WO2018061772A1 - Component measurement device, component measurement method, and component measurement program - Google Patents

Component measurement device, component measurement method, and component measurement program Download PDF

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Publication number
WO2018061772A1
WO2018061772A1 PCT/JP2017/033048 JP2017033048W WO2018061772A1 WO 2018061772 A1 WO2018061772 A1 WO 2018061772A1 JP 2017033048 W JP2017033048 W JP 2017033048W WO 2018061772 A1 WO2018061772 A1 WO 2018061772A1
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Prior art keywords
measurement
component
wavelength
measured
absorbance
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PCT/JP2017/033048
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French (fr)
Japanese (ja)
Inventor
嘉哉 佐藤
健行 森内
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テルモ株式会社
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Priority to JP2018542362A priority Critical patent/JP6952046B2/en
Publication of WO2018061772A1 publication Critical patent/WO2018061772A1/en

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N21/78—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator producing a change of colour
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/52—Use of compounds or compositions for colorimetric, spectrophotometric or fluorometric investigation, e.g. use of reagent paper and including single- and multilayer analytical elements

Definitions

  • the body fluid includes a portion including the component to be measured and a component to be measured.
  • a method is known in which the amount and concentration of a component to be measured are measured by separating them into parts that cannot be measured. For example, in order to measure the glucose concentration (mg / dL) in plasma of blood (whole blood), there is a method of measuring the glucose concentration in plasma by performing a step of separating plasma components from blood using a filter or the like. is there.
  • Patent Document 2 discloses a component measurement apparatus and a component measurement method for removing the influence of disturbance factors in measuring the glucose concentration in blood. Specifically, the component measuring device and the component measuring method described in Patent Document 2 estimate the disturbance factor at the measurement wavelength from the measurement value in the long wavelength region longer than the measurement wavelength, and calculate the measurement value at the measurement wavelength. After the correction using the estimated disturbance factor, the measurement value at the measurement wavelength is further corrected using the hematocrit value, thereby measuring the glucose concentration in the plasma component.
  • the glucose concentration of glucose as a component to be measured contained in blood as a body fluid can be measured with high accuracy.
  • the position of the measurement space in which the mixture containing the coloring component generated by the color reaction between the body fluid and the reagent is stored to measure the optical properties
  • the optical path length of the measurement space varies and varies, leading to the knowledge that the measurement accuracy of the component to be measured decreases.
  • an object of the present disclosure is to provide a component measurement device, a component measurement method, and a component measurement program that can suppress a decrease in measurement accuracy of a component to be measured due to variations or fluctuations in the optical path length of the measurement space.
  • the component measuring apparatus is configured such that the position of the gap when the predetermined wavelength is the first wavelength, the measurement light is the first measurement light, and the measurement value is the first measurement value.
  • the mixture is irradiated with the second measurement light having a second wavelength that belongs to the long wavelength region and is in the vicinity of the absorption band specific to the water or the absorption band specific to the water.
  • a second measurement value having an absorbance smaller than the first measurement value is acquired, and the component to be measured is derived based on a difference between the first measurement value and the second measurement value.
  • the measurement wavelength belongs to a shorter wavelength range than the first wavelength and the second wavelength.
  • the measurement wavelength belongs to a wavelength range corresponding to the full width at half maximum of the peak wavelength range in the absorbance spectrum of the color developing component.
  • the measurement wavelength belongs to the visible region.
  • a component measurement device a component measurement method, and a component measurement program that can suppress a decrease in measurement accuracy of a component to be measured due to variations or fluctuations in the optical path length of the measurement space.
  • FIG. 2 is a top view of a single component measurement chip shown in FIG. 1. It is II-II sectional drawing of FIG. It is III-III sectional drawing of FIG. It is an electrical block diagram of the component measuring apparatus shown in FIG. It is a functional block diagram of the calculating part shown in FIG. It is a figure which shows the light absorbency spectrum of the mixture obtained by color-reacting a blood sample and a reagent. It is a figure which shows the light absorbency spectrum of two types of blood specimens.
  • FIG. 17A is a graph showing the variation in absorbance at the measurement wavelength for “no correction” shown in FIG. 13, and FIG. 17B is the graph for the measurement wavelength for “correction during measurement” shown in FIG. It is a graph which shows the dispersion
  • FIG. 1 is a top view showing a component measuring device set 100 in which the component measuring chip 2 is mounted on the component measuring device 1 in the present embodiment.
  • FIG. 2 is an enlarged cross-sectional view of the vicinity of a portion where the component measurement chip 2 is mounted in the cross section taken along the line II of FIG.
  • the component measuring device set 100 includes a component measuring device 1 and a component measuring chip 2.
  • the component measuring apparatus 1 of this embodiment is a blood glucose level measuring apparatus capable of measuring the concentration (mg / dL) of glucose in a plasma component as a component to be measured in blood.
  • the component measurement chip 2 of the present embodiment is a blood glucose measurement chip that can be attached to the tip of a blood glucose measurement device as the component measurement device 1. “Blood” as used herein means whole blood that is not separated for each component but includes all components.
  • the component measuring apparatus 1 is composed of, for example, a housing 10 made of a resin material, a button group provided on the upper surface of the housing 10, a liquid crystal or LED (abbreviation of Light Emitting Diode) provided on the upper surface of the housing 10, and the like. And a removal lever 12 that is operated when removing the component measurement chip 2 attached to the component measurement device 1.
  • the button group of this embodiment includes a power button 13 and an operation button 14.
  • the housing 10 is provided with the above-described button group and the display unit 11 on the upper surface (see FIG. 1).
  • the main body 10a has a substantially rectangular outer shape when viewed from above, and protrudes outward from the main body 10a. (See FIG. 1) and a chip mounting portion 10b provided with a removal lever 12. As shown in FIG. 2, inside the chip mounting portion 10b, a chip mounting space S having a tip opening formed at the tip surface of the chip mounting portion 10b as one end is partitioned. When mounting the component measuring chip 2 on the component measuring apparatus 1, the component measuring chip 2 is inserted into the chip mounting space S from the outside through the tip opening.
  • the chip mounting portion 10b of the component measuring apparatus 1 is in a state where the component measuring chip 2 is locked. With this locked state, the mounting of the component measuring chip 2 to the component measuring apparatus 1 is completed.
  • the locking of the component measuring chip 2 by the component measuring device 1 can be realized by various configurations, for example, by providing a claw portion that can be engaged with a part of the component measuring chip 2 in the chip mounting portion 10b.
  • the above-described removal lever 12 is operated from the outside of the housing 10.
  • the component measuring chip 2 is released from the locked state by the chip mounting portion 10b of the component measuring apparatus 1, and the eject pin 26 (see FIG. 2) in the housing 10 is moved in conjunction with the component measuring chip 1. 2 can be removed from the component measuring apparatus 1.
  • the housing 10 of the present embodiment is configured to include a substantially rectangular main body 10a in a top view (see FIG. 1) and a chip mounting portion 10b that protrudes outward from the main body 10a.
  • the configuration is not limited to the shape of the housing 10 of the present embodiment as long as the configuration includes a chip mounting portion to which the measurement chip 2 can be mounted. Therefore, in addition to the shape of the housing 10 of the present embodiment, for example, various shapes that are easy for the user to hold with one hand can be adopted.
  • the display unit 11 displays, for example, information on the component to be measured measured by the component measuring device 1.
  • the glucose concentration (mg / dL) measured by the blood sugar level measuring device as the component measuring device 1 can be displayed on the display unit 11.
  • the display unit 11 may display not only information on the component to be measured but also various information such as measurement conditions of the component measuring apparatus 1 and instruction information for instructing a user to perform a predetermined operation. The user can operate the power button 13 and the operation button 14 of the button group while confirming the content displayed on the display unit 11.
  • FIG. 3 is a top view showing the component measuring chip 2.
  • 4 is a cross-sectional view taken along the line II-II in FIG.
  • FIG. 5 is a sectional view taken along line III-III in FIG.
  • the component measuring chip 2 defines a flow path 23 therein.
  • a coloring reagent 22 as a reagent is disposed in the flow channel 23 of the component measuring chip 2 with a gap 28 between the inner wall facing the flow channel 23 so as not to close the flow channel 23.
  • the component measurement chip 2 of the present embodiment includes a base member 21 having a substantially rectangular plate-shaped outer shape, a cover member 25 disposed so as to cover the base member 21, and the base member 21. And two spacer members 27 for maintaining the distance between the cover member 25 and the cover member 25 at a predetermined interval.
  • the flow path 23 of the component measurement chip 2 of this embodiment is formed by being surrounded by the base member 21, the cover member 25, and the two spacer members 27.
  • the coloring reagent 22 as the reagent of the present embodiment is arranged by being applied to the upper surface of the base member 21 as the inner wall that defines the flow path 23.
  • a gap 28 is formed between the applied coloring reagent 22 and the lower surface of the cover member 25 as an inner wall that defines the flow path 23.
  • the flow path 23 extends in a direction orthogonal to the thickness direction of the component measurement chip 2 and penetrates from one side end of the component measurement chip 2 to another side end.
  • One side end of the component measuring chip 2 on which one end of the flow path 23 is formed constitutes a supply unit 24 that can supply blood into the flow path 23 from the outside.
  • the blood supplied to the supply unit 24 from the outside moves along the flow path 23 by, for example, capillary action, reaches the gap 28 of the flow path 23, and contacts the color reagent 22.
  • glucose as a component to be measured in the blood and the coloring reagent 22 cause a color reaction.
  • a coloring component is generated by this color reaction. Therefore, a mixture containing blood and the coloring component generated by the above-described color reaction is generated at the holding position where the coloring reagent 22 is held and the position of the gap 28.
  • the flow path 23 of the present embodiment is partitioned by the base member 21, the cover member 25, and the two spacer members 27.
  • the number of members that partition the flow path and the shape of the flow path are limited to the configuration of the present embodiment. I can't.
  • a flow path is formed by only two members: a base member in which a groove is formed on one surface in the thickness direction and a cover member attached so as to cover the one surface on which the groove is formed. It is also possible to do.
  • the flow path of the component measurement chip may be configured to be partitioned by three or less members.
  • the flow path divided by five or more members may be sufficient.
  • the flow path 23 of the present embodiment extends linearly in a top view (see FIG. 3) or a cross-sectional view shown in FIG. 5, but for example, is bent in a top view or a cross-sectional view similar to FIG. It may extend or may be curved and extended uniformly.
  • a transparent material for light transmission As the material of the base member 21 and the cover member 25, it is preferable to use a transparent material for light transmission.
  • transparent organic resin materials such as polyethylene terephthalate (PET), polymethyl methacrylate (PMMA), polystyrene (PS), cyclic polyolefin (COP), cyclic olefin copolymer (COC), and polycarbonate (PC); glass, quartz, etc.
  • PET polyethylene terephthalate
  • PMMA polymethyl methacrylate
  • PS polystyrene
  • COP cyclic polyolefin
  • COC cyclic olefin copolymer
  • PC polycarbonate
  • the coloring reagent 22 as a reagent reacts with the component to be measured in the blood to cause a color reaction that develops a color corresponding to the blood concentration of the component to be measured.
  • the coloring reagent 22 of the present embodiment Is applied on the base member 21.
  • the coloring reagent 22 of this embodiment reacts with glucose as a component to be measured in blood.
  • Examples of the coloring reagent 22 of the present embodiment include (i) glucose oxidase (GOD), (ii) peroxidase (POD), and (iii) 1- (4-sulfophenyl) -2,3-dimethyl-4-amino.
  • the peak wavelength in the absorbance spectrum of the coloring component generated by the color reaction between glucose in the blood and the coloring reagent 22 is the peak wavelength resulting from the light absorption characteristics of hemoglobin in the blood cell. And use something different.
  • the coloring reagent 22 of the present embodiment has a peak wavelength in the vicinity of 650 nm of the absorbance spectrum of the coloring component generated by the color reaction between glucose in the blood and the coloring reagent 22, but is limited to the peak wavelength in the vicinity of 650 nm. Absent. Details of this will be described later.
  • the component measuring apparatus 1 includes a calculation unit 60 in addition to the housing 10 (see FIG. 1), the display unit 11, the removal lever 12 (see FIG. 1), the power button 13 and the operation button 14 described above. And a memory 62, a power supply circuit 63, and a measurement optical system 64.
  • the calculation unit 60 is configured by an MPU (Micro-Processing Unit) or a CPU (Central Processing Unit), and can read out and execute a program stored in the memory 62 or the like, thereby realizing control operations of the respective units.
  • the memory 62 is composed of a non-transitory storage medium that is volatile or nonvolatile, and can read or write various data (including a component measurement program) necessary for executing the component measurement method shown here. is there.
  • the power supply circuit 63 supplies power to each unit in the component measuring apparatus 1 including the calculation unit 60 or stops supplying the power according to the operation of the power button 13.
  • the measurement optical system 64 is an optical system capable of acquiring the optical characteristics of a mixture containing a color developing component generated by a color reaction between blood and the color developing reagent 22 as a reagent.
  • the measurement optical system 64 includes a light emitting unit 66, a light emission control circuit 70, a light receiving unit 72, and a light reception control circuit 74.
  • various photoelectric conversion elements including a PD (abbreviation of Photo Diode) element, a photoconductor (photoconductor), and a phototransistor (abbreviation of Photo Transistor) can be applied.
  • a PD abbreviation of Photo Diode
  • photoconductor photoconductor
  • phototransistor abbreviation of Photo Transistor
  • the light emission control circuit 70 turns on or turns off the first light source 67a to the fifth light source 68 by supplying driving power signals to the first light source 67a to the fifth light source 68, respectively.
  • the light reception control circuit 74 obtains a digital signal (hereinafter referred to as a detection signal) by performing logarithmic conversion and A / D conversion on the analog signal output from the light receiving unit 72.
  • FIG. 7 is a functional block diagram of the calculation unit 60 shown in FIG.
  • the calculation unit 60 realizes the functions of a measurement instruction unit 76 that instructs a measurement operation by the measurement optical system 64 and a concentration measurement unit 77 that measures the concentration of the component to be measured using various data.
  • the concentration measurement unit 77 includes an absorbance acquisition unit 78 and an absorbance correction unit 84.
  • the memory 62 stores the absorbance measurement value data 85 at each of the first wavelength ⁇ 1 to the fifth wavelength ⁇ 5 measured by the measurement optical system 64 and the measurement value data 85 or the measurement value data 85.
  • Correction data 86 including a group of correction coefficients correlated with the calculated secondary data, and a measured value of the absorbance of the mixture actually measured at the measurement wavelength, or a corrected measured value obtained by correcting this measured value with the correction data 86
  • calibration curve data 90 such as a calibration curve indicating the relationship between the amount of each physical quantity (for example, glucose concentration) and a calibration curve indicating the relationship between the absorbance of the hemoglobin in the mixture and the hematocrit value are stored.
  • the “hematocrit value” is a percentage of the volume ratio of blood cell components in blood to blood (whole blood).
  • the color reaction between glucose in blood as a component to be measured in the body fluid and the coloring reagent 22 is performed, and blood (whole blood) and the coloring reagent 22 are separated without separating the plasma component containing glucose from the blood.
  • the component measurement method for measuring the glucose concentration in the blood based on the optical characteristics of the mixture that is executed by the above-described method and that includes the color-forming component generated by the color reaction will be described.
  • FIG. 8 shows an absorbance spectrum of a mixture obtained by color reaction of a blood sample having a known hematocrit value and glucose concentration with the coloring reagent 22.
  • the blood sample used here has a hematocrit value of 40% and a glucose concentration of 400 mg / dL (indicated as “Ht40 bg400” in FIG. 8).
  • the absorbance spectra of blood samples having the same hematocrit value are approximately the same.
  • the absorbance of the first blood sample (hematocrit value is 20%). Only the spectrum and the absorbance spectrum of the second blood sample (hematocrit value is 40%) are shown.
  • the measurement result of the color developing component may be affected by the occurrence of an optical phenomenon. For example, “light scattering” due to blood cell components in the blood, and “light absorption” due to a component (specifically, hemoglobin) different from the color developing component occurs, thereby measuring an absorbance greater than the true value. Tend to be.
  • the absorbance spectra of the two blood samples shown in FIG. 9 have a trend curve in which the absorbance gradually decreases as the wavelength increases, and have two peaks centered around 540 nm and 570 nm. These two peaks are mainly due to the light absorption of hemoglobin in red blood cells.
  • the absorbance gradually decreases in a substantially linear manner as the wavelength increases in the wavelength region of 600 nm or more. This substantially linear portion is mainly caused by light scattering by a blood cell component or the like.
  • the absorbance of the blood sample in the wavelength region longer than 600 nm is predominantly affected by light scattering due to blood cell components and the like, and the absorbance of the blood sample in the wavelength region shorter than 600 nm is The effect of light absorption by hemoglobin is greater than the effect of light scattering by blood cell components and the like.
  • the absorbance spectrum of the mixture shown in FIG. 8 has a trend curve in which the absorbance gradually decreases as the wavelength increases, similar to the absorbance spectrum of the blood sample shown in FIG.
  • the absorbance increases in the visible region around 600 nm to 700 nm.
  • the absorbance increasing from about 600 nm to 700 nm is mainly due to the light absorption characteristics of the coloring component generated by the color reaction between glucose in the blood and the coloring reagent 22.
  • the influence (noise) of light scattering by blood cell components and light absorption by hemoglobin at a predetermined measurement wavelength (for example, 650 nm) where the light absorption rate of the color developing component to be measured is high is estimated. It is necessary to correct the measured value of absorbance at the measurement wavelength.
  • the height h of the gap 28 where the mixture is located reflects the amount of sample flowing in. That is, in order to obtain the amount (concentration) of the measurement target contained in the specimen, the height h of the gap 28 is regarded as a constant value (constant) determined according to the type of the component measurement chip and the color development in the mixture. It is necessary to derive the absorbance of the component. However, the existing component measuring device does not take into account the fluctuation of the height h of the gap 28. Further, the height h of the gap 28 is, for example, the presence or absence of moisture absorption of the coloring reagent 22 in the natural environment, the influence of swelling or dissolution of the coloring reagent 22 due to the color reaction, and the dimensional tolerance in manufacturing the component measuring chip.
  • FIG. 10 is a graph showing the difference in water absorbance based on the difference in the height H (see FIG. 5) of the flow path 23.
  • FIG. 10 shows the absorbance spectrum in the near-infrared region of the empty chip in the state where the coloring reagent 22 is removed from the component measurement chip 2 shown in FIGS. More specifically, in FIG. 10, the absorbance spectrum of the first empty chip in which the height H of the flow path 23 is 30 ⁇ m and there is no water in the flow path 23 (in FIG. 10, “30 ⁇ m nomwater” Notation), the absorbance spectrum of the second empty chip in which the height H of the flow path 23 is 50 ⁇ m and there is no water in the flow path 23 (indicated as “50 ⁇ m no water” in FIG.
  • the height h of the gap 28 of each component measuring chip 2 is actually measured by a film thickness meter, for example, and a correction value corresponding to the measured value is taken into the individual component measuring apparatus 1 as calibration information. Takes a lot of time and effort to users such as patients and medical workers, and leads to an increase in component measurement values, thereby impairing user convenience. In addition, it is not easy in manufacturing to make the allowable dimensional tolerance of the height h of the gap 28 of the component measuring chip 2 so small that it is unnecessary to correct the optical path length of the measurement space. Furthermore, the height h of the gap 28 as the optical path length of the measurement space in a state where the body fluid as the specimen is in contact with the reagent and the mixture is generated in the gap 28 is not reflected.
  • the gap 28 as the optical path length of the measurement space when measuring the absorbance of the color developing component in the mixture (hereinafter simply referred to as “during measurement”) using the above-described characteristics.
  • the height h is estimated.
  • the blood plasma contains moisture
  • the mixture located in the gap 28 is irradiated with light belonging to an absorption band unique to water, it is contained in the mixture located in the gap 28 at the time of measurement. It is possible to obtain a measured value of water absorbance according to the amount of water, in other words, according to the amount of blood located in the gap 28 at the time of measurement.
  • Step S2 Irradiating the first measurement light of the first wavelength ⁇ 1 belonging to the absorption band specific to water in the region to measure the absorbance, and deriving the component to be measured based on the measured value of the absorbance measured in step S1 Step S2 for deriving the glucose concentration in the blood.
  • the first measurement light having the first wavelength ⁇ 1 is emitted from the first light source 67a via the light emission control circuit 70 according to an instruction from the calculation unit 60.
  • the first wavelength ⁇ 1 is a predetermined wavelength belonging to an absorption band specific to water in the near infrared region, and in this embodiment, the wavelength at which the absorbance of water reaches a peak value in the absorption band specific to water. .
  • 1820 nm to 2000 nm at which the water absorbance peak appears noticeably is used as the absorption band unique to water.
  • the wavelength at which the water absorbance reaches a peak value in this absorption band is 1940 nm.
  • the first measurement light having the first wavelength ⁇ 1 passes through the component measurement chip 2 in the thickness direction of the component measurement chip 2 at the position of the gap 28 of the component measurement chip 2.
  • the transmitted light that has passed through the component measuring chip 2 is received by the light receiving unit 72.
  • the absorbance of the mixture located in the gap 28 at the first wavelength ⁇ 1 belonging to the absorption band specific to water can be measured.
  • the measured value of the absorbance measured here is referred to as “first measured value”.
  • the mixture at the position of the gap 28 belongs to a long wavelength region that is greater than or equal to the near infrared region, and By irradiating the second measurement light having the second wavelength ⁇ 2 in the vicinity of the absorption band specific to water or the absorption band specific to water, a second measurement value having an absorbance smaller than the first measurement value is acquired.
  • the glucose concentration is derived based on the difference between the first measurement value and the second measurement value.
  • the step of obtaining the above-described second measurement value is shown as step S1-2.
  • the absorbance acquisition unit 78 of the component measuring apparatus 1 can acquire the measurement value data 85 from the memory 62.
  • the means by which the absorbance acquisition unit 78 acquires the above-described measurement value is not limited to the above-described means, and can be acquired by various known means.
  • the measurement wavelength for measuring the absorbance of the color developing component to be measured is a wavelength at which the light absorption rate of the color developing component is relatively large and a wavelength that is relatively less affected by the light absorption of hemoglobin is used.
  • the wavelength may correspond to the full width at half maximum of the peak wavelength range in the absorbance spectrum of the color developing component to be measured, and the wavelength may belong to a wavelength range in which the ratio of absorbance due to light absorption of hemoglobin to the total absorbance is relatively small.
  • the wavelength range “corresponds to the full width at half maximum of the peak wavelength range” refers to the half value at the long wavelength side from the wavelength at which the half wavelength at the short wavelength side is specified when the full width at half maximum of the peak wavelength range in the absorbance spectrum is specified.
  • the wavelength range up to the wavelength In the absorbance spectrum of the color developing component to be measured in this embodiment, the peak wavelength is around 600 nm, and the wavelength range corresponding to the full width at half maximum is about 500 nm to about 700 nm. Further, the influence of light absorption of hemoglobin on the total absorbance is relatively small in the wavelength region of 600 nm or more. Therefore, in this embodiment, the wavelength range corresponding to the full width at half maximum of the peak wavelength range in the absorbance spectrum of the color developing component to be measured and having a relatively small ratio of absorbance due to light absorption of hemoglobin to the total absorbance is 600 nm. Above and 700 nm or less.
  • the measurement wavelength is not limited to 650 nm in the present embodiment, and another wavelength belonging to the range of 600 nm to 700 nm may be used as the measurement wavelength.
  • the absorbance of the chromogenic component can be measured more accurately when the signal representing the absorbance of the chromogenic component is stronger and the ratio of absorbance due to light absorption of hemoglobin to the total absorbance is in a very small wavelength range. It is preferable to set the measurement wavelength near 650 nm, which is slightly longer than the peak wavelength near 630 nm.
  • the height h of the gap 28 at each point shown in FIG. 16 is measured with an Optical MicroGauge thickness meter (C11011-01) manufactured by Hamamatsu Photonics Co., Ltd. as a film thickness meter.
  • the measured values of the absorbance at each point shown in FIG. 16 are the absorbance at a wavelength specific to water, and the 9-second value, which is the absorbance 9 seconds after the specimen contacts the coloring reagent 22, It is measured by calculating the difference between the initial value which is the absorbance before contact with the color reagent 22. More specifically, first, a difference between the above-described first measurement value as a 9-second value at 1940 nm and the above-described second measurement value as a 9-second value at 1820 nm is calculated.
  • the glucose water having a glucose concentration of 100 mg / dL and 400 mg / dL is evaluated by a value (2SD value) twice the standard deviation of the deviation from the true value divided by the glucose concentration. Further, the measured value of the height h of the gap 28 before the measurement is measured with an Optical MicroGauge thickness meter (C11011-01) manufactured by Hamamatsu Photonics.
  • FIG. 17B is a graph showing the variation in absorbance at the measurement wavelength (here, 650 nm is used) for “with correction during measurement” shown in FIG.
  • the horizontal axis in FIG. 17 (b) is the absorbance at the measurement wavelength as in the horizontal axis in FIG. 17 (a), and the vertical axis in FIG. 17 (b) is the glucose concentration of the mixture at the position of the gap 28.
  • there is a correlation between the glucose concentration of the mixture at the position of the gap 28 and the absorbance at the measurement wavelength (correlation coefficient R 0.999).
  • FIG. 14 shows the influence on the measured value of the glucose concentration in the case where the variation in the height h (see FIG. 5) of the gap 28 of the allowable component measurement chip 2 is very small. Specifically, FIG. 14 shows the results of an experiment using a plurality of component measurement chips 2 that vary in the range where the height h of the gap 28 is 40 ⁇ 1 ⁇ m. The width of each gap 28 is constant.
  • the variation in the height h (see FIG. 5) of the gap 28 of the component measurement chip 2 is very small, as shown in FIG. 14, even if the optical path length of the measurement space is not corrected, the derived glucose concentration The variation of can be reduced.
  • the height h of the gap 28 at the time of measurement is estimated as the optical path length of the measurement space at the time of measurement, and the optical path length of the measurement space is corrected using this estimated value. It can also be seen that the variation in the derived glucose concentration can be reduced.
  • the measured value of the derived glucose concentration is corrected in consideration of the height h of the gap 28 at the time of measurement as the optical path length of the measurement space at the time of measurement as in this embodiment. Even if the variation in the height h (see FIG. 5) of the gap 28 of the component measuring chip 2 is very small, the accuracy of the derived glucose concentration can be made high, and the variation in the clearance amount It can be understood that the accuracy of the derived glucose concentration can be greatly improved when is large.
  • FIG. 15 shows the optical path length of the measurement space for blood adjusted to have a glucose concentration of zero, blood adjusted to have a glucose concentration of 100 mg / dL, and blood to have a glucose concentration of 400 mg / dL.
  • the variation in the measured value of the derived glucose concentration is shown.
  • the variation in the measured values shown in FIG. 15 is evaluated based on twice the standard deviation (2SD) of deviation from the true value of the absolute value of the concentration (mg / dL) for water not containing the glucose concentration.
  • the glucose waters of 100 mg / dL and 400 mg / dL are evaluated by a value (2SD value) twice the standard deviation of the deviation from the true value divided by the glucose concentration.
  • the measured value of the height h of the gap 28 before the measurement is measured with an Optical MicroGauge thickness meter (C11011-01) manufactured by Hamamatsu Photonics.
  • first light source 67a to fifth light source 68 have been described as examples of the light emitting unit 66.
  • a single light source and a plurality of types arranged in front of the light source are described. These optical filters (bandpass type) may be combined. Or you may comprise combining a single light source and multiple types of light-receiving part.
  • the light receiving unit 72 that receives the transmitted light that passes through the component measuring chip 2 is used. However, the light receiving unit that receives the reflected light reflected from the component measuring chip 2 may be used.
  • Component measuring device 2 Component measuring chip 10: Housing 10a: Main body part 10b: Chip mounting part 11: Display part 12: Removal lever 13: Power button 14: Operation button 21: Base member 22: Coloring reagent (reagent) 23: channel 24: supply unit 25: cover member 26: eject pin 27: spacer member 28: gap 60: calculation unit 62: memory 63: power supply circuit 64: measurement optical system 66: light emitting units 67a to 67d: first light source To fourth light source 68: fifth light source 70: light emission control circuit 72: light receiving unit 74: light reception control circuit 76: measurement instruction unit 77: concentration measurement unit 78: absorbance acquisition unit 84: absorbance correction unit 85: measurement value data 86: Correction data 90: Calibration curve data 100: Component measuring device set H: Channel height h: Gap height S: Chip mounting space W: Channel width ⁇ 1 to ⁇ 5: First wavelength to fifth wavelength

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Abstract

The component measurement device pertaining to the present invention measures a component to be measured in a liquid on the basis of an optical characteristic of a mixture including a coloring component generated by a color reaction of a reagent and the component to be measured in the liquid, wherein a flow path is partitioned inside thereof, a component measurement chip having the reagent is mountable in the flow path, the component measurement chip being disposed in a state of being separated via a gap from a facing inner wall so as not to block the flow path, and the component to be measured being derived on the basis of the measured value of light absorbance measured using a predetermined wavelength of measurement light belonging to an absorption band specific to water in a near-infrared or longer long-wavelength region that is radiated to the mixture at the position of the gap.

Description

成分測定装置、成分測定方法及び成分測定プログラムComponent measuring device, component measuring method and component measuring program
　本開示は、成分測定装置、成分測定方法及び成分測定プログラムに関し、特に、体液中の被測定成分を測定する成分測定装置、成分測定方法及び成分測定プログラムに関する。 The present disclosure relates to a component measurement device, a component measurement method, and a component measurement program, and more particularly, to a component measurement device, a component measurement method, and a component measurement program for measuring a component to be measured in a body fluid.
　従来から、生化学分野や医療分野において、検体としての体液中に含まれる目的成分（被測定成分ともいう）を測定する手法として、体液を被測定成分が含まれる部分と、被測定成分が含まれない部分とに分離し、被測定成分の量や濃度を測定する方法が知られている。例えば、血液（全血）の血漿中のグルコース濃度（ｍｇ／ｄＬ）を測定するため、フィルタ等を用いて、血液から血漿成分を分離する工程を行い、血漿中のグルコース濃度を測定する方法がある。 Conventionally, in the biochemical field and the medical field, as a method for measuring a target component (also referred to as a component to be measured) contained in a body fluid as a specimen, the body fluid includes a portion including the component to be measured and a component to be measured. A method is known in which the amount and concentration of a component to be measured are measured by separating them into parts that cannot be measured. For example, in order to measure the glucose concentration (mg / dL) in plasma of blood (whole blood), there is a method of measuring the glucose concentration in plasma by performing a step of separating plasma components from blood using a filter or the like. is there.
　また、体液から被測定成分が含まれる部分を分離することなく、体液中の被測定成分を測定する一手法として、吸光光度法を用いた測定が知られている。この手法によれば、上述した被測定成分の分離工程を含む手法と比較して、被測定成分の測定に要する時間を短縮することができる。ただし、体液中に被測定成分と異なる別の成分が多く含まれる場合、この別の成分が光吸収・光散乱等の光学的現象を引き起こし、その結果、測定上の外乱因子として作用することがある。そこで、被測定成分の測定精度を維持すべく、この外乱因子の影響を除去することが必要であり、外乱因子の影響を除去する手法が種々提案されている。 In addition, as one technique for measuring a component to be measured in a body fluid without separating a portion containing the component to be measured from the body fluid, measurement using an absorptiometry is known. According to this method, the time required for measuring the component to be measured can be shortened as compared with the method including the separation step of the component to be measured. However, if the body fluid contains many other components that are different from the component to be measured, these other components may cause optical phenomena such as light absorption and light scattering, and as a result, may act as a disturbance factor in measurement. is there. Therefore, in order to maintain the measurement accuracy of the component to be measured, it is necessary to remove the influence of the disturbance factor, and various methods for removing the influence of the disturbance factor have been proposed.
　このような外乱因子の影響を除去する装置及び方法として、特許文献２には、血液中のグルコース濃度の測定において、外乱因子の影響を除去する成分測定装置及び成分測定方法が記載されている。具体的に、特許文献２の記載の成分測定装置及び成分測定方法は、測定波長よりも長波長側の長波長域の測定値から、測定波長における外乱因子を推定し、測定波長における測定値を推定した外乱因子を用いて補正した後、ヘマトクリット値を用いて測定波長における測定値を更に補正することにより、血漿成分におけるグルコース濃度を測定するものである。 As an apparatus and method for removing the influence of such disturbance factors, Patent Document 2 discloses a component measurement apparatus and a component measurement method for removing the influence of disturbance factors in measuring the glucose concentration in blood. Specifically, the component measuring device and the component measuring method described in Patent Document 2 estimate the disturbance factor at the measurement wavelength from the measurement value in the long wavelength region longer than the measurement wavelength, and calculate the measurement value at the measurement wavelength. After the correction using the estimated disturbance factor, the measurement value at the measurement wavelength is further corrected using the hematocrit value, thereby measuring the glucose concentration in the plasma component.
特公平７－３４７５８号公報Japanese Patent Publication No. 7-34758 国際公開第２０１５／１３７０７４号International Publication No. 2015/137074
　特許文献２に記載の成分測定装置及び成分測定方法によれば、体液としての血液に含まれる被測定成分としてのグルコースのグルコース濃度を高い精度で測定することができるが、本願発明者は、被測定成分の測定精度を更に向上させるべく鋭意検討を重ねた結果、体液と試薬との呈色反応により生じる発色成分を含む混合物がその光学的特性を測定するために収容されている測定空間の位置や、この測定空間を区画する部材の製造上の寸法公差等により、測定空間の光路長にばらつきや変動が生じ、これにより被測定成分の測定精度が低下するという知見を得るに至った。 According to the component measuring apparatus and the component measuring method described in Patent Document 2, the glucose concentration of glucose as a component to be measured contained in blood as a body fluid can be measured with high accuracy. As a result of intensive studies to further improve the measurement accuracy of the measurement components, the position of the measurement space in which the mixture containing the coloring component generated by the color reaction between the body fluid and the reagent is stored to measure the optical properties In addition, due to dimensional tolerances in the manufacture of the members that partition the measurement space, the optical path length of the measurement space varies and varies, leading to the knowledge that the measurement accuracy of the component to be measured decreases.
　そこで本開示は、測定空間の光路長のばらつきや変動による被測定成分の測定精度の低下を抑制可能な成分測定装置、成分測定方法及び成分測定プログラムを提供することを目的とする。 Therefore, an object of the present disclosure is to provide a component measurement device, a component measurement method, and a component measurement program that can suppress a decrease in measurement accuracy of a component to be measured due to variations or fluctuations in the optical path length of the measurement space.
　本発明の第１の態様としての成分測定装置は、体液中の被測定成分と試薬との呈色反応により生じる発色成分を含む混合物の光学的特性に基づいて前記体液中の前記被測定成分を測定する成分測定装置であって、内部に流路を区画し、前記流路内で、前記流路を閉塞しないように対向する内壁との間に間隙を隔てた状態で配置された前記試薬を有する成分測定チップが装着可能であり、前記間隙の位置で前記混合物に照射される、近赤外領域以上の長波長域で水に固有の吸収帯域に属する所定波長の測定光、により測定された吸光度の測定値に基づいて、前記被測定成分を導出する。 The component measuring apparatus according to the first aspect of the present invention is configured to determine the component to be measured in the body fluid based on the optical characteristics of the mixture including the color developing component generated by the color reaction between the component to be measured in the body fluid and the reagent. A component measuring apparatus for measuring, wherein the reagent is disposed in a state where a flow path is defined in the flow path and a gap is provided between the flow path and an opposing inner wall so as not to block the flow path. A component measuring chip having a predetermined wavelength belonging to an absorption band specific to water in a long wavelength region longer than the near infrared region, which is irradiated to the mixture at the position of the gap. The measured component is derived based on the measured value of absorbance.
　本発明の１つの実施形態としての成分測定装置は、前記所定波長を第１波長とし、前記測定光を第１測定光とし、前記測定値を第１測定値とした場合に、前記間隙の位置で前記混合物に照射される、前記長波長域に属し、かつ、前記水に固有の吸収帯域又は前記水に固有の吸収帯域の近傍の第２波長の第２測定光、により測定された、前記第１測定値よりも小さい吸光度である第２測定値を取得し、前記第１測定値と前記第２測定値との差分に基づいて、前記被測定成分を導出する。 The component measuring apparatus according to one embodiment of the present invention is configured such that the position of the gap when the predetermined wavelength is the first wavelength, the measurement light is the first measurement light, and the measurement value is the first measurement value. The mixture is irradiated with the second measurement light having a second wavelength that belongs to the long wavelength region and is in the vicinity of the absorption band specific to the water or the absorption band specific to the water. A second measurement value having an absorbance smaller than the first measurement value is acquired, and the component to be measured is derived based on a difference between the first measurement value and the second measurement value.
　本発明の１つの実施形態としての成分測定装置は、前記体液と接触する前の前記試薬に照射される前記第１波長の第３測定光により測定された吸光度である第３測定値と、前記体液と接触する前の前記試薬に照射される前記第２波長の第４測定光により測定された吸光度である第４測定値と、を取得し、前記第１測定値と前記第２測定値との差分と、前記第３測定値と前記第４測定値との差分と、の間の差分である補正差分値に基づいて、前記被測定成分を導出する。 The component measurement apparatus according to one embodiment of the present invention includes a third measurement value that is an absorbance measured by the third measurement light having the first wavelength irradiated to the reagent before contacting the body fluid, A fourth measurement value that is an absorbance measured by the fourth measurement light of the second wavelength irradiated on the reagent before contacting the body fluid, and the first measurement value and the second measurement value The measured component is derived based on a correction difference value that is a difference between the difference between the third measurement value and the difference between the third measurement value and the fourth measurement value.
　本発明の１つの実施形態としての成分測定装置は、前記間隙の位置で前記混合物に照射される、前記水に固有の吸収帯域とは異なる波長域に属する測定波長の第５測定光、により測定された吸光度である第５測定値を取得し、前記第５測定値を、前記補正差分値に基づいて、補正する。 The component measuring apparatus according to one embodiment of the present invention is configured to measure with a fifth measuring light having a measurement wavelength that irradiates the mixture at the position of the gap and belongs to a wavelength range different from the absorption band specific to the water. A fifth measurement value that is the absorbed absorbance is acquired, and the fifth measurement value is corrected based on the correction difference value.
　本発明の１つの実施形態として、前記測定波長は、前記第１波長及び前記第２波長よりも短波長域に属する。 As one embodiment of the present invention, the measurement wavelength belongs to a shorter wavelength range than the first wavelength and the second wavelength.
　本発明の１つの実施形態として、前記測定波長は、前記発色成分の吸光度スペクトルにおけるピーク波長域の半値全幅域に対応する波長範囲に属する。 As one embodiment of the present invention, the measurement wavelength belongs to a wavelength range corresponding to the full width at half maximum of the peak wavelength range in the absorbance spectrum of the color developing component.
　本発明の１つの実施形態として、前記測定波長は、可視領域に属する。 As one embodiment of the present invention, the measurement wavelength belongs to the visible region.
　本発明の１つの実施形態として、前記間隙に位置する前記混合物に照射される光で得られる吸光度スペクトルにおいて、前記第１波長は、前記水に固有の吸収帯域で水の吸光度がピーク値となる又は前記ピーク値の近傍となる波長であり、前記第２波長は、前記水に固有の吸収帯域の裾部近傍の波長である。 As one embodiment of the present invention, in the absorbance spectrum obtained by light irradiated on the mixture located in the gap, the first wavelength has a peak value of the absorbance of water in an absorption band unique to the water. Or it is a wavelength which becomes the vicinity of the said peak value, and a said 2nd wavelength is a wavelength of the bottom part of the absorption zone peculiar to the said water.
　本発明の第２の態様としての成分測定方法は、体液中の被測定成分と試薬との呈色反応により生じる発色成分を含む混合物の光学的特性に基づいて前記体液中の前記被測定成分を測定する成分測定方法であって、流路内で、前記流路を閉塞しないように対向する内壁との間に間隙を隔てた状態で配置された前記試薬と、前記間隙に供給された前記体液と、により生成された前記間隙に位置する前記混合物に対して、近赤外領域以上の長波長域で水に固有の吸収帯域に属する所定波長の測定光を照射して吸光度を測定するステップと、測定された吸光度の測定値に基づいて、前記被測定成分を導出するステップと、を含む。 The component measuring method according to the second aspect of the present invention is a method for measuring the component to be measured in the body fluid based on the optical characteristics of the mixture containing the color developing component produced by the color reaction between the component to be measured in the body fluid and the reagent. A component measurement method for measuring, wherein the reagent is arranged in a state where a gap is provided between the opposing inner walls so as not to block the flow path, and the body fluid supplied to the gap And irradiating the mixture located in the gap generated by irradiating measurement light having a predetermined wavelength belonging to an absorption band specific to water in a long wavelength region longer than the near infrared region, and measuring the absorbance; Deriving the component to be measured based on the measured absorbance value.
　本発明の第３の態様としての成分測定プログラムは、体液中の被測定成分と試薬との呈色反応により生じる発色成分を含む混合物の光学的特性に基づいて前記体液中の前記被測定成分を測定するための成分測定プログラムであって、流路内で、前記流路を閉塞しないように対向する内壁との間に間隙を隔てた状態で配置された前記試薬と、前記間隙に供給された前記体液と、により生成された前記間隙に位置する前記混合物に対して、近赤外領域以上の長波長域で水に固有の吸収帯域に属する所定波長の測定光を照射して吸光度を測定するステップと、測定された吸光度の測定値に基づいて、前記被測定成分を導出するステップと、を成分測定装置に実行させる。 The component measurement program according to the third aspect of the present invention is a program for measuring the component to be measured in the body fluid based on the optical characteristics of the mixture containing the color developing component produced by the color reaction between the component to be measured in the body fluid and the reagent. A component measurement program for measuring, wherein the reagent is disposed in a flow path with a gap between the opposing inner walls so as not to block the flow path, and supplied to the gap Absorbance is measured by irradiating the mixture located in the gap generated by the bodily fluid with measurement light having a predetermined wavelength belonging to an absorption band unique to water in a long wavelength region longer than the near infrared region. The component measuring device is caused to execute a step and a step of deriving the component to be measured based on the measured absorbance value.
　本開示によれば、測定空間の光路長のばらつきや変動による被測定成分の測定精度の低下を抑制可能な成分測定装置、成分測定方法及び成分測定プログラムを提供することができる。 According to the present disclosure, it is possible to provide a component measurement device, a component measurement method, and a component measurement program that can suppress a decrease in measurement accuracy of a component to be measured due to variations or fluctuations in the optical path length of the measurement space.
一実施形態としての成分測定装置に成分測定チップが装着された成分測定装置セットの上面図である。It is a top view of the component measuring device set by which the component measuring chip | tip was mounted | worn with the component measuring device as one Embodiment. 図１のI-I断面図のうち、成分測定チップが装着されている箇所近傍の拡大断面図である。It is an expanded sectional view of the vicinity of the location where the component measuring chip is mounted in the II sectional view of FIG. 図１に示す成分測定チップ単体の上面図である。FIG. 2 is a top view of a single component measurement chip shown in FIG. 1. 図３のII-II断面図である。It is II-II sectional drawing of FIG. 図３のIII-III断面図である。It is III-III sectional drawing of FIG. 図１に示す成分測定装置の電気ブロック図である。It is an electrical block diagram of the component measuring apparatus shown in FIG. 図６に示す演算部の機能ブロック図である。It is a functional block diagram of the calculating part shown in FIG. 血液検体と試薬とを呈色反応させることにより得られる混合物の吸光度スペクトルを示す図である。It is a figure which shows the light absorbency spectrum of the mixture obtained by color-reacting a blood sample and a reagent. ２種の血液検体それぞれの吸光度スペクトルを示す図である。It is a figure which shows the light absorbency spectrum of two types of blood specimens. 図３に示す成分測定チップのうち試薬を取り除いた状態の空チップの近赤外領域における吸光度スペクトルを示す図である。It is a figure which shows the light absorbency spectrum in the near-infrared area | region of the empty chip | tip of the state which removed the reagent among the component measurement chips | tips shown in FIG. 図３に示す成分測定チップの近赤外領域における吸光度スペクトルを示す図である。It is a figure which shows the light absorbency spectrum in the near infrared region of the component measurement chip | tip shown in FIG. 成分測定装置により実行される、一実施形態としての成分測定方法を示すフローチャートである。It is a flowchart which shows the component measuring method as one Embodiment performed by a component measuring apparatus. 測定時の間隙の高さによる、グルコース濃度の測定値への影響についての検証実験の実験結果を示す図である。It is a figure which shows the experimental result of the verification experiment about the influence on the measured value of the glucose concentration by the height of the gap | interval at the time of a measurement. 測定時の間隙の高さによる、グルコース濃度の測定値への影響についての検証実験の実験結果を示す図である。It is a figure which shows the experimental result of the verification experiment about the influence on the measured value of the glucose concentration by the height of the gap | interval at the time of a measurement. 測定時の間隙の高さによる、グルコース濃度の測定値への影響についての検証実験の実験結果を示す図である。It is a figure which shows the experimental result of the verification experiment about the influence on the measured value of the glucose concentration by the height of the gap | interval at the time of a measurement. 間隙の高さと、近赤外領域での水に固有の吸収帯域に属する光を間隙に位置する混合物に対して照射することにより得られる吸光度と、の間の相関関係を示すグラフである。It is a graph which shows the correlation between the height of a gap | interval, and the light absorbency obtained by irradiating the light which belongs to the absorption band intrinsic | native to the water in a near infrared region with respect to the mixture located in a gap | interval. 図１７（ａ）は、図１３に示す「補正なし」について、測定波長における吸光度のばらつき示すグラフであり、図１７（ｂ）は、図１３に示す「測定時補正あり」について、測定波長における吸光度のばらつき示すグラフである。FIG. 17A is a graph showing the variation in absorbance at the measurement wavelength for “no correction” shown in FIG. 13, and FIG. 17B is the graph for the measurement wavelength for “correction during measurement” shown in FIG. It is a graph which shows the dispersion | variation in a light absorbency.
　以下、成分測定装置、成分測定方法及び成分測定プログラムの実施形態について、図１～図１７を参照して説明する。各図において共通の部材には、同一の符号を付している。 Hereinafter, embodiments of a component measuring device, a component measuring method, and a component measuring program will be described with reference to FIGS. In each figure, the same code | symbol is attached | subjected to the common member.
　まず、成分測定装置の１つの実施形態について説明する。図１は、本実施形態における成分測定装置１に成分測定チップ２が装着された成分測定装置セット１００を示す上面図である。図２は、図１のI-I線に沿う断面のうち、成分測定チップ２が装着されている箇所近傍の拡大断面図である。 First, one embodiment of a component measuring device will be described. FIG. 1 is a top view showing a component measuring device set 100 in which the component measuring chip 2 is mounted on the component measuring device 1 in the present embodiment. FIG. 2 is an enlarged cross-sectional view of the vicinity of a portion where the component measurement chip 2 is mounted in the cross section taken along the line II of FIG.
　成分測定装置セット１００は、成分測定装置１と、成分測定チップ２と、を備えている。本実施形態の成分測定装置１は、血液中の被測定成分としての血漿成分中のグルコース、の濃度（ｍｇ／ｄＬ）を測定可能な血糖値測定装置である。また、本実施形態の成分測定チップ２は、成分測定装置１としての血糖値測定装置の先端部に装着可能な血糖値測定チップである。ここで言う「血液」とは、成分毎に分離されておらず、すべての成分を含む全血を意味する。 The component measuring device set 100 includes a component measuring device 1 and a component measuring chip 2. The component measuring apparatus 1 of this embodiment is a blood glucose level measuring apparatus capable of measuring the concentration (mg / dL) of glucose in a plasma component as a component to be measured in blood. In addition, the component measurement chip 2 of the present embodiment is a blood glucose measurement chip that can be attached to the tip of a blood glucose measurement device as the component measurement device 1. “Blood” as used herein means whole blood that is not separated for each component but includes all components.
　成分測定装置１は、例えば樹脂材料からなるハウジング１０と、このハウジング１０の上面に設けられたボタン群と、ハウジング１０の上面に設けられた液晶又はＬＥＤ（Ｌｉｇｈｔ　Ｅｍｉｔｔｉｎｇ　Ｄｉｏｄｅの略）等で構成される表示部１１と、成分測定装置１に装着された状態の成分測定チップ２を取り外す際に操作される取り外しレバー１２と、を備えている。本実施形態のボタン群は、電源ボタン１３と、操作ボタン１４とにより構成されている。 The component measuring apparatus 1 is composed of, for example, a housing 10 made of a resin material, a button group provided on the upper surface of the housing 10, a liquid crystal or LED (abbreviation of Light Emitting Diode) provided on the upper surface of the housing 10, and the like. And a removal lever 12 that is operated when removing the component measurement chip 2 attached to the component measurement device 1. The button group of this embodiment includes a power button 13 and an operation button 14.
　ハウジング１０は、上述したボタン群及び表示部１１が上面（図１参照）に設けられている、上面視の外形が略矩形の本体部１０ａと、本体部１０ａから外方に突設され、上面（図１参照）に取り外しレバー１２が設けられたチップ装着部１０ｂと、を備えている。図２に示すように、チップ装着部１０ｂの内部には、チップ装着部１０ｂの先端面に形成された先端開口を一端とするチップ装着空間Ｓが区画されている。成分測定装置１に対して成分測定チップ２を装着する際は、外方から先端開口を通じてチップ装着空間Ｓ内に成分測定チップ２を挿入する。成分測定チップ２が所定位置まで押し込まれると、成分測定装置１のチップ装着部１０ｂが成分測定チップ２を係止した状態となる。この係止した状態とすることにより、成分測定チップ２の成分測定装置１への装着が完了する。成分測定装置１による成分測定チップ２の係止は、例えば、チップ装着部１０ｂ内に成分測定チップ２の一部と係合可能な爪部を設ける等、各種構成により実現可能である。 The housing 10 is provided with the above-described button group and the display unit 11 on the upper surface (see FIG. 1). The main body 10a has a substantially rectangular outer shape when viewed from above, and protrudes outward from the main body 10a. (See FIG. 1) and a chip mounting portion 10b provided with a removal lever 12. As shown in FIG. 2, inside the chip mounting portion 10b, a chip mounting space S having a tip opening formed at the tip surface of the chip mounting portion 10b as one end is partitioned. When mounting the component measuring chip 2 on the component measuring apparatus 1, the component measuring chip 2 is inserted into the chip mounting space S from the outside through the tip opening. When the component measuring chip 2 is pushed to a predetermined position, the chip mounting portion 10b of the component measuring apparatus 1 is in a state where the component measuring chip 2 is locked. With this locked state, the mounting of the component measuring chip 2 to the component measuring apparatus 1 is completed. The locking of the component measuring chip 2 by the component measuring device 1 can be realized by various configurations, for example, by providing a claw portion that can be engaged with a part of the component measuring chip 2 in the chip mounting portion 10b.
　逆に、成分測定装置１に装着されている成分測定チップ２を成分測定装置１から取り外す際は、ハウジング１０の外部から上述した取り外しレバー１２を操作する。その操作により、成分測定装置１のチップ装着部１０ｂによる成分測定チップ２の係止状態が解除されると共に、ハウジング１０内のイジェクトピン２６（図２参照）が連動して移動し、成分測定チップ２を成分測定装置１から取り外すことができる。 Conversely, when the component measuring chip 2 mounted on the component measuring device 1 is detached from the component measuring device 1, the above-described removal lever 12 is operated from the outside of the housing 10. By this operation, the component measuring chip 2 is released from the locked state by the chip mounting portion 10b of the component measuring apparatus 1, and the eject pin 26 (see FIG. 2) in the housing 10 is moved in conjunction with the component measuring chip 1. 2 can be removed from the component measuring apparatus 1.
　本実施形態のハウジング１０は、上面視（図１参照）で略矩形の本体部１０ａと、本体部１０ａから外方に突設されているチップ装着部１０ｂと、を備える構成であるが、成分測定チップ２を装着可能なチップ装着部を備える構成であればよく、本実施形態のハウジング１０の形状に限られない。したがって、本実施形態のハウジング１０の形状の他に、例えば、ユーザにとって片手で把持し易くするための形状を種々採用することも可能である。 The housing 10 of the present embodiment is configured to include a substantially rectangular main body 10a in a top view (see FIG. 1) and a chip mounting portion 10b that protrudes outward from the main body 10a. The configuration is not limited to the shape of the housing 10 of the present embodiment as long as the configuration includes a chip mounting portion to which the measurement chip 2 can be mounted. Therefore, in addition to the shape of the housing 10 of the present embodiment, for example, various shapes that are easy for the user to hold with one hand can be adopted.
　表示部１１は、例えば、成分測定装置１により測定された被測定成分の情報を表示する。本実施形態では、成分測定装置１としての血糖値測定装置により測定されたグルコース濃度（ｍｇ／ｄＬ）を表示部１１に表示することができる。表示部１１には、被測定成分の情報のみならず、成分測定装置１の測定条件やユーザに所定の操作を指示する指示情報等、各種情報を表示できるようにしてもよい。ユーザは、表示部１１に表示された内容を確認しながら、ボタン群の電源ボタン１３や操作ボタン１４を操作することができる。 The display unit 11 displays, for example, information on the component to be measured measured by the component measuring device 1. In the present embodiment, the glucose concentration (mg / dL) measured by the blood sugar level measuring device as the component measuring device 1 can be displayed on the display unit 11. The display unit 11 may display not only information on the component to be measured but also various information such as measurement conditions of the component measuring apparatus 1 and instruction information for instructing a user to perform a predetermined operation. The user can operate the power button 13 and the operation button 14 of the button group while confirming the content displayed on the display unit 11.
　次に、成分測定チップ２単体について説明する。図３は、成分測定チップ２を示す上面図である。また、図４は、図３のII-II線に沿う断面図である。図５は、図３のIII-III線に沿う断面図である。図３～図５に示すように、成分測定チップ２は、内部に流路２３を区画している。また、成分測定チップ２の流路２３内には、この流路２３を閉塞しないように対向する内壁との間に間隙２８を隔てた状態で試薬としての発色試薬２２が配置されている。 Next, the component measuring chip 2 alone will be described. FIG. 3 is a top view showing the component measuring chip 2. 4 is a cross-sectional view taken along the line II-II in FIG. FIG. 5 is a sectional view taken along line III-III in FIG. As shown in FIGS. 3 to 5, the component measuring chip 2 defines a flow path 23 therein. Further, a coloring reagent 22 as a reagent is disposed in the flow channel 23 of the component measuring chip 2 with a gap 28 between the inner wall facing the flow channel 23 so as not to close the flow channel 23.
　より具体的に、本実施形態の成分測定チップ２は、略矩形板状の外形を有するベース部材２１と、このベース部材２１を覆うように対向して配置されたカバー部材２５と、ベース部材２１とカバー部材２５との間の距離を所定間隔に維持する２つのスペーサ部材２７と、を備えている。本実施形態の成分測定チップ２の流路２３は、ベース部材２１、カバー部材２５及び２つのスペーサ部材２７に囲まれることにより形成されている。また、本実施形態の試薬としての発色試薬２２は、流路２３を区画する内壁としてのベース部材２１の上面に塗布されることにより配置されている。この塗布された発色試薬２２と、流路２３を区画する内壁としてのカバー部材２５の下面と、の間に間隙２８が形成されている。 More specifically, the component measurement chip 2 of the present embodiment includes a base member 21 having a substantially rectangular plate-shaped outer shape, a cover member 25 disposed so as to cover the base member 21, and the base member 21. And two spacer members 27 for maintaining the distance between the cover member 25 and the cover member 25 at a predetermined interval. The flow path 23 of the component measurement chip 2 of this embodiment is formed by being surrounded by the base member 21, the cover member 25, and the two spacer members 27. Further, the coloring reagent 22 as the reagent of the present embodiment is arranged by being applied to the upper surface of the base member 21 as the inner wall that defines the flow path 23. A gap 28 is formed between the applied coloring reagent 22 and the lower surface of the cover member 25 as an inner wall that defines the flow path 23.
　流路２３は、成分測定チップ２の厚み方向と直交する方向に延在しており、成分測定チップ２の１つの側端から別の側端まで貫通している。流路２３の一端が形成されている成分測定チップ２の１つの側端は、外方から血液を流路２３内に供給可能な供給部２４を構成している。外方から供給部２４に供給された血液は、例えば毛細管現象によって流路２３に沿って移動し、流路２３の間隙２８まで到達し、発色試薬２２と接触する。血液と発色試薬２２とが接触すると、血液中の被測定成分としてのグルコースと発色試薬２２とが呈色反応を引き起こす。この呈色反応により発色成分が生成される。そのため、発色試薬２２が保持されている保持位置及び間隙２８の位置で、血液と、上述の呈色反応で生成された発色成分と、を含む混合物が生成される。 The flow path 23 extends in a direction orthogonal to the thickness direction of the component measurement chip 2 and penetrates from one side end of the component measurement chip 2 to another side end. One side end of the component measuring chip 2 on which one end of the flow path 23 is formed constitutes a supply unit 24 that can supply blood into the flow path 23 from the outside. The blood supplied to the supply unit 24 from the outside moves along the flow path 23 by, for example, capillary action, reaches the gap 28 of the flow path 23, and contacts the color reagent 22. When the blood and the coloring reagent 22 come into contact with each other, glucose as a component to be measured in the blood and the coloring reagent 22 cause a color reaction. A coloring component is generated by this color reaction. Therefore, a mixture containing blood and the coloring component generated by the above-described color reaction is generated at the holding position where the coloring reagent 22 is held and the position of the gap 28.
　本実施形態の流路２３は、ベース部材２１、カバー部材２５及び２つのスペーサ部材２７により区画されているが、流路を区画する部材数や流路の形状は、本実施形態の構成に限られない。例えば、厚み方向の一方側の面に溝が形成されたベース部材と、この溝が形成された一方側の面を覆うように取り付けられたカバー部材と、の２つの部材のみで流路を形成することも可能である。このように、成分測定チップの流路は、３つ以下の部材により区画される構成であってもよい。また、５つ以上の部材により区画される流路であってもよい。本実施形態の流路２３は、上面視（図３参照）や図５に示す断面視で直線状に延在しているが、例えば、上面視や図５と同様の断面視において、折れ曲がって延在していてもよく、一様に湾曲して延在していてもよい。 The flow path 23 of the present embodiment is partitioned by the base member 21, the cover member 25, and the two spacer members 27. However, the number of members that partition the flow path and the shape of the flow path are limited to the configuration of the present embodiment. I can't. For example, a flow path is formed by only two members: a base member in which a groove is formed on one surface in the thickness direction and a cover member attached so as to cover the one surface on which the groove is formed. It is also possible to do. As described above, the flow path of the component measurement chip may be configured to be partitioned by three or less members. Moreover, the flow path divided by five or more members may be sufficient. The flow path 23 of the present embodiment extends linearly in a top view (see FIG. 3) or a cross-sectional view shown in FIG. 5, but for example, is bent in a top view or a cross-sectional view similar to FIG. It may extend or may be curved and extended uniformly.
　ベース部材２１およびカバー部材２５の材質としては、光の透過のために透明な素材を用いることが好ましい。例えば、ポリエチレンテレフタレート（ＰＥＴ）、ポリメチルメタクリレート（ＰＭＭＡ）、ポリスチレン（ＰＳ）、環状ポリオレフィン（ＣＯＰ）や環状オレフィンコポリマー（ＣＯＣ）、ポリカーボネード（ＰＣ）等の透明な有機樹脂材料；ガラス、石英等の透明な無機材料；が挙げられる。 As the material of the base member 21 and the cover member 25, it is preferable to use a transparent material for light transmission. For example, transparent organic resin materials such as polyethylene terephthalate (PET), polymethyl methacrylate (PMMA), polystyrene (PS), cyclic polyolefin (COP), cyclic olefin copolymer (COC), and polycarbonate (PC); glass, quartz, etc. Transparent inorganic materials.
　また、スペーサ部材２７は、透明か不透明かを問わず、ベース部材２１およびカバー部材２５と同様の材料により形成することができる。例えば、ポリエチレンテレフタレート（ＰＥＴ）、ポリメチルメタクリレート（ＰＭＭＡ）、ポリスチレン（ＰＳ）、環状ポリオレフィン（ＣＯＰ）や環状オレフィンコポリマー（ＣＯＣ）、ポリカーボネード（ＰＣ）等の有機樹脂材料；ガラス、石英等の無機材料；が挙げられる。これらの材料から形成されたスペーサ部材２７は、接着剤を用いて、ベース部材２１及びカバー部材２５に接着されるが、このような構成に代えて、上述の材料から形成された基材を有する両面テープを用いてもよい。 The spacer member 27 can be formed of the same material as the base member 21 and the cover member 25 regardless of whether it is transparent or opaque. For example, organic resin materials such as polyethylene terephthalate (PET), polymethyl methacrylate (PMMA), polystyrene (PS), cyclic polyolefin (COP), cyclic olefin copolymer (COC), and polycarbonate (PC); inorganic materials such as glass and quartz ; The spacer member 27 formed from these materials is bonded to the base member 21 and the cover member 25 using an adhesive, but instead of such a configuration, the spacer member 27 includes a base material formed from the above-described materials. Double-sided tape may be used.
　試薬としての発色試薬２２は、血液中の被測定成分と反応して、被測定成分の血中濃度に応じた色に呈色する呈色反応を引き起こすものであり、本実施形態の発色試薬２２は、ベース部材２１上に塗布されている。本実施形態の発色試薬２２は、血液中の被測定成分としてのグルコースと反応する。本実施形態の発色試薬２２としては、例えば、（ｉ）グルコースオキシダーゼ（ＧＯＤ）と（ｉｉ）ペルオキシダーゼ（ＰＯＤ）と（ｉｉｉ）１－（４－スルホフェニル）－２，３－ジメチル－４－アミノ－５－ピラゾロンと（ｉｖ）Ｎ－エチル－Ｎ－（２－ヒドロキシ－３－スルホプロピル）－３，５－ジメチルアニリン，ナトリウム塩，１水和物（ＭＡＯＳ）との混合試薬、あるいはグルコースデヒドロゲナーゼ（ＧＤＨ）とテトラゾリウム塩及び電子メディエーターとの混合試薬などが挙げられる。さらに、リン酸緩衝液のような緩衝剤が含まれていてもよい。発色試薬２２の種類、成分については、これらに限定されない。 The coloring reagent 22 as a reagent reacts with the component to be measured in the blood to cause a color reaction that develops a color corresponding to the blood concentration of the component to be measured. The coloring reagent 22 of the present embodiment. Is applied on the base member 21. The coloring reagent 22 of this embodiment reacts with glucose as a component to be measured in blood. Examples of the coloring reagent 22 of the present embodiment include (i) glucose oxidase (GOD), (ii) peroxidase (POD), and (iii) 1- (4-sulfophenyl) -2,3-dimethyl-4-amino. -Mixed reagent of 5-pyrazolone and (iv) N-ethyl-N- (2-hydroxy-3-sulfopropyl) -3,5-dimethylaniline, sodium salt, monohydrate (MAOS), or glucose dehydrogenase Examples thereof include a mixed reagent of (GDH), a tetrazolium salt, and an electron mediator. Furthermore, a buffering agent such as a phosphate buffer may be included. The types and components of the coloring reagent 22 are not limited to these.
　但し、本実施形態の発色試薬２２としては、血液中のグルコースと発色試薬２２との呈色反応により生じる発色成分の吸光度スペクトルにおけるピーク波長が、血球中のヘモグロビンの光吸収特性に起因するピーク波長と異なるものを使用している。本実施形態の発色試薬２２は、血液中のグルコースと発色試薬２２との呈色反応により生じる発色成分の吸光度スペクトルが６５０ｎｍ付近にピーク波長を有するが、ピーク波長が６５０ｎｍ付近になるものに限られない。この詳細は後述する。 However, as the coloring reagent 22 of the present embodiment, the peak wavelength in the absorbance spectrum of the coloring component generated by the color reaction between glucose in the blood and the coloring reagent 22 is the peak wavelength resulting from the light absorption characteristics of hemoglobin in the blood cell. And use something different. The coloring reagent 22 of the present embodiment has a peak wavelength in the vicinity of 650 nm of the absorbance spectrum of the coloring component generated by the color reaction between glucose in the blood and the coloring reagent 22, but is limited to the peak wavelength in the vicinity of 650 nm. Absent. Details of this will be described later.
　図２に示すように、成分測定装置１により被測定成分を測定する際には、成分測定チップ２をチップ装着部１０ｂ内に装着する。そして、成分測定チップ２の一端に設けられている供給部２４に血液を供給すると、血液は、例えば毛細管現象により流路２３内を移動し、流路２３の間隙２８まで到達し、上述したように、発色試薬２２の保持位置及び間隙２８の位置で、血液と、血液と発色試薬２２との呈色反応で生じる発色成分と、を含む混合物が生成される。 As shown in FIG. 2, when the component to be measured is measured by the component measuring apparatus 1, the component measuring chip 2 is mounted in the chip mounting portion 10b. Then, when blood is supplied to the supply unit 24 provided at one end of the component measurement chip 2, the blood moves in the flow path 23 by, for example, a capillary phenomenon and reaches the gap 28 of the flow path 23, as described above. In addition, a mixture containing blood and a coloring component generated by the color reaction of the blood and the coloring reagent 22 is generated at the holding position of the coloring reagent 22 and the position of the gap 28.
　いわゆる比色式の成分測定装置１は、発色試薬２２の保持位置及び間隙２８の位置に生成される混合物に向かって光を照射し、その透過光量（又は反射光量）を検出し、血中濃度に応じた発色の強度に相関する検出信号を得る。そして、成分測定装置１は、予め作成された検量線を参照することにより、被測定成分を測定することができる。本実施形態の成分測定装置１は、血液中の血漿成分におけるグルコース濃度（ｍｇ／ｄＬ）を測定する。 The so-called colorimetric component measuring apparatus 1 irradiates light toward the mixture generated at the holding position of the coloring reagent 22 and the position of the gap 28, detects the amount of transmitted light (or the amount of reflected light), and the blood concentration. A detection signal that correlates with the intensity of color development according to. And the component measuring apparatus 1 can measure a to-be-measured component by referring the calibration curve created beforehand. The component measuring apparatus 1 of this embodiment measures the glucose concentration (mg / dL) in the plasma component in blood.
　図６は、図１及び図２に示す成分測定装置１の電気ブロック図である。図６には、説明の便宜上、成分測定装置１に装着された状態の成分測定チップ２の断面（図４と同じ断面）を併せて示している。また、図６では、成分測定チップ２の近傍を拡大したものを左上に別途示している。以下、成分測定装置１の更なる詳細について説明する。 FIG. 6 is an electrical block diagram of the component measuring apparatus 1 shown in FIGS. 1 and 2. For convenience of explanation, FIG. 6 also shows a cross section (the same cross section as FIG. 4) of the component measurement chip 2 mounted on the component measurement device 1. Moreover, in FIG. 6, what expanded the vicinity of the component measurement chip | tip 2 is shown separately on the upper left. Hereinafter, further details of the component measuring apparatus 1 will be described.
　図６に示すように、成分測定装置１は、上述したハウジング１０（図１参照）、表示部１１、取り外しレバー１２（図１参照）、電源ボタン１３及び操作ボタン１４の他に、演算部６０と、メモリ６２と、電源回路６３と、測定光学系６４と、を更に備えている。 As shown in FIG. 6, the component measuring apparatus 1 includes a calculation unit 60 in addition to the housing 10 (see FIG. 1), the display unit 11, the removal lever 12 (see FIG. 1), the power button 13 and the operation button 14 described above. And a memory 62, a power supply circuit 63, and a measurement optical system 64.
　演算部６０は、ＭＰＵ（Micro-Processing Unit）又はＣＰＵ（Central Processing Unit）で構成されており、メモリ６２等に格納されたプログラムを読み出し実行することで、各部の制御動作を実現可能である。メモリ６２は、揮発性又は不揮発性である非一過性の記憶媒体で構成され、ここで示す成分測定方法を実行するために必要な各種データ（成分測定プログラムを含む）を読出し又は書込み可能である。電源回路６３は、電源ボタン１３の操作に応じて、演算部６０を含む成分測定装置１内の各部に電力を供給し、又はその供給を停止する。 The calculation unit 60 is configured by an MPU (Micro-Processing Unit) or a CPU (Central Processing Unit), and can read out and execute a program stored in the memory 62 or the like, thereby realizing control operations of the respective units. The memory 62 is composed of a non-transitory storage medium that is volatile or nonvolatile, and can read or write various data (including a component measurement program) necessary for executing the component measurement method shown here. is there. The power supply circuit 63 supplies power to each unit in the component measuring apparatus 1 including the calculation unit 60 or stops supplying the power according to the operation of the power button 13.
　測定光学系６４は、血液と試薬としての発色試薬２２との呈色反応により生じる発色成分を含む混合物の光学的特性を取得可能な光学システムである。測定光学系６４は、具体的には、発光部６６と、発光制御回路７０と、受光部７２と、受光制御回路７４と、を備えている。 The measurement optical system 64 is an optical system capable of acquiring the optical characteristics of a mixture containing a color developing component generated by a color reaction between blood and the color developing reagent 22 as a reagent. Specifically, the measurement optical system 64 includes a light emitting unit 66, a light emission control circuit 70, a light receiving unit 72, and a light reception control circuit 74.
　本実施形態の発光部６６は５種類の光源６７ａ、６７ｂ、６７ｃ、６７ｄ及び６８を備えている。光源６７ａ～６７ｄ及び６８は、分光放射特性が異なる光（例えば、可視光と近赤外光）を放射することができる。以下、説明の便宜上、光源６７ａを「第１光源６７ａ」、光源６７ｂを「第２光源６７ｂ」、光源６７ｃを「第３光源６７ｃ」、光源６７ｄを「第４光源６７ｄ」、光源６８を「第５光源６８」と記載する。 The light emitting unit 66 of this embodiment includes five types of light sources 67a, 67b, 67c, 67d and 68. The light sources 67a to 67d and 68 can emit light having different spectral emission characteristics (for example, visible light and near infrared light). Hereinafter, for convenience of explanation, the light source 67a is “first light source 67a”, the light source 67b is “second light source 67b”, the light source 67c is “third light source 67c”, the light source 67d is “fourth light source 67d”, and the light source 68 is “ 5th light source 68 ".
　以下、第１光源６７ａから発光される光の波長を第１波長λ１とする。また、第２光源６７ｂから発光される光の波長を第２波長λ２とする。更に、第３光源６７ｃから発光される光の波長を第３波長λ３とする。また更に、第４光源６７ｄから発光される光の波長を第４波長λ４とする。第５光源６８から発光される光の波長を第５波長λ５とする。本実施形態では、第１波長λ１及び第２波長λ２が、近赤外領域に属し、第３波長λ３、第４波長λ４及び第５波長λ５が、可視領域に属する。第１波長λ１～第５波長λ５の具体的な値やその特性については後述する。 Hereinafter, the wavelength of light emitted from the first light source 67a is referred to as a first wavelength λ1. The wavelength of the light emitted from the second light source 67b is assumed to be the second wavelength λ2. Further, the wavelength of light emitted from the third light source 67c is set to a third wavelength λ3. Furthermore, the wavelength of light emitted from the fourth light source 67d is set to a fourth wavelength λ4. Let the wavelength of the light emitted from the fifth light source 68 be the fifth wavelength λ5. In the present embodiment, the first wavelength λ1 and the second wavelength λ2 belong to the near infrared region, and the third wavelength λ3, the fourth wavelength λ4, and the fifth wavelength λ5 belong to the visible region. Specific values and characteristics of the first wavelength λ1 to the fifth wavelength λ5 will be described later.
　本実施形態の第１光源６７ａ、第２光源６７ｂ、第３光源６７ｃ、第４光源６７ｄ及び第５光源６８としては、ＬＥＤ素子、有機ＥＬ（Ｅｌｅｃｔｒｏ－Ｌｕｍｉｎｅｓｃｅｎｃｅの略）素子、無機ＥＬ素子、ＬＤ（Ｌａｓｅｒ　Ｄｉｏｄｅの略）素子を含む種々の発光素子を適用することができる。近赤外領域の光を発光する光源としては、例えば、ＬＥＤ素子、白熱電球、ハロゲンランプなどを使用することができる。また、本実施形態では、第１波長λ１～第５波長λ５それぞれの波長の光を別々の光源により発光しているが、例えば、可視領域における複数の波長の光を発光可能な１つの光源を利用することも可能である。更に、図６では、模式的に、第１光源６７ａ、第２光源６７ｂ、第３光源６７ｃ、第４光源６７ｄ及び第５光源６８を一列に並べて描いているが、このような配置に限られない。 The first light source 67a, the second light source 67b, the third light source 67c, the fourth light source 67d, and the fifth light source 68 of the present embodiment include an LED element, an organic EL (abbreviation of Electro-Luminescence) element, an inorganic EL element, and an LD. (Abbreviation of Laser Diode) Various light-emitting elements including an element can be used. As a light source that emits light in the near infrared region, for example, an LED element, an incandescent lamp, a halogen lamp, or the like can be used. In the present embodiment, light of each wavelength of the first wavelength λ1 to the fifth wavelength λ5 is emitted by separate light sources. For example, one light source capable of emitting light of a plurality of wavelengths in the visible region is used. It can also be used. Further, in FIG. 6, the first light source 67a, the second light source 67b, the third light source 67c, the fourth light source 67d, and the fifth light source 68 are schematically shown in a line. However, the arrangement is limited to such an arrangement. Absent.
　図２、図６に示すように、本実施形態の受光部７２は、発光部６６と成分測定チップ２を挟んで対向して配置された１個の受光素子により構成されている。受光部７２は、発光部６６の第１光源６７ａ～第５光源６８から成分測定チップ２の発色試薬２２の保持位置及び間隙２８の位置の両方を透過するように照射され、成分測定チップ２を透過した透過光を受光する。受光部７２としては、ＰＤ（Ｐｈｏｔｏ　Ｄｉｏｄｅの略）素子、フォトコンダクタ（光導電体）、フォトトランジスタ（Ｐｈｏｔｏ　Ｔｒａｎｓｉｓｔｏｒの略）を含む種々の光電変換素子を適用することができる。 As shown in FIGS. 2 and 6, the light receiving unit 72 of the present embodiment is configured by a single light receiving element disposed so as to face the light emitting unit 66 with the component measurement chip 2 interposed therebetween. The light receiving unit 72 is irradiated from the first light source 67a to the fifth light source 68 of the light emitting unit 66 so as to pass through both the holding position of the coloring reagent 22 of the component measuring chip 2 and the position of the gap 28, and the component measuring chip 2 is irradiated. The transmitted transmitted light is received. As the light receiving unit 72, various photoelectric conversion elements including a PD (abbreviation of Photo Diode) element, a photoconductor (photoconductor), and a phototransistor (abbreviation of Photo Transistor) can be applied.
　発光制御回路７０は、第１光源６７ａ～第５光源６８それぞれに駆動電力信号を供給することで、第１光源６７ａ～第５光源６８を点灯させ、又は消灯させる。受光制御回路７４は、受光部７２から出力されたアナログ信号に対して、対数変換及びＡ／Ｄ変換を施すことでデジタル信号（以下、検出信号という）を取得する。 The light emission control circuit 70 turns on or turns off the first light source 67a to the fifth light source 68 by supplying driving power signals to the first light source 67a to the fifth light source 68, respectively. The light reception control circuit 74 obtains a digital signal (hereinafter referred to as a detection signal) by performing logarithmic conversion and A / D conversion on the analog signal output from the light receiving unit 72.
　図７は、図６に示す演算部６０の機能ブロック図である。演算部６０は、測定光学系６４による測定動作を指示する測定指示部７６、及び、各種データを用いて被測定成分の濃度を測定する濃度測定部７７の各機能を実現する。 FIG. 7 is a functional block diagram of the calculation unit 60 shown in FIG. The calculation unit 60 realizes the functions of a measurement instruction unit 76 that instructs a measurement operation by the measurement optical system 64 and a concentration measurement unit 77 that measures the concentration of the component to be measured using various data.
　濃度測定部７７は、吸光度取得部７８と、吸光度補正部８４と、を備えている。 The concentration measurement unit 77 includes an absorbance acquisition unit 78 and an absorbance correction unit 84.
　図７では、メモリ６２には、測定光学系６４により測定された第１波長λ１～第５波長λ５それぞれにおける吸光度の測定値データ８５と、この測定値データ８５又はこの測定値データ８５に基づいて算出される二次データと相関する一群の補正係数等を含む補正データ８６と、測定波長で実測された混合物の吸光度の測定値又はこの測定値を補正データ８６により補正して得られる補正測定値と各種物理量（例えば、グルコース濃度）との関係を示す検量線や、混合物中のヘモグロビンの吸光度とヘマトクリット値との関係を示す検量線などの、検量線データ９０と、が格納されている。「ヘマトクリット値」とは、血液中の血球成分の血液（全血）に対する容積比を百分率で示したものである。 In FIG. 7, the memory 62 stores the absorbance measurement value data 85 at each of the first wavelength λ1 to the fifth wavelength λ5 measured by the measurement optical system 64 and the measurement value data 85 or the measurement value data 85. Correction data 86 including a group of correction coefficients correlated with the calculated secondary data, and a measured value of the absorbance of the mixture actually measured at the measurement wavelength, or a corrected measured value obtained by correcting this measured value with the correction data 86 And calibration curve data 90 such as a calibration curve indicating the relationship between the amount of each physical quantity (for example, glucose concentration) and a calibration curve indicating the relationship between the absorbance of the hemoglobin in the mixture and the hematocrit value are stored. The “hematocrit value” is a percentage of the volume ratio of blood cell components in blood to blood (whole blood).
　以下、体液中の被測定成分としての血液中のグルコースと、発色試薬２２と、の呈色反応を、グルコースを含む血漿成分を血液から分離することなく、血液（全血）と発色試薬２２とにより実行し、この呈色反応により生じる発色成分を含む混合物の光学的特性に基づいて、血液中のグルコース濃度を測定する成分測定方法について説明する。 Hereinafter, the color reaction between glucose in blood as a component to be measured in the body fluid and the coloring reagent 22 is performed, and blood (whole blood) and the coloring reagent 22 are separated without separating the plasma component containing glucose from the blood. The component measurement method for measuring the glucose concentration in the blood based on the optical characteristics of the mixture that is executed by the above-described method and that includes the color-forming component generated by the color reaction will be described.
　まず、図８及び図９を参照しつつ、血液中の被測定成分を、血液（全血）を用いた吸光度測定に基づいて推定しようとする際の問題点について言及する。以降の実施例では、発色試薬２２としてグルコースデヒドロゲナーゼ（ＧＤＨ）とテトラゾリウム塩（ＷＳＴ－４）及び電子メディエーターとの混合試薬を用いた。 First, referring to FIG. 8 and FIG. 9, a problem when trying to estimate a component to be measured in blood based on absorbance measurement using blood (whole blood) will be mentioned. In the following examples, a mixed reagent of glucose dehydrogenase (GDH), tetrazolium salt (WST-4), and an electron mediator was used as the coloring reagent 22.
　図８は、ヘマトクリット値及びグルコース濃度が既知である血液検体を発色試薬２２と呈色反応させることにより得られる混合物の吸光度スペクトルを示している。ここで用いている血液検体は、ヘマトクリット値が４０％で、グルコース濃度が４００ｍｇ／ｄＬ（図８中では「Ｈｔ４０　ｂｇ４００」と表記）のものである。 FIG. 8 shows an absorbance spectrum of a mixture obtained by color reaction of a blood sample having a known hematocrit value and glucose concentration with the coloring reagent 22. The blood sample used here has a hematocrit value of 40% and a glucose concentration of 400 mg / dL (indicated as “Ht40 bg400” in FIG. 8).
　また、図９は、ヘマトクリット値及びグルコース濃度が既知である２種の血液検体それぞれの吸光度スペクトルを示している。この２種の血液検体を第１血液検体、第２血液検体とする。第１血液検体は、ヘマトクリット値が２０％で、グルコース濃度が４００ｍｇ／ｄＬ（図９中では「Ｈｔ２０　ｂｇ４００」と表記）のものである。第２血液検体は、ヘマトクリット値が４０％で、グルコース濃度が４００ｍｇ／ｄＬ（図９中では「Ｈｔ４０　ｂｇ４００」と表記）のものである。第２血液検体は、図８に示す血液検体と同じものである。実際は、図９に示す第１血液検体及び第２血液検体に加えて、ヘマトクリット値が２０％で、グルコース濃度が０ｍｇ／ｄＬの第３血液検体、ヘマトクリット値が２０％で、グルコース濃度が１００ｍｇ／ｄＬの第４血液検体、ヘマトクリット値が４０％で、グルコース濃度が０ｍｇ／ｄＬの第５血液検体、及び、ヘマトクリット値が４０％で、グルコース濃度が１００ｍｇ／ｄＬの第６血液検体についても、吸光度スペクトルを求めているが、ヘマトクリット値が等しい血液検体の吸光度スペクトルは略一致するため、図９ではヘマトクリット値が異なる２つの血液検体の一例として、第１血液検体（ヘマトクリット値が２０％）の吸光度スペクトル、及び第２血液検体（ヘマトクリット値が４０％）の吸光度スペクトルのみを示している。 FIG. 9 shows the absorbance spectra of each of the two blood samples whose hematocrit value and glucose concentration are known. These two types of blood samples are referred to as a first blood sample and a second blood sample. The first blood sample has a hematocrit value of 20% and a glucose concentration of 400 mg / dL (indicated as “Ht20 bg400” in FIG. 9). The second blood sample has a hematocrit value of 40% and a glucose concentration of 400 mg / dL (indicated as “Ht40 bg400” in FIG. 9). The second blood sample is the same as the blood sample shown in FIG. Actually, in addition to the first blood sample and the second blood sample shown in FIG. 9, a third blood sample having a hematocrit value of 20%, a glucose concentration of 0 mg / dL, a hematocrit value of 20%, and a glucose concentration of 100 mg / d Absorbance of the fourth blood sample of dL, the fifth blood sample having a hematocrit value of 40% and a glucose concentration of 0 mg / dL, and the sixth blood sample having a hematocrit value of 40% and a glucose concentration of 100 mg / dL Although the spectra are obtained, the absorbance spectra of blood samples having the same hematocrit value are approximately the same. In FIG. 9, as an example of two blood samples having different hematocrit values, the absorbance of the first blood sample (hematocrit value is 20%). Only the spectrum and the absorbance spectrum of the second blood sample (hematocrit value is 40%) are shown.
　一般的に、測定対象となる発色成分以外の成分が試料中に含まれるとき、光学的現象の発生によって発色成分の測定結果に影響を与えることがある。例えば、血液中の血球成分等による「光散乱」や、発色成分とは別の成分（具体的には、ヘモグロビン）による「光吸収」が発生することで、真の値よりも大きい吸光度が測定される傾向がある。 Generally, when a component other than the color developing component to be measured is included in the sample, the measurement result of the color developing component may be affected by the occurrence of an optical phenomenon. For example, “light scattering” due to blood cell components in the blood, and “light absorption” due to a component (specifically, hemoglobin) different from the color developing component occurs, thereby measuring an absorbance greater than the true value. Tend to be.
　具体的に、図９に示す２つの血液検体の吸光度スペクトルは、波長が長くなるにつれて吸光度が次第に小さくなるトレンド曲線を有し、且つ、５４０ｎｍ付近及び５７０ｎｍ付近を中心とする２つのピークを有する。この２つのピークは、主に、赤血球中のヘモグロビンの光吸収に起因する。また、図９に示す２つの血液検体の吸光度スペクトルでは、６００ｎｍ以上の波長域において、波長が長くなるにつれて、吸光度が略直線状になだらかに減少している。この略直線状の部分は、主に、血球成分等による光散乱に起因する。 Specifically, the absorbance spectra of the two blood samples shown in FIG. 9 have a trend curve in which the absorbance gradually decreases as the wavelength increases, and have two peaks centered around 540 nm and 570 nm. These two peaks are mainly due to the light absorption of hemoglobin in red blood cells. In the absorbance spectra of the two blood samples shown in FIG. 9, the absorbance gradually decreases in a substantially linear manner as the wavelength increases in the wavelength region of 600 nm or more. This substantially linear portion is mainly caused by light scattering by a blood cell component or the like.
　換言すれば、６００ｎｍ付近より長波長側の波長域における血液検体の吸光度は、血球成分等による光散乱の影響が支配的であり、６００ｎｍ付近より短波長側の波長域における血液検体の吸光度は、血球成分等による光散乱の影響よりも、ヘモグロビンによる光吸収の影響が大きい。 In other words, the absorbance of the blood sample in the wavelength region longer than 600 nm is predominantly affected by light scattering due to blood cell components and the like, and the absorbance of the blood sample in the wavelength region shorter than 600 nm is The effect of light absorption by hemoglobin is greater than the effect of light scattering by blood cell components and the like.
　一方、図８に示す混合物の吸光度スペクトルでは、図９に示す血液検体の吸光度スペクトルと同様、波長が長くなるにつれて吸光度が次第に小さくなるトレンド曲線を有しているが、図９に示す曲線と比較して、可視領域である６００ｎｍ～７００ｎｍ辺りにわたって吸光度が増加していることがわかる。この６００ｎｍ～７００ｎｍ辺りにわたって増加している吸光度は、主に、血液中のグルコースと発色試薬２２との呈色反応により生じた発色成分の吸光特性に起因する。 On the other hand, the absorbance spectrum of the mixture shown in FIG. 8 has a trend curve in which the absorbance gradually decreases as the wavelength increases, similar to the absorbance spectrum of the blood sample shown in FIG. Thus, it can be seen that the absorbance increases in the visible region around 600 nm to 700 nm. The absorbance increasing from about 600 nm to 700 nm is mainly due to the light absorption characteristics of the coloring component generated by the color reaction between glucose in the blood and the coloring reagent 22.
　このように、測定対象となる発色成分の他に、図９に示す吸光特性を有する血液を含む混合物を用いて、色素成分由来の発色成分の吸光度を正確に測定する場合には、所定の測定波長（例えば６５０ｎｍ）における吸光度の測定値から、血球成分等による光散乱やヘモグロビンによる光吸収などの影響（ノイズ）を除去する必要がある。 In this way, in addition to the color developing component to be measured, when using a mixture containing blood having light absorption characteristics shown in FIG. It is necessary to remove influences (noise) such as light scattering by blood cell components and light absorption by hemoglobin from the measurement value of absorbance at a wavelength (for example, 650 nm).
　より具体的には、測定対象となる発色成分の光吸収率が高い所定の測定波長（例えば６５０ｎｍ）における、血球成分等による光散乱やヘモグロビンによる光吸収などの影響（ノイズ）を推定し、同測定波長における吸光度の測定値を補正することが必要となる。 More specifically, the influence (noise) of light scattering by blood cell components and light absorption by hemoglobin at a predetermined measurement wavelength (for example, 650 nm) where the light absorption rate of the color developing component to be measured is high is estimated. It is necessary to correct the measured value of absorbance at the measurement wavelength.
　ここで、混合物が位置する間隙２８の高さｈは、流入する検体量を反映するものである。すなわち、検体に含まれる測定対象の量（濃度）を求めるためには、間隙２８の高さｈを成分測定チップの種類等に応じて定まる一定値（定数）として捉えた上で、混合物における発色成分の吸光度を導出する必要がある。しかしながら、既存の成分測定装置は、間隙２８の高さｈの変動を考慮していない。さらに、間隙２８の高さｈは、例えば、自然環境下における発色試薬２２の水分吸収の有無や、呈色反応による発色試薬２２の膨潤又は溶解の影響や、成分測定チップの製造上の寸法公差などにより、変動する。間隙２８の高さｈが変動すると、間隙２８に位置する血液の量も変動する。そのため、間隙２８の高さｈの変動を考慮しない場合には、例えば、血液中のグルコース濃度の測定など、血液中の被測定成分の測定において測定精度が低下し、正確な血液中のグルコース濃度を測定することができない。 Here, the height h of the gap 28 where the mixture is located reflects the amount of sample flowing in. That is, in order to obtain the amount (concentration) of the measurement target contained in the specimen, the height h of the gap 28 is regarded as a constant value (constant) determined according to the type of the component measurement chip and the color development in the mixture. It is necessary to derive the absorbance of the component. However, the existing component measuring device does not take into account the fluctuation of the height h of the gap 28. Further, the height h of the gap 28 is, for example, the presence or absence of moisture absorption of the coloring reagent 22 in the natural environment, the influence of swelling or dissolution of the coloring reagent 22 due to the color reaction, and the dimensional tolerance in manufacturing the component measuring chip. It fluctuates by such as. When the height h of the gap 28 varies, the amount of blood located in the gap 28 also varies. Therefore, when the fluctuation of the height h of the gap 28 is not taken into account, for example, the measurement accuracy is lowered in measurement of the measured component in blood such as measurement of the glucose concentration in blood, and the accurate glucose concentration in blood Can not be measured.
　図１０は、流路２３の高さＨ（図５参照）の相違に基づく水の吸光度の相違を示すグラフである。具体的に、図１０では、図３～図５に示す成分測定チップ２のうち発色試薬２２を取り除いた状態の空チップの近赤外領域における吸光度スペクトルを示している。より具体的に、図１０では、流路２３の高さＨが３０μｍであって、流路２３内に水がない状態の第１空チップでの吸光度スペクトル（図１０では「３０μｍ　ｎｏ ｗａｔｅｒ」と表記）と、流路２３の高さＨが５０μｍであって、流路２３内に水がない状態の第２空チップでの吸光度スペクトル（図１０では「５０μｍ　ｎｏ ｗａｔｅｒ」と表記）と、流路２３の高さＨが６０μｍであって、流路２３内に水がない状態の第３空チップでの吸光度スペクトル（図１０では「６０μｍ　ｎｏ ｗａｔｅｒ」と表記）と、流路２３の高さＨが３０μｍであって、流路２３内が水で満たされた状態の第４空チップでの吸光度スペクトル（図１０では「３０μｍ　ｗａｔｅｒ」と表記）と、流路２３の高さＨが５０μｍであって、流路２３内が水で満たされた状態の第５空チップでの吸光度スペクトル（図１０では「５０μｍ　ｗａｔｅｒ」と表記）と、流路２３の高さＨが６０μｍであって、流路２３内が水で満たされた状態の第６空チップでの吸光度スペクトル（図１０では「６０μｍ　ｗａｔｅｒ」と表記）と、示している。流路２３の幅Ｗ（図３参照）は第１空チップ～第６空チップで同じである。また、図１０に示す吸光度スペクトルは、流路２３の延在方向における一部の測定空間において、流路２３の高さ方向（空チップの厚み方向と同じ方向）において流路２３を貫通するように照射した光による吸光度を示している。 FIG. 10 is a graph showing the difference in water absorbance based on the difference in the height H (see FIG. 5) of the flow path 23. Specifically, FIG. 10 shows the absorbance spectrum in the near-infrared region of the empty chip in the state where the coloring reagent 22 is removed from the component measurement chip 2 shown in FIGS. More specifically, in FIG. 10, the absorbance spectrum of the first empty chip in which the height H of the flow path 23 is 30 μm and there is no water in the flow path 23 (in FIG. 10, “30 μm noｍwater” Notation), the absorbance spectrum of the second empty chip in which the height H of the flow path 23 is 50 μm and there is no water in the flow path 23 (indicated as “50 μm no water” in FIG. 10), Absorbance spectrum (expressed as “60 μm no water” in FIG. 10) at the third empty chip in which the height H of the channel 23 is 60 μm and there is no water in the channel 23, and the height of the channel 23 Absorbance spectrum (indicated as “30 μm water” in FIG. 10) in the fourth empty chip in which H is 30 μm and the flow path 23 is filled with water, and the height H of the flow path 23 is 50 μm. And the flow path 23 is filled with water. The absorbance spectrum (shown as “50 μm water” in FIG. 10) of the fifth empty chip in a state where it is in a state where the height H of the flow path 23 is 60 μm and the flow path 23 is filled with water. The absorbance spectrum of the sixth empty chip (shown as “60 μm water” in FIG. 10) is shown. The width W of the flow path 23 (see FIG. 3) is the same for the first to sixth empty chips. Further, the absorbance spectrum shown in FIG. 10 penetrates the flow path 23 in the height direction of the flow path 23 (the same direction as the thickness direction of the empty chip) in a part of the measurement space in the extending direction of the flow path 23. The light absorbency by the light irradiated to is shown.
　図１０に示すように、流路２３内に水がない状態の第１空チップ～第３空チップの吸光度スペクトルは、流路２３の高さＨにかかわらず、同様の形状を有している。また、第１空チップ～第３空チップの吸光度スペクトルはいずれも、水に固有の吸収帯域の１つである１８２０ｎｍ～２０００ｎｍにおいて吸光度のピーク値を有していない。「水に固有の吸収帯域」とは、吸光度スペクトルにおいて、水の吸光度が特異なピークとして現れるピーク波長域を意味しており、例えば、近赤外領域（８００ｎｍ～２５００ｎｍ）における１８２０ｎｍ～２０００ｎｍの波長域や、近赤外領域における１３００ｎｍ～１６５０ｎｍの波長域、などが挙げられる。 As shown in FIG. 10, the absorbance spectra of the first empty chip to the third empty chip in a state where there is no water in the flow path 23 have the same shape regardless of the height H of the flow path 23. . Further, none of the absorbance spectra of the first empty chip to the third empty chip has an absorbance peak value at 1820 nm to 2000 nm, which is one of the absorption bands unique to water. “Water-specific absorption band” means a peak wavelength region where the absorbance of water appears as a unique peak in the absorbance spectrum, for example, a wavelength of 1820 nm to 2000 nm in the near infrared region (800 nm to 2500 nm). And a wavelength range of 1300 nm to 1650 nm in the near infrared region.
　一方で、流路２３内が水で満たされている状態の第４空チップ～第６空チップの吸光度スペクトルは、全体としては同様のトレンドを示しているが、いずれも水に固有の吸収帯域である１８２０ｎｍ～２０００ｎｍにおいて吸光度のピーク値を有している。そして、流路２３内が水で満たされている状態の第４空チップ～第６空チップは、流路２３の高さＨに応じて水の吸光度のピーク値が異なる吸光度スペクトルとなる。具体的に、第４空チップ～第６空チップを比較すると、流路２３の高さＨが高くなるほど、水の吸光度のピーク値が高くなることがわかる。 On the other hand, the absorbance spectrum of the fourth empty chip to the sixth empty chip in the state where the flow path 23 is filled with water shows a similar trend as a whole, but both have absorption bands specific to water. It has a peak value of absorbance at 1820 nm to 2000 nm. Then, the fourth empty chip to the sixth empty chip in a state where the flow path 23 is filled with water have absorbance spectra with different water absorbance peak values depending on the height H of the flow path 23. Specifically, comparing the fourth empty chip to the sixth empty chip, it can be seen that the peak value of the absorbance of water increases as the height H of the flow path 23 increases.
　このように、流路２３中の測定空間の光路長が異なると、光路長を満たす水分量も異なるため、水に固有の吸収帯域での水の吸光度についても、水分量に応じて異なる値を示すことがわかる。 Thus, when the optical path length of the measurement space in the flow path 23 is different, the amount of water that satisfies the optical path length is also different. Therefore, the absorbance of water in the absorption band unique to water also varies depending on the amount of water. You can see that
　図１１は、発色試薬２２を有する成分測定チップ２の近赤外領域における吸光度スペクトルを示す図である。具体的に、図１１には、検体としてグルコースが含まれていない水を使用した場合の間隙２８の位置での吸光度スペクトル（図１１では「ｂｇ０」と表記）と、検体としてグルコース濃度が１００ｍｇ／ｄＬのグルコース水を使用した場合の間隙２８の位置での吸光度スペクトル（図１１では「ｂｇ１００」と表記）と、検体としてグルコース濃度が４００ｍｇ／ｄＬのグルコース水を使用した場合の間隙２８の位置での吸光度スペクトル（図１１では「ｂｇ４００」と表記）と、流路２３内に検体を入れない状態（間隙２８は空隙の状態）での、成分測定チップ２における発色試薬２２の吸光度スペクトル（図１１では「ｉｎｉ」と表記）と、の４つの吸光度スペクトルを示している。 FIG. 11 is a diagram showing an absorbance spectrum in the near-infrared region of the component measuring chip 2 having the coloring reagent 22. Specifically, FIG. 11 shows an absorbance spectrum (indicated as “bg0” in FIG. 11) at the position of the gap 28 when water containing no glucose is used as a sample, and a glucose concentration of 100 mg / kg as a sample. The absorbance spectrum at the position of the gap 28 when dL glucose water is used (indicated as “bg100” in FIG. 11), and the position of the gap 28 when glucose water having a glucose concentration of 400 mg / dL is used as the specimen. 11 (indicated as “bg400” in FIG. 11), and the absorbance spectrum of the coloring reagent 22 in the component measurement chip 2 (FIG. 11) in a state where the sample is not put in the flow path 23 (the gap 28 is a void). In FIG. 4, four absorbance spectra are shown.
　図１１に、高さＨ＝５０μｍのチップを用い、検体として水及びグルコース水を使用している３つの吸光度スペクトルを示した。図１１に示すように、検体として水及びグルコース水を使用している３つの吸光度スペクトルは、略一致している。そして、これら３つの吸光度スペクトルはいずれも、水に固有の吸収帯域である１８２０ｎｍ～２０００ｎｍの波長域において同程度の吸光度のピークを有している。すなわち、水に固有の吸収帯域でのピーク値（水に固有の１つの吸収帯域での極大吸光度）は、グルコースの有無や、グルコースの濃度の相違にかかわらないことがわかる。また、図１１に示すように、検体を入れない発色試薬２２の吸光度スペクトルは、上述した３つの吸光度スペクトルとは一致していない。但し、検体を入れない状態での発色試薬２２の吸光度スペクトルであっても、水に固有の吸収帯域において小さいピークを有することがわかる。これは、発色試薬２２自体に多少の水分が含まれているためである。 FIG. 11 shows three absorbance spectra using a chip having a height of H = 50 μm and using water and glucose water as specimens. As shown in FIG. 11, the three absorbance spectra using water and glucose water as specimens are substantially coincident. These three absorbance spectra all have similar absorbance peaks in the wavelength range of 1820 nm to 2000 nm, which is an absorption band unique to water. That is, it can be seen that the peak value in the absorption band specific to water (the maximum absorbance in one absorption band specific to water) does not depend on the presence or absence of glucose or the difference in glucose concentration. Further, as shown in FIG. 11, the absorbance spectrum of the coloring reagent 22 without the sample does not match the above-described three absorbance spectra. However, it can be seen that even the absorbance spectrum of the chromogenic reagent 22 in a state where no sample is put has a small peak in the absorption band specific to water. This is because the coloring reagent 22 itself contains some moisture.
　図１０及び図１１より、間隙２８に位置する混合物に対して水に固有の吸収帯域に属する波長の光を照射すれば、混合物に含まれる被測定成分の量によらず、混合物に含まれる水分量に応じて、異なる吸光度を測定することができることがわかる。 10 and 11, when the mixture located in the gap 28 is irradiated with light having a wavelength belonging to the absorption band specific to water, the moisture contained in the mixture regardless of the amount of the component to be measured contained in the mixture. It can be seen that different absorbances can be measured depending on the amount.
　但し、１つ１つの成分測定チップ２の間隙２８の高さｈを、例えば膜厚計等により実測し、その測定値に応じた補正値を個別の成分測定装置１に校正情報として取り込ませることは、患者や医療従事者などの使用者に多大な手間をかけることや、成分測定値の大型化につながり、使用者の利便性を損なう。また、成分測定チップ２の間隙２８の高さｈの許容される寸法公差を、測定空間の光路長について補正不要なほど極めて小さくすることも、製造上容易なことではない。更に、検体としての体液が試薬に接触し、間隙２８に混合物が生成されている状態での測定空間の光路長としての間隙２８の高さｈを反映していない。 However, the height h of the gap 28 of each component measuring chip 2 is actually measured by a film thickness meter, for example, and a correction value corresponding to the measured value is taken into the individual component measuring apparatus 1 as calibration information. Takes a lot of time and effort to users such as patients and medical workers, and leads to an increase in component measurement values, thereby impairing user convenience. In addition, it is not easy in manufacturing to make the allowable dimensional tolerance of the height h of the gap 28 of the component measuring chip 2 so small that it is unnecessary to correct the optical path length of the measurement space. Furthermore, the height h of the gap 28 as the optical path length of the measurement space in a state where the body fluid as the specimen is in contact with the reagent and the mixture is generated in the gap 28 is not reflected.
　そこで、成分測定装置１では、上述した特性を利用して、混合物における発色成分の吸光度を測定する際（以下、単に「測定時」と記載する。）の、測定空間の光路長としての間隙２８の高さｈを推定する。具体的には、血液の血漿中には水分が含まれるため、水に固有の吸収帯域に属する光を間隙２８に位置する混合物に照射すれば、測定時において間隙２８に位置する混合物に含まれる水分量に応じた、換言すれば、測定時において間隙２８に位置する血液量に応じた、水の吸光度の測定値を取得することができる。そのため、例えば水の吸光度と、間隙２８の高さｈと、の相関を示す検量線を使用すれば、測定時の測定空間の光路長としての測定時の間隙２８の高さｈを推定することが可能となる。成分測定装置１では、測定時の間隙２８の高さｈを推定し、この推定に基づいて、体液中の被測定成分の測定値を補正する。これにより被測定成分の測定精度を向上させることができる。 Therefore, in the component measuring apparatus 1, the gap 28 as the optical path length of the measurement space when measuring the absorbance of the color developing component in the mixture (hereinafter simply referred to as “during measurement”) using the above-described characteristics. The height h is estimated. Specifically, since the blood plasma contains moisture, if the mixture located in the gap 28 is irradiated with light belonging to an absorption band unique to water, it is contained in the mixture located in the gap 28 at the time of measurement. It is possible to obtain a measured value of water absorbance according to the amount of water, in other words, according to the amount of blood located in the gap 28 at the time of measurement. Therefore, for example, if a calibration curve showing a correlation between the absorbance of water and the height h of the gap 28 is used, the height h of the gap 28 at the time of measurement as the optical path length of the measurement space at the time of measurement is estimated. Is possible. The component measuring apparatus 1 estimates the height h of the gap 28 at the time of measurement, and corrects the measured value of the measured component in the body fluid based on this estimation. Thereby, the measurement accuracy of the component to be measured can be improved.
　以下、成分測定装置１により実行される、一実施形態としての成分測定方法について詳細に説明する。 Hereinafter, the component measurement method as one embodiment executed by the component measurement apparatus 1 will be described in detail.
　成分測定装置１は、体液中の被測定成分と試薬との呈色反応により生じる発色成分を含む混合物の光学的特性に基づいて、体液中の被測定成分を測定可能である。具体的に、本実施形態では、体液中の被測定成分としての血液中のグルコースと、試薬としての発色試薬２２と、により生じる発色成分を含む混合物の光学的特性を利用し、血液中の血漿成分に含まれるグルコースの濃度を測定する。 The component measuring apparatus 1 can measure the component to be measured in the body fluid based on the optical characteristics of the mixture containing the color developing component generated by the color reaction between the component to be measured and the reagent in the body fluid. Specifically, in the present embodiment, plasma in blood is utilized by utilizing the optical characteristics of a mixture containing a color developing component produced by glucose in blood as a component to be measured in body fluid and color developing reagent 22 as a reagent. The concentration of glucose contained in the component is measured.
　図１２は、成分測定装置１により実行される成分測定方法を示すフローチャートである。図１２に示すように、成分測定装置１により実行される成分測定方法は、流路２３（図５等参照）内で、流路２３を閉塞しないように内壁との間に間隙２８（図５等参照）を隔てた状態で配置された発色試薬２２と、間隙２８に供給された体液としての血液と、により生成された間隙２８に位置する混合物に対して、近赤外領域以上の長波長域で水に固有の吸収帯域に属する第１波長λ１の第１測定光を照射して吸光度を測定するステップＳ１と、ステップＳ１で測定された吸光度の測定値に基づいて、被測定成分の導出として、血液中のグルコース濃度を導出するステップＳ２と、を含む。 FIG. 12 is a flowchart showing a component measurement method executed by the component measurement apparatus 1. As shown in FIG. 12, the component measuring method executed by the component measuring apparatus 1 is such that a gap 28 (FIG. 5) is provided between the inner wall and the channel 23 so as not to close the channel 23 (see FIG. 5 etc.). Etc.) and a mixture of the coloring reagent 22 arranged in a state of being separated from each other and blood as a body fluid supplied to the gap 28, and a long wavelength longer than the near infrared region. Irradiating the first measurement light of the first wavelength λ1 belonging to the absorption band specific to water in the region to measure the absorbance, and deriving the component to be measured based on the measured value of the absorbance measured in step S1 Step S2 for deriving the glucose concentration in the blood.
　ステップＳ１では、成分測定装置１が、成分測定装置１に装着された成分測定チップ２における測定時の測定空間の光路長としての測定時の間隙２８の高さｈを推定する。具体的に、成分測定装置１は、間隙２８に位置する混合物に対して、近赤外領域以上の長波長域であり水に固有の吸収帯域に属する所定波長の測定光を照射し、この測定光による吸光度の測定値を取得する。 In step S1, the component measuring apparatus 1 estimates the height h of the gap 28 at the time of measurement as the optical path length of the measurement space at the time of measurement in the component measuring chip 2 attached to the component measuring apparatus 1. Specifically, the component measuring apparatus 1 irradiates the mixture located in the gap 28 with measuring light having a predetermined wavelength belonging to an absorption band that is longer than the near infrared region and unique to water. Obtain a measurement of absorbance by light.
　本実施形態の成分測定装置１では、第１波長λ１の第１測定光が、演算部６０の指示により発光制御回路７０を介して、第１光源６７ａから発光される。第１波長λ１は、近赤外領域で、かつ、水に固有の吸収帯域に属する所定波長であり、本実施形態では、水に固有の吸収帯域で水の吸光度がピーク値となる波長としている。具体的に、本実施形態では、水に固有の吸収帯域として、水の吸光度のピークが顕著に現れる１８２０ｎｍ～２０００ｎｍを利用している。そして、この吸収帯域で水の吸光度がピーク値となる波長は、１９４０ｎｍである。 In the component measurement apparatus 1 of the present embodiment, the first measurement light having the first wavelength λ1 is emitted from the first light source 67a via the light emission control circuit 70 according to an instruction from the calculation unit 60. The first wavelength λ1 is a predetermined wavelength belonging to an absorption band specific to water in the near infrared region, and in this embodiment, the wavelength at which the absorbance of water reaches a peak value in the absorption band specific to water. . Specifically, in the present embodiment, 1820 nm to 2000 nm at which the water absorbance peak appears noticeably is used as the absorption band unique to water. The wavelength at which the water absorbance reaches a peak value in this absorption band is 1940 nm.
　図２、図６に示すように、第１波長λ１の第１測定光は、成分測定チップ２の間隙２８の位置で、成分測定チップ２の厚み方向に、成分測定チップ２を透過する。そして、成分測定チップ２を透過した透過光は、受光部７２により受光される。これにより、間隙２８に位置する混合物の、水に固有の吸収帯域に属する第１波長λ１での吸光度を測定することができる。以下、説明の便宜上、ここで測定される吸光度の測定値を「第１測定値」と記載する。 2 and 6, the first measurement light having the first wavelength λ1 passes through the component measurement chip 2 in the thickness direction of the component measurement chip 2 at the position of the gap 28 of the component measurement chip 2. The transmitted light that has passed through the component measuring chip 2 is received by the light receiving unit 72. As a result, the absorbance of the mixture located in the gap 28 at the first wavelength λ1 belonging to the absorption band specific to water can be measured. Hereinafter, for convenience of explanation, the measured value of the absorbance measured here is referred to as “first measured value”.
　例えば、水の吸光度と間隙２８の高さｈとの相関を示す検量線を利用することにより、第１測定値から、測定時の測定空間の光路長としての測定時の間隙２８の高さｈを推定することができる。そして、後述するステップＳ２では、第１測定値に基づいて、血液中のグルコース濃度を導出する。 For example, by using a calibration curve indicating the correlation between the absorbance of water and the height h of the gap 28, the height h of the gap 28 at the time of measurement as the optical path length of the measurement space at the time of measurement from the first measurement value. Can be estimated. And in step S2 mentioned later, glucose concentration in blood is derived based on the 1st measured value.
　ここで、本実施形態では、測定時の間隙２８の高さｈの推定精度をより高めるために、間隙２８の位置で混合物に対して、近赤外領域以上の長波長域に属し、かつ、水に固有の吸収帯域又は水に固有の吸収帯域の近傍の第２波長λ２の第２測定光を照射することにより、第１測定値よりも小さい吸光度である第２測定値を取得する。そして、ステップＳ２では、第１測定値と第２測定値との差分に基づいて、グルコース濃度を導出する。図１２では、上述の第２測定値を取得する工程を、ステップＳ１－２として示している。 Here, in the present embodiment, in order to further increase the estimation accuracy of the height h of the gap 28 at the time of measurement, the mixture at the position of the gap 28 belongs to a long wavelength region that is greater than or equal to the near infrared region, and By irradiating the second measurement light having the second wavelength λ2 in the vicinity of the absorption band specific to water or the absorption band specific to water, a second measurement value having an absorbance smaller than the first measurement value is acquired. In step S2, the glucose concentration is derived based on the difference between the first measurement value and the second measurement value. In FIG. 12, the step of obtaining the above-described second measurement value is shown as step S1-2.
　このような差分値を利用すれば、例えば血球散乱等による影響など、水以外の成分による吸光度への影響を除去することができるので、測定時の測定空間の光路長としての測定時の間隙２８の高さｈをより精度よく推定することが可能となる。 By using such a difference value, for example, the influence on the absorbance due to components other than water, such as the influence of blood cell scattering, can be removed, so the gap 28 at the time of measurement as the optical path length of the measurement space at the time of measurement. The height h can be estimated with higher accuracy.
　更に、本実施形態では、間隙２８に位置する混合物に照射される光で得られる吸光度スペクトルにおいて、第１波長λ１は、水に固有の吸収帯域で水の吸光度がピーク値となる又はピーク値の近傍となる波長とし、第２波長λ２は、水に固有の吸収帯域の裾部近傍の波長としている。このようにすれば、水以外の成分による吸光度への影響を除去しつつ、水分量に応じた吸光度の相違をより明確に識別することができるようになる。本実施形態では、第１波長λ１を１９４０ｎｍとし、第２波長λ２を水に固有の吸収帯域の裾部に相当する１８２０ｎｍとしている。第２波長λ２としては、水に固有の吸収帯域の裾部近傍であってもよいため、例えば、１７６０ｎｍなどを利用してもよい。 Furthermore, in the present embodiment, in the absorbance spectrum obtained by the light irradiated to the mixture located in the gap 28, the first wavelength λ1 has a peak value of the absorbance of water in an absorption band unique to water. The second wavelength λ2 is a wavelength in the vicinity of the bottom of the absorption band specific to water. In this way, it is possible to more clearly identify the difference in absorbance according to the amount of water while removing the influence on the absorbance due to components other than water. In the present embodiment, the first wavelength λ1 is set to 1940 nm, and the second wavelength λ2 is set to 1820 nm corresponding to the bottom of the absorption band specific to water. The second wavelength λ2 may be in the vicinity of the bottom of the absorption band specific to water, and for example, 1760 nm may be used.
　また更に、本実施形態では、測定時の測定空間の光路長としての測定時の間隙２８の高さｈの推定精度をより一層高めるために、体液としての血液と接触する前の発色試薬２２に照射される第１波長λ１の第３測定光により測定された吸光度である第３測定値と、血液と接触する前の発色試薬２２に照射される第２波長λ２の第４測定光により測定された吸光度である第４測定値と、を取得する。そして、ステップＳ２では、第１測定値と第２測定値との差分と、第３測定値と第４測定値との差分と、の間の更なる差分である補正差分値に基づいて、グルコース濃度を導出する。図１２では、上述の第３測定値及び第４測定値を取得する工程を、ステップＳ１－０として示している。 Furthermore, in this embodiment, in order to further increase the estimation accuracy of the height h of the gap 28 at the time of measurement as the optical path length of the measurement space at the time of measurement, the coloring reagent 22 before contact with blood as body fluid is added. Measured by the third measurement value, which is the absorbance measured by the third measurement light of the first wavelength λ1 to be irradiated, and the fourth measurement light of the second wavelength λ2, which is irradiated to the coloring reagent 22 before coming into contact with blood. And a fourth measured value that is the absorbance. In step S2, glucose is calculated based on a corrected difference value that is a further difference between the difference between the first measurement value and the second measurement value and the difference between the third measurement value and the fourth measurement value. Deriving the concentration. In FIG. 12, the step of acquiring the third measurement value and the fourth measurement value described above is shown as step S1-0.
　このようにすれば、試薬自体に含まれていた水分による吸光度への影響を除去することができ、測定時の測定空間の光路長としての測定時の間隙２８の高さｈの推定精度をより一層高めることが可能となる。 In this way, the influence of the moisture contained in the reagent itself on the absorbance can be removed, and the estimation accuracy of the height h of the gap 28 at the time of measurement as the optical path length of the measurement space at the time of measurement can be further increased. This can be further enhanced.
　成分測定装置１の吸光度取得部７８は、上述した第１波長λ１及び第２波長λ２それぞれでの測定値を取得する。具体的には、発光部６６の第１光源６７ａ及び第２光源６７ｂから第１波長λ１及び第２波長λ２の照射光が混合物に対してそれぞれ照射される。そして、受光部７２は、それぞれの照射光のうち成分測定チップ２を透過する透過光を受光する。そして、演算部６０は、照射光と透過光との関係から算出される各波長における吸光度の測定値を、測定値データ８５としてメモリ６２に格納させる。また、成分測定装置１の吸光度取得部７８は、メモリ６２から測定値データ８５を取得することができる。吸光度取得部７８が上述の測定値を取得する手段は、上述した手段に限られず、各種公知の手段により取得することが可能である。 The absorbance acquisition unit 78 of the component measuring apparatus 1 acquires the measurement values at the first wavelength λ1 and the second wavelength λ2 described above. Specifically, the first light source 67a and the second light source 67b of the light emitting unit 66 are irradiated with irradiation light of the first wavelength λ1 and the second wavelength λ2, respectively. And the light-receiving part 72 receives the transmitted light which permeate | transmits the component measurement chip | tip 2 among each irradiation light. Then, the calculation unit 60 stores the measurement value of the absorbance at each wavelength calculated from the relationship between the irradiation light and the transmitted light in the memory 62 as the measurement value data 85. In addition, the absorbance acquisition unit 78 of the component measuring apparatus 1 can acquire the measurement value data 85 from the memory 62. The means by which the absorbance acquisition unit 78 acquires the above-described measurement value is not limited to the above-described means, and can be acquired by various known means.
　以下、ステップＳ２において、グルコース濃度を導出する方法を詳細に説明する。 Hereinafter, the method for deriving the glucose concentration in step S2 will be described in detail.
　まず、本実施形態で用いる発色試薬２２は、血液中のグルコースと呈色反応することにより生じる発色成分の吸光度が６００ｎｍ付近にピークを有するものを使用しているが、本実施形態において発色成分の吸光度を測定する測定波長は６５０ｎｍとしている。 First, as the coloring reagent 22 used in the present embodiment, a coloring component having a peak in the vicinity of 600 nm of the coloring component generated by color reaction with glucose in blood is used. The measurement wavelength for measuring the absorbance is 650 nm.
　測定対象となる発色成分の吸光度を測定するための測定波長は、発色成分の光吸収率が相対的に大きくなる波長であって、かつ、ヘモグロビンの光吸収による影響が比較的小さい波長を用いればよい。例えば、測定対象となる発色成分の吸光度スペクトルにおけるピーク波長域の半値全幅域に対応し、かつ、全吸光度に対するヘモグロビンの光吸収による吸光度の割合が比較的小さい波長範囲に属する波長とすればよい。「ピーク波長域の半値全幅域に対応する」波長範囲とは、吸光度スペクトルにおけるピーク波長域の半値全幅域を特定した際に、短波長側の半値を示す波長から、長波長側の半値を示す波長までの範囲を意味している。本実施形態の測定対象となる発色成分の吸光度スペクトルは、６００ｎｍ付近がピーク波長となり、約５００ｎｍ～約７００ｎｍが半値全幅域に対応する波長範囲となる。また、全吸光度におけるヘモグロビンの光吸収による影響は、６００ｎｍ以上の波長域で比較的小さくなる。したがって、本実施形態において、測定対象となる発色成分の吸光度スペクトルにおけるピーク波長域の半値全幅域に対応し、かつ、全吸光度に対するヘモグロビンの光吸収による吸光度の割合が比較的小さい波長範囲は、６００ｎｍ以上、かつ、７００ｎｍ以下である。そのため、測定波長としては、本実施形態の６５０ｎｍに限られず、６００ｎｍ～７００ｎｍの範囲に属する別の波長を測定波長としてもよい。発色成分の吸光度を表すシグナルが強く、全吸光度に対するヘモグロビンの光吸収による吸光度の割合が非常に小さい波長範囲である方が、発色成分の吸光度をより正確に測定できるため、発色成分の吸光度スペクトルにおけるピーク波長となる６３０ｎｍ付近よりやや長波長となる６５０ｎｍ付近を測定波長とすることが好ましい。より具体的には、測定波長を６３０ｎｍ～６８０ｎｍの範囲に属する波長とすることが好ましく、６４０ｎｍ～６７０ｎｍの範囲に属する波長とすることがより好ましく、本実施形態のように６５０ｎｍとすることが特に好ましい。このような色素成分の例としてはテトラゾリウム塩が好ましく、例えばＷＳＴ－４が最も好ましい。 The measurement wavelength for measuring the absorbance of the color developing component to be measured is a wavelength at which the light absorption rate of the color developing component is relatively large and a wavelength that is relatively less affected by the light absorption of hemoglobin is used. Good. For example, the wavelength may correspond to the full width at half maximum of the peak wavelength range in the absorbance spectrum of the color developing component to be measured, and the wavelength may belong to a wavelength range in which the ratio of absorbance due to light absorption of hemoglobin to the total absorbance is relatively small. The wavelength range “corresponds to the full width at half maximum of the peak wavelength range” refers to the half value at the long wavelength side from the wavelength at which the half wavelength at the short wavelength side is specified when the full width at half maximum of the peak wavelength range in the absorbance spectrum is specified. It means the range up to the wavelength. In the absorbance spectrum of the color developing component to be measured in this embodiment, the peak wavelength is around 600 nm, and the wavelength range corresponding to the full width at half maximum is about 500 nm to about 700 nm. Further, the influence of light absorption of hemoglobin on the total absorbance is relatively small in the wavelength region of 600 nm or more. Therefore, in this embodiment, the wavelength range corresponding to the full width at half maximum of the peak wavelength range in the absorbance spectrum of the color developing component to be measured and having a relatively small ratio of absorbance due to light absorption of hemoglobin to the total absorbance is 600 nm. Above and 700 nm or less. Therefore, the measurement wavelength is not limited to 650 nm in the present embodiment, and another wavelength belonging to the range of 600 nm to 700 nm may be used as the measurement wavelength. In the absorbance spectrum of the chromogenic component, the absorbance of the chromogenic component can be measured more accurately when the signal representing the absorbance of the chromogenic component is stronger and the ratio of absorbance due to light absorption of hemoglobin to the total absorbance is in a very small wavelength range. It is preferable to set the measurement wavelength near 650 nm, which is slightly longer than the peak wavelength near 630 nm. More specifically, the measurement wavelength is preferably a wavelength belonging to a range of 630 nm to 680 nm, more preferably a wavelength belonging to a range of 640 nm to 670 nm, and particularly preferably 650 nm as in the present embodiment. preferable. An example of such a dye component is preferably a tetrazolium salt, and most preferably, for example, WST-4.
　更に、本実施形態では、発色成分の吸光度スペクトルにおけるピーク波長域の半値全幅域が約５００ｎｍ～約７００ｎｍとなるような発色試薬２２を使用しているが、ピーク波長域の半値全幅域がこの範囲と異なるような発色試薬を使用してもよい。但し、上述したとおり、ヘモグロビンの吸光特性を考慮し、ヘモグロビンの光吸収による吸光度が大きくなる波長域（６００ｎｍ以下）と、発色成分の吸光度スペクトルにおける測定波長とが重ならないようにすることが望ましい。 Further, in the present embodiment, the coloring reagent 22 is used such that the full width at half maximum of the peak wavelength range in the absorbance spectrum of the color forming component is about 500 nm to about 700 nm. The full width at half maximum of the peak wavelength range is within this range. Coloring reagents different from those described above may be used. However, as described above, in consideration of the absorption characteristics of hemoglobin, it is desirable that the wavelength region (600 nm or less) in which the absorbance due to light absorption of hemoglobin increases does not overlap with the measurement wavelength in the absorbance spectrum of the color developing component.
　また、測定波長は、水に固有の吸収帯域に属しない波長とすることが望ましい。本実施形態の測定波長は、第１波長λ１及び第２波長λ２よりも短波長域に属している。具体的に、本実施形態では、水に固有の吸収帯域として近赤外領域（８００ｎｍ～２５００ｎｍ）の波長域を用いており、測定波長としては、近赤外領域より短波長域である可視領域（３８０ｎｍ～８００ｎｍ未満）に属する波長を使用している。 Also, it is desirable that the measurement wavelength is a wavelength that does not belong to the absorption band specific to water. The measurement wavelength of the present embodiment belongs to a shorter wavelength range than the first wavelength λ1 and the second wavelength λ2. Specifically, in the present embodiment, a wavelength region in the near infrared region (800 nm to 2500 nm) is used as an absorption band unique to water, and a measurement wavelength is a visible region that is shorter than the near infrared region. Wavelengths belonging to (380 nm to less than 800 nm) are used.
　以下、本実施形態の測定波長である６５０ｎｍにおける発色成分の吸光度を推定するための方法について説明する。成分測定装置１は、測定波長（６５０ｎｍ）とは異なる２つの第３波長λ３及び第４波長λ４における混合物の吸光度をそれぞれ測定し、この２つの測定値と、予め定めた補正データ８６とを用いて、測定波長における混合物の吸光度の測定値を補正し、測定波長における発色成分の吸光度を推定する。以下、説明の便宜上、測定波長を「第５波長λ５」と記載する。また、測定波長における混合物の吸光度の測定値を「第５測定値」と記載する。 Hereinafter, a method for estimating the absorbance of the coloring component at 650 nm, which is the measurement wavelength of the present embodiment, will be described. The component measuring apparatus 1 measures the absorbance of the mixture at two third wavelengths λ3 and λ4 different from the measurement wavelength (650 nm), and uses these two measured values and predetermined correction data 86. Then, the measurement value of the absorbance of the mixture at the measurement wavelength is corrected, and the absorbance of the coloring component at the measurement wavelength is estimated. Hereinafter, for convenience of explanation, the measurement wavelength is referred to as “fifth wavelength λ5”. In addition, the measurement value of the absorbance of the mixture at the measurement wavelength is referred to as “fifth measurement value”.
　具体的に、成分測定装置１は、上述した２つの測定値として、測定波長である第５波長λ５よりも長波長側の第３波長λ３における混合物の吸光度の測定値と、測定波長である第５波長λ５よりも短波長側の第４波長λ４における混合物の吸光度の測定値と、を利用する。 Specifically, the component measuring apparatus 1 has, as the above-described two measurement values, the absorbance measurement value of the mixture at the third wavelength λ3 longer than the fifth wavelength λ5, which is the measurement wavelength, and the measurement wavelength. The measurement value of the absorbance of the mixture at the fourth wavelength λ4 shorter than the five wavelengths λ5 is used.
　より具体的には、上述した２つの測定値として、測定波長である第５波長λ５よりも長波長側で、全吸光度において血球成分等の光散乱による影響が支配的な波長域に属し、水に固有の吸収帯域とは異なる波長域に属する第３波長λ３における混合物の吸光度の測定値と、測定波長である第５波長λ５よりも短波長側で、全吸光度においてヘモグロビンの光吸収による影響が大きい波長域に属する第４波長λ４における混合物の吸光度の測定値と、を利用する。 More specifically, the two measured values described above belong to a wavelength region on the longer wavelength side than the fifth wavelength λ5, which is the measurement wavelength, in which the influence of light scattering such as blood cell components is dominant in the total absorbance, The measurement value of the absorbance of the mixture at the third wavelength λ3 belonging to a wavelength region different from the intrinsic absorption band of the light source, and the influence of hemoglobin light absorption on the total absorbance on the shorter wavelength side than the fifth wavelength λ5 that is the measurement wavelength The measurement value of the absorbance of the mixture at the fourth wavelength λ4 belonging to the large wavelength region is used.
　第３波長λ３における混合物の吸光度の測定値を利用することにより、測定波長である第５波長λ５における、血球成分等の光散乱による影響を推定することができる。また、第４波長λ４における混合物の吸光度の測定値を利用することにより、測定波長である第５波長λ５における、ヘモグロビンの光吸収による影響の推定や、ヘマトクリット値の算出が可能となる。本実施形態では、第３波長λ３として７６０ｎｍを利用し、第４波長λ４として５４０ｎｍを利用している。 By using the measurement value of the absorbance of the mixture at the third wavelength λ3, it is possible to estimate the influence of light scattering such as blood cell components at the fifth wavelength λ5 that is the measurement wavelength. Further, by using the measurement value of the absorbance of the mixture at the fourth wavelength λ4, it is possible to estimate the influence of light absorption of hemoglobin and calculate the hematocrit value at the fifth wavelength λ5 that is the measurement wavelength. In the present embodiment, 760 nm is used as the third wavelength λ3, and 540 nm is used as the fourth wavelength λ4.
　成分測定装置１の吸光度取得部７８は、上述した第３波長λ３及び第４波長λ４それぞれでの測定値と、第５波長λ５での第５測定値と、を取得する。具体的には、発光部６６の第３光源６７ｃ、第４光源６７ｄ及び第５光源６８から第３波長λ３、第４波長λ４及び第５波長λ５の照射光が混合物に対してそれぞれ照射される。そして、受光部７２は、それぞれの照射光のうち混合物を透過する透過光を受光する。そして、演算部６０は、照射光と透過光との関係から算出される各波長における混合物の吸光度の測定値を、測定値データ８５としてメモリ６２に格納する。成分測定装置１の吸光度取得部７８は、メモリ６２から測定値データ８５を取得することができる。吸光度取得部７８が上述の測定値を取得する手段は、上述した手段に限られず、各種公知の手段により取得することが可能である。 The absorbance acquisition unit 78 of the component measuring apparatus 1 acquires the above-described measurement values at the third wavelength λ3 and the fourth wavelength λ4 and the fifth measurement value at the fifth wavelength λ5. Specifically, irradiation light of the third wavelength λ3, the fourth wavelength λ4, and the fifth wavelength λ5 is irradiated to the mixture from the third light source 67c, the fourth light source 67d, and the fifth light source 68 of the light emitting unit 66, respectively. . And the light-receiving part 72 receives the transmitted light which permeate | transmits a mixture among each irradiation light. Then, the calculation unit 60 stores the measurement value of the absorbance of the mixture at each wavelength calculated from the relationship between the irradiation light and the transmitted light in the memory 62 as the measurement value data 85. The absorbance acquisition unit 78 of the component measuring apparatus 1 can acquire the measurement value data 85 from the memory 62. The means by which the absorbance acquisition unit 78 acquires the above-described measurement value is not limited to the above-described means, and can be acquired by various known means.
　そして、成分測定装置１の吸光度補正部８４は、ステップＳ１で測定した第１測定値～第４測定値並びにステップＳ２で測定した第３波長λ３及び第４波長λ４での吸光度の測定値に基づいて、血液中のグルコース濃度を導出する。より具体的に、成分測定装置１の吸光度補正部８４は、ステップＳ１で導出した差分補正値と、ステップＳ２で導出した第３波長λ３での測定値及び第４波長λ４での測定値と、を用いて第５波長λ５での第５測定値を補正し、測定波長である第５波長λ５（本例では６５０ｎｍ）における発色成分の吸光度を推定する。 Then, the absorbance correction unit 84 of the component measuring apparatus 1 is based on the first to fourth measurement values measured in step S1 and the absorbance measurement values at the third wavelength λ3 and the fourth wavelength λ4 measured in step S2. To derive the glucose concentration in the blood. More specifically, the absorbance correction unit 84 of the component measuring apparatus 1 includes the difference correction value derived in step S1, the measurement value at the third wavelength λ3 and the measurement value at the fourth wavelength λ4 derived in step S2. Is used to correct the fifth measurement value at the fifth wavelength λ5, and the absorbance of the coloring component at the fifth wavelength λ5 (650 nm in this example), which is the measurement wavelength, is estimated.
　以下、成分測定装置１の吸光度補正部８４による補正手法について説明する。 Hereinafter, a correction method by the absorbance correction unit 84 of the component measurement apparatus 1 will be described.
　上述したように、成分測定装置１のメモリ６２には、測定光学系６４により測定された第１波長λ１～第５波長λ５それぞれにおける吸光度の測定値である測定値データ８５と、上記各測定値に対応する一群の補正データ８６と、第５波長λ５で実測された混合物の吸光度を補正データ８６により補正して得られる混合物中の発色成分の吸光度とグルコース濃度等の各種物理量との関係を示す検量線データ９０と、が格納されている。 As described above, in the memory 62 of the component measuring apparatus 1, the measured value data 85 that is the measured value of the absorbance at each of the first wavelength λ1 to the fifth wavelength λ5 measured by the measuring optical system 64, and the above measured values. A relationship between a group of correction data 86 corresponding to 1 and the absorbance of the color mixture in the mixture obtained by correcting the absorbance of the mixture measured at the fifth wavelength λ5 by the correction data 86 and various physical quantities such as glucose concentration. Calibration curve data 90 is stored.
　吸光度補正部８４は、吸光度取得部７８が取得した、メモリ６２に格納されている測定値データ８５、補正データ８６及び検量線データ９０に基づき、測定波長である第５波長λ５における発色成分の吸光度を導出する。 The absorbance correction unit 84 is based on the measurement value data 85, the correction data 86, and the calibration curve data 90 that are acquired by the absorbance acquisition unit 78 and stored in the memory 62, and the absorbance of the coloring component at the fifth wavelength λ5 that is the measurement wavelength. Is derived.
　ここで、間隙２８の高さｈと、近赤外領域での水に固有の吸収帯域に属する光を間隙２８に位置する混合物に対して照射することにより得られる吸光度と、の間の相関関係についての更なる詳細について説明する。図１６は、間隙２８の高さｈと、近赤外領域での水に固有の吸収帯域に属する光を間隙２８に位置する混合物に対して照射することにより得られる吸光度と、の間の相関関係を示すグラフである。具体的に、図１６では、間隙２８の高さｈが異なる複数の成分測定チップ２それぞれについて、膜厚計により測定された間隙２８の高さｈの測定値と、水に固有の吸収帯域に属する光を間隙２８に位置する混合物に対して照射することにより得られる吸光度の測定値と、を示している（図１６においてプロットされている点を参照）。発色試薬２２の塗布厚さについては、いずれの成分測定チップ２においても略一定である。また、図１６において示す直線は、図１６においてプロットされている点の近似直線である。図１６に示すように、間隙２８の高さｈと、水に固有の波長の光を間隙２８に位置する混合物に対して照射することにより得られる吸光度と、の間には相関関係があり、図１６に示す近似直線のように、両者の関係式（グラフ、相関係数）を導出することができることがわかる。 Here, there is a correlation between the height h of the gap 28 and the absorbance obtained by irradiating the mixture located in the gap 28 with light belonging to an absorption band specific to water in the near infrared region. Further details about will be described. FIG. 16 shows the correlation between the height h of the gap 28 and the absorbance obtained by irradiating the mixture located in the gap 28 with light belonging to the absorption band specific to water in the near infrared region. It is a graph which shows a relationship. Specifically, in FIG. 16, for each of a plurality of component measurement chips 2 having different heights h of the gaps 28, the measured values of the height h of the gaps 28 measured by the film thickness meter and the absorption band specific to water are obtained. FIG. 16 shows measured absorbance values obtained by irradiating the light belonging to the mixture located in the gap 28 (see the points plotted in FIG. 16). The coating thickness of the coloring reagent 22 is substantially constant in any component measurement chip 2. Moreover, the straight line shown in FIG. 16 is an approximate straight line of the points plotted in FIG. As shown in FIG. 16, there is a correlation between the height h of the gap 28 and the absorbance obtained by irradiating the mixture located in the gap 28 with light having a wavelength unique to water. It can be seen that a relational expression (graph, correlation coefficient) of both can be derived as an approximate straight line shown in FIG.
　図１６に示す各点の間隙２８の高さｈは、膜厚計としての、浜松ホトニクス株式会社製のOptical MicroGauge 厚み計（Ｃ１１０１１－０１）により測定している。また、図１６に示す各点の吸光度の測定値は、水に固有の波長における吸光度を測定し、検体が発色試薬２２に接触してから９秒後の吸光度である９秒値と、検体が発色試薬２２に接触する前の吸光度であるイニシャル値と、の間で差分を算出することにより測定している。より具体的には、まず、１９４０ｎｍでの９秒値としての上述した第１測定値と、１８２０ｎｍでの９秒値としての上述した第２測定値と、の差分を算出する。次いで、１９４０ｎｍでのイニシャル値としての上述した第３測定値と、１８２０ｎｍでのイニシャル値としての上述した第４測定値と、の差分を算出する。そして、９秒値の差分とイニシャル値の差分と、の間の更なる差分を算出し、図１６では、この差分値を、各点の吸光度の測定値としている。ここでは水に固有の吸収帯域の裾部近傍の波長として１８２０ｎｍを使用しているが、これに代えて、１７６０ｎｍを使用してもよい。 The height h of the gap 28 at each point shown in FIG. 16 is measured with an Optical MicroGauge thickness meter (C11011-01) manufactured by Hamamatsu Photonics Co., Ltd. as a film thickness meter. In addition, the measured values of the absorbance at each point shown in FIG. 16 are the absorbance at a wavelength specific to water, and the 9-second value, which is the absorbance 9 seconds after the specimen contacts the coloring reagent 22, It is measured by calculating the difference between the initial value which is the absorbance before contact with the color reagent 22. More specifically, first, a difference between the above-described first measurement value as a 9-second value at 1940 nm and the above-described second measurement value as a 9-second value at 1820 nm is calculated. Next, the difference between the above-described third measurement value as the initial value at 1940 nm and the above-described fourth measurement value as the initial value at 1820 nm is calculated. Then, a further difference between the 9-second value difference and the initial value difference is calculated. In FIG. 16, this difference value is used as a measured value of absorbance at each point. Here, 1820 nm is used as the wavelength in the vicinity of the bottom of the absorption band specific to water, but 1760 nm may be used instead.
　最後に、測定時の測定空間の光路長としての測定時の間隙２８の高さｈによる、グルコース濃度の測定値への影響の大きさについて、グルコースを含まない水及びグルコース水を用いて検証実験を行った。図１３及び図１４は、グルコースが含まれていない水、グルコース濃度が１００ｍｇ／ｄＬのグルコース水（図１３及び図１４では「ｂｇ１００」と表記）、及びグルコース濃度が４００ｍｇ／ｄＬのグルコース水（図１３及び図１４では「ｂｇ４００」と表記）について、測定空間の光路長についての補正を行わない場合（図１３及び図１４では「補正なし」と表記）、測定前の間隙２８の高さｈの測定値を用いて測定空間の光路長についての補正を行う場合（図１３では「測定前補正あり」と表記し、図１４では未掲載）、及び、本実施形態のように、測定時の間隙２８の高さｈを推定し、この推定値を用いて測定空間の光路長についての補正を行う場合（図１３及び図１４では「測定時補正あり」と表記）それぞれの、導出されたグルコース濃度の測定値のばらつきを示している。図１３及び図１４に示す測定値のばらつきは、グルコース濃度が含まれていない水については濃度の絶対値（ｍｇ／ｄＬ）の真値からのズレの標準偏差の２倍（２ＳＤ）により評価し、グルコース濃度が１００ｍｇ／ｄＬ及び４００ｍｇ／ｄＬのグルコース水については、真値からのズレをグルコース濃度で割り返したものの標準偏差の２倍の値（２ＳＤ値）により評価している。また、測定前の間隙２８の高さｈの測定値は、浜松ホトニクス株式会社製のOptical MicroGauge 厚み計（Ｃ１１０１１－０１）により測定している。 Finally, a verification experiment using glucose-free water and glucose water on the magnitude of the influence on the measured value of the glucose concentration by the height h of the gap 28 at the time of measurement as the optical path length of the measurement space at the time of measurement. Went. FIGS. 13 and 14 show water containing no glucose, glucose water having a glucose concentration of 100 mg / dL (indicated as “bg100” in FIGS. 13 and 14), and glucose water having a glucose concentration of 400 mg / dL (FIG. 13 and FIG. 14 (indicated as “bg400”), when the optical path length of the measurement space is not corrected (indicated as “no correction” in FIGS. 13 and 14), the height h of the gap 28 before the measurement When the measurement path is used to correct the optical path length of the measurement space (indicated in FIG. 13 as “pre-measurement correction” and not shown in FIG. 14), and as in this embodiment, the gap at the time of measurement 28 is estimated and the estimated value is used to correct the optical path length of the measurement space (indicated as “correction at the time of measurement” in FIGS. 13 and 14). It shows the variation of the measured values of over scan density. The dispersion of the measured values shown in FIGS. 13 and 14 is evaluated by double (2SD) the standard deviation of deviation from the true value of the absolute value of the concentration (mg / dL) for water not containing the glucose concentration. The glucose water having a glucose concentration of 100 mg / dL and 400 mg / dL is evaluated by a value (2SD value) twice the standard deviation of the deviation from the true value divided by the glucose concentration. Further, the measured value of the height h of the gap 28 before the measurement is measured with an Optical MicroGauge thickness meter (C11011-01) manufactured by Hamamatsu Photonics.
　更に、図１３は、許容される成分測定チップ２の間隙２８の高さｈ（図５参照）のばらつきが大きい場合についての、グルコース濃度の測定値への影響を示している。具体的に、図１３では、間隙２８の高さｈが２０．４μｍ～５３．４μｍの範囲でばらつきがある１５個の成分測定チップ２を用いた実験の結果である。間隙２８の幅はいずれも一定である。 Furthermore, FIG. 13 shows the influence on the measured value of the glucose concentration when the variation in the height h (see FIG. 5) of the gap 28 of the component measurement chip 2 allowed is large. Specifically, FIG. 13 shows the results of an experiment using 15 component measurement chips 2 having variations in the height h of the gap 28 in the range of 20.4 μm to 53.4 μm. The width of each gap 28 is constant.
　図１３に示すように、測定空間の光路長に関して補正しない場合は、導出されるグルコース濃度のばらつきが大きく、導出されるグルコース濃度の精度が低いことがわかる。これに対して、測定前の間隙２８の高さｈの測定値を利用して、測定空間の光路長に関して補正する場合は、導出されるグルコース濃度のばらつきが、補正しない場合と比較して、非常に小さくなることがわかる。更に、本実施形態のように、測定時の測定空間の光路長としての測定時の間隙２８の高さｈを推定し、この推定値を利用して測定空間の光路長に関して補正する場合は、導出されるグルコース濃度のばらつきが、補正しない場合及び測定前の間隙２８の高さｈの測定値を利用して補正する場合と比較して、更に小さくなり、導出されるグルコース濃度の精度が非常に高いことが確認できる。 As shown in FIG. 13, when the optical path length of the measurement space is not corrected, it can be seen that the variation in the derived glucose concentration is large and the accuracy of the derived glucose concentration is low. On the other hand, when correcting the optical path length of the measurement space using the measurement value of the height h of the gap 28 before the measurement, the variation in the derived glucose concentration is compared with the case where the correction is not performed, It turns out that it becomes very small. Furthermore, as in the present embodiment, when the height h of the gap 28 at the time of measurement as the optical path length of the measurement space at the time of measurement is estimated and the optical path length of the measurement space is corrected using this estimated value, The variation in the derived glucose concentration is further reduced as compared with the case where the correction is not performed and the case where the measurement is performed using the measurement value of the height h of the gap 28 before the measurement, and the accuracy of the derived glucose concentration is very high. It can be confirmed that it is high.
　また、図１７（ａ）は、図１３に示す「補正なし」について、測定波長（ここでは６５０ｎｍを使用）における吸光度のばらつき示すグラフである。具体的に、図１７（ａ）の横軸は、測定波長における吸光度であり、縦軸は、検体のグルコース濃度である。図１７（ａ）に示すように、検体のグルコース濃度が１００ｍｇ／ｄＬであっても、測定波長における吸光度に大きなばらつきが生じることがわかる。これは、間隙２８の高さｈの相違による影響である。同様に、検体のグルコース濃度が４００ｍｇ／ｄＬであっても、間隙２８の高さｈの相違によって、測定波長における吸光度に大きなばらつきが生じていることがわかる。このように、間隙２８の高さｈの相違により、間隙２８に流入する検体の体積が異なってくるため、測定光路内で観察される発色成分量、すなわち、測定波長における吸光度にばらつきが生じることが確認できる。図１７（ａ）に示す直線は強引に引いた近似直線であるが、グルコース濃度と測定波長における吸光度との間に相関関係（図１７（ａ）において各点が１つの直線上に並ぶ直線性）がない。 FIG. 17A is a graph showing variations in absorbance at a measurement wavelength (here, 650 nm is used) for “no correction” shown in FIG. Specifically, the horizontal axis of FIG. 17A is the absorbance at the measurement wavelength, and the vertical axis is the glucose concentration of the specimen. As shown in FIG. 17 (a), it can be seen that even when the glucose concentration of the sample is 100 mg / dL, the absorbance at the measurement wavelength varies greatly. This is due to the difference in the height h of the gap 28. Similarly, it can be seen that even when the glucose concentration of the specimen is 400 mg / dL, the absorbance at the measurement wavelength varies greatly due to the difference in the height h of the gap 28. As described above, since the volume of the sample flowing into the gap 28 varies depending on the difference in the height h of the gap 28, the amount of color components observed in the measurement optical path, that is, the absorbance at the measurement wavelength varies. Can be confirmed. The straight line shown in FIG. 17 (a) is an approximate straight line drawn forcibly, but there is a correlation between the glucose concentration and the absorbance at the measurement wavelength (in FIG. 17 (a), the linearity in which each point is arranged on one straight line. )
　これに対して図１７（ｂ）は、図１３に示す「測定時補正あり」について、測定波長（ここでは６５０ｎｍを使用）における吸光度のばらつきを示すグラフである。図１７（ｂ）の横軸は、図１７（ａ）の横軸と同様、測定波長における吸光度であり、図１７（ｂ）の縦軸は、間隙２８の位置での混合物のグルコース濃度である。図１７（ｂ）に示すように、間隙２８の位置での混合物のグルコース濃度と測定波長における吸光度には相関関係がみられる（相関係数Ｒ＝０．９９９）。この関係を用いれば、近赤外領域の水に固有の吸収を測定することで、間隙２８の高さｈを考慮した補正を行うことができる。換言すれば、近赤外領域の水に固有の吸収を測定し、間隙２８の高さｈを補正することにより、測定波長における吸光度から、間隙２８の位置での混合物のグルコース量ひいては間隙２８の位置でのグルコース濃度をより正確に算出することができる。 On the other hand, FIG. 17B is a graph showing the variation in absorbance at the measurement wavelength (here, 650 nm is used) for “with correction during measurement” shown in FIG. The horizontal axis in FIG. 17 (b) is the absorbance at the measurement wavelength as in the horizontal axis in FIG. 17 (a), and the vertical axis in FIG. 17 (b) is the glucose concentration of the mixture at the position of the gap 28. . As shown in FIG. 17B, there is a correlation between the glucose concentration of the mixture at the position of the gap 28 and the absorbance at the measurement wavelength (correlation coefficient R = 0.999). By using this relationship, it is possible to perform correction in consideration of the height h of the gap 28 by measuring absorption inherent in water in the near infrared region. In other words, by measuring the absorption inherent in water in the near infrared region and correcting the height h of the gap 28, the amount of glucose in the mixture at the position of the gap 28 and hence the gap 28 The glucose concentration at the position can be calculated more accurately.
　また、図１４は、許容される成分測定チップ２の間隙２８の高さｈ（図５参照）のばらつきが非常に小さい場合についての、グルコース濃度の測定値への影響を示している。具体的に、図１４では、間隙２８の高さｈが４０±１μｍの範囲でばらつきがある複数の成分測定チップ２を用いた実験の結果である。間隙２８の幅はいずれも一定である。 FIG. 14 shows the influence on the measured value of the glucose concentration in the case where the variation in the height h (see FIG. 5) of the gap 28 of the allowable component measurement chip 2 is very small. Specifically, FIG. 14 shows the results of an experiment using a plurality of component measurement chips 2 that vary in the range where the height h of the gap 28 is 40 ± 1 μm. The width of each gap 28 is constant.
　成分測定チップ２の間隙２８の高さｈ（図５参照）のばらつきが非常に小さいため、図１４に示すように、測定空間の光路長に関して補正しない場合であっても、導出されるグルコース濃度のばらつきを小さくすることができる。但し、本実施形態のように測定時の測定空間の光路長としての測定時の間隙２８の高さｈを推定し、この推定値を利用して測定空間の光路長に関して補正する場合であっても、導出されるグルコース濃度のばらつきを小さくできることがわかる。 Since the variation in the height h (see FIG. 5) of the gap 28 of the component measurement chip 2 is very small, as shown in FIG. 14, even if the optical path length of the measurement space is not corrected, the derived glucose concentration The variation of can be reduced. However, as in the present embodiment, the height h of the gap 28 at the time of measurement is estimated as the optical path length of the measurement space at the time of measurement, and the optical path length of the measurement space is corrected using this estimated value. It can also be seen that the variation in the derived glucose concentration can be reduced.
　したがって、本実施形態のように測定時の測定空間の光路長としての測定時の間隙２８の高さｈを考慮して、導出されるグルコース濃度の測定値を補正するようにすれば、許容される成分測定チップ２の間隙２８の高さｈ（図５参照）のばらつきがたとえ非常に小さい場合であっても、導出されるグルコース濃度の精度を高い状態とすることができ、クリアランス量のばらつきが大きい場合には、導出されるグルコース濃度の精度を大きく向上させることができることが理解できる。 Therefore, it is acceptable if the measured value of the derived glucose concentration is corrected in consideration of the height h of the gap 28 at the time of measurement as the optical path length of the measurement space at the time of measurement as in this embodiment. Even if the variation in the height h (see FIG. 5) of the gap 28 of the component measuring chip 2 is very small, the accuracy of the derived glucose concentration can be made high, and the variation in the clearance amount It can be understood that the accuracy of the derived glucose concentration can be greatly improved when is large.
　次に、測定時の測定空間の光路長としての測定時の間隙２８の高さｈによる、グルコース濃度の測定値への影響の大きさについて、グルコース濃度が既知の血液を用いて検証実験を行った。図１５は、グルコース濃度がゼロになるように調整した血液、グルコース濃度が１００ｍｇ／ｄＬとなるように調整した血液、及びグルコース濃度が４００ｍｇ／ｄＬとなるように血液について、測定空間の光路長についての補正を行わない場合、測定前の間隙２８の高さｈの測定値を用いて測定空間の光路長について補正を行う場合、及び、本実施形態のように、測定時の間隙２８の高さｈを推定し、この推定値を用いて測定空間の光路長について補正を行う場合それぞれの、導出されたグルコース濃度の測定値のばらつきを示している。図１５に示す測定値のばらつきは、グルコース濃度が含まれていない水については濃度の絶対値（ｍｇ／ｄＬ）の真値からのズレの標準偏差の２倍（２ＳＤ）により評価し、グルコース濃度が１００ｍｇ／ｄＬ及び４００ｍｇ／ｄＬのグルコース水については、真値からのズレをグルコース濃度で割り返したものの標準偏差の２倍の値（２ＳＤ値）により評価している。また、測定前の間隙２８の高さｈの測定値は、浜松ホトニクス株式会社製のOptical MicroGauge 厚み計（Ｃ１１０１１－０１）により測定している。 Next, a verification experiment was performed using blood with a known glucose concentration on the magnitude of the effect on the measurement value of the glucose concentration due to the height h of the gap 28 at the time of measurement as the optical path length of the measurement space at the time of measurement. It was. FIG. 15 shows the optical path length of the measurement space for blood adjusted to have a glucose concentration of zero, blood adjusted to have a glucose concentration of 100 mg / dL, and blood to have a glucose concentration of 400 mg / dL. When correction is not performed, when the optical path length of the measurement space is corrected using the measurement value of the height h of the gap 28 before measurement, and the height of the gap 28 at the time of measurement as in the present embodiment. When h is estimated and this estimated value is used to correct the optical path length of the measurement space, the variation in the measured value of the derived glucose concentration is shown. The variation in the measured values shown in FIG. 15 is evaluated based on twice the standard deviation (2SD) of deviation from the true value of the absolute value of the concentration (mg / dL) for water not containing the glucose concentration. The glucose waters of 100 mg / dL and 400 mg / dL are evaluated by a value (2SD value) twice the standard deviation of the deviation from the true value divided by the glucose concentration. Further, the measured value of the height h of the gap 28 before the measurement is measured with an Optical MicroGauge thickness meter (C11011-01) manufactured by Hamamatsu Photonics.
　更に、図１５は、許容される成分測定チップ２の間隙２８の高さｈ（図５参照）のばらつきが３７．３μｍ～４０．６μｍの場合についての、グルコース濃度の測定値への影響を示している。間隙２８の幅はいずれも一定である。 Further, FIG. 15 shows the influence on the measurement value of glucose concentration when the variation in the height h (see FIG. 5) of the gap 28 of the component measurement chip 2 allowed is 37.3 μm to 40.6 μm. ing. The width of each gap 28 is constant.
　図１５に示すように、測定空間の光路長に関して補正しない場合は、導出されるグルコース濃度のばらつきが大きく、導出されるグルコース濃度の精度が低いことがわかる。これに対して、測定前の間隙２８の高さｈの測定値を利用して、測定空間の光路長に関して補正する場合は、導出されるグルコース濃度のばらつきが、補正しない場合と比較して、小さくなることがわかる。更に、本実施形態のように測定時の間隙２８の高さｈを推定し、この推定値を利用して測定空間の光路長に関して補正する場合は、導出されるグルコース濃度のばらつきが、補正しない場合及び測定前の間隙２８の高さｈの測定値を利用して補正する場合と比較して、更に小さくなり、導出されるグルコース濃度の精度を高めることができることがわかる。 As shown in FIG. 15, it can be seen that when the optical path length of the measurement space is not corrected, the derived glucose concentration varies greatly and the accuracy of the derived glucose concentration is low. On the other hand, when correcting the optical path length of the measurement space using the measurement value of the height h of the gap 28 before the measurement, the variation in the derived glucose concentration is compared with the case where the correction is not performed, It turns out that it becomes small. Further, when the height h of the gap 28 at the time of measurement is estimated as in the present embodiment and correction is made with respect to the optical path length of the measurement space using this estimated value, variations in the derived glucose concentration are not corrected. It can be seen that the accuracy of the derived glucose concentration can be further increased compared to the case where the correction is performed using the measured value of the height h of the gap 28 before the measurement.
　本発明に係る成分測定装置、成分測定方法及び成分測定プログラムは、上述した実施形態の具体的な記載に限られず、請求の範囲の記載した発明の主旨を逸脱しない範囲で種々の変更が可能である。 The component measuring apparatus, the component measuring method, and the component measuring program according to the present invention are not limited to the specific description of the above-described embodiment, and various modifications can be made without departing from the gist of the invention described in the claims. is there.
　上述の実施形態では、被測定成分としてのグルコースの測定として、グルコース濃度を測定しているが、濃度に限られず、別の物理量を測定してもよい。また、上述の実施形態では、血液中の被測定成分として、血漿成分中のグルコースを例示しているが、これに限られず、例えば血液中のコレステロールを被測定成分とすることも可能である。更に、上述の実施形態では、血液中の被測定成分を測定しているが、血液に限られず、別の体液中の被測定成分を測定するものであってもよい。したがって、成分測定装置は、血糖値測定装置に限られない。 In the above-described embodiment, the glucose concentration is measured as the measurement of glucose as a component to be measured. However, the measurement is not limited to the concentration, and another physical quantity may be measured. In the above-described embodiment, glucose in the plasma component is exemplified as the component to be measured in blood. However, the present invention is not limited to this, and for example, cholesterol in blood can be used as the component to be measured. Furthermore, in the above-described embodiment, the component to be measured in blood is measured, but is not limited to blood, and the component to be measured in another body fluid may be measured. Therefore, the component measuring device is not limited to the blood glucose level measuring device.
　更に、上述の実施形態では、発光部６６として、複数種類の第１光源６７ａ～第５光源６８を例に挙げて説明したが、単一の光源と、該光源の前方に配置された複数種類の光学フィルタ（バンドパス型）を組み合わせて構成してもよい。あるいは、単一の光源と、複数種類の受光部を組み合わせて構成してもよい。また更に、上述の実施形態では、成分測定チップ２を透過する透過光を受光する受光部７２としているが、成分測定チップ２から反射する反射光を受光する受光部としてもよい。 Furthermore, in the above-described embodiment, a plurality of types of first light source 67a to fifth light source 68 have been described as examples of the light emitting unit 66. However, a single light source and a plurality of types arranged in front of the light source are described. These optical filters (bandpass type) may be combined. Or you may comprise combining a single light source and multiple types of light-receiving part. Furthermore, in the above-described embodiment, the light receiving unit 72 that receives the transmitted light that passes through the component measuring chip 2 is used. However, the light receiving unit that receives the reflected light reflected from the component measuring chip 2 may be used.
　本開示は、成分測定装置、成分測定方法及び成分測定プログラムに関し、特に、体液中の被測定成分を測定する成分測定装置、成分測定方法及び成分測定プログラムに関する。 The present disclosure relates to a component measurement device, a component measurement method, and a component measurement program, and more particularly, to a component measurement device, a component measurement method, and a component measurement program for measuring a component to be measured in a body fluid.
１：成分測定装置
２：成分測定チップ
１０：ハウジング
１０ａ：本体部
１０ｂ：チップ装着部
１１：表示部
１２：取り外しレバー
１３：電源ボタン
１４：操作ボタン
２１：ベース部材
２２：発色試薬（試薬）
２３：流路
２４：供給部
２５：カバー部材
２６：イジェクトピン
２７：スペーサ部材
２８：間隙
６０：演算部
６２：メモリ
６３：電源回路
６４：測定光学系
６６：発光部
６７ａ～６７ｄ：第１光源～第４光源
６８：第５光源
７０：発光制御回路
７２：受光部
７４：受光制御回路
７６：測定指示部
７７：濃度測定部
７８：吸光度取得部
８４：吸光度補正部
８５：測定値データ
８６：補正データ
９０：検量線データ
１００：成分測定装置セット
Ｈ：流路の高さ
ｈ：間隙の高さ
Ｓ：チップ装着空間
Ｗ：流路の幅
λ１～λ５：第１波長～第５波長 1: Component measuring device 2: Component measuring chip 10: Housing 10a: Main body part 10b: Chip mounting part 11: Display part 12: Removal lever 13: Power button 14: Operation button 21: Base member 22: Coloring reagent (reagent)
23: channel 24: supply unit 25: cover member 26: eject pin 27: spacer member 28: gap 60: calculation unit 62: memory 63: power supply circuit 64: measurement optical system 66: light emitting units 67a to 67d: first light source To fourth light source 68: fifth light source 70: light emission control circuit 72: light receiving unit 74: light reception control circuit 76: measurement instruction unit 77: concentration measurement unit 78: absorbance acquisition unit 84: absorbance correction unit 85: measurement value data 86: Correction data 90: Calibration curve data 100: Component measuring device set H: Channel height h: Gap height S: Chip mounting space W: Channel width λ1 to λ5: First wavelength to fifth wavelength

Claims (10)

  1. 　体液中の被測定成分と試薬との呈色反応により生じる発色成分を含む混合物の光学的特性に基づいて前記体液中の前記被測定成分を測定する成分測定装置であって、
    　内部に流路を区画し、前記流路内で、前記流路を閉塞しないように対向する内壁との間に間隙を隔てた状態で配置された前記試薬を有する成分測定チップが装着可能であり、
    　前記間隙の位置で前記混合物に照射される、近赤外領域以上の長波長域で水に固有の吸収帯域に属する所定波長の測定光、により測定された吸光度の測定値に基づいて、前記被測定成分を導出する成分測定装置。     A component measuring device for measuring the component to be measured in the body fluid based on the optical characteristics of a mixture containing a coloring component produced by a color reaction between the component to be measured and a reagent in the body fluid,
    A component measuring chip having the reagent arranged in a state where a channel is partitioned inside the channel and a gap is provided between the channel and the opposing inner wall so as not to block the channel can be mounted. ,
    Based on the measurement value of the absorbance measured by the measurement light having a predetermined wavelength belonging to the absorption band inherent to water in the long wavelength region longer than the near infrared region, which is irradiated to the mixture at the position of the gap. Component measuring device for deriving measured components.
  2. 　前記所定波長を第１波長とし、前記測定光を第１測定光とし、前記測定値を第１測定値とした場合に、
    　前記間隙の位置で前記混合物に照射される、前記長波長域に属し、かつ、前記水に固有の吸収帯域又は前記水に固有の吸収帯域の近傍の第２波長の第２測定光、により測定された、前記第１測定値よりも小さい吸光度である第２測定値を取得し、
    　前記第１測定値と前記第２測定値との差分に基づいて、前記被測定成分を導出する、請求項１に記載の成分測定装置。     When the predetermined wavelength is the first wavelength, the measurement light is the first measurement light, and the measurement value is the first measurement value,
    Measured by the second measurement light having a second wavelength that irradiates the mixture at the position of the gap and that belongs to the long wavelength range and is in the vicinity of the absorption band specific to the water or the absorption band specific to the water A second measured value having an absorbance smaller than the first measured value is obtained,
    The component measurement apparatus according to claim 1, wherein the component to be measured is derived based on a difference between the first measurement value and the second measurement value.
  3. 　前記体液と接触する前の前記試薬に照射される前記第１波長の第３測定光により測定された吸光度である第３測定値と、前記体液と接触する前の前記試薬に照射される前記第２波長の第４測定光により測定された吸光度である第４測定値と、を取得し、
    　前記第１測定値と前記第２測定値との差分と、前記第３測定値と前記第４測定値との差分と、の間の差分である補正差分値に基づいて、前記被測定成分を導出する、請求項２に記載の成分測定装置。     A third measurement value that is an absorbance measured by the third measurement light of the first wavelength irradiated to the reagent before contact with the body fluid, and the first irradiation to the reagent before contact with the body fluid. A fourth measured value that is an absorbance measured by a second measuring light of two wavelengths,
    Based on a corrected difference value that is a difference between the difference between the first measurement value and the second measurement value and the difference between the third measurement value and the fourth measurement value, the component to be measured is The component measuring apparatus according to claim 2, which is derived.
  4. 　前記間隙の位置で前記混合物に照射される、前記水に固有の吸収帯域とは異なる波長域に属する測定波長の第５測定光、により測定された吸光度である第５測定値を取得し、前記第５測定値を、前記補正差分値に基づいて、補正する、請求項３に記載の成分測定装置。 Obtaining a fifth measurement value that is an absorbance measured by a fifth measurement light having a measurement wavelength belonging to a wavelength range different from the absorption band specific to the water, which is irradiated to the mixture at the position of the gap; The component measurement apparatus according to claim 3, wherein the fifth measurement value is corrected based on the correction difference value.
  5. 　前記測定波長は、前記第１波長及び前記第２波長よりも短波長域に属する、請求項４に記載の成分測定装置。 The component measurement apparatus according to claim 4, wherein the measurement wavelength belongs to a shorter wavelength range than the first wavelength and the second wavelength.
  6. 　前記測定波長は、前記発色成分の吸光度スペクトルにおけるピーク波長域の半値全幅域に対応する波長範囲に属する、請求項４又は５に記載の成分測定装置。 The component measurement apparatus according to claim 4 or 5, wherein the measurement wavelength belongs to a wavelength range corresponding to a full width at half maximum of a peak wavelength range in an absorbance spectrum of the color forming component.
  7. 　前記測定波長は、可視領域に属する、請求項４乃至６のいずれか１つに記載の成分測定装置。 The component measurement apparatus according to any one of claims 4 to 6, wherein the measurement wavelength belongs to a visible region.
  8. 　前記間隙に位置する前記混合物に照射される光で得られる吸光度スペクトルにおいて、前記第１波長は、前記水に固有の吸収帯域で水の吸光度がピーク値となる又は前記ピーク値の近傍となる波長であり、前記第２波長は、前記水に固有の吸収帯域の裾部近傍の波長である、請求項２乃至７のいずれか１つに記載の成分測定装置。 In the absorbance spectrum obtained by the light irradiated to the mixture located in the gap, the first wavelength is a wavelength at which the absorbance of water has a peak value or is close to the peak value in an absorption band specific to the water. The component measurement apparatus according to claim 2, wherein the second wavelength is a wavelength in the vicinity of a skirt portion of an absorption band specific to the water.
  9. 　体液中の被測定成分と試薬との呈色反応により生じる発色成分を含む混合物の光学的特性に基づいて前記体液中の前記被測定成分を測定する成分測定方法であって、
    　流路内で、前記流路を閉塞しないように対向する内壁との間に間隙を隔てた状態で配置された前記試薬と、前記間隙に供給された前記体液と、により生成された前記間隙に位置する前記混合物に対して、近赤外領域以上の長波長域で水に固有の吸収帯域に属する所定波長の測定光を照射して吸光度を測定するステップと、
    　測定された吸光度の測定値に基づいて、前記被測定成分を導出するステップと、を含む成分測定方法。     A component measurement method for measuring the component to be measured in the body fluid based on the optical characteristics of a mixture containing a coloring component generated by a color reaction between the component to be measured and a reagent in the body fluid,
    In the flow path, the reagent is disposed with a gap between the opposing inner walls so as not to block the flow path, and the body fluid supplied to the gap includes the gap generated by the reagent. Irradiating measurement light having a predetermined wavelength belonging to an absorption band specific to water in the long wavelength region of the near-infrared region or higher to the mixture, and measuring the absorbance;
    Deriving the component to be measured based on a measured value of the measured absorbance.
  10. 　体液中の被測定成分と試薬との呈色反応により生じる発色成分を含む混合物の光学的特性に基づいて前記体液中の前記被測定成分を測定するための成分測定プログラムであって、
    　流路内で、前記流路を閉塞しないように対向する内壁との間に間隙を隔てた状態で配置された前記試薬と、前記間隙に供給された前記体液と、により生成された前記間隙に位置する前記混合物に対して、近赤外領域以上の長波長域で水に固有の吸収帯域に属する所定波長の測定光を照射して吸光度を測定するステップと、
    　測定された吸光度の測定値に基づいて、前記被測定成分を導出するステップと、を成分測定装置に実行させる成分測定プログラム。     A component measurement program for measuring the component to be measured in the body fluid based on the optical characteristics of a mixture containing a coloring component produced by a color reaction between the component to be measured and a reagent in the body fluid,
    In the flow path, the reagent is disposed with a gap between the opposing inner walls so as not to block the flow path, and the body fluid supplied to the gap includes the gap generated by the reagent. Irradiating measurement light having a predetermined wavelength belonging to an absorption band specific to water in the long wavelength region of the near-infrared region or higher to the mixture, and measuring the absorbance;
    A component measurement program for causing a component measurement device to execute the step of deriving the component to be measured based on the measured absorbance value.
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