platform. Our methodology involves characterizing the electrochemical properties of rGO, which are influenced by adhesion layers between SiO2 and rGO, such as (3-aminopropyl)trimethoxysilane (APTMS) and hexamethyldisilazane (HMDS). The hydrophilic nature of APTMS facilitates the acceptance of oxygen-rich rGO, resulting in a noteworthy pH sensitivity of 56.8 mV/pH at the rGO-solution interface. Conversely, hydrophobic HMDS significantly suppresses the pH sensitivity from the rGO-solution interface, attributed to the graphitic carbon-rich surface of rGO. Consequently, the carbon-rich surface facilitates a denser arrangement of 1-pyrenebutyric acid N-hydroxysuccinimide ester linkers for functionalizing capturing probes on rGO, resulting in an enhanced sensitivity of lead ions by 32% in our proof-of-concept test.

Rapid, Sensitive, Label-Free Electrical Detection of SARS-CoV-2 in Nasal Swab Samples.

Rapid diagnosis of coronavirus disease 2019 (COVID-19) is key for the long-term control of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) amid renewed threats of mutated SARS-CoV-2 around the world. Here, we report on an electrical label-free detection of SARS-CoV-2 in nasopharyngeal swab samples directly collected from outpatients or in saliva-relevant conditions by using a remote floating-gate field-effect transistor (RFGFET) with a 2-dimensional reduced graphene oxide (rGO) sensing membrane. RFGFET sensors demonstrate rapid detection (<5 min), a 90.6% accuracy from 8 nasal swab samples measured by 4 different devices for each sample, and a coefficient of variation (CV) < 6%. Also, RFGFET sensors display a limit of detection (LOD) of pseudo-SARS-CoV-2 that is 10 000-fold lower than enzyme-linked immunosorbent assays, with a comparable LOD to that of reverse transcription-polymerase chain reaction (RT-PCR) for patient samples. To achieve this, comprehensive systematic studies were performed regarding interactions between SARS-CoV-2 and spike proteins, neutralizing antibodies, and angiotensin-converting enzyme 2, as either a biomarker (detection target) or a sensing probe (receptor) functionalized on the rGO sensing membrane. Taken together, this work may have an immense effect on positioning FET bioelectronics for rapid SARS-CoV-2 diagnostics.

Remote Floating-Gate Field-Effect Transistor with 2-Dimensional Reduced Graphene Oxide Sensing Layer for Reliable Detection of SARS-CoV-2 Spike Proteins.

Despite intensive research of nanomaterials-based field-effect transistors (FETs) as a rapid diagnostic tool, it remains to be seen for FET sensors to be used for clinical applications due to a lack of stability, reliability, reproducibility, and scalability for mass production. Herein, we propose a remote floating-gate (RFG) FET configuration to eliminate device-to-device variations of two-dimensional reduced graphene oxide (rGO) sensing surfaces and most of the instability at the solution interface. Also, critical mechanistic factors behind the electrochemical instability of rGO such as severe drift and hysteresis were identified through extensive studies on rGO-solution interfaces varied by rGO thickness, coverage, and reduction temperature. rGO surfaces in our RFGFET structure displayed a Nernstian response of 54 mV/pH (from pH 2 to 11) with a 90% yield (9 samples out of total 10), coefficient of variation (CV) < 3%, and a low drift rate of 2%, all of which were calculated from the absolute measurement values. As proof-of-concept, we demonstrated highly reliable, reproducible, and label-free detection of spike proteins of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a saliva-relevant media with concentrations ranging from 500 fg/mL to 5 µg/mL, with an R2 value of 0.984 and CV < 3%, and a guaranteed limit of detection at a few pg/mL. Taken together, this new platform may have an immense effect on positioning FET bioelectronics in a clinical setting for detecting SARS-CoV-2.

Suppression of Ionic Doping by Molecular Dopants in Conjugated Polymers for Improving Specificity and Sensitivity in Biosensing Applications.

Ionic doping effects in conjugated polymers often cause nonspecific signaling and a low selectivity of bioelectronic sensing. Using remote-gate field-effect transistor characterization of molecular and ionic doping in poly(3-hexylthiophene) (P3HT) and acid-functionalized polythiophene, poly[3-(3-carboxypropyl) thiophene-2,5-diyl] (PT-COOH), we discovered that proton doping effects on the interfacial potential occurring in P3HT could be suppressed by sequentially doping P3HT by 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane (F4TCNQ). To be specific, intrinsic pH sensitivity shown by pure P3HT (18 mV/pH in a range from pH 3 to 9) was fully dissipated for doped P3HT:F4TCNQ. However, F4TCNQ sequential doping instead increases pH sensitivity of acid-functionalized polythiophene, PT-COOH (40 mV/pH), compared to that of a pure PT-COOH (30 mV/pH). Interactions between polythiophene backbone and side chains, which constrain the activity of COOH, are weakened by stronger F4TCNQ doping leaving behind responsive COOH groups exposed to aqueous solutions. This is supported by the reduced pH sensitivity of PT-COOH sequentially doped by a weaker dopant, tetracyanoethylene (TCNE) (21 mV/pH). Thus, doping is shown to stabilize a nonpolar conjugated polymer to pH-induced fluctuations on one hand, and to activate a COOH side chain to pH-induced response on the other.

Analytical Platform To Characterize Dopant Solution Concentrations, Charge Carrier Densities in Films and Interfaces, and Physical Diffusion in Polymers Utilizing Remote Field-Effect Transistors.

Characterizing doping effects in a conductive polymer and physical diffusion in a passive polymer were performed using a remote-gate field-effect transistor (RG FET) detection system that was able to measure the electrical potential perturbation of a polymer film coupled to the gate of a silicon FET. Poly(3-hexylthiophene) (P3HT) film doped using various concentrations of 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane (F4TCNQ) solutions imposed additional positive potentials on the P3HT RG, resulting in a lower threshold voltage ( Vth) on the n-channel silicon FET. Changes in Vth were related to the induced hole concentrations and hole mobility in P3HT films by using our Vth shifting model for the RG FET. We discovered that the electron-donating P3HT and even inorganic materials, indium tin oxide and gold, showed similar electrical potential perturbations dependent on the concentration of F4TCNQ in overlying solutions as the dopant radical anions maximally covered the surfaces. This suggests that there are limited electroactive sites for F4TCNQ binding on electron donor surfaces which results in a similar number of positive charges in film materials forming dipoles with the F4TCNQ radical counteranions. The effect of electron acceptors such as 7,7,8,8-tetracyanoquinodimethane and tetracyanoethylene was compared to that of F4TCNQ in terms of Vth shift using our analytical tool, with differences attributed to acceptor size and reduction potential. Meanwhile, this FET analysis tool offered a means of monitoring the physical diffusion of small molecules, exemplified by F4TCNQ, in the passive polymer polystyrene, driven by concentration gradients. The technique allows for nondestructive, nonspectroscopic, ambient characterization of electron donor-acceptor interactions at surfaces.

Chemical and Biomolecule Sensing with Organic Field-Effect Transistors.

The strong and controllable chemical sensitivity of organic semiconductors (OSCs) and the amplification capability of transistors in circuits make use of OSC-based field-effect transistors compelling for chemical sensors. Analytes detected and assayed range from few-atom gas-phase molecules that may have adverse health and security implications to biomacromolecules (proteins, nucleic acids) that may be markers for physiological processes and medical conditions. This review highlights recent progress in organic field-effect transistor (OFET) chemical sensors, emphasizing advances from the past 5 years and including aspects of OSC morphology and the role of adjacent dielectrics. Design elements of the OSCs and various formats for the devices are illustrated and evaluated. Challenges associated with the present state of the art and future opportunities are also discussed.

Electronic Cortisol Detection Using an Antibody-Embedded Polymer Coupled to a Field-Effect Transistor.

A field-effect transistor-based cortisol sensor was demonstrated in physiological conditions. An antibody-embedded polymer on the remote gate was proposed to overcome the Debye length issue (λD). The sensing membrane was made by linking poly(styrene- co-methacrylic acid) (PSMA) with anticortisol before coating the modified polymer on the remote gate. The embedded receptor in the polymer showed sensitivity from 10 fg/mL to 10 ng/mL for cortisol and a limit of detection (LOD) of 1 pg/mL in 1× PBS where λD is 0.2 nm. A LOD of 1 ng/mL was shown in lightly buffered artificial sweat. Finally, a sandwich ELISA confirmed the antibody binding activity of antibody-embedded PSMA.

Top-down Fabrication and Enhanced Active Area Electronic Characteristics of Amorphous Oxide Nanoribbons for Flexible Electronics.

Inorganic amorphous oxide semiconductor (AOS) materials such as amorphous InGaZnO (a-IGZO) possess mechanical flexibility and outstanding electrical properties, and have generated great interest for use in flexible and transparent electronic devices. In the past, however, AOS devices required higher activation energies, and hence higher processing temperatures, than organic ones to neutralize defects. It is well known that one-dimensional nanowires tend to have better carrier mobility and mechanical strength along with fewer defects than the corresponding two-dimensional films, but until now it has been difficult, costly, and impractical to fabricate such nanowires in proper alignments by either "bottom-up" growth techniques or by "top-down" e-beam lithography. Here we show a top-down, cost-effective, and scalable approach for the fabrication of parallel, laterally oriented AOS nanoribbons based on lift-off and nano-imprinting. High mobility (132 cm2/Vs), electrical stability, and transparency are obtained in a-IGZO nanoribbons, compared to the planar films of the same a-IGZO semiconductor.

Extended Solution Gate OFET-based Biosensor for Label-free Glial Fibrillary Acidic Protein Detection with Polyethylene Glycol-Containing Bioreceptor Layer.

A novel organic field effect transistor (OFET) -based biosensor is described for label-free glial fibrillary acidic protein (GFAP) detection. We report the first use of an extended solution gate structure where the sensing area and the organic semiconductor are separated, and a reference electrode is not needed. Different molecular weight polyethylene glycols (PEGs) are mixed into the bio-receptor layer to help extend the Debye screening length. The drain current change was significantly increased with the help of higher molecular weight PEGs, as they are known to reduce the dielectric constant. We also investigated the sensing performance under different gate voltage (Vg). The sensitivity increased after we decreased Vg from -5 V to -2 V, because the lower Vg is much closer to the OFET threshold voltage and the influence of attached negatively charged proteins become more apparent. Finally, the selectivity experiments toward different interferents were performed. The stability and selectivity are promising for clinical applications.

Transcriptional regulation of cathelicidin genes in chicken bone marrow cells.

Cathelicidins form a family of vertebrate-specific immune molecules with an evolutionarily conserved gene structure. We analyzed the expression patterns of cathelicidin genes (CAMP, CATH3, and CATHB1) in chicken bone marrow cells (BMCs) and chicken embryonic fibroblasts (CEFs). We found that CAMP and CATHB1 were significantly up-regulated in BMCs, whereas the expression of CATH3 did not differ significantly between BMCs and CEFs. To study the mechanism underlying the up-regulation of cathelicidin genes in BMCs, we predicted the transcription factors (TFs) that bind to the 5'-flanking regions of cathelicidin genes. CEBPA, EBF1, HES1, MSX1, and ZIC3 were up-regulated in BMCs compared to CEFs. Subsequently, when a siRNA-mediated knockdown assay was performed for MSX1, the expression of CAMP and CATHB1 was decreased in BMCs. We also showed that the transcriptional activity of the CAMP promoter was decreased by mutation of the MSX1-binding sites present within the 5'-flanking region of CAMP. These results increase our understanding of the regulatory mechanisms controlling cathelicidin genes in BMCs.

Electrical signaling of enzyme-linked immunosorbent assays with an ion-sensitive field-effect transistor.

Optical laboratory-based immunoassays, such as enzyme-linked immunosorbent assay (ELISA) give a high sensitivity and specificity of various fatal diseases. However, these assays are no longer efficient in on-spot diagnostics of wide-spreading and contagious infections. At this point in time, portable and handhold devices play a pivotal role in infectious diseases with quick diagnostics at or near the site of the disease propagation. In this paper, we demonstrated a novel electrical immunoassay of ELISA that was not based on optical signaling but on electrical signaling. This was done by combining an ion-sensitive field-effect transistor (ISFET) with ELISA. By harnessing the catalytic reaction of alkaline phosphatase that precipitated silver particles, we effectively overcame the chronic Debye screening length issue of the ISFET. Ultimately, small signal ranging from 1 pg/mL to 10 ng/mL was immensely amplified with the ALP label, regardless of buffer conditions. The sensor platform herein surpassed a sensing capability of conventional ELISA that is considered to have a LOD on the order of ~1 ng/mL. The results were compared with those of horseradish peroxidase label, which is generally used for optical analyses in ELISA. Our newly developed ISFET-based portable sensor holds a large potential for point-of-care tools in a variety of diseases, without being limited by the need for expensive equipment such as spectrophotometers.

Performance enhancement of capacitive-coupling dual-gate ion-sensitive field-effect transistor in ultra-thin-body.

Recently, thin-film transistor based-ISFETs with the dual-gate (DG) structures have been proposed, in order to beat the Nernst response of the standard ISFET, utilizing diverse organic or inorganic materials. The immutable Nernst response can be dramatically transformed to an ultra-sensing margin, with the capacitive-coupling arisen from the DG structure. In order to advance this platform, we here embedded the ultra-thin body (UTB) into the DG ISFET. The UTB of 4.3 nm serves to not only increase its sensitivity, but also to strongly suppress the leakage components, leading to a better stability of the DG ISFET. In addition, we first provide a comprehensive analysis of the body thickness effects especially how the thick body can render the degradation in the device performance, such as sensitivity and stability. The UTB DG ISFET will allow the ISFET-based biosensor platform to continue enhancement into the next decade.

3D-transistor array based on horizontally suspended silicon nano-bridges grown via a bottom-up technique.

Integrated surround-gate field-effect-transistors enabled by bottom-up synthesis of nano-bridges are demonstrated. Horizontally oriented silicon nano-bridge devices are fabricated avoiding the rigorous processes for aligning and contacting nanowires grown via a bottom-up technique. Evaluation of electrical properties and a memory device application of the transistors are presented.

High performance of silicon nanowire-based biosensors using a high-k stacked sensing thin film.

High performance silicon nanowire (SiNW) sensors with SiO2/HfO2/Al2O3 (OHA) engineered sensing thin films were fabricated. A lower interface state density, a larger capacitance and a stronger chemical immunity, which are essential for enhancing the performance of devices, were accomplished by stacking thin SiO2, HfO2, and Al2O3 layers, respectively, in sequence on the SiNW channel. Compared with the conventional single SiO2 thin film, the staked OHA thin films demonstrated improved sensing performances; a higher sensitivity, a lower hysteresis voltage, and a smaller drift rate, as well as a higher output current. Therefore, the SiNW sensors with OHA stacked sensing thin films are very promising to biological and chemical sensor applications.