JP2004329888A - Method and apparatus for measuring concentration of specific component - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To stably and easily measure the concentration of a specific component contained in an organism, without dispersion even when liquid such as water, saliva or sweat is interposed between an optical element and the organism, and even when measuring a plurality of organisms. <P>SOLUTION: An analytical curve for correction is computed to correct the influence by fluctustion of thickness of the liquid, or the like, interposed between the organism and the optical element. A measured value is corrected by the analytical curve, and concentration is determined from the obtained corrected value. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a method and an apparatus for optically measuring the concentration of a specific component such as blood sugar level, water or cholesterol in a living body by measuring return light from the living body.

Conventionally, various methods have been proposed for measuring a specific component of a sample, particularly a living body, using an optical measurement device. For example, a method has been proposed in which a transparent attenuated total reflection (ATR) element having a pair of reflecting surfaces facing in parallel is used as an optical element, and upper and lower lips are brought into close contact with this optical element to measure a blood glucose level. (Patent Documents 1 and 2).
Specifically, in this method, an ATR element made of zinc selenide, silicon, germanium, or the like is held in the mouth and pressed down by a lip, and light is incident on the ATR element in this state. The incident light repeats total reflection at the boundary between the reflection surface of the ATR element and the lip, and then exits outside the ATR element. By analyzing the emitted light, information on the concentration of the component contained in the lips can be obtained.

Further, a method has been proposed in which a laser beam having a wavelength of 9 to 11 micrometers is incident on an ATR element made of a ZnSe optical crystal or the like adhered to the mucous membrane of the lip, and multiple reflection is performed inside the ATR element. By analyzing the attenuated total reflection light or the scattered reflection light after the multiple reflection, the blood glucose level or the blood ethanol concentration can be measured.
According to these methods, the concentration of a specific component such as glucose or cholesterol can be measured in real time and non-invasively. In these methods, evanescent light (so-called exudation light) is applied to quantitative analysis.

Thus, by measuring the return light from the living body, it is possible to obtain information on the concentrations of various components of the body fluid, but the liquid present at the boundary between the optical element and the living body affects the measurement accuracy. There's a problem. The information on the density includes the density itself, the absolute value of the density, the temporal change of the density, and the like.
JP-A-9-113439 JP-A-11-178799

However, the conventional optical measuring device for performing the above method has the following problems. In other words, light traveling in the ATR element slightly enters the lip when total reflection is repeated at the boundary between the reflection surface of the ATR element and the lip. At this time, the light is affected by the components in the body fluid existing there.
For example, glucose has absorption peaks near the wave numbers of 1033 cm ^-1 and 1080 cm ^-1 . Therefore, when a living body is irradiated with light having this wave number, the amount of light absorbed differs depending on the glucose concentration in the living body.

More specifically, when measuring the density information of the lip, which is a living body, using an optical element, if a liquid such as saliva is interposed between the optical element and the lip, the amount of light reaching the lip is changed by a liquid layer. Varies depending on the thickness of As a result, the amount of signal detected based on the amount of light greatly changes, causing variation in the measurement result, and a stable measurement result cannot be obtained.
At this time, when only the glucose peak value is obtained as the concentration information, for example, the absorbance measured is low because the saliva layer is thick despite the fact that the glucose concentration is high, or the saliva layer is thin despite the fact that the glucose concentration is low. For this reason, the measured absorbance may be high, or erroneous concentration information may be obtained.

Further, when measuring a plurality of subjects, the signal amount greatly changes depending on the individual difference in the refractive index, and the same problem occurs.
Further, when measurement is performed at a site other than the lips, if a body fluid such as sweat is interposed between the site and the optical element, the amount of light reaching the living body changes due to the thickness of the body fluid layer, and the measurement result varies. And a similar problem occurs.

Generally, in the ATR method, the depth at which the evanescent light penetrates the measurement target is on the order of wavelength. This light returns from the surface of the living body after passing through the surface tissue in the wavelength range. The penetration depth of the evanescent light is determined by the refractive index of the living body and the angle of incidence of the light on the optical element.
When a liquid or the like is interposed between the living body and the optical element, if the thickness of the interposed liquid changes, the depth of the evanescent light entering the living body changes. Further, when there are a plurality of living body parts to be measured, the penetration depth changes because the refractive index differs for each part to be measured. For this reason, the above problem is remarkable in an optical measurement device using an ATR element.

Also, even in the method of measuring transmitted light instead of evanescent light, when a liquid intervenes at the boundary between a living body and an optical element and the thickness of the liquid layer changes, the effect of changing the wavenumber signal information is not affected. The same is true.
That is, in the conventional measurement method, there is a problem that a change in the state of the boundary portion between the living body and the optical element affects the wavenumber signal information, and the present invention solves such a problem. Even when a liquid such as water, saliva or sweat intervenes between the two or when measuring at a plurality of living body parts, a method capable of stably and easily measuring the concentration information of a specific component contained in the living body and It is intended to provide a device.

In order to solve the above problems, the present invention is a method for measuring the concentration of a specific component contained in a living body,
(1) entering light into an optical element, absorbing and reflecting the light to a living body in contact with the optical element, and then emitting the light from the optical element;
(2) detecting light emitted from the optical element and obtaining a wave number signal from the detected light;
(3) a step of correcting the wavenumber signal using a calibration curve for correcting an influence of a state change of a boundary portion between the living body and the optical element on the wavenumber signal; and (4) a step after the correction. A method for measuring the concentration of a specific component, comprising a step of obtaining a concentration of the specific component contained in the living body from a wave number signal.

Furthermore, the present invention also provides a measuring device for performing the above measuring method. This measuring device comprises: (a) an optical element for making contact with a living body;
(B) a light source for causing light to enter the optical element;
(C) light detection means for detecting light emitted from the optical element, and (d) signal processing means for processing a wave number signal obtained by the light detection means,
The signal processing means corrects the wave number signal using one or more kinds of calibration curve data.

  According to the present invention, even when a liquid such as water, saliva, or sweat is interposed between the optical element and the living body, or even when measurement is performed at a plurality of sites in the living body, The concentration information of the specific component contained can be measured stably and easily.

The present invention is a method for measuring the concentration of a specific component contained in a living body,
(1) entering light into an optical element, absorbing and reflecting the light to a living body in contact with the optical element, and then emitting the light from the optical element;
(2) detecting light emitted from the optical element and obtaining a wave number signal from the detected light;
(3) a step of correcting the wavenumber signal using a calibration curve for correcting an influence of a state change of a boundary portion between the living body and the optical element on the wavenumber signal; and (4) a step after the correction. A step of obtaining a concentration of the specific component contained in the living body from a wave number signal.

  In the present invention, (3a) a step of obtaining i spectra corresponding to i (i is an integer of 2 to n) kinds of states at the boundary portion in advance, and (3b) j for each of the i spectra (J is an integer of 2 to n) i points determined by j wave number signals corresponding to the kinds of wave numbers are plotted on a coordinate system, and the points are connected to obtain a calibration curve, whereby the calibration curve is created. Keep it. Then, at the time of actual measurement, the wave number signal obtained from the detection light is corrected using this calibration curve.

  The step (3a) is a step of obtaining a first spectrum and a second spectrum corresponding to two states of the boundary portion, and the step (3b) is a step of obtaining two kinds of wave numbers in the first spectrum. Are plotted on a coordinate system at a point (x1, y1) determined by two wavenumber signals corresponding to the above, and at a point (x2, y2) determined by two wavenumber signals corresponding to two kinds of wavenumbers in the second spectrum, It is preferable to obtain a calibration curve by connecting the points.

  In the step (3), a second calibration curve passing through a point determined by the wave number signal obtained from the detection light at a plurality of different wave numbers and having the same gradient as the calibration curve is created, and the wave number signal is generated. It is effective to include a step of performing conversion based on the second calibration curve and provisional conditions.

  Further, in the present invention, (3A) a step of previously obtaining i (i is an integer of 2 to n) spectra in a single operation in a state where the living body and the optical element are in contact with each other, and (3B) In each of the i spectra, i points determined by j wave number signals corresponding to j (j is an integer of 2 to n) kinds of wave numbers are plotted on a coordinate system, and a calibration curve is obtained by connecting the points. The calibration curve is prepared in accordance with the process. Then, at the time of actual measurement, the wave number signal obtained from the detection light is corrected using this calibration curve.

  The step (3A) is a step of obtaining a first spectrum and a second spectrum, and the step (3B) is determined by two wave number signals corresponding to two kinds of wave numbers in the first spectrum. (X1, y1) and a point (x2, y2) determined by two wave number signals corresponding to two kinds of wave numbers in the second spectrum are plotted on a coordinate system, and a calibration curve is obtained by connecting the points. Preferably it is.

  Also in this case, the step (3) creates a second calibration curve passing through a point determined by the wave number signal obtained from the detection light at a plurality of different wave numbers and having the same gradient as the calibration curve. It is effective to include a step of converting the signal based on the second calibration curve and the provisional condition.

It is preferable that the change in the state of the boundary portion is a change in the thickness of the liquid layer.
Further, when creating the calibration curve, it is effective to use wave number signals at two or more wave numbers in the range of 700 to 3200 cm ⁻¹ and to use wave number signals at any of the two or more wave numbers as the provisional condition. It is.

Furthermore, the present invention also relates to a measuring device for performing the above measuring method. This measuring device is a device for measuring the concentration of a specific component contained in the living body,
(A) an optical element for contacting a living body,
(B) a light source for causing light to enter the optical element;
(C) light detection means for detecting light emitted from the optical element, and (d) signal processing means for processing a wave number signal obtained by the light detection means,
The signal processing means corrects the wave number signal using one or more kinds of calibration curves.

It is effective that the signal processing means stores the calibration curve as data.
Further, it is effective that the signal processing means has a function of calculating the calibration curve.
Further, the signal processing means creates a second calibration curve passing through a point determined by the wave number signal obtained from the detection light at a different wave number and having the same gradient as the calibration curve, and converting the wave number signal into the second It is effective to have a function of performing conversion based on the calibration curve and the provisional conditions.

Further, it is effective that the calibration curve is a calibration curve for correcting the influence of a change in the thickness of the liquid layer at the boundary between the living body and the optical element on the wavenumber signal.
It is effective that the provisional condition is a wave number signal at two or more wave numbers in the range of 700 to 3200 cm ⁻¹ used when creating the calibration curve.

A measuring method and a measuring apparatus according to the present invention will be described with reference to the drawings. 1 and 6 are diagrams showing a configuration of a measuring device according to one embodiment of the present invention. In these figures, the path of light emitted from the light source is indicated by a dotted line. The present invention is not limited to this embodiment.
The measuring method according to the present invention includes the following four steps.

Step (1):
In step 1, after the optical element is brought into contact with the measurement site of the living body, light is incident on the optical element, and the light is absorbed and reflected by the living body in contact with the optical element, and then emitted from the optical element.
As shown in FIG. 1, light incident on the ATR type optical element 2 from the light source 1 propagates through the optical element 2 while repeating total reflection. This light exudes to a distance (depth) about several times the wavelength in a medium in contact with the outside of the optical element. At this time, the exuded light is absorbed by an amount corresponding to a specific component contained in the living body 5 that is in close contact with the optical element 2. Thereafter, light is emitted from the optical element 2.

  On the other hand, in the case of the measuring device shown in FIG. 6, the living body 5 is brought into contact with the substantially V-shaped portion 13 formed on the sensing surface of the optical element 12. In this case, the living body 5 partially rises and comes into contact with the substantially V-shaped portion 13. Light incident on the transmitted light type optical element 12 from the light source 1 is absorbed and reflected by the living body 15 and propagates through the optical element 12. At this time, this light is absorbed by an amount corresponding to a specific component contained in the living body 5 that is in close contact with the optical element 12. Thereafter, light is emitted from the optical element 12.

Step (2):
In step 2, the light emitted from the optical element 2 or 12 is detected by, for example, the light detection means 3, and a wave number signal is obtained from the detected light. The wave number signal includes an absorbance and a transmittance corresponding to the wave number.

Step (3):
Next, in step 3, the wave number signal obtained from the detection light is corrected using a calibration curve.
This calibration curve represents information in which the wave number signal fluctuates as a gradient line. Specifically, the calibration curve is data for correcting the effect of a change in the state of the boundary between the living body 5 and the optical element 2 or 12 on the wavenumber signal obtained from the detection light.

The calibration curve is
(3a) a step of obtaining i spectra corresponding to i (i is an integer of 2 to n) kinds of states at the boundary portion; and (3b) j (j is 2 to n) in each of the i spectra. It can be created by plotting i points determined by j wave number signals corresponding to (integer) kinds of wave numbers in a coordinate system, and connecting the points to obtain a calibration curve.

  Here, water, liquid such as saliva or sweat, air, or the like may exist in the boundary portion. The above-mentioned steps (3a) and (3) are represented by the case where the living body 5 is a lip, the specific component is glucose, and a liquid layer such as saliva exists at the boundary between the optical elements 2 and 12 and the lip. 3b) will be described.

As the two states of the boundary portion, a case where the thickness of the saliva layer is 0.01 μm and a case where the thickness is 1 μm are set. First, a calibration curve (saliva layer variation gradient line) K for correcting the effect of the saliva layer between the optical element 2 or 12 and the lip as the living body 5 on the wave number signal obtained from the detection light is created. . FIG. 2 assumes that the thickness of the salivary layer is 0.01 μm or 1 μm, and for a specific glucose concentration, the absorbance at a wave number of 2100 cm ⁻¹ is plotted on the horizontal axis and the absorbance at a wave number of 1080 cm ⁻¹ is plotted on the vertical axis. It is a calibration curve K.
This calibration curve K shows how the absorbance at the absorption peak of 1080 cm ^-1 changes depending on the thickness of the saliva layer even when the glucose concentration is the same.

First, in step (3a), optical information such as the refractive index of the lips, which is the living body 5, the refractive index of the optical element 2 or 12, the incident angle of light incident on the optical element 2 or 12, and the internal reflection angle are set. . Then, a specific glucose concentration is set, and a spectrum when the thickness of the saliva layer is 0.01 μm and a spectrum when the thickness of the saliva layer is 1 μm are obtained by calculation.
The conditions for calculating the spectrum are made to match the conditions used when performing the actual measurement. Specifically, the conditions include the refractive index of the lips, the refractive index of the used optical element 2 or 12, the incident angle of light incident on the optical element 2 or 12, and the like.
In FIG. 2, the glucose concentration was set so as to correspond to a blood sugar level of 80 mg / dl.

Next, in the step (3b), the absorbance at a wave number of 2100 cm ^-1 of the spectrum when the thickness of the saliva layer is 0.01 μm is x1, and the absorbance at a wave number of 1080 cm ^-1 is y1. At this wave number of 2100 cm ⁻¹ , the spectral shape greatly changes due to the influence of water. At the wave number of 1080 cm ⁻¹ , one of glucose absorption peaks appears.
Similarly, in the spectrum of the case where the thickness of the saliva layer is 1 [mu] m, the absorbance at the wave number 2100 cm ^-1 and x2, the absorbance at the wave number 1080 cm ^-1 and y2.

The two points (x1, y1) and (x2, y2) obtained as described above are plotted with the absorbance at a wave number of 2100 cm ^-1 as the horizontal axis and the absorbance at a wave number of 1080 cm ^-1 as the vertical axis. Is plotted in a coordinate system (xy plane) to create a graph. Finally, the two points are connected by a straight line to obtain a calibration curve K.

In the above example, the spectrum was calculated assuming that the thickness of the saliva layer was 0.01 μm or 1 μm, and a calibration curve was created. However, a spectrum may be obtained by assuming three or more thicknesses as the thickness of the saliva layer, and a calibration curve may be created by connecting three or more points from these spectra.
Furthermore, in the above example, in each spectrum, a set of absorbances at two kinds of wave numbers was set as a point in the coordinate system. However, the absorbance at three or more wave numbers may be obtained from each spectrum, and a calibration curve may be created using a set of these absorbances as a point and using a three-dimensional or more coordinate system.

In general, a substance has a specific absorption pattern in the mid-infrared region, and a region where such an absorption peak appears is called a fingerprint region. An example is a range around 650 to 1800 cm ^-1 .
Glucose has absorption peaks of various sizes in the wave number range of 700 to 3200 cm ^-1 . Above all, an absorption peak in a region of 950 to 1550 cm ^-1 which is a fingerprint region is often used for measuring a glucose concentration.

When measuring a substance containing various components such as a living body, moisture affects the absorption peak in the fingerprint region, and other components also affect the absorption peak. Therefore, even if the wave number of the region is used to correct the influence of moisture, the influence of components other than moisture cannot be excluded, which is not preferable.
The absorption peak of water appears in the wave number region of 1700 to 3000 cm ^-1 . Therefore, it is preferable to use the region of 1700 to 3000 cm ^-1 which is more strongly affected by water, instead of the fingerprint region, for correcting the effect of moisture. That is, in the step (3b), it is preferable to perform the measurement at least in a region of 950 to 1550 cm ^{−1 and} a region of 1700 to 3000 cm ⁻¹ .

  As the refractive index of the living body used for calculating the spectrum, a known numerical value may be used or it may be obtained by measurement. For example, a method of measuring the absorbance of a living body in two polarization states of P-polarized light and S-polarized light and calculating the refractive index from the obtained result, measuring the absorbance of the living body with light incident at two different incident angles, The method of back calculation of the refractive index, the method of Kramers-Kronig, the method of Drube, the method of ellipsometry and the like can be mentioned.

Next, a method of correcting the wave number signal obtained from the detection light using the above calibration curve will be described. First, as a step (3c), the signal passes through a point (xm, ym,...) Represented by a wave number signal measured at j kinds of wave numbers used to create the calibration curve data, and Create a second calibration curve with the same slope.
Then, as a step (3d), a wave number signal at least one (one or more) of the j kinds of wave numbers is set as a provisional condition, and the wave number signal under the provisional condition is set on the second calibration curve. Is converted into a wave number signal at a wave number different from the wave number under the provisional condition to obtain a corrected wave number signal.

The wave number used to create the calibration curve is the same as the wave number selected from the measured spectrum.
Further, plotted on the horizontal axis and the absorbance from the measured data in the same manner as above 2100 cm ^-1, the point obtained by plotting the absorbance at 1080 cm ^-1 on the vertical axis is s1. A second calibration curve passing through this point s1 and having the same gradient as the calibration curve K is a calibration curve H.

Step (4):
Finally, in step (4), information on the concentration is obtained from the corrected wavenumber signal, and this information is output to the outside.
For example, a case will be described in which the correction is performed assuming that the thickness of the saliva layer is always 0.2 μm. When the correction is performed assuming that the saliva layer is 0.2 μm, the absorbance at 2100 cm ⁻¹ corresponding to the thickness is obtained as 0.7 by calculating in the same manner as in the above step (3a). On the second calibration curve H, a point that intersects with the provisional condition of 0.7 is a star J, and the absorbance at 1080 cm ⁻¹ indicated by this point J is represented by R.

In the measured data, the absorbance at 1080 cm ⁻¹ , which is the absorption peak of glucose, is represented by P. If the absorbance 0.7 at 2100 cm ⁻¹ is given to the calibration curve K representing the variation gradient of the salivary layer thickness, , An absorbance R is obtained. In other words, by performing the correction with the thickness of the salivary layer always set to 0.2 μm, it is possible to obtain density information that is not affected by the fluctuation of the salivary layer thickness.
When the specific component to be measured is glucose, the blood glucose level can be calculated from the corrected measured value using the basic information for converting the wave number signal at the absorption peak wave number of glucose into the blood glucose level.

  The measurement is preferably performed a plurality of times at one location of the living body 5. In the method of the present invention, the same provisional conditions are used in each measurement to correct the measured values. By doing so, even if the state of the boundary between the living body 5 and the optical element 2 or 12 is different in each measurement, the actual measured value is converted into the measured value under a specific provisional condition, thereby obtaining the boundary portion. Can be obtained when the states are the same. For this reason, variations in measured values are reduced, and stable measurement results can be obtained.

  In the method of the present invention, the refractive index of the living body 5 is used to calculate the spectrum. If the measurement site of the living body 5 is different, the spectrum can be calculated using the refractive index of each site. For this reason, the method of the present invention can also be used when measuring at a plurality of locations in the living body 5.

When measuring a plurality of parts of the living body 5, one calibration curve cannot be used for correcting the measurement values of all parts, and therefore, it is necessary to use a calibration curve corresponding to each part. As described above, such a calibration curve can be created by calculating a spectrum using the condition including the refractive index of each part of the living body 5 and using the calculated spectrum. The calibration curve corresponding to each site obtained in this way is used to correct the measured value.
The refractive index of the living body 5 used for calculating the spectrum may be an existing value, or may be obtained by measurement when performing the method of the present invention.

  As described above, the method of the present invention can correct the measured values even when measuring a plurality of parts of the living body 5 using the calibration curves corresponding to the respective parts. Therefore, a stable measurement result can be obtained without being affected by the difference between the parts.

The calibration curve is
(3A) a step of performing i (i is an integer of 2 to n) measurements in a state where the living body and the optical element are in contact with each other to obtain i spectra, and (3B) in each of the i spectra. It may be created by plotting i points determined by j wave number signals corresponding to j (j is an integer of 2 to n) kinds of wave numbers in a coordinate system, and connecting the points to obtain a calibration curve. .

  Here, in order to perform the step (3A), the data immediately after the start of measurement and the data after a lapse of a predetermined time may be automatically acquired by a single start operation using a measurement start switch or the like. The predetermined time can be appropriately selected. The former data capture and the latter data capture may be performed continuously without time delay, or may be performed after a lapse of several seconds to several minutes. In short, measurement data is continuously taken at least twice while the living body 5 and the optical element 2 or 12 are in contact with each other.

  In the step (3A), data may be acquired by performing two or more measurements by one operation. As the number of times of measurement is large and the number of data is large, a calibration curve having a precise gradient can be obtained.

Then, in the step (3B), as shown in FIG. 4, the absorbance at 2100 cm ^-1 of the spectrum of the data acquired first is a1 and the absorbance at 1080 cm ^-1 is b1. Similarly, the absorbance at 2100 cm ^-1 of the spectrum of the data captured second time is a2, and the absorbance at 1080 cm ^-1 is b2.

As shown in FIG. 5, the two points (a1, b1) and (a2, b2) obtained in this way are plotted with the absorbance at 2100 cm ^-1 on the horizontal axis and the absorbance at 1080 cm ^-1 on the vertical axis. Plot in the xy plane with the axes. A calibration curve L can be obtained by connecting the two points C1 and C2 with a straight line.

  In the above example, a calibration curve was created from two types of measurement data. However, a calibration curve may be created by obtaining two or more spectra and connecting three or more points from these spectra. Furthermore, as described above, the absorbance at three or more wave numbers may be obtained from each spectrum, and a calibration curve may be created by using these absorbances as a set and using coordinates of three or more dimensions.

  In the above step (4), when the specific component to be measured is glucose, the blood glucose level is converted from the corrected measurement value using the basic information for converting the wave number signal at the absorption peak wave number of glucose into the blood glucose level. Values can also be calculated.

  Next, a measuring apparatus for performing the measuring method of the present invention will be described again with reference to FIG. As shown in FIG. 1 or 6, the measuring apparatus according to the present invention includes a light source 1, an optical element 2 or 12, a light detecting means 3, a signal processing means 4, a polarizing element 6, and a light source 1 and an optical element 2. And a spectroscopic means (not shown) provided in the apparatus. Furthermore, it has a program for executing the function of the measuring device and a recording medium storing the program.

As the light source 1, any light source that emits light having the same wave number as the wave number of light absorbed by the specific component to be measured can be used. Examples include a global light source, a CO ₂ laser, and a tungsten lamp obtained by sintering silicon carbide (SiC) into a rod shape.
The material constituting the optical elements 2 and 12 is not particularly limited, and a material known in the art can be used. Examples include Si, Ge, SiC, diamond, ZnSe, ZnS and KrS.

Here, as glucose, in the case of measuring the substance showing an absorption peak in the infrared region of the wavenumber 1033cm ^-1 and 1080 cm ^-1, from the viewpoint of high transmittance in the infrared wavelength of about 9 to 10 microns, It is preferable to use a material composed of silicon or germanium and having a low content of impurities such as boron and phosphorus and a resistivity of 100 Ωcm or more. Those having a resistivity of 1500 Ωcm or more are more preferable.

The light detecting means 3 is not particularly limited, and any known light detecting means in the art can be used. Examples include pyroelectric sensors and MCT detectors.
The signal processing unit 4 is not particularly limited, and may be any device that can perform correction of a wave number signal obtained from the light detected by the light detection unit 3 using the calibration curve data. For example, a computer can be used as the signal processing means.

If the object to be measured is specified, the signal processing means 4 may hold (store) a reference calibration curve obtained by calculation according to the object in advance, and the signal processing means 4 performs calculation in actual measurement. It may be obtained each time.
When measuring a plurality of living bodies or a plurality of parts of one living body, the signal processing unit 4 performs a plurality of reference calibrations corresponding to the case where the refractive index and the optical angle of the living body 5 and the optical element 2 or 12 are different. A line may be prepared, and a reference calibration curve suitable for a living body or an optical element to be measured may be selected.

  Further, the signal processing means 4 may determine the refractive index of the living body 5 and calculate the spectrum using the refractive index. In this case, calibration curve data is created for each living body by the signal processing means. The calculation of the refractive index is performed by measuring the living body 5 in two states of a P-polarized state and an S-polarized state using a polarizing element 6 that changes the polarization state of light.

  Further, when the specific component is glucose, the signal processing means 4 holds basic information for converting the absorbance value at the glucose absorption peak wave number into a blood glucose level, and converts the corrected absorbance value into a blood glucose level. The value can be converted to an external output.

  The polarizing element 6 is not particularly limited, and a polarizing element known in the art can be used. Examples include wire grid polarizers, prism polarizers, dielectric prism polarizers, film polarizers, and reflective polarizers.

The specific component may be any substance that can be measured optically. Examples include blood sugar, water, cholesterol, neutral fat, lactic acid, blood ethanol, various components of body fluid, and the like in a living body.
The living body 5 only needs to contain a substance that can be measured optically. Examples of the measurement site of the living body 5 include skin and living tissues such as lips. Lips that are more likely to adhere to the optical element 2 or 12 due to the presence of the liquid layer are more preferable.

Examples of the concentration information include an absolute value of the concentration of the specific component to be measured, a component ratio, a composition, a temporal change thereof, and the like.
Furthermore, by providing the measuring device according to the present invention with spectral means, it is possible to measure the wavelength dependence of absorption of a specific component contained in a living body. It is preferable to perform measurement by an FT-IR method using an interferometer because highly sensitive measurement can be performed.

In particular, the specific component, the wave number 1033Cm ^-1, in the case of materials such as glucose having an absorption peak in the infrared region of 1080 cm ^-1, as a light source, it is preferable to use a global light source. This is because this global light source can cover a relatively wide wavelength range and can emit light well even in a long wavelength region of about 10 microns.

  In addition, since the optical element 2 or 12 has a high transmittance at an infrared wavelength of about 9 to 10 microns, silicon or germanium having a small content of impurities such as boron and phosphorus and a resistivity of 100 Ωcm or more is preferable. Further, the resistance value is more preferably 1500 Ωcm or more. It is preferable to use a wire grid type polarizer as the polarizing element.

  The measurement apparatus according to the present invention has the above-described configuration, and can be measured by a plurality of living bodies 5 when there is one living body 5 and one measurement site, when one living body 5 is one and there are a plurality of measurement sites. Even when there is one site, or when there are a plurality of measurement sites in a plurality of living organisms 5, the concentration measurement of the specific component can be easily performed.

  Further, the measuring device according to the present invention may include a program for causing a computer to execute the functions of all or a part of the measuring device. This program causes a computer to function as the signal processing means for calculating a calibration curve, and operates in cooperation with the computer.

  This program may be stored in a recording medium and used. This recording medium carries a program for causing a computer to execute all or a part of the functions of all or part of the measuring device according to the present invention. Further, the program is readable by a computer, and the read program executes the function in cooperation with the computer. In addition, a part means one or some of all of the plurality of means.

Further, as a mode of using the program, the program may be recorded on a recording medium readable (processable) by a computer, and may be operated in cooperation with the computer.
Further, the program may be transmitted through a transmission medium, read by a computer, and operated in cooperation with the computer.
Further, examples of the data structure include a database and a data format, and examples of the recording medium include a ROM. Transmission media include transmission media such as the Internet, light, radio waves, and sound waves.

Further, the computer is not limited to pure hardware such as a CPU, but may include firmware, an OS, and peripheral devices.
As described above, the configuration of the present invention may be realized by software or hardware.

In this example, the glucose concentration was measured by the measuring method according to the present invention using the measuring device shown in FIG. FIG. 3 is a diagram for explaining a method for correcting the wave number signal of glucose.
In this measurement, the measurement was performed on the lips as the living body 5. The wave numbers used when creating the calibration curve K were 2100 cm ^-1 and 1080 cm ^-1 .

  In the measuring apparatus used in this example, a SiC light source was used as the light source 1 and a germanium ATR element was used as the optical element 2. Further, a pyroelectric sensor was used as the light detecting means 3 and a computer was used as the signal processing means 4. Further, although not shown, a spectral unit is provided between the light source 1 and the ATR element.

  The spectrum measurement was performed as follows. First, the lip, which is the living body 5, was brought into close contact with the ATR element of this device. Next, light from the light source 1 was incident on the ATR element at a predetermined angle. Then, light emitted from the ATR element was detected by a pyroelectric sensor to obtain a measurement spectrum including a wave number signal.

Then, in the computer, from the data measured spectrum sent from the pyroelectric sensor, to determine the absorbance at the wave number 2100 cm ^-1 and 1080 cm ^-1 was used to create the calibration curve K. Then, as shown in FIG. 3, a point represented by the absorbance at a wave number of 2100 cm ^-1 and the absorbance at 1080 cm ^-1 was obtained as a point s1. A second calibration curve H for correction passing through this point s1 and parallel to the calibration curve K was obtained. That is, the calibration curve K representing the saliva layer variation gradient was applied to one point s1 of the measurement data, thereby estimating the saliva layer thickness variation at the time of the measurement.

Here, the correction was performed assuming that the thickness of the saliva layer was always 0.2 μm. The absorbance at 2100 cm ^-1 corresponding to this thickness was determined to be 0.7 by the same calculation as when the calibration curve K was determined. On the second calibration curve H, a point that intersects with the provisional condition of 0.7 is a star J, and the absorbance at 1080 cm ⁻¹ indicated by this point J is represented by R.
In the measured data, the absorbance at 1080 cm ⁻¹ , which is the absorption peak of glucose, is represented by P, and when the absorbance 0.7 at 2100 cm ⁻¹ is given to the calibration curve K representing the variation gradient of the thickness of the salivary layer, the absorbance becomes A corrected wavenumber signal of R was obtained. The absorbance R was output.

Such a measurement was repeated several times for one part of the lips of the living body 5. At this time, in all the measurements, the provisional condition was an absorbance of 0.7 at 2100 cm ^-1 . The measured values obtained by these measurements showed little variation, and it was found that stable measurement results were obtained according to the present invention.
In the present embodiment, the value of the absorbance 0.7 at 2100 cm ⁻¹ was used as a provisional condition for obtaining the calculated value indicated by the star J in FIG. 3, but the present invention is not limited to this. For example, a wave number other than 2100 cm ^-1 which is easily affected by moisture may be used. Further, the absorbance at 2100 cm ^-1 was set to 0.7 in order to provisionally make the thickness of the saliva layer 0.2 μm, but the absorbance at 2100 cm ^-1 is not limited to this value. Further, the thickness of the saliva layer is not limited to 0.2 μm.

  On the other hand, in the spectrum measurement using the measuring device shown in FIG. 6, for example, the lips of the living body 5 are brought into close contact with the optical element 12. As shown in FIG. 7, the closely adhered living body 5 fits into the substantially V-shaped portion 13 of the optical element 12 via the saliva layer 14, and light from the light source 1 is incident on this portion. The incident light is absorbed by an amount corresponding to a specific component in the living body 5 and emitted. After that, a second calibration curve H for correction parallel to the calibration curve K is obtained, and the provisional condition is given as described above to perform the correction.

  Conventionally, it is difficult to control the thickness of the saliva layer interposed between the living body 5 and the optical element 2 or 12 to be constant, and the thickness of the saliva layer varies every measurement. For this reason, the amount of light reaching the living body 5 became unstable, and the absorbance varied. However, according to the present embodiment, the reference relationship between the thickness of the saliva layer interposed between the optical element 2 or 12 and the living body 5 and the absorbance at the glucose absorption peak wavenumber was obtained in advance by calculation. Using this relationship for correction, the absorbance when the saliva layer had a certain set thickness was converted from the actual measurement value.

For this reason, it is possible to always obtain the absorbance when the thickness of the saliva layer during measurement is constant. As described above, since the variation in the measurement result is reduced, it is possible to perform the measurement in which the measurement value is stable.
Although the living body 5 is the living lip and the change information used for the correction is saliva, it may be skin and sweat.

Also in this example, the concentration of glucose was measured by the measuring method according to the present invention using the measuring device shown in FIG.
FIG. 4 shows the first and second spectra obtained by performing two measurements while keeping the ATR element 2 in close contact with the lips, which is the living body 5. When the living body 5 and the ATR element 2 are in close contact with each other, the thickness of the saliva layer gradually changes, and the amount of light reaching the living body 5 changes. Therefore, the first and second signal information changes, and two types of spectra are obtained.

Next, as shown in FIG. 5, in the first of the spectrum of 2100 cm ^-1 and 1080 cm ^-1 absorbance a1, 2100 cm of the spectrum of the point C1,2 time points represented by b1 ^-1 and 1080 cm ^-1 in The point represented by the absorbances a2 and b2 was designated as point C2. Then, these two points were connected by a straight line, and a calibration curve L was obtained.

Using this calibration curve L, the absorbance at 2,100 cm ^-1 was given as a provisional condition, and the absorbance at 1080 cm ^-1 (star M in FIG. 5) was calculated. Such a measurement was repeated several times. At this time, in all the measurements, the provisional condition was an absorbance of 0.7 at 2100 cm ^-1 .
The measured values obtained by these measurements have little variation, and it has been found that stable measurement results can be obtained according to the present invention.
In the present example, the value of the absorbance 0.7 at 2100 cm ⁻¹ was used as a provisional condition for obtaining the calculated value indicated by the star M, but the present invention is not limited to this.

In the first data, the absorbance at 1080 cm ^-1 which is the glucose absorption peak was P, and in the second data, the absorbance at 1080 cm ^-1 which was the glucose absorption peak was Q.
Assuming that the absorbance at the provisional condition 2100 cm ^-1 on the calibration curve L is 0.7, the absorbance R at 1080 cm ^-1 which is the glucose absorption peak at that time was obtained as a corrected wave number signal.

When the measuring apparatus shown in FIG. 6 is used, the measurement is performed twice while the living body 5 and the optical element 12 are kept in close contact with each other, and the first and second spectra are obtained. I took it in.
Here, the appearance of the substantially V-shaped portion 13 of the optical element 12 and the thickness P of the saliva layer 14 of the living body 5 are schematically shown in FIGS. As shown in FIGS. 7 and 8, the saliva gradually escaped outward by bringing the lips as the living body 5 into close contact, and the thickness P of the saliva layer 14 fluctuated. As a result, the first and second wave number signals changed, and two types of spectra were obtained.
Thereafter, a second calibration curve L for correction was obtained, and the calibration curve L was used to perform the correction by providing the provisional conditions as described above.

As described above, in the present embodiment, the actual thickness fluctuation of the saliva interposed between the optical element 2 or 12 and the lip as the living body 5 is used for correction. Specifically, the absorbance in the case of saliva thickness under provisional conditions set in advance was estimated from actual measurement values based on the calibration curve L due to thickness variation. By doing so, it is possible to always obtain information assuming that the thickness of the salivary layer at the time of measurement is constant, and it is possible to reduce measurement variations.
Although the measurement is performed on the lips of the living body 5 and the variation information used for correction is saliva, the factor measured on the skin of the living body 5 and used for correction may be sweat.

In Embodiment 1 and 2, the absorbance at 2100 cm ^-1, was carried out the measurement method according to the present invention on the basis of the absorbance at 1080 cm ^-1 which is one of the absorption peaks of glucose, for example, a plurality of wave number signals Baseline-corrected information or the like may be used.
As described above, according to the present invention, even when a liquid such as water, saliva, or sweat is interposed between the optical element and the living body, or even when measuring a plurality of parts of the living body, The concentration of the specific component contained in the measurement site can be measured stably and easily.

  According to the measurement method and the measurement apparatus according to the present invention, even when a liquid such as water, saliva, or sweat is interposed between the optical element and the living body, or when measurement is performed at a plurality of parts of the living body Even in this case, the concentration information of the specific component contained in the living body can be stably and easily measured. Therefore, the present invention is useful for measuring body fluid components in medical applications.

It is a schematic diagram showing one embodiment of a measuring device concerning the present invention. It is a graph which uses the light absorbency in one Embodiment of this invention as a coordinate. 5 is a graph for explaining a method of performing correction according to the embodiment of the present invention. FIG. 3 is a diagram illustrating a spectrum obtained by measuring a specific component according to the embodiment of the present invention. 9 is a graph for explaining a method of performing correction according to another embodiment of the present invention. It is a schematic diagram showing one embodiment of a measuring device of the present invention. It is an expanded sectional view showing one embodiment of a measuring device of the present invention. It is another expanded sectional view which shows one Embodiment of the measuring device of this invention.

Explanation of reference numerals

DESCRIPTION OF SYMBOLS 1 Light source 2 Optical element 3 Light detection means 4 Signal processing means 5 Living body 6 Polarization element

Claims (15)

A method for measuring the concentration of a specific component contained in a living body,
(1) entering light into an optical element, absorbing and reflecting the light to a living body in contact with the optical element, and then emitting the light from the optical element;
(2) detecting light emitted from the optical element and obtaining a wave number signal from the detected light;
(3) a step of correcting the wavenumber signal using a calibration curve for correcting an influence of a state change of a boundary portion between the living body and the optical element on the wavenumber signal; and (4) a step after the correction. A method for measuring the concentration of a specific component, comprising a step of obtaining a concentration of the specific component contained in the living body from a wave number signal. The calibration curve is
(3a) a step of obtaining i spectra corresponding to i (i is an integer of 2 to n) kinds of states at the boundary portion; and (3b) j (j is 2 to n) in each of the i spectra. 2. The specific component concentration measurement according to claim 1, wherein i points determined by j wave number signals corresponding to (integer) kinds of wave numbers are plotted on a coordinate system, and the points are connected to obtain a calibration curve. Method. The step (3a) is a step of obtaining a first spectrum and a second spectrum corresponding to two states of the boundary portion;
The step (3b) includes a step (x1, y1) determined by two wave number signals corresponding to two wave numbers in the first spectrum and two points corresponding to two wave numbers in the second spectrum. 3. The method for measuring the concentration of a specific component according to claim 2, wherein a point (x2, y2) determined by the wave number signal is plotted on a coordinate system and a calibration curve is obtained by connecting the points.   The step (3) creates a second calibration curve passing through a point determined by the wave number signal obtained from the detection light at a plurality of different wave numbers and having the same gradient as the calibration curve, and The method for measuring the concentration of a specific component according to claim 2 or 3, further comprising a step of converting based on the calibration curve of (2) and provisional conditions. The calibration curve is
(3A) a step of obtaining i (i is an integer of 2 to n) spectra in a state where the living body and the optical element are in contact with each other; and (3B) j (j is 2 to n) in each of the i spectra. 2. The method according to claim 1, wherein i points determined by j wave number signals corresponding to the (number of) wave types are plotted on a coordinate system, and the points are connected to obtain a calibration curve. Measuring method. The step (3A) is a step of obtaining a first spectrum and a second spectrum,
The step (3B) includes a step (x1, y1) determined by two wave number signals corresponding to two kinds of wave numbers in the first spectrum and two points corresponding to two kinds of wave numbers in the second spectrum. 6. The method for measuring the concentration of a specific component according to claim 5, wherein the step of plotting a point (x2, y2) determined by the wave number signal on a coordinate system and obtaining a calibration curve by connecting the points is performed.   The step (3) creates a second calibration curve passing through a point determined by the wave number signal obtained from the detection light at a plurality of different wave numbers and having the same gradient as the calibration curve, and 7. The method for measuring the concentration of a specific component according to claim 6, further comprising a step of performing conversion based on the calibration curve and the provisional conditions.   The method for measuring the concentration of a specific component according to claim 1, wherein the change in the state of the boundary portion is a change in the thickness of the liquid layer. 8. The wave number signal at two or more wave numbers in the range of 700 to 3200 cm ⁻¹ is used when creating the calibration curve, and the wave number signal at any one of the two or more wave numbers is used as the provisional condition. 9. The method for measuring the concentration of the specific component described in the above. An apparatus for measuring the concentration of a specific component contained in a living body,
(A) an optical element for contacting a living body,
(B) a light source for causing light to enter the optical element;
(C) light detection means for detecting light emitted from the optical element, and (d) signal processing means for processing a wave number signal obtained by the light detection means,
An apparatus for measuring a specific component concentration, wherein the signal processing means corrects the wave number signal using one or more kinds of calibration curves.   The measuring device for a specific component concentration according to claim 10, wherein the signal processing means stores the calibration curve.   The measuring device for a specific component concentration according to claim 10, wherein the signal processing unit calculates the calibration curve.   The signal processing means creates a second calibration curve passing through a point determined by the wave number signal obtained from the detection light at a different wave number and having the same gradient as the calibration curve, and converts the wave number signal into the second calibration curve. The apparatus for measuring the concentration of a specific component according to claim 10, wherein the conversion is performed based on a line and provisional conditions.   The specification according to any one of claims 10 to 13, wherein the calibration curve is a calibration curve for correcting an influence of a change in thickness of a liquid layer at a boundary portion between the living body and the optical element on the wavenumber signal. Device for measuring component concentration. 15. The measuring device for measuring the concentration of a specific component according to claim 13, wherein the provisional condition is a wavenumber signal at two or more wavenumbers in a range of 700 to 3200 cm < ^-1 > used when creating the calibration curve.

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