A Nanoscale Multichannel Closed Bipolar Electrode Array for

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A Nanoscale Multi-channel Closed Bipolar Electrode Array for Electrochemiluminescence Sensing Platform Qingfeng Zhai, Xiaowei Zhang, Yanchao Han, Junfeng Zhai, Jing Li, and Erkang Wang Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.5b03685 • Publication Date (Web): 24 Nov 2015 Downloaded from http://pubs.acs.org on November 28, 2015

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Analytical Chemistry

A Nanoscale Multi-channel Closed Bipolar Electrode Array for Electrochemiluminescence Sensing Platform Qingfeng Zhai, †‡ Xiaowei Zhang, †‡ Yanchao Han, † Junfeng Zhai, † Jing Li,*,†

Erkang Wang*,† †

State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of

Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, 130022, China. ‡

University of Chinese Academy of Sciences, Beijing, 100039, China.

*Corresponding Author E-mail: [email protected] (J. Li);[email protected] (E. Wang) Tel: +86-431-85262003. Fax: +86-431-85689711.

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ABSTRACT In this work, We reported a nanoscale multi-channel closed bipolar electrode (BPE) array based on poly(ethylene terephthalate) (PET) membrane for the first time. With our design, oxidants, co-reactants, quenchers even biomarkers can be detected in Ru(bpy)32+/TPA (tripropylamine) electrochemiluminescence (ECL) system. The multi-channel PET membrane was etched according to our desire by NaOH, and then Au nanofibers were decorated in the inner of the channel as BPE array. Using ECL as signal readout, a series of targets including TPA, Ru(bpy)32+, dopamine, H2O2, alpha-fetoprotein (AFP) and carcino-embryonic antigen (CEA) can be detected with this device. The practical application of the proposed multi-channel closed BPE array was verified in the detection of AFP and CEA in human serum with satisfying result. This kind of nanoscale device holds promising potential for multi-analysis. More importantly, as the PET membrane used in this device can be etched with desirable diameter (nano to micro scale) and different BPE array density (ion tracks of 108/cm2, 106/cm2, 104/cm2), our design can be served as a useful platform for future advances in nanoscale bipolar electrochemistry.

INTRODUCTION Electrochemiluminescence (ECL) is the process in which electrochemical species are generated at the surface of the electrode, and then undergo highly-energetic electron transfer (redox or enzymatic) reactions to emit light from excited states.,1,2 It does not require the use of external light sources and has been 2


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widely applied in various fields as a powerful analytical technique due to high sensitivity and nearly zero background signal in DNA analysis,3,4 environmental detection5,6 and clinic diagnostics7,8. In 2001, ECL was first introduced to bipolar electrode (BPE) system as signal readout for the detection of co-reactants and quenchers by Manz and co-workers9. Since then, BPE system with ECL as analytical tool has attracted considerable attention and was widely used in various sensing devices.10-12 BPE is an electronic conductor that is immersed into the solution, when the power is supplied without any electrical connection; it can act as both anode and cathode.13,14 According to the current flow path, BPE can be classified as open and closed BPE. Particularly necessary to point out that the anode and cathode in the closed BPE system are physically separated from each other, and the only way that the current can pass through two separated electrolytic cells is by BPE15. In addition, the reporting reaction and supporting reaction occur respectively in two separated electrolytic cells so that it can provided 100% current efficiency. Based on this special design, it has been widely used for the detection of co-reactants18,23,24, prostate-specific antigen (PSA),16 DNA,10 cancer biomarkers,14 etc. Recently, Zhang’s group have fabricated a large electrochemical array containing thousands or more parallel bipolar microelectrodes using 10 µm diameter carbon fiber electrode, and demonstrated its imaging transient and heterogeneous electrochemical properties with the electrochemical processes of fluorescence-enabled electrochemical microscopy (FEEM).17,18 Because it needs to use an array of thousands or more individually and 3



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simultaneously addressable microelectrodes, so there are several major challenges including microelectrodes array fabrication. However, the microfluidic channel was mostly fabricated on the substrate of ITO glass based on traditional photolithography and wet chemical etching techniques, the construction process was much more complex. Furthermore, the diameter of the channel could only be achieved to several micrometres based on above strategy, while the nanoscale channel was difficult to obtain. Poly(ethylene terephthalate) (PET) membrane, with good electrical insulation and mechanical stability, has attracted extensive interest of researchers.19,20 Moreover, one unique feature of PET membrane is that the diameter of the ion channel embedded in the PET membrane can be etched according to our desires, which provided a facile approach to fabricate nanoscale multi-channel. Combined with target recognition molecule and two reporting signals including resistive-pulse sensing (RPS)21 and ion-current rectification (ICR)22, PET membrane with nanoscale channel has been widely used in bioanalysis23,24, ion gates25 and other fields.26,27 Based on the above consideration, we make full use of the native embedded nanochannel in the PET membrane to design a nanoscale multi-channel BPE array; it addressed the challenges in fabrication microelectrodes or smaller size electrodes array. The fabricated nanoscale multi-channel BPE array has been used for the sensitive detection of various analytes using the powerful ECL technique as reporting signal. Au nanofibers as BPE array were decorated into the inner channel of PET through electrochemical or chemical deposition. Two driving electrodes were inserted into the cell between the two ends of the BPE to supply the power to induce the 4


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wireless faradaic reactions (Scheme 1). The PET membrane with deposited Au nanofibers was placed between the two cells as BPE array, and two Pt electrodes connecting with external power supply were respectively inserted into the two cells as driving electrodes to induce faradaic reactions.

EXPERIMENTAL SECTION Chemicals and Reagents. PET membranes (diameter = 3 cm, thickness = 12 µm, with ion track of 108/cm2) that had been irradiated with heavy ions of 2.2 GeV kinetic energy to create a multi damage track through the membrane were obtained from GSI, Darmstadt, Germany. NaOH, KCl, Na2HPO4 and NaH2PO4 were purchased from Beijing

Chemical

Ru(bpy)3Cl2·6H2O,

Reagent TPA,

and

Company DA

(Beijing,

were

China).

purchased

from

HAuCl4·4H2O, Sigma-Aldrich.

alpha-fetoprotein (AFP), carcino-embryonic antigen (CEA), streptavidin labeled magnetic bead (MB), capture probe labeled with biotin and detector probe labeled with Ru(bpy)32+ were purchased from Biocell Company (Zhengzhou, China). The standard stock solutions of TPA and Ru(bpy)3Cl2·6H2O were prepared in the 0.1 M phosphate buffer solution (PBS, pH 7.4). DA (in pH 7.4 PBS) and H2O2 (in pH 7.4 PBS) standard solutions should be prepared freshly. All of the chemicals were of at least analytical grade and the water used throughout all experiments was purified by a Milli-Q system (Millipore, Bedford, MA, USA). Nanochannel Etch and Nanoscale Closed BPE Array Fabrication. Multi-channel cylindrical nanochannel was fabricated according to a previously

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reported chemical etching method.28,29 Briefly, before etching, each side of the PET membrane was treated with UV light (4 mW/cm2) for one hour to allow the activation of the polymer foil. Then the PET membrane was immersed into 2 M NaOH at 65℃ for 30 min. After the etching process was completed, the PET membrane was immersed into the stopping solution (1 M HCOOH) for 5 min to neutralize the etching solution in the pore. Finally, the above PET membrane was thoroughly washed with purified water and ethanol, and dried under nitrogen flow for next step. Template-based method was used to synthetize Au nanofibers.30 In this work, two typical methods including electrochemical deposition31,32 and chemical deposition33,34 were used to synthetize Au nanofibers in the channel of the PET membrane (more experimental details are shown in Supporting Information). After the depositional process was completed, the nanochannel was blocked by Au nanofibers completely. The above PET membrane was thoroughly washed with water and ethanol, and then dried with nitrogen for fabrication of multi-channel closed BPE for ECL. ECL Measurement. A home-made electrochemical reaction cell was used for ECL measurement (Figure S7). Two Pt wire electrodes were placed on both sides of the membrane to supply the driving voltage, which was generated by the electrochemical workstation integrated in the same instrument at the range of 0-5 V. And ECL signals were obtained by a model MPI-A capillary electrophoresis ECL system (Xi’an Remex Electronics Co. Ltd.) at room temperature. In order to achieve the highest ECL stability and the sampling rate was set at 10 T/s. 6


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RESULTS AND DISCUSSION Design Principle. A multi-channel PET membrane with the ion-tracked intensity of 108/cm2 was employed to fabricate the nanoscale multi-channel closed BPE array for ECL sensing, as shown in Scheme 1. The PET membrane with deposited Au nanofibers was placed between the two cells as BPE array, and two Pt electrodes connecting with external power supply were inserted into the two cells as driving electrodes to induce faradaic reactions. The mechanism of the closed BPE was demonstrated in our previous work35-37. Briefly, at the surface of the Pt driving cathode (cathodic cell), H2O was reduced (eq. 1). Meanwhile, the oxidation of H2O occurred at the anodic pole of the BPE due to the principle of electric neutrality (eq. 2).13 In addition, according to the “connected in series” design in the closed BPE, a reverse procedure occurred at the pole of BPE cathode (eq. 3) and driving anode (eq. 4), respectively. When the Ru(bpy)32+/TPA ECL platform is employed in the BPE, this design can be used for the detection of oxidants, co-reactants, quenchers, even biomarkers in one device. Pt cathode: 4H2O+4e- → 2H2+ 4OH-

(eq. 1)

BPE anode: 2H2O–4e- → O2+ 4H+

(eq. 2)

BPE cathode: 4H2O+4e- → 2H2+ 4OH-

(eq. 3)

Pt anode: 7



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2H2O–4e- → O2+ 4H+ or H2O2–2e- → 2H+ + O2

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(eq. 4)

Fabrication and Characterization of the Multi-channel Closed BPE System. Wet etched multi-channel PET membrane with NaOH (the diameter ≈420 nm) was used as a template to fabricate the nanoscale closed BPE array. The cross section SEM images of the PET membrane before and after deposited Au nanofibers are shown in Figure 1A and 1B, respectively. By comparing the two diagrams we are found that the deposited Au nanofibers had blocked the channel completely. The nanoscale Au nanofibers were embedded in the PET membrane and forming a completely independent gold electrode in BPE system. The ECL performance based on the Au nanofibers as BPE array is recorded in the Figure 1C and 1D. At the driving voltage range of 0-5V, a strong ECL signal was observed when the driving voltage was greater than 4 V. In contrast, the PET membrane without the decoration of the Au nanofibers had no ECL signal. In addition, the visual experiment has also proved the above results (Figure S8). So all the experimental phenomena indicate that the Au nanofibers in the PET membrane play the role of BPE and the oxidation and reduction reaction occurred in the pole of BPE system, so it can be applied for the detection of analytes using ECL signal as readout. Analytes Detection. To investigate the potential application of our design, several model targets including oxidants, co-reactants, quenchers and biomarkers were chosen to detect with a nanoscale multi-channel closed BPE array. TPA and Ru(bpy)32+ were chosen as the model targets of co-reactants and ECL probes to prove the sensing function of the nanoscale multi-channel closed BPE array 8


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in the reporting cell. Briefly, different concentrations of TPA were injected into ECL solution with 1 mM Ru(bpy)32+ in the reporting cell and 10 mM H2O2 in the supporting cell. As shown in Figure 2A, the ECL signal increased with the increase of TPA concentration, and the increased ECL signals were directly related to the concentration of TPA. The linear ECL relationship between the logarithm of ECL signal and logarithm of the concentrations of TPA from 0.1 to100 µM was obtained. (Figure 2B), and the calibration curve can be represented as lgIECL =0.48 × lgCTPA+6.47 (R＝0.987, where IECL is the ECL intensity and CTPA is the concentration of TPA). The detection limit of TPA was calculated as 0.05 µM based on three times the average standard deviation of the blank (3S/N). The same results were found in the detection of Ru(bpy)32+. When different concentrations of Ru(bpy)32+ were injected into ECL solution with 100 mM TPA in reporting cell, as shown in Figure 2C, the increased ECL signals were directly related to the concentration of Ru(bpy)32+ and a linear regression equation was lgIECL =0.40×lgCRu +6.56 (where IECL is the ECL intensity and CRu is the concentration of Ru(bpy)32+) in a dynamic range from 1 nM to 10 µM with a correlation coefficient of 0.975 (Figure 2D). The detection limit of Ru(bpy)32+ was 0.05 nM (3S/N). These results manifested that our device can be applied for the detection of the co-reactants and ECL probes using ECL signal as readout. Due to the high sensitivity of this device, this work has been extended to the determination of AFP and CEA according to the captured Ru-labeled antibody. AFP 9



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and CEA, as the diagnostic and prognostic tumor marker, not only can implicate the development of human hepatocellular carcinoma38, but also can indicate a variety of tumors and estimate curative effect, patient's condition, and prognosis for some cancers39. The sensing principle was based on the sandwich strategy using magnetic bead–based ECL assay, where the capture probe labeled with biotin and a detector probe labeled with Ru(bpy)32+ were needed. In the presence of target, a sandwich complex can be formed and captured on the surface of the electrode with the aid of external magnetic field (Figure 3(I)). The obtained ECL signal curves are shown in Figure 3(II) A, we have found that there was no ECL signal in the absence of AFP; however, when AFP was injected into the detection system, there was a strong ECL signal in the voltage scanning from 0 to 5 V. In addition, the ECL signal increased with the increase of AFP concentration and the relationship between ECL signals and the concentration of AFP is shown in Figure 3(II) A. The linear relationship was obtained from 20 to 200 ng/mL, and the regression equation was IECL = 28.39×CAFP-297.97 (R＝0.994, IECL is the ECL intensity, CAFP is the concentration of AFP). The detection limit of AFP was 10 ng/mL (3S/N), which was much lower than the level of normal human in blood (20 ng/mL)40. The same results were found in the detection of CEA. When different concentrations of CEA were injected into ECL solution with 100 mM TPA in reporting cell (Figure 3(II) B), the increased ECL signals were directly related to the concentration of CEA and a linear regression equation was IECL=257.69+50.47×CCEA (where IECL is the ECL intensity and CCEA is the concentration of CEA) in the range from 0 to 40 ng/mL with a correlation 10


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coefficient of 0.977). The detection limit of CEA was 2 ng/mL (3S/N). The practical applications of the nanoscale multi-channel closed BPE array was further demonstrated in real human serum (obtained from First Hospital of Jilin University, Changchun). The results are given in Table S1 in the Supporting Information. The AFP and CEA contents of real sample of human serum determined by our device were in good agreement with the values found by Roche Immunoassay Analyzer (Elecsys2010). According to the reported literature, phenols and benzoquinone compounds can effectively quench the ECL of the Ru(bpy)32+/TPA system, and the mechanism is based on the energy-transfer quenching from the excited state emitter to the analytes.41 In this experiment, DA was used as the model target to illustrate the performance of our design for quencher detection. Different concentrations of DA were injected into ECL solution with 1 mM Ru(bpy)32+ and 10 mM TPA in the reporting cell. As shown in Figure 4A, the ECL signal decreased with the increase of DA concentration and reached platform value after 5 µM. The decreased ECL signals were directly related to the concentration of DA as shown in Figure 4B. In addition, a linear relationship between the logarithmic ECL signal and logarithmic concentrations of DA was obtained from 1 nM to 4 µM, and it can be represented as lgIECL =-0.40×lgCDA+1.45 (R＝0.989, IECL is the ECL intensity and CDA is the concentration of DA). The detection limit of DA was 0.3 nM (3S/N), which was much better than that of reported literatures.42 All the above analytes were detected in reporting cell of our design, according to 11



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the principle of electric neutrality, some samples can be detected in the supporting cell using ECL signal as indirect readout. In order to illustrate this point, H2O2 as the typical target was detected in our experiment, and the result is shown in Figure 5A. As depicted, the increased ECL signals were related to the concentration of H2O2, and the relationship between logarithmic ECL intensity and logarithm of H2O2 concentration was from 10 µM to10 mM (Figure 5B), and it can be represented as lgIECL = 1.40×CH2O2+8.20, R＝0.9891, where IECL is the ECL intensity and CH2O2 is the concentration of H2O2. The detection limit of H2O2 was 5 µM (3S/N). From all the above results, we can conclude that the proposed nanoscale multi-channel closed BPE array sensing platform is suitable for detection of various targets, even biomarkers in real samples, with good performance.

CONCLUSIONS In conclusion, a nanoscale multi-channel closed BPE array system based on a PET membrane has been presented for the first time. With our design, all the oxidants, co-reactants, quenchers and even biomarkers studied can be detected either in the reporting or supporting cell in a single device, which greatly expanded the application of ECL-BPE system. Wet etched multi-channel PET membrane was blocked through Au nanofibers deposited in the channel to fabricate the multi-channel closed BPE array. Then, TPA, Ru(bpy)32+, H2O2, AFP and CEA were detected with good performance. Besides, it has been demonstrated that this device can be used for the detection of AFP and CEA in human serum. Thus, the proposed device holds

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promising potential in environmental monitoring, clinical diagnosis, etc.; and more importantly, it also can be designed according to our desires with different diameter and different electrode density for future advanced application in nanoscale bipolar electrochemistry. ASSOCIATED CONTENT

Additional information about the deposition of Au in the channel, SEM image of the nanopores under different etching time, ECL performance of different diameter Au nanofibers, electrochemical reaction cell that used for ECL measurement and the Table of AFP and CEA concentration in human serum detected by our device. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION

Corresponding Author *E-mail: [email protected] (J. Li);[email protected] (E. Wang) Tel: +86-431-85262003. Fax: +86-431-85689711. Notes The authors declare no competing financial interest. ACKNOWLEDGMENTS

Thanks for the National Natural Science Foundation of China with Grant No. 21190040, 21427811 and 21405148, the 863 Project 2013AA065601, and the Program of Chinese Academy of Sciences YZ201203. 13



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FIGURE CAPTIONS

Scheme 1. Fundamental principle of the multi-channel closed bipolar electrodes ECL sensor for analytes detection.

Figure 1. The cross section SEM of the wet etched multichannel PET membrane that used for closed BPE system with the diameter of about 420 nm, (A) before and after (B) deposited Au nanofibers in the nanochannel. (C) and (D) are the linear sweep voltammetry curves of the sensor before and after deposited Au nanofibers. 17



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Figure 2. (I) The schematic diagram of the device for the detection of co-reactants in reporting cell. (II) The ECL response of the sensing interface for co-reactants. (A) and (C) ECL-voltage curves of the device in the presence of TPA and Ru(bpy)32+ with different concentration. (B) and (D) ECL signal as a function of the concentrations of TPA and Ru(bpy)32+. Inset: the linear relationship between co-reactants concentration and ECL intensity.

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Figure 3. (I) The schematic diagram of the device for the detection bio-markers in reporting cell. (A) ECL-voltage curves of the device in the present of AFP with different concentration from 0 to 200 ng/mL. (B) ECL-voltage curves of the device in the presence of CEA with different concentration from 0 to 40 ng/mL. Insert: the linear relationship between analyte concentration and ECL intensity, and the result for the detection in human serum.

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Figure 4. (I) The schematic diagram of the device for the detection of quenchers. (II) The ECL response of the sensing interface for the different analytes. (A) ECL-voltage curves of the device in the presence of DA with different concentration from 1 nM to 10 µM. (B) ECL signal as a function of the concentrations of DA. Inset: the linear relationship between DA concentration and ECL intensity.

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Figure 5. (I) The schematic diagram of the device for the detection of oxidants in supporting cell. (II) (A) ECL-voltage curves of the device in the presence of H2O2 with different concentration. (B) ECL signal as a function of the concentrations of H2O2. Inset: the linear relationship between H2O2 concentration and ECL intensity.

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For TOC only

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A Nanoscale Multichannel Closed Bipolar Electrode Array for

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