WO2008047842A1 - Procédé de mesure de valeur hématocrite de prélèvement sanguin, procédé de mesure de concentration d'analyte dans un prélèvement sanguin, puce de capteur et unité de détection - Google Patents
Procédé de mesure de valeur hématocrite de prélèvement sanguin, procédé de mesure de concentration d'analyte dans un prélèvement sanguin, puce de capteur et unité de détection Download PDFInfo
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- WO2008047842A1 WO2008047842A1 PCT/JP2007/070289 JP2007070289W WO2008047842A1 WO 2008047842 A1 WO2008047842 A1 WO 2008047842A1 JP 2007070289 W JP2007070289 W JP 2007070289W WO 2008047842 A1 WO2008047842 A1 WO 2008047842A1
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- blood sample
- electrode
- counter electrode
- working electrode
- sensor chip
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/28—Electrolytic cell components
- G01N27/30—Electrodes, e.g. test electrodes; Half-cells
- G01N27/327—Biochemical electrodes, e.g. electrical or mechanical details for in vitro measurements
- G01N27/3271—Amperometric enzyme electrodes for analytes in body fluids, e.g. glucose in blood
- G01N27/3274—Corrective measures, e.g. error detection, compensation for temperature or hematocrit, calibration
Definitions
- the present invention relates to a method for measuring a hematocrit (Hct) value of a blood sample, a method for measuring the concentration of an analyte in a blood sample, a sensor chip and a sensor unit suitable for the measurement.
- Hct hematocrit
- a sensor chip is used to measure the concentration of an analyte in a blood sample, for example, blood glucose concentration (blood glucose level).
- a sensor chip is used to measure the amount of current flowing in a blood sample after an enzyme cycling reaction involving the analyte, and the concentration of the analyte is calculated based on this amount of current.
- This amount of current varies with the Hct value of the blood sample in addition to the analyte concentration.
- the Hct value of a blood sample varies depending on the health status of the animal that provided the blood sample.
- the standard Hct value for humans is 39-50% for adult males and 36-45% for adult females.
- the Hct value of a blood sample is measured on the sensor chip to accurately identify the analyte concentration in the blood sample, and to know the properties of the blood sample, such as blood dryness and anemia. Desirable to target!
- JP-T 8-500190, JP-T 2003-501627, WO 2005/0 54839 pamphlet and WO 2005/054840 pamphlet are sensors for measuring the Hct value of blood samples.
- a chip is disclosed. These known sensor chips include an electrode system including a working electrode and a counter electrode, and a flow path (blood sample holding unit) for holding a blood sample between the working electrode and the counter electrode.
- the sensor chip described in Tokuhei Heisei 8-No. 500190 and No. 2003-No. 501627 has an electronic mediator placed in the blood sample holder so that it can be eluted into the blood sample. .
- the electron mediator adheres to the working electrode and the counter electrode by introducing the blood sample into the blood sample holder, contributing to the movement of electrons at the interface between the blood sample and each electrode.
- the Hct value of the blood sample is specified by measuring the amount of current flowing in the blood sample as a result of the redox reaction of the electron mediator adhering to each electrode.
- the electron is only on the counter electrode of the electrode system including the working electrode and the counter electrode for performing the Hct value measurement.
- a mediator is placed.
- a pure blood sample that does not include an electron mediator comes into contact with the working electrode by introducing the blood sample into the blood sample holder.
- electrons move at the interface between the blood sample and the working electrode due to the redox reaction of blood components in the blood sample, such as ascorbic acid, uric acid and water.
- the electron mediator placed on the counter electrode contributes to the movement of electrons at the interface between the blood sample and the counter electrode.
- the sensor chip described in Tokuhei Hei 8-No. 500190 and Tokuyuki No. 2003-No. 501627 has a current that flows in the blood sample when measuring the Hct value relative to the fluctuation rate of the Hct value of the blood sample ( The variation rate of the amount of (redox current) is small and the detection sensitivity is not sufficient. For example, even if the Hct value of a blood sample fluctuates by 20%, the redox current amplitude may fluctuate only by about 8%.
- the voltage (Hct value measurement voltage) applied between the working electrode and the counter electrode is reduced when measuring the Hct value.
- the fluctuation of the redox current amplitude becomes severe, and the Hct value of the blood sample may not be measured stably! /.
- the present invention relates to a method for measuring an Hct value of a blood sample, which can stably measure the Hct value of a blood sample with sufficient detection sensitivity even if the Hct value measurement voltage is lowered, and an analyte in the blood sample It is an object of the present invention to provide a method for measuring the concentration of selenium, a sensor chip and a sensor unit suitable for the measurement.
- non-electrolytically oxidizable metals such as silver, copper and nickel are not suitable as the working electrode material of the sensor chip. This is because the working electrode was easily oxidized by applying a voltage to the electrode system of the sensor chip, making it difficult to accurately measure the amount of current that reflects the concentration of the analyte.
- the inventor has a working electrode of a sensor chip. If the electrode is composed of an electro-oxidizable metal, an oxidation current will be generated due to the oxidation of the easily electro-oxidative metal when a voltage is applied between both electrodes with the working electrode as the positive electrode and the counter electrode as the negative electrode.
- a voltage is applied between the working electrode and the counter electrode in contact with the blood sample in a state where the oxidized form of the redox substance is in contact with the counter electrode and is not substantially in contact with the working electrode.
- the surface that is at least part of the surface of the working electrode and is in contact with the blood sample is made of a material containing an easily electrolyzed metal, and the voltage applied between the working electrode and the counter electrode
- a method for measuring the Hct value of a blood sample which causes oxidation of the easily electrolytically oxidizable metal and reduction of the oxidant, and measures a current associated with the oxidation and reduction.
- the present invention electrochemically detects a current A reflecting the Hct value of a blood sample, and the data corresponding to the Hct value, which is the current A or a converted value of the current A.
- A is obtained, and the analyte in the blood sample is oxidized or reduced by an oxidoreductase using the analyte as a substrate in the presence of a redox substance, and accompanying the oxidation or reduction of the analyte.
- the concentration of the analyte in the blood sample electrochemically comprising the step of electrochemically measuring the concentration of the analyte in the blood sample, wherein the current A is a redox substance Table of at least part of the working electrode in contact with the oxidant of A voltage is applied between the working electrode that is in contact with the blood sample and the counter electrode in a state that is not substantially in contact with the blood sample to oxidize an easily electrolytically oxidizable metal that constitutes the at least part of the surface of the working electrode.
- the present invention provides a sensor chip including an Hct analysis unit for electrochemically detecting a current reflecting the Hct value of a blood sample, wherein the Hct value analysis unit An electrode and a counter electrode; a blood sample holder for holding a blood sample so as to be in contact with the working electrode and the counter electrode; and a blood sample inlet for introducing the blood sample into the blood sample holder And at least a part of the surface of the working electrode facing the blood sample holding portion is made of a material containing an easily electrolytically oxidizable metal, and the surface of the counter electrode facing the blood sample holding portion.
- An oxidant of a redox substance is disposed in contact with or in proximity to the surface of the counter electrode.
- a sensor chip including an Hct analysis unit for electrochemically detecting a current that reflects an Hct value of a blood sample, the Hct value analysis unit comprising a working electrode and A counter electrode; a blood sample holder for holding the blood sample so as to be in contact with the working electrode and the counter electrode; and a blood sample inlet for introducing the blood sample into the blood sample holder.
- the blood sample holding part has an introduction part communicating with the blood sample introduction port, and a first branch part and a second branch part branched from the introduction part, and the first branch part faces the counter electrode.
- the second branch part faces the working electrode, and at least a part of the surface of the working electrode facing the second branch part is made of a material containing an easily electrolytically oxidizable metal, and the second electrode of the counter electrode 1 in contact with the surface facing the branch or the surface of the counter electrode Apart al, the oxidant of the redox substance is disposed in the first branch portion, to provide a sensor chip.
- the present invention provides a sensor unit including the sensor chip and a sensor body including a voltage application circuit for applying a predetermined voltage between the working electrode and the counter electrode.
- the sensor chip is detachable from the sensor body, and the predetermined voltage is applied between the working electrode and the counter electrode from the voltage application circuit in a state where the sensor chip is attached to the sensor body.
- the sensor unit has a voltage of 3.0 V or less when the predetermined voltage 1S is expressed as a positive electrode and the counter electrode as a negative electrode.
- the Hct value of a blood sample can be stably measured with sufficient detection sensitivity even when the Hct value measurement voltage is lowered.
- FIG. 1 is an exploded perspective view showing an example of a sensor chip for Hct value measurement according to the present invention.
- FIG. 2 is a plan view showing an example of a sensor chip for Hct value measurement according to the present invention.
- FIG. 3 is an exploded perspective view showing another example of the sensor chip for measuring Hct value of the present invention.
- FIG. 4 is a plan view showing another example of the sensor chip for measuring Hct value of the present invention.
- FIG. 5 is an exploded perspective view showing another example of the sensor chip for measuring Hct value of the present invention.
- FIG. 6 is a plan view showing another example of the sensor chip for measuring Hct value of the present invention.
- FIG. 7 is a graph showing an example of a measurement result of Hct value by the sensor chip of Example 1.
- FIG. 8 is a graph showing another example of the Hct value measurement result by the sensor chip of Example 1.
- FIG. 9 is a graph showing another example of the Hct value measurement result by the sensor chip of Example 1.
- FIG. 10 is a graph showing another example of the Hct value measurement result by the sensor chip of Example 1.
- FIG. 11 is a graph showing another example of the Hct value measurement result by the sensor chip of Example 1.
- FIG. 12 is a graph showing another example of the Hct value measurement result by the sensor chip of Example 1.
- FIG. 13 is a graph showing another example of the Hct value measurement result by the sensor chip of Example 1.
- FIG. 14 is a graph showing an example of a measurement result of Hct value by the sensor chip of Example 2.
- FIG. 15 is a graph showing another example of the Hct value measurement result by the sensor chip of Example 2.
- FIG. 16 is a graph showing another example of the Hct value measurement result by the sensor chip of Example 2.
- FIG. 17 is a graph showing another example of the Hct value measurement result by the sensor chip of Example 2.
- FIG. 18 is a graph showing another example of the Hct value measurement result by the sensor chip of Example 2.
- FIG. 19 is a graph showing another example of the Hct value measurement result by the sensor chip of Example 2.
- FIG. 20 is a graph showing another example of the Hct value measurement result by the sensor chip of Example 2.
- FIG. 21 is a graph showing another example of the Hct value measurement result by the sensor chip of Example 2.
- FIG. 22 is a graph showing another example of the Hct value measurement result by the sensor chip of Example 2.
- FIG. 23 is a graph showing another example of the Hct value measurement result by the sensor chip of Example 2.
- FIG. 24 is a graph showing an example of a measurement result of Hct value by the sensor chip of Example 3.
- FIG. 25 is a graph showing another example of the Hct value measurement result by the sensor chip of Example 3.
- FIG. 26 is a graph showing another example of the Hct value measurement result by the sensor chip of Example 3.
- FIG. 27 is a graph showing another example of the Hct value measurement result by the sensor chip of Example 3.
- FIG. 28 is a graph showing another example of the Hct value measurement result by the sensor chip of Example 3.
- FIG. 29 is a graph showing an example of a measurement result of Hct value by the sensor chip of Example 4.
- FIG. 30 is a graph showing another example of the Hct value measurement result by the sensor chip of Example 4.
- FIG. 31 is a graph showing another example of the Hct value measurement result by the sensor chip of Example 4.
- FIG. 32 is a graph showing another example of the Hct value measurement result by the sensor chip of Example 4.
- FIG. 33 is a graph showing another example of the Hct value measurement result by the sensor chip of Example 4.
- FIG. 34 is a graph showing another example of the Hct value measurement result by the sensor chip of Example 4.
- FIG. 35 is a graph showing another example of the Hct value measurement result by the sensor chip of Example 4.
- FIG. 36 is a graph showing another example of the Hct value measurement result by the sensor chip of Example 4.
- FIG. 37 is a graph showing an example of a measurement result of Hct value by the sensor chip of Comparative Example 1.
- FIG. 38 is a graph showing another example of the Hct value measurement result by the sensor chip of Comparative Example 1.
- FIG. 39 is a graph showing another example of the Hct value measurement result by the sensor chip of Comparative Example 1.
- FIG. 40 is a graph showing an example of a measurement result of Hct value by the sensor chip of Comparative Example 2.
- FIG. 41 is a perspective view showing an example of a sensor unit for Hct value measurement according to the present invention.
- FIG. 42 is a diagram showing an example of a circuit configuration of a sensor unit for Hct value measurement according to the present invention.
- FIG. 43 is an exploded perspective view showing an example of a sensor chip for analyte concentration measurement of the present invention.
- FIG. 44 is a plan view showing an example of a sensor chip for analyte concentration measurement of the present invention.
- FIG. 45 is an exploded perspective view showing another example of the sensor chip for analyte concentration measurement of the present invention.
- FIG. 46 is a plan view showing another example of the sensor chip for analyte concentration measurement of the present invention.
- FIG. 47 is an exploded perspective view showing another example of the sensor chip for analyte concentration measurement of the present invention.
- FIG. 48 is a plan view showing another example of the sensor chip for analyte concentration measurement of the present invention.
- FIG. 49 is a diagram showing an example of a circuit configuration of an analyte concentration measuring sensor unit of the present invention.
- the contact pattern between the oxidant and the electrode is controlled so that the oxidant of the redox substance contacts the counter electrode and does not substantially contact the working electrode.
- the state in which the oxidized form of the redox substance is in contact with the counter electrode may be, for example, a state in which a blood sample containing the oxidized form is in contact with the counter electrode, or the oxidized form is disposed on the counter electrode, for example. Even if it is in a state of being. Thus, the oxidant is dissolved in the blood sample when the Hct value is measured. You can touch the electrode in a wet state! /, And you can touch the electrode as a solid! /!
- An oxidant is a substance that electrochemically reduces at the counter electrode when a voltage of 3. OV or less is applied when the working electrode is represented as a positive electrode and the counter electrode is represented as a negative electrode.
- oxidants include oxidants of reversible electron active compounds such as ferricyanide, p-benzoquinone, p-benzoquinone derivatives, oxidized phenazine methosulfate, methylene blue, ferricinum, and ferricinum derivatives.
- a preferred oxidant is ferricyanide.
- a preferred ferricyanide is potassium ferricyanide.
- the amount of oxidant that is brought into contact with the counter electrode when measuring the Hct value is, for example, a night sample that is brought into contact with the counter electrode. 0.;! To 1000mM, more than 100mM;! To 500mM J: It can be controlled by adding 10 to 200 mM oxidant.
- the Hct value when the Hct value is measured, it is not limited that the oxidized form of the redox substance inherently contained in the blood sample (for example, human blood) contacts the working electrode.
- the state in which the redox substance inherently contained in the blood sample is in contact with the electrode is in a state where the redox substance is substantially in contact with the electrode.
- Na! / Treated as a state.
- a blood sample containing an amount of redox substance that is essentially contained in human blood is treated as substantially free of redox substance.
- At least a part of the working electrode is made of a material containing an easily electrolytically oxidizable metal, and the at least part of the surface comes into contact with the blood sample when the Hct value is measured.
- the easily electrolysable metal is, for example, a standard electrode potential (V vs. V) that is equal to or lower than the standard electrode potential of silver (0.799 V vs. SHE) represented by at least one metal selected from silver, copper, and nickel. SHE).
- At least a part of the surface of the working electrode may be formed by using one or a plurality of easily electrolytically oxidizable metals, or a conductive material other than the easily electrolytically oxidizable metal and the easily electrolytically oxidizable metal. You may form using the material which mixed the metal.
- the surface of the counter electrode that comes into contact with the blood sample when measuring the Hct value can be made of a known conductive material such as palladium, platinum, gold, silver, titanium, copper, nickel, or carbon. Further, for example, a polymer film may be formed on the counter electrode core, and the surface of the polymer film may be the above-mentioned surface of the counter electrode.
- Examples of the material for the polymer membrane include carboxymethylenoresolerose, hydroxyethinoresenorelose, hydroxypropinoresenorelose, Chinoresenorelose, ethinoresenorelose, ethinorehydroxyethinoresenololose, force noreoxy echenoresenorelose, polyvinylenorenoreconole, polyvininorepyrrolidone and polyzine when polyamino acid, polystyrene sulfone Acid, gelatin and derivatives thereof, polyacrylic acid and salts thereof, polymethacrylic acid and salts thereof, starch and derivatives thereof, maleic anhydride polymer and salts thereof, agarose gel and derivatives thereof, and force S. These compounds may be used alone or in combination of two or more.
- the shape and size of the working electrode and the counter electrode are not particularly limited! /.
- the arrangement pattern of the working electrode and the counter electrode on the insulating substrate is not particularly limited, but the closest distance between the working electrode and the counter electrode is 0.05 mm or more, further 0.1 mm or more, and in some cases 0.5 mm or more. Then, it becomes easy to stably measure the Hct value of the blood sample.
- the upper limit of the closest distance is not particularly limited.
- the voltage applied between the working electrode and the counter electrode (Hct value measurement voltage) is 3.0 V or less when the working electrode is displayed as the positive electrode and the counter electrode as the negative electrode. Let the voltage be a magnitude. According to the present invention, even when the Hct value measurement voltage is reduced to a range of 3.0 V or less when the working electrode is represented as a positive electrode and the counter electrode is represented as a negative electrode, and further to 1.0 V or less, the working electrode The current flowing due to the oxidation of the easily electrolytically oxidizable metal contained in and the reduction of the oxidant in contact with the counter electrode can be detected stably immediately after the start of voltage application.
- the time for applying the Hct value measurement voltage is, for example, 0.00;! To 60 seconds, preferably 0.01 to 10 seconds, more preferably 0.0;! To 5 seconds, and still more preferably 0.0. ; ⁇ 3 seconds.
- the Hct value measurement voltage may be, for example, 0.75 V or less, 0.5 V or less, 0.25 V or less, 0.15 V or less, 0.1 IV or less when the working electrode is displayed as a positive electrode and the counter electrode as a negative electrode.
- the lower limit of the Hct value measurement voltage is not particularly limited as long as oxidation of easily electrolytically oxidizable metal at the working electrode and reduction of the oxidant at the counter electrode occur. It is desirable that the voltage is a positive value! /.
- the Hct value of the blood sample flows between the working electrode and the counter electrode by applying the Hct value measurement voltage. It is calculated based on the above current.
- the Hct value can be calculated, for example, by referring to a calibration curve or a calibration curve table displaying the relationship between the Hct value measurement voltage application start force and the current amount and the Hct value after a predetermined time.
- the Hct value described above can be measured using a sensor chip for Hct value measurement which is an example of the sensor chip of the present invention.
- the sensor chip for Hct value measurement has an Hct value analysis unit for electrochemically detecting a current reflecting the Hct value of the blood sample.
- the Hct value analysis unit has an electrode system including a working electrode and a counter electrode, and a blood sample holding unit for holding a blood sample so as to be in contact with the working electrode and the counter electrode.
- the blood sample holding part communicates with a blood sample introduction port for introducing a blood sample into the blood sample holding part.
- At least a part of the working electrode and the counter electrode faces the blood sample holding portion so as to come into contact with the blood sample when the blood sample is introduced into the blood sample holding portion.
- At least a part of the surface of the working electrode facing the blood sample holding portion is made of a material containing an easily electrolytically oxidizable metal represented by, for example, silver.
- the at least part of the surface may be, for example, the surface of an electrode core formed using a material containing an easily electrolytically oxidizable metal! / It may be a surface of a conductive film that is formed using a conductive material other than metal and that is formed on the electrode core and includes an easily electrolytically oxidizable metal. Further, at least a part of the surface is made of a material containing an easily electrolytically oxidizable metal instead of being composed of a material containing an easily electrolytically oxidizable metal.
- a film may be formed and constituted by the surface of the polymer film. The polymer film can be formed using a material similar to the material of the polymer film that can be disposed on the counter electrode core.
- the surface of the counter electrode facing the blood sample holding portion may be the surface of an electrode core formed using a known conductive material! /, And the above-mentioned surface formed on the electrode core. It may be the surface of the polymer film.
- the electrode core of the working electrode and the counter electrode can be formed by, for example, a screen printing method, a sputtering method, and a vapor deposition method.
- the polymer film can be formed, for example, by applying a polymer solution for forming the film onto the electrode core and drying it.
- Working electrode and The shape, size, and arrangement pattern on the insulating substrate of the counter electrode are not particularly limited. However, if the closest distance between the working electrode and the counter electrode is set within the range illustrated above, the Hct value of the blood sample can be stabilized. It becomes easy to measure.
- the Hct value analysis unit when the blood sample is introduced into the blood sample holding unit and a voltage is applied between the working electrode and the counter electrode, the oxidized form of the redox substance contacts the counter electrode and is substantially in contact with the working electrode.
- the arrangement pattern of the reagent containing the oxidant, the shape of the blood sample holder, and the counter electrode and the working electrode Set the relative arrangement pattern.
- the working electrode is arranged upstream of the counter electrode with respect to the flow of the blood sample introduced from the blood sample introduction port into the blood sample holding unit, and is in contact with the surface of the counter electrode facing the blood sample holding unit, or the surface A reagent containing an oxidized form of a redox substance is placed in the vicinity of
- the reagent is preferably disposed on or in contact with the surface of the counter electrode, but may be disposed between the counter electrode and the working electrode without contacting the counter electrode surface and the working electrode surface.
- the Hct value measurement method of the present invention is carried out in the state where an oxidant is present on the surface of the counter electrode when the Hct value measurement voltage is applied.
- the reagent when the reagent is placed on the counter electrode surface or in contact with the counter electrode surface, the reagent is not in contact with the counter electrode surface so that it is difficult for the reagent to flow when the blood sample is introduced.
- the reagent it is desirable that the reagent be set so that the reagent is easily flown when the blood sample is introduced.
- the reagent containing the oxidant is disposed by, for example, dropping or applying a reagent solution prepared by dissolving or dispersing the oxidant in water or a known buffer solution to a predetermined site and then drying it. fi.
- the blood sample holding portion has an introduction portion communicating with the blood sample introduction port, a first branch portion and a second branch portion branched from the introduction portion, the first branch portion faces the counter electrode, and When the two branch portions face the working electrode, the reagent may be disposed on the first branch portion in contact with the surface of the counter electrode facing the first branch portion or away from the surface of the counter electrode.
- Reagents containing an oxidant include, for example, amino acids (crystal homogenizing agents) such as taurine, glycine, serine, proline, threonine and lysine, carboxymethylcellulose, hydroxyethylenosolerose, hydroxypropenoresenorelose, Methinoresenorelose, ethinoresenorero Polyamino acids such as nolecol, polybutyrrolidone and polyzine, polystyrene sulfonic acid, gelatin and its derivatives, polyacrylic acid and its salts, polymethacrylic acid and its salts, starch and its derivatives, maleic anhydride polymer and its salts, An agarose gel may further be included.
- amino acids such as taurine, glycine, serine, proline, threonine and lysine
- carboxymethylcellulose such as hydroxyethylenosolerose, hydroxypropenoresenorelose, Methinoresenore
- the amount of oxidant placed in the Hct value analyzer is such that the amount of oxidant in contact with the counter electrode during Het value measurement is, for example, 0.1 to 1000 mM, further 1 to 500 mM, and in some cases 10 to 200 mM. Should be set.
- FIGS .;! To 6 illustrate specific examples of an arrangement pattern of a reagent containing an oxidant, a shape of a blood sample holding portion, and a relative arrangement pattern of a counter electrode and a working electrode in a sensor chip for Hct value measurement. It is a figure for doing.
- FIG. 1 is an exploded perspective view of the sensor chip A for Hct value measurement
- FIG. 2 is a plan view thereof.
- the sensor chip AlOOa for measuring the Hct value leaves one end (the right end in the figure) of the insulating substrate 101 through the spacer 102 in which the rectangular cutout 104 is formed.
- a cover 103 is disposed on the insulating substrate 101.
- the members 101, 102, and 103 are integrated by, for example, adhesion or heat welding.
- the notch 104 of the spacer 102 becomes the blood sample holding part 14 after the integration of the members.
- the blood sample holder 14 extends along the long side of the chip 100a and communicates with the outside at one end of the spacer 102 (the left end in the figure).
- the blood sample holding unit 14 communicates with the blood sample introduction port 16 that opens to the outside of the chip 100a.
- the cover 103 has an exhaust port 15 at a portion corresponding to the end of the blood sample holding unit 14 opposite to the end communicating with the outside.
- the working electrode 11 and the counter electrode 12 are configured such that a part (part 31) of the working electrode 11 and a part (part 32) of the counter electrode 12 face the blood sample holding part 14 and the part 31 is closer to the blood sample inlet 16 than the part 32. It is disposed on the insulating substrate 101 so as to be close to each other.
- the working electrode 11 and the counter electrode 12 are each connected to a lead (not shown).
- One end of the lead is exposed to the outside of the chip 100a at the end of the insulating substrate 101 not covered with the spacer 102 and the cover 103 so that a voltage can be applied between the working electrode and the counter electrode.
- At least a part of the surface of the portion 31 of the working electrode 11 is made of a material containing silver, copper, nickel, and an easily electrolytically oxidizable metal.
- the material constituting the surface of the portion 32 of the counter electrode 12 is not particularly limited as described above.
- the reagent 13 containing the oxidized form of the redox substance is disposed in contact with the portion 32 of the counter electrode 12.
- the reagent 13 may be in a state where it is difficult to dissolve in the blood sample, or in a state where it is easily dissolved in the blood sample.
- the reagent 13 is not disposed in contact with the portion 31 of the working electrode 11, but is disposed closer to the blood sample inlet 16 than the portion 31 in a state where it is easily dissolved in the blood sample. Also! /
- the reagent 13 is preferably disposed in contact with only the counter electrode portion 32 in the blood sample holding portion 14. With this reagent arrangement, when measuring the Hct value, a large number of pure blood samples that do not substantially contain an oxidized form of the redox substance can be placed between the working electrode and the counter electrode. It is because it can improve.
- Materials for the insulating substrate, the spacer, and the cover are not particularly limited as long as a material that does not short-circuit the working electrode and the counter electrode is used when they are integrated.
- the materials include polyethylene terephthalate (PET), polycarbonate (PC), polyimide (PI), polyethylene (PE), polypropylene (PP), polystyrene (PS), polychlorinated butyl (PVC), polyoxymethylene (POM), Examples include monomer cast nylon (MC), polybutylene terephthalate (PBT), methacrylate resin (PMMA), ABS resin (ABS), and glass.
- the Hct value measuring sensor chip of the present invention is derived from a reagent placed in the sensor chip when a blood sample is introduced into the blood sample holding part and a voltage is applied between the working electrode and the counter electrode. As long as the blood sample is in contact with the counter electrode and the working electrode without being substantially in contact with the working electrode, the shape of the blood sample holding part and the arrangement pattern of the reagent containing the oxidant are formed. And the relative arrangement pattern between the counter electrode and the working electrode can be changed.
- the structure of another example of the sensor chip for measuring the Hct value of the present invention will be described.
- FIG. 3 is an exploded perspective view of the sensor chip B for Hct value measurement
- FIG. 4 is a plan view thereof.
- the Hct value measuring sensor chip BlOOb is separated from the portion 32 of the counter electrode 12 and closer to the blood sample inlet 16 than the portion 32 in the blood sample holding portion 14. Except that reagent 13 is placed between part 31 of working electrode 11 and part 32 of counter electrode 12 in a state of being easily dissolved in a blood sample, the structure is similar to that of sensor chip A for measuring Hct value. Have.
- FIG. 5 is an exploded perspective view of the Hct value measuring sensor chip C
- FIG. 6 is a plan view thereof.
- the sensor chip ClOOc for measuring the Hct value leaves one end (the right end in the figure) of the insulating substrate 201 through the spacer 202 in which the T-shaped notch 204 is formed.
- a cover 203 is disposed on the insulating substrate 201.
- the members 201, 202, 203 are integrated by, for example, adhesion or heat welding.
- the notch 204 of the spacer 202 becomes the blood sample holding part 24 after the integration of the members.
- the blood sample holding unit 24 includes an introduction part 27 extending along the long side of the chip 100c and two branch parts 28a and 28b branched from the introduction part 27 and extending along the short side of the chip 100c. Has been.
- the introduction portion 27 communicates with the outside at one end of the spacer 202 (the left end in the figure). In other words, the blood sample holding unit 24 communicates with the blood sample inlet 26 that opens to the outside of the chip 100c.
- the cover 203 has an exhaust port 25 at portions corresponding to the tips of the branch portions 28a and 28b.
- the working electrode 21 and the counter electrode 22 are arranged on the insulating substrate 201 so that a part (part 41) of the working electrode 21 and a part (part 42) of the counter electrode 22 face different branch portions 28a and 28b, respectively.
- the working electrode 21 and the counter electrode 22 are connected to leads (not shown), respectively. One end of the lead is exposed to the outside of the chip 100c at the end of the insulating substrate 201 not covered with the spacer 202 and the cover 203 so that a voltage can be applied between the working electrode and the counter electrode.
- At least a part of the surface of the portion 41 of the working electrode 21 is made of a material containing silver, copper and nickel and an easily electrolytically oxidizable metal.
- the material constituting the surface of the portion 42 of the counter electrode 22 is not particularly limited as described above.
- the reagent 23 containing an oxidized form of a redox substance is disposed in contact with the portion 42 of the counter electrode 22.
- the arrangement of the reagent 23 may be in a state where it is difficult to dissolve in the blood sample, or may be in a state where it is easily dissolved in the blood sample.
- the reagent 23 is not disposed in contact with the portion 41 of the working electrode 21 and is easily applied to a blood sample. In the state in which it is dissolved, it is not arranged closer to the introduction part 27 than the part 41 of the working electrode 21 in the introduction part 27 and in the branch part 28a.
- the reagent 23 is preferably disposed in contact with only the counter electrode portion 42 in the blood sample holding portion 24. However, in the branch portion 28b, the reagent 23 is easily dissolved in the blood sample 42. It is located farther away and closer to the introduction part 27 than the part 42! /.
- the measurement of the Hct value of the blood sample using the sensor chip for Hct value measurement can be performed using, for example, a sensor unit for Hct value measurement which is an example of the sensor unit of the present invention.
- the sensor unit for Hct value measurement has a sensor chip for Hct value measurement and a sensor main body to which the sensor chip can be detachably attached.
- the sensor body has a voltage application circuit that can apply a predetermined voltage between the working electrode and the counter electrode of the sensor chip in a state where the sensor chip is mounted.
- the voltage application circuit applies a voltage of 3.0 V or less between the electrodes when the working electrode is represented as a positive electrode and the counter electrode is represented as a negative electrode.
- the applied voltage may be, for example, 1.0 V or less, 0.75 V or less, 0.5 V or less, 0.25 V or less, 0.15 V or less, or 0.1 IV or less.
- the lower limit of the voltage is not particularly limited as long as oxidation of an easily electrolytically oxidizable metal at the working electrode and oxidant reduction at the counter electrode occur, but it may be 0 V or higher when displayed in the same manner as described above.
- FIG. 41 is a diagram illustrating an example of a sensor unit for Hct value measurement.
- the sensor unit 126 for Hct value measurement has a flat hexahedral sensor body 123 and a sensor chip 121 for Hct value measurement.
- a mounting port 125 which is a rectangular hole is formed on the side wall surface of the sensor body 123.
- the sensor chip 121 is detachably attached to the attachment opening 125 and connected to the sensor body 123.
- a display unit 124 for displaying the measurement result of the Hct value is disposed at a substantially central portion of one main surface of the sensor body 123.
- FIG. 42 is a diagram showing an example of a circuit configuration for measuring the Hct value in the sensor unit 126 for Hct value measurement.
- the sensor body 123 includes a voltage application circuit 110 for applying a predetermined voltage between the working electrode 11 and the counter electrode 12 of the sensor chip 121, and a liquid crystal display device (LCD) 115 corresponding to the display unit 124.
- the voltage application circuit 110 includes two connectors 11 la and 11 lb, a current / voltage conversion circuit 112, an A / D conversion circuit 113, and a central operation.
- An arithmetic unit (CPU) 114 and a reference voltage source 116 are included. Each element ll la, 111b, 112, 113, 114, 115, 116 is connected to an electrical spring so that it can be displayed as a real spring.
- the measurement of the Hct value of the blood sample using the sensor unit 126 is performed as follows, for example. First, a blood sample is introduced from the blood sample introduction port 122 of the sensor chip 121 into the blood sample holding part 14 of the sensor chip 121. Thereafter, the predetermined Hct value measurement voltage is applied between the working electrode 11 and the counter electrode 12 from the current / voltage conversion circuit 112 and the reference voltage source 116 in accordance with a command from the CPU 114.
- the application time of the Hct value measurement voltage is, for example, 0.00;! To 60 less, preferably 0.01 to 10; more preferably 0.0;! To 5 less, and more preferably 0.01. Adjusted in the range of ⁇ 3 seconds. When the Hct value measurement voltage is applied!
- the value of the current flowing between the working electrode 11 and the counter electrode 12 is converted into a voltage value by the current / voltage conversion circuit 112 and then converted to a digital value by the A / D conversion circuit 113. It is converted into a value and input to CPU114.
- the CPU 114 calculates an Hct value based on this digital value.
- the calculation of the Hct value is performed, for example, with reference to a calibration curve or a calibration curve table that displays the relationship between the amount of the current and the Hct value of the blood sample after a predetermined time from the start of application of the Hct value measurement voltage.
- the calculation result is displayed on the LCD 115 as an image.
- the measurement accuracy of the analyte concentration in the blood sample can be improved.
- Analyte concentration in the blood sample is determined based on provisional measurement data of the analyte in the blood sample (data C obtained by correcting the data) using data A corresponding to the Hct value of the blood sample.
- Data A corresponding to the Hct value of the blood sample is obtained by the method for measuring the Hct value of the blood sample of the present invention.
- the data A is a value obtained by converting the current A that reflects the Hct value of the blood sample flowing between the working electrode and the counter electrode for measuring the Hct value (the working electrode for correction and the counter electrode for correction) into an Hct value. It may be a value obtained by converting the current A into a parameter value different from the Hct value, or the current A itself.
- the conversion of the current A to the Hct value is performed, for example, by referring to a calibration curve or a calibration curve table that displays the relationship between the current A and the Hct value after a predetermined time from the start of application of the Hct value measurement voltage.
- the current B is detected.
- the current B is related to the analyte in the blood sample. After reacting the oxidoreductase with the analyte as a substrate in the blood sample for a certain period of time, between the working electrode in contact with the blood sample (working electrode for temporary measurement) and the counter electrode (counter electrode for temporary measurement) It is a current that flows between both electrodes by applying a voltage (temporary measurement voltage).
- the data B may be, for example, a value obtained by converting the current B into the temporary measurement concentration of the analyte, or, for example, a value obtained by converting the current B into a parameter value different from the above temporary measurement concentration. However, the current B itself may be used.
- the conversion of the current B into the temporary measurement concentration is performed, for example, by referring to a calibration curve or a calibration curve table that displays the relationship between the current B and the temporary measurement concentration after a predetermined time from the start of application of the temporary measurement voltage.
- the current B is detected by mediating the electron transfer between the enzyme reaction and the electrode reaction via a redox substance, for example, a reversible electron active compound typified by ferricyanide.
- a redox substance for example, a reversible electron active compound typified by ferricyanide.
- the oxidation-reduction substance may be contained in the blood sample brought into contact with the working electrode for temporary measurement and the counter electrode for temporary measurement, for example, in the range of 0.;! To lOOOmM.
- the redox enzyme and the redox substance are brought into contact with both electrodes, for example, by contacting a blood sample containing them with the counter electrode for temporary measurement and the working electrode for temporary measurement.
- the oxidoreductase and redox substance may be in contact with the electrode in the state dissolved in the blood sample when the current B is detected, or may be in contact with the electrode as a solid.
- Analytes in the blood sample include substances other than blood cells, such as glucose, albumin, lactic acid, bilirubin, and cholesterol.
- the oxidoreductase include glucose oxidase, glucose dehydrogenase, latate oxidase, latate dehydrogenase, bilirubin oxidase and cholesterol oxidase.
- the amount of oxidoreductase reacted with the analyte is such that the content of oxidoreductase in the blood sample is, for example, 0.01 to; 100 units (U), or 0.05 to 10U, and in some cases 0. ; ⁇ Set it to 5U! /, ...
- the reaction time between the analyte and the oxidoreductase is, for example, 0 to 60 seconds, further 0.5 to 30 seconds, and in some cases;! To 10 seconds.
- the temporary measurement voltage is the temporary measurement working electrode as the positive electrode.
- the voltage may be 0.05 to IV, further 0 .;! To 0.8 V, or 0.2 to 0.5 V in some cases.
- the time for applying the temporary measurement voltage may be, for example, 0.0;! To 30 less, further 0 .;! To 10 less, and in some cases;! To 5 less.
- the temporary measurement counter electrode or the temporary measurement working electrode may be prepared separately from the correction counter electrode or the correction working electrode, or may be a part or all of the correction counter electrode or the correction working electrode. May be.
- the temporary measurement working electrode may also be used as the correction counter electrode.
- the temporary measurement counter electrode and the temporary measurement working electrode can be configured in the same manner as the above correction counter electrode.
- the shape and size of the temporary measurement counter electrode and the temporary measurement working electrode, and their arrangement pattern are not particularly limited.
- the order in which the current A and the current B are detected is not particularly limited. For example, when one electrode is used as both the temporary measurement working electrode and the correction counter electrode as described above, each current is detected. It is desirable to detect current A after detecting current B from the viewpoint of preventing a shortage of the redox substance of the type to be brought into contact with the one electrode and the redox reaction at the electrode from becoming the rate-limiting step. .
- the analyte concentration in the blood sample is determined based on the data C obtained by correcting the data B with the data A as described above.
- the value of data C obtained corresponds to data B.
- Data C can be, for example, the analyte concentration itself in the blood sample, or it can be a corrected current value, for example. If the value of data C is not the analyte concentration itself, determine the analyte concentration of the blood sample by referring to a calibration curve or a calibration curve table that displays the relationship between the value and the analyte concentration in the blood sample. To do.
- concentration of the analyte in the blood sample described above can be measured using an analyte concentration measurement sensor chip which is another example of the sensor chip of the present invention.
- the sensor chip for analyte concentration measurement has the same Hct value analysis unit as the sensor chip for Hct value measurement.
- the sensor chip for analyte concentration measurement has a temporary measurement analysis unit for electrochemically detecting the current B.
- the temporary measurement analysis unit may be formed separately from the Hct value analysis unit, or may be configured to share part or all of the Hct value analysis unit.
- an electrode system including a temporary measurement working electrode and a temporary measurement counter electrode, a temporary measurement working electrode, and a temporary measurement working electrode
- a blood sample holding part blood sample holding part B) for holding a blood sample in contact with the counter electrode for measurement, and a blood sample inlet (blood sample inlet B) communicating with the blood sample holding part B, respectively, have an Hct value.
- It may consist of an electrode system (electrode system A), a blood sample holder (blood sample holder A), and a blood sample inlet (blood sample inlet A) in the analyzer! /.
- the temporary measurement analysis unit and the Hct value analysis unit are formed separately, for example, regarding the flow of the blood sample when the blood sample is introduced into the sensor chip, the temporary measurement analysis unit Blood sample inlet B is located downstream of the Hct value analysis unit, and when the current A is detected, the redox substance oxidant is in contact with the working electrode for correction when the blood sample is introduced. It is good to prevent the formation.
- the temporary measurement analysis unit is configured by using part or all of the Hct value analysis unit, the arrangement pattern of the reagent containing oxidant, the shape of the blood sample holding unit, and the arrangement pattern of each electrode system It may be set as described later.
- the electrode system B is configured by using at least a part of the electrode system A, as described above, one electrode may be used as both the temporary measurement working electrode and the correction counter electrode.
- At least a part of the temporary measurement working electrode and the temporary measurement counter electrode faces the blood sample holding portion B so as to come into contact with the blood sample when the blood sample is introduced into the blood sample holding portion B.
- the above oxidoreductase and redox substance related to the enzyme citering reaction for temporarily measuring the analyte concentration may be arranged.
- the oxidoreductase may be arranged in a mixture with an enzyme stabilizer represented by a sugar alcohol such as maltitol, sorbitol and xylitol.
- the amount of oxidoreductase placed in the temporary measurement analyzer is such that the content of the oxidoreductase in the blood sample is, for example, 0.01 to 100 units (U), or 0.05 to 10 U. Should be set to 0.;! ⁇ 5U.
- the shape and volume of the blood sample holding part B be set so that the blood sample can be introduced into the inside by capillary action.
- FIGS. 43 to 48 are diagrams for explaining specific examples of the arrangement pattern of the reagent containing an oxidant, the shape of the blood sample holding portion, and the arrangement pattern of the electrode system in the sensor chip for analyte concentration measurement.
- the temporary measurement analysis unit and the Hct value analysis unit share a part of the configuration.
- one electrode is a working electrode for temporary measurement and correction
- the blood sample holding part A and the blood sample introduction port A also serve as the blood sample holding part B and the blood sample introduction port B, respectively.
- FIG. 43 is an exploded perspective view of the sensor chip A for analyte concentration measurement
- FIG. 44 is a plan view thereof.
- the analyte concentration measurement sensor chip A200a has a temporary measurement counter electrode 18, a part (part 33) of which branches in a U-shape, and the part 33 faces the blood sample holding part 14 and part thereof.
- the structure is the same as that of the Hct value measuring sensor chip AlOOa, except that it is arranged on the insulating substrate 101 so as to sandwich 32.
- the counter electrode 12 is also used as a working electrode for temporary measurement.
- the temporary measurement counter electrode 18 is connected to a lead (not shown). One end of the lead is exposed to the outside of the chip 200 a at the end of the insulating substrate 101 not covered with the spacer 102 and the cover 103.
- Another electrode may be arranged on the insulating substrate.
- a blood detection electrode for detecting that a sufficient amount of blood sample for carrying out each measurement has been introduced into the blood sample holder is used, and a part of the blood detection electrode faces the blood sample holder and a portion 33 It is placed on the insulating substrate so that it is farther from the blood sample introduction port.
- FIG. 45 is an exploded perspective view of the sensor chip B for analyte concentration measurement
- FIG. 46 is a plan view thereof.
- the analyte concentration measurement sensor chip B200b is separated from the portion 32 of the counter electrode 12 and closer to the blood sample inlet 16 than the portion 32 in the blood sample holding portion 14, and the working electrode 11. It has the same structure as the sensor chip A for analyte concentration measurement, except that the reagent 13 is disposed between the part 31 and the part 32 of the counter electrode 12 so as to be easily dissolved in the blood sample.
- FIG. 47 is an exploded perspective view of the sensor chip C for analyte concentration measurement
- FIG. 48 is a plan view thereof.
- the sensor chip C200c for analyte concentration measurement has an insulating substrate 201 such that the counter measurement electrode 29 has a part (part 43) facing the branch part 28b and closer to the introduction part 27 than the part 42. Except for being arranged above, it has the same structure as the sensor chip ClOOc for Hct value measurement.
- the counter electrode 22 is also used as a working electrode for temporary measurement. Provisional
- the measuring counter electrode 29 is connected to a lead (not shown). One end of the lead is exposed to the outside of the chip 200c at the end of the insulating substrate 201 not covered with the spacer 202 and the cover 203.
- the measurement of the analyte concentration of the blood sample by the analyte concentration measuring sensor chip is performed using force S, for example, using an analyte concentration measuring sensor unit which is another example of the sensor unit of the present invention.
- the analyte concentration measuring sensor unit includes an analyte concentration measuring sensor chip and a sensor body to which the sensor chip can be detachably attached.
- the sensor main body has a circuit for temporarily measuring the analyte concentration in the blood sample in addition to the circuit for measuring the Hct value, except that it has a circuit for temporarily measuring the analyte concentration in the blood sample. It has the same structure as the main body.
- FIG. 49 is a diagram showing an example of a circuit configuration for measuring the analyte concentration in the blood sample in the analyte concentration measurement sensor unit.
- the sensor body 223 is a voltage that applies a voltage between at least two of the correction working electrode 11, the correction counter electrode 12, the temporary measurement counter electrode 18 and the blood sample detection electrode 19 in the sensor chip 221 for analyte concentration measurement.
- An application circuit 210 and a liquid crystal display (LCD) 132 corresponding to a display unit in the sensor body are provided.
- the voltage application circuit 210 switches a potential applied to the electrode so that a predetermined voltage can be applied between the correction working electrode 11 and the correction counter electrode 12 and one electrode can be used as a positive electrode or a negative electrode. You can also.
- the voltage application circuit 210 includes four connectors 137a, 137b, 137c and 137d, a switching circuit 136, a current / voltage conversion circuit 135, an A / D conversion circuit 134, a reference voltage source 133 and a central processing unit (CPU) 131.
- a switching circuit 136 a current / voltage conversion circuit 135, an A / D conversion circuit 134, a reference voltage source 133 and a central processing unit (CPU) 131.
- CPU central processing unit
- the measurement of the analyte concentration in the blood sample using the analyte concentration measurement sensor unit is performed, for example, as follows.
- the working electrode 11 for correction is connected to the current / voltage conversion circuit 135 via the connector 137d and the blood sample detection electrode 19 is connected to the reference voltage via the connector 137b according to the command of the CPU 131. Connected to source 133. After that, a constant voltage is applied between both electrodes according to the command of CPU131.
- the voltage may be, for example, a voltage of 0.05 to 1 V when the correction working electrode is displayed as a positive electrode and the blood sample detection electrode is displayed as a negative electrode.
- This current value is converted into a voltage value by the current / voltage conversion circuit 135, converted to a digital value by the A / D conversion circuit 134, and input to the CPU 131.
- the CPU 131 detects that a blood sample has been introduced into the blood sample holder based on this digital value.
- the analyte in the blood sample is reacted with the oxidoreductase with a reaction time in the range of 0 to 60 seconds, and the analyte in the blood sample is temporarily measured as follows. Calculate the concentration. First, in response to a command from the CPU 131, the switching circuit 136 is activated, and the temporary measurement counter electrode serving as the correction counter electrode 12 is connected to the current / voltage conversion circuit 135 via the connector 137a, and the temporary measurement working electrode 18 is connected to the connector 137c. To the reference voltage source 133.
- the voltage exemplified above between both electrodes for example, a temporary measurement voltage that is 0.05 to 1 V when the temporary measurement working electrode is displayed as a positive electrode and the temporary measurement counter electrode is displayed as a negative electrode.
- the application time of the temporary measurement voltage is adjusted in the range of 0.0;! To 30 seconds, for example.
- the value of the current that flows between the electrodes due to the application of the temporary measurement voltage is converted to a voltage value by the current / voltage conversion circuit 135, then converted to a digital value by the A / D conversion circuit 134, and input to the CPU 131.
- the CPU 131 calculates a temporary measurement concentration of the analyte based on this digital value.
- the calculation of the temporary measurement concentration is performed with reference to a calibration curve or a calibration curve table that displays the relationship between the amount of current and the temporary measurement concentration of the analyte after a predetermined time from the start of applying the temporary measurement voltage.
- the Hct value of the blood sample is calculated as follows. First, in response to a command from the CPU 131, the switching circuit 136 is operated, the correction working electrode 11 is connected to the current / voltage conversion circuit 135 via the connector 1 37d, and the correction counter electrode 12 is connected to the reference voltage source via the connector 137a. Connected to 133. Thereafter, an Hct value measurement voltage having a magnitude of 3.0 V or less is applied between both electrodes in accordance with a command from the CPU 131 when the correction working electrode is displayed as a positive electrode and the correction counter electrode is displayed as a negative electrode.
- the application time of the Hct value measurement voltage is, for example, 0.001 Adjust in the range of ⁇ 60 seconds.
- the value of the current that flows between the two electrodes when the Hct value measurement voltage is applied is converted to a voltage value by the current / voltage conversion circuit 135, and then converted to a digital value by the A / D conversion circuit 134. Entered.
- the CPU 131 calculates the Hct value based on this digital value.
- the calculation of the Hct value is performed, for example, with reference to a calibration curve or a calibration curve table that displays the relationship between the amount of current and the Hct value after a predetermined time from the start of application of the Hct value measurement voltage.
- the CPU 131 corrects the temporary measurement concentration calculated as described above based on the Hct value, and determines the analyte concentration in the blood sample.
- the determined analyte concentration is displayed as an image on the LCD 132.
- the correction of the temporary measurement concentration based on the Hct value is performed, for example, by referring to a calibration or calibration curve table that displays the relationship between the Hct value and the temporary measurement concentration and the analyte concentration in the blood sample.
- the sensor chip of the present invention is designed to shield the surface of the working electrode for measuring the Hct value, which is configured by easy electrolytic oxidation, from outside air. It is preferable that the surface is covered with a substance that can be dissolved by the sample, for example, a water-soluble polymer, or that the entire sensor chip is packaged in an airtight manner.
- the surface of the working electrode for Hct value measurement is coated with sulfides, oxides and hydroxides of easily electrolytically oxidizable metals, such as silver sulfide and copper hydroxide, which constitute the surface by contact with outside air. This is because is easily formed.
- the sensor chip can be encapsulated in a sealed container made of a known material that is permeable to air and hardly corroded by air, and for example, a film made of such a material. Airtight packaging is possible by sandwiching between the two.
- a sensor chip A for Hct value measurement was produced.
- the working electrode and counter electrode cores were made of silver.
- a blood sample holder with a volume of 0 ⁇ 8 microliters (U was formed.
- the effective area of the working and counter electrodes in the blood sample holder was 1. Omm 2 , 1. and 8 mm 2, the closest distance between the working electrode and the counter electrode 2. 4 mm and the. surface of the working electrode facing the blood sample holder was an electrode core surface of the working electrode.
- the surface of the counter electrode facing the material holding part was the surface of the base layer made of a carboxymethyl cellulose (CMC) film disposed on the electrode core of the counter electrode.
- CMC carboxymethyl cellulose
- CMC aqueous solution (Daiichi Kogyo Seiyaku Co., Ltd.) to the surface of the electrode body of the counter electrode so as to be 2.5 mg / sensor, and then dry at 55 ° C for 10 minutes. And placed on the surface.
- a reaction reagent layer containing an oxidized form of a redox substance was disposed on the surface of the base layer.
- a reagent solution prepared by dissolving 50 mM potassium ferricyanide (manufactured by Kanto Chemical Co., Ltd.) in 0.5% by mass CMC aqueous solution was applied onto the underlayer so as to be 2.5 mg / sensor.
- the cloth was placed, it was placed on the surface of the underlayer by drying at 55 ° C. for 10 minutes.
- the closest distance between the working electrode and the reagent layer was 1.8 mm.
- the part corresponding to the blood sample inlet in the spacer and cover was hydrophilized.
- the hydrophilization treatment was performed by applying a 2-butanol solution of egg yolk lecithin (manufactured by Nacalai Testa Co.) so as to be 2 ⁇ L / sensor, and then air-drying the solution.
- the oxidized sample of the redox substance is in contact with the counter electrode and the blood sample is in contact with both electrodes without substantially contacting the working electrode.
- the reduced form that is the opposite form to the oxidized form does not substantially contact the working electrode and the counter electrode when measuring the response current.
- the measurement results of the response current are shown in the graphs of Figs.
- the graph (A) in each figure is a graph showing the change over time of the response current value ( ⁇ ) obtained from each blood sample.
- Graph (B) shows the relative values of the amplitudes of the response currents obtained from the other two blood samples, calculated based on the response current amplitude obtained from the blood sample having a Hct value of 45% (sensitivity difference ( %)) Is a graph showing the change over time.
- the horizontal axis of graphs (A) and (B) is the time (seconds: sec) from the start of voltage application.
- the sensor chip of Example 1 applied voltage even when a voltage of 3.0V or less was applied between both electrodes when the working electrode was displayed as a positive electrode and the counter electrode was displayed as a negative electrode. start Immediately thereafter, a response current reflecting the Hct value of the blood sample was detected with a stable and clear sensitivity difference.
- a sensor chip similar to that of Example 1 was produced except that a counter electrode core was formed using carbon paste (manufactured by Atchison).
- the above three types of blood samples are introduced into the blood sample holders of different sensor chips, and a voltage of 3.0 V or less is applied between both electrodes when the working electrode is indicated as positive and the counter electrode is indicated as negative.
- the response current flowing between the working electrode and the counter electrode was measured.
- the response current measurement results are shown in the graphs in Figs. As shown in each graph, when the sensor chip of Example 2 is displayed in the same manner as described above, even if a voltage of OV or less is applied between both electrodes, it is stable and clear immediately after the voltage application is started.
- the response current reflecting the Hct value of the blood sample was detected by the difference in sensitivity.
- a sensor chip similar to that of Example 1 was produced, except that a blood sample holding part having a volume of 2.5 L was formed using a spacer having a thickness of 180 m.
- a voltage of 3.0 V or less is applied between both electrodes when the working electrode is indicated as positive and the counter electrode is indicated as negative.
- the response current flowing between the working electrode and the counter electrode was measured.
- the response current measurement results are shown in the graphs in Figs. As shown in each graph, the sensor chip of Example 3 is stable and clear from the start of voltage application even if a voltage of 3.0 V or less is applied between both electrodes when displayed in the same manner as above.
- the response current reflecting the Hct value of the blood sample was detected with a large sensitivity difference.
- a sensor chip similar to that of Example 2 was produced, except that a blood sample holder having a volume of 2.3 L was formed using a spacer having a thickness of 260 m.
- a voltage of 3.0 V or less is applied between both electrodes when the working electrode is indicated as positive and the counter electrode is indicated as negative.
- the response current flowing between the working electrode and the counter electrode was measured.
- the response current measurement results are shown in the graphs in Figs. As shown in each graph, with the sensor chip of Example 4, even when a voltage of 3.0 V or less is applied between both electrodes when displayed in the same manner as described above, the voltage is stable and bright immediately after the start of voltage application.
- a response current reflecting the Hct value of the blood sample was detected with an accurate sensitivity difference.
- a conventional sensor chip was produced.
- the electrode core of the working electrode and the counter electrode is made of palladium
- a CMC film is disposed on the electrode core of the working electrode
- the surface of the CMC film faces the blood sample holder.
- the structure is the same as that of Example 1 except that the surface is formed and the reaction reagent layer is disposed on the electrode core body of the counter electrode without providing the base layer.
- the CMC membrane is prepared by adding 0.0;! To 2.0 mass% CMC aqueous solution (Daiichi Kogyo Co., Ltd.) 0.0;! To lOOmg on the surface of the electrode core of the working electrode and drying it. Was placed on the surface.
- the reaction reagent layer was prepared by dissolving a reagent solution prepared by dissolving 60 mM potassium ferricyanide (manufactured by Kanto Chemical Co., Ltd.) and 80 mM taurine (manufactured by Nacalai Testa Co., Ltd.) in 0.1% by mass CMC aqueous solution with 2.5 mg / sensor. After being applied to the surface of the electrode core body of the counter electrode, it was placed on the surface by drying at 55 ° C. for 10 minutes.
- the sensitivity difference fluctuates abruptly immediately after the start of voltage application, and the fluctuation gradually thereafter. However, even after 3 seconds from the start of voltage application, the force reached a steady state. As shown in Fig. 39, in the case of an applied voltage of 0.5 V when displayed in the same manner as described above, the sensitivity difference fluctuates rapidly immediately after the voltage application starts, and then the severe fluctuation continues and voltage application is continued. Even after 3 seconds from the start, the force reached a steady state.
- Comparative Example 2 An underlayer made of a CMC film is placed on the electrode core of the working electrode and the counter electrode, and the surface of the CMC film is used as a working electrode and a counter electrode surface facing the blood sample holding part, and the surface of the working electrode and the counter electrode A sensor chip similar to that of Comparative Example 1 was prepared, except that the reaction reagent layer was disposed on the substrate.
- the above three types of blood samples are introduced into the blood sample holders of different sensor chips, and a voltage of 2.5 V is applied between both electrodes when the working electrode is indicated as positive and the counter electrode is indicated as negative.
- the response current flowing between the working electrode and the counter electrode was measured. The response current measurement results are shown in the graph of FIG.
- the sensor chip of Comparative Example 2 has a small difference in sensitivity to fluctuations in the Hct value of the blood sample even when a voltage of 2.5 V is applied when displayed in the same manner as described above.
- the steady state was not reached even after 3 seconds from the start.
- the sensor chip for analyte concentration measurement (1) to (6) is the closest distance between the counter electrode and the counter electrode for temporary measurement when the counter electrode for temporary measurement with an effective area of 0.9 mm 2 is used in the blood sample holder.
- the working area of the working electrode is 0.9 mm 2 and the effective area of the counter electrode is 1. Omm 2.
- the present invention provides a method for measuring the Hct value of a blood sample, which can stably measure the Hct value of a blood sample with sufficient detection sensitivity even when the Hct value measurement voltage is lowered, and the analyte in the blood sample.
- a concentration measuring method, a sensor chip and a sensor unit suitable for the measurement can be provided.
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Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
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US12/377,497 US20100276303A1 (en) | 2006-10-19 | 2007-10-17 | Method for measuring hematocrit value of blood sample, method for measuring concentration of analyte in blood sample, sensor chip and sensor unit |
CN200780038967.7A CN101529236B (zh) | 2006-10-19 | 2007-10-17 | 血样的血细胞比容值的测定方法、血样中的分析物的浓度的测定方法、传感器芯片以及传感器单元 |
EP07830023.3A EP2045597B1 (en) | 2006-10-19 | 2007-10-17 | Method for measuring hematocrit value of blood sample, method for measuring concentration of analyte in blood sample, sensor chip and sensor unit |
JP2008539851A JP4814952B2 (ja) | 2006-10-19 | 2007-10-17 | 血液試料のヘマトクリット値の測定方法、血液試料中の分析物の濃度の測定方法、センサチップおよびセンサユニット |
Applications Claiming Priority (4)
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JP2006-285026 | 2006-10-19 | ||
JP2006-285025 | 2006-10-19 | ||
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PCT/JP2007/070289 WO2008047842A1 (fr) | 2006-10-19 | 2007-10-17 | Procédé de mesure de valeur hématocrite de prélèvement sanguin, procédé de mesure de concentration d'analyte dans un prélèvement sanguin, puce de capteur et unité de détection |
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US (1) | US20100276303A1 (ja) |
EP (1) | EP2045597B1 (ja) |
JP (1) | JP4814952B2 (ja) |
CN (1) | CN101529236B (ja) |
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JP2010032501A (ja) * | 2008-06-24 | 2010-02-12 | Panasonic Corp | バイオセンサ、その製造方法、及びそれを備える検出システム |
US9046479B2 (en) | 2008-06-24 | 2015-06-02 | Panasonic Healthcare Holdings Co., Ltd. | Biosensor, method of producing the same and detection system comprising the same |
JP2017151118A (ja) * | 2012-07-27 | 2017-08-31 | アセンシア・ダイアベティス・ケア・ホールディングス・アーゲーAscensia Diabetes Care Holdings AG | 既使用で乾燥したセンサを検出するシステム及び方法 |
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Also Published As
Publication number | Publication date |
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CN101529236B (zh) | 2013-04-03 |
JP4814952B2 (ja) | 2011-11-16 |
EP2045597A1 (en) | 2009-04-08 |
EP2045597A4 (en) | 2012-04-04 |
JPWO2008047842A1 (ja) | 2010-02-25 |
CN101529236A (zh) | 2009-09-09 |
US20100276303A1 (en) | 2010-11-04 |
EP2045597B1 (en) | 2013-04-24 |
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