A simple route for electrochemical glucose sensing using background current subtraction of cyclic voltammetry technique

Accepted Manuscript A simple route for electrochemical glucose sensing using background current subtraction of cyclic voltammetry technique

Nguyen Quoc Dung, Tran Thi Thuy Duong, Tran Dai Lam, Dang Duc Dung, Nguyen Nhat Huy, Dang Van Thanh PII: DOI: Article Number: Reference:

S1572-6657(19)30591-0 https://doi.org/10.1016/j.jelechem.2019.113323 113323 JEAC 113323

To appear in:

Journal of Electroanalytical Chemistry

Received date: Revised date: Accepted date:

12 April 2019 18 July 2019 19 July 2019

Please cite this article as: N.Q. Dung, T.T.T. Duong, T.D. Lam, et al., A simple route for electrochemical glucose sensing using background current subtraction of cyclic voltammetry technique, Journal of Electroanalytical Chemistry, https://doi.org/10.1016/ j.jelechem.2019.113323

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ACCEPTED MANUSCRIPT

A simple route for electrochemical glucose sensing using background current subtraction of cyclic voltammetry technique Nguyen Quoc Dung1,*, Tran Thi Thuy Duong2,3, Tran Dai Lam3, Dang Duc Dung4, Nguyen Nhat Huy5, Dang Van Thanh6,*

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Faculty of Basic Science, Thai Nguyen of Agriculture and Forestry, Vietnam

Graduate University of Science and Technology, Vietnam Academy of Science and Technology, Vietnam

Department of General Physics, School of Engineering Physics, Hanoi University of Science

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Department of Chemistry, Thai Nguyen University of Education, Vietnam

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and Technology, Vietnam

Faculty of Environment and Natural Resources, Ho Chi Minh City University of

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Technology, VNU-HCM, Vietnam Faculty of Basic Science, TNU-University of Medicine and Pharmacy, Vietnam

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Abstract

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This study reports a simple route for electrochemical glucose sensing using background

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subtraction of cyclic voltammetry (BS-CV) technique based on CuO/ITO electrode. The applied technique was not only useful for studying the electrochemical properties of CuO/ITO

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electrode but also successful for the first time in quantification of glucose with linear range of 0.01 - 4.00 mM, high sensitivity of 848.86 µAcm-2M-1, and detection limit of 3 μM. The model

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of glucose reaction at the electrode revealed that the current density of glucose oxidation was a logarithm equation. This technique overcomes the disadvantages of amperometric method that needs to stir the solution during the measurement process and has great potential for integration in handheld glucose sensors. Key words: copper oxide, glucose sensing, chronoamperometric deposition, cyclic voltammetry, background current subtraction. *Corresponding author (E-mail: [email protected], [email protected]) 1

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1. Introduction Rapid and early diagnosis of diabetes using portable devices at home has attracted many researchers in glucose sensor development. Generally, electrochemical glucose sensors can be classified in four generations [1]. Unlike enzymatic electrodes in the first three sensor

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generations which are unstable and susceptible to denaturation by heat and hazardous substances, non-enzymatic glucose sensors in the fourth generation using noble metals [2-7],

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transition metal [8-10], and alloys [11-16] are more stable and highly sensitive. Recently,

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electrodes based on CuO and NiO materials have been developed to overcome the disadvantages of low kinetic and easily poisoned by chloride anion of metal-based sensors

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[17-19]. So far, most of the researchers have focused on investigating electrochemical

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properties of glucose at the electrode by cyclic voltage method, followed by using amperometric method to establish the standard calibration curve for the dependence of

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glucose oxidation current density on glucose concentration [18,20]. In this technique, the

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solution must be under continuous stirring to eliminate the diffusion current, which is only suitable in laboratory but inapplicable for practical handheld devices. Therefore, a simple technique with a large detection range and a low detection limit is required in handheld

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glucose sensor development.

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The concept of background current subtraction was introduced by Howell et al. [21] and Hermans et al. [22] for studying rapid scan voltammetry by changing the device circuit. Another similar technique is fast-scan cyclic staircase voltammetry developed by Hayes et al. [23] in which protein–modified carbon fiber was used through direct intervention of the equipment program. Recently, Yoo and Park [24] described a method to subtract background signals electronically during a fast potential sweep using a customized waveform to improve detection limits of catecholamine neurotransmitter dopamine. However, these techniques 2

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require the stability of electrode response during each of the two scans and the usage of microelectrodes. Until now, there has not been any report on the quantification of glucose using background subtraction of cyclic voltammetry (BS-CV) technique based on CuO/ITO electrode.

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In this work, we proposed a simple route for electrochemical glucose sensing based on CuO/ITO electrode using background subtraction of cyclic voltammetry technique. The

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concept of background current subtraction refers to a subtraction of glucose oxidation current

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to the current without glucose to eliminate the reaction of background solution. Since the resulting current is Faraday current of glucose oxidation at the electrodes, the glucose

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oxidation at the electrode is deeply studied. In addition, due to background current

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subtraction, the peak of glucose oxidation appears more sharply and clearly, which minimizes

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the detection limit and widens the detection range.

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2. Experiment 2.1. Chemicals and materials

Analytical-grade chemicals and distilled water were used in this study. D-glucose,

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sodium hydroxide, human serum, and copper sulfate hexahydrate were purchased from

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Sigma-Aldrich (USA). Indium tin oxide (ITO) coated–glass substrates with the size of 0.5 cm × 2.0 cm was provided by Samsung Corning Co. Ltd. (Korea). 2.2. Preparation of CuO thin film on ITO substrate Cyclic voltammetry of ITO substrate was investigated in a solution of 0.1 M CuSO4 and 0.1 M Na2SO4 in voltage range from +0.6 V (vs Ag/AgCl) to -0.9 V with a rate of 20 mV/s (Figure S1 of Supporting information). Obviously, the current was almost zero in voltage range of +0.6 V to +0.1 V (negative scan) due to the inert of Cu2+ at low voltages. 3

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The current then slightly increased with the decrease of voltage up to -0.03 V and significantly increased with voltage below -0.03 V due to the electrolysis of Cu2+ as Cu2+ + 2e- → Cu. With more negative voltage, the current linearly increased and reached the highest

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value at voltage of -0.4 V. With further decrease of voltage, the current gradually decreased to reach saturated current which obeys diffusion-controlled regime. In positive scan, it was

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observed that the current remained unchanged up to the voltage of -0.2 V, which was more

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positive than the one reached highest intensity during negative scan (i.e., -0.4 V). This could be because the basic ITO substrate is responsible for the forward scan but the newly formed

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Cu/ITO (i.e, formed after forward scan) is responsible for the reverse scan. Based on these

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results, -0.5 V was chosen as voltage for the formation of Cu/ITO using chronoamperometry method. Briefly, Cu was deposited onto ITO substrate from a solution of 0.1 M CuSO4 and 0.1M Na2SO4 at -0.5 V, followed by oxidation in air at 400 oC. This temperature was chosen

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due to the thermal transformation of Cu to CuO at 400 oC and above [26] while avoiding the destruction of the structure and conductivity of ITO substrate at a high temperature. Non-

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conductive epoxy was then used to fix the electrode area of 0.5 cm × 0.5 cm, as shown in Fig.

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2.3. Structural characterization and electrochemical measurement The crystalline structure, surface morphology, and elemental composition of the synthesized electrodes were examined by X-ray diffraction (XRD, Bruker D8 Advance), scanning electron microscopy (SEM, Hitachi S-4800), and energy-dispersive X-ray spectroscopy (EDS, Hitachi S-4800), respectively. Electrochemical measurements were performed using a Potentisosat/Galvanostat instrument (Autolab 302N) and controlled by using its built-in software (Nova 1.10) and a three-electrode system. The synthesized 4

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CuO/ITO for glucose sensing was employed as a working electrode, while Pt sheet and Ag,AgCl|Cl- (saturated KCl) work as a counter electrode and a reference electrode (Ag/AgCl), respectively. The cyclic voltammetry was used to investigate the electrochemical properties of fabricated electrode as well as to quantify glucose concentration in sample

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solution. In order to test the applicability of this method for practical purposes, human serum samples were also employed for determination of glucose based on BS-CV method using

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CuO/ITO electrode.

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3. Results and discussion

3.1. Structure and characterization of CuO onto ITO substrate

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SEM images of CuO/ITO in Fig 2(a) revealed a porous structure of CuO cluster

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comprising of prismatic particles with size from 300 to 500 nm (inset of Fig 2(a)). XRD pattern of the material in Fig. 2(b) with 2 diffraction peaks at 35.4o, 38.5o, and 48.9o

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indicates the monoclinic phase of CuO (JCPDS 045-0937) while the diffraction peaks with

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symbol “*” belong to the ITO substrate. Fig. 2(c) shows EDS analysis of the material with O:Cu atom ratio of 55.3:44.7 which is near 1:1 ratio of CuO. The slightly higher ratio of O than that of Cu can be related to the adsorption of oxygen into the porous CuO layer or the

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formation of Cu(OH)2 from CuO.

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3.2. Electrochemical properties The cyclic voltammetry of glucose at the electrode (with copper deposition time of 240 seconds) in alkaline medium of 0.1M NaOH solution was tested, and the results of BSCV are presented in Fig. 3. As seen in Fig. 3(a), the cyclic voltammogram with 1 mM of glucose (red dash curve) was much higher than that without glucose (black solid line) in both positive and negative scans due to the irreversible oxidation of glucose at the electrode [18]. Moreover, a peak of 0.47V was observed in the positive scan but not in the negative scan; 5

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however, peaks appeared in both positive (0.47 V) and negative (0.6 V) scans after using BSCV technique (Fig. 3(b)). Fig. 3(c) shows the CVs of the electrode without glucose (black solid line), with 8 mM glucose (red dash line), and after BS-CV (blue dot line). Interestingly, no peak was observed in the positive scan, but a peak at 0.75V appeared after BS-CV,

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demonstrating that BS-CV technique can widen the detection range of glucose sensor. Fig. 3(d) exhibits the CVs of the electrode without glucose (black solid line), with 0.02 mM

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glucose (red dash line), and after BS-CV (inset of Fig. 3(d)). A very clear peak after BS-CV

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and a weak peak before BS-CV of glucose were observed at the electrode, suggesting the improvement of detection limit.

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CuO/ITO electrodes were fabricated by electrochemical deposition of copper from a

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solution of 0.1 M CuSO4 and 0.1 M NaOH with different deposition times of 120, 180, 240, 360, and 480 s, followed by heat treatment at 400 oC for oxidation of Cu to CuO. BS-CV curves of these electrodes with voltage range of 0 to 0.8 V in 0.1 M NaOH solution and scan

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rate of 20 mV/s for different glucose concentrations of 0.1 – 8.0 mM are displayed in Figure S2. It was found that BS-CV current density of glucose oxidation increased with the increase of deposition time up to 240 s, where it reached the highest value, and then decreased with

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further increase of deposition time from 240 to 480 s (Figure S2(f)). Therefore, 240 s was

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chosen as the optimum deposition time for further investigations. For comparison purpose, differential pulse voltametry (DPV) and square wave voltametry (SWV) methods were also applied in our study. As observed in Figure S3(a), the characteristic glucose oxidation peaks only appeared with glucose concentration of ≥ 2 mM. However, these peaks are very obtuse, indicating that this method is not suitable for glucose determination in our study. In Figure S3(b), the characteristic peaks were not observed in SWV method even after increasing the glucose concentration up to 0.1 mM. In addition, the 6

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current density decreased with further increase of glucose concentration to 0.2, 0.3, and 0.5 mM. Therefore, this SWV method is also not suitable for quantification of glucose in our study. The reason for the inappropriate application of these methods in our study could be the irreversible reaction of glucose at the electrode [18, 26-29] and its kinetic property.

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Fig. 4(a) shows the BS-CV of positive scan of the electrode to different concentrations of glucose from 0.1 to 8 mM, and the inset was the one performed at lower

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concentrations from 0.01 to 0.1 mM. It is obvious that the oxidation peak shifted to higher

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potential with the increase of glucose concentration. This could be explained by the accumulation of reaction products at the electrode surface with higher glucose concentrations,

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which prevents the diffusion of bulk phase glucose to the electrode surface. Current density

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of glucose oxidation peak versus glucose concentration is plotted in Fig. 4(b). With the increase of glucose concentration, the current increased linearly at low concentrations, and

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then the slope decreased with a perfect curvature and tended to be saturated at high

by a theoretical model.

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concentrations. This results suggests that glucose reaction at the electrode could be described

In order to explain these results, we assume that the high glucose oxidation production

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under high glucose concentrations prevents the diffusion of glucose in bulk liquid to the

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surface of electrode. Therefore, the current density does not increase linearly with the increase of glucose concentration, but the change of current density per unit of glucose concentration decreases correspondingly to the increase of glucose concentration. We assumes that the change is inversely proportional to the glucose concentration as below:

dJ 1  dC kC  b

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Where b and k are experimental constants. The k value depends on the oxidation of the glucose amount at the electrode, and the higher value of k means lower ability of glucose 7

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oxidation. From (1), we have:

dJ 

dC kC  b

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dC kC  b

(3)

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 dJ  

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Integrating both sides of (2), we obtain:

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1 J  A  ln( kC  b) (4) k

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To simplify this complex equation to an approximate level, we assume that the reaction occurs at a low concentration of glucose. Take Taylor expansion of J at C = 0, we

J  J (0) 

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have:

J ' (0) J '' (0) J '' (0) (C  0)  (C  0) 2  (C  0) 3  ... 1! 2! 3!

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We neglect the 3rd and higher terms to get the following approximation:

J  J (0) 

J ' (0) J '' (0) (C  0)  (C  0) 2 1! 2!

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1 1 k J  A  ln b  C  2 C 2 k b 2b

(5)

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At lower concentration, the 2nd term can be neglected to get the first equation of linear dependence of current density on concentration.

1 1 J  A  ln b  C k b

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In addition, equation (4) can be rewritten as the exponential function of C according to J.

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 b e kA kJ  e (7 ) k k 8

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The experimental results follow the equation (5) and (7) are shown in Fig. 5(a) and Fig. 5(b), respectively. As a result, the equations (5) and (7) become: J  1.97  848.86C  40.88 105 C 2 (8) J

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Equation (9) is rewritten by:

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(C  3.11) (10) 3.16

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J  3367.0  ln

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4

C  3.11  3.16  e 2.9710

Equation (10) is the overall equation expressing the dependence of glucose oxidation

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current density on the concentration. Equation (9) can be considered to be approximate to the equation (10) in low concentration range of glucose.

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In lower concentration range, the second term can be ignored, and equation (8) becomes:

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J  1.97  848.86C (11)

The sensitivity of CuO/ITO electrode for glucose is determined from the slope of Equation (11), and the linear range was up to 4 mM (Fig. 4(b)). The detection limit was

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determined to be 3 μM from the inset of Fig. 4(a) with a signal to noise ratio of 3. It is

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noticed that the stirring conditions is prerequisite to remove the diffusion current in other studies of glucose quantification [18,25]. In addition, the previous background current subtraction techniques required or needed to interfere with the measuring device or program and used a very high scan rate that can cause sample disturbance and complexity to control [21-24]. In this study, our technique does not require stirring the solution during the measurement and performs at a low scan rate to avoid over-oxidation and saturation. The CuO/ITO electrode was then applied for determination of glucose in human 9

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serum sample. BS-CV measurement was conducted before and after adding of 100 μL of human serum into 25 mL of 0.1M NaOH solution. Fig. 6 displays the BS-CV curve of CuO/ITO electrode for serum sample with glucose concentration of 4.4 mM after adding two times with 100 μL serum/time. It can be seen that the current density increased with the

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adding of glucose sample. As compared to the inset of Fig. 4 with similar glucose concentration, both synthetic glucose and human serum samples showed peak at 0.4 V of

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glucose oxidation. However, a peak at 0.6 V appeared in the measurement of serum sample,

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which could be the oxidation of other compounds existing in the human serum. The serum samples were also mixed with glucose or water to form solutions with different glucose

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concentrations. The BS-CV measurements for these mixed samples were conducted, and the

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results are presented in Figure S5 and Table 1. The results indicate that BS-CV method is comparable with the commercial one (measured by RGII glucose meter, as shown in Figure

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S4) and background subtraction of cyclic voltammetry (BS-CV) technique based on

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CuO/ITO electrode would be an effective approach for the development of non-enzymatic

4. Conclusion

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glucose sensors in practical applications.

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It is the first time that background current subtraction of the cyclic voltammetry using CuO/ITO electrode was successfully applied to determine and quantify glucose concentration in solution. A mathematical model was also proposed and established to explain the experimental results of BS-CV line peak current and glucose concentration. By this method, the determination of glucose concentration range was extended to lower concentrations of glucose. Thus, it is a very promising approach for the development of non-enzymatic glucose sensors in practical applications.

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Acknowledgement This research is funded by Vietnam National Foundation for Science and Technology Development (NAFOSTED) under grant number 103.02-2016.63. References

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Figure captions Figure 1. Scheme of CuO/ITO electrode fabrication

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Figure 2. (a) SEM images, (b) XRD pattern (the symbol “*” belongs to the ITO substrate),

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and (c) EDS analysis of CuO/ITO electrode Figure 3. (a) Cyclic voltammograms (CV) of CuO/ITO electrode in the absence (black solid

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line) and presence (red dot line) of 1 mM glucose; (b) The BS-CV of the electrode from (a); (c) the CV of the electrode in the absence (black solid line), presence of 8 mM glucose (red

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dash line) and its BS-CV (blue dot line); and (d) the CV of the electrode in the absence (black solid line), presence of 0.02 mM glucose (red dash line) (insert of (d) is its BS-CV in positive scan). Figure 4. (a) BS-CV of positive scan with different concentrations of glucose and (b) plot of glucose concentration vs. current of oxidation peak Figure 5. (a) Second order fitting and (b) exponential fitting of experimental data on the relationship of glucose concentration and current density 12

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Figure 6. BS-CV curve of CuO/ITO electrode for serum sample with glucose concentration of 4.4 mM after adding two times with 100 μL of serum/time: red line (lower curve) for the

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first time and green line (upper curve) for the second time.

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Table 1. BS-CV determination of glucose concentration in human serum Glucose concentration Glucose concentration by CuO/ITO Deviation Intended mixing ** RG II meter (mM) (our electrode) (%) 1 3.7 3.8 +2.7 3.8 2 4.4* 4.3 -2.3 4.4 3 5.2 5.6 +5.7 5.4 4 6.5 6.9 +6.1 6.7 5 9.0 8.5 -5.5 8.7 * Glucose concentration was determined in initial serum sample, which was the basis for the determination of glucose concentration in other samples ** Glucose meter from Sejong Biotechnology (Korea)

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Research highlights

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 Background subtraction of cyclic voltammetry (BS-CV) was applied for glucose determination  BS-CV technique as a simple route for electrochemical glucose sensing on CuO/ITO  A mathematical model was proposed and established to explain the obtained results  BS-CV is a promising and effective technique for non-enzymatic glucose sensors

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