WO2008120936A1 - Dispositif de mesure de concentration en glucose et procédé de mesure de concentration en glucose utilisant ledit dispositif - Google Patents

Dispositif de mesure de concentration en glucose et procédé de mesure de concentration en glucose utilisant ledit dispositif Download PDF

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Publication number
WO2008120936A1
WO2008120936A1 PCT/KR2008/001793 KR2008001793W WO2008120936A1 WO 2008120936 A1 WO2008120936 A1 WO 2008120936A1 KR 2008001793 W KR2008001793 W KR 2008001793W WO 2008120936 A1 WO2008120936 A1 WO 2008120936A1
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Prior art keywords
electrode
sensor unit
glucose
current
glucose concentration
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PCT/KR2008/001793
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English (en)
Inventor
In-Jun Yoon
Dae-Woo Han
Dong-Eon Cho
Jy-Young Jyoung
Oh-Hyun Kwon
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Kmh. Co., Ltd.
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Publication of WO2008120936A1 publication Critical patent/WO2008120936A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1486—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase

Definitions

  • the present invention relates to a reverse iontophoresis device for measuring a glucose concentration and a method of measuring a glucose concentration using the same.
  • a non-invasive glucose monitoring device using an iontophoresis and a patch for extracting glucose employed in the device have been disclosed.
  • Korean Patent Publication No. 1999-0077833 discloses a sampling system monitoring a concentration of a substance in a biological system, the sampling system including a storage unit including an ion conductive medium and an enzyme which reacts with the substance to produce hydrogen peroxide, a sampling means operably contacting with the storage unit and extracting the substance to the storage unit until the concentration of the substance is a sub-milimolar scale, and a sensor element comprising, a sensing electrode that reacts electrochemically with hydrogen peroxide to provide a detectable signal, said sensing electrode comprising a platinum-group metal, a geometric surface area that ranges from about 0.1 to about 3 cm 2 , a background current that ranges from about 2 to about 60 nA or less when measured in a buffer solution at 0.6V, and a sensitivity of at least about 6 to about 180 nA/ ⁇ M of hydrogen peroxid
  • Korean Patent Publication No. 2005-0026791 discloses an electrode assembly of a non-invasive glucose monitoring device including an ion conductive contact unit which contacts with the skin, an electrode assembly provided to the opposite side of the ion conductive contact unit, a unit measuring the amount of electricity and electrically connected to the electrode, and a monitoring unit connected to the unit measuring the amount of electricity, the electrode assembly comprising: a working electrode to which a voltage for measuring blood glucose level is applied, a first extraction electrode surrounding most part of the working electrode to which a current is applied to extract glucose in body fluids through the skin, a counter electrode surrounding most part of the extraction electrode and electrically connected to the working electrode through the ion conductive contact unit, an analysis unit formed at a peripheral portion of the extraction electrode to which the counter electrode does not extend and including the working electrode and a reference potential electrode, and an extraction unit separated from the analysis unit and including a second extraction electrode which applies an extraction current to the skin with the first extraction electrode of the analysis unit.
  • Glucose stored in the ion conductive contact unit reacts with a glucose oxidase immobilized on the surface of the hydrogel or in the hydrogel to produce hydrogen peroxide.
  • the hydrogen peroxide is oxidized by the voltage applied between the working electrode and the reference electrode to generate a current.
  • FIG. 1 is a graph illustrating change in the amount of electricity generated from glucose extracted by a conventional reverse iontophoresis device. The detected amount of the current is converted to a glucose concentration through algorithms using the area of the current.
  • the present invention provides a reverse iontophoresis device for measuring a glucose concentration that can accurately measure the glucose concentration by calibrating changes in the amount of electricity caused by interference substances and extrinsic factors.
  • the present invention also provides a method of measuring a body glucose concentration using the reverse iontophoresis device for measuring a glucose concentration.
  • the present invention provides a reverse iontophoresis device for measuring a body glucose concentration including: a first sensor unit including an ion conductive medium having a glucose oxidase, and an extraction electrode electrically connected to the ion conductive medium, a working electrode, a counter electrode and a reference electrode; and a second sensor unit including the same structure as the first sensor unit except for including an ion conductive medium without the glucose oxidase,
  • glucose concentration is calibrated by subtracting an interference signal value measured by the second sensor unit from a glucose concentration value measured by the first sensor unit.
  • the 'reverse iontophoresis' used herein is a technique for extraction of a substance through a skin by applying an electric field to the surface of the skin.
  • a reverse iontophoresis is well known in the art.
  • a method of using a reverse iontophoresis in order to extract ionic species (Na+, K+) through the surface of the skin is disclosed by Benjamin et al. (1954) J. Appl. Physiol. 6:401.
  • a method of applying a reverse iontophoresis to extraction of various substances through the surface of the skin is disclosed by Glikfeld et al. (1989) Pharma. Engineering and Computing 16(2): 125; and Burnette, R. and Marrero, D.
  • a reverse iontophoresis device is well known in the art.
  • Korean Patent Publication Nos. 1999-0077833 and 2005-0026791, and U.S. Patent No. 5,954,685 disclose reverse iontophoresis devices.
  • a reverse iontophoresis device according to the present invention has configurations commonly used in a conventional reverse iontophoresis device except for configurations described herein.
  • the ion conductive medium may be any medium that can transfer ionic substances when a current is applied thereto.
  • the ion conductive medium may be a conductive polymer gel and a hydrophilic polymer gel, and preferably an ion conductive hydrophilic polymer gel.
  • the ion conductive medium may be any medium that has a surface contacting with the skin, and can be electrically connected to an extraction electrode for extracting glucose from interstitial fluids by a reverse iontophoresis and a detection electrode for detecting the extracted glucose.
  • An enzyme included in the ion conductive medium may be any enzyme that reacts with glucose and generates a chemical signal, and preferably a glucose oxidase.
  • the chemical signal may be substances derived from glucose by the enzyme or derivatives thereof.
  • the chemical signal may be hydrogen peroxide.
  • the enzyme may be included in one of the ion conductive mediums.
  • the glucose oxidase may be homogenously dispersed in the ion conductive medium.
  • glucose oxide may be homogenously coated on the surface of the ion conductive medium.
  • the working electrode, the counter electrode and the reference electrode function as detection electrodes that detect electrical signals generated by electrochemically oxidizing hydrogen peroxide which is resulted from the reaction of glucose extracted from interstitial fluids in the skin by a reverse iontophoresis and stored in the ion conductive medium with a glucose oxidase immobilized in the ion conductive medium.
  • the 'electrode' used herein is a part of an electrochemical cell through which an electric current passes by moving electrons when it is in contact with an electrolyte.
  • the electrode which is essential of all of galvanic cells and electrolytic cells may be formed of an electrically conductive material such as Ag, Pb, Zn, Al, Co, Fe, Ni, Hg, graphite, Au, or Pt, an oxide thereof, and an alloy thereof.
  • the 'extraction electrode' used herein is an electrode to which a sufficient amount of current is applied so that body substances can be extracted by a reverse iontophoresis through the skin.
  • a current is applied to the extraction electrode, the direction of the current in the extraction electrode may be alternated at predetermined intervals.
  • An extraction of glucose and measurement of the signals generated from the glucose may be achieved in a predetermined period within each interval of the change of the current direction, respectively. For example, glucose can be extracted for 3 minutes by using the extraction eletrode and the signals can be generated for 7 minutes by using the working electrode from the extracted glucose, in each interval of the change of current direction.
  • the 'counter electrode' used herein is an electrode used in an electrochemical cell functioning to apply a constant voltage to a working electrode and a reference electrode.
  • the 'reference electrode' used herein is an electrode providing a reference potential.
  • the 'working electrode' used herein is an electrode measuring the amount of a current generated by oxidation-reduction with the substances by the applied voltage.
  • the extraction electrode, the working electrode, the counter electrode and the reference electrode may be: an electrode formed of Pt, Au and Ag; the electrode further including C; or a Ag/ AgCl electrode, but materials that are used to form the electrodes are not limited thereto. Those electrodes may be prepared on a substrate using a known method in the art such as screen printing, sputtering, or the like.
  • a reverse iontophoresis device for measuring a body glucose concentration provides a calibrated glucose concentration by subtracting an interference signal value measured by the second sensor unit from a glucose concentration value measured by the first sensor unit. Since the ion conductive medium of the first sensor unit includes a glucose oxidase, the current derived from the oxidation of hydrogen peroxide generated from reacting extracted glucose with a glucose oxidase is derived from glucose and other interference substances. Since an ion conductive medium of the second sensor unit does not include a glucose oxidase, the current is derived from other interference substances except for glucose.
  • a current value obtained by subtracting the current measured by the second sensor unit from the current measured by the first sensor unit is a current derived only from glucose concentration by eliminating the interference signal value.
  • a process of cal- ibrating the glucose concentration may be performed by a microprocessor or a program including algorithms performing the calculation.
  • the ion conductive medium of the reverse iontophoresis device is a hydrogel
  • the extraction electrode is in the shape of a disconnected ring
  • the working electrode is a circle formed inside of the extraction electrode
  • the counter electrode and the reference electrode are parts of a ring surrounding the extraction electrode in the first and second sensor units.
  • the structures of those electrodes in the reverse iontophoresis device are not limited thereto.
  • the glucose concentration is obtained in the following process.
  • a current is applied to each extraction electrode of the first and second sensor units for a predetermined period of time while the ion conductive medium is attached to the skin of an individual, and an opposite current is applied thereto for a predetermined period of time to extract glucose from the extraction electrodes to which a negative current is applied.
  • a current derived from interference signals except for glucose and measured by the working electrode of the second sensor unit is subtracted from a current derived from the oxidation of hydrogen peroxide generated from reacting extracted glucose with a glucose oxidase and measured by the working electrode of the first sensor unit to calibrate the glucose concentration.
  • the direction of the current is alternated.
  • An extraction of glucose and measurement of the signals generated from the glucose may be achieved in a predetermined period within each interval of the change of the current direction, respectively.
  • glucose can be extracted for 3 minutes by using the extraction eletrode and the signals can be generated for 7 minutes by using the working electrode from the extracted glucose, in each interval of the change of current direction.
  • the extraction electrode in the first and second sensor units is a negative electrode, glucose is extracted to the ion conductive medium.
  • the current measured by the working electrode of the first and second sensor units are values measured at a predetermined time interval.
  • the predetermined time interval may be 1-60 minutes, preferably 1-40 minutes, more preferably 1-20 minutes, most preferably 1-10 minutes.
  • the present invention also provides a method of measuring a body glucose concentration, the method including:
  • the individual includes a mammal.
  • the mammal may include human, monkey, pig, cow, horse, dog, sheep and cat, but is not limited thereto.
  • the current may be applied to the extraction electrode of the first and second sensor units using any power supplying means that is widely known in the art .
  • the time for applying the current may be adjusted, for example, the current may be applied for 1-60 minutes, preferably 1-40 minutes, more preferably 1-20 minutes, most preferably 1-10 minutes.
  • Electrical signals generated from glucose and interference substances in the ion conductive medium may be measured by the working electrode, the counter electrode and the reference electrode.
  • a value obtained by subtracting the current value measured by the working electrode of the second sensor unit from the current value measured by the working electrode of the first sensor unit is a current value derived only from glucose concentration by eliminating the interference signal value.
  • a process of calibrating the glucose concentration may be performed by a microprocessor or a program including algorithms performing the calculation.
  • the calibrated glucose concentration may be obtained by subtracting an area of the current measured by the second sensor unit as shown in a graph from an area of the current measured by the first sensor unit as shown in a graph.
  • the present invention also provides a reverse iontophoresis device for measuring a body glucose concentration including: a first sensor unit including an ion conductive medium including a glucose oxidase, an extraction electrode electrically connected to the ion conductive medium, a working electrode, a counter electrode and a reference electrode; a second sensor unit including the same structure as the first sensor unit except for including an ion conductive medium without the glucose oxidase, and a third sensor unit an extraction electrode electrically connected to the extraction electrodes of the first and second sensor units, wherein the glucose concentration is calibrated by subtracting an interference signal value measured by the second sensor unit from a glucose concentration value measured by the first sensor unit.
  • the reverse iontophoresis device including the first to third sensor units according to the present invention (hereinafter referred to as 'three-sensor device')
  • the configurations such as the reverse iontophoresis, the electrodes and the first and second sensor units are the same as those of the two-sensor device and described above with reference to the two-sensor device.
  • the reverse iontophoresis device including the first to third sensor units according to the present invention further includes a third sensor unit including an extraction electrode compared to the two-sensor device.
  • the third sensor unit may be separated from the first and second sensor units by the same distance.
  • the extraction of glucose may be performed by alternating the direction of the current applied to the extraction electrodes of the first and third sensor units and the second and third sensor units.
  • An extraction of glucose and measurement of the signals generated from the glucose may be achieved in a predetermined period within each interval of the change of the current direction, respectively. For example, glucose can be extracted for 3 minutes by using the extraction eletrode and the signals can be generated for 7 minutes by using the working electrode from the extracted glucose, in each interval of the change of current direction.
  • the ion conductive medium may be a hydrogel
  • the extraction electrode may be in the shape of a disconnected ring
  • the working electrode may be a circle formed inside of the extraction electrode
  • the counter electrode and the reference electrode may be parts of a ring surrounding the extraction electrode in the first and second sensor units
  • the extraction electrode of the third sensor unit may be in the shape of a ring, but the electrode structures are not limited thereto.
  • the glucose concentration is measured by:
  • glucose may be simultaneously extracted to the ion conductive mediums of the first and second sensor units, that is, there is no time difference in the glucose extraction between the first sensor unit and the second sensor unit.
  • a calibrated glucose concentration may be obtained without the time difference.
  • the present invention also provides a method of measuring a body glucose concentration, the method including:
  • the individual includes a mammal.
  • the mammal may include human, monkey, pig, cow, horse, dog, sheep and cat, but is not limited thereto.
  • the current may be applied to the extraction electrodes of the first and third sensor units and to the extraction electrodes of the second and third sensor units using any power supplying means that is widely known in the art.
  • the time for applying the current may be adjusted, for example, for 1-60 minutes, preferably 1-40 minutes, more preferably 1-20 minutes, most preferably 1-10 minutes.
  • glucose and interference substances may be simultaneously extracted to the ion conductive medium of the first and second sensor units, that is, there is no time difference in the glucose and interference substance extraction between the first sensor unit and the second sensor unit.
  • the electrical signals generated from the extracted glucose and interference substances in the ion conductive medium may be measured using the working electrode and the reference electrode.
  • a current value obtained by subtracting the current value measured by the second sensor unit from the current value measured by the first sensor unit is a current derived only from glucose concentration by eliminating the interference signal value.
  • a process of calibrating the glucose concentration may be performed by a microprocessor or a program including algorithms performing the calculation.
  • the calibrated glucose concentration may be obtained by subtracting an area of the current measured by the second sensor unit as shown in a graph from an area of the current measured by the first sensor unit as shown in a graph.
  • the body glucose concentration can be quickly and accurately measured.
  • FIG. 1 is a graph illustrating changes in the amount of electricity generated from glucose extracted by a conventional reverse iontophoresis device
  • FIG. 2 schematically illustrates the structure of electrodes of a conventional reverse iontophoresis device for measuring a body glucose concentration including two sensor units;
  • FIGS. 3A and 3B are graphs illustrating signals measured by a first sensor unit of the reverse iontophoresis device of FIG. 2;
  • FIG. 4 schematically illustrates the structure of electrodes of a reverse iontophoresis device for measuring a body glucose concentration including two sensor units according to an embodiment of the present invention
  • FIG. 5 is a graph illustrating interference signal values generated from interference substances measured by a second sensor unit
  • FIG. 6 is a graph illustrating signals measured by a first sensor unit and interference signals generated from interference substances measured by the second sensor unit;
  • FIGS. 7 A and 7B schematically illustrate the structure of electrodes of a reverse iontophoresis device for measuring a body glucose concentration including three sensor units according to an embodiment of the present invention.
  • FIGS. 8 A, 8B and 8C are graphs illustrating signals measured by working electrodes of a first and second sensor units by negatively charging extraction electrodes of the first and second sensor units and positively charging an extraction electrode of a third sensor unit, and applying a constant current to the extraction electrodes for 10 minutes and applying a constant voltage thereto for analysis, and then positively charging the extraction electrodes of the first and second sensor units and negatively charging the extraction electrode of the third sensor unit, and applying the same current and voltage thereto in the reverse iontophoresis device having the structure of electrodes shown in FIG. 7A. Best Mode
  • a reverse iontophoresis device for measuring a body glucose concentration including two sensor units having the structure of electrodes shown in FIG. 2 was prepared. Then, glucose was extracted from a human individual and the glucose concentration was measured using the reverse iontophoresis device.
  • FIG. 2 schematically illustrates the structure of electrodes of a conventional reverse iontophoresis device for measuring a body glucose concentration including two sensor units.
  • a first sensor unit is consisted of an extraction electrode 10, a working electrode 20, a counter electrode 30 and a reference electrode 40
  • a second sensor unit is consisted of only an extraction electrode 10a.
  • the structure of electrodes of both of the first and second sensor units are different from each other.
  • the first sensor unit includes an ion conductive medium having a glucose oxidase
  • the second sensor unit includes an ion conductive medium not having a glucose oxidase, wherein the ion conductive medium may be electrically connected to the extraction electrode.
  • the ion conductive medium was disposed between the skin and the electrode structure while extracting glucose and measuring the glucose concentration but is not shown in FIG. 2.
  • the conventional reverse iontophoresis device for measuring a body glucose concentration including two sensor units as shown in FIG. 2 may be GluCallTM (KMH Corporation, Korea).
  • the second sensor unit simply consisted of the extraction electrode and was used to extract glucose and interference substances.
  • the second sensor did not include electrodes for detecting electrical signals, it could not be used to calibrate interference signals.
  • the extraction electrode of the first and second sensor units, and the counter electrode and the reference electrode of the first sensor unit were formed of a Ag/ AgCl material, and the working electrode of the first sensor unit was formed of a Pt material.
  • Those electrodes were prepared on a polyethylene film which was an insulating material known in the art using screen printing.
  • FIGS. 3 A and 3B are graphs illustrating signals measured by a first sensor unit of the reverse iontophoresis device of FIG. 2.
  • the graphs of FIGS. 3 A and 3B illustrate currents measured by the reverse iontophoresis device having the structure of the electrodes as shown in FIG. 2 by the process including negatively charging the extraction electrode 10 of the first sensor unit and positively charging the extraction electrode 10a of the second sensor unit, and applying a current of 0.1 rnA to the extraction electrodes for 3 minutes and applying an oxidation potential of 0.4 V thereto for 7 minutes to extract glucose, and then measuring a current generated by the oxidation of hydrogen peroxide resulted from the reaction of the extracted glucose and the glucose oxidase.
  • 3A and 3B indicate signals generated from glucose and other interference substances extracted to the ion conductive medium of the first sensor unit through the skin when the extraction electrode of the first sensor unit was negatively charged.
  • the signals of the interference substances include signals generated from substances oxidized at 0.4 V or less, and signals generated from changes in moisture content, pressure, temperature and contact resistance in the sensor.
  • changes in moisture content, pressure, temperature and contact resistance in the sensor may be caused by movements of an individual, food intake, the degree of stress and body temperature change, and the like, but the causes are not limited thereto.
  • the ion conductive medium of the first sensor unit was an acrylate hydrogel, and the glucose oxidase homogenously dispersed in the hydrogel at the concentration of 200 unit/ml was used.
  • the hydrogel including the glucose oxidase was prepared by radical-polymerizing 2-hydroxypropyl methacrylate (HEMA) and (N,N-dimethylamino) ethylmethacrylate (DMA) in the presence of 200 unit/ml of the glucose oxidase.
  • FIGS. 3 A and 3B when glucose is extracted through the skin using the conventional reverse iontophoresis device shown in FIG. 2, signals are inaccurate and less sensible since the signals are also influenced by changes in moisture content of an ion conductive medium, pressure, temperature and contact resistance in a sensor according to extrinsic factors as well as glucose and interference substances.
  • a region indicated by a circle in FIGS. 3 A and 3B shows a signal change generated by changes in moisture content of an ion conductive medium, pressure, temperature and contact resistance in a sensor influenced by extrinsic factors.
  • Example 1 Reverse Iontophoresis Device for Measuring Glucose Concentration Including Two Sensor Units and Measurement of Glucose Concentration Using the Same
  • a reverse iontophoresis device for measuring a body glucose concentration including two sensor units having the structure of electrodes as shown in FIG. 4 was prepared. Then, glucose was extracted from a human individual and the glucose concentration of glucose was measured using the reverse iontophoresis device.
  • FIG. 4 schematically illustrates the structure of electrodes of a reverse iontophoresis device for measuring a body glucose concentration including two sensor units according to an embodiment of the present invention.
  • the electrode structures of the first sensor unit and the second sensor unit were the same except that the ion conductive medium electrically connected to the electrode structure of the first sensor unit included a glucose oxidase but the ion conductive medium of the second sensor unit did not include a glucose oxidase.
  • the ion conductive medium was disposed between the skin and the electrode structure while extracting glucose and measuring the glucose concentration, but is not shown in FIG. 4.
  • FIG. 4 schematically illustrates the structure of electrodes of a reverse iontophoresis device for measuring a body glucose concentration including two sensor units according to an embodiment of the present invention.
  • the electrode structures of the first sensor unit and the second sensor unit were the same except that the ion conductive medium electrically connected to the electrode structure of the first sensor unit included a glucose oxidase but the ion conductive medium
  • reference numerals 10, 20, 30 and 40 respectively indicate an extraction electrode, a working electrode, a counter electrode and a reference electrode of the first sensor unit
  • reference numerals 10a, 20a, 30a and 40a respectively indicate an extraction electrode, a working electrode, a counter electrode and a reference electrode of the second sensor unit.
  • Example 1 the extraction electrode, the counter electrode and the reference electrode of the first and second sensor units were formed of a Ag/AgCl material, and the working electrode was formed of a Pt material. Those electrodes were prepared on a polyethylene film which is an insulating material known in the art using screen printing.
  • FIG. 5 is a graph illustrating interference signal values generated from interference substances measured by a second sensor unit.
  • the graph of FIG. 5 illustrates currents measured by the reverse iontophoresis device having the structure of the electrodes as shown in FIG. 4 by the process including positively charging the extraction electrode 10 of the first sensor unit and negatively charging the extraction electrode 10a of the second sensor unit, and applying a current of 0.1 mA to the extraction electrodes for 3 minutes and applying an oxidation potential of 0.4 V thereto for 7 minutess to extract glucose, and then measuring a current generated by the oxidation of hydrogen peroxide resulted from the reaction of the extracted glucose and the glucose oxidase.
  • the signals of the interference substances include signals generated from materials oxidized at 0.4 V or less, and signals generated from changes in moisture content of the ion conductive medium, pressure, temperature and contact resistance in the sensor since the ion conductive medium did not include the glucose oxidase.
  • changes in moisture content of the ion conductive medium, pressure, temperature and contact resistance in the sensor may be caused by movements of an individual, food intake, the degree of stress and body temperature change, and the like, but the causes are not limited thereto.
  • signals measured by the working electrode of the first sensor unit include signals generated from the interference signals measured by the working electrode of the second sensor unit and signals generated from the oxidation of glucose.
  • signals only generated from the glucose concentration without the interference signals can be obtained by subtracting the signals generated from the working electrode of the second sensor unit from the signals generated from the working electrode of the first sensor unit.
  • the ion conductive medium of the first sensor unit was an acrylate hydrogel, and the glucose oxidase homogenously dispersed in the hydrogel at the concentration of 200 unit/ml was used.
  • the hydrogel including the glucose oxidase was prepared by radical-polymerizing 2-hydroxypropyl methacrylate (HEMA) and (N,N-dimethylamino) ethylmethacrylate (DMA) in the presence of 200 unit/ml of the glucose oxidase.
  • HEMA 2-hydroxypropyl methacrylate
  • DMA dimethylamino ethylmethacrylate
  • FIG. 6 is a graph illustrating signals measured by a first sensor unit (upper) and interference signals generated from interference substances measured by the second sensor unit (lower). The difference of the areas between the signals measured by the first sensor unit and the signals measured by the second sensor unit in FIG. 6 indicates the signals generated from glucose.
  • the process of extracting glucose and measuring the glucose concentration in FIG. 6 is the same as that described with reference to FIG. 5.
  • the signal values of the first sensor unit and the signal values of the second sensor unit shown in FIG. 6 has 10 minutes time difference that was taken to change the direction of the current.
  • the response time may be delayed although the signal values can be simply calibrated.
  • Example 2 Reverse Iontophoresis Device for Measuring Glucose Concentration Including three Sensor Units and Measurement of Glucose Concentration Using the Same
  • a reverse iontophoresis device for measuring a body glucose concentration including three sensor units having the structure of electrodes as shown in FIGS. 7 A and 7B was prepared. Then, glucose was extracted from a human individual and the glucose concentration of glucose was measured using the reverse iontophoresis device.
  • FIGS. 7 A and 7B schematically illustrate the structure of electrodes of a reverse iontophoresis device for measuring a body glucose concentration including three sensor units according to an embodiment of the present invention.
  • the electrode structures of the first sensor unit and the second sensor unit were the same except that the ion conductive medium electrically connected to the electrode structure of the first sensor unit included a glucose oxidase but the ion conductive medium of the second sensor unit did not include a glucose oxidase.
  • the ion conductive medium was disposed between the skin and the electrode structure while extracting glucose and measuring the glucose concentration, but is not shown in FIGS. 7A and 7B.
  • the third sensor unit only included an extraction electrode. In FIGS.
  • reference numerals 10, 20, 30 and 40 respectively indicate an extraction electrode, a working electrode, a counter electrode and a reference electrode of the first sensor unit
  • reference numerals 10a, 20a, 30a and 40a respectively indicate an extraction electrode, a working electrode, a counter electrode and a reference electrode of the second sensor unit
  • the 10b indicates an extraction electrode of the third sensor unit.
  • the reverse iontophoresis device for measuring a body glucose concentration including three sensor units according to the present invention as shown in FIGS. 7 A and 7B may include a program or a microprocessor applying the same directional current to the extraction electrodes of the first and second sensor units when the current is applied to each extraction electrode of the first and third sensor units, and each extraction electrode of the second and third sensor units.
  • Example 2 the extraction electrode of the first, second and third sensor units, and the counter electrode and the reference electrode of the first and second sensor units were formed of a Ag/ AgCl material, and the working electrode of the first and second sensor units was formed of a Pt material.
  • Those electrodes were prepared on a polyethylene film which is an insulating material known in the art using screen printing.
  • FIGS. 8 A, 8B and 8C illustrate currents measured by the reverse iontophoresis device having the electrode structure of FIG. 7A including negatively charging the extraction electrode 10 of the first sensor unit and the extraction electrode 10a of the second sensor unit and positively charging the extraction electrode 10b of the third sensor unit, and applying a current of 0.1 mA to the extraction electrodes for 3 minutes and applying an oxidation potential of 0.4 V thereto for 7 minutes to extract glucose, and then measuring a current generated by the oxidation of hydrogen peroxide resulted from the reaction of the extracted glucose and the glucose oxidase.
  • FIGS. 8 A, 8B and 8C illustrate the results obtained by repeating the process three times in the same conditions.
  • the signal values of the first and second sensor units shown in FIGS. 8A, 8B and 8C are measured without a time difference during the glucose extraction since the direction of the current applied to the first and second sensor units is the same.
  • the interference signal values measured by the working electrode of the second sensor unit are signal values generated from glucose and other interference substances extracted to the ion conductive medium of the second sensor unit through the skin when the extraction electrode of the second sensor unit is negatively charged.
  • the interference signal values include signals generated from materials oxidized at 0.4 V or less, and signals generated from changes in moisture content, pressure, temperature and contact resistance in the sensor since the ion conductive medium does not include the glucose oxidase.
  • signals measured by the working electrode of the first include signals generated from the interference signal values measured by the working electrode of the second sensor unit and signals generated from the oxidation of glucose.
  • signals only generated from the glucose concentration without the interference signals can be obtained by subtracting the signals generated from the working electrode of the second sensor unit from the signals generated from the working electrode of the first sensor unit.
  • the region shown as a circle in FIGS. 8 A, 8B and 8C indicates an irregular change of the glucose concentration due to the extrinsic factors.
  • the change can be calibrated by subtracting the interference signal values generated from the second sensor unit from the signal values generated from the first sensor unit
  • the ion conductive medium of the first sensor unit was an acrylate hydrogel, and the glucose oxidase homogenously dispersed in the hydrogel at the concentration of 200 unit/ml was used.
  • the hydrogel including the glucose oxidase was prepared by radical-polymerizing 2-hydroxypropyl methacrylate (HEMA) and (N,N-dimethylamino) ethylmethacrylate (DMA) in the presence of 200 unit/ml of the glucose oxidase.
  • the body glucose concentration can be quickly and accurately measured.

Abstract

L'invention concerne un dispositif d'iontophorèse inverse permettant de mesurer une concentration en glucose d'un corps. Ledit dispositif comprend: une unité de détection comportant un milieu conducteur d'ions incluant une glucose oxydase, une électrode d'extraction reliée électriquement au milieu conducteur d'ions, une électrode active, une contre-électrode et une électrode de référence; ainsi qu'une seconde unité de détection comprenant la même structure que la première unité de détection sauf qu'elle comporte un milieu conducteur d'ions sans la glucose oxydase, la concentration en glucose étant étalonnée par soustraction d'une valeur de signal d'interférence mesurée par la seconde unité de détection à partir d'une valeur de concentration en glucose mesurée par la première unité de détection,. L'invention concerne également un procédé de mesure de la concentration en glucose.
PCT/KR2008/001793 2007-03-29 2008-03-31 Dispositif de mesure de concentration en glucose et procédé de mesure de concentration en glucose utilisant ledit dispositif WO2008120936A1 (fr)

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KR1020070031111A KR100868566B1 (ko) 2007-03-29 2007-03-29 포도당 농도 측정 장치 및 그를 이용한 포도당 농도를측정하는 방법
KR10-2007-0031111 2007-03-29

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GB2502287A (en) * 2012-05-21 2013-11-27 Ndm Technologies Ltd Cumulative measurement of an analyte
WO2020152380A1 (fr) 2019-01-22 2020-07-30 Universidad De Sevilla Dispositif portable et procédé pour l'estimation non invasive du niveau de glucose dans le sang
EP4282331A1 (fr) * 2022-05-27 2023-11-29 Medtronic MiniMed, Inc. Capteur de glucose

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KR102363460B1 (ko) * 2020-03-12 2022-02-15 한국과학기술원 스마트 인공수정체
KR102505313B1 (ko) * 2021-09-23 2023-03-06 주식회사 알비티 패시브 레이어를 포함하는 마이크로 니들 바이오 센서 제조 방법

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US6587705B1 (en) * 1998-03-13 2003-07-01 Lynn Kim Biosensor, iontophoretic sampling system, and methods of use thereof
KR200433455Y1 (ko) * 2006-09-30 2006-12-08 케이엠에이치 주식회사 포도당 추출용 패치 및 그를 포함하는 무채혈 혈당 측정장치

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US6587705B1 (en) * 1998-03-13 2003-07-01 Lynn Kim Biosensor, iontophoretic sampling system, and methods of use thereof
KR200433455Y1 (ko) * 2006-09-30 2006-12-08 케이엠에이치 주식회사 포도당 추출용 패치 및 그를 포함하는 무채혈 혈당 측정장치

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2502287A (en) * 2012-05-21 2013-11-27 Ndm Technologies Ltd Cumulative measurement of an analyte
GB2502287B (en) * 2012-05-21 2016-11-23 Dermal Diagnostics Ltd Cumulative measurement of an analyte
WO2020152380A1 (fr) 2019-01-22 2020-07-30 Universidad De Sevilla Dispositif portable et procédé pour l'estimation non invasive du niveau de glucose dans le sang
EP4282331A1 (fr) * 2022-05-27 2023-11-29 Medtronic MiniMed, Inc. Capteur de glucose

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