Ultrathin Ionic Diodes with Electrostatically Heterogeneous Hybrid Interfaces of Nanoporous SiO2 Nanofilms and Polymer Layer-by-Layer Multilayers.

Nanofluidic ionic diodes have attracted much attention due to their unique functions as unidirectional ion transportation ability and promising applications from molecular sensing, and energy harvesting to emerging neuromorphic devices. However, it remains a challenge to fabricate diode-like nanofluidic systems with ultrathin film thickness <100 nm. Herein the formation of ultrathin ionic diodes from hybrid nanoassemblies of nanoporous (NP) SiO2 nanofilms and polyelectrolyte layer-by-layer (LbL) multilayers is described. Ultrathin ionic diodes are prepared by integrating polyelectrolyte multilayers onto photo-oxidized NP SiO2 nanofilms obtained from silsesquioxane-containing block copolymer thin films as a template. The obtained ultrathin ionic diodes exhibit ion current rectification (ICR) properties with high ICR factor = ≈20 under low ionic strength and asymmetric pH conditions. It is concluded that this ICR behavior arises from effective ion accumulation and depletion at the interface of NP SiO2 nanofilms and LbL multilayers attributed to high ion selectivity by combining the experimental data and theoretical calculations using finite element methods. These results demonstrate that the hybrid nano assemblies of NP SiO2 nanofilms and polyelectrolyte LbL multilayers have potential applications for (bio)sensing materials and integrated ionic circuits for seamless connection of human-machine interfaces.

Research Progress on Saccharide Molecule Detection Based on Nanopores.

Saccharides, being one of the fundamental molecules of life, play essential roles in the physiological and pathological functions of cells. However, their intricate structures pose challenges for detection. Nanopore technology, with its high sensitivity and capability for single-molecule-level analysis, has revolutionized the identification and structural analysis of saccharide molecules. This review focuses on recent advancements in nanopore technology for carbohydrate detection, presenting an array of methods that leverage the molecular complexity of saccharides. Biological nanopore techniques utilize specific protein binding or pore modifications to trigger typical resistive pulses, enabling the high-sensitivity detection of monosaccharides and oligosaccharides. In solid-state nanopore sensing, boronic acid modification and pH gating mechanisms are employed for the specific recognition and quantitative analysis of polysaccharides. The integration of artificial intelligence algorithms can further enhance the accuracy and reliability of analyses. Serving as a crucial tool in carbohydrate detection, we foresee significant potential in the application of nanopore technology for the detection of carbohydrate molecules in disease diagnosis, drug screening, and biosensing, fostering innovative progress in related research domains.

An Insulin-Modified pH-Responsive Nanopipette Based on Ion Current Rectification.

The properties of nanopipettes largely rely on the materials introduced onto their inner walls, which allow for a vast extension of their sensing capabilities. The challenge of simultaneously enhancing the sensitivity and selectivity of nanopipettes for pH sensing remains, hindering their practical applications. Herein, we report insulin-modified nanopipettes with excellent pH response performances, which were prepared by introducing insulin onto their inner walls via a two-step reaction involving silanization and amidation. The pH response intensity based on ion current rectification was significantly enhanced by approximately 4.29 times when utilizing insulin-modified nanopipettes compared with bare ones, demonstrating a linear response within the pH range of 2.50 to 7.80. In addition, insulin-modified nanopipettes featured good reversibility and selectivity. The modification processes were monitored using the I-V curves, and the relevant mechanisms were discussed. The effects of solution pH and insulin concentration on the modification results were investigated to achieve optimal insulin introduction. This study showed that the pH response behavior of nanopipettes can be greatly improved by introducing versatile molecules onto the inner walls, thereby contributing to the development and utilization of pH-responsive nanopipettes.

Ion Current Rectification Activity Induced by Boron Hydride Nanosheets to Enhance Magnesium Analgesia.

The limited analgesic efficiency of magnesium restricts its application in pain management. Here, we report boron hydride (BH) with ion currents rectification activity that can enhance the analgesic efficiency of magnesium without the risks of drug tolerance or addiction. We synthesize MgB2, comprising hexagonal boron sheets alternating with Mg2+. In pathological environment, Mg2+ is exchanged by H+, forming two-dimensional borophene-analogue BH sheets. BH interacts with the charged cations via cation-pi interaction, leading to dynamic modulation of sodium and potassium ion currents around neurons. Additionally, released Mg2+ competes Ca2+ to inhibit its influx and neuronal excitation. In vitro cultured dorsal root neurons show a remarkable increase in threshold potential from the normal -35.9 mV to -5.9 mV after the addition of MgB2, indicating potent analgesic effect. In three typical pain models, including CFA-induced inflammatory pain, CINP- or CCI-induced neuropathic pain, MgB2 exhibits analgesic efficiency approximately 2.23, 3.20, and 2.0 times higher than clinical MgSO4, respectively, and even about 1.04, 1.66, and 1.95 times higher than morphine, respectively. The development of magnesium based intermetallic compounds holds promise in addressing the non-opioid medical need for pain relief.

An ultrasensitive aptasensor of SARS-CoV-2 N protein based on ion current rectification with nanopipettes.

Since the outbreak of COVID-19 in the world, it has spread rapidly all over the world. Rapid and effective detection methods have been a focus of research. The SARS-CoV-2 N protein (NP) detection methods currently in use focus on specific recognition of antibodies, but the reagents are expensive and difficult to be produced. Here, aptamer-functionalized nanopipettes utilize the unique ion current rectification (ICR) of nanopipette to achieve rapid and highly sensitive detection of trace NP, and can significantly reduce the cost of NP detection. In the presence of NP, the surface charge at the tip of the nanopipette changes, which affects ion transport and changes the degree of rectification. Quantitative detection of NP is achieved through quantitative analysis. Relying on the high sensitivity of nanopipettes to charge fluctuations, this sensor platform achieves excellent sensing performance. The sensor platform exhibited a dynamic working range from 102-106 pg/mL with a detection limit of 73.204 pg/mL, which showed great potential as a tool for rapidly detecting SARS-CoV-2. As parallel and serial testing are widely used in the clinic to avoid missed diagnosis or misdiagnosis, we hope this platform can play a role in controlling the spread and prevention of COVID-19.

Peptide Assembled in a Nano-confined Space as a Molecular Rectifier for the Availability of Ionic Current Modulation.

Bioinspired nanochannels have emerged as a powerful tool for bioengineering and biomedical research due to their robust mechanical and controllable chemical properties. Inspired by inward-rectifier potassium (K+) channels, herein, the charged peptide assembly has been introduced into a nano-confined space for the modulation of ion current rectification (ICR). Peptide-responsive reaction-triggered sequence changes can contribute to polarity conversion of the surface charge; therefore, ICR reversal (ICRR) is generated. Compared with other responsive elements, natural charged peptides show the merit of controllable charge polarity. By electrochemically monitoring the ICRR as an output signal, one can utilize the peptide assembly-mediated ICRR to construct an ionic sensory platform. In addition, a logic gate has been established to demonstrate the availability of an ionic sensory platform for inhibitor screening. As peptide nanoassemblies may also have various structures and functions due to their diverse properties, the ionic modulation system can provide alternatives for the assay of peptide-associated biotargets with biomedical applications.

Ion current rectification behavior of a nanochannel having nonuniform cross-section.

Due to its versatile applications in biotechnology, ion current rectification (ICR), which arises from the asymmetric nature of the ion transport in a nanochannel, has drawn much attention, recently. Here, the ICR behavior of a pH-regulated nanochannel comprising two series connected cylindrical nanochannels of different radii is examined theoretically, focusing on the influences of the radii ratio, the length ratio, the bulk concentration, and the solution pH. The results of numerical simulation reveal that the rectification factor exhibits a local maximum with respect to both the radii ratio and the length ratio. The values of the radii ratio and the length ratio at which the local maximum in the rectification factor occur depend upon the level of the bulk salt concentration. The rectification factor also shows a local maximum as the solution pH varies. Among the factors examined, the solution pH influences the ICR behavior of the nanochannel most significantly.

Reversing current rectification to improve DNA-sensing sensitivity in conical nanopores.

Herein, we report the ultrasensitive DNA detection through designing an elegant nanopore biosensor as the first case to realize the reversal of current rectification direction for sensing. Attributed to the unique asymmetric structure, the glass conical nanopore exhibits the sensitive response to the surface charge, which can be facilely monitored by ion current rectification curves. In our design, an enzymatic cleavage reaction was employed to alter the surface charge of the nanopore for DNA sensing. The measured ion current rectification was strongly responsive to DNA concentrations, even reaching to the reversed status from the negative ratio (-6.5) to the positive ratio (+16.1). The detectable concentration for DNA was as low as 0.1 fM. This is an ultrasensitive and label-free DNA sensing approach, based on the rectification direction-reversed amplification in a single glass conical nanopore.

Regulating Current Rectification and Nanoparticle Transport Through a Salt Gradient in Bipolar Nanopores.

Tuning of ion and nanoparticle transport is validated through applying a salt gradient in two types of nanopores: the inner wall of a nanopore has bipolar charges and its outer wall neutral (type I), and both the inner and outer walls of a nanopore have bipolar charges (type II). The ion current rectification (ICR) behavior of these nanopores can be regulated by an applied salt gradient: if it is small, the degree of ICR in type II nanopore is more significant than that in type I nanopore; a reversed trend is observed at a sufficiently large salt gradient. If the applied salt gradient and electric field have the same direction, type I nanopore exhibits two significant features that are not observed in type II nanopore: (i) a cation-rich concentration polarization field and an enhanced funneling electric field are present near the cathode side of the nanopore, and (ii) the magnitude of the axial electric field inside the nanopore is reduced. These features imply that applying a salt gradient to type I nanopore is capable of simultaneously enhancing the nanoparticle capture into the nanopore and reducing its translocation velocity inside, so that high sensing performance and resolution can be achieved.

Scan-Rate-Dependent Ion Current Rectification in Bipolar Interfacial Nanopores.

This study presents a theoretical investigation into the voltammetric behavior of bipolar interfacial nanopores due to the effect of potential scan rate (1-1000 V/s). Finite element method (FEM) is utilized to explore the current-voltage (I-V) properties of bipolar interfacial nanopores at different bulk salt concentrations. The results demonstrate a strong impact of the scan rate on the I-V response of bipolar interfacial nanopores, particularly at relatively low concentrations. Hysteresis loops are observed in bipolar interfacial nanopores under specific scan rates and potential ranges and divided by a cross-point potential that remains unaffected by the scan rate employed. This indicates that the current in bipolar interfacial nanopores is not just reliant on the bias potential that is imposed but also on the previous conditions within the nanopore, exhibiting history-dependent or memory effects. This scan-rate-dependent current-voltage response is found to be significantly influenced by the length of the nanopore (membrane thickness). Thicker membranes exhibit a more pronounced scan-rate-dependent phenomenon, as the mass transfer of ionic species is slower relative to the potential scan rate. Additionally, unlike conventional bipolar nanopores, the ion current passing through bipolar interfacial nanopores is minimally affected by the membrane thickness, making it easier to detect.

Dynamic Response of Ionic Current in Conical Nanopores.

Ionic current rectification (ICR) of charged conical nanopores has various applications in fields including nanofluidics, biosensing, and energy conversion, whose function is closely related to the dynamic response of nanopores. The occurrence of ICR originates from the ion enrichment and depletion in conical pores, whose formation is found to be affected by the scanning rate of voltages. Here, through time-dependent simulations, we investigate the variation of ion current under electric fields and the dynamic formation of ion enrichment and depletion, which can reflect the response time of conical nanopores. The response time of nanopores when ion enrichment forms, i.e., at the "on" state is significantly longer than that with the formation of ion depletion, i.e., at the "off" state. Our simulation results reveal the regulation of response time by different nanopore parameters including the surface charge density, pore length, tip, and base radius, as well as the applied conditions such as the voltage and bulk concentration. The response time of nanopores is closely related to the surface charge density, pore length, voltage, and bulk concentration. Our uncovered dynamic response mechanism of the ionic current can guide the design of nanofluidic devices with conical nanopores, including memristors, ionic switches, and rectifiers.

Recent advances of small molecule detection in nanopore sensing.

Due to its advantages of label-free and highly sensitive, the resistive pulse sensing with a nanopore has recently become even more potent for the discrimination of analytes in single molecule level. Generally, a transient interruption of ion current originated from the captured molecule passing through a nanopore will provide the rich information on the structure, charge and translocation dynamics of the analytes. Therefore, nanopore sensors have been widely used in the fields of DNA sequencing, protein recognition, and the portable detection of varied macromolecules and particles. However, the conventional nanopore devices are still lack of sufficient selectivity and sensitivity to distinguish more metabolic molecules involving ATP, glucose, amino acids and small molecular drugs because it is hard to receive a large number of identifiable signals with the fabricated pores comparable in size to small molecules for nanopore sensing. For all this, a series of innovative strategies developed in the past decades have been summarized in this review, including host-guest recognition, engineering alteration of protein channel, the introduction of nucleic acid aptamers and various delivery carriers integrating signal amplification sections based on the biological and solid nanopore platforms, to achieve the high resolution for the small molecules sensing in micro-nano environment. These works have greatly enhanced the powerful sensing capabilities and extended the potential application of nanopore sensors.

A bioinspired heterostructured nanochannel based on dendrimer-gold network and aluminum oxide arrays for sensitive detection of miRNA.

BACKGROUND: MicroRNAs, as oncogenes or tumor suppressors, enable to up or down-regulate gene expression during tumorigenesis. The detection of miRNAs with high sensitivity is crucial for the early diagnosis of cancer. Inspired by biological ion channels, artificial nanochannels are considered as an excellent biosensing platform with relatively high sensitivity and stability. The current nanochannel biosensors are mainly based on homogeneous membranes, and their monotonous structure and functionality limit its further development. Therefore, it is necessary to develop a heterostructured nanochannel with high ionic current rectification to achieve highly sensitive miRNA detection. RESULTS: In this work, an asymmetric heterostructured nanochannel constructed from dendrimer-gold nanoparticles network and anodic aluminum oxide are designed through an interfacial super-assembly method, which can regulate ion transport and achieve sensitive detection of target miRNA. The symmetry breaking is demonstrated to endow the heterostructured nanochannels with an outstanding ionic current rectification performance. Arising from the change of surface charges in the nanochannels triggered by DNA cascade signal amplification in solution, the proposed heterogeneous nanochannels exhibits excellent DNA-regulated ionic current response. Relying on the nucleic acid's hybridization and configuration transformation, the target miRNA-122 associated with liver cancer can be indirectly quantified with a detection limit of 1 fM and a wide dynamic range from 1 fM to 10 pM. The correlation fitting coefficient R2 of the calibration curve can reach to 0.996. The experimental results show that the method has a good recovery rate (98%-105 %) in synthetic samples. SIGNIFICANCE: This study reveals how the surface charge density of nanochannels regulate the ionic current response in the heterostructured nanochannels. The designed heterogeneous nanochannels not only possess high ionic current rectification property, but also enable to induce superior transport performance by the variation of surface chemistry. The proposed biosensor is promising for applications in early diagnosis of cancers, life science research, and single-entity electrochemical detection.

Functionalized nanopores based on hybridization chain reaction: Fabrication and microRNA sensing.

Enzyme-free hybridization chain reaction (HCR) technology is often used as a signal amplification tool for the detection of different targets. In this study, an ultrasensitive and label-free method for detecting miRNA-21 was developed using the nanopore ionic current rectification (ICR) technology coupled with HCR technology. The probe oligonucleotide (DNA1) was combined with the gold-coated nanopore through the Au-S bond to form a DNA1-functionalized gold-coated nanopore (DNA1-Au-coated nanopore). Since miRNA-21 is partially complementary to DNA1, it can be selectively recognized by DNA1-functionalized gold-coated nanopores. The target (miRNA-21) can induce the opening of hairpin DNA and HCR reaction after the introduction of hairpin DNA H1 and H2. The concentration of miRNA-21 will affect the combination of H1 and H2 on the inner wall of the nanopore, and its surface charge will change with the internal modification, thereby changing the ion current rectification ratio. Under the condition that the concentration of H1, H2 and HCR reaction time are constant, the change of ICR ratio is linearly correlated with the logarithm of miRNA-21 concentration within a certain range, which shows that the sensing strategy we designed can achieve target miRNA-21 detection. This ultrasensitive miRNA holds great promise in the field of cancer diagnosis.

Effect of membrane thermal conductivity on ion current rectification in conical nanochannels under asymmetric temperature.

Nowadays, there have been extensively theoretical studies on the phenomenon of ion current rectification (ICR) induced by the asymmetric electrical double layer (EDL). As a key factor influencing the behavior of ion transport, temperature is given high priority by researchers. The thermal conductivity of the material commonly employed to prepare nanopores is 2-3 times higher than that of liquid solutions, which may affect ion transport within the nanochannel. However, it is often neglected in previous studies. Thus, we investigate the effect of membrane thermal conductivity on the ICR in conical nanochannels under asymmetric temperature. Based on the PNP-NS theoretical model, the ion current, the rectification ratio, as well as the temperature and ion concentration distributions along the nanochannel are calculated. It is found that the thermal conductivity of the solid membrane noticeably affects the temperature distribution across the nanochannel, altering the ion transport behavior. Larger membrane thermal conductivity tends to homogenize the temperature distribution in the nanochannel, leading to a decline of ionic thermal down-diffusion by a positive temperature difference and ionic thermal up-diffusion by a negative temperature difference, with the former promoting and the latter inhibiting ion current. As a result, the rectification ratio decreases under the positive temperature difference and increases under the negative temperature difference as the thermal conductivity of the membrane increases. These studies will be instructive for the design of nanofluidic diodes and biosensors.

Nanofluidic sensing platform for PNK assay using nonlinear hybridization chain reaction and its application in DNA logic circuit.

In this study, a polyethyleneimine (PEI)/Zr4+-functionalized nanofluidic sensing platform based on nonlinear hybridization chain reaction (NHCR) was developed for PNK activity assay. With the existence of PNK, the hairpin HPNK was cleaved by λ exonuclease, liberating the initiator T-DNA. Then T-DNA triggered the nonlinear HCR in solution and the reaction products were absorbed onto the nanopore, which changed the surface charge of nanofluidic device and could be detected by current-voltage characteristic curves. Compared to traditional linear HCR, the nonlinear HCR exhibits a higher sensitivity and order of growth kinetics, making it a powerful signal amplifier in bioanalysis. Due to the powerful amplification efficiency of nonlinear HCR, high sensitivity of the nanopore and specific recognition site of PNK/λ-Exo, an ultrasensitive and selective PNK sensing approach had been developed and applied to precisely quantitate the PNK activity with a LOD of 0.0001 U/mL. Moreover, utilizing this nanofluidic system as a foundation, we constructed a logic circuit that utilized PNK, adenosine diphosphate (ADP), and (NH4)2SO4 as input elements. ADP and (NH4)2SO4 had a crucial function in facilitating the PNK to regulate the DNA logic gate. By modifying the target and inhibitors, the nanofluidic device could detect a variety of stimuli and execute more advanced logical operations.

Cation pumping against a concentration gradient in conical nanopores characterized by load capacitors.

We study the cation transport against an external concentration gradient (cation pumping) that occurs in conical nanopores when zero-average oscillatory and white noise potentials are externally applied. This pumping, based on the electrically asymmetric nanostructure, is characterized here by a load capacitor arrangement. In the case of white noise signals, the conical nanopore acts as an electrical valve that allows extraction of order from chaos. No molecular carriers, specific ion pumps, and competitive ion-binding phenomena are required. The nanopore conductance on/off states mimic those of the voltage-gated ion channels in the cell membrane. These channels allow modulating membrane potentials and ionic concentration gradients along oscillatory pulses in circadian rhythms and the cell cycle. We show that the combination of asymmetric nanostructures with load capacitors can be useful for the understanding of nanofluidic processes based on bioelectrochemical gradients.

Multi-Layered Bipolar Ionic Diode Working in Broad Range Ion Concentration.

Ion current rectification (ICR) is the ratio of ion current by forward bias to backward bias and is a critical indicator of diode performance. In previous studies, there have been many attempts to improve the performance of this ICR, but there is the intrinsic problem for geometric changes that induce ionic rectification due to fabrication problems. Additionally, the high ICR could be achieved in the narrow salt concentration range only. Here, we propose a multi-layered bipolar ionic diode based on an asymmetric nanochannel network membrane (NCNM), which is realized by soft lithography and self-assembly of homogenous-sized nanoparticles. Owing to the freely changeable geometry based on soft lithography, the ICR performance can be explored according to the variation of microchannel shape. The presented diode with multi-layered configuration shows strong ICR performance, and in a broad range of salt concentrations (0.1 mM~100 mM), steady ICR performance. It is interesting to note that when each anion-selective (AS) and cation-selective (CS) NCNM volume was similar to each optimized volume in a single-layered device, the maximum ICR was obtained. Multi-physics simulation, which reveals greater ionic concentration at the bipolar diode junction under forward bias and less depletion under backward in comparison to the single-layer scenario, supports this tendency as well. Additionally, under different frequencies and salt concentrations, a large-area hysteresis loop emerges, which indicates fascinating potential for electroosmotic pumps, memristors, biosensors, etc.

Glass Capillary-Based Nanopores for Single Molecule/Single Cell Detection.

A glass capillary-based nanopore (G-nanopore), due to its tapered tip, easy tunability in orifice size, and especially its flexible surface modifications that can be tailored to effectively capture and enhance the ionic current signal of single entities (single molecules, single cells, and single particles), offers a powerful and nanoconfined sensing platform for diverse biological measurements of single cells and single molecules. Compared with other artificial two-dimensional solid-state nanopores, its conical tip and high spatial and temporal resolution characteristics facilitate noninvasive single molecule and selected area (subcellular) single cell detections (e.g., DNA mutations, highly expressed proteins, and small molecule markers that reflect the change characteristics of the tumor), as a small G-nanopore (≤100 nm) does negligible damage to cell functions and cell membrane integrity when inserted through the cell membrane. In this brief review, we summarize the preparation of G-nanopores and discuss the advantages of them as solid-state sensing platforms for single molecule and single cell detection applications as well as for cancer diagnosis and treatment applications. We also describe the current bottlenecks that limit the widespread use of G-nanopores in clinical applications and provide an outlook on future developments. The brief review will provide the reader with a quick survey of this field and facilitate the rapid development of a G-nanopore sensing platform for future tumor diagnosis and personalized medicine based on single-molecule/single-cell bioassay.

Asymmetric Nanochannel Network-Based Bipolar Ionic Diode for Enhanced Heavy Metal Ion Detection.

A higher rectification degree in ionic diodes is required to achieve better performance in applications. Nonetheless, the active geometrical change that is critical for inducing electrical potential asymmetry is difficult to realize in typical ionic diodes because of the intrinsic limitation of the fabrication method. Here, we propose a nanochannel-network-based bipolar diode with a high rectification degree of ∼1600─the highest value realized until now, to the best of our knowledge. Such a high rectification is obtained based on the synergetic effect of the bipolar surface charge and the optimization of the microchannel through experimental studies and multiphysics numerical simulations. It induces ion concentrations at the heterogeneous junction based on the accumulation effect under the forward potential bias. In particular, this proposed molecular concentration occurs in the ohmic region without vortex and instability that is inevitable at the conventional nano-electrokinetic concentration. Combining this accumulation with the horizontally aligned configuration of the nanochannel network membrane (NCNM), a highly sensitive and quantitative mercury ion (Hg2+) sensor based on a fluorescent signal is fabricated that allows direct measurement using a general fluorescent microscope. The detection limit of Hg2+ is 10 pM, which is ∼10 times lower than the best detection limit realized so far (∼100 pM) in fluorescent dye-based detection. This demonstrates the potential of asymmetric NCNM for high-performance ion transport in applications such as energy conversion, based on its design and material flexibility.