Nanogap Sensor Research Articles

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.

Bead‐based electrochemical gap sensors for detection of tau protein in blood to diagnosis and monitoring the tauopathy

AbstractBackgroundRecently, there is a need for a method for detecting biomarkers in blood that can be collected relatively easily for diagnosis and monitoring of dementia symptoms in Alzheimer's disease (AD) patients. Tau protein, a typical hallmark of AD, has six isoforms, and is divided into four repeating microtubule binding domains (4R) and three microtubule binding domains (3R) depending on whether exon 10 is included. According to the balance of 3R‐ and 4R‐tau, tauopathy can be distinguished. It is expected to be able to differentiate normal (NC) from AD and other dementias by measuring the tau protein in the blood.MethodIn this study, an electrochemical sensor with a novel structure was employed to detect tau in the plasma of living patients. The nanogap sensor consists of a gap electrode and a SU‐8 microwell for loading a single magnetic bead (Figure 1). A sample was prepared by reacting the surface of the magnetic beads with an antibody (total tau or anti 3R‐ or 4R‐tau antibody) and an antibody functionalized with a secondary O‐glycosylated tau (O‐g tau) antibody or phosphorylated tau (p‐tau) antibody.ResultAs a result of O‐g/p‐tau measurement, the impedance change by O‐g tau was large in NC (n=4), whereas the impedance change by p‐tau was large in AD (n=13). Patients with idiopathic Parkinson's disease (IPD) (n=3) also had more impedance changes due to p‐tau (Figure 2). As a result of measuring 3R‐ or 4R‐tau protein, the impedance change by 4R‐tau in NC was larger than that by 3R‐tau, whereas the opposite result was shown in AD. similar to the previous results, the impedance change by 3R‐tau was larger in IPD (Figure 3),ConclusionWe used a novel electrochemical gap sensor to detect tau protein in blood samples collected from living patients. As a result, it is expected to be able to differentiate NC from tauopathy and other dementias by measuring the tau protein in the blood (Figure 4).

Highly-sensitive single-step sensing of levodopa by swellable microneedle-mounted nanogap sensors

Microneedle (MN) sensing of biomarkers in interstitial fluid (ISF) can overcome the challenges of self-diagnosis of diseases by a patient, such as blood sampling, handling, and measurement analysis. However, the MN sensing technologies still suffer from poor measurement accuracy due to the small amount of target molecules present in ISF, and require multiple steps of ISF extraction, ISF isolation from MN, and measurement with additional equipment. Here, we present a swellable MN-mounted nanogap sensor that can be inserted into the skin tissue, absorb ISF rapidly, and measure biomarkers in situ by amplifying the measurement signals by redox cycling in nanogap electrodes. We demonstrate that the MN-nanogap sensor measures levodopa (LDA), medication for Parkinson disease, down to 100 nM in an aqueous solution, and 1 μM in both the skin-mimicked gelatin phantom and porcine skin.

Characterization of a Wake-Up Nano-Gap Gas Sensor for Ultra Low Power Operation

This paper reports the performance characterization of a wake-up nano-gap gas sensor with ultra-high-sensitivity due to its dependence on the electron tunneling distance that was experimentally modulated by a structural nano-gap, a chemistry linker length and a molecular size of target gases. The wake-up sensor became activated when the nano-gap was bridged for electron flow by the capture of specific target gas molecules. The fabricated nano-gap sensor demonstrated highly sensitive and selective responses to the dimensional variations in the gaps, the linkers and the target VOCs: (1) only 5-Å difference in either the nano-gap distance or the linker length produced the output signal ratios of two to five orders in magnitudes, indicating ultra-highly-sensitive characteristics; (2) only two carbon length difference of 2.3-Å between target gases with the identical functional group resulted in the output signal ratios of up to four orders in magnitudes, implying the unique distinguish capability of molecular-level length differences, and (3) the selectivity against 7 major interference gas groups in high concentrations (>1,000 ppm) was measured as at least by four orders in magnitude indicating the benefits of size-matching in gas detection on top of conventional chemistry-matching. The fabricated nano-gap gas sensor ultimately showed ultra-low power consumption of 20.08 pW during the sleep mode and repeatability of >10 cycles. These results indicated that the nano-gap sensor can be <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$a$ </tex-math></inline-formula> highly sensitive and selective alternative in gas sensing especially in resource-limited environments. [2022-0039]

Sensing performance of Pd nanogap supported on an elastomeric substrate in a wide temperature range of –40 to 70 °C

We examined the effect of environmental temperature (–40 to 70 °C) on the hydrogen sensing performance of a Pd nanogap sensor supported on an elastomeric polydimethylsiloxane (PDMS) substrate. Sensing tests were conducted using various sensors with different gap widths, prepared with different tensile strains. All sensors operated in an “On-Off” mode with a rapid response time of ~1 s at the operating temperatures. The sensing performance was significantly influenced by the high thermal contraction/expansion properties of the PDMS substrate, depending on the environmental temperature. At subzero temperatures (0, –20, and −40 °C), the sensing performance was improved owing to the gap narrowing. At high temperatures (above 40 °C), it decreased owing to the gap broadening. The detection limit was 300 ppm at subzero temperatures but >1% at high temperatures. The results reveal that the Pd nanogap sensor on PDMS is more suitable for detecting H2 at subzero temperatures. In addition, the sensor showed excellent reproducibility for hundreds of sensing cycles at 25 °C and −40 °C. Furthermore, the sensor was stable to high humidity (above 70 RH%) at 25 °C. Our study demonstrated that the Pd nanogap sensor on a PDMS substrate is a possible candidate for use as an on-board safety H2 sensor in hydrogen-electric vehicles.

Speculation of Nano-gap Sensor for DNA sequencing technology: A Review on Synthetic Nanopores

Nano-gap sensor is the next generation of single molecule analysis that consumes less resources, costs, times and spaces. The ultimate goal of this technology is rendering the ability to determine any living genetic code in several seconds using a portable device. In principle, DNA decryption was determined by tracking electrical signal change when DNA is passed through either natural or synthetic nanometer size gap. This review focuses on the synthetic nanopore, which is more robust, reliable and manageable with ease. Biological nanopore has been researched in parallel; however, the device reproducibility is a controversial issue. The history and development toward the future of this prospect technology will be elaborated attentively. The main limitation of nanopore sensor device is the controlling of DNA translocation dynamic through tiny pore. Many attempts had been tried and the synopsis will be contemplated in the review. Nonetheless, the present results of DNA sequencing have not been satisfied, the development of nanogap sensor is promising for genomic sequencing and molecular biology.

Scalable Nanogap Sensors for Non-Redox Enzyme Assays.

Clinical diagnostic assays that monitor redox enzyme activity are widely used in small, low-cost readout devices for point-of-care monitoring (e.g., a glucometer); however, monitoring non-redox enzymes in real-time using compact electronic devices remains a challenge. We address this problem by using a highly scalable nanogap sensor array to observe electrochemical signals generated by a model non-redox enzyme system, the DNA polymerase-catalyzed incorporation of four modified, redox-tagged nucleotides. Using deoxynucleoside triphosphates (dNTPs) tagged with para-aminophenyl monophosphate (pAPP) to form pAP-deoxyribonucleoside tetra-phosphates (AP-dN4Ps), incorporation of the nucleotide analogs by DNA polymerase results in the release of redox inactive pAP-triphosphates (pAPP3) that are converted to redox active small molecules para-aminophenol (pAP) in the presence of phosphatase. In this work, cyclic enzymatic reactions that generated many copies of pAP at each base incorporation site of a DNA template in combination with the highly confined nature of the planar nanogap transducers ( z = 50 nm) produced electrochemical signals that were amplified up to 100,000×. We observed that the maximum signal level and amplification level were dependent on a combination of factors including the base structure of the incorporated nucleotide analogs, nanogap electrode materials, and electrode surface coating. In addition, electrochemical signal amplification by redox cycling in the nanogap is independent of the in-plane geometry of the transducer, thus allowing the nanogap sensors to be highly scalable. Finally, when the DNA template concentration was constrained, the DNA polymerase assay exhibited different zero-order reaction kinetics for each type of base incorporation reaction, resolving the closely related nucleotide analogs.

A Suspended Low Power Gas Sensor With In-Plane Heater

An ultralow power suspended gas sensor with in-plane heater and nano gap sensor electrodes is presented. The heater and sensing electrodes, separated by 1-μm air gap, are processed using single lithography step with standard micro-fabrication techniques. Controlled electromigration is used to create a nanogap in the middle of the sensing electrode. The sol-gel grown ZnO is dispensed using a picoliter dispenser to bridge the nanogap electrode, created by electromigration, to get required metal oxide film as a sensing element. The gap between the electrode and heater is optimized by electrothermal simulation to obtain desired temperature profile on ZnO. The resulting device exhibits excellent sensing performance for hydrogen (~86% at 20 ppm) at 0.5 mW. A detailed characterization was carried out to analyze the performance of the device. This unique, in-plane structure is superior compared with the conventional out of plane structure in terms of the power efficiency and ease of processing.

Modulating Selectivity in Nanogap Sensors

Interference or crosstalk of coexisting redox species results in overlapping of electrochemical signals, and it is a major hurdle in sensor development. In nanogap sensors, redox cycling between two independently biased working electrodes results in an amplified electrochemical signal and an enhanced sensitivity. Here, we report new strategies for selective sensing of three different redox species in a nanogap sensor of a 2 fL volume. Our approach relies on modulating the electrode potentials to define specific potential windows between the two working electrodes; consequently, specific detection of each redox species is achieved. Finite element modeling is employed to simulate the electrochemical processes in the nanogap sensor, and the results are in good agreement with those of experiments.

Kinetic control of nanocrack formation in a palladium thin film on an elastomeric substrate for hydrogen gas sensing in air

We report the effects of various tensile velocities on the nanocrack formation in a Pd thin film on an elastomeric polydimethylsiloxane substrate and its H2 sensing properties. A tunable nanocrack along the x and y axes was created by mechanical stretching/compression cycles with varying tensile velocities. From the microstructural analyses, we found that the tensile velocity has a significant effect on the crack density but little effect on the average crack width. The Pd nanogap sensor prepared under a high tensile velocity showed a high performance with a low detection limit of 500ppm of H2 in air. Our results indicate that the higher crack density with the narrow nanocrack width (55–100nm) propagated over the entire film provides the enhanced H2 sensing properties in air.

Electrochemical redox cycling in a new nanogap sensor: Design and simulation

We propose a new geometry for nanogap electrochemical sensing devices. These devices consist of two closely spaced side-by-side electrodes which work under redox cycling conditions. Using finite element simulations, we investigate the effects of different geometric parameters on the redox cycling signal amplification to gain insight into the electrochemical sensing performance of the device design. This will allow optimizing the sensor performance of devices to be fabricated in the future.

An electronic sensor array for label-free detection of single-nucleotide polymorphisms

A highly sensitive and selective electronic sensor array for label-free detection of single-nucleotide polymorphisms (SNPs) is described in this work. Its sensing mechanism relies on building target DNA-templated silver nanowires (conductive paths) across a nanogap. Following hybridization with a SNP target, a cocktail of nucleases is applied to the nanogap sensor array. Free capture probes (CPs) and imperfectly hybridized CPs are digested while the perfectly hybridized CPs are covalently joined together over the nanogap at the mutation site. Detection of SNPs down to 0.10fM is realized by measuring the conductance of the nanogap after a simple DNA metallization step. The engagement of the nucleases grants the nanogap sensor excellent ability to discriminate against mismatched sequences and allows hybridization to be carried out at very low stringency (room temperature), enabling a highly selective approach for SNP genotyping. And hybridization at low stringency ensures that all targets will be preferably hybridized at equilibrium. A selectivity factor of 3000 is observed when a mixture of a wild-type and a mutated gene is analyzed by the sensor array. Attempts are made in applying the sensor array to the detection of SNPs in DNA samples extracted from tissues and cultured cells.

Nano-gap-Enhanced Surface Plasmon Resonance Sensors

This paper analyzes how dual-mode surface plasmon resonance sensors can be further improved if one were to introduce small (∼20 nm) gaps in the film surface. First, a figure of merit, the sensor’s limit of detection (LOD), is defined in order to optimize the design of the nano-gap sensor. Secondly, the LOD of this design is compared with that of an optimized planar dual-mode design. Through this analysis, it is shown that the LOD of the planar sensor can be improved upon by around a factor of 7 when compared with the nano-gap-enhanced design. Furthermore, with the nano-gap design, the lower wavelength plasmon mode demonstrates remarkably improved selectivity when compared with the conventional sensor. In order to explain these results, the dispersion of each plasmon mode along with the electromagnetic field profiles are modeled and analyzed.

Mass-Produced Nanogap Sensor Arrays for Ultrasensitive Detection of DNA

In this report, an electrical detection scheme for the quantification of DNA using a nanogap sensor array is detailed. The prime objective is to develop a novel sensing procedure, based on the electronic transduction mechanism, which would mitigate the problems intrinsic to nanostructure-based biosensing devices. Design considerations of the sensor array take into account the feasibility of mass production in a cost-effective way by using standard silicon microfabrication technologies. The sensing mechanism relies on bridging the nanogap upon hybridization of the two termini of a target DNA with two different surface-bound capture probes, followed by a simple metallization step. About 2 orders of magnitude enhancement in conductance, as referred to a clean background (<1.0 pS) observed at a control sensor, was obtained in the presence of as little as 1.0 fM target DNA. This sensitivity is comparable to the best of electrochemical/electrical biosensors. A linear relationship between the conductance and the DNA concentration was obtained from 1.0 fM to 1.0 pM with an exceptional signal intensity of 2.1 x 10(4)% change per unit concentration. This change in conductivity is so large that it can unambiguously detect the concentration of DNA quantitatively and may obviate the need for target amplification used in current DNA tests. Moreover, the sensor array exhibited excellent single-base mismatch discrimination due to its unique vertically aligned nanostructure and the two-probe configuration.

Detection of Rev peptides with impedance-sensors — Comparison of device-geometries

Two different impedance-sensor geometries have been compared for the detection of Rev peptides with a molecular weight of 2.4 kDa. Planar, two-dimensional interdigitated capacitor (IDC) sensors with electrode separations of 1.1 μm as well as three-dimensional nanogap-sensors with an electrode separation of 75 nm have been used. Both sensors have been operated at a fixed frequency of 980 MHz. We discuss the specific interaction of the Rev peptide to an immobilized RNA anti-Rev aptamer (9.2 kDa) for peptide concentrations in the range of 100 nM–2 μM. For the IDC sensor, only peptide concentrations above 500 nM gave detectable signals. For the nanogap sensor, the binding process was clearly visible for all concentrations applied. The higher sensitivity of the nanogap compared to the IDC is ascribed to the improved surface-to-volume ratio.

Theoretical and experimental study towards a nanogap dielectric biosensor

Theoretical and experimental studies of nanogap capacitors as potential label free biosensors are presented. The nanogap device is capable of detecting the existence of single stranded DNA (ssDNA) oligonucleotides (20-mer) in 100 nM aqueous solutions using a 20 nm gap of 1.2 pl in volume. While the dielectric properties of DNA solution have been widely investigated, early approaches are limited at low frequency by the parasitic noise due to the electrical double layer (EDL) impedance. Nanogap electrodes have the potential to serve as biomolecular junctions because their size (5–100 nm) minimizes electrode polarization effects regardless of frequency. In this paper, we modeled the effects of the EDL interaction between two parallel nanogap electrodes by solving the Poisson–Boltzmann (PB) equation for equilibrium state. When the gap size is smaller than the EDL thickness, the dependence of the nanogap capacitance on the ionic strength is insignificant. This is critical in using the capacitance change as an indicator of the existence of target molecules. The predicted capacitance of nanogaps filled with various ionic strength electrolytes was in quantitative agreement with the experimental measurements. The various concentrations of the target molecules in nanogap sensor were characterized. A capacitance change of a 20 nm × (10)1.5 μm × 4 mm gap from 3.5 to 4.1 nF at 200 Hz was recorded between deionized water (DI) and 100 nM ssDNA solution (about 70,000 molecules inside the gap for equilibrium state).