POTENTIOMETRIC WEARABLE SWEAT SENSOR
A potentiometric sensor that includes a housing and working electrode is provided. The housing includes a reference electrode, a first hydrogel that contains a reference solution, and a salt bridge. The sensor is wearable and can be used for continuous on-body sweat measurements.
This application is a divisional application of U.S. application Ser. No. 16/099,176 filed Nov. 5, 2018, now pending; which is a 35 USC § 371 National Stage application of International Application No. PCT/2017/031031 filed May 4, 2017, now expired; which claims the benefit under 35 USC § 119(e) to U.S. Application Ser. No. 62/332,949 filed May 6, 2016, now expired. The disclosure of each of the prior applications is considered part of and is incorporated by reference in the disclosure of this application.
BACKGROUND OF THE INVENTION Field of the InventionThe present invention relates to a potentiometric sensor for measuring the concentration of chloride ions in sweat.
Background InformationPotentiometric sensing is a method developed to measure the concentration of an ion in solution. This method measures the electrical potential difference between a reference and a working electrode (
Sweat chloride is a biomarker for cystic fibrosis (CF) and for electrolyte loss during exercise. The chloride ion concentration in the sweat of CF patients is typically 60 to 150 mM, much higher than in healthy individuals (typically 10-40 mM), and hence sweat chloride testing is the most widely used assay for diagnosis of CF. The assay involves collection of a sweat sample and analysis by coulometric titration, manual titration, or an ion selective electrode. Chloride is the most abundant ion in sweat, and hence is also a potential biomarker for electrolyte loss. The successful development of a wearable sweat chloride sensor can reduce the cost and time for laboratory-based sweat testing for CF patients, and can provide real-time information for healthy individuals during exercise.
The development of wearable sensors to measure biomarkers in sweat is recognized as a major technological challenge. There are three main candidate technologies for wearable sweat chloride sensors: titration devices, conductivity measurements, and potentiometric sensors. Wearable titration sensors have been reported, but require subsequent analysis on a separate instrument. Wearable conductivity sensors are readily miniaturized, but are not chloride specific. Potentiometric measurements rely on the relationship between the ion concentration and the electrochemical potential of an electrode. This is a well-established analytical technique that can be readily miniaturized. Chloride ion detection relies on the equilibrium between chloride ions and silver chloride (AgCl(s)+e−↔Cl-(aq)+Ag(s)), and can be measured using silver chloride electrodes that are widely employed in electrophysiology and analytical chemistry. There are relatively few examples of wearable sodium and potassium ion sweat sensors that use ion selective membranes, and wearable potentiometric chloride sensors.
Two publications describing miniaturized chloride sweat sensors are described (see below). Gonzalo-Ruiz et al. reports measurements immediately after inducing sweat in subjects but does not report measurements as a function of time. Lynch et al. reports only measurements in a test solution; neither reference reports any on-body measurements. Furthermore, neither reference reports the time response of its device.
Gonzalo-Ruiz's apparatus is used to sense chloride ions in sweat. The apparatus includes a screen-printed Ag/AgCl electrode covered by pHEMA hydrogel matrix containing KCl (the hydrogel matrix was used as a reservoir for the reference solution) as the reference electrode, a screen-printed Ag/AgCl electrode as the working electrode, and two other electrodes (cathode and anode) for sweat generation (
Lynch's apparatus is used to sense chloride, potassium, and sodium ions in a sweat sample. The apparatus is not wearable. The components for chloride ion sensing include a Ag/AgCl electrode covered by a hydrogel containing the reference solution as the reference electrode and a Ag/AgCl electrode as the working electrode (
In current designs of wearable sweat sensors (chloride ions as well as other ions) the reference electrode is covered with a gel containing the reference solution. Transport of ions between the reference solution and test solution (sweat) results in changes in the potential of the working electrode and results in measurement error. As a result, these devices cannot be used for continuous on-body measurements. Thus, there is a need for sweat sensors that are suitable for continuous on-body measurements.
SUMMARY OF THE INVENTIONThe present invention is based on the discovery that a sweat chloride sensor integrated with a salt bridge minimizes equilibration and enables stable measurements over extended periods of time.
One embodiment of the present invention is to provide a potentiometric sensor that includes a housing and a working electrode. The housing includes a reference electrode, a first hydrogel that contains a reference solution, and a salt bridge.
In another embodiment, the salt bridge includes a second hydrogel.
In another embodiment, the first and second hydrogels are the same.
In another embodiment, the hydrogel is agarose.
In another embodiment, the housing includes polydimethylsiloxane (PDMS).
In another embodiment, the reference and working electrodes are Ag/AgCl electrodes.
In another embodiment, the reference solution includes 1M KCl.
In another embodiment, the salt bridge includes an ion selective polymer.
In another embodiment, the ion selective polymer is Nafion or polydiallyldimethylammonium chloride (polyDADMAC).
In another embodiment, the sensor monitors the concentration of an ion in sweat.
In another embodiment, the sensor is wearable.
In another embodiment, the ion is selected the ion can be chloride, potassium or sodium.
In another embodiment, the sensor is used to monitor chloride ion concentration in a cystic fibrosis (CF) subject.
In another embodiment, the sensor is used to monitor chloride ion concentration as a function of workout intensity.
Another embodiment of the present invention is to provide a method of measuring an ion concentration in sweat. The method includes a step of placing a potentiometric sensor on the skin of a subject. The potentiometric sensor includes a reference electrode, a first hydrogel containing a reference solution, a salt bridge, and a working electrode. The salt bridge is in direct contact with the skin. Another step includes generating sweat under the salt bridge. The ions in the sweat form an ionic circuit between the reference electrode and the working electrode. A third step includes measuring a potential difference proportional to the ion concentration in the sweat, thereby measuring the ion concentration.
In another embodiment, the salt bridge used in the method includes a second hydrogel.
In another embodiment, the step of measuring the ion concentration is continuous.
In another embodiment, the ion being measured can be chloride, potassium or sodium.
In another embodiment, the ion being measure is chloride.
In another embodiment, the method includes the step of diagnosing whether the subject has cystic fibrosis (CF) based upon the chloride ion concentration.
In another embodiment, the method includes assessing an intensity of a workout based upon the chloride ion concentration.
Other aspects and advantages of the invention will be apparent from the following description and the appended claims.
Other aspects and advantages of the invention will be apparent from the following description.
A challenge in developing wearable potentiometric sensors is that equilibration between the reference solution and the test solution over time results in a measurement error. In recent work, the critical role of the salt bridge in determining the sensor performance has been reported. An analytical model to assess the rate of equilibration between the reference and test solutions, and hence to predict the measurement error as a function of salt bridge geometry was used. The model was validated by a series of parametric studies, which allowed the design of rules for specific applications. The present invention uses these criteria to design and optimize a wearable thin film chloride sweat sensor. Building on previous work, the present invention makes the following key advances: (1) a fabrication process to integrate the salt bridge into a thin film sensor is described; (2) the reliability and reproducibility of the sensor is described; and (3) and in vivo results from in vivo testing which indicate that sweat chloride concentration is dependent on exercise intensity are presented. The device is fabricated on a plastic substrate and can be easily and comfortably worn on the body using a commercial adhesive bandage. The device shows reliable performance over 12 hours. The accuracy of the device is evaluated over the concentration range of about 10 to 150 mM, and the calibration curve and dose response of the fabricated devices are also presented. Finally, the concentration changes during an exercise with graded exercise load are presented.
To overcome problems discussed in the Background of the Invention section, a salt bridge between the reference solution and the working electrode and test solution was introduced. The present invention describes a sweat sensor to reliably measure the concentration of chloride ions in sweat. By introducing a salt bridge, ion transport between the reference solution and test solution is very slow and hence the potential of the reference electrode remains constant for extended times. Therefore, reliable on-body measurements can be made over time.
As shown in
On generation of sweat under the sensor, the ionic circuit between the working electrode and the reference electrode is completed, resulting in a potential difference that is related to the chloride ion concentration in sweat. Using a calibration curve determined for the sensor prior to use, the potential difference can be related directly to a chloride concentration.
Transport of ions between the reference solution and the test solution (sweat) is dependent on the salt bridge geometry, and the materials used in the sensor. The design of the sensor has been optimized to minimize ion transport and maximize the time of measurement. Designs using an ion selective polymer for the salt bridge have been tested.
Parametric StudiesTo optimize the geometry of the salt bridge, parametric studies have been performed.
In another embodiment, the use of ion selective polymers in the salt bridge to reduce ion transport and improve measurement stability was explored. For example, polymers such as Nafion and polyDADMAC (polydiallyldimethylammonium chloride) have been tested (
One example of the fabrication process is described in
Step 1. Fabrication of the polydimethylsiloxane (PDMS) housing for the reference electrode chamber (
After removal of the PDMS housing from the mold, a hole punch is used to form the reference solution chamber. An additional hole is punched in the housing that is later used to seal the reference electrode wire into the housing. The diameter of the reference electrode chamber is typically about 5 mm, but can also be smaller to reduce the size of the sensor.
Step 2. Fabrication of the PDMS base with the salt bridge channel (
The PDMS base that contains the salt bridge channel is also formed by a similar casting process using a metal wire template. Typically a metal wire of 100 μm in diameter is used to form a cylindrical channel in PDMS. The PDMS with the template wire still in place are removed from the mold. Next the template wire is removed from the PDMS. The PDMS is then cut into slices with a thickness that defines the length of the salt bridge. Each slice forms the base of a sensor with a hole that will be the salt bridge channel. Typically the thickness of the PDMS base is 3 mm. The wire diameter defines the diameter if the salt bridge channel and can be changed by using a different diameter template wire. The length of the salt bridge is dependent on the thickness of the slice cut from the PDMS block.
Step 3. The PDMS housing with the reference electrode chamber and PDMS base with the salt bridge channel are plasma bonded (
Step 4. The second hole in the PDMS housing is then filled with PDMS to fix the reference electrode wire into the housing. The PDMS is then cured at 75° C. for 1 hour (
Step 5. The reference electrode chamber is filled with a hydrogel containing the reference solution. In many experiments, 1 M KCl in agarose was used (4% w/v ration agarose gel, 1 M KCl solution: agarose gel=20 ml: 0.8 g). Vacuum is applied to the chamber through the salt bridge channel to fill the salt bridge with the hydrogel (
Step 6. The top of the reference electrode chamber is sealed with PDMS. The device is placed in an oven at 45° C. for 5 hours to cure the PDMS on the top of the housing. The PDMS cap prevents evaporation of the reference solution in the reference chamber (
Step 7. Working electrode. A hole is formed in the housing for the working electrode using a 1 mm hole punch. A Ag/AgCl wire electrode is inserted into the hole (
Other methods for fabrication and other configurations have been developed. For example, in one embodiment, planar Ag/AgCl electrodes are used.
On-body tests to monitor chloride concentration in sweat were performed. Three human subjects participated in these tests and did a constant-load exercise on an exercise bike for an hour. The devices were attached at various locations including forearm, chest, and back. The output voltage of the sensor was measured during the test by DAQ (data acquisition) systems and LABVIEW.
The chloride concentrations measured during the exercise was in the range 5-40 mM, typical of a normal individual. Ten on-body tests with 14 sensors were performed, and the measured chloride concentrations are in the normal range (Table 1.)
In this invention, to minimize a measurement error caused by transport of ions between the reference solution and the test solution (sweat), the salt bridge with an optimized geometry is adopted. To verify that the salt bridge can minimize the measurement error, the chloride concentration was compared to that obtained from a device fabricated to mimic the design in Gonzalo-Ruiz et al. 2009 and Lynch et al. 2002.
The sensor is fabricated on a 125 μm thick PET (Polyethylene terephthalate, Melinex® ST) film (
Calibration of the sensors was performed prior to all measurements. All devices were calibrated in the following way: (1) the working electrode was rinsed in running deionized (DI) water for 40 s, (2) 100 μL of 10 mM NaCl (Fisher Scientific) solution was placed on the working electrode of the sensor using a micropipette, (3) the sensor voltage was measured and recorded for 3 minutes, (4) steps 1-3 were repeated with 50 and 100 mM NaCl solutions, (5) the sensor voltage for each solution was determined by averaging the recorded voltages over last 1 min, and (6) using a linear least squares fit (V-log C), the relationship between the measured voltage and the concentration of the test solution was established. All calibrations were performed at room temperature. The output voltage of the sensors was measured and recorded by a data acquisition (DAQ) system (USB-6363, National Instruments) and Labview software (National Instrument).
Role of the Salt Bridge on Sensor PerformanceTo assess the influence of the salt bridge on performance, sensors were fabricated with 30 μm, 500 μm, and 1 mm diameter holes and their output voltages measured for 2 hours in contact with 110 μL of 10 mM NaCl solution. To prevent evaporation of the test solution, the sensor was mounted in a custom chamber, and the edges of the sensor sealed with Kapton tape (Uline). The chamber was fabricated from a 2.2 mm thick PDMS (polydimethylsiloxane, Sylgard 184, Dow Corning) film with an 8 mm diameter hole. The PDMS film was prepared by a conventional curing process (75° C. in a convection oven for 1 hour), and the hole was punched manually. A glass slide was then oxygen plasma bonded to one side of the PDMS film.
Device AccuracyTo assess device accuracy, the chloride concentration determined from the sensor measurement was compared to the known values of the test solutions in the concentration range 10-150 mM. Each test solution was prepared independently, and not from a diluted stock solution. The procedure was as follows: (1) a sensor was calibrated as described in Section 2.2., (2) 100 μL of a test solution was introduced onto the working electrode using a micropipette, (3) the sensor voltage was measured for 5 min. and the average sensor voltage determined for the last 1 minute, (4) the sensor working electrode was rinsed for 40 s using DI water and the measurement repeated with a new test solution. The measured voltages were converted to concentration values using the calibration curve, and the measured concentration compared to the concentration of the test solution.
Dose Response CurvesTo assess the sensor performance in real time, dose response curves were obtained in the following way. A sensor was partially immersed into 100 mL of DI water so that the working electrode was completely submerged. Then, 1 mL of 1 M KCl solution was added to the solution every minute, and the output voltage was continuously recorded. To ensure good mixing, the test solution was agitated using a stirring bar.
On-Body TestsOn-body tests with a healthy subject while exercising on a stationary bike were performed in compliance with a protocol approved by the institutional review board (IRB) at Johns Hopkins University (HIRB00004232). Tests were performed at a constant load or with three incrementally increasing loads. The sensor was attached to the middle of the flexor aspect of the forearm with a commercial adhesive bandage (Nexcare, Tegaderm™). Before attaching the sensor, the area on the forearm was swabbed with alcohol and DI water. Prior to the test, the subject was asked to spin on a stationary bike at 45 W for 10 min as a warm-up. For the constant load test, the subject was asked to spin on the exercise bike at 100 W for one hour. During the test, the sensor voltage was continuously monitored. For the graded load test, the subject was asked to spin sequentially at 100, 125, and 150 W for 30 min, 15 min and 15 min, respectively. Each test was performed three times on different days. Each sensor was calibrated at room temperature (22° C.) before each test. The skin temperature during on-body tests was typically around 32° C., and the differences in sensor voltage between 22° C. and 32° C. (V32° C.-V22° C.) were verified to be in agreement with the values predicted by the Nernst equation. Therefore, all calibration curves were recorded at room temperature and adjusted for skin temperature using the Nernst equation. A paired-sample Students' t-test was performed to check the dependency of the sweat chloride concentration on the exercise load (* indicates p<0.05).
Influence of Temperature on Sensor CalibrationThe voltage of a potentiometric sensor is dependent on temperature. According to the Nernst equation, the voltage of a potentiometric chloride sensor is given by:
where R is the gas constant, F is Faraday's constant, T is temperature, aCl
The sensors in this study were pre-calibrated at room temperature (22° C.), however, the skin temperature during on-body was about 32° C. To assess the influence of temperature on sensor voltage, calibration curves at 32° C. were measured (
The wearable potentiometric sensor consists of planar Ag/AgCl reference and working electrodes located on opposite sides of a PET film and connected by a laser drilled hole that defines the salt bridge (
Devices were calibrated in test solutions of 10, 50, and 100 mM NaCl (
To compare the slopes of the calibration curves to the Nernst equation, the activity coefficients need to be taken into account. The activity coefficients are significantly less than 1.0 at the concentrations reported here: =0.903 for 10 mM NaCl, =0.822 for 50 mM NaCl, =0.779 for 100 mM NaCl), and =0.604 for 1 M KCl (reference solution). In addition, for the sensor configuration described here, the junction potential lowers the measured potential by about 2.0 mV. Replotting the sensor voltage versus activity and taking into account the junction potential, the slope of the calibration curves is 58.5 mV, identical to the theoretical value of 58.5 V predicted by the Nernst equation at 22° C. (
The deviation in sensor voltage from the average values (
A junction potential Vjunction is developed at the interface between liquids with different ion compositions. The junction potential between the test solution and the salt bridge which has the same composition as the reference solution, was calculated from the Henderson equation:
where VTS is the potential of the test solution, VSB is the potential of the salt bridge (reference solution), R is the gas constant, T is temperature, F is Faraday's constant, z, is the valency of ion i, ui is mobility, and ai is activity. N is total number of ions in all solutions and the superscripts of TS and SB refer to test solution and salt bridge, respectively. The relative mobility uCL−/uK+=1.036 and uNa+/uK++=0.677 at 22° C.
The calculated junction potentials at 22° C. in 10, 50 and 100 mM NaCl test solutions and 1 M KCl reference solution are −1.8, −0.5 and 0.3 mV, respectively. The calculated junction potentials at 32° C. in 10, 50 and 100 mM NaCl test solutions and 1 M KCl reference solution are −1.7, −0.4 and 0.3 mV, respectively. The sensor potential V=VNernst+Vjunction.
The Role of the Salt Bridge on Sensor PerformanceTo assess the role of the salt bridge on performance, sensors were fabricated with salt bridge diameters of 30 μm, 500 μm or 1 mm. The length of the salt bridge is defined by the thickness of the PET substrate (125 μm). The sensors were mounted in a holder with 110 μL of 10 mM NaCl (
The changes in sensor voltage and the corresponding chloride ion concentration are due to equilibration between the reference and test solutions. The concentration of the reference solution (1 M) is much larger than the test solution (10 mM), and hence the changes are dominated by the concentration change in the test solution. Since the concentration change is dependent on the volume of the test solution, the equilibration problem is more significant when the test (sweat) volume is very small. These results illustrate the important role of the salt bridge in potentiometric chloride sweat sensors.
To test the long-term performance of sensors with a 30 μm diameter salt bridge, the sensor output over 12 hours with 110 μL of the test solution was recorded (
The groves in skin have a depth of about 40 μm and the androgenic (body) hair on forearm is about 30 μm in diameter. Assuming the gap between the sensor and skin is 30 μm, the sweat volume (v) under the sensor (the sensing area is 2.5 cm by 2.5 cm) is about 20 μL. To estimate the maximum measurement error during on-body tests, the sensor voltage in a test solution volume of 20 μL of 10 mM NaCl for 2 hours was recorded. The concentration increase was about 2.2 mM for 2 hours (
To further evaluate measurement accuracy and sensor performance, test solutions over the concentration range 10-150 mM were measured (
To assess reproducibility, the chloride ion concentration was measured repeatedly in 150 mM solution (
To assess the sensor response time, dose response curves were recorded. 1 mL of 1 M NaCl solution was pipetted every minute into 100 mL of DI water, and the output voltage of the sensor was recorded as a function of time (
To assess sensor performance, trials were performed with a healthy subject while exercising on a stationary bike. Two types of tests were performed. In the first set of trials, the subject was requested to spin at constant power (100 W) for 60 minutes (
At constant exercise load, the measured chloride concentrations were in the normal range for healthy individuals (10-40 mM). To assess changes in the sweat concentration during the test, values at 30 (C1), 45 (C2), and 60 minutes (C3) were compared (
To assess the role of exercise intensity on sweat chloride concentration, a graded exercise load test was performed (
In sum, a thin film, potentiometric sweat chloride sensor with integrated salt bridge was fabricated and tested. The salt bridge minimizes equilibration between the reference solution and sweat sample and enables stable measurements over extended periods of time. The sensor showed a very small concentration drift (<4 mM) over 12 hours even though the volume of the test solution was only 110 μL. The measurement variation was less than 2 mM at low chloride ion concentration (10 mM) and 5 mM at high concentration (150 mM), spanning the range for healthy individuals and CF patients, typically 10-150 mM, and hence the device could be used as a diagnostic tool for CF. In on-body tests, the sweat chloride concentration in healthy individuals was shown to be dependent on exercise intensity, indicating that the sensor has a potential for a fitness monitoring applications.
ApplicationsThis sensor can be used as a wearable sensor to monitor sweat concentration of CF (cystic fibrosis) patients.
One current technology, the Macroduct® Sweat Collection System (ELITech Group) includes (1) Webster sweat inducer that administers pilocarpine using iontophoresis (
This wearable chloride sensor could also be used to measure electrolyte balance during workouts and hence could be integrated into a fitness sensor.
REFERENCESThe following references are each relied upon and incorporated herein in their entirety.
- Bandodkar, A. J., Molinnus, D., Mirza, O., Guinovart, T., Windmiller, J. R., Valdes-Ramirez, G., Andrade, F. J., Schoning, M. J., Wang, J., 2014. Epidermal tattoo potentiometric sodium sensors with wireless signal transduction for continuous non-invasive sweat monitoring. Biosens Bioelectron 54, 603-609.
- Barben, J., Ammann, R. A., Metlagel, A., Schoeni, M. H., Swiss Paediatric Respiratory Research, G., 2005. Conductivity determined by a new sweat analyzer compared with chloride concentrations for the diagnosis of cystic fibrosis. J Pediatr 146(2), 183-188.
- Barry, P. H., Lewis, T. M., Moorhouse, A. J., 2013. An optimised 3 M KCl salt-bridge technique used to measure and validate theoretical liquid junction potential values in patch-clamping and electrophysiology. Eur Biophys J 42(8), 631-646.
- Choi, D.-H., Kim, J. S., Cutting, G. R., Searson, P. C., 2016. Wearable Potentiometric Chloride Sweat Sensor: The Critical Role of the Salt Bridge. Analytical Chemistry 88(24), 12241-12247.
- Costill, D. L., Cote, R., Fink, W., 1976. Muscle water and electrolytes following varied levels of dehydration in man. J Appl Physiol 40(1), 6-11.
- Coury, A. J., Fogt, E. J., Norenberg, M. S., Untereker, D. F., 1983. Development of a screening system for cystic fibrosis. Clin Chem 29(9), 1593-1597.
- Dam, V. A. T. Z., M. A. G.; van Schaijk, R., 2016. Toward wearable patch for sweat analysis. Sensors and Actuators B: Chemical 236(29), 5.
- Dill, D. B., Hall, F. G., Van Beaumont, W., 1966. Sweat chloride concentration: sweat rate, metabolic rate, skin temperature, and age. J Appl Physiol 21(1), 99-106.
- Dussaud, A. D., Adler, P. M., Lips, A., 2003. Liquid transport in the networked microchannels of the skin surface. Langmuir 19(18), 7341-7345.
- Emrich, H. M., Stoll, E., Friolet, B., Colombo, J. P., Richterich, R., Rossi, E., 1968. Sweat composition in relation to rate of sweating in patients with cystic fibrosis of the pancreas. Pediatr Res 2(6), 464-478.
- Fernandes, A. D., Amorim, P. R. D., Brito, C. J., de Moura, A. G., Moreira, D. G., Costa, C. M. A., Sillero-Quintana, M., Marins, J. C. B., 2014. Measuring skin temperature before, during and after exercise: a comparison of thermocouples and infrared thermography. Physiol Meas 35(2), 189-203.
- Gao, W., Emaminejad, S., Nyein, H. Y., Challa, S., Chen, K., Peck, A., Fahad, H. M., Ota, H., Shiraki, H., Kiriya, D., Lien, D. H., Brooks, G. A., Davis, R. W., Javey, A., 2016. Fully integrated wearable sensor arrays for multiplexed in situ perspiration analysis. Nature 529(7587), 509-514.
- Gibson, L. E., Cooke, R. E., 1959. A test for concentration of electrolytes in sweat in cystic fibrosis of the pancreas utilizing pilocarpine by iontophoresis. Pediatrics 23(3), 545-549.
- Gonzalo-Ruiz, J., Mas, R., de Haro, C., Cabruja, E., Camero, R., Alonso-Lomillo, M. A., Munoz, F. J., 2009. Early determination of cystic fibrosis by electrochemical chloride quantification in sweat. Biosens Bioelectron 24(6), 1788-1791.
- Guinovart, Tomas et al, Analyst, 2013, 138, 7031-7038.
- Hamer, W. J., Wu, Y.-C., 1972. Osmotic coefficients and mean activity coefficients of uni-univalent electrolytes in water at 25° C. Journal of Physical and Chemical Reference Data 1(4), 1047-1100.
- Hammond, K B., Turcios, N. L., Gibson, L. E., 1994. Clinical evaluation of the macroduct sweat collection system and conductivity analyzer in the diagnosis of cystic fibrosis. J Pediatr 124(2), 255-260.
- Heikenfeld, J., 2016. Non-invasive Analyte Access and Sensing through Eccrine Sweat: Challenges and Outlook circa 2016. Electroanalysis 28(6), 8.
- Kshirsagar, S. V. S., B.; Fulari, S. P., 2009. Comparative study of human and animal hair in relation with diameter and medullary index. Indian Journal of Forensic Medicine and Pathology 2(3), 105-108.
- Latzka, W. A., Montain, S. J., 1999. Water and electrolyte requirements for exercise. Clin Sports Med 18(3), 513-524.
- LeGrys, V. A., Yankaskas, J. R., Quitted, L. M., Marshall, B. C., Mogayzel, P. J., Jr., Cystic Fibrosis, F., 2007. Diagnostic sweat testing: the Cystic Fibrosis Foundation guidelines. J Pediatr 151(1), 85-89.
- Lynch, Aogán et al. Analyst, 125 (2002) 2264-2267.
- Macroduct sweat collection system, ELITechGroup.
- Otberg, N. R., H.; Shaefer H.; Blume-Peytavi, U.; Sterry, W.; Lademann, J, 2004. Variation of Hair Follicle Size and Distribution in Different Body Sites. Journal of Investigative Dermatology 122, 14-19.
- Quinton, P. M., 2007. Cystic fibrosis: lessons from the sweat gland. Physiology (Bethesda) 22, 212-225.
- Robinson, S., Robinson, A. H., 1954. Chemical composition of sweat. Physiol Rev 34(2), 202-220.
- Rock, M. J., Makholm, L., Eickhoff, J., 2014. A new method of sweat testing: the CF Quantum® sweat test. J Cyst Fibros 13(5), 520-527.
- Rose, D. P., Ratterman, M. E., Griffin, D. K., Hou, L., Kelley-Loughnane, N., Naik, R. R., Hagen, J. A., Papautsky, I., Heikenfeld, J. C., 2015. Adhesive RFID Sensor Patch for Monitoring of Sweat Electrolytes. IEEE Trans Biomed Eng 62(6), 1457-1465.
- Sonner, Z., Wilder, E., Heikenfeld, J., Kasting, G., Beyette, F., Swaile, D., Sherman, F., Joyce, J., Hagen, J., Kelley-Loughnane, N., Naik, R., 2015. The microfluidics of the eccrine sweat gland, including biomarker partitioning, transport, and biosensing implications. Biomicrofluidics 9(3), 031301.
- Taylor, N. A., Machado-Moreira, C. A., 2013. Regional variations in transepidermal water loss, eccrine sweat gland density, sweat secretion rates and electrolyte composition in resting and exercising humans. Extrem Physiol Med 2(1), 4.
Although the present invention has been described in terms of specific exemplary embodiments and examples, it will be appreciated that the embodiments disclosed herein are for illustrative purposes only and various modifications and alterations might be made by those skilled in the art without departing from the spirit and scope of the invention as set forth in the following claims.
Claims
1. A method of measuring an ion concentration comprising:
- placing a potentiometric sensor on the skin of a subject, wherein the potentiometric sensor comprises: a reference electrode; a first hydrogel containing a reference solution; a salt bridge; and a working electrode,
- wherein the salt bridge is in direct contact with the skin;
- generating sweat under the salt bridge, wherein the ions in the sweat form an ionic circuit between the reference electrode and the working electrode; and
- measuring a potential difference proportional to the ion concentration, thereby measuring the ion concentration.
2. The method of claim 1, wherein the salt bridge comprises a second hydrogel.
3. The method of claim 1, wherein measuring the ion concentration is continuous.
4. The method of claim 1, wherein the ion is selected from the group consisting of chloride, potassium and sodium.
5. The method of claim 4, wherein the ion is chloride.
6. The method of claim 5, further comprising diagnosing whether the subject has cystic fibrosis (CF) based upon the chloride ion concentration.
7. The method of claim 5, further comprising assessing an intensity of a workout based upon the chloride ion concentration.
8. A method of manufacturing a potentiometric sensor comprising:
- forming a through hole in a substrate;
- forming a working electrode on a first side of the substrate;
- forming a reference electrode on a second side of the substrate surface opposite to the first side of the substrate;
- forming a salt bridge within the through hole;
- forming a reference solution hydrogel on the reference electrode and the salt bridge; and
- forming an encapsulating layer on the reference solution hydrogel.
9. The method of claim 8, wherein the through hole is formed by a laser drilling process or a molding process.
Type: Application
Filed: Feb 9, 2022
Publication Date: Aug 25, 2022
Inventors: Dong-Hoon Choi (Baltimore, MD), Peter Searson (Baltimore, MD), Garry R. Cutting (Baltimore, MD)
Application Number: 17/668,181