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Glucose Sensing Using Functionalized Amorphous In-Ga-Zn-O Field Effect Transistors Xiaosong Du, Yajuan Li, Joshua R. Motley, William F. Stickle, and Gregory S. Herman ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.5b12058 • Publication Date (Web): 08 Mar 2016 Downloaded from http://pubs.acs.org on March 13, 2016

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ACS Applied Materials & Interfaces

Glucose Sensing Using Functionalized Amorphous In-Ga-Zn-O Field Effect Transistors Xiaosong Du,1,* Yajuan Li,1,2 Joshua R. Motley,1 William F. Stickle,3 and Gregory S. Herman1,* 1

School of Chemical, Biological, and Environmental Engineering, Oregon State

University, Corvallis, Oregon, 97331, USA 2

College of Science, Civil Aviation University of China, Tianjin, 300300, China

3

Hewlett Packard Company, Corvallis, Oregon, 97330, USA

*Electronic mail: [email protected]; [email protected]

KEYWORDS: transparent amorphous oxide semiconductor, field effect transistor, glucose sensor, back channel surface functionalization, type I diabetes.

ACS Paragon Plus Environment

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Abstract Recent advances in glucose sensing have focused on the integration of sensors into contact lenses to allow noninvasive continuous glucose monitoring. Current technologies focus primarily on enzyme-based electrochemical sensing which require multiple nontransparent electrodes to be integrated. Herein, we leverage amorphous indium gallium zinc oxide (IGZO) field effect transistors (FETs), which have found use in a wide range of display applications and can be made fully transparent. Bottom-gated IGZO-FETs can have significant changes in electrical characteristics when the back channel is exposed to different environments. We have functionalized the back channel of IGZO-FETs with aminosilane groups that are cross-linked to glucose oxidase, and have demonstrated that these devices have high sensitivity to changes in glucose concentrations. Glucose sensing occurs through the decrease in pH during glucose oxidation, which modulates the positive charge of the aminosilane groups attached to the IGZO surface. The change in charge affects the number of acceptor-like surface states which can deplete electron density in the n-type IGZO semiconductor. Increasing glucose concentrations leads to an increase in acceptor states and a decrease in drain-source conductance due to a positive shift in the turn on voltage. The functionalized IGZO-FET devices are effective in minimizing detection of interfering compounds including acetaminophen and ascorbic acid. These studies suggest that IGZO FETs can be effective for monitoring glucose concentrations in a variety of environments, including those where fully transparent sensing elements may be of interest.


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Introduction In the U.S. more than 1 million people have been diagnosed with type I diabetes mellitus. Extremes in blood glucose levels can lead to major health issues, where high blood sugar (hyperglycemia) can cause complications such as macrovascular and kidney disease, and low blood sugar (hypoglycemia) can lead to seizures and loss of consciousness.1, 2 Glucose sensors are a critical component of an artificial pancreas and have been extensively studied over the past several decades.3, 4 For these applications the sensors need to be sensitive and reliable while measuring glucose concentrations over the normal physiological range (i.e., 2–30 mM in the interstitial fluid5 and 0.1-0.4 mM in tear fluid6-8). The recent development of continuous glucose sensors allows real-time monitoring of sugar levels and continuous subcutaneous infusion of insulin/glucagon to assist in maintaining glycemic control.9, 10 Common amperometric sensors include a Ag/AgCl counter/reference electrode and a platinum working electrode which is coated with a sensing enzyme and a permselective membrane.11-14 The disadvantage of the enzyme-based amperometric sensor is the high oxidation potential required on the working electrodes for glucose sensing.4 Potentially other methods may have advantages for glucose sensing, including field-effect transistors (FET) which can be a simple and cost-effective approach. FET-based glucose sensors utilizing boronic acid functionalized carbon nanotubes, as the channel material, have recently been developed.15 These sensors have high sensitivity and selectivity for glucose in the range of 1 µM-100 mM. An organic electrochemical FET has also been fabricated as a glucose sensor where all the electrodes (source/drain and gate electrodes) and channel materials were made of poly(3,4ethyelenedioxythiphene):poly(styrene sulfonate).16 The reaction between glucose and sensing enzyme generates H2O2 which can reduce positively charged poly(3,4-ethyelenedioxythiphene) to


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its neutral state. Therefore, the current change between the source/drain electrodes is proportional to glucose concentration. FET sensors using graphene as the sensing material have also been demonstrated.17 By measuring the differential source-drain current, graphene-based sensors were able to detect glucose levels in the range of interest for diabetes diagnostics. Indium gallium zinc oxide field effect transistors (IGZO-FETs) are a promising technology that are currently being commercialized in displays.18 IGZO-FETs have relatively high average electron mobilities (µavg>10 cm2/Vs) and can be processed at low temperatures that are compatible with flexible transparent substrates.19 Interest in IGZO-FETs for a range of sensing applications has recently increased in areas including temperature,20 light,21 pressure,22 chemical and biochemical sensors.23, 24 For example, DNA molecules were detected through electrostatic interactions of negatively charged phosphate groups with a chemically unmodified IGZO surface. 23, 24

Organic-capping layers have been used to improve selectivity of IGZO-FETs used as

sensitive gas sensors.25 Flexible IGZO-FETs, with a compressible dielectric layer, have also been proposed as pressure sensors that can be integrated into contact lenses.22 In this study, we have functionalized IGZO-FET back channel surfaces with aminosilane coupling agents and glucose oxidase enzymes. The interaction of glucose with the sensing enzyme resulted in concentration-dependent changes in the electrical response of IGZO-FETs. Herein we demonstrate that functionalized IGZO-FETs can be used to sensitively and selectively quantify subtle changes in glucose concentrations in physiological buffer solutions. These results provide insight into a route to develop low-cost transparent biochemical sensors based on the emerging a-IGZO FET technology. Experimental Section


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Materials. Glucose was obtained from Alfa Aesar. HCl, NaCl, KCl, NaH2PO4, and Na2HPO4 were acquired from Macron. Aminopropyltrimethoxysilane, acetaminophen and ascorbic acid were purchased from Sigma-Aldrich. Glutaraldehyde was acquired from Electron Microscopy Sciences. Glucose oxidase was obtained from Amresco. IGZO and indium tin oxide (ITO) targets have been purchased from AJA International Inc. and Kurt J. Lesker Inc., respectively. The photoresist S1818 was acquired from Microchem. Sylgard 184 PDMS was obtained from Dow Corning. Milli-Q water (18.2 MΩ cm) was used in all sample preparation. Device Fabrication. IGZO-FET test structures (Figure 1) were fabricated using a heavily pdoped Si substrate as the gate and thermally grown SiO2 (100 nm thick) as the gate dielectric.26 ITO films (160 nm thick, measured by ellipsometry) were deposited on Si/SiO2 substrates using RF magnetron sputter deposition using a 3 inch ITO target (composition: In2O3:SnO2 = 90:10 wt%), 120W RF power, ~4 mTorr chamber pressure, and 20 sccm flow rate of Ar. Source/drain (S/D) electrodes were patterned using photolithography and etched in diluted HCl (1:20, HCl:H2O) giving a width/length (W/L) ratio of 100 µm/20 µm. The ITO films were then annealed in air at 300 °C for one hour to increase their resistance to the HCl etch, increase their electrical conductivity, and improve their transparency.27 Amorphous IGZO films (~50 nm thick) were deposited by sputter deposition using a 3 inch IGZO sputter target (molar composition: In2O3:Ga2O3:ZnO), 100W RF power, ~4 mTorr chamber pressure, and 20 sccm flow rate with a 1:19 (O2:Ar) ratio. The IGZO channel was patterned on top of the ITO S/D by photolithography. The etching solution was diluted HCl (1:200, HCl:H2O). The fabricated FETs were subsequently annealed in air at 300 °C to improve the electrical performance and stability. Surface Functionalization. IGZO surfaces were cleaned in an oxygen plasma (50 W power for 2 mins)

to

remove

contaminants.

The

sample

was

immediately soaked


in

a

1%

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aminopropyltrimethoxysilane (APTMS, H2N(CH2)3Si(OCH3)3) ethanol solution for 2 hours, rinsed with ethanol, and then dried with flowing nitrogen.28 The ATPMS-IGZO film was then immersed in 20 mM glutaraldehyde (GA, OHC(CH2)3CHO) in a phosphate buffer solution (160 mM PBS, containing 137 mM NaCl, 3 mM KCl, 4 mM NaH2PO4, and 16 mM Na2HPO4, pH 7.4) for 2 hours. GA acts as a cross-linker molecule to immobilize the sensing enzyme glucose oxidase (GOx).29 Finally, the device was transferred to and kept in 10 g/L GOx in PBS for 2 hours.30 The sample was rinsed with water and then dried with flowing nitrogen prior to electrical measurements. X-ray Photoelectron Spectroscopy (XPS). XPS measurements were performed with a PHI Quantera Scanning ESCA system using monochromatized Al Kα radiation (photon energy = 1486.6 eV) with a 200 µm spot size. The energy scale of the spectrometer was calibrated to Au 4f7/2 at 84.0 eV and Cu 2p3/2 at 932.7 eV. Charge compensation was accomplished using a combination of low energy ion and electron beams coincident on the sample. The data was quantified using instrument standard relative sensitivity factors corrected for the transmission function of the analyzer and were acquired with a 45° emission angle and an electron analyzer pass energy of 69 eV. The XPS data was fit using CasaXPS, where the most intense peak in the spectrum was used to define the core-level full-width-half-maximum (FWHM) and GaussianLorentzian mixing. A linear background was used to fit all spectra. The binding energies were charge corrected to the C 1s aliphatic carbon peak at 284.6 eV. Glucose Detection. All IGZO-FET electrical measurements were performed in the dark at room temperature using an Agilent 4155C precision semiconductor parameter analyzer. Forward (low voltage to high voltage) and backward (high voltage to low voltage) sweep drain-to-source current versus gate voltage (ID-VG) transfer curves were measured with the drain voltage (VD) set


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to 100 mV at a VG sweep step of 0.2 V and a sweep rate of VG = 0.2 V•s-1. The low VD was used to minimize electrochemical reactions that could occur since the source and drain electrodes were in contact with the analyte solution. A PBS solution was used to dilute glucose to the range of concentrations of interest for testing. A PDMS well was attached to the top of the exposed IGZO channel to define the contact area of the analyze solution and the back channel of the FET. Aqueous solution with/without glucose was purged with Ar in order to reduce oxygen levels to that of mammalian interstitial fluid (45 torr or 0.08 mM). Solutions for each analyte (100 µl) were introduced into the PDMS well (volume ~ 0.25 µl) using a syringe, where the glucose concentration was varied between 0-32 mM, which corresponds to the relevant clinical interstitial (2-30 mM)5 and tear (0.35 ± 0.04 mM)6-8 fluid glucose levels of diabetic patients. Results and Discussions Silanization of APTMS on the IGZO surface occurs through a condensation reaction, which promotes the formation of uniform monolayer of aminosilane. In order to confirm the presence of amino groups on the silanized IGZO surface, we used XPS to measure N 1s spectra before and after the silanization process where the spectra are shown in Figure 1. For the clean IGZO surface no N 1s peak was observed. After silanization an intense N 1s peak was observed indicating the presence of NH2 at the surface. Immobilization of the GOx enzyme was confirmed using XPS, where the O 1s and C 1s spectra were obtained from the IGZO surface after different functionalization procedures, and the data are shown in Fig 2 a and b, respectively. For the O 1s spectra the low-energy peak at 529.7 eV corresponds to lattice oxygen ions in IGZO.26 When APTMS was adsorbed on IGZO the mid-energy O 1s components can be attributed to Si-O-In/SiO-Ga/Si-O-Zn.31, 32 On the IGZO surface, the C 1s spectra had three fairly well-separated peaks with the lower energy peak having an energy of 284.6 eV, which is assigned to aliphatic carbon


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(C–C or C–H bonds), and the two higher energy peaks at 286.2 eV and 288.8 eV which can be assigned to C–O and O–C=O groups on the surface, respectively.33 As shown in the middle portion of Fig. 2b, most of the C 1s intensity from APTMS/IGZO surface comes from aliphatic carbons in the APTMS molecules, and a higher energy peak at 285.9 eV due to –CH2– bonded to the -SiO3- group. For the GOx functionalized IGZO surface high-energy peak intensities at 286.1 and 287.7 eV were enhanced. These two peaks can be attributed to the characteristic –CH2– bonded to the peptide linkage groups (–HN–C=O–) and peptide groups (–HN–C*=O–) in proteins.34 These results confirm that GOx was immobilized on the IGZO surface using the described procedures.

Figure 1. N 1s XPS data obtained from a blanket IGZO film functionalized with APTMS.


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Figure 2. (a) O 1s and (b) C 1s XPS data obtained from a blanket IGZO film functionalized with GOx (upper), IGZO film functionalized with APTMS (middle), and bare IGZO film (lower). In Figure 3 we compare transfer characteristics of IGZO-FETs after different surface functionalization procedures. These measurements were performed in air, where ID was measured while VG was scanned from -10 V up to 25 V and back down to -10 V with a constant VD. The IGZO-FETs without functionalization have good electrical characteristics and do not have significant hysteresis between the up and down sweeps of VG in the ID-VG data suggesting traps are able to stay in equilibrium with the VG sweep rate.26 The main change in the transfer characteristics after functionalization of the IGZO with ATPMS and GOx is an increase in the hysteresis of the devices. In all three cases the turn-on voltage (VON) remains at ~0.5 V when increasing VG, and the hysteresis is due to an increase in the turn off voltage (VOFF) when decreasing VG. A summary of the data is given in Table 1, where we have determined the average electron mobility (µavg), VON, drain current on-to-off ratio (ION/IOFF), and hysteresis for devices with different surface treatments. Both µavg and VON were extracted using methods


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described previously.35 The IGZO-FETs have high ION/IOFF ratio ~ 105, due in part to low IOFF, which is very important for sensors, a high µavg> 14 cm2/Vs, and low gate leakage currents (IG ~ 10-11 A). The major difference after adsorption of APTMS or GOx on the back channel surface is a slight decrease in µavg and ION/IOFF, and an increase in hysteresis.

Figure 3. Transfer characteristics of FETs with IGZO channel layer (a) without functionalization, (b) with APTMS and (c) with APTMS/GOx. (VD = 100 mV). Table 1. Average mobility, turn on voltage, drain current on-to-off ratio and hysteresis for IGZO FETs without passivation, with APTMS and GOx. (VD = 100 mV).

Surface treatment

µavg (cm2/Vs)

VON (V) ION/IOFF

IGZO-FET

14.6

0.5

2.8×105

0.6

APTMS

14.5

0.5

1.5×105

3.3

GOx

14.1

0.5

1.4×105

5.4

Hysteresis (V)

In Figure 4 we show a schematic of the device structure used for sensing, where a PDMS well was used to define the contact area of the analyte solution and the back channel of the IGZO-FET. Initial measurements were performed on APTMS functionalized IGZO-FET where the pH of the solution was varied. As shown in Figure 5 there is a significant increase in the VON


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for devices in direct contact to solution compared to those tested in air, as well as a decrease in the ION/IOFF ratio to ~ 103, primarily due to an increase in IOFF while in solution. We also observe a significant increase in VON with decreasing pH. At lower pH values the adsorption of protons to the aminosilane groups results in protonation of -NH2 to − NH 3+ on the silanized IGZO surface.36 The positively charged aminosilane groups on the IGZO surface can introduce acceptor-like surface states which can deplete electron carriers in the n-type IGZO film, thereby increasing the upward surface band bending.37 For our IGZO-FET sensor the adsorbed aminosilane on the IGZO back channel surface is a short-chain molecule (< 1 nm). The accumulated electrons close to the top IGZO surface could tunnel through this acceptor-like layer (depletion) due to the short tunneling distance. This leads to a decrease in conductance and requires a more positive VG to obtain the same initial current. We have found that the conductance between S/D contacts increased in proportional to pH with a sensitivity ~ 1.0×10-7 A/pH. A double gate mechanism has recently been proposed for ZnO-FET sensors,38 where the top protein layer acted as a virtual gate and the antibody layer acted as a virtual insulator, i.e. forming a pseudo-double gated field-effect conduction scheme. In this model the positively charged protein layer results in the accumulation of negative carriers within the oxide channel. This carrier accumulation close to back channel, in addition to the conduction path created near the gate results in an increase in the current flow and requires a more negative VG to obtain the same initial current. The proposed acceptor state model described above is more consistent with the operation of our IGZO-FETs compared to the pseudo-double gated field-effect conduction scheme.


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Figure 4. (a) Optical images of IGZO-TFT device with W/L ratio of 100 µm/20 µm. (b) Schematic illustration of experimental apparatus for IGZO-FET sensor under electrochemical test.

Figure 5: (a) Transfer characteristics for a ATPMS functionalized IGZO FET after exposing to varying pH. (b) ∆ID versus pH. Transfer characteristics are shown in Figure 6 for IGZO-FETs functionalized with the GOx enzyme, and with varying concentrations of glucose. We found that the ION/IOFF ratio in solution decreased to ~ 103, primarily due to an increase in IOFF. We found that VON shifted to positive values with increasing glucose concentration. This observation can be attributed to the reaction between GOx enzyme and glucose. Glucose is biocatalytically oxidized and forms


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gluconic acid in the presence of GOx, which can result in the acidification at IGZO/electrolyte interface through proton dissociation.30 The generated protons lower the pH in the vicinity of pHsensitive aminosilane groups which then results in a more positive VON and a decreased S/D conductance of the underlying IGZO-FETs as mentioned above. The GOx functionalized IGZO FETs were tested for device stability for > 1000 s in a phosphate buffer solution (PBS) with a fixed gate voltage, VG = 11 V. As shown in the Figure S1 the change in drain current (∆ID) remains constant for the entire time indicating excellent stability for these sensors. To illustrate the importance of functionalizing the back channel with GOx we compare the transfer characteristics of devices with and without GOx in Figure S2. In contrast to GOx functionalized devices, there is no significant change in VON or ∆ID after increasing the glucose for bare back channel IGZO-FET. These results indicate that enzyme functionalization is essential for glucose sensing.

Figure 6: (a) Transfer characteristics for a GOx functionalized IGZO FET after exposing to varying concentrations of glucose. (b) Schematic diagram showing the role of positively charged aminosilane groups as an electron acceptor and the impact of positively charged aminosilane groups on band bending at IGZO surface.


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To quantify the sensor response to glucose we measured ID with VG set to the maximum in sub-threshold slope (VG = 11 V) for the IGZO-FET in PBS solution. In Figure 7 we plot the continuous monitoring of ID versus glucose concentration (Cglucose) when a buffered solution is flushed over the device. Significant changes in ID were observed in this glucose concentration range and the current decreases/increases in a stepwise fashion as Cglucose was increased or decreased, respectively. The conductance changes are fully reversible for increasing and/or decreasing Cglucose. The response time for glucose sensing was less than 10 s (see Figure S3). The arrows in Figure 7a indicate when interfering compounds (acetaminophen and ascorbic acid) were added to the electrolyte at the end of the experiment. The concentrations used for acetaminophen and ascorbic acid are based on typical concentrations found in normal human plasma which is ~ 0.13 mM.39, 40 We found that interference of acetaminophen and ascorbic acid was completely suppressed. This suggests that GOx functionalized IGZO-FET selectively detected glucose and that the device is effective in minimizing interference from acetaminophen and ascorbic acid. This can be attributed to the specific catalysis reaction between GOx enzyme and glucose. The ∆ID is plotted versus Cglucose in Figure 7b and a linear relationship was obtained using a semi-log plot. The slope of ∆ID change versus log(Cglucose) was -2.2×10-8 A•mM−1 and a coefficient of determination (R2) of 0.999 was found for Cglucose up to 28 mM. Figure 7a illustrates good stability and reversibility of the devices, where ∆ID is found to decrease for increasing glucose concentrations, and the same value of ∆ID was obtained whether increasing or decreasing glucose to a given concentration. These data suggest that several complimentary measurements allow the determination of glucose concentrations, and the combination of measuring ID at a fixed VG may allow improved accuracy for sensing glucose.


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Figure 7: (a) Measurement of ∆ID for a GOx-functionalized IGZO FET in PBS after varying concentrations of glucose. Arrow 1 and 2 indicates addition of 0.13 mM acetaminophen and ascorbic acid, respectively. (b) ∆ID versus logarithmic glucose concentrations. The current change observed for our sensors is comparable to prior studies of carbon nanomaterial41, metal-oxide42 and polymer43 enabled glucose sensors. The electrical response to various glucose concentrations can be clearly identified for the GOx functionalized IGZO-FETs due to the excellent stability and low noise (±0.3 nA) during measurements. To further the functionality of these sensors the sensitivity can be improved by increasing VD, the width/length ratio, and/or the surface/volume ratio. In these studies, we have found that VON shifted significantly positive in aqueous media. Our device processing was optimized for IGZO TFT operation in air where the turn-on voltage (VON) was ~ 0 V. There are several approaches that can be undertaken to reduce VON for the IGZO TFTs in aqueous media so that low-voltage operation can be obtained. For example, to reduce the operating voltage a thin high k dielectric (e.g., Al2O3,44 HfO2,45 etc.) can be used as opposed to the relatively thick SiO2 used in these studies. Other methods include varying IGZO thickness,46 deposition (oxygen free deposition) and


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annealing conditions (temperature and ambient conditions) can increase the number of free carriers in the channel and result in a negative VON shift.47,

48

Finally, fabrication of fully

transparent, flexible sensors will open up new opportunities for ubiquitous sensing for human health. Conclusions In summary, we have demonstrated that IGZO FETs show promise as a transparent glucose sensor. Highly sensitive IGZO-FETs in aqueous media were fabricated by functionalization of the oxide back channel surface with GOx as a sensing enzyme. The generated protons from glucose/GOx reactions in the vicinity of pH-sensitive aminosilane groups on IGZO surfaces induced the drain-source current decrease and more positive turn-on voltage in the transfer curve. It was also found that the drain-source current change was proportional to logarithmic glucose concentrations over the normal range found in patients with type I diabetes. The specific catalysis reaction between GOx enzyme and glucose minimize interference from acetaminophen and ascorbic acid. This study advances the development of oxide-based FETs for applications to glucose biosensors with the potential to integrate fully transparent sensors into contact lenses. Acknowledgements This work was funded in part by the Oregon Nanoscience and Microtechnologies Institute (ONAMI). X. Du acknowledges funding support from the Juvenile Diabetes Research Foundation (3-PDF-2014-113-A-N).

Y.L. acknowledges the support of China Scholarship

Council and the Science Foundation of Civil Aviation University of China (3122013k006). Supporting Information. Stability test for GOx-functionalized IGZO FET in PBS. Electrical response of blanket IGZO-FET to glucose. Schematics of GOx-functionalized IGZO FET


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