JP7541301B2 - Blood substance concentration measuring device, blood substance concentration measuring method and program - Google Patents

Description

This disclosure relates to an apparatus and method for measuring the concentration of a substance contained in blood flowing through a blood vessel of a living body using a non-invasive measurement method.

In the prevention and treatment of lifestyle-related diseases, it is important to routinely check the state of blood substances such as blood glucose levels and blood lipid levels. In particular, for patients with diabetes, which is one of the lifestyle-related diseases, daily management of blood glucose levels by measuring the glucose concentration in the blood is required to prevent complications, and invasive methods have traditionally been used to draw blood from patients and perform chemical analysis of the blood.

In response to this, in recent years, simple non-invasive methods have been proposed for optically measuring the state of blood in the body without blood sampling. For example, Patent Document 1 discloses a blood substance concentration measuring device that measures blood glucose concentration in a non-invasive and simple configuration by irradiating a living body with high-intensity mid-infrared light through a waveguide and guiding the reflected light to a photodetector through the waveguide.

International Publication No. 2016/117520

However, the conventional blood substance concentration measuring device using a waveguide described in Patent Document 1 had the problem that the measured value fluctuates depending on the positional variation between individuals in the depth of the part to be measured within the living body being measured, making it difficult to perform stable and normal measurements.

The present disclosure has been made in consideration of the above-mentioned problems, and aims to provide a blood substance concentration measuring device, a blood substance concentration measuring method, and a program that can stably perform highly accurate measurements regardless of inter-individual variation in the depth of the measurement target part in the living body.

In order to achieve the above object, a blood substance concentration measuring device according to one aspect of the present disclosure is a blood substance concentration measuring device for measuring the concentration of a blood substance contained in the blood of a subject part of a living organism, comprising: a light irradiating unit that irradiates a laser light onto an irradiation area including a measurement target part in the subject part; a photodetector that receives reflected light based on the irradiated laser light and detects the intensity of the reflected light; a first lens that is disposed between the subject part and the photodetector and at a position where the reflected light from a specific area in the subject part can be imaged on the photodetector; and a blood substance concentration measuring device that measures the concentration of the blood substance in the specific area based on the intensity of the reflected light, the blood substance concentration measuring device including: a light irradiating unit that irradiates an irradiation area including a measurement target part in the subject part with a laser light; the light irradiating unit is configured to selectively irradiate a first laser light for subject measurement which is absorbed by a first blood substance that is a measurement target substance, and a second laser light for reference measurement which is absorbed by a second blood substance that is a reference substance, the second laser light being irradiated before the first laser light, and an absorption rate of the second laser light by the second blood substance in the reference measurement is greater than an absorption rate of the first laser light by the first blood substance in the subject measurement .

The blood substance concentration measuring device, blood substance concentration measuring method, and program according to one aspect of the present disclosure can stably perform highly accurate measurements regardless of individual differences in the measurement subject.

1 is a schematic diagram showing a configuration of a blood substance concentration measuring device 1 according to a first embodiment. 2A and 2B are enlarged cross-sectional views of part A in FIG. 2 is a schematic diagram showing the configuration of a light irradiation unit 20 in the blood substance concentration measuring device 1. FIG. 2 is a diagram for explaining an overview of a light receiving side optical path in the blood substance concentration measuring device 1. FIG. 2 is a schematic diagram showing an outline of an optical path from a light irradiating unit 20 to a light detector 30 in a blood substance concentration measuring device 1. FIG. 11 is a schematic diagram for explaining the operation of adjusting the optical path length in the configuration of a blood substance concentration measuring device according to a comparative example devised by the inventor. FIG. 10 is a schematic diagram for explaining the operation of adjusting the optical path length from a measurement target portion Mp to a photodetector 30 by the blood substance concentration measuring device 1. FIG. 1 is a diagram showing the relationship between the position of a photodetector and the measured value of hemoglobin concentration measured using an embodiment of the blood substance concentration measuring device 1. FIG. 1 is a diagram showing the relationship between the position of a photodetector and the measured glucose concentration value measured using an embodiment of the blood substance concentration measuring device 1. FIG. 1A is a schematic diagram for explaining an overview of the optical path in the blood substance concentration measuring device 1, and FIG. 1B is a schematic diagram for explaining an overview of the optical path from the light irradiation unit 20 in the comparative example to a photodetector PD representing the subject portion Mp0. 1A is a graph showing the variation in the measurement results of the concentration of a substance in blood in the blood substance concentration measuring device 1, and FIG. 1B is a graph showing the variation in the measurement results of the concentration of a substance in blood in a blood substance concentration measuring device according to a comparative example. 2 is a diagram showing the laser light irradiation position on the surface of a living body when the blood substance concentration measuring device 1 measures the blood substance concentration. FIG. 1A is a graph showing the variation in the measurement results of the concentration of a substance in blood in an example of the blood substance concentration measuring device 1, and FIG. 1B is a graph showing the variation in the measurement results of the concentration of a substance in blood in a comparative example. 4 is a flowchart showing one aspect of the blood substance measurement operation performed by the blood substance concentration measuring device 1. 10 is a flowchart showing another aspect of the blood substance measurement operation by the blood substance concentration measuring device 1. 13 is a flowchart showing still another aspect of the blood substance measuring operation by the blood substance concentration measuring device 1A. 1 is a schematic diagram showing the configuration of a conventional blood substance concentration measuring device 1X.

<<How the invention was developed>>
In recent years, non-invasive methods for measuring the concentration of a substance in blood that do not involve blood sampling have been proposed for the purpose of managing the daily blood glucose levels of diabetic patients, and FIG. 17 is a schematic diagram showing the configuration of a conventional blood substance concentration measuring device 1X (hereinafter, sometimes referred to as "device 1X") using a non-invasive method, as disclosed in Patent Document 1.

As shown in FIG. 17, the device 1X includes a subject placement section 10X on which the living body Ob to be examined is placed, a light irradiation section 20X that irradiates pulsed laser light L1 consisting of mid-infrared light, a light guide section 90X in which an entrance side waveguide 91X and an exit side waveguide 92X consisting of through holes are opened, a photodetector 30X that receives reflected light LX2 from the living body Ob and detects its intensity, and a measurement control section 60X for these. Patent Document 1 describes that the device 1X can measure blood glucose concentration in a non-invasive and simple configuration by irradiating high-intensity mid-infrared light.

However, as described above, the inventors' experiments revealed that with device 1X, which uses a non-invasive method, measurement values fluctuate depending on the condition of the skin surface of the living body being measured and slight changes in the conditions of the irradiated laser light, making it difficult to perform stable, normal measurements.

In addition, the depth and location of the area beneath the skin surface inside the body that contains the blood glucose, the actual measurement target, differs from subject to subject, which may be a factor in the variation in measurement values.

To solve this problem, it becomes necessary to set up the optical system for each subject and measurement, for example, to suit the subject's biological conditions and measurement conditions.

However, adjusting the optical system appropriately for each living body and each time a measurement is performed requires advanced skill, and performing this procedure in blood glucose measurements that patients themselves perform on a daily basis would significantly reduce the convenience of non-invasive methods.

The inventors therefore conducted extensive research into the configuration of an optical system that can stably achieve highly accurate measurements in a non-invasive method for measuring the concentration of a substance in blood, regardless of inter-individual variations in the depth of the area to be measured in the living body or variations in the conditions for irradiating the laser light, and arrived at the following embodiment.

<Overview of the embodiment of the present invention>
A blood substance concentration measuring device according to an embodiment of the present disclosure is a blood substance concentration measuring device that measures the concentration of a blood substance contained in the blood of a subject part of a living organism, and includes a light irradiating unit that irradiates a region including a measurement target part in the subject part with laser light, a photodetector that receives reflected light based on the irradiated laser light and detects the intensity of the reflected light, a first lens that is disposed between the subject part and the photodetector at a position where the reflected light from a specific region in the subject part can be imaged on the photodetector, and a measurement control unit that measures the concentration of the blood substance in the specific region as the concentration of the blood substance in the measurement target part based on the intensity of the reflected light, and is characterized in that the light irradiating unit is configured to selectively irradiate a first laser light for subject measurement that is absorbed by a first blood substance, which is the measurement target substance, and a second laser light for reference measurement that is absorbed by a second blood substance, which is a reference substance.

This configuration allows for stable, highly accurate measurements to be performed regardless of individual differences in the measurement subject.

In another aspect, in any of the above aspects, the absorption rate of the second laser light by the second blood substance in the reference measurement may be greater than the absorption rate of the first laser light by the first blood substance in the subject measurement.

In another aspect, in any of the above aspects, the reference substance may be configured to have a more stable concentration in blood than the measurement target substance.

With this configuration, the measurement accuracy of the measurement target can be improved by performing a reference measurement on the reference substance before performing a target measurement.

In another aspect, in any of the above aspects, the measurement control unit may be configured to measure the concentration of the second blood substance when the specific region is included in a vascular region in the subject part based on the irradiation of the second laser light, and to be able to measure the concentration of the first blood substance in the specific region as the concentration of the first blood substance in the measurement target part based on the irradiation of the first laser light.

This configuration makes it possible to measure the concentration of the first blood substance when the specific region is included in the blood vessel region of the subject part.

In another aspect, in any of the above aspects, the depth of the specific region in the living body can be changed by moving the photodetector along an optical path from the subject part to the photodetector, and the position of the photodetector can be adjusted along the optical path so that the specific region is included in a vascular region in the subject part based on the concentration of the second blood substance.

With this configuration, the light irradiation unit irradiates the first laser light at the detector position where the reflected light from the blood vessels is detected, and the detector receives the reflected light from the specific region, making it possible to consistently and stably measure the concentration of the first blood substance with high accuracy, regardless of individual differences in the position of the blood vessels in the depth direction from the skin surface of the subject.

In another aspect, in any of the above aspects, the light irradiating unit may be configured to modulate the wavelength of the laser light to vary the types of detectable blood substances. Alternatively, the light irradiating unit may be configured to have an optical oscillator that emits the first laser light and an optical oscillator that irradiates the second laser light.

This configuration makes it possible to measure multiple types of blood substances.

In another aspect, in any of the above aspects, the blood substance may be glucose, and the wavelength of the laser light may be a predetermined wavelength selected from the range of 2.5 μm or more and 12 μm or less. In this case, the wavelength of the first laser light may be selected from the range of 6.0 μm or more and 12 μm or less.

This configuration makes it possible to measure the concentration of glucose as the first blood substance.

In another aspect, in any of the above aspects, the blood substance may be hemoglobin, and the wavelength of the laser light may be a predetermined wavelength selected from the range of 5.0 μm or more and 12 μm or less.

This configuration makes it possible to detect the vascular region in the subject part of the living body, and to detect whether the specific region to be the measurement target part of the first blood substance is included in the vascular region in the subject part.

In another aspect, any of the above aspects may be configured to include a second lens located between the light irradiating unit and the subject unit in the optical path of the laser light, which focuses the laser light on the irradiation area, and an aperture located between the light irradiating unit and the second lens.

This configuration can reduce the variation in the measurement results of blood substance concentrations for each measurement.

In another aspect, any of the above aspects may be configured to include a target placement section against which the surface of the living body is in contact, the target placement section having a through-hole in the area against which the surface of the living body is in contact, the laser light is irradiated onto the surface of the living body through the through-hole, and the reflected light is received by the photodetector through the through-hole.

This configuration makes it possible to suppress total reflection on the surface of the living body Ob, and furthermore, the laser light irradiated from the light irradiating unit can be irradiated directly onto the surface of the living body, thereby improving the intensity of the laser light.

In another aspect, any of the above aspects may be configured to include a target placement section against which the surface of the living body is in contact, the target placement section having a recess formed in the area against which the surface of the living body is in contact, the laser light passes through the target placement section and is irradiated onto the surface of the living body, and the reflected light passes through the target placement section and is received by the photodetector.

This configuration makes it possible to suppress total reflection on the surface of the living body, and since the subject placement section does not have an opening, it is possible to prevent dust, dirt, water vapor, etc. from entering the atmosphere in which the optical system, such as the light irradiation section, is present, thereby providing the subject placement section with a dustproof function.

In another aspect, in any of the above aspects, the measurement target portion may be a blood vessel region in the subject located inside the epidermis, and the first lens may be configured to transfer the irradiation area of the laser light in the measurement target portion onto the light receiving surface of a detector.

This configuration reduces false signal (noise) components caused by reflected light scattered on the skin surface, and improves the S/N ratio in optical measurements, compared to conventional devices using a waveguide.

With this configuration, glucose is more absorbed by the light than near-infrared light, and the transmittance is low, so only the epidermis can be observed, and blood glucose concentration can be measured stably.

In another aspect, in any of the above aspects, the blood substance may be lactic acid, and the wavelength of the laser light may be a predetermined wavelength selected from the range of 5.0 μm to 12 μm. In this case, the wavelength of the first laser light may be in the range of 5.77 μm, 6.87 μm, 7.27 μm, 8.23 μm, 8.87 μm, or 9.55 μm, and may be in the range of -0.05 μm to +0.05 μm.

With this configuration, the blood lactate concentration can be measured.
In another aspect, in any of the above aspects, in the section from the target placement portion to the photodetector in the optical path from the subject portion to the photodetector, the reflected light may propagate through space except for the section passing through the first lens, and in the section from the light irradiation portion to the subject portion in the optical path from the light irradiation portion to the subject portion, the laser light may propagate through space except for the section passing through the second lens.

This configuration reduces false signal (noise) components caused by reflected light scattered on the skin surface, and improves the S/N ratio in optical measurements, compared to conventional devices using a waveguide.

In addition, the blood substance concentration measurement method according to this embodiment is a blood substance concentration measurement method for measuring the concentration of a blood substance contained in the blood of a subject part of a living body, and includes irradiating an irradiation area including a measurement target part in the subject part with a first laser light for target measurement that is absorbed by a first blood substance that is the measurement target substance from a light irradiation unit, forming an image of the reflected light of the first laser light reflected from a specific area in the subject part on the photodetector using a first lens located between the subject part and a photodetector, receiving the reflected light of the first laser light by the photodetector, and calculating the concentration of the first blood substance based on the reflected light from the measurement target part. In a blood substance concentration measurement method for measuring the concentration of the first blood substance in a target portion, a reference measurement may be performed in which, prior to the target measurement, the light irradiation unit irradiates the irradiation area with a second laser light for reference measurement that is absorbed by a second blood substance that is a reference substance, and the first lens is used to form an image of the reflected light of the second laser light reflected from the specific area on the photodetector, the photodetector receives the reflected light of the second laser light, and the concentration of the second blood substance based on the reflected light is measured as the concentration of the second blood substance in the measurement target portion.

This configuration provides a method for measuring the concentration of a substance in blood that can stably perform highly accurate measurements regardless of individual differences in the subject being measured.

In another aspect, in any of the above aspects, the absorption rate of the second laser light by the second blood substance in the reference measurement may be greater than the absorption rate of the first laser light by the first blood substance in the subject measurement.

In another aspect, in any of the above aspects, the reference substance may be configured to have a more stable concentration in blood than the measurement target substance.

With this configuration, the measurement accuracy of the measurement target can be improved by performing a reference measurement on a reference substance with a relatively high absorption rate before performing a target measurement.

In another aspect, in any of the above aspects, prior to detecting the concentration of the first blood substance, the position of the photodetector may be varied along the optical path from the subject part to the photodetector to measure the concentration of the second blood substance, thereby adjusting the position of the photodetector along the optical path so that the specific region is included in the vascular region in the subject part.

With this configuration, a method can be provided for consistently and stably measuring the concentration of a first blood substance with high accuracy, regardless of individual differences in the position of blood vessels in the depth direction from the skin surface of the subject, by irradiating a first laser light from the light irradiation unit at the position of the detector where reflected light from the blood vessels is detected, and receiving reflected light from the specific region by the detector.

In another aspect, in any of the above aspects, the first laser light and the second laser light may be irradiated to the irradiation area using a second lens located between the light irradiating unit and the subject part in the optical path from the light irradiating unit to the subject part and configured to focus the first laser light and the second laser light on the irradiation area, and an aperture located between the light irradiating unit and the second lens and configured to narrow the light irradiated from the light irradiating unit.

This configuration can reduce the variation in the measurement results of blood substance concentrations for each measurement.

In another aspect, in any of the above aspects, the surface of the living body may be brought into contact with the target placement section, the first laser light and the second laser light may be irradiated onto the surface of the living body through a through hole provided in the target placement section, and the reflected light may be received by the photodetector through the through hole.

With this configuration, the laser light emitted from the light irradiating unit can be irradiated directly onto the surface of the living body, improving the intensity of the laser light.

In addition, the program according to this embodiment is a program for causing a computer to perform a blood substance concentration measurement process for measuring the concentration of a blood substance contained in the blood of a subject part of a living body, and the blood substance concentration measurement process includes irradiating an irradiation area including a measurement target part in the subject part with a first laser light for target measurement that is absorbed by a first blood substance that is the measurement target substance from a light irradiation unit, forming an image of the reflected light of the first laser light reflected from a specific area in the subject part on the photodetector using a first lens located between the subject part and a photodetector, receiving the reflected light of the first laser light by the photodetector, and measuring the concentration of the first blood substance based on the reflected light. In a blood substance concentration measurement method for subjecting a substance to concentration as the concentration of the first blood substance in the portion to be measured, a reference measurement may be performed in which, prior to the subject measurement, the light irradiation unit irradiates the irradiation region with a second laser light for reference measurement that is absorbed by a second blood substance that is a reference substance, the first lens is used to form an image of the reflected light of the second laser light reflected from the specific region on the photodetector, the photodetector receives the reflected light of the second laser light, and the concentration of the second blood substance based on the reflected light is measured as the concentration of the second blood substance in the portion to be measured.

This configuration makes it possible to provide a program that can stably perform highly accurate measurements regardless of individual differences in the measurement subject.

First Embodiment
The blood substance concentration measuring device 1 according to the present embodiment will be described with reference to the drawings. Here, in this specification, the positive direction in the height direction may be referred to as the "up" direction, and the negative direction may be referred to as the "down" direction, and the surface facing the positive direction in the height direction may be referred to as the "front" surface, and the surface facing the negative direction may be referred to as the "rear" surface. Also, the scale of the components in each drawing is not necessarily the same as the actual one. Also, in this specification, the symbol "-" used to indicate a numerical range includes the numerical values at both ends. Also, the materials, numerical values, etc. described in this embodiment are merely examples of preferred ones, and are not limited thereto.

<Overall composition>
The blood substance concentration measuring device 1 (hereinafter sometimes referred to as "device 1") is a medical device that non-invasively measures the blood substance concentration of the living body Ob at the measurement target portion Mp of the living body Ob by irradiating the measurement target portion Mp of the living body Ob with laser light of a specific wavelength from a light source and detecting the intensity of the reflected light from the measurement target portion Mp. The laser light used is light of a specific wavelength that can be absorbed by the substance to be measured. When the blood substance concentration is high, the intensity of the reflected light from the measurement target portion Mp decreases due to absorption by the substance, so the device 1 measures the blood substance concentration by measuring the intensity of the reflected light with a photodetector.

Figure 1 is a schematic diagram showing the configuration of device 1 according to embodiment 1. As shown in Figure 1, device 1 has a target placement section 10, a light irradiation section 20, a light detector 30, a focusing lens 50, an imaging lens 40, a measurement control section 60, a light detection unit 70, and an aperture 80.

The following describes the configuration of each part of device 1.

<Components>
(Target placement unit 10)
The subject placement section 10 is a plate-like guide member for restricting the measurement target portion Mp included in the subject portion Mp0 of the subject Ob to a specified position and angle suitable for measurement by abutting the surface of the skin of the subject Ob against its surface 10a. By covering the optical system of the subject placement section 10, such as the light irradiation section 20, with a housing (not shown) and providing the subject placement section 10 on the outer periphery of the housing, the subject placement section 10 can function as an irradiation window through which the laser light L1 is irradiated from the inside.

The subject placement section 10 is made of a material, such as ZnSe, that is transparent to mid-infrared light, which is the specific wavelength used for measurement, and may have an anti-reflective coating layer on its surface. The surface 10a of the subject placement section 10 is marked with a measurement position, and by bringing the living body Ob containing the measurement target portion Mp into contact with the surface 10a of the subject placement section 10 with a predetermined pressure while aligning the living body Ob with the measurement target portion Mp, the measurement target portion Mp, which is a portion of the living body Ob located inside the epidermis, such as the dermis, can be held at a predetermined distance from the surface 10a of the subject placement section 10.

The subject placement section 10 is arranged so that the laser light L1 emitted from the light irradiation section 20 enters from the back surface 10d side, and the relative angle with the light irradiation section 20 is regulated so that the incident angle θ of the optical axis L1 on the incident side of the front surface 10a is a predetermined angle. Here, the incident angle θ refers to the angle of the optical axis L1 based on the normal to the front surface 10a on which the living body Ob is placed in the subject placement section 10.

2(a) and (b) are enlarged cross-sectional views showing the aspect of part A in FIG. 1. The enlarged view shows the part where the subject part Mp0 of the living body Ob is abutted against the subject placement part 10. As shown in FIG. 2(a), an opening 10b may be formed in the surface 10a of the subject placement part 10 in the area in contact with the surface of the living body Ob. The opening 10b allows the laser light L1 irradiated from the light irradiation part 20 to be irradiated to the surface of the living body Ob through the through hole 10b opened in the subject placement part 10. In addition, by providing the opening 10b, an air layer can be formed in the part where the surface 10a of the subject placement part 10 and the living body Ob are in contact, and total reflection on the surface of the living body Ob can be suppressed compared to the case where the subject placement part 10 is in contact with the subject placement part 10. In addition, by providing the opening 10b, a configuration can be made in which the living body Ob is more easily attached to the surface 10a of the subject placement part 10 around the opening 10b of the surface 10a. In this embodiment, as an example, the thickness of the target placement portion 10 may be 500 μm, and the width of the opening 10b may be 700 μm.

Alternatively, as shown in FIG. 2(b), a recess 10c may be formed on the surface 10a of the subject placement section 10 so that a gap is formed between the subject placement section 10 and the living body Ob. In this case, the laser light L1 irradiated from the light irradiation section 20 passes through the bottom surface of the recess 10c in the subject placement section 10 and is irradiated onto the surface of the living body Ob. Since the subject placement section 10 does not have an opening, it is possible to prevent dust, dirt, water vapor, etc. from entering the atmosphere in which the optical system such as the light irradiation section 20 exists, and the subject placement section 10 can have a dustproof function.

In this case, by providing the recess 10c, an air layer is formed between the surface 10a of the subject placement part 10 and the living body Ob, as in the case of providing the opening 10b, and total reflection on the surface of the living body Ob can be suppressed compared to the case of contacting the subject placement part 10. Furthermore, by providing the recess 10c, the living body Ob can be more easily attached to the surface 10a of the subject placement part 10 in the portion other than the recess. In this embodiment, as an example, the thickness of the subject placement part 10 may be 500 μm, the width of the recess 10c may be 700 μm, and the depth d1 of the recess 10c, i.e., the thickness of the air layer, may be about 400 μm.

(Light irradiation unit 20)
The light irradiating unit 20 is a light source that irradiates a laser light of a specific wavelength toward the subject part Mp0 of the living body Ob. The light irradiating unit 20 is configured to be capable of irradiating a laser light for measuring a target (hereinafter, sometimes referred to as a "first laser light") that oscillates at a wavelength that is absorbed by a first blood substance (hereinafter, sometimes referred to as a "first blood substance") that is a measurement target substance.

Furthermore, in the device 1, the light irradiation unit 20 is configured to selectively irradiate the reference measurement laser light (hereinafter sometimes referred to as "second laser light"), which oscillates at a wavelength absorbed by the second blood substance (hereinafter sometimes referred to as "second blood substance"), which is the reference substance, by modulating the wavelength of the laser light, with the laser light for subject measurement. This allows for different types of detectable blood substances.

FIG. 3 is a schematic diagram showing the configuration of the light irradiation unit 20 in the blood substance concentration measuring device 1. As shown in FIG. 3 , the light irradiation unit 20 has a light source 21 that oscillates pump light L0 with a wavelength shorter than the pulsed mid-infrared light, and an optical parametric oscillator (OPO) 22 that converts the pump light L0 to a long wavelength, amplifies it, and emits it as laser light L1. In the optical parametric oscillator 22, the pump light L0 is incident on an internal nonlinear optical crystal, so that light of two different wavelengths is oscillated, and a short-wavelength signal light and a long-wavelength idler light are generated. In the light irradiation unit 20, the idler light is output to the subsequent stage as laser light L1 and used for measuring blood glucose levels. The optical parametric oscillator 22 may use a configuration described in a known document, for example, JP 2010-281891 A.

In this embodiment, as an example, glucose can be used as the first blood substance to be measured. In that case, the irradiated laser light is light of a wavelength selected from mid-infrared light, and as the wavelength oscillated by optical parametric oscillation, mid-infrared light is used as a wavelength that is more absorbed by glucose than the near-infrared light conventionally used, and the predetermined wavelength may be selected from the range of 2.5 μm to 12 μm. More preferably, the predetermined wavelength is selected from the range of 6.0 μm to 12 μm. Specifically, in this embodiment, the selected wavelength is 9.26 μm. For example, it may be 9.26±0.05 μm (9.21 μm to 9.31 μm). Alternatively, the wavelength may be selected from 7.05 μm, 7.42 μm, 8.31 μm, 8.7 μm, 9.0 μm, 9.57 μm, 9.77 μm, 10.04 μm, or 10.92 μm in the range of -0.05 μm or more and +0.05 μm or less.

This allows the glucose concentration in the subject's blood to be measured as the blood glucose level. In this case, it is necessary to measure the glucose concentration in the blood vessels inside the skin, and mid-infrared light, which does not penetrate deep into the body, is directly irradiated onto the blood vessels (capillaries) inside the skin. Since this mid-infrared light has a lower transmittance into the body than the near-infrared light that was previously used to measure blood glucose levels, by identifying the position of the blood vessels inside the skin and irradiating them with mid-infrared light, it is possible to observe only the blood vessels, which has the effect of being less affected by other biological components present deep inside. In addition, the use of mid-infrared light has less adverse effects on the measurement due to overlapping harmonics and combination tones of the fundamental vibration, and has the effect of being able to measure glucose more accurately than near-infrared light.

On the other hand, the reference substance (second blood substance) to be used in the reference measurement is selected as a blood substance that has a higher absorption rate of laser light than the substance to be measured, and therefore has high measurement sensitivity, high stability of blood concentration, and small variability in the measurement results.

In other words, it is preferable that the absorption rate of the laser light in the reference measurement by the reference substance (second blood substance) is greater than the absorption rate of the laser light for the target measurement by the measurement target substance (first blood substance) in the target measurement. And/or, it is preferable that the reference substance (second blood substance) has a higher stability of concentration in blood than the measurement target substance (first blood substance).

By performing a reference measurement on a reference substance having such a configuration and then performing a target measurement, the measurement accuracy of the measurement target can be improved.

In this embodiment, hemoglobin can be selected as an example of the reference substance (second blood substance). By detecting hemoglobin in blood vessels, the position of capillaries in the living body can be detected, and the optimal position of the measurement target portion Mp in the test portion Mp0 in the living body Ob can be identified when measuring the measurement target substance (first blood substance).

When the first blood substance or the second blood substance is hemoglobin, the laser light to be irradiated for measurement is light of a wavelength selected from mid-infrared light, and is a predetermined wavelength selected from the range of 5.0 μm or more and 12 μm or less. Specifically, for example, the wavelength may be 8.00±0.1 μm (7.9 μm or more and 8.1 μm or less). Alternatively, the wavelength may be selected from the range of 5.26 μm or more and 6.76 μm or less, the range of 7.17 μm to -0.1 μm to +0.1 μm or less, the range of 7.58 μm to -0.1 μm to +0.1 μm or less, the range of 7.58 μm to 8.33 μm or less, or the range of 8.55 μm to -0.1 μm to +0.1 μm or less.

The light source 21 may be equipped with a Q-switched Nd:YAG laser (oscillation wavelength 1.064 μm) or a Q-switched Yb:YAG laser (oscillation wavelength 1.030 μm). This allows the pump light L0, which has a wavelength shorter than mid-infrared light, to be oscillated in a pulsed manner. The pump light L0 may have a pulse width of about 8 ns and a frequency of 10 Hz or more, for example. In addition, the Q-switched Nd:YAG laser or Yb:YAG laser operates as a passive Q-switch that performs a passive switching operation using a saturable absorber, allowing the light source 21 to be simplified and miniaturized.

3 , the optical parametric oscillator 22 includes an incident side semi-mirror 221, an exit side semi-mirror 222, and a nonlinear optical crystal 223, and the nonlinear optical crystal 223 is disposed in an optical resonator in which the incident side semi-mirror 221 and the exit side semi-mirror 222 face each other. Light L01 transmitted through the incident side semi-mirror 221 enters the nonlinear optical crystal 223 and is converted into light having a wavelength determined by the nonlinear optical crystal 223, and is optically parametrically amplified between the incident side semi-mirror 221 and the exit side semi-mirror 222. The amplified light is transmitted through the exit side semi-mirror 222 and output as laser light L1.

In the nonlinear optical crystal 223, AgGaS suitable for wavelength conversion is used under phase matching conditions. By adjusting the type of nonlinear optical crystal 223 and matching conditions, the wavelength of the oscillated laser light L1 can be adjusted. For the nonlinear optical crystal, GaSe, ZnGeP ₂ , CdSiP ₂ , LiInS ₂ , LiGaSe ₂ , LiInSe ₂ , LiGaTe ₂ , etc. may be used. The laser light L1 emitted from the optical parametric oscillator 22 has a repetition frequency corresponding to the pump light L0, for example, a pulse width of about 8 ns, and the short pulse width can achieve a high intensity peak output of 10 W to 1 kW.

In this way, by using the light source 21 and the optical parametric oscillator 22 in the light irradiation unit 20, it is possible to obtain laser light L1 with an intensity approximately 10 ³ to 10 ⁵ times higher than that of conventional light sources such as quantum cascade lasers.

To change the wavelength of the light emitted by the light irradiation unit 20, the oscillation wavelength of the optical parametric oscillator 22 of the light irradiation unit 20 can be changed to a different mode, thereby changing the phase matching condition of the nonlinear crystal 223 in the optical parametric oscillator 22, or the device can be realized by changing the optical parametric oscillator 22 that has a different phase matching condition of the nonlinear crystal 223.

This configuration makes it possible to measure blood glucose using mid-infrared light, which has low transmittance into the body.

The light irradiation unit 20 is electrically connected to the measurement control unit 60 described below, and outputs laser light L1 based on a control signal from the measurement control unit 60.

(Condenser lens 50)
In the optical path Op1 of the laser light L1 from the light irradiating unit 20 to the subject part Mp0 of the living body Ob, a condenser lens 50 (sometimes referred to as a "second lens" in this specification) is arranged to condense the irradiated light on a specific region (measurement target part Mp) in the subject part Mp0, as shown in Fig. 1. In the section on the optical path Op1 from the light irradiating unit 20 to the surface of the living body Ob (when the configuration of Fig. 2(a) is adopted) or from the light irradiating unit 20 to the back surface 10d of the subject placement part 10 (when the configuration of Fig. 2(b) is adopted), the laser light L1 is configured to propagate through a space such as a gas, except for the section passing through the condenser lens 50.

The focusing lens 50 is optically designed so that the laser light L1 emitted from the light irradiation unit 20 is focused at a depth corresponding to a specific region that is the measurement target portion Mp of the living body Ob, which is a predetermined distance away from the surface 10a of the target placement unit 10, for example, a biological part located inside the epidermis such as the dermis. The incidence angle θ of the laser light L1 on the specific region that is the measurement target portion Mp is determined by the angle of the light irradiation unit 20 with respect to the surface 10a of the target placement unit 10 and the refraction angle of the laser light L1 incident on the target placement unit 10. In this embodiment, the incidence angle θ may be, for example, 45 degrees or more, and may be 60 degrees or more and 70 degrees or less.

At this time, a beam splitter (not shown) made of a semi-transparent mirror may be disposed between the light irradiation unit 20 and the focusing lens 50 to split off a portion of the laser light L1 as a reference signal, and a monitor photodetector (not shown) may be used to detect changes in the intensity of the laser light L1 and to use this for normalization processing of the detection signal in the photodetector 30. The output of the photodetector 30 may be compensated based on the fluctuations in the intensity of the laser light L1.

The laser light L1 that passes through the focusing lens 50 passes through the target placement section 10 and enters the living body Ob, passes through the epithelial interstitial tissue of the living body, is scattered or diffusely reflected, and passes through the target placement section 10 again as reflected light L2, which is emitted toward the photodetector 30.

(Aperture 80)
In the optical path Op1 of the laser light L1 from the light irradiating unit 20 to the subject part Mp0 of the living body Ob, a diaphragm 80 is disposed in a section between the light irradiating unit 20 and the condenser lens 50. The diaphragm 80 is made of a plate-like member having light-shielding properties, and has an opening 80a (aperture) in the center.

The center of the aperture 80a coincides with the optical axis of the laser light L1. The aperture 80a may be configured to narrow the beam diameter of the laser light L1 to, for example, about 1/3. The focusing lens 50 may be configured to be disposed at a position that divides the distance between the light irradiation unit 20 and the aperture 80 internally at a:b, where f is the focal length of the focusing lens 50 and 1/f=1/a+1/b.

In this way, by providing the aperture 80 between the light irradiation unit 20 and the focusing lens 50 in the optical path Op1, it is possible to reduce the variation in the irradiation position of the laser light L1 irradiated onto the living body Ob.

(Imaging lens 40)
4 is a diagram for explaining an overview of the light receiving side optical path in the blood substance concentration measuring device 1, and is a schematic diagram drawn in a state in which the subject part Mp0 of the living body Ob and the screen 30a of the photodetector 30 are viewed in cross section. As shown in FIGS. 1 and 4, an imaging lens 40 (sometimes referred to as a "first lens" in this specification) is arranged in the optical path Op2 of the reflected light L2 from the subject part Mp0 of the living body Ob to the photodetector 30 to image the reflected light L2 diffusely reflected in a specific area in the subject part Mp0 on the photodetector 30. In the section of the optical path Op2 from the surface of the living body Ob including the subject part Mp0 to the photodetector 30 (when the configuration of FIG. 2(a) is adopted) or from the back surface 10d of the subject placement part 10 to the photodetector 30 (when the configuration of FIG. 2(b) is adopted), the reflected light L2 is configured to propagate in space except for the section passing through the imaging lens 40 .

The imaging lens 40 is optically designed so that an image Im1 of a specific region corresponding to the measurement target portion Mp in the subject portion Mp0 is diffusely reflected and imaged as reflected light L2 by the imaging lens 40 onto the screen 30a of the photodetector 30 as image Im2.

In this embodiment, the distance Op21 between the center of the imaging lens 40 and the specific region (measurement target portion Mp) of the living body Ob is set to an equivalent length to the distance Op22 between the screen 30a of the photodetector 30 and the center of the imaging lens 40. This realizes a positional relationship in which an image Im1 at a depth corresponding to the specific region (measurement target portion Mp) in the subject portion Mp0 irradiated with mid-infrared light is transferred as an image Im2 of equivalent size onto the screen 30a of the photodetector 30.

Here, it is preferable that the specific region (measurement target portion Mp) is located, for example, in a portion of the living body located inside the epidermis, such as the dermis (hereinafter, sometimes referred to as the "inner portion of the living body"). In this case, when the focal length of the imaging lens 40 with respect to the focus Fp is F, the distances Op21 and Op22 may both be 2F.

However, the lengths of the distances Op21 and Op22 are not limited to the above, and the magnifications of the distances Op21 and Op22 may be set so that the image Im1 of the target placement section 10 irradiated with mid-infrared light fits just inside the screen 30a of the photodetector 30, and the imaging lens 40 may be set to achieve that magnification.

The angle of incidence of the reflected light L2 on the imaging lens 40 is determined by the angle of the imaging lens 40 with respect to the surface 10a of the target placement unit 10 and the refraction angle of the reflected light L2 emitted from the target placement unit 10. In this embodiment, for example, the angle may be between 0 degrees and 40 degrees, and more preferably between 20 degrees and 30 degrees.

(Photodetection unit 70)
The blood substance concentration measuring device 1 adopts a configuration in which, while irradiating the second laser light for reference measurement from the light irradiating section 20, the detector 30 is moved along an optical path Op2 from the subject section Mp0 to the photodetector 30 to vary the distance of the photodetector 30 from the imaging lens 40. For this reason, the light detection unit 70 includes the photodetector 30 and a movable mechanism 71, as shown in Fig. 1. Each configuration will be described below.

[Photodetector 30]
The photodetector 30 is a near-infrared and mid-infrared sensor that receives reflected light from a specific region (measurement target portion Mp) based on the irradiated laser light L1 and detects the intensity of the reflected light. The photodetector 30 outputs an electrical signal according to the intensity of the received reflected light. The photodetector 30 may be, for example, an infrared sensor consisting of a single element that outputs the intensity of the reflected light as a one-dimensional voltage value.

In the blood substance concentration measuring device 1, the light irradiating unit 20 increases the intensity of the irradiated laser light L1, and the imaging lens 40 forms an image of the reflected light reflected from the measurement target portion Mp on the photodetector 30, so that the photodetector 30 can receive reflected light with a sufficiently high intensity compared to the background light, achieving a high S/N ratio and enabling highly accurate measurement. In this way, since the laser light L1 and the reflected light L2 are monochromatic and of high intensity, the only processing required for the photodetector 30 is the detection of light intensity, and there is no need to perform spectrum analysis based on wavelength sweeping or multivariate analysis, as in the photoacoustic optical method using a quantum cascade laser. Therefore, the accuracy required for detection is relaxed, and a simple electronic cooling method can be used.

The light detector 30 may be, for example, a HgCdTe infrared detector cooled with liquid nitrogen. In this case, by cooling the detector to about 77 K with liquid nitrogen, the light intensity of the reflected light L2 can be detected with a higher S/N ratio.

The photodetector 30 is electrically connected to the measurement control unit 60 described below, and outputs the intensity of the received reflected light to the measurement control unit 60 as a one-dimensional voltage value based on a control signal from the measurement control unit 60.

[Movable mechanism 71]
The movable mechanism 71 is a linear transport mechanism capable of reversibly moving the detector 30 along an optical path Op2 from the subject part Mp0 to the photodetector 30. A general-purpose linear transport mechanism such as a linear motor, a ball screw, or a rack and pinion can be used for the movable mechanism 71. The movable mechanism 71 is electrically connected to a measurement control unit 60 described later, and transports the detector 30 to a predetermined position based on a control signal supplied from the measurement control unit 60.

(Measurement control unit 60)
The measurement control unit 60 is electrically connected to the light irradiation unit 20, the photodetector 30 and the movable mechanism 71, and drives the light source 21 of the light irradiation unit 20 to oscillate pulsed pump light L0, and detects the light intensity of the reflected light L2 based on the output signal from the photodetector 30, to calculate the blood substance concentration in a specific region in the subject part Mp0.

Alternatively, the measurement control unit 60 may input the output of the monitor photodetector, and as described above, even if the intensity of the laser light L1 emitted from the light irradiation unit 20 fluctuates, the output of the monitor photodetector may be used to normalize the output of the photodetector 30, thereby compensating for the effect of the fluctuation in the intensity of the laser light L1 and calculating the blood substance concentration.

Furthermore, the measurement control unit 60 outputs a control signal to the movable mechanism 71 to drive the movable mechanism 71 and transport the detector 30 to a predetermined position along the optical path Op2.

The measurement control unit 60 performs the above-mentioned operations of transporting the detector 30, irradiating the laser light L1 from the light irradiating unit 20, and calculating the blood substance concentration based on the signal from the light detector 30, based on a preset program, and performs the blood substance concentration measurement process described below.

<Effects of the blood substance concentration measuring device 1>
(Improvement of S/N ratio)
The improvement of the S/N ratio during measurement by the optical system of the device 1 will be described.

Figure 5 is a schematic diagram showing an overview of the optical path from the light irradiating unit 20 to the photodetector 30 in the device 1. As shown in Figure 5, in the device 1, the laser light L1 irradiated from the light irradiating unit 20 enters the living body Ob at an incident angle θ along an optical path toward a specific area (measurement target part Mp) in the subject part Mp0, and is absorbed by substances in the blood, generating a reflected light component (Im11) from the specific area (measurement target part Mp) in the inner part of the living body below the skin surface, as well as a reflected light component (Im12) from the skin surface.

However, in the device 1, the imaging lens 40 is configured so that, of these reflected light components (Im11, Im12), the reflected light component (Im11) from a specific region (measurement target portion Mp) inside the living body is mainly imaged on the screen 30a of the photodetector 30.

The reflected light component (Im12) from the skin surface enters the imaging lens 40, but because the angle of incidence on the imaging lens 40 is different from the reflected light component (Im11) from the inside of the body, the light is guided outside the range of the screen 30a of the photodetector 30, or even if the light is guided within the range of the screen 30a of the photodetector 30, it is not imaged (is blurred), reducing the amount of light and the signal strength detected by the photodetector 30.

As a result, the reflected light component (Im12) from the skin surface, which is detected as noise, has a small effect on the light measurement.

In other words, in the device 1, the reflected light component (Im11) from a specific region (measurement target portion Mp) in the inside of the body below the surface of the skin that is to be mainly measured is imaged on the screen 30a of the photodetector 30 and reflected in the optical measurement by the photodetector 30, so that measurement results that are highly correlated with the blood glucose measurement results by SMBG (Self Monitoring of Blood Glucose) and have high reproducibility can be obtained.

In this way, compared to the conventional device 1X that uses a waveguide, the device 1 can reduce false signal (noise) components caused by reflected light scattered on the skin surface, improving the S/N ratio in optical measurements.

(Regarding detection of blood vessel region in subject part Mp0)
The improvement of the measurement accuracy based on the detection of the blood vessel region in the subject part Mp0 by the optical system of the device 1 will be described.

Figure 6 is a schematic diagram for explaining a similar optical path length adjustment operation in the configuration of a blood substance concentration measurement device according to a comparative example conceived by the inventor.

As shown in FIG. 6, the blood substance concentration measuring device according to the comparative example is configured so that it can be positioned so that its relative positional relationship with respect to the specific region to be the measurement target portion Mp is equivalent to that of the photodetector 30, and is configured with a two-dimensional imaging means 71A that receives reflected light from the specific region and detects whether an image based on the reflected light has been formed.

The two-dimensional imaging means 71A is a two-dimensional infrared imaging element array in which a plurality of light receiving elements capable of detecting mid-infrared light are arranged in a matrix on the light receiving surface 71Aa. As shown in FIG. 6, the two-dimensional imaging means 71A is integrated with the light detector 30 to form the light detection unit 70A, and the light detection unit 70A is configured to be slidable in a direction perpendicular to the light path L2 from the subject part Mp0 to the imaging lens 40. When the two-dimensional imaging means 71A is positioned on the light path L2, the relative positional relationship of the light receiving surface 71Aa of the two-dimensional imaging means 71A to the specific area is equivalent to the relative positional relationship of the screen 30a of the light detector 30 to the specific area.

With this configuration, in the blood substance concentration measuring device of the comparative example, the process of adjusting the optical path length from the specific area to the optical detector 30 in order to image the reflected light from the specific area to be the measurement target portion Mp on the optical detector 30 can be performed by replacing the optical detector 30 with the two-dimensional imaging means 71A, making it easy to adjust the optical path length.

On the other hand, FIG. 7 is a schematic diagram for explaining the operation of adjusting the optical path length from the specific area (measurement target portion Mp) to the photodetector 30 by the device 1.

As shown in FIG. 7, the device 1 is configured such that, while the light irradiation unit 20 is irradiating the laser light (second laser light) L1 for reference measurement, the movable mechanism 71 moves the detector 30 along the optical path Op2 from the subject portion Mp0 to the photodetector 30, thereby varying the distance of the photodetector 30 from the imaging lens 40.

This configuration realizes the function of varying the position of a specific region in the subject part Mp0 where reflected light that is imaged on the screen 30a of the detector 30 is generated. Here, the specific region is the focus region in the subject part Mp0 where the imaging lens 40 is focused. This function makes it possible to adjust the position of the photodetector 30 involved in measuring the measurement target substance (first blood substance) so that it is focused on the position of the capillaries in the living body.

In other words, the device 1 irradiates a laser light (second laser light) L1 for reference measurement, receives reflected light L2 reflected from a specific region, and measures the concentration of a reference substance (second blood substance) that has a higher absorption rate of laser light and/or a more stable blood concentration than the substance to be measured (first blood substance), thereby stably measuring whether an image Im11 based on reflected light from a blood vessel that is to be the measurement target portion Mp is formed on the photodetector 30.

Therefore, while gradually moving the detector 30, the reflected light from the blood vessels can be detected based on the reflected light of the reference measurement laser light ( second laser light).

Figure 8 shows the relationship between the position of the photodetector and the measured value of hemoglobin concentration measured using an embodiment of the device 1. The results are from an experiment under conditions in which laser light for reference measurement (second laser light) is irradiated from the light irradiating unit 20. In Figure 8, the horizontal axis represents the depth from the skin surface of the living body Ob in a specific region, and the vertical axis represents the ratio of the intensity of the reflected light L2 received by the detector 30 to the intensity of the laser light L1 irradiated from the light irradiating unit 20 after passing through the aperture 80 (hereinafter, sometimes referred to as the "input/output ratio").

As shown in Figure 8, the input/output ratio shows a minimum value at a depth of 1.5 mm from the skin surface of the living body Ob in a specific region, and it can be seen that a vascular region exhibiting a high hemoglobin concentration exists at a depth of 1.5 mm where the laser light for reference measurement (second laser light) is highly absorbed by hemoglobin.

In this way, by irradiating the target measurement laser light (first laser light) from the light irradiating unit 20 at the position of the detector 30 where the reflected light from the blood vessels is detected, and receiving the reflected light from the specific region by the detector 30, the concentration of the measurement target substance (first blood substance) can be measured when the specific region is included in the blood vessel region in the subject part (see the annotation in Figure 8).

Next, as a verification experiment, the blood concentration of glucose, which is the substance to be measured, was measured using an embodiment of the device 1. Figure 9 is a diagram showing the relationship between the position of the photodetector (measurement depth) and the measured glucose concentration value measured using an embodiment of the device 1. In Figure 9, as in Figure 8, the horizontal axis is the depth from the skin surface of the living body Ob in a specific region, and the vertical axis is the input/output ratio of the intensity of the reflected light L2 received by the detector 30 to the intensity of the laser light L1 (after passing through the aperture 80). The values shown in parentheses for each subject are the results of blood glucose measurement by SMBG (self-blood sampling measurement) performed simultaneously with the laser measurement.

As shown in Figure 9, the same results as the relationship between the photodetector position and hemoglobin concentration shown in Figure 8 were obtained for glucose, which is the substance to be measured, and in this test, the input/output ratio also showed a minimum value for glucose at a depth of 1.5 mm from the skin surface of the living body Ob in a specific region. In other words, according to the results of this test, a vascular region exhibiting a high glucose concentration exists at a depth of 1.5 mm where hemoglobin showed a high absorption value of the laser light for reference measurement (second laser light), and it can be seen that the depth at which the input/output ratio shows a minimum value is constant at a depth of 1.5 mm regardless of the subject.

In the results shown in Figure 9, the depth at which the input/output ratio showed a minimum value was 1.5 mm for all subjects. However, this depth may vary depending on the lancet insertion depth and individual differences between subjects, such as young children and the elderly. Even in such cases, the vascular region can be detected by searching for the depth at which the input/output ratio showed a minimum value using a reference measurement.

In addition, the SMBG measurement results and laser measurement results for each subject showed that subjects with higher SMBG blood glucose measurement values showed greater changes in the input/output ratio of laser intensity with respect to the measurement depth, indicating that there is a dependency between blood glucose levels and the magnitude of change in the intensity of received laser light.

As a result, it is possible to perform highly accurate measurements stably regardless of the condition of the skin surface, which varies from subject to subject and measurement, or the individual differences in the position of blood vessels in the depth direction from the skin surface. Furthermore, by adjusting the position of the photodetector, it is possible to change the optical path length L on the light receiving side, making it possible to measure subjects with thick skin.

(Reduction of measurement variation by aperture 80)
The improvement in variability in the measurement results of blood substance concentrations due to the optical system of device 1 was verified.

Figure 10 (a) is a schematic diagram for explaining the outline of the optical path in the blood substance concentration measuring device 1, and (b) is a schematic diagram for explaining the outline of the optical path from the light irradiation unit 20 in the comparative example to the photodetector PD assuming the subject unit Mp0.

As shown in FIG. 10(a), in the device 1, an aperture 80 is disposed in the section between the light irradiation unit 20 and the condenser lens 50 in the optical path of the laser light L1 from the light irradiation unit 20 to the photodetector PD. The aperture 80a is configured to narrow the beam diameter of the laser light L1 to 1/3, and the condenser lens 50 is configured to be disposed at a position that divides the distance between the light irradiation unit 20 and the aperture 80 internally at a:b, where f is the focal length of the condenser lens 50 and 1/f=1/a+1/b.

On the other hand, the comparative example had a configuration in which collimated laser light L1 was focused on a photodetector PD by a focusing lens 50, as shown in FIG. 10(b).

11(a) shows the variation in the measurement results of blood substance concentrations in the blood substance concentration measuring device 1, and (b) shows the variation in the measurement results in the blood substance concentration measuring device according to the comparative example. In Fig . 11 (a) and (b), the horizontal axis shows the division of measurement events performed at different times, and each plot in the figure shows measurement data performed four times consecutively in each measurement event. The vertical axis shows the normalized value of the ratio of the intensity of the reflected light L2 received by the photodetector PD to the intensity of the laser light L1 irradiated from the light irradiating unit 20 after passing through the aperture 80.

As shown in Figures 11(a) and (b), in Device 1, the variation in the measurement results within a measurement event was reduced from 14% to 5.3% compared to the comparative example, and the variation in the measurement results between measurement events was reduced from a maximum of 13% to within 3%.

In other words, in the device 1 in which the aperture 80 is provided in the optical path from the light irradiation unit 20 to the photodetector PD, a significant improvement was observed both within and between measurement events compared to the comparative example in which the aperture 80 is not provided.

The reason for this is believed to be that the provision of the aperture 80 makes the beam diameter uniform regardless of variations in the size of the emission part of the light irradiation part 20 of the laser light L1, and that the center of the optical axis of the laser light L1 coincides with the optical axis of the focusing lens 50.

(Reduction of measurement variability when measuring inside the skin of a living body Ob)
The reduction in measurement variability when measuring inside the skin of a living body Ob using the optical system of the device 1 was verified.

Using the device 1, the concentration of a reference substance (second blood substance) in the photodetector 30 was measured in a comparative example in which the position of the photodetector 30 was adjusted so that a specific area was set on the skin surface of the living body Ob, and in an example in which the position of the photodetector 30 was adjusted so that it was set inside the skin of the living body Ob.

12 is a diagram showing the laser light irradiation positions on the surface of a living body when measuring the concentration of a substance in blood by the device 1. Using the index finger as the living body Ob, the reference substance concentration was measured at a center line toward the fingertip, measurement position 1 on a cutting line shifted by δ from the base of the nail toward the base of the finger, measurement positions 2 and 3 offset by 3 mm above and below the center line, and measurement positions 4 and 5 offset by 3 mm to the left and right on the cutting line.

13(a) is a diagram showing the variation of the measurement results of the reference substance concentration in the working example, and (b) is a diagram showing the variation of the measurement results in the comparative example. In Fig. 13(a) and (b), the numbers of the measurement positions shown in Fig. 12 are shown, and each plot in the figure is the measurement data of four consecutive measurements at each measurement position. The vertical axis is a normalized value of the ratio of the intensity of the reflected light L2 received by the photodetector PD to the intensity of the laser light L1 irradiated from the light irradiating unit 20 after passing through the aperture 80.

As shown in Figures 13(a) and (b), in the embodiment, the variability of the measurement results within a measurement event was reduced from an average of 40% to an average of 9%, or approximately 32%, compared to the comparative example.

As shown in Figures 13(a) and 13(b), in both the Example and Comparative Example, the input/output ratio was small at measurement positions 4 and 5, indicating that blood vessel regions with high hemoglobin concentrations exist at measurement positions 4 and 5, where the laser light is absorbed more by hemoglobin. In particular, there was a noticeable tendency for the variation in the measurement results to vary in the Example compared to the Comparative Example, with respect to the magnitude of the input/output ratio at the measurement positions.

In addition, at a measurement position in the planar direction where reflected light indicating the vascular region is detected, laser light for measuring the object (first laser light) is irradiated from the light irradiating unit 20, and the reflected light at the measurement position is received by the detector 30, so that the concentration of the substance to be measured can be measured when the measurement position in the planar direction is included in the vascular region in the subject part.

As a result, it is possible to consistently perform highly accurate measurements regardless of individual differences in the position of blood vessels in the planar direction between subjects or measurements.

<Operation of Blood Substance Concentration Measuring Device 1>
Next, an outline of the operation of the blood substance concentration measuring device 1 will be described with reference to FIGS .

(Operation of determining whether a specific region belongs to a blood vessel region in a subject part)
FIG. 14 is a flow chart showing one embodiment of the operation of measuring a substance in blood by the device 1.

In FIG. 14, steps S11 and S12 are steps for performing a reference measurement to measure the concentration of a reference substance (a second blood substance) in a specific region and determine whether the specific region is included in a vascular region in the subject part.

Steps S21 and S22 are steps of measuring the concentration of the measurement target substance (first blood substance) when the specific region is included in the vascular region of the subject part.

In FIG. 14, first it is determined whether or not to perform a reference measurement (step S1). This determination may be made based on operational input from the operator or on identification information such as the subject's ID. For example, when the same subject is repeatedly measured daily, the results of a reference measurement already obtained can be used and the reference measurement can be omitted. If the result of the determination in step S1 is that a reference measurement is to be performed (step S1: Yes), the process proceeds to step S11; if not (step S1: No), the process proceeds to step S21.

Next, in steps S11 and S12, a reference measurement is performed. First, the measurement control unit 60 irradiates the specific region with a laser light for reference measurement (second laser light) from the light irradiating unit 20 based on a control signal (step S11), measures the concentration of the reference substance (second blood substance) in the specific region with the photodetector 30 (step S12), and determines whether the measured concentration of the reference substance is equal to or higher than a standard value (step S13 ).

In step S13 , if the concentration is not equal to or greater than the reference value (step S13 : No), the process is terminated, whereas if the concentration is equal to or greater than the reference value (step S13 : Yes), the specific region is determined to be included in the vascular region of the subject part, and the concentration of the measurement target substance (first blood substance) is measured in steps S21 and S22. Specifically, the light irradiating unit 20 irradiates the specific region with laser light for target measurement (first laser light) (step S21), the photodetector 30 measures the concentration of the measurement target substance in the specific region (target measurement), and the measurement result is output (step S22), and the process is terminated.
(Operation of adjusting the position of the photodetector along the optical path)
FIG. 15 is a flow chart showing another aspect of the blood substance measuring operation by the blood substance concentration measuring device 1.

In FIG. 15, steps S10 to S16 are steps for measuring the concentration of a reference substance (second blood substance) in a specific region as a reference measurement, and adjusting the position of the photodetector along the optical path based on the concentration of the reference substance in the specific region so that the specific region is included in the vascular region of the subject.

Steps S21 and S22 are steps of the target measurement in which the concentration of the measurement target substance (first blood substance) is measured when the specific region is included in the vascular region of the subject part. The same processes as those in FIG. 14 are indicated with the same numbers as those in FIG. 14.

15, if the result of the determination in step S1 is that a reference measurement is to be performed (step S1: Yes), the reference measurement is performed in steps S10 to S16. First, the measurement control unit 60 drives the movable mechanism 71 based on a control signal to move the photodetector 30 to a start position (step S10), irradiates the specific region with laser light for reference measurement (second laser light) from the light irradiating unit 20 (step S11), and measures the concentration of the reference substance (second blood substance) in the specific region with the photodetector 30 (reference measurement, step S12).

Next, it is determined whether the photodetector 30 is at the end position (step S14), and if it is not at the end position (step S14: No), the position of the photodetector is gradually moved (step S15) and the process returns to step S11, and if it is at the end position (step S14: Yes), it is assumed that the concentration measurement of the reference substance in the specific region has been completed at all photodetector positions, and the process proceeds to step S16.

In step S16, the photodetector is moved to the optimal position where the highest concentration of the reference substance is obtained based on the concentration measurement results of the reference substance in the specific region at all positions of the photodetector. At the optimal position, the specific region is estimated to be included in the vascular region of the subject part.

Next, in steps S21 and S22, the concentration of the measurement target substance (first blood substance) is measured. Specifically, the light irradiating unit 20 irradiates the specific region with a laser beam for measuring the target (first laser beam) (step S21), the photodetector 30 measures the concentration of the measurement target in the specific region, and the result is output (target measurement, step S22), ending the process.
(Operation of Adjusting the Irradiation Position of the Laser Light L1 in the Planar Direction)
FIG. 16 is a flow chart showing still another aspect of the blood substance measuring operation by the blood substance concentration measuring device 1.

In FIG. 16, steps S10A to S16A are steps for measuring the concentration of a reference substance (second blood substance) in a specific region by varying the planar position at which the laser light L1 is irradiated as a reference measurement, and adjusting the planar irradiation position based on the concentration of the reference substance at the different irradiation positions so that the irradiation position is included in the blood vessel region in the planar direction of the subject part.

Steps S21 and S22 are steps of measuring the concentration of the measurement target substance (first blood substance) when the irradiation position is included in the blood vessel region in the planar direction of the subject part.

The same processes as those in Figures 14 and 15 are indicated with the same numbers.

16, if the result of the determination in step S1 is that a reference measurement is to be performed (step S1: Yes), the reference measurement is performed in steps S10A to S16A. First, the measurement control unit 60 moves the position in the planar direction where the laser light L1 is irradiated to the starting position based on the control signal (step S10A ), irradiates the specific area with the laser light for reference measurement (second laser light) from the light irradiating unit 20 (step S11), and measures the concentration of the reference substance (second blood substance) in the specific area with the photodetector 30 (step S12).

Next, it is determined whether the irradiation position is at the end point position (step S14). If it is not at the end point position (step S14: No), the irradiation position is changed (step S15A) and the process returns to step S11. If it is at the end point position (step S14: Yes), it is determined that the concentration measurement of the reference substance in the specific area at all irradiation positions has been completed, and the process proceeds to step S16A.

In step S16A, the reference material (second) in the specific region at all irradiation positions is
Based on the result of the measurement of the concentration of the blood substance, the irradiation position is changed to the optimum position where the highest concentration of the reference substance is obtained. At the optimum position, the irradiation position is estimated to be included in the blood vessel region in the planar direction of the subject part.

Next, in steps S21 and S22, the concentration of the measurement target substance (first blood substance) is measured. Specifically, the light irradiation unit 20 irradiates the specific area with laser light for measuring the target (first laser light) (step S21), the light detector 30 measures the concentration of the measurement target in the specific area, and the result is output (target measurement, step S22), ending the process.

<Summary>
As described above, the blood substance concentration measuring device 1 according to the embodiment for measuring the concentration of a blood substance is a blood substance concentration measuring device 1 contained in the blood of a subject part Mp0 of a living organism Ob, and includes a light irradiating unit 20 that irradiates a region including a measurement target part Mp in the subject part with laser light, a photodetector 30 that receives reflected light L2 based on the irradiated laser light L1 and detects the intensity of the reflected light, a first lens 40 that is disposed between the subject part Mp0 and the photodetector 30 at a position where the reflected light L2 from a specific region Mp in the subject part Mp0 can be imaged on the photodetector 30, and a measurement control unit 60 that measures the concentration of the blood substance in the specific region Mp as the concentration of the blood substance in the measurement target part Mp based on the intensity of the reflected light L2, and is characterized in that the light irradiating unit 20 is configured to be able to selectively irradiate laser light for target measurement that is absorbed by the measurement target substance (first blood substance) and laser light for reference measurement (second laser light) that is absorbed by a reference substance (second blood substance).

The absorption rate of the laser light (second laser light) in the reference measurement by the second blood substance may be greater than the absorption rate of the laser light for the target measurement by the first blood substance in the target measurement. Furthermore, the reference substance may be configured to have a more stable concentration in blood than the measurement target substance.

The measurement control unit 60 may also be configured to measure the concentration of a reference substance (second blood substance) when the specific region Mp is included in a vascular region in the subject region based on irradiation with a laser light (second laser light) for reference measurement, and to measure the concentration of a measurement target substance (first blood substance) in the specific region Mp based on irradiation with a laser light for target measurement.

The optical detector 30 is configured to be able to change the depth of the specific region Mp in the living body by moving it along an optical path Op2 from the subject portion Mp0 to the optical detector 30, and the position of the optical detector 30 may be configured to be able to be adjusted along the optical path OP2 so that the specific region Mp is included in the vascular region in the subject portion Mp0 based on the concentration of the reference substance (second blood substance).

This configuration makes it possible to stably perform highly accurate measurements regardless of inter-individual variations in the depth of the measurement target area in the living body or variations in the conditions for irradiating the laser light. As a result, in blood glucose level measurements that are performed daily by patients themselves, work such as appropriately adjusting the optical system for each living body or each time a measurement is performed can be eliminated, realizing a non-invasive and simple measurement method.

<<Variations>>
Although the specific configuration of the present disclosure has been described above using the embodiments as examples, the present disclosure is not limited to the above embodiments except for its essential characteristic components. For example, the present disclosure also includes forms obtained by applying various modifications to the embodiments and forms realized by arbitrarily combining the components and functions of each embodiment within the scope of the present invention.

(1) In the above embodiment, glucose is used as an example of the measurement target substance (first blood substance) to be detected by the blood substance concentration measuring device. However, the blood components detectable by the blood substance concentration measuring device according to the present disclosure are not limited to the above, and the device can be widely used for other detection targets by varying the wavelength of the laser light L1 emitted by the light irradiating unit 20 depending on the type of blood component.

For example, the wavelength of the laser light L1 emitted by the light irradiating unit 20 may be 8.23±0.05 μm (8.18 μm or more and 8.28 μm or less), and the blood component may be lactic acid. Alternatively, the wavelength may be in the range of 5.77 μm, 6.87 μm, 7.27 μm, 8.87 μm, or 9.55 μm, and in the range of -0.05 μm or more and +0.05 μm or less. Experiments by the inventors have confirmed that the lactate concentration measured by a photodetector when the wavelength of light emitted by the light irradiating unit 20 is 8.23 μm generally correlates with the lactate level measurement results from a self-blood sample.

(2) In the above embodiment, hemoglobin is used as an example of the reference substance (second blood substance) to be detected in the reference measurement. However, the reference substance according to the present disclosure is not limited to the above, and can be used for other reference substances by varying the wavelength of the laser light L1 emitted by the light irradiation unit 20 depending on the type of blood component used as the reference substance.

(3) In the above embodiment, the wavelength of the oscillated laser light L1 can be switched and adjusted by adjusting the type and matching conditions of the nonlinear optical crystal 223 in the optical parametric oscillator 22.

However, the light irradiation unit 20 may be configured to selectively use multiple optical parametric oscillators 22 and selectively irradiate laser light L1 of multiple wavelengths, thereby making it possible to make the device capable of measuring multiple types of blood components. The light emitted from the light source 21 may be switched to enter multiple optical parametric oscillators that emit light of different wavelengths, and each optical parametric oscillator may selectively emit light of a different wavelength, allowing a reference measurement and an actual measurement of the measurement target to be selectively performed depending on each wavelength.

Alternatively, a configuration may be used in which multiple light emitting units 20 emitting light of different wavelengths are used, and light from two of the light emitting units 20 is selectively emitted as laser light L1 using an optical coupler, mirror, or the like. In this case, unlike a configuration that employs an optical system in which the width or thickness of the optical path differs depending on the wavelength of light, for example, an optical system for multiple blood components can share an optical system consisting of a focusing lens 50, a target placement unit 10, an imaging lens 40, and a photodetector 30 capable of detecting mid-infrared light.

(4) In the above embodiment, the light irradiation unit 20 is configured such that the first laser light for object measurement and the second laser light for reference measurement have different wavelengths. However, as long as the first laser light for object measurement is absorbed by the substance to be measured and the second laser light for reference measurement is absorbed by the reference substance, the first laser light and the second laser light may be configured to have different irradiation conditions other than wavelength. For example, the first laser light and the second laser light may have different intensities of light emitted from the irradiation unit.

(5) In the above embodiment, the measurement target substance and the reference substance are different blood substances. However, the reference measurement may be performed using the same substance as the measurement target substance.

(6) In the above embodiment, the blood substance concentration measuring device is an optical system having an imaging lens 40 between the measurement target portion Mp and the photodetector 30. However, the blood substance concentration measuring device according to the present disclosure may be configured to image the reflected light L2 reflected from the measurement target portion Mp of the living body Ob on the photodetector 30, and may be changed to another aspect as appropriate as the light receiving optical system. For example, it may be configured using multiple lenses or may be configured with a mirror disposed midway along the optical path.

(7) The order in which steps are performed in the embodiments is merely an example to specifically explain the present invention, and orders other than those described above may also be used. In addition, some of the steps may be performed simultaneously (in parallel) with other steps.

Furthermore, at least some of the functions of each embodiment and its modified examples may be combined.

<Additional Information>
The above-described embodiments each show a preferred specific example of the present invention. The numerical values, shapes, materials, components, the arrangement and connection of the components, steps, and the order of steps shown in the embodiments are merely examples and are not intended to limit the present invention. Furthermore, among the components in the embodiments, those not described in the independent claims showing the highest concept of the present invention are described as optional components constituting a more preferred embodiment.

The order in which the above methods are performed is merely an example to specifically explain the present invention, and orders other than those described above may also be used. A part of the above methods may also be performed simultaneously (in parallel) with other methods.

In order to facilitate understanding of the invention, the scale of the components in the figures shown in the above embodiments may differ from the actual scale. Furthermore, the present invention is not limited to the description of the above embodiments, and may be modified as appropriate without departing from the gist of the present invention.

Furthermore, all the numbers used above are merely examples to specifically explain the present invention, and the present invention is not limited to the numbers exemplified.

The blood substance concentration measuring device and blood substance concentration measuring method according to one aspect of the present disclosure can be widely used as medical equipment for measuring blood substance conditions such as blood glucose levels and blood lipid levels on a daily basis in the prevention and treatment of lifestyle-related diseases.

REFERENCE SIGNS LIST 1 Blood substance concentration measuring device 10, 10X Object placement section 20, 20X Light irradiation section 21 Light source 22 Optical parametric oscillator 221 Incident side semi-transparent mirror 222 Exit side semi-transparent mirror 223 Nonlinear optical crystal 30 Photodetector 40 Imaging lens (first lens)
50 Condenser lens (second lens)
60 Measurement control section 70, 70A Light detection unit 71 Movable mechanism 71A Two-dimensional imaging means 80 Aperture 80a Opening

Claims (23)

A blood substance concentration measuring device for measuring a concentration of a blood substance contained in blood of a subject part of a living body, comprising:
a light irradiation unit that irradiates an irradiation area including a measurement target portion in the subject with laser light;
a photodetector that receives reflected light based on the irradiated laser light and detects the intensity of the reflected light;
a first lens disposed between the object and the photodetector at a position capable of forming an image of the reflected light from a specific region in the object on the photodetector;
a measurement control unit that measures the concentration of the blood substance in the specific region as the concentration of the blood substance in the measurement target portion based on the intensity of the reflected light,
the light irradiating unit is configured to selectively irradiate a first laser light for subject measurement, which is absorbed by a first substance in blood that is a measurement target substance, and a second laser light for reference measurement , which is absorbed by a second substance in blood that is a reference substance, and irradiates the second laser light before the first laser light;
An absorption rate of the second laser light by the second blood substance in the reference measurement is greater than an absorption rate of the first laser light by the first blood substance in the subject measurement.
Blood substance concentration measuring device. The blood substance concentration measuring device according to claim 1 , wherein the reference substance has a more stable concentration in blood than the measurement target substance. the measurement control unit measures a concentration of the second blood substance in a state in which the specific region is included in a blood vessel region in the subject portion based on the irradiation of the second laser light,
3. The blood substance concentration measuring device according to claim 1 or 2, wherein the concentration of the first blood substance in the specific region is measurable as the concentration of the first blood substance in the measurement target portion based on the irradiation of the first laser light. the photodetector is configured to be moved along an optical path from the subject portion to the photodetector, so that a depth of the specific region in the living body can be changed;
4. The blood substance concentration measuring device according to claim 1 , wherein the position of the photodetector is adjustable along the optical path so that the specific region is included in a blood vessel region in the subject part based on the concentration of the second blood substance. 5. The blood substance concentration measuring device according to claim 1 , wherein the light irradiating unit selectively irradiates the first laser light and the second laser light by modulating a wavelength to differentiate types of detectable blood substances. The blood substance concentration measuring device according to claim 1 , wherein the light irradiating section includes an optical oscillator that emits the first laser light and an optical oscillator that irradiates the second laser light. 7. The blood substance concentration measuring device according to claim 1, wherein the first blood substance is glucose, and the wavelength of the first laser light is a predetermined wavelength selected from the range of 2.5 μm or more and 12 μm or less. 8. The blood substance concentration measuring device according to claim 1, wherein the second blood substance is hemoglobin, and the wavelength of the second laser light is a predetermined wavelength selected from the range of 5.0 μm or more and 12 μm or less. 9. The blood substance concentration measuring device according to claim 1 , further comprising: a second lens located between the light irradiating unit and the test subject in an optical path from the light irradiating unit to the test subject, the second lens focusing the first laser light and the second laser light onto the irradiation area; and an aperture located between the light irradiating unit and the second lens. a subject placement section on which a surface of the living body is placed,
The subject placement portion has a through hole in a region where the surface of the living body comes into contact,
The first laser light and the second laser light are irradiated onto a surface of the living body through the through hole,
The blood substance concentration measuring device according to claim 1 , wherein the reflected light is received by the photodetector through the through hole. a subject placement section on which a surface of the living body is placed,
the subject placement portion has a recess formed in a region where the surface of the living body comes into contact;
the first laser light and the second laser light are transmitted through the subject placement unit and irradiated onto a surface of the living body;
The blood substance concentration measuring device according to claim 1 , wherein the reflected light is transmitted through the subject placement section and received by the photodetector. the measurement target portion is a blood vessel region in the subject portion located inside the epidermis,
The blood substance concentration measuring device according to claim 1 , wherein the first lens transfers an irradiation area of the first laser light and the second laser light in the measurement target portion onto a light receiving surface of the photodetector. The blood substance concentration measuring device according to claim 7 , wherein the wavelength of the first laser light is a predetermined wavelength selected from the range of 6.0 μm or more and 12 μm or less. 7. The blood substance concentration measuring device according to claim 1, wherein the first blood substance is lactic acid, and the wavelength of the first laser light is a predetermined wavelength selected from the range of 5.0 μm or more and 12 μm or less. a subject placement section on which a surface of the living body is placed,
10. The blood substance concentration measuring device according to claim 9, wherein in a section from the light irradiation unit to the subject part in an optical path from the light irradiation unit to the subject part, the first laser light and the second laser light propagate through space except for a section passing through the second lens. a subject placement section on which a surface of the living body is placed,
In a section from the object placement section to the photodetector in the optical path from the object section to the photodetector, the reflected light propagates in a space except for a section passing through the first lens.
The blood substance concentration measuring device according to claim 1 . A method for measuring a concentration of a substance in blood, comprising the steps of:
a light irradiation unit irradiates an irradiation area including a measurement target portion in the subject part with a first laser light for measuring a target substance, the first laser light being absorbed by a first substance in blood, the first substance being the measurement target substance;
using a first lens located between the object and a photodetector, forming an image of the reflected light of the first laser light reflected from a specific region in the object on the photodetector;
a photodetector receiving reflected light of the first laser light and measuring a concentration of the first blood substance based on the reflected light as a concentration of the first blood substance in the measurement target portion,
Prior to the target measurement,
irradiating the irradiation area with a second laser light for reference measurement, the second laser light being absorbed by a second blood substance as a reference substance from the light irradiation unit;
using the first lens to form an image of the reflected light of the second laser light reflected from the specific region on the photodetector;
performing a reference measurement in which reflected light of the second laser light is received by the photodetector and a concentration of the second blood substance based on the reflected light is measured as the concentration of the second blood substance in the measurement target portion;
In the reference measurement, an absorption rate of the second laser light by the second blood substance is greater than an absorption rate of the first laser light by the first blood substance in the subject measurement.
Blood substance concentration measurement method. The method for measuring the concentration of a substance in blood according to claim 17 , wherein the reference substance has a more stable concentration in blood than the measurement target substance. In the reference measurement,
19. The method for measuring a concentration of a substance in blood according to claim 17 or 18, further comprising: measuring the concentration of the second blood substance by varying a position of the photodetector along an optical path from the subject part to the photodetector, thereby adjusting a position of the photodetector along the optical path so that the specific region is included in a blood vessel region in the subject part . 20. The method for measuring a concentration of a substance in blood according to any one of claims 17 to 19, wherein the first laser light and the second laser light are irradiated to the irradiation area using a second lens that is located between the light irradiator and the test subject in an optical path from the light irradiator to the test subject and that focuses the first laser light and the second laser light on the irradiation area, and a diaphragm that is located between the light irradiator and the second lens and that narrows down the light irradiated from the light irradiator. A surface of the living body is brought into contact with a subject placement portion;
The first laser light and the second laser light are irradiated onto a surface of the living body through a through hole provided in the target placement portion;
The method for measuring a concentration of a substance in blood according to claim 17 , wherein the reflected light is received by the photodetector through the through hole. A program for causing a computer to perform a blood substance concentration measurement process for measuring a concentration of a blood substance contained in blood of a subject part of a living body,
The blood substance concentration measuring process includes:
a light irradiation unit irradiates an irradiation area including a measurement target portion in the subject part with a first laser light for measuring a target substance, the first laser light being absorbed by a first substance in blood, the first substance being the measurement target substance;
using a first lens located between the object and a photodetector, forming an image of the reflected light of the first laser light reflected from a specific region in the object on the photodetector;
a blood substance concentration measurement process for receiving reflected light of the first laser light by the photodetector and measuring a concentration of the first blood substance based on the reflected light as a concentration of the first blood substance in the measurement target portion ,
Prior to the target measurement,
irradiating the irradiation area with a second laser light for reference measurement, the second laser light being absorbed by a second blood substance as a reference substance from the light irradiation unit;
using the first lens to form an image of the reflected light of the second laser light reflected from the specific region on the photodetector;
performing a reference measurement in which reflected light of the second laser light is received by the photodetector and a concentration of the second blood substance based on the reflected light is measured as the concentration of the second blood substance in the measurement target portion;
In the reference measurement, an absorption rate of the second laser light by the second blood substance is greater than an absorption rate of the first laser light by the first blood substance in the subject measurement.
program. In the reference measurement,
The program according to claim 22, further comprising: measuring the concentration of the second blood substance by varying the position of the photodetector along an optical path from the subject part to the photodetector, thereby adjusting the position of the photodetector along the optical path so that the specific region is included in a blood vessel region in the subject part.

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