Swift and precise detection of unlabeled pathogens using a nanogap electrode impedimetric sensor facilitated by electrokinetics.

For the protection of human health and environment, there is a growing demand for high-performance, user-friendly biosensors for the prompt detection of pathogenic bacteria in samples containing various substances. We present a nanogap electrode-based purely electrical impedimetric sensor that utilizes the dielectrophoresis (DEP) mechanism. Our nanogap sensor can directly and sensitively detect pathogens present at concentrations as low as 1-10 cells/assay in buffers and drinking milk without the need for separation, purification, or specific ligand binding. This is achieved by minimizing the electrical double-layer effect and electrode polarization in nanogap impedance sensors, reducing signal loss. In addition, even at low DEP voltages, nanogap sensors can quickly establish strong DEP forces between the nanogap electrodes to control the spatial concentration of pathogens around the electrodes. This activates and stabilizes inter-electrode signal transmission along the nanogap-aligned pathogens, increasing sensitivity and reducing errors during repeated measurements. The DEP-enabled nanogap impedance sensor developed in this study is valuable for a variety of pathogen detection and monitoring systems including point-of-care testing (POCT) as it can detect pathogens in diverse samples containing multiple substances quickly and with high sensitivity, is compatible with complex solutions such as food and beverages, and provides highly reproducible results without the need for separate binding and separation processes.

Electric-Field-Driven Localization of Molecular Nanowires in Wafer-Scale Nanogap Electrodes.

As integrated circuits continue to scale toward the atomic limit, bottom-up processes, such as epitaxial growth, have come to feature prominently in their fabrication. At the same time, chemistry has developed highly tunable molecular semiconductors that can perform the functions of ultimately scaled circuit components. Hybrid techniques that integrate programmable structures comprising molecular components into devices however are sorely lacking. Here we demonstrate a wafer-scale process that directs the localization of a conductive polymer, Mw = 20 kg mol-1 polyaniline, from dilute solutions into 50 nm vertical nanogap device architectures using electric-field-driven self-assembly. The resulting metal-polymer-metal junctions were characterized by electron microscopy, Raman spectroscopy and transport measurements demonstrating that our technique is highly selective, assembling conductive polymers only in electrically activated nanogaps. Our results represent a step toward scalable hybrid nanoelectronics that seamlessly integrate established lithographic top-down fabrication with bottom-up synthesized molecular functional circuit components.

Rapid and ultrasensitive detection of thiram and carbaryl pesticide residues in fruit juices using SERS coupled with the chemometrics technique.

A gold nanogap substrate was used to measure the thiram and carbaryl residues in various fruit juices using surface-enhanced Raman scattering (SERS). The gold nanogap substrates can detect carbaryl and thiram with limits of detection of 0.13 ppb (0.13 µgkg-1) and 0.22 ppb (0.22 µgkg-1). Raw SERS data were first preprocessed to reduce noise and undesirable effects and, were later used for model creation, implementing classification, and regression analysis techniques. The partial least-squares regression models achieved the highest prediction correlation coefficient (R2) of 0.99 and the lowest root mean square of prediction value below 0.62 ppb for both pesticide-infected juice samples. Furthermore, to differentiate between juice samples contaminated by both pesticides and control (pesticide-free), logistic-regression classification models were produced and achieved the highest classification accuracies of 100% and 99% for contaminated juice containing thiram and 100% accurate results for contaminated juice containing carbaryl. This indicates that the gold nanogap surface has significant potential for achieving high sensitivity in detecting trace contaminants in food samples.

Optimization of e-beam lithography parameters for nanofabrication of sub-50 nm gold nanowires and nanogaps based on a bilayer lift-off process.

Electron beam lithography (EBL) stands out as a powerful direct-write tool offering nanometer-scale patterning capability and is especially useful in low-volume R&D prototyping when coupled with pattern transfer approaches like etching or lift-off. Among pattern transfer approaches, lift-off is preferred particularly in research settings, as it is cost-effective and safe and does not require tailored wet/dry etch chemistries, fume hoods, and/or complex dry etch tools; all-in-all offering convenient, 'undercut-free' pattern transfer rendering it useful, especially for metallic layers and unique alloys with unknown etchant compatibility or low etch selectivity. Despite the widespread use of the lift-off technique and optical/EBL for micron to even sub-micron scales, existing reports in the literature on nanofabrication of metallic structures with critical dimension in the 10-20 nm regime with lift-off-based EBL patterning are either scattered, incomplete, or vary significantly in terms of experimental conditions, which calls for systematic process optimization. To address this issue, beyond what can be found in a typical photoresist datasheet, this paper reports a comprehensive study to calibrate EBL patterning of sub-50 nm metallic nanostructures including gold nanowires and nanogaps based on a lift-off process using bilayer polymethyl-methacrylate as the resist stack. The governing parameters in EBL, including exposure dose, soft-bake temperature, development time, developer solution, substrate type, and proximity effect are experimentally studied through more than 200 EBL runs, and optimal process conditions are determined by field emission scanning electron microscope imaging of the fabricated nanostructures reaching as small as 11 nm feature size.

Gouy phase effects on photocurrents in plasmonic nanogaps driven by single-cycle pulses.

The investigation of optical phenomena in the strong-field regime requires few-cycle laser pulses at field strengths exceeding gigavolts per meter (GV/m). Surprisingly, such conditions can be reached by tightly focusing pJ-level pulses with nearly octave spanning optical bandwidth onto plasmonic nanostructures, exploiting the field-enhancement effect. In this situation, the Gouy phase of the focused beam can deviate significantly from the monochromatic scenario. Here, we study the effect of the Gouy phase of a pulse exploited to drive coherent strong-field photocurrents within a plasmonic gap nanoantenna. While the influence of the specific Gouy phase profile in the experiment approaches the monochromatic case closely, this scheme may be utilized to identify more intricate phase profiles at sub-diffraction scale. Our results pave the way for Gouy phase engineering at picojoule (pJ) pulse energy levels, enabling the optimization of strong-field optical phenomena.

Electromigrated Gold Nanogap Tunnel Junction Arrays: Fabrication and Electrical Behavior in Liquid and Gaseous Media.

Tunnel junctions have been suggested as high-throughput electronic single molecule sensors in liquids with several seminal experiments conducted using break junctions with reconfigurable gaps. For practical single molecule sensing applications, arrays of on-chip integrated fixed-gap tunnel junctions that can be built into compact systems are preferable. Fabricating nanogaps by electromigration is one of the most promising approaches to realize on-chip integrated tunnel junction sensors. However, the electrical behavior of fixed-gap tunnel junctions immersed in liquid media has not been systematically studied to date, and the formation of electromigrated nanogap tunnel junctions in liquid media has not yet been demonstrated. In this work, we perform a comparative study of the formation and electrical behavior of arrays of gold nanogap tunnel junctions made by feedback-controlled electromigration immersed in various liquid and gaseous media (deionized water, mesitylene, ethanol, nitrogen, and air). We demonstrate that tunnel junctions can be obtained from microfabricated gold nanoconstrictions inside liquid media. Electromigration of junctions in air produces the highest yield (61-67%), electromigration in deionized water and mesitylene results in a lower yield than in air (44-48%), whereas electromigration in ethanol fails to produce viable tunnel junctions due to interfering electrochemical processes. We map out the stability of the conductance characteristics of the resulting tunnel junctions and identify medium-specific operational conditions that have an impact on the yield of forming stable junctions. Furthermore, we highlight the unique challenges associated with working with arrays of large numbers of tunnel junctions in batches. Our findings will inform future efforts to build single molecule sensors using on-chip integrated tunnel junctions.

Development of nanogap-rich hybrid gold nanostructures by use of two non-lithographic deposition techniques for a sensitive and reliable SERS biosensor.

Practical application of surface-enhanced Raman spectroscopy (SERS) has suffered from several limitations by heterogeneous distribution of hot-spots, such as high signal fluctuation and the resulting low reliability in detection. Herein, we develop a strategy of more sensitive and reliable SERS platform through designing spatially homogeneous gold nanoparticles (GNPs) on a uniform gold nanoisland (GNI) pattern. The proposed SERS substrate is successfully fabricated by combining two non-lithographic techniques of electron beam evaporation and convective self-assembly. These bottom-up methods allow a simple, cost-effective, and large-area fabrication. Compared to the SERS substrates obtained from two separate nanofabrication methods, Raman spectra measured by the samples with both GNPs and GNIs present a significant increase in the signal intensity as well as a notable improvement in signal fluctuation. The simulated near-field analyses demonstrate the formation of highly amplified plasmon modes within and at the gaps of the GNP-GNI interfaces. Moreover, the suggested SERS sensor is evaluated to detect the glucose concentration, exhibiting that the detection sensitivity is improved by more than 10 times compared to the sample with only GNI patterns and a fairly good spatial reproducibility of 7% is accomplished. It is believed that our suggestion could provide a potential for highly sensitive, low-cost, and reliable SERS biosensing platforms that include many advantages for healthcare devices. Supplementary Information: The online version contains supplementary material available at 10.1007/s13534-024-00381-4.

Metal Nanogap Memory: Performances and Switching Mechanism.

The nanogap memory (NGM) device, emerging as a promising nonvolatile memory candidate, has attracted increasing attention for its simple structure, nano/atomic scale size, elevated operating speed, and robustness to high temperatures. In this study, nanogap memories based on Pd, Au, and Pt were fabricated by combining nanofabrication with electromigration technology. Subsequent evaluations of the electrical characteristics were conducted under ambient air or vacuum conditions at room temperature. The investigation unveiled persistent challenges associated with metal NGM devices, including (1) prolonged SET operation time in comparison to RESET, (2) the potential generation of error bits when enhancing switching speeds, and (3) susceptibility to degradation during program/erase cycles. While these issues have been encountered by predecessors in NGM device development, the underlying causes have remained elusive. Employing molecular dynamics (MD) simulation, we have, for the first time, unveiled the dynamic processes of NGM devices during both SET and RESET operations. The MD simulation highlights that the adjustment of the tunneling gap spacing in nanogap memory primarily occurs through atomic migration or field evaporation. This dynamic process enables the device to transition between the high-resistance state (HRS) and the low-resistance state (LRS). The identified mechanism provides insight into the origins of the aforementioned challenges. Furthermore, the study proposes an effective method to enhance the endurance of NGM devices based on the elucidated mechanism.

Precision Basecalling of Single DNA Nucleotide from Overlapped Transmission Readouts with Machine Learning Aided Solid-State Nanogap.

DNA sequencing with the quantum tunneling technique heralds a paradigm shift in genetic analysis, promising rapid and accurate identification for diverging applications ranging from personalized medicine to security issues. However, the widespread distribution of molecular conductance, conduction orbital alignment for resonant transport, and decoding crisscrossing conductance signals of isomorphic nucleotides have been persistent experimental hurdles for swift and precise identification. Herein, we have reported a machine learning (ML)-driven quantum tunneling study with solid-state model nanogap to determine nucleotides at single-base resolution. The optimized ML basecaller has demonstrated a high predictive basecalling accuracy of all four nucleotides from seven distinct data pools, each containing complex transmission readouts of their different dynamic conformations. ML classification of quaternary, ternary, and binary nucleotide combinations is also performed with high precision, sensitivity, and F1 score. ML explainability unravels the evidence of how extracted normalized features within overlapped nucleotide signals contribute to classification improvement. Moreover, electronic fingerprints, conductance sensitivity, and current readout analysis of nucleotides have promised practical applicability with significant sensitivity and distinguishability. Through this ML approach, our study pushes the boundaries of quantum sequencing by highlighting the effectiveness of single nucleotide basecalling with promising implications for advancing genomics and molecular diagnostics.

Trace level detection of melamine and cyanuric acid extracted from pet liquid food (milk) using a SERS Au nanogap substrate.

This study reported an application of Au nanogap substrates for surface-enhanced Raman scattering (SERS) measurements to quantitatively analyze melamine and its derivative products at trace levels in pet liquid food (milk) combined with a waveband selection approach, namely variable importance in projection (VIP). Six different concentrations of melamine, cyanuric acid, and melamine combined with cyanuric acid were created, and SERS spectra were acquired from 550 to 1620cm-1. Detection was possible up to 200 pM for melamine-contaminated samples, and 400 pM concentration detection for other two groups. The VIP-PLSR models obtained correlation coefficient (R2) values of 0.997, 0.985, and 0.981, with root mean square error of prediction (RMSEP) values of 18.492 pM, 19.777 pM, and 15.124 pM for prediction datasets. Additionally, partial least square discriminant analysis (PLS-DA) was used to classify both pure and different concentrations of spiked samples. The results showed that the maximum classification accuracy for melamine was 100%, for cyanuric acid it was 96%, and for melamine coupled with cyanuric acid it was 95%. The results obtained clearly demonstrated that the Au nanogap substrate offers low-concentration, rapid, and efficient detection of hazardous additive chemicals in pet consuming liquid food.

Plasmonic Annular Nanotrenches with 1 nm Nanogaps for Detection of SARS-CoV-2 Using SERS-Based Immunoassay.

This study represents the synthesis of a novel class of nanoparticles denoted as annular Au nanotrenches (AANTs). AANTs are engineered to possess embedded, narrow circular nanogaps with dimensions of approximately 1 nm, facilitating near-field focusing for detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via a surface-enhanced Raman scattering (SERS)-based immunoassay. Notably, AANTs exhibited an exceedingly low limit of detection (LOD) of 1 fg/mL for SARS-CoV-2 spike glycoproteins, surpassing the commercially available enzyme-linked immunosorbent assay (ELISA) by 6 orders of magnitude (1 ng/mL from ELISA). To assess the real-world applicability, a study was conducted on 50 clinical samples using an SERS-based immunoassay with AANTs. The results revealed a sensitivity of 96% and a selectivity of 100%, demonstrating the significantly enhanced sensing capabilities of the proposed approach in comparison to ELISA and commercial lateral flow assay kits.

Intra-nanoparticle plasmonic nanogap based spatial-confinement SERS analysis of polypeptides.

Sensing and characterizing water-soluble polypeptides are essential in various biological applications. However, detecting polypeptides using Surface-Enhanced Raman Scattering (SERS) remains a challenge due to the dominance of aromatic amino acid residues and backbones in the signal, which hinders the detection of non-aromatic amino acid residues. Herein, intra-nanoparticle plasmonic nanogap were designed by etching the Ag shell in Au@AgNPs (i.e., obtaining AuAg cores) with chlorauric acid under mild conditions, at the same time forming the outermost Au shell and the void between the AuAg cores and the Au shell (AuAg@void@Au). By varying the Ag to added chloroauric acid molar ratios, we pioneered a simple, controllable, and general synthetic strategy to form interlayer-free nanoparticles with tunable Au shell thickness, achieving precise regulation of electric field enhancement within the intra-nanogap. As validation, two polypeptide molecules, bacitracin and insulin B, were successfully synchronously encapsulated and spatial-confined in the intra-nanogap for sensing. Compared with concentrated 50 nm AuNPs and Au@AgNPs as SERS substrates, our simultaneous detection method improved the sensitivity of the assay while benefiting to obtain more comprehensive characteristic peaks of polypeptides. The synthetic strategy of confining analytes while fabricating plasmonic nanostructures enables the diffusion of target molecules into the nanogap in a highly specific and sensitive manner, providing the majority of the functionality required to achieve peptide detection or sequencing without the hassle of labeling.

Adaptive Gap-Tunable Surface-Enhanced Raman Spectroscopy.

Gap plasmon (GP) resonance in static surface-enhanced Raman spectroscopy (SERS) structures is generally too narrow and not tunable. Here, we present an adaptive gap-tunable SERS device to selectively enhance and modulate different vibrational modes via active flexible Au nanogaps, with adaptive optical control. The tunability of GP resonance is up to ∼1200 cm-1 by engineering gap width, facilitated by mechanical bending of a polyethylene terephthalate substrate. We confirm that the tuned GP resonance selectively enhances different Raman spectral regions of the molecules. Additionally, we dynamically control the SERS intensity through the wavefront shaping of excitation beams. Furthermore, we demonstrate simulation results, exhibiting the mechanical and optical properties of a one-dimensional flexible nanogap and their advantage in high-speed biomedical sensing. Our work provides a unique approach for observing and controlling the enhanced chemical responses with dynamic tunability.

Suppression of Resistive Coupling in Nanogap Electrochemical Cell: Resolution of Dual Pathways for Dopamine Oxidation.

A nanogap cell involves two working electrodes separated by a nanometer-wide solution to enable unprecedented electrochemical measurements. The powerful nanogap measurements, however, can be seriously interfered with by resistive coupling between the two electrodes to yield erroneous current responses. Herein, we employ the nanogap cell based on double carbon-fiber microelectrodes to suppress resistive coupling for the assessment of intrinsic current responses. Specifically, we modify a commercial bipotentiostat to compensate the Ohmic potential drop shared by the two electrodes through the common current pathway with a fixed resistance in the solution. Resistive coupling through both non-Faradaic and Faradaic processes is suppressed to eliminate erroneous current responses. Our approach is applied to investigate the mechanism of dopamine oxidation at carbon-fiber microelectrodes as important electrochemical sensors for the crucial neurotransmitter. Resistive coupling is suppressed to manifest the intrinsic current responses based on the oxidation of both adsorbed and non-adsorbed forms of dopamine to the respective forms of dopamine-o-quinone. The simultaneous dual oxidation pathways are observed for the first time and can be mediated through either non-concerted or concerted mechanisms of adsorption-coupled electron transfer. The two mechanisms are not discriminated for the two-electron oxidation of dopamine because it can not be determined whether the intermediate, dopamine semi-quinone, is adsorbed on the electrode surface. Significantly, our approach will be useful to manifest intrinsic current responses without resistive coupling for nanogaps and microgaps, which are too narrow to eliminate the common solution resistance by optimizing the position of a reference electrode.

Vapor phase detection of explosives by surface enhanced Raman scattering under ambient conditions with metal nanogap structures.

Non-invasive and passive detection of explosives in the vapor phase is advantageous for military, counter-terrorism, and homeland security applications. Detection of explosives using SERS has been an active research topic. However, the vapor pressures of most explosives are low at room temperature, and consequently, the vapor phase detection by SERS is highly challenging without intentionally heating explosive powder to increase the vapor pressure. In this work, we report the rapid and sensitive detection of 2,4,6-trinitrotoluene (TNT) and 2,4-dinitrotoluene (2,4-DNT) in the vapor phase, using a gold nanogap (AuNG) SERS substrate. The AuNG SERS substrate was fabricated with electron beam evaporation, rapid thermal annealing, and wet etching. SERS measurements were carried out with an incident power as low as 0.56 mW at 785 nm. To prevent the condensation effect, the TNT and 2,4-DNT powders inside the cuvette were taken out before inserting the nanogap substrate. Our SERS results demonstrate the feasibility of the non-invasive detection of vapor phase explosives under ambient conditions.

Periodic Folded Gold Nanostructures with a Sub-10 nm Nanogap for Surface-Enhanced Raman Spectroscopy.

Surface-enhanced Raman spectroscopy has emerged as a powerful spectroscopy technique for detection with its capacity for label-free, nondestructive analysis, and ultrasensitive characterization. High-performance surface-enhanced Raman scattering (SERS) substrates with homogeneity and low cost are the key factors in chemical and biomedical analysis. In this study, we propose the technique of atomic force microscopy (AFM) scratching and nanoskiving to prepare periodic folded gold (Au) nanostructures as SERS substrates. Initially, folded Au nanostructures with tunable nanogaps and periodic structures are created through the scratching of Au films by AFM, the deposition of Ag/Au films, and the cutting of epoxy resin, reducing fabrication cost and operational complexity. Periodic folded Au nanostructures show the three-dimensional nanofocusing effect, hotspot effect, and standing wave effect to generate an extremely high electromagnetic field. As a typical molecule to be tested, p-aminothiophenol has the lowest detection limit of up to 10-9 M, owing to the balance between the electromagnetic field energy concentration and the transmission loss in periodic folded Au nanostructures. Finally, by precisely controlling the periods and nanogap widths of the folded Au nanostructures, the synergistic effect of surface plasmon resonance is optimized and shows good SERS properties, providing a new strategy for the preparation of plasmonic nanostructures.

Three-Dimensional Au Octahedral Nanoheptamers: Single-Particle and Bulk Near-Field Focusing for Surface-Enhanced Raman Scattering.

Herein, we present a synthetic approach to fabricate Au nanoheptamers composed of six individual Au nanospheres interconnected through thin metal bridges arranged in an octahedral configuration. The resulting structures envelop central Au nanospheres, producing Au nanosphere heptamers with an open architectural arrangement. Importantly, the initial Pt coating of the Au nanospheres is a crucial step for protecting the inner Au nanospheres during multiple reactions. As-synthesized Au nanoheptamers exhibit multiple hot spots formed by nanogaps between nanospheres, resulting in strong electromagnetic near-fields. Additionally, we conducted surface-enhanced Raman-scattering-based detection of a chemical warfare agent simulant in the gas phase and achieved a limit of detection of 100 ppb, which is 3 orders lower than that achieved using Au nanospheres and Au nanohexamers. This pseudocore-shell nanostructure represents a significant advancement in the realm of complex nanoparticle synthesis, moving the field one step closer to sophisticated nanoparticle engineering.

Light-Emitting Plasmonic Tunneling Junctions: Current Status and Perspectives.

Quantum tunneling, in which electrons can tunnel through a finite potential barrier while simultaneously interacting with other matter excitation, is one of the most fascinating phenomena without classical correspondence. In an extremely thin metallic nanogap, the deep-subwavelength-confined plasmon modes can be directly excited by the inelastically tunneling electrons driven by an externally applied voltage. Light emission via inelastic tunneling possesses a great potential application for next-generation light sources, with great superiority of ultracompact integration, large bandwidth, and ultrafast response. In this Perspective, we first briefly introduce the mechanism of plasmon generation in the inelastic electron tunneling process. Then the state of the art in plasmonic tunneling junctions will be reviewed, particularly emphasizing efficiency improvement, precise construction, active control, and electrically driven optical antenna integration. Ultimately, we forecast some promising and critical prospects that require further investigation.

The combination of DNA nanostructures and materials for highly sensitive electrochemical detection.

Due to the wide range of electrochemical devices available, DNA nanostructures and material-based technologies have been greatly broadened. They have been actively used to create a variety of beautiful nanostructures owing to their unmatched programmability. Currently, a variety of electrochemical devices have been used for rapid sensing of biomolecules and other diagnostic applications. Here, we provide a brief overview of recent advances in DNA-based biomolecular assays. Biosensing platform such as electrochemical biosensor, nanopore biosensor, and field-effect transistor biosensors (FET), which are equipped with aptamer, DNA walker, DNAzyme, DNA origami, and nanomaterials, has been developed for amplification detection. Under the optimal conditions, the proposed biosensor has good amplification detection performance. Further, we discussed the challenges of detection strategies in clinical applications and offered the prospect of this field.

Surface-Plasmon-Polaritons for Reversible Assembly of Gold Nanoparticles, In Situ Nanogap Tuning, and SERS.

A transportable reversible assembly of gold nanoparticles (AuNPs) in an aqueous environment addresses the need for in situ surafce-enhanced Raman spectroscopy (SERS) hotspot creation for biological applications. Usually, light-directed AuNP assembly methods use higher laser powers and surfactants and are, hence, unsuitable for biological applications. Here, surface plasmon polaritons-assisted dynamic assembly of AuNPs are demonstrated at laser power density as low as 100 nW µm-2 . The AuNP assembly with multiple controllable hotspots is generated in an Au-water interface for solution-based SERS measurements. The major advantage of the method is that the interparticle nanogap is tunable to achieve analyte and AuNP-specific optimum SERS enhancement. The SERS intensity is reproducible on multiple reassembly cycles and assembly attempts, proving repeatability in the produced nanogap pattern. The assembly experiments reveal the influence of AuNP surface charge and the resulting polarizability on the SPP forces. The developed system and method can detect sulforhodamine 101 (SR101) dye molecules at concentrations as low as 10-10  m. Further, the SERS measurements on double-stranded DNA suggest that the molecules are oriented in a fashion to expose adenosine to the enhanced field, leading to its dominance in the recorded spectra.