Wearable, Flexible, and Multifunctional Healthcare Device with an

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Wearable, flexible, and multifunctional healthcare device with an ISFET chemical sensor for simultaneous sweat pH and skin temperature monitoring Shogo Nakata, Takayuki Arie, Seiji Akita, and Kuniharu Takei ACS Sens., Just Accepted Manuscript • DOI: 10.1021/acssensors.7b00047 • Publication Date (Web): 03 Mar 2017 Downloaded from http://pubs.acs.org on March 4, 2017

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Wearable, flexible, and multifunctional healthcare device with an ISFET chemical sensor for simultaneous sweat pH and skin temperature monitoring

Shogo Nakata, Takayuki Arie, Seiji Akita, Kuniharu Takei*

Department of Physics and Electronics, Osaka Prefecture University, Sakai, Osaka, Japan *Corresponding author: [email protected]

Keywords: sweat sensors, pH sensors, flexible sensors, sensor integration, wearable devices, ISFET

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Abstract: Real-time daily healthcare monitoring may increase the chances of predicting and diagnosing diseases in their early stages which, currently, occurs most frequently during medical check-ups. Next-generation non-invasive healthcare devices, such as flexible multifunctional sensor sheets designed to be worn on skin, are considered to be highly suitable candidates for continuous real-time health monitoring. For healthcare applications, acquiring data on the chemical state of the body, alongside physical characteristics such as body temperature and activity, are extremely important for predicting and identifying potential health conditions. To record these data, in this study we developed a wearable, flexible sweat chemical sensor sheet for pH measurement, consisting of an ion-sensitive field-effect transistor (ISFET) integrated with a flexible temperature sensor: we intend to use this device as the foundation of a fully integrated, wearable healthcare patch in the future. After characterizing the performance, mechanical flexibility, and stability of the sensor, real-time measurements of sweat pH and skin temperature are successfully conducted through skin contact. This flexible integrated device has the potential to be developed into a chemical sensor for sweat for applications in healthcare and sports.

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Monitoring of day-to-day health data is of great interest as it may improve the probability of predicting or lead to early diagnosis of disease, which currently often occurs by chance during medical check-ups. Wearable devices which detect health parameters and activity are considered to be one of the most effective and viable methods for everyday health monitoring: although there are commercially available devices for this purpose, these are inflexible. The next generation of monitoring devices currently being developed in research settings are often fabricated on flexible substrates which improve their wearability1-5. The body’s chemical state is an important indicator in health monitoring—in particular, parameters such as pH, glucose, potassium, calcium, and heavy metal ions—and combining these data with physical data such as activity, body temperature, and heart rate can greatly increase the chances of detecting adverse health conditions6; however, conventional wearable devices are not currently able to carry out chemical monitoring. In the medical field, blood tests are typically used to analyze the various chemical states in the body; however, taking blood is an invasive procedure which carries a risk of infection, and is therefore considered to be unsuitable for home healthcare monitoring. A possible non-invasive solution is monitoring chemical contents in sweat through direct contact of a device with the skin, although this method requires that the wearer produce sufficient volumes of sweat, which may be achieved, for example, through sport. Several approaches may be taken to monitor sweat chemical content using wearable devices,

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notably the use of chemically reactive films to selectively monitor specific chemical components7-11. Most reports of wearable, flexible, chemical sensors have chosen to use cyclic voltammetry (CV) for these measurements, and chemical content of sweat has been successfully monitored by this method7-8,10-11. Another possible route employs ion-sensitive field-effect transistors (ISFETs), which have been proposed as an alternative to CV-based devices: ISFETs require a simple direct current measurement, as opposed to the more complex measurements required by CV, and are compatible with integrated circuits; to this point, this approach has mainly been applied to inflexible, Si-based devices12-15. The pH level is a fundamental chemical property of sweat, and is a crucial indicator in disease diagnosis: if the pH can be adequately measured, it greatly increases the probability of measuring the chemical components of sweat, which can be achieved by studying chemical reaction membranes on pH sensors14. However, integrated, flexible, and multifunctional sensor concepts incorporating ISFET-based chemical sensors have yet to be demonstrated, and these have not hitherto been incorporated into wearable devices. The integration of chemical sensors into multifunctional monitoring devices is of key importance, as monitoring of complementary parameters is required to aid prediction and diagnosis of adverse health conditions. For example, by monitoring pH level in sweat and skin temperature, it can be most likely possible to predict dehydration during exercise, which both pH and skin temperature are increased when dehydration is caused16-17. In addition,

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although there are some reports to monitor chemical contents and physical properties in real-time

4, 7-8, 11

, correlation between sweat chemical and physical condition has yet to be

evaluated in detail to date. By developing multi-functional wearable devices, it may be able to understand health condition deeply in the future. In this study, we demonstrate a flexible ISFET-based sweat pH sensor, integrated with a flexible printed temperature sensor (Figure 1a) which monitors both skin temperature, as well as compensating for the temperature effect of the ISFET. For the ISFET, an InGaZnO thin-film18 and Al2O3 layer were used for the n-type field-effect transistor (FET) material and the pH sensing membrane, respectively. It should be noted that the use of InGaZnO thin-films has been already reported for some ISFET demonstrations on both rigid and flexible substrates13,15; however, these have yet to be used in demonstrations of either flexible sensor integration or wearable applications, as is proposed in this study. Fundamental characteristics of ISFETs such as the sensitivity, mechanical flexibility & reliability, and temperature dependence are discussed, followed by a wearable device demonstration as a first proof-of-concept for ISFET-based flexible and wearable sweat pH and skin temperature monitoring.

EXPERIMENTAL SECTION ISFET. For the flexible ISFET substrate, a polyimide (PI) precursor solution of

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poly(pyromelitic dianhydride-co-4,4’-oxydianiline), amic acid (Sigma-Aldrich, USA) was spin-coated on a carrier Si wafer and cured at 350 °C to form the PI film. To improve adhesion between the PI film and metal layers, a SiOx layer (10 nm thick) was deposited by an electron-beam (EB) evaporation. Al back-gate electrodes (100 nm thick) were sputtered and patterned using a wet etching method. (Figure S1(1)), after which, to form a contact on the Al gate electrode, Cr/Au (5 nm/30 nm) was evaporated on the electrode pads. Subsequently, a 50 nm thick Al2O3 layer was deposited by an atomic layer deposition (ALD) at 200 °C (Arradiance, USA), followed by EB evaporation of 10 nm of SiOx (Figure S1(2)). For the FET semiconductor channel, an amorphous InGaZnO (30 nm thick) film was sputtered (Figure S1(3)), followed by deposition of Cr/Au source and drain electrodes. After using a lift-off process to pattern the S/D electrodes (Figure S1(4)), via-holes were created in the Al2O3/SiO2 dielectric layer by etching with a buffered hydrogen fluoride (BHF), enabling contact with the gate electrode. After annealing at 200 °C for 90 min to activate the InGaZnO film, a 50 nm layer of Al2O3 was deposited by ALD, forming the ion-sensitive membrane (Figure S1(5)). After using the BHF solution to create vias in the Al2O3 layer, a Ag/AgCl reference electrode (ALS Co., Ltd, Japan) was printed under an optical microscope and cured at 120 °C for 5 min in air ambient. The PI substrate bearing the device was then detached from the carrier wafer. Temperature sensor. Ag ink (Asahi Chem. Res. Lab., Japan) was printed on 38 µm thick

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polyethylene terephthalate (PET) film and cured at 70 °C (Figure S1(6)(7)), forming the electrical interconnection for the temperature sensor. Then, a solution of carbon nanotube (CNT) ink (SWeNT, USA) and 1.3 wt% poly(3,4-ethylenedioxyhiophene) polystyrene sulfonate (PEDOT:PSS) in water (Sigma Aldrich, USA) was mixed in a 1:3 ratio, then printed and cured at 70 °C, completing the fabrication of the resistive temperature sensor19 (Figure S1(8)). ISFET and temperature sensor assembly and demonstration. The ISFET and temperature sensor sheets were laminated using double-sided tape (Figure S1(9)), and the device was covered with PI tape to protect the components from sweat ingress, leaving only the ISFET channel and the reference electrode exposed. (Figure S1(10)). It should be noted that a PI film and a PET film were used for ISFET and temperature sensor, respectively, due to thermal budget for the ISFET fabrication and material cost. The fabrication of ISFET needs to use relatively high temperature process at 200 °C for ALD deposition and InGaZnO film annealing, which high temperature process cannot be applied to the PET film. To withstand such process temperature, a PI film with thermal capability up to ~350 °C was used for the ISFET film material. Because the printing process for the temperature sensor was used, it can be also formed on the PI film. However, in terms of material cost, other plastic films including a PET film are suitable compared to the PI film. By considering more sensor integration in the future, a PET film was chosen to use as one of possible ways to integrate different sensors. Lastly, a

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wired connector with a 2.54 mm pitch was used to link the device with the measurement setup. All results including real-time sweat pH and skin temperature monitoring were conducted using this wired setup. The skin-contact demonstration was performed in compliance with a protocol approved by Osaka Prefecture University.

RESULTS AND DISCUSSION The final device structure is displayed in Figures 1b-e, with general handling suggesting that the device is mechanically flexible and not damaged under bending. For the FET channel and pH reactive membrane material, an amorphous thin-film of InGaZnO (~30 nm thickness) and Al2O3 layer (~50 nm) were used, respectively. It should be noted that IDS–VGS behaviors before and after Al2O3 deposition exhibited significant differences: Figure S2 indicates that, although the InGaZnO transistor showed a large on/off IDS current ratio before Al2O3 deposition, the ratio was found to be much smaller after deposition for multiple samples. The field-effect mobilities before and after Al2O3 deposition at VGS=3 V are 9.01 cm2/Vs and 11.8 cm2/Vs, respectively. We speculate that n-type doping of the InGaZnO transistor occurs during processing, either through exposure to trimethylaluminium used in Al2O3 deposition, or through thermal damage of the InGaZnO film during ALD processing (200 °C). However, the high IDS current measured at VGS = 0 V after Al2O3 deposition actually simplifies the real-time

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pH monitoring, and as such, further investigation into the change in ISFET characteristics was not conducted in this study, although it is noted that a future exploration of this phenomena would be of great help in improving our understanding of the material system. Extraction of pH values from the ISFET is achieved by measuring the concentration of hydrogen ions corresponding to a positive potential that is well-known for the device. The Al2O3 layer was selected as the ion-sensitive membrane in this study: the interaction of this layer with hydrogen ions acts to change the top-gate bias of the InGaZnO transistor, resulting in pH-dependent changes in threshold voltage or IDS at constant gate voltage. By monitoring these changes, pH values can be extracted: the transfer characteristics of the ISFET shows that IDS increased with increasing acidity (lower pH values). To characterize the ISFET performance, a back-gate structure controlled by electrical bias was also fabricated: Figure 2a shows that IDS at VDS = 1.0 V increased when the pH value was changed from 11.0 to 3.3, suggesting that the threshold voltage was shifted to a negative gate bias, while Figure 2b shows that the VGS shift at IDS = 0.9 µA changed linearly with a rate of 51.2 mV/pH at 25 °C, a trend which is in good agreement with the change in hydrogen ion concentration. This potential change, E, as a function of pH value can be understood through the Nernst equation, = +

ln

where EREF is the reference voltage (EREF = 0 V in this study), R is the gas constant, T is the

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absolute temperature, n is the number of electrons transferred, F is the Faraday constant, and is the hydrogen ion concentration. Based on this equation, the theoretical pH sensitivity limit is 59.2 mV/pH at 298 K. Since the sensitivity of the device in this study was observed to be 51.2 mV/pH at room temperature, we can conclude that the ISFET is suitable as a pH ion sensor, albeit with a small degree of detection loss. To demonstrate the possibility of wearable device applications, and to show that the results were not caused by hysteresis of the InGaZnO transistor, real-time monitoring of a set of solutions at different pH values was conducted, as shown in Figure 2c. Here, IDS at VDS = 1 V and VGS = 0 V (i.e. common to source ground line) indicate consistent changes in output on immersion in different pH solutions (3.3, 7.1, and 11.4), and stable current levels when held in solution, suggesting that the InGaZnO ISFET is almost hysteresis-free. It should be noted that there was a small IDS change after the ISFET was moved to the following solution, most likely arising from residual solution on the surface of the device: as the solution samples used in this experiment were rather small, the diffusion of old solution into the new ones caused measurable changes in the device output. The current level between Figure 2a and 2c shows relatively large difference due to batch-to-batch variation of the fabricated InGaZnO transistors with an Al2O3 layer, which needs to improve and optimize the fabrication process and materials in the future. As the Nernst equation shows, the pH potential is proportional to temperature, and

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thus the temperatures of both the solution and the environment are required for precise measurement of the solution pH levels. To assess the effects of temperature on the ISFET, the temperature dependence of the device was explored using a pH 7.2 solution. Figure 3a shows the transfer characteristics of the ISFET at VDS = 1 V when the device temperature was changed from 24.2 °C to 47.2 °C. IDS was observed to increase with increasing the device temperature, which is not consistent with the Nernst equation. This trend was observed because, as Figure S3 reveals, the InGaZnO transistor is more sensitive to temperature change than to the pH chemical reaction, as calculated by the equation. To summarize this change, IDS at VGS = 0 V was measured at different temperatures, as plotted in Figure 3b, demonstrating that IDS increased linearly with temperature. For wearable device applications, this temperature dependence is a significant problem, as the temperature of sweat readily changes depending on both the temperature of the body and the environment. To compensate for these temperature effects, a flexible temperature sensor was integrated with the ISFET, which can be also used for monitoring skin temperature in flexible healthcare sensors: the sensor’s detection mechanism depends on changes in electron-hopping conduction at the interface between the CNTs and PEDOT:PSS induced by changes in temperature2. Firstly, the temperature sensor was characterized by measuring the resistance change of the sensor as a function of temperature between 22 °C (room temperature) and

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36.5 °C (Figure 3c), which showed that resistance decreased linearly with increasing temperature. The sensitivity of the temperature sensor is defined as ∆R/R0 per change in unit temperature, where R is the measured resistance and R0 the resistance at RT, and ∆R = R-R0: using linear curve fitting, the extracted sensitivity was found to be 0.85 %/°C, which is relatively high compared to flexible temperature sensors based on other materials, such as Pt electrodes20. When conducting simultaneous measurement pH level and temperature using this sensor, it is possible to compensate for the potential shift arising from pH and temperature, enabling precise pH monitoring over a range of temperatures. Figure 3d clearly indicates that, after compensation, the recorded pH from a pH 7.2 solution is relatively stable over the range 29 °C to 44 °C, whereas the non-compensated measurement of the same solution yielded a steady drop in pH (to more acidic values) with increasing temperature. By compensating for the ISFET temperature effect at 43.4 °C the measurement error was reduced from ~7.64% to ~0.97%. To shed light on the mechanical flexibility and stability of the ISFET under bending, its transfer characteristics were measured at VGS = 0 V and VDS = 1 V as a function of bending radius: curvature of up to 13 mm was used, and the tests were carried out both under ambient conditions and with the device immersed in a pH 7.2 solution (Figure 4a). The rate of drain-source current change, ∆I(=I–I0)/I0 (where I0 and I are the drain-source current at flat and

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bending conditions, respectively), at different bending radii, r, shows almost no change over the bending range used, with a maximum recorded IDS change of only ~0.32%. The observed stable operation is largely attributed to solution wetting on the sensor: due to the surface tension and high wettability of the solution on the Al2O3 membrane (contact angle of pH 7.2 solution on the surface was ~17°, as shown in Figure S4), the effective sensing area remains almost unchanged, even under bending. Furthermore, repeatable bending test was also conducted as shown in Figure 4c. The result depicts that the ratio of current change, ∆I/I0, at least 1500 bending cycles in radius of 32.5 mm was ~0.43 %. Although the current change ratio is small, this bending effect causes inaccurate pH monitoring for the wearable device application such as dehydration prediction, which requires the resolution of 0.1 pH and 0.1 °C detections. This strain effect should be improved by considering the strain distribution and material formations in the future. These results demonstrate that the InGaZnO-based ISFET can be considered as a candidate for incorporation into the flexible chemical sensing platform. Finally, for the proof-of-concept of the first flexible, wearable sweat ISFET-based pH sensor integrated with a temperature sensor, the device was attached on a test subject’s neck using a double-side tape, leaving only the ISFET channel and the reference electrode exposed to sweat from skin (Figure 5a), and the sweat pH and temperature were measured concurrently in real-time. It should be noted that there is a gap between the ISFET and skin, resulting in that

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sweat can be in the gap to measure sweat pH value. Threshold sweat volume should be different depending on the gap distance between them. Further concern is that it needs to refresh sweat to monitor real-time and long-term measurements, which is a challenge and a bottleneck for the practical use. To address these, further optimization of device structure and/or development of the measurement system/program are required, and that is out of scope in this study because this is more focused on the sensor fabrication. During the measurement, VDS = 1 V and VGS = 0 V were used for pH monitoring by the ISFET, while the resistance values of the temperature sensor were measured under an applied voltage of 0.1 V, and the sampling rates of both measurements were 1 Hz. Much lower sampling rate would also be acceptable as the human body does not present changes on such a rapid timescale. After exercising for about 15 minutes with a jump rope and running, the sweat pH and the skin temperature were monitored. To evaluate the accuracy of these measurements, control experiments were conducted using a commercial pH sensor and an infrared (IR) temperature sensor. For the control pH measurement, sweat was collected by pipette and applied onto the sensor. Figure 5b displays the real-time skin temperature and pH values, compared with the controls: the reading from the flexible pH sensor was almost constant at pH 4.0, and the values from the flexible temperature sensor fell within the range of 30.0 °C to 31.7 °C during the real-time measurements. The pH level shown in Figure 5b was calibrated using the measured temperature value. The control values measured by

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the commercial pH and IR sensors were also found to be largely constant, pH 4.0 and ~31 °C, respectively, and agree well with the real-time measurements from the flexible sensors. Although there was a small fluctuation in pH level during real-time measurements which require further investigation, this flexible, wearable pH and temperature sensor sheet has been successfully demonstrated to monitor the sweat pH and skin temperature without substantial errors, as confirmed by comparison to the measurements from the commercially available pH and temperature sensors. It is also worth mentioning that real-time monitoring in this experiment was conducted using wired connections between the sensors and the measurement system. To monitor precise chemical changes during exercise, a wireless system should be incorporated with the sensor, and this would be the next step in investigating these devices; however, wireless system integration is beyond the scope of the present study which focused on the integration of pH and temperature sensing, and will be covered by our research in the future. In this study, the InGaZnO transistor used as the basis for the pH sensor was fabricated by the semiconductor process using evaporator, ALD, and lithography methods. We consider InGaZnO to be an extremely well-suited material for this application, taking into account both device cost and possibilities surrounding integration into different systems. If cost-reducing considerations are incorporated into the design of these monitoring devices, for example the use of disposable sensing components, InGaZnO would be a highly suitable candidate as several

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groups have reported successful solution-processing and printing of thin-films of this semiconductor, alongside other oxide-based materials21-23. On the other hand, if a manufacturer selects an integrated system akin to those found in conventional electronics, InGaZnO thin-films may also be deposited by vacuum-based display manufacturing-type processes, allowing the integration of InGaZnO-based ISFETs with signal processing circuits. The processing flexibility of the InGaZnO material system makes it an excellent candidate to be studied for a variety of monitoring devices, including the flexible and wearable sensors outlined in this study. In terms of various chemical detections in sweat, this ISFET pH sensor cannot distinguish each chemical such as urea and lactic acid because these chemicals also change the pH values. However, for precise health condition monitoring, each chemical most likely needs to monitor selectively depending on the application. For selective monitoring, each chemical sensitive membrane, which converts the chemical into ion potential, is required to form on ISFET. Fortunately, several chemical membranes have been already discovered and used for selective chemical sensing reported previously

4, 7, 11

. By applying these, it may be possible to

detect each chemical selectively using the ISFET pH sensor. This is next step to expand this technology to practical multi-functional flexible devices.

CONCLUSION

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In conclusion, we developed a mechanically flexible sweat pH sensor using an InGaZnO-based ISFET, integrated with a printed flexible temperature sensor. The results suggest that precise pH measurements could be attained by compensating for the ISFET temperature effect by integrating this component with a flexible temperature sensor; furthermore, the temperature sensor can simultaneously be employed for skin temperature monitoring. After characterizing the sensors, the pH level of sweat and skin temperature were successfully recorded in real-time by attaching the device to a test subject’s neck during exercise, demonstrating the first proof-of-concept operation of such a device. The real-time monitoring results show that the sweat pH and skin temperature were analyzed precisely, which was confirmed by control measurements using commercially available sensors. As discussed above, the InGaZnO material system is an extremely promising candidate for future applications in low-cost, disposable, and flexible electronics, or in highly integrated multifunctional devices, due to the variety of synthetic routes available to the material, including solution-based or semiconductor display manufacturing processes. In moving towards the realization of multifunctional, wearable, and flexible healthcare devices, the integration of additional functionality, for example acceleration sensors, other chemical sensors, signal processing components, and wireless circuits must be demonstrated on flexible films. We believe that these developments may help to open the door to the design of the next generation of wearable

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healthcare devices which combine various flexible sensor platforms, as have been reported in the literature1, 7, 9-11, 24, in order to greatly improve prediction and diagnosis of adverse health conditions in their early stages.

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Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Schematic fabrication process of the device. Electrical characteristics of InGaZnO transistor before and after Al2O3 deposition. Electrical characteristics of InGaZnO ISFET as a function of temperature. Contact angle of pH 7.2 solution on Al2O3 layer.

Notes The authors declare no competing financial interest.

Acknowledgments This work was partially supported by the JGC-S scholarship foundation and a grant for faculty innovation of Osaka Prefecture University.

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Figure 1. (a) A schematic of a wearable device integrating flexible pH and temperature sensors, (b) a cross-sectional diagram of the device, and (c) a photograph of the fabricated device. (d) Optical micrograph of the ISFET component prior to covering with polyimide, and (e) magnified picture showing the temperature sensor.

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Figure 2. (a) IDS–VGS characteristics of the ISFET at VDS = 1 V in solutions of different pH. (b) VGS at IDS = 9×10-7 A as a function of pH, extracted from (a). (c) Results from real-time measurement of solutions with different pH.

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Figure 3. (a) IDS–VGS curves measured from ISFET at different temperatures in a pH 7.2 solution. (b) IDS at VGS = 0 V as a function of measured temperature. (c) Normalized resistance change of the temperature sensor at different temperatures. (d) pH values extracted from IDS with (blue) and without (red) temperature compensation.

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Figure 4. (a) Photograph of the flexible integrated ISFET/temperature sensor device under bending, where r is the curvature radius. (b) Normalized drain-source current change (∆I/I0) recorded from the ISFET as a function of curvature radius in air (blue) and in pH 7.2 solution (red). (c) Normalized ∆I/I0 as a function of bending cycle at 32.5 mm curvature radius.

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Figure 5. (a) Photograph showing attachment of the flexible pH and temperature sensors to the test subject’s neck, and (b) real-time pH and skin temperature acquired by the device. Red and blue dots represent the control experiment data for pH and skin temperature, respectively, measured using commercially available pH and IR sensors.

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TOC figure

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Wearable, Flexible, and Multifunctional Healthcare Device with an

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