Capacitive Sensing of Glucose in Electrolytes Using Graphene

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Capacitive Sensing of Glucose in Electrolytes Using Graphene Quantum Capacitance Varactors Yao Zhang, Rui Ma, Xue Zhen, Yogish Kudva, Philippe Buhlmann, and Steven J. Koester ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.7b14864 • Publication Date (Web): 12 Oct 2017 Downloaded from http://pubs.acs.org on October 17, 2017

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ACS Applied Materials & Interfaces

Capacitive Sensing of Glucose in Electrolytes Using Graphene Quantum Capacitance Varactors Yao Zhang,1 Rui Ma,2 Xue V. Zhen,1 Yogish C. Kudva,3 Philippe Bühlmann,1 and Steven J. Koester2* 1

Department of Chemistry, University of Minnesota, 207 Pleasant St. SE, Minneapolis, MN 55455

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Department of Electrical & Computer Engineering, University of Minnesota, 200 Union St. SE, Minneapolis, MN 55455 3

Division of Endocrinology, Mayo Clinic, 200 1st St. SW, Rochester, MN 55905 *Ph: (612) 625-1316, FAX: (612) 625-4583, Email: [email protected]

ABSTRACT A novel graphene-based variable capacitor (varactor) that senses glucose based on the quantum capacitance effect was successfully developed. The sensor utilizes a metal-oxide–graphene varactor device structure that is inherently compatible with passive wireless sensing, a key advantage for in vivo glucose sensing. The graphene varactors were functionalized with pyrene1-boronic acid (PBA) by self-assembly driven by π-π interactions. Successful surface functionalization was confirmed by both Raman spectroscopy and capacitance–voltage characterization of the devices. Through glucose binding to the PBA, the glucose concentration in the buffer solutions modulates the level of electrostatic doping of the graphene surface to different degrees, which leads to capacitance changes and Dirac voltage shifts. These responses to the glucose concentration were shown to be reproducible and reversible over multiple measurement cycles, suggesting promise for eventual use in wireless glucose monitoring.

KEYWORDS Label-free biosensing, Graphene, Varactor, Glucose, Pyrene-1-boronic acid.

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1. INTRODUCTION In the past few years, graphene has attracted much attention in the field of biological and chemical sensors due to its numerous unique properties, such as high room-temperature carrier mobility,1 high mechanical strength,2 a strong quantum capacitance effect,3 and the capability to sense a wide range of analytes using customized surface functionalization. 4 The successful detection of a wide variety of analytes, including proteins,5 deoxyribonucleic acid (DNA),6,7 and gas molecules, 8 , 9 has already been demonstrated, showing the potential of graphene-based devices for real-life sensing applications. Binding between target molecules and surface receptors results in transfer of charge to graphene and, thereby, alters the carrier density, which can be detected electrically. 10 , 11 Biosensor platforms based on graphene benefit from the advantages of small sensor size, label-free detection, and the capability for electronic readout.5-11 A particularly important application of graphene-based sensors is glucose detection for diabetes mellitus treatment, particularly if implemented in the form of wearable or implantable sensors. There have been several examples of graphene-based glucose sensors reported in the literature.12 For instance, enzyme-based functionalization 13 has been shown to provide selective glucose detection, and more recently, affinity-based detection methods have been demonstrated using Concanavalin A/dextran 14 and pyrene-1-boronic acid (PBA) 15 functionalization. However, graphene sensors reported to date required direct electrical contact to the sensors in order to detect glucose, a configuration that has limitations particularly for in vivo sensing applications. Therefore, a need exists to develop graphene-based glucose sensors that can be interrogated wirelessly. Recently, a capacitance-based graphene-based sensor platform has been described. 16-19 This technique relies upon the quantum capacitance effect to create a graphene-based variable


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capacitor (varactor) whose capacitance changes upon exposure to an analyte.16 A change in the concentration of adsorbed analyte molecules on the graphene surface will cause a change in the carrier density of the graphene. Due to the low density of states in graphene, this carrier concentration difference leads to a measurable shift in the Fermi energy, thus changing the quantum capacitance. Due to the thin HfO2 dielectric in our device, this quantum capacitance change can be observed experimentally as a shift in the overall capacitance of the varactor. If the varactor is integrated with an inductor, it forms a resonant electromagnetic circuit whose resonant frequency can be shifted in response to adsorbed molecules. This sensing scheme has been demonstrated using simple analytes such as water vapor.19 However, to date, it has been unclear as to whether or not this sensing mechanism can operate in biological environments, particularly in the presence of electrolytes. The label-free detection of glucose in high ionic strength solutions has remained a challenge due to Debye screening in electrolyte solutions. Because a charged surface attracts counter-ions, an electrical double layer forms at the solution– graphene interface and partially screens the doping effect that results from analyte adsorption to the graphene surface. 20 , 21 Furthermore, electrolyte solutions can lead to extensive parasitic capacitive coupling that can overwhelm the intrinsic sensor response. Here, we introduce a method for the real-time detection of glucose in phosphate-buffered saline (PBS) solution using graphene quantum capacitance varactors functionalized chemically for selective electrical responses, as shown in Figure 1. We point out that quantum capacitance effects are expected to still be observable in the presence of an electronic double layer, as pointed out by Zhan, et al., 22 who noted that the quantum capacitance plays has a strong influence on the capacitance of single-layer graphene in an ionic liquid environment. However, it remains an open question as to the detailed capacitance sensing mechanism of functionalized


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graphene in an electrolyte environment. Previously, we reported preliminary results showing as a proof of concept that graphene varactors functionalized with PBA provide a capacitance response towards glucose in PBS.23 However, those results did not positively link the device response to either the functionalization or the quantum capacitance effect directly. Here, we report definitive results showing the capacitive sensing of glucose in an electrolyte solution as the result of the glucose–PBA receptor interaction, along with electrical verification of the PBA functionalization, independent graphene surface characterization, and control experiments with pyrene functionalization. Through this work, we have rigorously verified that changes in the quantum capacitance can be observed after functionalization using PBA, and we describe the procedure for creating an effective isolation scheme to minimize the impact of the electrolyte solution on the capacitance measurements. As noted above, due to the fact that our devices are fabricated using single-layer CVD graphene and that our data is extracted close to the charge neutrality point, it is reasonable to assume that any EDL capacitance variation that may be occurring does not substantially influence the capacitive response to glucose. We observe reversible, concentration-dependent capacitance sensitivity to glucose under zero-bias conditions and demonstrate that the sensitivity arises due to the boronic-acid-based functionalization. This work represents a first step toward enabling passive, wireless graphene-based glucose sensors for continuous glucose monitoring. 2. EXPERIMENTAL SECTION 2.1. Graphene varactor fabrication Graphene varactors were fabricated using a similar procedure as described in a previous paper,17 and the process flow is shown schematically in Figure 2. A thick layer of SiO2 was grown on Si substrate by thermal oxidation as the insulating field area. Then the gate electrode


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patterns were exposed and developed using photolithography for the following SiO2 recess etching. Using a combination of reactive ion etching in SF6 and wet etching using buffered oxide etch (BOE), the recessed regions for the gate electrode were formed with a depth of approximately 50 nm. A metallization layer of Ti/Pd (10/40 nm) was then deposited by electronbeam evaporation and lifted off, so that the resulting metallization was approximately planar with the surrounding SiO2. A dielectric layer of HfO2 (8 nm) was then deposited by atomic-layer deposition (ALD) at 300 °C, followed by a 5 minute anneal in nitrogen at 400 °C. In order to ensure the ability to subsequently contact the gate electrode, photoresist openings above the Pd gate metal were then patterned using photolithography, and the HfO2 was reactive-ion etched in SF6 for 60 seconds, followed by removal of the photoresist. Next, single-layer graphene was transferred onto the sample. The graphene was grown on a polished copper foil by chemical vapor deposition (CVD). After graphene growth, a layer of 4% polymethylmethacrylate (PMMA) in chlorobenzene was spin-coated onto one side of the foil at 3000 rpm for 60 seconds and baked on a hot plate at 180 °C for 10 minutes. A 15 second O2 plasma etching process was applied to remove the graphene grown on the backside of the foil. After etching in a solution of ferric chloride overnight to remove the copper, the sample was transferred to 10% diluted hydrochloric acid for 1 hour to remove the copper ion residue. Next, the sample was rinsed three times in deionized water for 10 minutes. Using an aqueous transfer method, the graphene was transferred onto the substrate with pre-patterned gate electrodes and HfO2 dielectric layer. The sample was baked at 80 °C for 30 minutes and 180 °C for 30 minutes. Finally the PMMA was removed in acetone, followed by an isopropanol (IPA) and DI water rinse.


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After the transfer process, the active area of the varactors was defined using photolithography, and the graphene was etched in an O2 plasma, followed by resist stripping. Ohmic contacts regions were defined next using photolithography, and Cr/Au (10/80 nm) was deposited using electron-beam evaporation and lifted off. In order to make contact to the gate and Ohmic electrodes and create contact regions for electrical probing, a pad-level pattern was formed. After exposure and development, thick Cr/Al (10/300 nm) is deposited and lifted off, where the thicker metal was used in order to minimize parasitic resistance associated with the long contact lines. Finally, to minimize the parasitic capacitance and prevent excess leakage through the electrolyte, a 5-µm-thick polymer isolation layer (SU-8) was spin-coated and photo-patterned on the chip surface, isolating the extrinsic regions of the sensor from the electrolytes. The SU-8 was hard baked at 250 °C in vacuum to make it insoluble in conventional solvents. An optical micrograph of a completed device is shown in Figure 3. A multi-finger device structure was utilized in order to enable high overall capacitance while minimizing series resistance. For the device shown in the figure, a total of 16 gate fingers were used, each with a length and width of 100 µm and 5 µm, respectively. 2.2. Functionalization and measurement procedure Functionalization of the graphene varactors was carried out by adsorption from acetonitrile containing PBA in the concentration range from 1 µM to 2 mM. Samples were incubated for 2 hours in the PBA acetonitrile solution, followed by rinsing with IPA and then DI water. For measurement of the glucose response, a sensor chip functionalized with PBA was placed in the chamber of a custom-built flow-cell test fixture. PBS solution adjusted to pH 9.0 was prepared to contain three different glucose concentrations (0 g/L, 2.0 g/L, 5.0 g/L) and then cycled into and out of the test chamber using a peristaltic pump via tubing connected to the chamber. The testing


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in PBS required significant measures to reduce interference from ambient electromagnetic signals. Therefore, after filling the flow cell with each new solution, valves were utilized to isolate the device and the test solution from the electrolytes in the long tubes connected to the peristaltic pump. A detailed diagram of the flow cell geometry and sensor chip is provided in the Supporting Information. Finally, measurements were performed by probing the contact pads of the varactors and using an Agilent B1500A device analyzer equipped with a capacitancemeasurement unit to measure the capacitance-voltage (C−V) characteristics. All capacitance measurements were performed at a frequency of 1 MHz with an AC oscillator voltage of 50 mV rms. 3. RESULTS AND DISCUSSION 3.1. Response of PBA functionalized graphene varactor to glucose Due to the operation principle of the quantum capacitance effect, which is a result of the intrinsic band structure that arises due to the sp2 hybridization and the linear energy-momentum dispersion relation of mobile π electrons in graphene,3 it is necessary that the surface functionalization avoids covalent bonds that alter the band structure of graphene. Therefore, noncovalent chemical functionalization must be used for the purpose of retaining the quantum capacitance effect. As shown in Figure 4, we used PBA as the surface functionalization for glucose detection since, as has been shown previously, the boronic acid group provides saccharide-selective binding of glucose.15,24,25 Furthermore, PBA molecules self-attach onto the graphene surface with significant stability due to strong π-π interactions. 26 , 27 , 28 The sensing mechanism is based on selective covalent binding of glucose to the PBA receptor to form a boronate anion with a stable cyclic ester structure, whereby the pKa of the receptor is shifted, leading to graphene doping and, as a consequence, a capacitance change through the quantum


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capacitance effect.15,29 Furthermore, since the distance separating the graphene from the pyrene ring system (≈ 4 Å) is smaller than the Debye length in our PBS buffer solutions (7.3 Å), the electrostatic effect of glucose binding to the PBA is not be screened by counter-ions in the buffer solution.21 3.2. Surface functionalization analysis Experiments were performed to determine the appropriate concentration of PBA in the selfassembly solution that provides complete coverage of the graphene surface. A series of graphene varactors were fabricated, and capacitance–voltage (C–V) measurements were performed after functionalization with acetonitrile solutions containing PBA in the range from 1 µM to 2 mM to confirm the success of the PBA functionalization. All C–V measurements were performed in ambient atmosphere. The shift in the Dirac voltage of the C–V curve (defined as the voltage where the capacitance is at its minimum due to the symmetric nature of the density of states in graphene) provides indirect evidence for the presence of PBA on the graphene surface. A total of six varactors were tested for each concentration to provide for an estimate of the statistical variation, and all measurements were performed in air. An example of the shift in the C-V characteristic before and after functionalization is shown in Figure 5a. Here, we found that, for concentrations of PBA in acetonitrile starting from ~ 0.1 mM, the surface functionalization resulted in a positive shift in the Dirac voltage that increased with PBA concentrations up to 2 mM. Furthermore, no degradation of the capacitance tuning ratio (defined as the ratio of the maximum to minimum capacitance values) was observed, indicating that no covalent bonding occurs during functionalization, consistent with previous results.18 As shown in Figure 5b, low concentrations of PBA (< 10 µM) were not sufficient to shift the Dirac voltage, while at higher concentrations, a significant shift was observed, and at 2 mM (the solubility limit of PBA in


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acetonitrile) the Dirac point shifted by as much as +0.4 V. This shift is strong evidence of surface functionalization due to the electron-accepting behavior of PBA, consistent with the expectation that the boronic acid group decreases the electron density on the pyrene group attached to the graphene. Though saturation of the Dirac point shift was not observed before the solubility limit was reached, the significant shift provided by the PBA provides a good indication that strong surface absorption is occurring. Therefore, a solution of 2 mM PBA in acetonitrile was used for the surface functionalization in all subsequent sensing experiments. Finally, as an additional confirmation of the surface functionalization, Raman spectroscopy measurements were performed on blank and PBA-functionalized CVD graphene samples transferred onto Si/SiO2 substrates. The results, shown in Figure 5c, further confirm the presence of PBA on the surface, as evidenced by the strong 1286 cm-1 and 1378 cm-1 Raman peaks. We also performed Raman spectroscopy measurements on graphene samples functionalized by solutions with different PBA concentrations (Figure 5d). We observed height ratios of the B-OH (1283 cm-1) and graphene G peak (1600 cm-1) of 0.048 and 0.083 for 1 mM and 2 mM solutions, respectively. The height ratios of the B-OH (1283 cm-1) and graphene 2D peaks (2692 cm-1) were 0.045 and 0.098 for 1 mM and 2 mM solutions, respectively. The fact that the height ratio of the B-OH and G/2D peaks increased as the self-assembly concentration increased from 1 mM to 2 mM provides further evidence of the success of the PBA functionalization of graphene. To calculate the surface coverage of PBA on graphene, XPS measurements were performed on functionalized graphene samples. XPS of boron was not sensitive enough to detect the boronic acid, but self-assembly of the boronic acid on graphene resulted in distinct changes in the amount of oxygen detected by XPS. Fitting the surface concentration of oxygen with a Langmuir adsorption isotherm gave a surface adsorption equilibrium constant of 2.51 × 103, with an error


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range of 9.33 × 102 to 4.07 × 103. Based on these results, we estimate a surface coverage of approximately 83% for the self-assembly from a 2 mM PBA solution (see the Supporting Information for details). 3.3. Glucose sensing results In order to test the sensor response to glucose, we utilized a custom-built flow-cell test fixture described previously in this manuscript to measure the C-V characteristics as a function of glucose concentration. Different glucose solutions were pumped into the chamber sequentially to perform the sensing experiments, and for each concentration, twenty C–V sweeps were performed, each using a gate voltage, Vg, range of −2 and +2 V to test the sensor response as well its stability and reproducibility. Though a double layer is formed due to the applied voltage on the charged sensor, the electric field between the gate electrode and the graphene mainly drops across the HfO2 dielectric layer, and so the surface potential difference is not high enough for electrolysis of water between the device structure and the electrolyte in the insulated chamber. In these measurements, both the capacitance at Vg = 0 V (C0V) and the Dirac voltage (VDirac) were monitored for different glucose concentrations. It should be noted that for eventual use in passive wireless sensors, where the varactor is integrated with an inductor to form a resonator whose oscillation frequency shifts with glucose concentration, Vg would not be swept. Rather, the device would operate at Vg = 0 V, and so the C0V characteristic provides a measure of the suitability of the sensors for passive-mode wireless operation. Additional information on the zero-bias mode of operation is provided in the Supporting Information. Results of sensing measurements are shown in Figures 6a and 6b, which show that the functionalized graphene varactors have a clear and reproducible response towards glucose in PBS solution. As the glucose concentration increases, the Dirac voltage shifts negatively,


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reducing the capacitance at Vg = 0 V. The response is observed to be reversible, with increasing responses for increasing glucose concentrations. A small degree of drift was observed in the results, but the changes in capacitance were found to be larger than the drift-induced measurement error. We believe that the measurement drift is caused by two main effects, both of which can be minimized with process and measurement optimization. First of all, we have found that some degree of delamination of the isolation layer occurred due to repeated testing. We believe that increasing the temperature utilized in these experiments to cure the SU-8 isolation layer would reduce the measurement drift. Secondly, we have found that the gate voltage sweep itself can induce drift in the C–V curves. The gate voltage sweep effect on the C–V curves was investigated by performing a series of continuous gate voltage scans (in the range of +2 V) that were separated by long delay periods in between. The Dirac voltage was found to be shifted in proportion to the number of scans, irrespective of the delay time between scans. (Complete details of these experiment are provided in the Supporting Information). For this reason, we expect that improvement in the device stability can be expected when the devices are operated in passive wireless mode, since in the case Vg = 0 V, and, therefore, drift associated with the gate voltage sweep will not arise. To understand the results in Figure 6a and 6b better, the C–V measurements for selected conditions are shown in Figure 6c. Here, it is clear that the glucose shifts the C–V curve toward more negative values, essentially counteracting the p-type doping effect of the PBA functionalization. Such n-type doping is expected due to the near-surface negative charge on the boronic acid after binding with glucose. At Vg = 0 V, this shift results in a decrease in capacitance, and it is at this value that the wireless sensors would be expected to operate. Finally, the relative change in capacitance in response to the glucose concentration is shown in Figure 6d,


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where no attempt to compensate for drift was performed. It can be seen that the capacitance change in response to the 0, 2.0, and 5.0 g/L (0, 200 and 500 mg/dL) glucose concentrations are discernable above the experimental error. Finally, a control experiment was also performed (details are provided in the Supporting Information) where the graphene varactors were functionalized with pyrene only and re-tested under the same conditions as the PBA functionalization. Pyrene was selected as the control graphene functionalization, due to its high similarity to graphene while featuring no function group for specific binding of glucose. 30 Though a slight response to glucose is observed, it is significantly lower (~ 3×) compared to the response of devices with PBA functionalization. This remnant sensitivity suggests nonspecific adsorption of glucose to the graphene sensor, which is expected when the voltage is scanned.31 4. CONCLUSION In summary, we have demonstrated a glucose sensor that utilizes the quantum capacitance effect as its basis of operation. Given the previous demonstration that that wireless sensing is possible based upon quantum-capacitance sensing,19 this work has provided a deeper understanding of the underlying capacitive glucose sensing mechanism. A robust fabrication process has also been demonstrated that minimizes parasitic shorting of the device response as a result of the electrolyte environment. The sensor demonstrates strong and reversible sensitivity to glucose, as indicated by the change in the capacitance under zero-bias conditions. This response can be positively attributed to the PBA functionalization attached to the graphene surface. Further studies are needed to improve the sensing dynamic range to be clinically relevant for continuous glucose monitors (CGMs) under biological pH conditions. We believe that there could be several paths to improving the sensor sensitivity and dynamic range. To improve the sensor sensitivity, thinning the dielectric layer and decreasing disorder in graphene should


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provide a sharper capacitance vs. voltage curve, which will enable larger capacitance changes for a given “shift” in the capacitance-voltage curve. Controlling the Dirac voltage to ensure the device operates in the most sensitive region of the capacitance curve could also be important. Although the biocompatibility and the anti-biofouling characteristics of graphene-based materials have been studied previously,32,33 future studies of implanted graphene varactor sensors will require an investigation of inflammatory responses and the characterization of the electrical properties in a biological sensing environment, especially in view of possible doping effect from biogenic amines. Sensing at biological pH levels also poses a critical challenge that has not been solved yet for the glucose sensor based on graphene varactors, though local pH control using additional proton-accepting functional groups has been shown to be possible in carbon nanotube glucose sensors based on a similar PBA-based sensing process.15 Therefore, it is conceivable that such additional surface modification could also be utilized for graphene varactors to increase the local pH and thus enable sensing in biological fluids. Eventual application for in vivo CGMs will also require integration of on-chip inductors for wireless readout, which will make these devices a promising new platform technology for treatment of diabetes mellitus. SUPPORTING INFORMATION Supporting information associated with this article can be found in the online version, including: chemical and materials, background on the quantum capacitance effect, experimental setup, XPS analysis, data processing details, drift analysis and control experiments. AUTHOR INFORMATION Corresponding Author *Steven J. Koester, Ph: (612) 625-1316. FAX: (612) 625-4583. Email: [email protected] AUTHOR CONTRIBUTIONS


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Y.Z., S.J.K. and P.B. designed and directed this study and analyzed the results. Y.Z. fabricated all graphene varactor devices and performed all device characterization and sensing measurements. Y.Z. and X.V.Z. developed and characterized the surface functionalization. Y.Z. and R.M. performed the data fitting and processing. Y.Z., S.J.K. P.B. and Y.C.K. wrote the manuscript. ACKNOWLEDGEMENTS This work was supported by the Minnesota Partnership for Biotechnology and Medical Genomics Decade of Discovery in Diabetes Program and the Alice M. O'Brien Foundation. Device fabrication was performed at the Minnesota Nanofabrication Center at the University of Minnesota, which receives partial support from the National Science Foundation (NSF) through the National Nanotechnology Coordinated Infrastructure under award no. ECCS-1542202. Portions of this work were also carried out in the University of Minnesota Characterization Facility, which received capital equipment funding from the University of Minnesota MRSEC under NSF award no. DMR-1420013.


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Fig. 1. Schematic and glucose sensing mechanism of a graphene varactor with pyrene-1-boronic acid as surface functionalization. Different values of the glucose concentration, ∆M, result in different levels of charge doping of the graphene, ∆n, which leads to a shift in the Fermi energy, ∆EF, and causes a change in the quantum capacitance, ∆CQ. If this oxide capacitance, Cox, is on the same order as the quantum capacitance, CQ, then the total device capacitance will also change. If the varactor is integrated with an inductor, L, the glucose concentration can be detected wirelessly through a change in the resonant frequency, ∆f, of the resulting LC oscillator. In this work, the varactor portion of the sensor, indicated by the dashed red line, is demonstrated.


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Fig. 2. Schematic of the graphene varactor fabrication sequence.


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Fig. 3. Optical micrograph of a graphene varactor, with the approximate graphene location highlighted for clarity.


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Fig. 4. Chemical equilibria of boronic acid esters with glucose in neutral and alkaline solutions.


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Fig. 5. Characterization of the pyrene-1-boronic acid functionalization of graphene. (a) Capacitance–voltage characteristics of a graphene varactor before and after functionalization with 1 mM PBA. The shift in Dirac voltage indicates p-type doping induced by the PBA. (b) Dirac voltage shift of graphene varactors functionalized with PBA solutions of different concentrations. (c) Raman spectra of graphene before and after functionalization with 1 mM PBA. Characteristic absorption peaks of the boronic acid were observed only after PBA functionalization. (d) Raman spectra of graphene functionalized with PBA solutions of different concentrations (0, 0.01 mM, 0.1 mM, 1 mM, 2 mM).


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Fig. 6. Sensing signal of a PBA-functionalized graphene varactor at different values of glucose concentration in PBS solution. (a) Dirac voltage (black) and glucose concentration (blue) vs. measurement count. (b) Capacitance at Vg = 0 V (black) and glucose concentration (blue) vs. measurement count. (c) Smoothed C–V curves for selected glucose concentrations, showing shift of the C–V curve toward negative gate voltages with increasing glucose concentration. The capacitance values at Vg = 0 V at each glucose concentration are highlighted by the solid circles. (d) Relative capacitance change at Vg = 0 V vs. glucose concentration for graphene varactors functionalized with PBA (black squares) and pyrene only (green circles).


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Capacitive Sensing of Glucose in Electrolytes Using Graphene

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