Wireless Bipolar Nanopore Electrode for Single Small Molecule

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A Wireless Bipolar Nanopore Electrode for Single Small Molecule Detection Rui Gao, Yi-Lun Ying, Yong-Xu Hu, Yuan-Jie Li, and Yi-Tao Long Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.7b00729 • Publication Date (Web): 27 Jun 2017 Downloaded from http://pubs.acs.org on June 27, 2017

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Analytical Chemistry

A Wireless Bipolar Nanopore Electrode for Single Small Molecule Detection Rui Gao, Yi-Lun Ying*, Yong-Xu Hu, Yuan-Jie Li and Yi-Tao Long* Key Laboratory for Advanced Materials & School of Chemistry and Molecular Engineering, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, P. R. China. E-mail: [email protected]; [email protected]. Phone: +86-021-6425-2339. ABSTRACT: Solid-state nanopore-based techniques have become a promising strategy for diverse single molecule detections. Owing to the challenge in well and rapid fabrication of solid-state nanopores with the diameter less than 2 nm, small molecule detection is hard to be addressed by existing label-free nanopore methods. In this work, we for the first time propose a metal-coated wireless nanopore electrode (WNE) which offers a novel and generally accessible detection method for analyzing small molecules and ions at single molecule/ion level. Here, a silver-coated WNE is developed as a proof-of-principle model which achieves to detect the self-generated H2, the smallest known molecule, and Ag+ at single molecule/ion level by monitoring the enhanced ionic signatures. Under a bias potential of -800 mV, the WNE could accomplish the distinction of as low as 14 H2 molecules and 28 Ag+ from one spike signal. The finite element simulation is introduced to suggest that the generation of H2 at the orifice of the WNE results in the enhanced spike of ionic current. As a proof-of-concept experiment, the WNE is further utilized to directly detect Hg2+ from 100 pM to 100 nM by monitoring the frequency of the spike signals. This novel nanoelectrode provides a brand new labelfree, ultra-sensitive and simple detection mechanism for various small molecules/ions detection, especially for redox analytes.

Solid-state nanopore has been widely employed for single-molecule detection over the past two decades.1 Generally, the single-molecule detection by using nanopore is based on the resistive-pulse sensing, which utilizes a bias potential to drive a single molecule through the confined space.2 As a single molecule blocks the ionic current of nanopore, it causes a temporary pulse correlating to the characteristics of the analytes. By analyzing the ionic signatures, nanopores act as the distinct electroanalytical tools for studying DNAs, RNAs, peptides and proteins, especially the DNA sequencing.3-10 Due to the confined space effect of nanopores, the dimension of analytes should be comparable to the pore size in order to ensure a high signal-to-noise ratio. However, it is hard to rapidly fabricate a solid-state nanopore with a well controllable diameter less than 2 nm. Therefore, it brings the big challenges of solid-state nanopores for directly detecting small molecules such as small gasotransmitters, neurotransmitters, or other signaling molecules, more less the metal ions. Previous studies proposed to employ the modification of nanopores and/or to introduce the binding aptamer of analytes to realize the detection of amino acid,11,12 organic small molecules,13,14 and metal ions.15-17 However, these approaches need the complicated design as well as introduction of additional probes. To the best of our knowledge, no reports have achieved to develop easily applicable nanopores to directly detect single small molecule without labeling and modification.

Figure 1. (a) Illustration of H2 and Ag+ sensing by a WNE at single-molecule level. Since the silver layer of a WNE could be polarized under the electric field, the generation of H2 and Ag+ occurs at the two extremities of the silver layer, respectively. The applied potential is provided by a pair of Ag/AgCl electrodes. The working electrode is inserted in the WNE, and the other electrode at the outside solution of WNE is defined as the virtual ground in the opposite side of nanopore. The bulk area out of the orifice and the area inside the WNE are defined as trans side and cis side, respectively. (b) The raw current traces of the bare nanopore and the WNE at -800 mV. Compared to the stable current trace of the bare nanopore, large amounts of spike signals are observed from the WNE. The pentagram denotes the typical spike signal shown in the insert.

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Here, we present a wireless nanopore electrode (WNE) which offers a novel and generally accessible detection mechanism for the detection of single small molecules and ions (Figure 1a). Taking advantages of bipolar electrochemistry, as exposed to an external electric field in a solution, the conductive WNE ensures a certain polarization potential difference at its two terminals. Therefore, the WNE could behave as an anode and a cathode simultaneously.18 As a proof-of-principle model, the silver coated WNE is applied to monitor H2, the smallest known molecule, and Ag+ respectively. These two species are generated at two poles of the WNE. By observing the continuous abundant enhanced spike signals in the current trace of the WNE under a bias potential (Ebias) of -800 mV (Figure 1b), the WNE has achieved the distinction of as low as 14 H2 molecule and 28 Ag+ from one spike signal. The finite element method simulation (FEM) results suggest that the generation of H2 at the orifice of the nanopore produces the enhanced spike of ionic current. By employing the reduction of Hg2+ as a prior reduction reaction to the reduction of H+, the decrease of the spike signals reveals an outstanding ability of the WNE to achieve the direct detection of Hg2+ from picomole to nanomole. Therefore, WNE proposes a novel analysis method with label-free, ultra-sensitive and simple detection mechanism for small molecules and ions detection.

EXPERIMENTAL SECTION Chemicals. KCl and absolute ethanol were purchased from SigmaAldrich Co., Ltd. (St. Louis, MO). H2SO4 and H2O2 were purchased from Sinopharm Chemical Reagent Co., Ltd (Shanghai, China). Mercuric (II) acetate was purchased from the Guanghua Sci-Tech Co., Ltd (Guangdong, China). The solutions were prepared using ultrapure water (18.2 MΩ cm at 25 °C) from a Milli-Q system (Billerica, MA). All reagents and materials are of analytical grade. Fabrication of wireless nanopore electrode. The quartz pipettes with 0.5 mm inner diameter and 1 mm outer diameter (QF100-50-10, Sutter Instrument Co., USA) were used to fabricate the WNEs. The pipettes were treated with lab-prepared piranha solution (3:1 98% H2SO4 / 30% H2O2) for 30 min to wipe off the organics on the surface. [Warning: piranha solution reacts strongly with organic compounds and should be handled with extreme caution] Then, the pipettes were rinsed by absolute ethanol and the deionized water and dried at 100 °C before pulling. The bare nanopores with diameter of ~50 nm were fabricated by using a P-2000 CO2-laser puller (Sutter Instrument Co., USA) with the following parameter: Heat = 625, Fil =4, Vel = 60, Del = 150, Pull = 192. Then, a silver nanolayer was coated on the surface of bare nanopores by electron beam evaporation technique with a deposition speed of 1 Å/s. In order to guarantee the evaporated silver could stick on the inner wall of the nanopipette through the orifice, the nanopipette is placed in the center area in the vacuum cell (Figure S1). Electrical Measurements and Data Analysis. A PDMS flow cell with two compartments was utilized to hold a WNE. Both two compartments were filled with KCl solution as the electrolyte. After adding solution, the device was degassed under vacuum for five minutes to remove the air bubbles. The potential is applied by using a pair of Ag/AgCl electrodes. The electrical measurements were per-

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formed on a patch clamp amplifier (Axon 200B, Molecular Devices Co., USA) with the integrated bessel low-pass filters (5 kHz) and acquired at a sampling rate of 100 kHz with an Analog-Digital converter (Digidata 1550A, Molecular Devices, USA). The electric measurements were performed at room temperature (25 °C). The data analysis was performed by home-designed software (people.bath.ac.uk/yl505/nanoporeanalysis.html),19 the data plot was drawn by Matlab 2014b and OriginLab 9.0 (OriginLab Corporation, Northampton, MA). Finite-Element Simulations. The finite element simulation was calculated by COMSOL Multiphysics software (COMSOL Inc.) on a high-performance desktop workstation (Intel Xeon 1620 CPU, 32 G RAM). In our simulations, the geometry parameters of the WNE including the nanopore diameters, the length of the Ag layer, and the half-cone angle of the conical-shaped pore (θ) were set to be 45 nm, 5 µm, and 6°, respectively. The ionic current through the WNE is calculated by the general current calculation equation.20 Details of the FEM simulation are provided in Figure S2-4 and the section of “FEM simulation process for the WNE” concludes in Supporting Information.

RESULTS AND DISCUSSION Characterization and FEM Simulation of WNE. To fabricate the WNE, the pulled bare nanopore with a diameter of ~50 nm was coated with a silver nano-layer by the electron beam evaporation technique. Here, the scanning electron microscope (SEM) images of the bare nanopore and the WNE were showed in Figure 2a-b, respectively. With a silver coating layer, the diameter of WNE is ~ 45 nm. The Current-Voltage (I-V) characterization was demonstrated in Figure 2c by applying Ebias ranging from -1000 mV to 1000 mV in 10 mM KCl solution. The rectification ratio (defined as R value) of negative absolute current values to the positive current values at ±1000 mV indicates the high reproducibility of WNEs (Figure 2c, insert). Here, the FEM simulation was used to compute I-V curves of the bare nanopore and the WNE, respectively. For the bare nanopore, there is a negative surface charge on the walls, resulting in the R value of 3.06. Since the polarization could significantly influence the surface charge density of the silver layer, we described the surface charge density distribution of the WNE by the following logistic-type function equation:21,22 2 σ = σ − 1 1 1 + exp − − where σ is the surface charge density of the silver layer, σ0 is the maximum polarization potential at the orifice of the WNE, k is associated with the confined geometry of polarization region, z0 is the position of the midpoint on the silver layer. k = 107 was set in this simulation according to the previous study.22 In our FEM simulation, the coupled Poisson-NernstPlanck (PNP) equation and Navier-Stokes equation were used to simulate the I-V curves. The geometry of the model is based on the dark-field image and the SEM characterization of the WNE shown in Figure 2 and Figure S4-S5, respectively. As a bipolar electrode, the polarized degree of the conductive metal depends on the length of the silver layer. In order to estimate the length of bipolar silver layer, the focused ion beam (FIB) was utilized to sculpt the side-


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wall of the WNE from the tip area to the tail area (Figure S5). Combining with the energy dispersive spectroscopy (EDS), the effective length of the silver layer is measured as approximately 5 µm (Figure S5). Therefore, the modeling of our experimental conditions is d = 45 nm, θ = 12°, lAg film = 5 µm and lnanopore = 25 µm. The electrolyte solution parameters for the ionic species were chosen to reflect a 10 mM KCl solution which are Dk+ = 1.957 × 10-9 m2/s, cK+ = 0.01 M, D -9 2 Cl = 2.032 × 10 m /s, c Cl = 0.01 M at T = 298 K (Figure S2-3). According to the simulation results, the I-V curves computed by FEM simulation are consistent with the experiment results, which suggest the following mechanisms: 1) the silver layer endures the polarization under applied potential; 2) the polarization accounts for the rectification of WNEs.

Figure 2. Characterizations of WNEs. The SEM image of the (a) bare nanopore and (b) of the WNE. (c) The I-V curves of the bare nanopore and the WNE from the experiments and the FEM simulations, respectively. R values of 5 individual WNEs shown in the insert. The R value of negative absolute current values to the positive current values at ±1000 mV was used to quantify the ion current rectification properties.

Single Molecule Level Ag+/H2 Detection via a WNE. Conventional bipolar electrochemistry indicates the faradic reactions could take place at its two terminals when a sufficient Ebias applied.23 Here, the maximum polarization potential difference of presented WNE occurs between two extremities of the silver-coated part along the applied electric field orientation, which is used to induce the electrochemical reaction at the interface of inner wall of WNEs. In this experiment, the applied potential is provided by a pair of Ag/AgCl electrodes. The working electrode is inserted in the WNE, and the other electrode is defined as the virtual ground in the opposite side of nanopore. The 10 mM KCl solution is used as the only electrolyte. This simple device ensures the easily accessibility of this method. We hypothesize the following reactions happen at the cathodic and anodic poles of the WNE under a sufficient Ebias, respectively: 2H + 2 → = 0 mV versus SHE 2

Ag s → ' + 2 = 799.6 mV versus SHE 3 According to the equation (1) and (2), the minimum potential difference (∆Vmin) is ideally 799.6 mV for this pair of electrochemical reactions. Figure 3 shows the current traces with different Ebias from -700 mV to -1000 mV. When the Ebias is -700 mV, merely few signals could be observed which reveal the electrochemical reaction in WNE could hardly take place at such potential. Then, with the rise of the Ebias from -800 mV to -1000 mV, increased abundant signals were presented with a higher frequency (Figure S6). Interestingly, the faradic reaction could intensively occur at the Ebias higher than -800 mV, as the ideally ∆Vmin is equal to 799.6 mV. Therefore, the ∆Vmin is approximately equal to the absolute value of the Ebias for this WNE system. When the Ebias is lower than the potential difference of the two faradic reactions (∆Vmin = -700 mV), the WNE is difficult to induce the electrochemical reactions (Figure S7). As the reaction rate increases with the rise of the bias potential, the sufficient amount of H2 gas is rapidly produced within our WNEs. Therefore, at high Ebias, both frequency of spike signals and the current amplitude could be enhanced with the violent reactions. It should be note that the high Ebias leads the wide length of the cathodic pole of WNE to reach the required ∆Vmin for the pair of redox reaction in our experiments. Therefore, the H2 nanobubble could generated at a wide length of the conical tip in WNEs, which might produce a board current distribution (Figure 3). As demonstrated in previous studies, 24,25 H2 in water solution prefer to absorb OH- on gas/water interface. As described in previous studies,20,26,27 the translocation of charged nanoparticles including “soft” and “hard” particles through a tip of conical nanopore could induce an increased ionic conductivity. Therefore, enhanced spike signals observed from the entire ionic current trace may attribute to the generation of H2 nanobubbles as “soft” nanoparticles. As suggested by the previous studies,28,29 the effective sensing length of the conical nanopore is on the order of 200 nm from its orifice where the occurrence of the analytes will induce a current oscillation. Under the sufficient negative Ebias, the generation of H2 occurs at the orifice where is very sensitive to the existence of the analyte. In order to verify the proposed mechanism, we applied positive Ebias on the working electrode. On this occasion, H2 nanobubbles could be produced at the other side of the WNE because the orifice has been polarized as an anodic electrode which induces the stripping of Ag+. With the Ebias consistently increases from 0 mV to higher positive potential, spike signals were scarcely observed either. These results reveal that the generation of H2 at the cathodic pole could not influence the ionic current through the nanopore. Oppositely, when the working electrode position is swapped with the virtual ground electrode, the H2 nanobubbles could be generated at the orifice under the sufficient positive Ebias. Accordingly, the spike frequency is increased with the positive potential rising (Figure S8). Overall, these results further suggest that the spike signals originate to the generation of H2 at the orifice of the WNE.



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Figure 3. The current traces (right column) and the peak current distribution (left column) of the WNE at different Ebias from -700 mV to -1000 mV (up to bottom). The pentagrams denote the typical spike signals shown in the insert.

Bipolar Electrochemistry Based Detection Mechanism of a WNE. To further explore the bipolar electrochemical process, we employed the FEM to simulate the potential distribution in the WNE. The result demonstrates that the largest fraction of the voltage drop occurs within a confined silver-coated region at the narrowest tip of the WNE (Figure 4a). The potential drop from the cathodic pole (z = 0 µm) to the anodic pole of the silver layer (z = -5 µm) at applied voltage of 1000 mV is approximated to 980 mV. The conductance from non-coated conical area of the nanopore as well as the KCl solution has limited contribution to the potential decrease. Therefore, we further revealed that the potential drop fraction in WNE is close to the bias potential. For conventional bipolar electrochemistry, a high Ebias, usually 3 order larger than the bias potential,23 is needed so that the conductive bipolar electrode could gain a sufficient potential difference for the reactions. While benefitted from the geometry property of nanopores, it enables the electrochemical reaction taking place under such a low bias potential without the demands of high voltage power supply. More importantly, it is convenient to direct regulate the Ebias to induce the different bipolar reactions. The insert 2D plot in Figure 4a shows the potential distribution in the nanopore and the trans side solution. Moreover, the conical part of the nanopore determines a higher electric field efficiency than the traditional bipolar system. Here, the electric field for electrodissolution of silver could be estimated at more than 160 kV m-1 at an applied bias potential of only 1 V according to the simulation results of electric potential distribution. While in the traditional bipolar system, the potential of hundreds of kilovolt is required to reach the same electric field intensity. Therefore, it could achieve the electrochemical reactions by the simple, inexpensive and safe WNE techniques. The profile of silver layer surface charge density from the anodic pole to the cathodic pole is showed in Figure 4b. Owing to the polarization of the silver layer in an electric field, from the anodic pole (z = -5 µm) to the middle of the silver layer (point B, z = -2.5 µm), there exists a positive surface charge distribution. Oppositely, from point B to the cathodic pole (z = 0 µm), the charge density is negative.

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Figure 4c indicates the silver layer/KCl solution interfacial potential profile when applying the bias potential. Owing to the polarization of the silver layer under the electric field, the interfacial potentials own a reversed polarity for the anodic pole and the cathodic pole, which enable the bipolar electrochemical reactions. There is a distinct interfacial potential at points A (z = -3.0 µm) and C (z = -2.0 µm), respectively, while the interfacial potential at point B is not observed clearly because the it is uncharged at this point of the silver layer. From previous study,30 H2 generated on Pt nanodisk electrodes has the critical diameter (d) of 6 - 8 nm. Therefore, we suggest the H2 nanobubbles could undergo an appearingdisappearing process on the surface of nanoelectrodes. Here, we performed the FEM simulation to rationalize the suggestion that the generation of negatively charged H2 at the sensing zone of WNE oscillates the ionic current through the WNE. The nanobubble was introduced in the surface of the cathodic pole (z = 0 µm) of WNE by using a 2D model of the WNE (Figure S3). In the FEM simulation, the diameter of nanobubble increased incrementally from 1 nm to 10 nm to simulate the growth-dissolution of the nanobubble, respectively. The H2 with surface charge density of -0.005 C/m2 30 was set in the simulation. Figure 4d (I-V) indicates the concentration profile of KCl with the presence of a H2 nanobubble in different diameters. The concentration of KCl around the nanobubble could be influenced greatly with the size increase of the nanobubble. The simulated currentdiameter curve (I-d curve) for a 10 nm-diameter nanobubble generation into the solution at Ebias = -800 mV in 10 mM KCl solution shows a dramatically enhanced trend of the ionic current (Figure 4d, VI). This simulation result is similar to the experiment result in Figure 3, which indicates the result predicts the shape of the spike current observed in experiments. We suggested that the nanobubble gradually releases its pressure after equilibrium reached to the critical supersaturations.30 The conversion of the simulated I-d curve to the experimentally recorded I-t curve requires knowing the dissolving rate of H2 nanobubbles, which is complicated by the heterogeneous nucleation and electrostatic interactions between nanobubbles and the WNE. As a result, the simulated I-d curve may support our hypothesis in which rapid growth of the nanobubble enhances ion accumulation followed by a dissolution. The bipolar electrochemistry suggests that the electrons required at the cathodic pole originate from a proportional oxidative reporting reaction at the anodic pole. As the concentration of stripped Ag+ increased from -700 mV to -1000 mV, the events frequency from H2 bubbles at the cathodic pole increased from 50 s-1 to 111 s-1. Therefore, the quantity of stripped Ag+ at the anodic pole could be roughly evaluated by the volume of H2 bubbles. The ideal H2 volume of a 10 nm diameter nanobubble generated in our experiments is approximately 523 nm3 amounting to around 14 H2 molecules (standard state). Owing to charge conservation in electrochemical reactions, it reflects 28 Ag+ stripped during the entire 10 nm diameter H2 bubble generation process. Therefore, the WNE could address the challenge of detecting small molecules and ions at single molecular level.


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Analytical Chemistry 0.73 to 0.15. We anticipant that this WNE could be capable of the quantitative detection of various electroactive ions and/or molecules by optimizing the detection process.

Figure 4. (a) The FEM simulation of the distributed biased potential along the position of the nanopore. The blue area marks the conical part of the nanopore and the yellow area marks the length of the silver layer inside the WNE (5 µm). (b) The surface charge density profile of silver layer from the anodic pole (z = -5 µm) to the cathodic pole (z = 0 µm). (c) The silver layer/solution interfacial potentials of point A, B, and C in (b) under the electric field. (d) The simulated size-dependent distributions of KCl concentration (I-V) and the I-d trace (VI) for a 10 nm-diameter nano-bubble generation process.

Detection of Hg2+ via the WNE. The formation of nanobubbles leads to an intense spikelike current response after applying the sufficient bias potential. By designing the specific electrochemical reactions on the WNE, the electroactive target molecules and/or ions could be precisely monitored in real time. To prove this sensing mechanism, here, a direct and label-free Hg2+ detection was achieved by incorporating with this silver-coated WNE. Figure 5a shows the raw current traces and the histograms of WNE before and after the addition of Hg2+ with concentrations from 100 pM to 100 nM under the -800 mV bias potential, respectively. Since the reduction potential of the reaction from Hg2+ to Hg is higher than the reduction potential of the H2 generation from H+, the reduction of Hg2+ could replace the reduction of H+ as a prior reaction taking place at the cathodic pole. Therefore, frequency of the spike signals is decreased after addition of Hg2+. By calculating the f ratio before and after addition of Hg2+ (fWNE/ fWNE-Hg), there is a positive correlation between the Hg2+ concentration and the value of fWNE /fWNE-Hg (Figure 5b). The increasing concentration of Hg2+ in trans side from 100 pM to 100 nM leads to the frequency of spike signals (f) decreasing from

Figure 5. (a) The original current traces (left) and the histograms (right) of a WNE before (i) and after addition of Hg2+ in the trans side with the concentration of 100 pM (ii), 1 nM (iii), 10 nM (iv), and 100 nM (v), respectively. (b) The ratio of frequency (fWNE/ fWNE-Hg) for the Hg2+ concentration of 100 pM (red), 1 nM (yellow), 10 nM (green), and 100 nM (blue), respectively.

CONCLUSIONS In summary, the novel WNE is an easy-fabricated single molecule detection tool for the detection of small molecules and ions. In this proof-of-principle experiment, the WNE was introduced to detect H2 and silver ions by observing the ionic current signatures. The FEM simulation suggests the H2 nanobubbles could induce the enhanced spike signals under the electric field. Furthermore, the detection of Hg2+ from 100 pM to 100 nM was implemented by monitoring the decrease of the spike signal frequency. The WNE confines electrochemistry into a nanopore, which exhibits a promising ability in regulating charge density and electric field along the nanopore. Therefore, this characteristic enables the WNE to amplify the single molecule signal via charged nanobubbles. By designing sophisticated bipolar reactions, the ultralow-concentration electroactive small



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molecules and/or ions such as neurotransmitters, signaling molecules could be detected by WNEs. Taking advantages of multi bipolar electrode arrays, 32-34 WNEs could further achieve the simultaneous multiplexing detections of electroactive molecules. In a WNE, a sufficiently high electric field is generated at the narrowest tip of nanopore, which only require millivolts bias potential to induce the electrochemical reaction. In contrast to the high applied potential of kilovolts desired by the traditional bipolar electrode, this method could be widely utilized in non-invasive cellular detection. The wireless capacity of WNE further ensures remote transportation and delivery of selected molecules and ions to its targets in cells. Promisingly, WNE will achieve image of redox signalling molecules in- and outside of the living cells as Scanning Electrochemical Microscope (SECM) and other advanced electrochemical detection methods.35-37 Combining these features, WNEs could also play an important role in accurate, high-efficiency and rapid nanofabrication with low energy consumption.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. The illustration of the electron beam evaporation coating set-up (Figure S1), the FEM simulation process for WNE, the description of the finite-element simulation model (Figure S2 and S3), the dark-field image of the WNE (Figure S4), the characterization of the WNE with FIB and EDS (Figure S5), The spike frequency under different applied potentials (Figure S6) and raw current traces for the WNE at different bias potentials (Figure S7 and S8).

AUTHOR INFORMATION Corresponding Author * E-mail: [email protected]; [email protected]. Phone: +86-021-6425-2339.

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT This work was supported by the National Natural Science Foundation of China (21421004,21327807, and 21505043) and the Fundamental Research Funds for the Central Universities (222201718001, 222201717003, and 222201714012). The authors would like to thank Center for Advanced Electronic Materials and Devices, Shanghai Jiao Tong University for providing the SEM characterization.

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