JP7080480B2 - Non-invasive blood sugar meter - Google Patents

Description

Applied biological light measurement field that measures the inside of a living body by shining light on the living body.

The idea of a conventional non-invasive glucose meter using light focuses on the absorbance of sugar molecules, and a typical example is to irradiate a finger with incident light I0 and measure transmitted light It as shown in Fig. 1. Is.
Then, (1) holds.

The intention is to measure It and calculate α from ( 1 ) .
However, in practice, everything has failed. The reason is that αd is too large or the signal level of It is too small to detect α with the current detector.
FIG. 2 is a conventional example. It aims to penetrate the fingers and earlobe. The source is the following non-patent document.
This is also a failure example.
Therefore, an idea as shown in FIG. 3 has been devised for the purpose of making d as small as possible in view of the conventional transmission example.
As shown in FIG. 3, the incident light I0 is obliquely incident so as to be in contact with the thick surface of the finger. The transmitted light It diffuses and emits diagonally so as to touch the thick surface of the finger. This is configured to be obliquely incident on the epidermis of the finger and obliquely diffused and emitted with the aim of making d as small as possible.
In this case, diffuse reflected light (= transmitted light = light that enters the skin and exits from the skin to the outside air area again) is measured. An example of a recently published application in this case is shown in the following patent document.
Although the oblique ray incident is devised so that it can be read in FIG. 4, it has failed practically.

M. Noda et al. : Diabetologia, 35 (suppl), pA204 (1994)
Near Infrared Sensing Technology Science Forum Co., Ltd.

Non-invasive blood glucose meters using conventional light have focused on transmitted light or diffusely reflected light, in which transmitted light that has entered the skin exits the air region again. As a result, the signal level of It was small and there was a problem in measurement accuracy.
On the other hand, the present invention does not pay attention to the transmitted light or the diffusely reflected light in which the transmitted light entering the skin goes out to the air region again, and at the boundary surface between the air region and the medium (skin). Pay attention to the change in reflectance and the sugar concentration in the interstitial fluid of the human body.
The present invention utilizes the fact that the sugar concentration in the interstitial fluid of the human body and the sugar concentration in the blood are close to each other, and measures the sugar concentration in the interstitial fluid in the skin from the change in the reflectance of the skin surface to measure the sugar concentration in the blood. It is a non-invasive blood glucose measuring device that calculates the sugar concentration of.

For example, FIG. 6 shows a state in which light is incident and reflected on the skin surface of the human body and the reflectance is measured. The light required for the finger is incident, the light is received by the light receiving element D at the specular reflection angle, and the reflectance of the interface of the complex refractive index that reflects the sugar concentration of the interstitial fluid of the human body is measured by the electric signal. Is displayed as M in a non-invasive manner.
Next, we explain how reflectance measurement is related to sugar concentration.
The sugar concentration in the interstitial fluid of the human body is close to the sugar concentration in the blood, indicating that the sugar concentration in the interstitial fluid can be obtained by measuring the reflectance.
The point is that it is not a transmittance measurement.
FIG. 5 schematically shows an interstitial fluid medium of a human body having a complex index of refraction N that is in contact with air at the ab plane.
As shown in Fig. 5, the incident angle: Ψ0, the reflection angle: Ψ0. The reflectance is expressed by the following equation.
For example, Internet HP
home.sato-gallery.com/hikaribussei/chap3.html
Than

here
N ＝ n ＋ iK
N: Complex index of refraction
n: Refractive index of the real part
K: K extinction coefficient: α = 4πK / λ: wavelength-dependent absorption coefficient: proportional to concentration This K is the blood sugar concentration to be obtained.
Rp: Reflectance of electric field strength perpendicular to the incident ray and reflected ray on the paper surface (on the paper surface in Fig. 5),
Rs: Reflectance qualitatively (3.11) of the electric field strength perpendicular to the paper surface (vertical to the paper surface in Fig. 5) to the incident and reflected rays Ψ0 = 0
Consider the case of vertical incident and vertical reflection.
Then (3.11) is

Rp = Rs, and if you replace it with R

K extinction coefficient: α = 4πk / λ: Wavelength-dependent absorption coefficient: Proportional to concentration: Proportional to interstitial fluid sugar content: Proportional to blood sugar content

(2) shows that K can be found from the measurement of R with n as a parameter. n may vary depending on race, gender, age, occupation, food, etc.
Therefore, in practice, it is necessary to cover the measurement range of blood sugar concentration in advance, and it is possible to prepare a correspondence table of R and K according to the conditions that do not cause any problem in practical use, and to obtain K from the measured R. ..
Alternatively, there is no problem with function approximation of the relationship between R and K according to the attributes instead of the table.
The relationship between blood glucose level and K is priced by the blood sampling method in advance.
Next, we show that the relationship between R and K holds regardless of the value of n.

The suggestion of (7) is that R0 can be measured in advance and (2) the blood sugar concentration K can be obtained from R at the time of measurement regardless of the real part n of the complex number N.
The meaning of R0 is the reflectance corresponding to the real part refractive index when the wavelength dependence of the blood sugar content (absorption coefficient) is zero, and corresponds to the total real part refractive index of other molecules including sugar molecules. .. Assuming that the absorption wavelength region K is only sugar molecules, R0 near the absorption region corresponds to the total real number refraction in the absorption region. Here, we apply that the change of n with respect to the wavelength is smaller than K. Further, the method of eliminating n from (2) can be obtained by experimentally obtaining a plurality of independent equations of R and K with the wavelength as a parameter. The wavelength dependence of the absorption coefficient (extinction coefficient) of blood sugar is shown to be 8.5 μ to 10.0 μ (Frontiers Med. Bio. Engng , Vol. 9, No. 2, pp. 137-153 (1999)). As a result, a wavelength of 8.5μ to 10.0μ is used for the measurement of R, and a wavelength of less than 8.5μ or longer than 10.0μ is used for the measurement of R0. Strictly speaking, the relationship between R0 and n according to (5) may change depending on race, gender, age, food, etc. Therefore, in practice, the measurement range of blood sugar concentration should be measured in advance. It is necessary to cover it, and it is possible to prepare a correspondence table of R and K according to the biological classification of n, which is not a problem in practice, and to obtain K from the measured R. However , there is no problem. The relationship between the blood glucose level and K is priced by the blood sampling method in advance.

The above is the basic theoretical outline of the present invention.
However, in reality, R is a mixture of Rs and Rp, which are strictly different from Rs, and the fine structure of the interface also affects the reflectance, so the corresponding data of reflectance R and blood sugar content (K proportional) is necessary and sufficient. It must be R, R0, K data or R, n, K data of the area where there is no practical problem (taking into consideration age distribution, race distribution, gender difference, food, etc.) by various experiments.
Further, consider the case where the surface to be measured is equivalently covered with a transmission filter, for example, dirt. Let X be the transmission factor of this filter. There are two factors, incident and reflection.
Then (2) and (5) are

R'is the reflection in the absorption wavelength range based on X, and R0'is the reflectance outside the absorption wavelength range.
From (9), X can also be classified according to gender, age, occupation, race, food, etc., and measured in advance to create a R', X, n, K classification table for living organisms from R'. It is also possible to obtain the K value from the correspondence table.
(9) (10) is two unknowns X and n, and there are two independent expressions (the value of K can be selected independently and two or more independent expressions can be obtained), and X and n are set. Can be asked.
If X is obtained, R and R0 can be obtained from (9) and (10), and development of (2) and (5) is possible.
In this case, it is also possible to obtain R0'from R0'and K from R'from the biological classification table including the data of X for the biological classification. Ideally, the light incident angle should be zero, but if the incident angle is less than 35 degrees, it will be put to practical use.

As an example of the present invention, the reflectance is measured using any of the absorption wavelengths of blood sugar of 8.5 μ to 10.0 μ to which (2) or (9) is applied, and the light incident angle is near zero using a CO2 gas laser. It is a non-invasive blood glucose meter that measures blood sugar concentration with a biological classification table with an incident angle of less than 35 degrees.

As another example of the present invention, the reflectance is measured using any wavelength of the absorption wavelength of blood sugar of 8.5 μ to 10.0 μ to which (5) or (10) is applied, and the wavelength without absorption of blood sugar is measured. Use a wavelength shorter than 8.5μ, which is close to 8.5μ, or use a CO2 gas laser with a wavelength longer than 10.0μ to measure the blood sugar concentration with an incident angle of less than 35 degrees near zero light incident angle. It is a non-invasive blood meter. FIG. 6 is a main block diagram of another example of the present invention. L is a CO2 gas laser light source, and is emitted at an oscillation frequency of 1 KHZ to 100 KHZ having a wavelength of 9.2 to 10.8 μm and a luminous flux diameter of a plurality of emission lines of about several mm. The level of the emitted light is monitored by the light receiving element Mr by the branch mirror of Ms. L is not limited to CO2 laser light sources. It may be an optical parametric oscillator separately. F is a device that extracts the required wavelength from L. The wavelength dependence of the absorption coefficient (extinction coefficient) of blood sugar is 8.5μ to 10.0μ ( Frontiers ).
It is shown as Med.Biol.Engng , Vol.9, No.2, pp.137-153 (1999)). For example, as shown in Fig. 7, select three wavelengths required: 9.6μ, 10.2μ, and bl shading. The rtb rotating plate is provided with a light passage window so that the selection of 9.6μ diffraction filter, 10.2μ diffraction filter, and shading can be circulated. The cycle of rtb rotation is adjusted to the response of the light receiving element. In the case of a thermocouple, it should be approximately 1 Hz. With these diffraction filters, the light intensity level is also adjusted with an ND filter or the like. These diffraction filters may be interference filters. Alternatively, the rotating plate may be a means having a reciprocating mechanism for lateral slide.
Alternatively, it may be an immovable optical filter that changes the constant of the diffraction grating by electromagnetic or acoustic. Alternatively, there may be two types, 9.6μ and shading. The Laser in FIG. 7 is a laser beam. M1, M2, and M3 in FIG. 6 are mirrors for changing the optical path, and one or more mirrors are used. The FX is an object to be measured, for example, a fixing device shown in FIG. 8, and is fixed within the measurement time. For example, when using a thick epidermis from the first joint of the thumb to the fingertip, fix it in the incident light hole with a holding plate so that the fingertip does not move from the first joint as shown in FIG. The holding plate is fixed on one side with spring-loaded metal, and the thumb is inserted and pressed and fixed on the other side with a rotating screw, for example, as shown in the figure. In order to make it easier to fix the thumb, a moat with a thick finger is provided on the fixing plate, and an incident light hole is made in the center. This holding plate is a tape that can be used repeatedly and may be, for example, magically fixed on at least one side. Alternatively, it may be a clothespin-like finger holder. In addition, this fixing device can automatically or manually move the mechanism three-dimensionally so that the reflected light Ir is maximized. Although the mechanism is not shown, a known means such as an assembly robot is used. The principle of the automation mechanism is shown in Fig. 9 for example. At least the stm straight-ahead means (first means) that moves in the normal direction of nn, the means (second means) having a rotation axis (rt1 rotation 1) perpendicular to the paper surface around the incident point, and the normal on the paper centering on the incident point. It has means (third means) having a right-angled rotation axis (rt2 rotation 2), and uses these means to automatically or manually fix the fxb fixing jig and the D light receiving element to the optimum position. The optimization method is, for example, to obtain the local maximum value while observing the increase / decrease of Ir reflected light by the minute fluctuation of one means, then to obtain the local maximum value while observing the increase / decrease of Ir by the minute fluctuation of the second means. The position is fixed by finding the local maximum value while observing the increase / decrease of Ir by the minute fluctuation of the three means. Do these automatically or manually. pb is a crimp plate. D is a light receiving element. Make the angle of incidence and the angle of reflection as 0 degrees as possible and increase the amount of light received. Therefore, the incident light passes near the edge of the light receiving element, and the light receiving portion and the measured portion are brought close to each other. The light receiving element has a sensitivity of 9.2μ to 10.8μ, and the higher the sensitivity, the better. It may be a forced cooling type element or a normal temperature type thermocouple. M is a device that calculates and displays necessary displays such as blood glucose concentration, time, and time, and also outputs a correspondence table of R and K for each biological category, memory for each measurement, and output for each measurement, which are necessary in advance. ..
For 9.6μ wavelength
Ir = reflectance R x I9 ... (11)
I9 incident light is measured by Mr, and Ir is measured by D.
R is measured by (11). For shading, the noise level is measured by shading.
Let Ir and I9 be the values obtained by subtracting the noise level from each measured value.
For 10.2μ, it is a near wavelength outside the sugar absorption.

K = 0
Ir0 = R0 × I0 ・ ・ ・ ・ ・ (12)
I0 is measured by Mr and Ir0 is measured by D.
R0 is measured by (12).

In this case as well, the noise level at the time of shading is measured.
This noise value is subtracted from the incident value and reflection value, respectively.
The values are Ir0 and I0, and R0 is obtained from (12).
Furthermore, (3.11) can be applied not only to the blood sugar content of the human body, but a similar application can be applied to the measurement of the biosugar content of fruits of plants and the like.
The object to be measured may be changed to a living body of a plant.
Although the present invention focuses on sugar molecules as a specific example, it can also be applied to molecular weight measurement when molecules suggested in (3.11) have an absorption wavelength and are mixed in a liquid even if they are non-sugar molecules. ..

Instead of measuring the blood sugar content of transmitted light, the reflectance of the boundary surface is measured to measure the non-invasive blood sugar content.

Conceptual diagram of transmittance measurement Conventional example using near infrared light Conceptual diagram using the transmitted light of the epidermis Conventional example using oblique incident light Explanatory drawing of the reflectance of the boundary surface Main block diagram of the present invention Explanatory drawing of selection wavelength of this invention Explanatory drawing of finger fixing of this invention Adjustment explanatory view of finger fixation of this invention

It consists of the necessary means shown in FIG.

I0: incident light, It: transmitted light, air: air, N: complex index of refraction, n: real index of refraction
K: Refractive index of imaginary part = Consumption coefficient (∝ Blood sugar concentration), Ms: Branched mirror
L: Laser light source, F: Filter, Mr: Light receiving part, M1: Mirror
M2: Mirror, M3: Mirror, Fx: Fixed device, D: Light receiving part, M: Display arithmetic unit
Laser: laser light, rtb: rotating plate, bl: shading plate, 9.6μ: 9.6μ laser
10.2μ: 10.2μ laser, rt: rotation, rta: rotation axis, stm: straight movement,
fxb: Fixed plate, rt1: Rotation 1, rt2: Rotation 2, pb: Crimping plate, D: Light receiving part,
I9: Incident light, nn: Normal, Ir: Reflected light

Claims (18)

A measuring unit that measures the reflectance of the skin surface of the part where interstitial fluid exists inside the surface skin of the human body as a measuring part, which measures at a specular reflection angle that almost corresponds to the incident angle of light.
The reflectance measured by the measuring unit and the wavelength dependence of the sugar concentration in the blood are based on the calculation formula in which the real refractive index n is eliminated from the formula 3 assuming that the Rp of the formula 1 and the Rs of the formula 2 are equal. A non-invasive blood glucose meter equipped with an arithmetic calculation unit that calculates the sugar concentration in the blood corresponding to the extinction coefficient K from the reflectance corresponding to the real refractive index when the sex is zero .

n: Real index of refraction (N = n + iK, N is complex index of refraction)
K: Extinction coefficient
Rp: Reflectance of electric field strength perpendicular to the incident and reflected rays on the paper
Rs: Reflectance of electric field strength perpendicular to the incident and reflected rays The non-invasive glucose meter according to claim 1, wherein a CO2 gas laser is used for measuring the reflectance and the angle of incidence is less than 35 degrees. The non-invasive glucose meter according to claim 2, wherein the reflectance is measured by using any wavelength of blood sugar absorption wavelengths of 8.5μ to 10.0μ for measuring the reflectance. Measure the reflectance using one of the wavelengths of blood sugar absorption wavelength of 8.5μ to 10.0μ, and use a wavelength shorter than 8.5μ, which is close to 8.5μ, as the wavelength without blood sugar absorption, or 10.0μ. The non-invasive blood glucose meter according to claim 3, wherein a CO2 gas laser using a wavelength longer than 10.0 μ is used. The non-invasive glucose meter according to claim 3, further comprising a means for fixing the measured part to the fixing plate with a crimping plate or the like. The non-invasive glucose meter according to claim 4 , further comprising a means for fixing the measured part to the fixing plate with a crimping plate or the like. The non-invasive glucose meter according to claim 6 , which has a function of adjusting the relationship between the measured portion, the incident light, the reflected light, and the light receiving element so that the specular reflected light can be received by the light receiving element. The 7 . Non-invasive blood glucose meter. The non-invasive glucose meter according to claim 8 , wherein a diffraction filter and a light-shielding plate are attached to a rotating plate as a means of using 10.2μ as a wavelength without absorption of blood sugar. The non-invasive glucose meter according to claim 9 , wherein a correspondence table of the reflectance and the sugar concentration according to the absorption wavelength of blood sugar is prepared in advance according to the target biological category, and the blood glucose level is calculated from the reflectance. The non-invasive glucose meter according to claim 7 , wherein a correspondence table of the reflectance and the sugar concentration according to the absorption wavelength of blood sugar is prepared in advance according to the target biological category, and the blood glucose level is calculated from the reflectance. The non-invasive glucose meter according to claim 8 , wherein a correspondence table of the reflectance and the sugar concentration according to the absorption wavelength of blood sugar is prepared in advance according to the target biological category, and the blood glucose level is calculated from the reflectance. The non-invasive glucose meter according to claim 4 , which has a function of adjusting the relationship between the measured part, the incident light, the reflected light, and the light receiving element so that the specular reflected light can be received by the light receiving element. The thirteenth aspect of claim 13 , wherein the reflectance is measured using any of the absorption wavelengths of blood sugar of 9.3 μ, 9.4 μ, 9.5 μ, or 9.6 μ, and each diffraction filter and light-shielding plate are attached to a rotating plate. Non-invasive blood glucose meter. The non-invasive glucose meter according to claim 14 , wherein a correspondence table of the reflectance and the sugar concentration according to the absorption wavelength of blood sugar is prepared in advance according to the target biological category, and the blood glucose level is calculated from the reflectance. A measuring unit that measures the reflectance of the skin surface of the part where interstitial fluid exists inside the surface skin of the living body excluding the human body, which measures at the specular reflection angle that almost corresponds to the incident angle of light.
The reflectance measured by the measuring unit and the wavelength dependence of the sugar concentration in the blood are based on the calculation formula in which the real refractive index n is eliminated from the formula 3 assuming that the Rp of the formula 1 and the Rs of the formula 2 are equal. A non-invasive sugar content meter equipped with an arithmetic calculation unit that calculates the sugar concentration in the living body corresponding to the extinction coefficient K from the reflectance corresponding to the real part refractive index when the sex is zero .

n: Real index of refraction (N = n + iK, N is complex index of refraction)
K: Extinction coefficient
Rp: Reflectance of electric field strength perpendicular to the incident and reflected rays on the paper
Rs: Reflectance of electric field strength perpendicular to the incident and reflected rays The non-invasive sugar content meter according to claim 16 , wherein a CO2 gas laser is used for measuring the reflectance and the angle of incidence is less than 35 degrees. The reflectance is measured using one of the sugar absorption wavelengths of 8.5μ to 10.0μ, and the wavelength without sugar absorption is either shorter than 8.5μ, which is close to 8.5μ, or 10.0μ, which is close to 10.0μ. The non-invasive sugar content meter according to claim 17 , which uses a longer wavelength.

Images