JP6952046B2 - Component measuring device, component measuring method and component measuring program - Google Patents

Description

The present disclosure relates to a component measuring device, a component measuring method and a component measuring program, and more particularly to a component measuring device, a component measuring method and a component measuring program for measuring a component to be measured in a body fluid.

Conventionally, in the fields of biochemistry and medical care, as a method of measuring a target component (also referred to as a component to be measured) contained in a body fluid as a sample, the body fluid contains a portion containing the component to be measured and a component to be measured. There is known a method of measuring the amount and concentration of the component to be measured by separating it into a part that cannot be measured. For example, in order to measure the glucose concentration (mg / dL) of blood (whole blood) in plasma, a method of separating plasma components from blood using a filter or the like and measuring the glucose concentration in plasma is performed. be.

Further, as a method for measuring the component to be measured in the body fluid without separating the portion containing the component to be measured from the body fluid, measurement using the absorptiometry is known. According to this method, the time required for the measurement of the component to be measured can be shortened as compared with the above-mentioned method including the step of separating the component to be measured. However, if the body fluid contains a large amount of another component different from the component to be measured, this other component may cause optical phenomena such as light absorption and light scattering, and as a result, act as a disturbing factor in measurement. be. Therefore, in order to maintain the measurement accuracy of the component to be measured, it is necessary to remove the influence of this disturbance factor, and various methods for removing the influence of the disturbance factor have been proposed.

As an apparatus and method for removing the influence of such a disturbing factor, Patent Document 2 describes a component measuring device and a component measuring method for removing the influence of the disturbing factor 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 measured value in the long wavelength region on the longer wavelength side than the measurement wavelength, and obtain the measured value at the measured wavelength. After correction using the estimated disturbance factor, the glucose concentration in the plasma component is measured by further correcting the measured value at the measurement wavelength using the hematocrit value.

Special Fair 7-34758 Gazette International Publication No. 2015/137704

According to the component measuring device 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 diligent studies to further improve the measurement accuracy of the measurement components, the position of the measurement space in which the mixture containing the color-developing components generated by the color-developing reaction between the body fluid and the reagent is housed for measuring its optical characteristics. In addition, it has been found that the optical path length of the measurement space varies or fluctuates due to the manufacturing dimensional tolerance of the member that divides the measurement space, which reduces the measurement accuracy of the component to be measured.

Therefore, an object of the present disclosure is to provide a component measuring device, a component measuring method, and a component measuring program capable of suppressing 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 device as the first aspect of the present invention measures 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-developing reaction between the component to be measured in the body fluid and the reagent. A component measuring device for measuring, wherein a flow path is partitioned inside, and the reagent is arranged in the flow path with a gap between the flow path and an opposing inner wall so as not to block the flow path. The component measuring chip to have is mountable, and the mixture is irradiated with the measurement light having a predetermined wavelength belonging to the absorption band peculiar to water in the long wavelength region above the near infrared region, which is irradiated at the position of the gap. The component to be measured is derived based on the measured value of absorbance.

In the component measuring device as one embodiment of the present invention, 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 position of the gap. Measured by a second measurement light of a second wavelength belonging to the long wavelength region and in the vicinity of the water-specific absorption band or the water-specific absorption band, which is irradiated to the mixture. A second measured value having an absorbance smaller than that of the first measured value is acquired, and the component to be measured is derived based on the difference between the first measured value and the second measured value.

The component measuring device as one embodiment of the present invention includes a third measured value which is an absorbance measured by a third measurement light of the first wavelength irradiated to the reagent before contact with the body fluid, and the above. The fourth measurement value, which is the absorbance measured by the fourth measurement light of the second wavelength, which is irradiated on the reagent before contacting with the body fluid, is obtained, and the first measurement value and the second measurement value are obtained. The component to be measured is derived based on the correction difference value which is the difference between the difference between the third measurement value and the fourth measurement value.

The component measuring device as one embodiment of the present invention measures by the fifth measurement light having a measurement wavelength belonging to a wavelength range different from the absorption band peculiar to water, which is irradiated to the mixture at the position of the gap. The fifth measured value, which is the measured absorbance, is acquired, and the fifth measured value is corrected based on the corrected difference value.

As one embodiment of the present invention, the measurement wavelength belongs to a wavelength region shorter than the first wavelength and the second wavelength.

As one embodiment of the present invention, the measurement wavelength belongs to the wavelength range corresponding to the full width at half maximum of the peak wavelength region in the absorbance spectrum of the color-developing component.

As one embodiment of the present invention, the measurement wavelength belongs to the visible region.

As one embodiment of the present invention, in the absorbance spectrum obtained by the light irradiating the mixture located in the gap, the first wavelength has a peak value of the absorbance of water in the absorption band peculiar to the water. Alternatively, it is a wavelength near the peak value, and the second wavelength is a wavelength near the hem of the absorption band peculiar to water.

In the method for measuring a component as a second aspect of the present invention, the component to be measured in the body fluid is measured based on the optical characteristics of the mixture containing the color-developing component generated by the color-developing reaction between the component to be measured in the body fluid and the reagent. A component measuring method for measuring, wherein the reagent is arranged in a flow path with a gap between the inner wall facing the flow path so as not to block the flow path, and the body fluid supplied to the gap. And, the step of irradiating the mixture located in the gap generated by the above with a measurement light having a predetermined wavelength belonging to the absorption band peculiar to water in a long wavelength region equal to or higher than the near infrared region to measure the absorbance. , A step of deriving the component to be measured based on the measured value of the measured absorbance.

The component measurement program as a third aspect of the present invention measures 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-developing reaction between the component to be measured in the body fluid and the reagent. It is a component measurement program for measurement, and is supplied to the gap with the reagent arranged in the flow path with a gap between the inner wall facing the flow path so as not to block the flow path. The absorptivity is measured by irradiating the body fluid and the mixture located in the gap generated by the body liquid with a measurement light having a predetermined wavelength belonging to an absorption band peculiar to water in a long wavelength region equal to or higher than the near infrared region. The component measuring device is made to perform the step and the step of deriving the component to be measured based on the measured value of the measured absorbance.

According to the present disclosure, it is possible to provide a component measuring device, a component measuring method, and a component measuring program capable of suppressing 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.

It is a top view of the component measuring apparatus set which attached the component measuring chip to the component measuring apparatus as one Embodiment. Of the I-I cross-sectional views of FIG. 1, it is an enlarged cross-sectional view of the vicinity of the portion where the component measurement chip is mounted. It is a top view of the component measurement chip alone shown in FIG. FIG. 2 is a sectional view taken along line II-II of FIG. FIG. 3 is a sectional view taken along line III-III of FIG. It is an electric block diagram of the component measuring apparatus shown in FIG. It is a functional block diagram of the arithmetic unit shown in FIG. It is a figure which shows the absorbance spectrum of the mixture obtained by color-reacting a blood sample and a reagent. It is a figure which shows the absorbance spectrum of each of two kinds of blood samples. It is a figure which shows the absorbance spectrum in the near-infrared region of the empty chip in the state which removed the reagent from the component measurement chip shown in FIG. It is a figure which shows the absorbance spectrum in the near infrared region of the component measurement chip shown in FIG. It is a flowchart which shows the component measurement method as one Embodiment executed by the component measuring apparatus. It is a figure which shows the experimental result of the verification experiment about the influence on the measured value of glucose concentration by the height of the gap at the time of measurement. It is a figure which shows the experimental result of the verification experiment about the influence on the measured value of glucose concentration by the height of the gap at the time of measurement. It is a figure which shows the experimental result of the verification experiment about the influence on the measured value of glucose concentration by the height of the gap at the time of measurement. It is a graph which shows the correlation between the height of a gap and the absorbance obtained by irradiating a mixture located in the gap with light belonging to an absorption band peculiar to water in the near infrared region. FIG. 17A is a graph showing the variation in absorbance at the measurement wavelength with respect to “without correction” shown in FIG. 13, and FIG. 17B is a graph showing variation in absorbance at the measurement wavelength with respect to “with correction at the time of measurement” shown in FIG. It is a graph which shows the variation of the absorbance.

Hereinafter, the component measuring device, the component measuring method, and the embodiment of the component measuring program will be described with reference to FIGS. 1 to 17. The common members in each figure are designated by the same reference numerals.

First, one embodiment of the component measuring device will be described. FIG. 1 is a top view showing a component measuring device set 100 in which a 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 cross section along the line I-I of FIG. 1 in the vicinity of the portion where the component measuring chip 2 is mounted.

The component measuring device set 100 includes a component measuring device 1 and a component measuring chip 2. The component measuring device 1 of the present embodiment is a blood glucose level measuring device capable of measuring the concentration (mg / dL) of glucose in a plasma component as a component to be measured in blood. Further, the component measuring chip 2 of the present embodiment is a blood glucose level measuring chip that can be attached to the tip of the blood glucose level measuring device as the component measuring device 1. The term "blood" as used herein means whole blood containing all the components without being separated for each component.

The component measuring device 1 is composed of, for example, a housing 10 made of a resin material, a group of buttons provided on the upper surface of the housing 10, and a liquid crystal or LED (abbreviation of Light Emitting Video) provided on the upper surface of the housing 10. The display unit 11 and the removal lever 12 that are operated when removing the component measurement chip 2 mounted on the component measurement device 1 are provided. The button group of this embodiment is composed of a power button 13 and an operation button 14.

The housing 10 has a main body portion 10a having a substantially rectangular outer shape in terms of top view, in which the above-mentioned button group and display portion 11 are provided on the upper surface (see FIG. 1), and the housing 10 is projected outward from the main body portion 10a and has an upper surface. (See FIG. 1) is provided with a chip mounting portion 10b provided with a removal lever 12. As shown in FIG. 2, a chip mounting space S having a tip opening formed on the tip surface of the chip mounting portion 10b is partitioned inside the chip mounting portion 10b. When the component measuring chip 2 is mounted on the component measuring device 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 device 1 is in a state of locking the component measuring chip 2. By setting the locked state, the mounting of the component measuring chip 2 on the component measuring device 1 is completed. Locking of the component measuring chip 2 by the component measuring device 1 can be realized by various configurations such as providing a claw portion that can engage with a part of the component measuring chip 2 in the chip mounting portion 10b.

On the contrary, when the component measuring chip 2 mounted on the component measuring device 1 is removed from the component measuring device 1, the above-mentioned removal lever 12 is operated from the outside of the housing 10. By this operation, the locked state of the component measuring chip 2 by the chip mounting portion 10b of the component measuring device 1 is released, and the eject pin 26 (see FIG. 2) in the housing 10 moves in conjunction with the component measuring chip. 2 can be removed from the component measuring device 1.

The housing 10 of the present embodiment has a configuration including a substantially rectangular main body portion 10a in a top view (see FIG. 1) and a chip mounting portion 10b projecting outward from the main body portion 10a. The configuration is not limited to the shape of the housing 10 of the present embodiment as long as it is configured to include a chip mounting portion on which the measuring chip 2 can be mounted. Therefore, in addition to the shape of the housing 10 of the present embodiment, it is possible to adopt various shapes, for example, to make it easier for the user to hold the housing 10 with one hand.

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 glucose level measuring device as the component measuring device 1 can be displayed on the display unit 11. The display unit 11 may be capable of displaying not only information on the component to be measured but also various information such as measurement conditions of the component measuring device 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 checking the contents displayed on the display unit 11.

Next, the component measurement chip 2 alone will be described. FIG. 3 is a top view showing the component measuring chip 2. Further, FIG. 4 is a cross-sectional view taken along the line II-II of FIG. FIG. 5 is a cross-sectional view taken along the line III-III of FIG. As shown in FIGS. 3 to 5, the component measuring chip 2 has a flow path 23 internally partitioned. Further, in the flow path 23 of the component measurement chip 2, a color-developing reagent 22 as a reagent is arranged with a gap 28 separated from an inner wall facing the flow path 23 so as not to block the flow path 23.

More specifically, the component measuring chip 2 of the present embodiment includes a base member 21 having a substantially rectangular plate-like outer shape, a cover member 25 arranged so as to cover the base member 21, and a base member 21. It includes two spacer members 27 that maintain a predetermined distance between the cover member 25 and the cover member 25. The flow path 23 of the component measurement chip 2 of the present embodiment is formed by being surrounded by a base member 21, a cover member 25, and two spacer members 27. Further, the color-developing 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 for partitioning the flow path 23. A gap 28 is formed between the applied color-developing reagent 22 and the lower surface of the cover member 25 as an inner wall for partitioning the flow path 23.

The flow path 23 extends in a direction orthogonal to the thickness direction of the component measuring chip 2, and penetrates from one side end to the other side end of the component measuring chip 2. 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 capable of supplying blood into the flow path 23 from the outside. The blood supplied from the outside to the supply unit 24 moves along the flow path 23 due to, for example, a capillary phenomenon, reaches the gap 28 of the flow path 23, and comes into contact with the color-developing reagent 22. When the blood comes into contact with the color-developing reagent 22, glucose as a component to be measured in the blood and the color-developing reagent 22 cause a color reaction. A color-developing component is generated by this color reaction. Therefore, at the holding position where the color-developing reagent 22 is held and the position of the gap 28, a mixture containing blood and the color-developing component produced by the above-mentioned color reaction is produced.

The flow path 23 of the present embodiment is partitioned by a base member 21, a cover member 25, and two spacer members 27, but the number of members for partitioning 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 only by two members, a base member having a groove 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 partitioned by three or less members. Further, the flow path may be partitioned by five or more members. The flow path 23 of the present embodiment extends linearly in the top view (see FIG. 3) and the cross-sectional view shown in FIG. 5, but is bent, for example, in the top view and the same cross-sectional view as in FIG. It may be extended, or it may be uniformly curved and extended.

As the material of the base member 21 and the cover member 25, it is preferable to use a transparent material for transmitting light. For example, transparent organic resin materials such as polyethylene terephthalate (PET), polymethylmethacrylate (PMMA), polystyrene (PS), cyclic polyolefin (COP), cyclic olefin copolymer (COC), polycarbonate (PC); glass, quartz and the like. Transparent inorganic materials;

Further, the spacer member 27 can be formed of the same material as the base member 21 and the cover member 25 regardless of whether the spacer member 27 is transparent or opaque. For example, organic resin materials such as polyethylene terephthalate (PET), polymethylmethacrylate (PMMA), polystyrene (PS), cyclic polyolefin (COP), cyclic olefin copolymer (COC), and polycarbonate (PC); inorganic materials such as glass and quartz. ; Can be mentioned. The spacer member 27 formed of these materials is adhered to the base member 21 and the cover member 25 using an adhesive, but instead of such a configuration, it has a base material formed of the above-mentioned materials. Double-sided tape may be used.

The color-developing reagent 22 as a reagent reacts with a component to be measured in blood to cause a color reaction in which a color is developed according to the blood concentration of the component to be measured. Is applied on the base member 21. The color-developing reagent 22 of the present embodiment reacts with glucose as a component to be measured in blood. Examples of the color-developing reagent 22 of the present embodiment include (i) glucose oxidase (GOD), (ii) peroxidase (POD), and (iii) 1- (4-sulfophenyl) -2,3-dimethyl-4-amino. A 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 electronic mediator. In addition, a buffer such as a phosphate buffer may be included. The types and components of the color-developing reagent 22 are not limited to these.

However, in the color-developing reagent 22 of the present embodiment, the peak wavelength in the absorbance spectrum of the color-developing component generated by the color reaction between glucose in blood and the color-developing reagent 22 is the peak wavelength due to the light absorption characteristics of hemoglobin in blood cells. I am using something different from. The color-developing reagent 22 of the present embodiment has a peak wavelength in the vicinity of 650 nm in the absorbance spectrum of the color-developing component generated by the color reaction between glucose in blood and the color-developing reagent 22, but is limited to those having a peak wavelength in the vicinity of 650 nm. No. The details will be described later.

As shown in FIG. 2, when the component to be measured is measured by the component measuring device 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 due to, for example, a capillary phenomenon, reaches the gap 28 of the flow path 23, and is as described above. At the holding position of the color-developing reagent 22 and the position of the gap 28, a mixture containing blood and a color-developing component generated by a color reaction between the blood and the color-developing reagent 22 is produced.

The so-called colorimetric component measuring device 1 irradiates light toward the mixture generated at the holding position of the color-developing reagent 22 and the position of the gap 28, detects the amount of transmitted light (or the amount of reflected light), and detects the blood concentration. A detection signal that correlates with the intensity of color development corresponding to the above is obtained. Then, the component measuring device 1 can measure the component to be measured by referring to the calibration curve created in advance. The component measuring device 1 of the present embodiment measures the glucose concentration (mg / dL) in the plasma component in blood.

FIG. 6 is an electric block diagram of the component measuring device 1 shown in FIGS. 1 and 2. For convenience of explanation, FIG. 6 also shows a cross section (same cross section as in FIG. 4) of the component measuring chip 2 mounted on the component measuring device 1. Further, in FIG. 6, an enlarged view of the vicinity of the component measuring chip 2 is separately shown in the upper left. Further details of the component measuring device 1 will be described below.

As shown in FIG. 6, the component measuring device 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. A memory 62, a power supply circuit 63, and a measurement optical system 64 are further provided.

The arithmetic unit 60 is composed of an MPU (Micro-Processing Unit) or a CPU (Central Processing Unit), and can realize control operations of each unit by reading and executing a program stored in a memory 62 or the like. The memory 62 is composed of a non-transient storage medium that is volatile or non-volatile, and can read or write various data (including a component measurement program) necessary for executing the component measurement method shown here. be. The power supply circuit 63 supplies or stops the supply of electric power to each unit in the component measuring device 1 including the arithmetic unit 60 in response 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 a color-developing reagent 22 as a reagent. Specifically, the measurement optical system 64 includes a light emitting unit 66, a light emitting control circuit 70, a light receiving unit 72, and a light receiving control circuit 74.

The light emitting unit 66 of the present 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 radiation characteristics (for example, visible light and near-infrared light). Hereinafter, for convenience of explanation, the light source 67a is the "first light source 67a", the light source 67b is the "second light source 67b", the light source 67c is the "third light source 67c", the light source 67d is the "fourth light source 67d", and the light source 68 is " The fifth light source 68 ”is described.

Hereinafter, the wavelength of the light emitted from the first light source 67a is referred to as the first wavelength λ1. Further, the wavelength of the light emitted from the second light source 67b is defined as the second wavelength λ2. Further, the wavelength of the light emitted from the third light source 67c is defined as the third wavelength λ3. Further, the wavelength of the light emitted from the fourth light source 67d is set to the fourth wavelength λ4. The wavelength of the light emitted from the fifth light source 68 is defined as 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 of the first wavelength λ1 to the fifth wavelength λ5 and their characteristics will be described later.

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 Light Source) Various light emitting elements including an element can be applied. As a light source that emits light in the near infrared region, for example, an LED element, an incandescent light bulb, a halogen lamp, or the like can be used. Further, in the present embodiment, the light having each wavelength of the first wavelength λ1 to the fifth wavelength λ5 is emitted by different light sources. For example, one light source capable of emitting light of a plurality of wavelengths in the visible region is used. It is also possible to use it. 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 drawn side by side in a row, but the arrangement is limited to such an arrangement. No.

As shown in FIGS. 2 and 6, the light receiving unit 72 of the present embodiment is composed of one light receiving element arranged so as to face each other with the light emitting unit 66 and 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 color-developing reagent 22 of the component measuring chip 2 and the position of the gap 28, and causes the component measuring chip 2 to pass through. Receives transmitted transmitted light. 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 PhotoTransistor) can be applied.

The light emission control circuit 70 turns on or off the first light source 67a to the fifth light source 68 by supplying a drive power signal to each of the first light source 67a to the fifth light source 68. The light receiving control circuit 74 acquires 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 each function of the measurement instruction unit 76 that instructs the measurement operation by the measurement optical system 64 and the concentration measurement unit 77 that measures the concentration of the component to be measured using various data.

The concentration measuring unit 77 includes an absorbance acquisition unit 78 and an absorbance correction unit 84.

In FIG. 7, the memory 62 is stored in the memory 62 based on the measurement value data 85 of the absorbance 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 that correlate with the calculated secondary data, and the measurement value of the absorbance of the mixture measured at the measurement wavelength or the correction measurement value obtained by correcting this measurement value with the correction data 86. It stores calibration curve data 90 such as a calibration curve showing the relationship between and various physical quantities (for example, glucose concentration) and a calibration curve showing the relationship between the absorbance of hemoglobin in the mixture and the hematocrit value. The "hematocrit value" is a percentage of the volume ratio of blood cell components in blood to blood (whole blood).

Hereinafter, the coloration reaction of glucose in blood as a component to be measured in body fluid and the color-developing reagent 22 is carried out with blood (whole blood) and color-developing reagent 22 without separating the plasma component containing glucose from blood. A component measuring method for measuring the glucose concentration in blood based on the optical properties of the mixture containing the color-developing component generated by this color-developing reaction will be described.

First, with reference to FIGS. 8 and 9, the problem in trying to estimate the component to be measured in blood based on the 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.

FIG. 8 shows an absorbance spectrum of a mixture obtained by color-reacting a blood sample having a known hematocrit value and glucose concentration with a color-developing reagent 22. The blood sample used here has a hematocrit value of 40% and a glucose concentration of 400 mg / dL (denoted as "Ht40 pg400" in FIG. 8).

In addition, 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 (denoted as "Ht20 pg400" in FIG. 9). The second blood sample has a hematocrit value of 40% and a glucose concentration of 400 mg / dL (denoted 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% and a glucose concentration of 0 mg / dL, a hematocrit value of 20%, and a glucose concentration of 100 mg / The absorbance of the 4th blood sample of dL, the 5th blood sample having a hematocrit value of 40% and a glucose concentration of 0 mg / dL, and the 6th 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 with the same hematocrit value are substantially the same. Therefore, in FIG. 9, the absorbance of the first blood sample (hematocrit value is 20%) is taken as an example of two blood samples having different hematocrit values. Only the spectrum and the absorbance spectrum of the second blood sample (hematocrit value is 40%) are shown.

Generally, when a component other than the color-developing component to be measured is contained in the sample, the occurrence of an optical phenomenon may affect the measurement result of the color-developing component. For example, "light scattering" due to blood cell components in blood and "light absorption" due to a component other than the color-developing component (specifically, hemoglobin) are generated, so that the absorbance larger than the true value is measured. Tends to be.

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 becomes longer, and have two peaks centered around 540 nm and 570 nm. These two peaks are mainly due to the light absorption of hemoglobin in erythrocytes. Further, in the absorbance spectra of the two blood samples shown in FIG. 9, in the wavelength range of 600 nm or more, the absorbance gradually decreases in a substantially linear manner as the wavelength becomes longer. This substantially linear portion is mainly caused by light scattering by blood cell components and the like.

In other words, the absorbance of the blood sample in the wavelength range on the longer wavelength side than around 600 nm is dominated by the influence of light scattering by blood cell components and the like, and the absorbance of the blood sample in the wavelength range on the shorter wavelength side than around 600 nm is dominant. The effect of light absorption by hemoglobin is greater than the effect of light scattering by blood cell components and the like.

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 becomes longer, similar to the absorbance spectrum of the blood sample shown in FIG. 9, but is compared with the curve shown in FIG. As a result, it can be seen that the absorbance increases over the visible region of 600 nm to 700 nm. The absorbance increasing from around 600 nm to 700 nm is mainly due to the absorbance characteristics of the color-developing component generated by the color reaction between glucose in blood and the color-developing reagent 22.

In this way, when the absorbance of the color-developing component derived from the dye component is accurately measured by using a mixture containing blood having the absorption characteristics shown in FIG. 9 in addition to the color-developing component to be measured, a predetermined measurement is performed. It is necessary to remove the influence (noise) such as light scattering by blood cell components and light absorption by hemoglobin from the measured value of absorbance at a wavelength (for example, 650 nm).

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 and the same. It is necessary to correct the measured value of absorbance at the measurement wavelength.

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 sample, 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 then the color is developed in the mixture. It is necessary to derive the absorbance of the component. However, the existing component measuring device does not consider 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 water absorption of the color-developing reagent 22 in the natural environment, the influence of swelling or dissolution of the color-developing reagent 22 due to the color reaction, and the dimensional tolerance in manufacturing the component measurement chip. It fluctuates due to such factors. When the height h of the gap 28 fluctuates, the amount of blood located in the gap 28 also fluctuates. Therefore, when the fluctuation of the height h of the gap 28 is not taken into consideration, the measurement accuracy is lowered in the measurement of the component to be measured in the blood, for example, the measurement of the glucose concentration in the blood, and the accurate glucose concentration in the blood is reduced. Cannot be measured.

FIG. 10 is a graph showing the difference in the absorbance of water 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 color-developing reagent 22 is removed from the component measurement chips 2 shown in FIGS. 3 to 5. More specifically, in FIG. 10, the height H of the flow path 23 is 30 μm, and the absorbance spectrum at the first empty chip in the state where there is no water in the flow path 23 (in FIG. 10, “30 μm no water”). (Notation), the absorbance spectrum of the second empty chip in the state where the height H of the flow path 23 is 50 μm and there is no water in the flow path 23 (denoted as “50 μm no water” in FIG. 10), and the flow. The absorptivity spectrum (denoted as "60 μm no water" in FIG. 10) of the third empty chip in a state where the height H of the road 23 is 60 μm and there is no water in the flow path 23, and the height of the flow path 23. The absorbance spectrum of the fourth empty chip in a state where H is 30 μm and the inside of the flow path 23 is filled with water (denoted as “30 μm water” in FIG. 10) and the height H of the flow path 23 is 50 μm. The absorbance spectrum of the fifth empty chip (denoted as "50 μm water" in FIG. 10) in a state where the inside of the flow path 23 is filled with water, and the height H of the flow path 23 is 60 μm, and the flow It is shown as an absorbance spectrum (denoted as "60 μm water" in FIG. 10) at the sixth empty chip in a state where the inside of the road 23 is filled with water. The width W of the flow path 23 (see FIG. 3) is the same for the first empty chip to the sixth empty chip. 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. It shows the absorbance by the light irradiated to.

As shown in FIG. 10, the absorbance spectra of the first empty chip to the third empty chip in the 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 a peak value of absorbance at 1820 nm to 2000 nm, which is one of the absorption bands peculiar to water. The "absorption band peculiar to water" means a peak wavelength region in which the absorbance of water appears as a peculiar 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). Examples thereof include a region and a wavelength region of 1300 nm to 1650 nm in the near infrared region.

On the other hand, the absorbance spectra of the 4th to 6th empty chips in the state where the flow path 23 is filled with water show the same trend as a whole, but all of them have an absorption band peculiar to water. It has a peak value of absorbance at 1820 nm to 2000 nm. The fourth to sixth empty chips in a state where the inside of the flow path 23 is filled with water have an absorbance spectrum in which the peak value of the absorbance of water differs depending on the height H of the flow path 23. Specifically, when the fourth empty chip to the sixth empty chip are compared, it can be seen that the higher the height H of the flow path 23, the higher the peak value of the absorbance of water.

In this way, if 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 peculiar to water also has a different value depending on the amount of water. It can be seen that it shows.

FIG. 11 is a diagram showing an absorbance spectrum in the near infrared region of the component measuring chip 2 having the color-developing reagent 22. Specifically, FIG. 11 shows the absorbance spectrum at the position of the gap 28 when water containing no glucose was used as the sample (denoted as “bg0” in FIG. 11), and the glucose concentration as the sample was 100 mg / mg /. The absorbance spectrum at the position of the gap 28 when dL glucose water was used (denoted as “bg100” in FIG. 11) and the position of the gap 28 when glucose water having a glucose concentration of 400 mg / dL was used as the sample. (Indicated as "bg400" in FIG. 11) and the absorbance spectrum of the color-developing reagent 22 in the component measuring chip 2 in a state where no sample is placed in the flow path 23 (the gap 28 is a void state) (FIG. 11). In the above, it is expressed as "ini") and four absorbance spectra.

FIG. 11 shows three absorbance spectra using a chip having a height of H = 50 μm and using water and glucose water as samples. As shown in FIG. 11, the three absorbance spectra using water and glucose water as the sample are substantially in agreement. All of these three absorbance spectra have similar absorbance peaks in the wavelength range of 1820 nm to 2000 nm, which is an absorption band peculiar to water. That is, it can be seen that the peak value in the absorption band peculiar to water (maximum absorbance in one absorption band peculiar to water) is not related to the presence or absence of glucose and the difference in glucose concentration. Further, as shown in FIG. 11, the absorbance spectra of the color-developing reagent 22 containing no sample do not match the three absorbance spectra described above. However, even in the absorbance spectrum of the color-developing reagent 22 without a sample, it can be seen that it has a small peak in the absorption band peculiar to water. This is because the color-developing reagent 22 itself contains some water.

From FIGS. 10 and 11, if the mixture located in the gap 28 is irradiated with light having a wavelength belonging to the absorption band peculiar to water, the water content contained in the mixture is not limited to 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.

However, the height h of the gap 28 of each component measuring chip 2 is actually measured by a film thickness meter or the like, and the correction value corresponding to the measured value is taken into the individual component measuring device 1 as calibration information. Causes a great deal of time and effort for users such as patients and medical staff, and leads to an increase in the size of measured component values, which impairs the convenience of the user. Further, it is not easy in manufacturing to make the allowable dimensional tolerance of the height h of the gap 28 of the component measurement chip 2 extremely small so that the optical path length of the measurement space does not need to be corrected. Further, it does not reflect the height h of the gap 28 as the optical path length of the measurement space in the state where the body fluid as a sample is in contact with the reagent and a mixture is formed in the gap 28.

Therefore, in the component measuring device 1, when measuring the absorbance of the color-developing component in the mixture by utilizing the above-mentioned characteristics (hereinafter, simply referred to as “at the time of measurement”), the gap 28 as the optical path length of the measurement space 28 Estimate the height h of. Specifically, since blood plasma contains water, if the mixture located in the gap 28 is irradiated with light belonging to the absorption zone peculiar 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, by using a calibration curve showing a 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 can be estimated. Is possible. The component measuring device 1 estimates the height h of the gap 28 at the time of measurement, and based on this estimation, corrects the measured value of the component to be measured in the body fluid. This makes it possible to improve the measurement accuracy of the component to be measured.

Hereinafter, a component measuring method as an embodiment, which is executed by the component measuring device 1, will be described in detail.

The component measuring device 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 in the body fluid and the reagent. Specifically, in the present embodiment, plasma in blood is utilized by utilizing the optical properties of a mixture containing glucose in blood as a component to be measured in body fluid and a color-developing reagent 22 as a reagent. Measure the concentration of glucose contained in the component.

FIG. 12 is a flowchart showing a component measuring method executed by the component measuring device 1. As shown in FIG. 12, the component measuring method executed by the component measuring device 1 is a gap 28 (FIG. 5) in the flow path 23 (see FIG. 5 and the like) between the flow path 23 and the inner wall so as not to block the flow path 23. Etc.), and the mixture located in the gap 28 produced by the color-developing reagent 22 arranged at a distance from the gap 28 and the blood as a body fluid supplied to the gap 28, has a long wavelength longer than the near infrared region. Derivation of the component to be measured based on step S1 in which the absorbance is measured by irradiating the first measurement light of the first wavelength λ1 belonging to the absorption band peculiar to water in the region and the measured value of the absorbance measured in step S1. The step S2 for deriving the glucose concentration in the blood is included.

In step S1, the component measuring device 1 estimates the height h of the gap 28 at the time of measurement as the optical path length of the measuring space at the time of measurement in the component measuring chip 2 mounted on the component measuring device 1. Specifically, the component measuring device 1 irradiates the mixture located in the gap 28 with measurement light having a predetermined wavelength which is a long wavelength region equal to or higher than the near infrared region and belongs to an absorption band peculiar to water, and this measurement is performed. Obtain the measured value of absorbance by light.

In the component measuring device 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 the instruction of the calculation unit 60. The first wavelength λ1 is a predetermined wavelength in the near-infrared region and belongs to an absorption band peculiar to water, and in the present embodiment, it is a wavelength at which the absorbance of water reaches a peak value in the absorption band peculiar to water. .. Specifically, in the present embodiment, 1820 nm to 2000 nm, in which the peak of water absorbance is prominent, is used as the absorption band peculiar to water. The wavelength at which the absorbance of water reaches its peak value in this absorption band is 1940 nm.

As shown in FIGS. 2 and 6, the first measurement light having the first wavelength λ1 passes through the component measurement chip 2 at the position of the gap 28 of the component measurement chip 2 in the thickness direction of the component measurement chip 2. Then, the transmitted light transmitted through the component measuring chip 2 is received by the light receiving unit 72. Thereby, the absorbance of the mixture located in the gap 28 at the first wavelength λ1 belonging to the absorption band peculiar to water can be measured. Hereinafter, for convenience of explanation, the measured value of absorbance measured here will be referred to as “first measured value”.

For example, by using a calibration curve showing 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 is obtained from the first measured value. Can be estimated. Then, in step S2, which will be described later, the glucose concentration in blood is derived based on the first measured value.

Here, in the present embodiment, in order to further improve the estimation accuracy of the height h of the gap 28 at the time of measurement, the mixture belongs to the long wavelength region equal to or larger than the near infrared region with respect to the mixture at the position of the gap 28, and By irradiating the second measurement light of the second wavelength λ2 in the vicinity of the absorption band peculiar to water or the absorption band peculiar to water, the second measurement value having an absorbance smaller than the first measurement value is acquired. Then, in step S2, the glucose concentration is derived based on the difference between the first measured value and the second measured value. In FIG. 12, the step of acquiring the above-mentioned second measured value is shown as step S1-2.

By using such a difference value, it is possible to remove the influence on the absorbance by components other than water, such as the influence due to blood cell scattering, etc., so that 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 more accurately.

Further, in the present embodiment, in the absorbance spectrum obtained by the light irradiating the mixture located in the gap 28, the first wavelength λ1 has a peak value or a peak value of the absorbance of water in the absorption band peculiar to water. The wavelength is set to be in the vicinity, and the second wavelength λ2 is set to the wavelength near the hem of the absorption band peculiar to water. In this way, it becomes possible to more clearly identify the difference in absorbance depending on the amount of water while removing the influence of components other than water on the absorbance. In the present embodiment, the first wavelength λ1 is set to 1940 nm, and the second wavelength λ2 is set to 1820 nm, which corresponds to the hem of the absorption band peculiar to water. As the second wavelength λ2, since it may be near the hem of the absorption band peculiar to water, for example, 1760 nm may be used.

Furthermore, in the present embodiment, in order to further improve 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 color-developing reagent 22 before contact with blood as a body fluid is used. It is 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 contacting with blood. The fourth measured value, which is the absorptivity, is obtained. Then, in step S2, glucose is based on a corrected difference value which is a further difference between the difference between the first measured value and the second measured value and the difference between the third measured value and the fourth measured value. Derivation of concentration. In FIG. 12, the step of acquiring the above-mentioned third measured value and the fourth measured value is shown as step S1-0.

By doing so, it is possible to remove the influence of the water content contained in the reagent itself on the absorbance, and to improve 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. It will be possible to further increase it.

The absorbance acquisition unit 78 of the component measuring device 1 acquires the measured values at the first wavelength λ1 and the second wavelength λ2 described above, respectively. Specifically, the mixture is irradiated with the irradiation light of the first wavelength λ1 and the second wavelength λ2 from the first light source 67a and the second light source 67b of the light emitting unit 66, respectively. Then, the light receiving unit 72 receives the transmitted light transmitted through the component measurement chip 2 among the respective irradiation lights. Then, the calculation unit 60 stores the measured 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 measured value data 85. Further, the absorbance acquisition unit 78 of the component measuring device 1 can acquire the measured value data 85 from the memory 62. The means for the absorbance acquisition unit 78 to acquire the above-mentioned measured value is not limited to the above-mentioned means, and can be acquired by various known means.

Hereinafter, in step S2, a method for deriving the glucose concentration will be described in detail.

First, the color-developing reagent 22 used in the present embodiment uses a reagent having a peak in the absorbance of the color-developing component generated by the color reaction with glucose in blood at around 600 nm. The measurement wavelength for measuring the absorbance is 650 nm.

If 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 the influence of the light absorption of hemoglobin is relatively small, the wavelength is used. good. For example, the wavelength may be a wavelength that corresponds 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 that the ratio of the absorbance due to the light absorption of hemoglobin to the total absorbance belongs to a relatively small wavelength range. The wavelength range "corresponding to the full width at half maximum of the peak wavelength range" means the half value on the long wavelength side from the wavelength showing the half value on the short wavelength side when the half width full width range of the peak wavelength range is specified in the absorbance spectrum. It means the range up to the wavelength. The absorbance spectrum of the color-developing component to be measured in this embodiment has a peak wavelength of about 600 nm and a wavelength range of about 500 nm to about 700 nm corresponding to the full width at half maximum. In addition, the effect of light absorption of hemoglobin on the total absorbance is relatively small in the wavelength range of 600 nm or more. Therefore, in the present 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 the ratio of the absorbance due to the light absorption of hemoglobin to the total absorbance is 600 nm. It is more than 700 nm and less than 700 nm. Therefore, the measurement wavelength is not limited to 650 nm of 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 wavelength range where the signal indicating the absorbance of the color-developing component is strong and the ratio of the absorbance by light absorption of hemoglobin to the total absorbance is very small, the absorbance of the color-developing component can be measured more accurately. It is preferable that the measurement wavelength is around 650 nm, which is a slightly longer wavelength than the peak wavelength of around 630 nm. More specifically, the measurement wavelength is preferably a wavelength belonging to the range of 630 nm to 680 nm, more preferably a wavelength belonging to the range of 640 nm to 670 nm, and particularly preferably 650 nm as in the present embodiment. preferable. As an example of such a pigment component, a tetrazolium salt is preferable, and for example, WST-4 is most preferable.

Further, in the present embodiment, the color-developing reagent 22 is used so that the full width at half maximum of the peak wavelength region in the absorbance spectrum of the color-developing component is about 500 nm to about 700 nm, but the full width at half maximum of the peak wavelength region is in this range. You may use a color-developing reagent different from the above. However, as described above, in consideration of the absorbance characteristics of hemoglobin, it is desirable that the wavelength range (600 nm or less) in which the absorbance of hemoglobin due to light absorption increases and the measurement wavelength in the absorbance spectrum of the color-developing component do not overlap.

Further, it is desirable that the measurement wavelength is a wavelength that does not belong to the absorption band peculiar to water. The measurement wavelength of the present embodiment belongs to a shorter wavelength region 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 peculiar to water, and the measurement wavelength is a visible region which is a shorter wavelength region than the near infrared region. Wavelengths belonging to (380 nm to less than 800 nm) are used.

Hereinafter, a method for estimating the absorbance of the color-developing component at the measurement wavelength of 650 nm of the present embodiment will be described. The component measuring device 1 measures the absorbance of the mixture at two third wavelengths λ3 and the fourth wavelength λ4, which are different from the measurement wavelength (650 nm), respectively, and uses these two measured values and predetermined correction data 86. Then, the measured value of the absorbance of the mixture at the measurement wavelength is corrected, and the absorbance of the color-developing component at the measurement wavelength is estimated. Hereinafter, for convenience of explanation, the measurement wavelength will be referred to as “fifth wavelength λ5”. Further, the measured value of the absorbance of the mixture at the measurement wavelength is described as "fifth measured value".

Specifically, the component measuring device 1 has, as the above-mentioned two measured values, a measured value of the absorbance of the mixture at the third wavelength λ3 on the longer wavelength side than the fifth wavelength λ5, which is the measured wavelength, and the measured wavelength. The measured value of the absorbance of the mixture at the fourth wavelength λ4 on the shorter wavelength side than the fifth wavelength λ5 is used.

More specifically, as the above-mentioned two measured values, water belongs to a wavelength range in which the influence of light scattering such as blood cell components is dominant in the total absorbance on the longer wavelength side than the fifth wavelength λ5 which is the measurement wavelength. The measured value of the absorbance of the mixture in the third wavelength λ3, which belongs to a wavelength range different from the absorption band peculiar to The measured value of the absorbance of the mixture at the fourth wavelength λ4 belonging to the large wavelength region is used.

By using the measured value of the absorbance of the mixture at the third wavelength λ3, it is possible to estimate the influence of light scattering of blood cell components and the like at the fifth wavelength λ5, which is the measurement wavelength. Further, by using the measured value of the absorbance of the mixture at the fourth wavelength λ4, it is possible to estimate the influence of the light absorption of hemoglobin at the fifth wavelength λ5, which is the measurement wavelength, and to calculate the hematocrit value. In this embodiment, 760 nm is used as the third wavelength λ3, and 540 nm is used as the fourth wavelength λ4.

The absorbance acquisition unit 78 of the component measuring device 1 acquires the measured values at the third wavelength λ3 and the fourth wavelength λ4 described above, and the fifth measured value at the fifth wavelength λ5. Specifically, the mixture is irradiated with irradiation light of the third wavelength λ3, the fourth wavelength λ4, and the fifth wavelength λ5 from the third light source 67c, the fourth light source 67d, and the fifth light source 68 of the light emitting unit 66, respectively. .. Then, the light receiving unit 72 receives the transmitted light transmitted through the mixture among the respective irradiation lights. Then, the calculation unit 60 stores the measured 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 measured value data 85. The absorbance acquisition unit 78 of the component measuring device 1 can acquire the measured value data 85 from the memory 62. The means for the absorbance acquisition unit 78 to acquire the above-mentioned measured value is not limited to the above-mentioned means, and can be acquired by various known means.

Then, the absorbance correction unit 84 of the component measuring device 1 is based on the first to fourth measured values measured in step S1 and the measured values of absorbance 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 device 1 includes the difference correction value derived in step S1, the measured value at the third wavelength λ3 derived in step S2, and the measured value at the fourth wavelength λ4. Is used to correct the fifth measurement value at the fifth wavelength λ5, and the absorbance of the color-developing component at the fifth wavelength λ5 (650 nm in this example), which is the measurement wavelength, is estimated.

Hereinafter, the correction method by the absorbance correction unit 84 of the component measuring device 1 will be described.

As described above, in the memory 62 of the component measuring device 1, the measured value data 85 which 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 each of the above measured values. The relationship between the group of correction data 86 corresponding to and the absorbance of the color-developing component in the mixture obtained by correcting the absorbance of the mixture measured at the fifth wavelength λ5 with the correction data 86 and various physical quantities such as glucose concentration is shown. The calibration curve data 90 and is stored.

The absorbance correction unit 84 has the absorbance of the color-developing component at the fifth wavelength λ5, which is the measurement wavelength, based on the measurement value data 85, the correction data 86, and the calibration curve data 90 stored in the memory 62 acquired by the absorbance acquisition unit 78. Is derived.

Here, 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 peculiar to water in the near infrared region. Further details 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 peculiar to water in the near infrared region. It is a graph which shows the relationship. Specifically, in FIG. 16, for each of the plurality of component measuring chips 2 having different heights h of the gap 28, the measured value of the height h of the gap 28 measured by the film thickness meter and the absorption band peculiar to water are set. The measured values of absorbance obtained by irradiating the mixture located in the gap 28 with the light to which it belongs are shown (see the points plotted in FIG. 16). The coating thickness of the color-developing reagent 22 is substantially constant in any of the component measuring chips 2. 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 peculiar to water. It can be seen that the relational expression (graph, correlation coefficient) between the two can be derived as shown by the approximate straight line shown in FIG.

The height h of the gap 28 at each point shown in FIG. 16 is measured by an Optical MicroGauge thickness meter (C11011-01) manufactured by Hamamatsu Photonics Co., Ltd. as a film thickness meter. Further, the measured absorbance at each point shown in FIG. 16 is a 9-second value, which is the absorbance 9 seconds after the sample comes into contact with the color-developing reagent 22 by measuring the absorbance at a wavelength peculiar to water, and the sample is It is measured by calculating the difference between the initial value, which is the absorbance before contacting the color-developing reagent 22, and the difference. More specifically, first, the difference between the above-mentioned first measured value as a 9-second value at 1940 nm and the above-mentioned second measured value as a 9-second value at 1820 nm is calculated. Next, the difference between the above-mentioned third measured value as the initial value at 1940 nm and the above-mentioned fourth measured value as the initial value at 1820 nm is calculated. Then, a further difference between the difference of the 9-second value and the difference of the initial value is calculated, and in FIG. 16, this difference value is used as the measured value of the absorbance at each point. Here, 1820 nm is used as the wavelength near the hem of the absorption band peculiar to water, but 1760 nm may be used instead.

Finally, a verification experiment was conducted using glucose-free water and glucose water to determine the magnitude of the effect of the height h of the gap 28 during measurement as the optical path length of the measurement space during measurement on the measured value of glucose concentration. Was done. 13 and 14 show glucose-free water, glucose water having a glucose concentration of 100 mg / dL (denoted as “bg100” in FIGS. 13 and 14), and glucose water having a glucose concentration of 400 mg / dL (FIG. 13 and 14). When the optical path length of the measurement space is not corrected (indicated as "no correction" in FIGS. 13 and 14) for 13 and FIG. 14 (indicated as "bg400"), the height h of the gap 28 before measurement When correcting the optical path length of the measurement space using the measured value (indicated as "pre-measurement correction" in FIG. 13 and not shown in FIG. 14), and as in the present embodiment, the gap at the time of measurement. When the height h of 28 is estimated and the optical path length of the measurement space is corrected using this estimated value (indicated as “corrected at the time of measurement” in FIGS. 13 and 14), the derived glucose concentration is obtained. It shows the variation of the measured value of. The variation in the measured values shown in FIGS. 13 and 14 was evaluated by doubling the standard deviation (2SD) of the deviation from the true value of the absolute value (mg / dL) of the concentration for water containing no glucose concentration. , Glucose water having a glucose concentration of 100 mg / dL and 400 mg / dL is evaluated by a value (2SD value) that is 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 by an Optical MicroGauge thickness gauge (C11011-01) manufactured by Hamamatsu Photonics Co., Ltd.

Further, FIG. 13 shows the influence on the measured value of the glucose concentration in the case where the height h (see FIG. 5) of the gap 28 of the permissible component measurement chip 2 varies widely. Specifically, FIG. 13 shows the results of an experiment using 15 component measuring chips 2 in which the height h of the gap 28 varies in the range of 20.4 μm to 53.4 μm. The width of the gap 28 is constant.

As shown in FIG. 13, when the optical path length of the measurement space is not corrected, it can be seen that the derived glucose concentration varies widely and the accuracy of the derived glucose concentration is low. On the other hand, when the measured value of the height h of the gap 28 before the measurement is used to correct the optical path length of the measurement space, the deviation of the derived glucose concentration is compared with the case where the measurement is not corrected. It turns out to be very small. Further, 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 this estimated value is used to correct the optical path length of the measurement space, The variation in the derived glucose concentration is even smaller than when it is not corrected and when it is corrected using the measured 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 expensive.

Further, FIG. 17A is a graph showing the variation in absorbance at the measurement wavelength (here, 650 nm is used) for “without 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 sample. As shown in FIG. 17A, it can be seen that even if 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 height h of the gap 28. Similarly, even if the glucose concentration of the sample is 400 mg / dL, it can be seen that the absorbance at the measurement wavelength varies greatly due to the difference in the height h of the gap 28. In this way, the volume of the sample flowing into the gap 28 differs due to the difference in the height h of the gap 28, so that the amount of color-developing component observed in the measurement optical path, that is, the absorbance at the measurement wavelength varies. Can be confirmed. The straight line shown in FIG. 17A is an approximate straight line drawn forcibly, but there is a correlation between the glucose concentration and the absorbance at the measurement wavelength (the linearity in which each point is aligned on one straight line in FIG. 17A). ) Is missing.

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 at the time of measurement” shown in FIG. Similar to the horizontal axis of FIG. 17 (a), the horizontal axis of FIG. 17 (b) is the absorbance at the measurement wavelength, and the vertical axis of 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 make a correction in consideration of the height h of the gap 28 by measuring the absorption peculiar to water in the near infrared region. In other words, by measuring the absorption peculiar to water in the near infrared region and correcting the height h of the gap 28, the amount of glucose of the mixture at the position of the gap 28 and thus the gap 28 can be determined from the absorbance at the measurement wavelength. The glucose concentration at the position can be calculated more accurately.

Further, FIG. 14 shows the effect on the measured value of the glucose concentration when the variation in the height h (see FIG. 5) of the gap 28 of the permissible component measurement chip 2 is very small. Specifically, FIG. 14 shows the results of an experiment using a plurality of component measuring chips 2 in which the height h of the gap 28 varies within a range of 40 ± 1 μm. The width of the gap 28 is constant.

Since the variation in the height h (see FIG. 5) of the gap 28 of the component measurement chip 2 is very small, the derived glucose concentration is derived even when the optical path length of the measurement space is not corrected as shown in FIG. Variation can be reduced. However, as in the present embodiment, 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 this estimated value is used to correct the optical path length of the measurement space. However, it can be seen that the variation in the derived glucose concentration can be reduced.

Therefore, it is permissible 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 the present embodiment. Even when 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 can be achieved. When is large, it can be understood that the accuracy of the derived glucose concentration can be greatly improved.

Next, a verification experiment was conducted using blood having a known glucose concentration to determine the magnitude of the effect 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 on the measured value of glucose concentration. rice field. 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 adjusted to have a glucose concentration of 400 mg / dL. When the measurement value of the height h of the gap 28 before the measurement is used to correct the optical path length of the measurement space, and when the height of the gap 28 at the time of measurement is corrected as in the present embodiment. When h is estimated and the optical path length of the measurement space is corrected using this estimated value, the variation of the measured value of the derived glucose concentration is shown. The variation in the measured values shown in FIG. 15 is evaluated by doubling the standard deviation (2SD) of the deviation from the true value of the absolute value (mg / dL) of the concentration for water that does not contain the glucose concentration, and the glucose concentration. However, 100 mg / dL and 400 mg / dL of glucose water are evaluated by a value (2SD value) that is 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 by an Optical MicroGauge thickness gauge (C11011-01) manufactured by Hamamatsu Photonics Co., Ltd.

Further, FIG. 15 shows the effect on the measured value of the glucose concentration when the variation in the height h (see FIG. 5) of the gap 28 of the permissible component measurement chip 2 is 37.3 μm to 40.6 μm. ing. The width of the gap 28 is constant.

As shown in FIG. 15, when the optical path length of the measurement space is not corrected, it can be seen that the derived glucose concentration varies widely and the accuracy of the derived glucose concentration is low. On the other hand, when the measured value of the height h of the gap 28 before the measurement is used to correct the optical path length of the measurement space, the deviation of the derived glucose concentration is compared with the case where the measurement is not corrected. It turns out that it becomes smaller. Further, when the height h of the gap 28 at the time of measurement is estimated and the optical path length of the measurement space is corrected by using this estimated value as in the present embodiment, the variation in the derived glucose concentration is not corrected. It can be seen that the size is further reduced and the accuracy of the derived glucose concentration can be improved as compared with the case and the case where the measurement value of the height h of the gap 28 before the measurement is used for correction.

The component measuring device, 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 changes can be made without departing from the gist of the invention described in the claims. be.

In the above-described embodiment, the glucose concentration is measured as the measurement of glucose as the component to be measured, but the concentration is not limited, and another physical quantity may be measured. Further, in the above-described embodiment, glucose in the plasma component is exemplified as the component to be measured in the blood, but the present invention is not limited to this, and for example, cholesterol in the blood can be used as the component to be measured. Further, in the above-described embodiment, the component to be measured in blood is measured, but the component to be measured 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.

Further, in the above-described embodiment, as the light emitting unit 66, a plurality of types of the first light source 67a to the fifth light source 68 have been described as an example, but a single light source and a plurality of types arranged in front of the light source. It may be configured by combining the optical filters (bandpass type) of. Alternatively, a single light source and a plurality of types of light receiving units may be combined and configured. Further, in the above-described embodiment, the light receiving unit 72 receives the transmitted light transmitted through the component measuring chip 2, but the light receiving unit may receive the reflected light reflected from the component measuring chip 2.

The present disclosure relates to a component measuring device, a component measuring method and a component measuring program, and more particularly to a component measuring device, a component measuring method and a component measuring program for measuring a component to be measured in a body fluid.

1: Component measuring device 2: Component measuring chip 10: Housing 10a: Main body 10b: Chip mounting part 11: Display part 12: Removal lever 13: Power button 14: Operation button 21: Base member 22: Coloring reagent (reagent)
23: Flow path 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 unit 67a to 67d: First light source -Fourth light source 68: Fifth light source 70: Light emission control circuit 72: Light receiving unit 74: Light receiving 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: Flow path height h: Gap height S: Chip mounting space W: Flow path width λ1 to λ5: 1st to 5th wavelengths

Claims (7)

A component measuring device that measures 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 in the body fluid and the reagent.
A component measurement chip having the reagent can be mounted by partitioning the flow path inside and arranging the flow path in the flow path with a gap between the flow path and the facing inner wall so as not to block the flow path. ,
Is irradiated to the mixture at the location of the gap, a first measurement of the absorbance measured by the first measuring light, the first wavelength belonging to the inherent absorption bands of water in the long wavelength region of the above near-infrared region , The second measurement light of the second wavelength belonging to the long wavelength region and in the vicinity of the water-specific absorption band or the water-specific absorption band, which irradiates the mixture at the position of the gap. The measured second measured value, which has an absorbance smaller than that of the first measured value, is obtained.
The third measured value, which is the absorbance measured by the third measurement light of the first wavelength, which is irradiated to the reagent before contact with the body fluid, and the first, which is irradiated to the reagent before contact with the body fluid. Obtain the 4th measured value, which is the absorbance measured by the 4th measurement light of 2 wavelengths,
The component to be measured is determined based on a correction difference value which is a difference between the difference between the first measured value and the second measured value and the difference between the third measured value and the fourth measured value. Derived and
The fifth measurement value, which is the absorbance measured by the fifth measurement light having a measurement wavelength belonging to a wavelength range different from the absorption band peculiar to the water, which is irradiated to the mixture at the position of the gap, is obtained, and the said A component measuring device that corrects a fifth measured value based on the corrected difference value. The measurement wavelength, the belonging to the short wavelength range than the first wavelength and the second wavelength, component measuring device according to claim 1. The component measuring apparatus according to claim 1 or 2 , wherein 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 component measuring apparatus according to any one of claims 1 to 3 , wherein the measurement wavelength belongs to the visible region. In the absorbance spectrum obtained by the light irradiating the mixture located in the gap, the first wavelength is a wavelength at which the absorbance of water reaches or is close to the peak value in the absorption band peculiar to water. The component measuring apparatus according to any one of claims 1 to 4 , wherein the second wavelength is a wavelength near the hem of the absorption band peculiar to water. A component measuring method for measuring the component to be measured in the body fluid based on the optical characteristics of a mixture containing a color-developing component generated by a color reaction between the component to be measured in the body fluid and a reagent.
In the gap generated by the reagent arranged in the flow path with a gap between the inner wall facing the flow path so as not to block the flow path, and the body fluid supplied to the gap. The located mixture is irradiated with the first measurement light of the first wavelength belonging to the absorption band peculiar to water in the long wavelength region equal to or higher than the near infrared region , and the absorbance as the first measurement value is measured .
The mixture located in the gap is irradiated with the second measurement light of the second wavelength belonging to the long wavelength region and in the vicinity of the absorption band peculiar to the water or the absorption band peculiar to the water. , The absorbance as the second measurement value, which is smaller than the first measurement value, is measured.
The reagent before contact with the body fluid was irradiated with the third measurement light of the first wavelength, and the absorbance as the third measurement value was measured.
The reagent before contact with the body fluid was irradiated with the fourth measurement light of the second wavelength, and the absorbance as the fourth measurement value was measured.
The component to be measured is determined based on a correction difference value which is a difference between the difference between the first measured value and the second measured value and the difference between the third measured value and the fourth measured value. Derived and
At the position of the gap, the mixture is irradiated with the fifth measurement light having a measurement wavelength belonging to a wavelength range different from the absorption band peculiar to the water, and the absorbance as the fifth measurement value is measured. 5 A component measuring method for correcting a measured value based on the corrected difference value. A component measurement 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 generated by the color reaction between the component to be measured in the body fluid and the reagent.
In the gap generated by the reagent arranged in the flow path with a gap between the inner wall facing the flow path so as not to block the flow path, and the body fluid supplied to the gap. The located mixture is irradiated with the first measurement light of the first wavelength belonging to the absorption band peculiar to water in the long wavelength region equal to or higher than the near infrared region , and the absorbance as the first measurement value is measured .
The mixture located in the gap is irradiated with the second measurement light of the second wavelength belonging to the long wavelength region and in the vicinity of the absorption band peculiar to the water or the absorption band peculiar to the water. , The absorbance as the second measurement value, which is smaller than the first measurement value, is measured.
The reagent before contact with the body fluid was irradiated with the third measurement light of the first wavelength, and the absorbance as the third measurement value was measured.
The reagent before contact with the body fluid was irradiated with the fourth measurement light of the second wavelength, and the absorbance as the fourth measurement value was measured.
The component to be measured is determined based on a correction difference value which is a difference between the difference between the first measured value and the second measured value and the difference between the third measured value and the fourth measured value. Derived and
At the position of the gap, the mixture is irradiated with the fifth measurement light having a measurement wavelength belonging to a wavelength range different from the absorption band peculiar to the water, and the absorbance as the fifth measurement value is measured. 5 A component measurement program for causing a component measuring device to correct a measured value based on the correction difference value.

Images