JPH11188007A - Method and device for determing glucose concentration - Google Patents

Abstract

PROBLEM TO BE SOLVED: To reduce an error of concentration determination because of the change in ambient air temperature or a body temperature to practically acceptable level by correcting each light absorption property according to a temperature distribution of a chamber aqueous humor in an anterior chamber and finding a glucose concentration in the chamber aqueous humor component based on the light absorption property. SOLUTION: It exposes multiple lights to an eye ball 200, which are different types of wave length band region, at sequentially or the same time with a light absorption property detecting means 10 to find the light absorption property of the chamber aqueous humor component in the anterior chamber in every wave length and takes the outside air temperature and the surface temperature of cornea and tympanic membrane to find the temperature distribution of the eye ball 200. According to the temperature distribution of the eye ball 200 found with the temperature distribution detecting means 70, it corrects each of multiple light absorption properties of the chamber aqueous humor component which is got using the light absorption property detecting means 10 with the correcting means 80. Then the glucose concentration in the chamber aqueous humor component is found with the glucose concentration calculating means 90 based on each light absorption properties corrected with the correcting means 80.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method and an apparatus for measuring a glucose concentration in a living body, and more particularly to an improvement of a method and an apparatus for non-invasively measuring a glucose concentration in an anterior aqueous humor of an eyeball. is there.

[0002]

2. Description of the Related Art The average glucose level in blood varies depending on individual differences, but it is an important index value for determining whether or not medication is necessary particularly for diabetic diseases.

[0003] Incidentally, the blood glucose concentration has a characteristic that fluctuates greatly in a very short time due to diet, physical activity, comorbidity of other diseases, etc., and is urgently required due to a rapid rise in blood glucose concentration. In many cases, medication is required.

[0004] For this reason, it is desired to monitor the blood glucose concentration of patients having such a disease at as short an interval as possible. On the other hand, the monitoring of the blood glucose concentration is usually performed by cutting a fingertip. And actually collect blood,
The blood is analyzed to measure the concentration of glucose contained in the blood (hereinafter, simply referred to as blood glucose concentration). It is difficult to force measurement.

In recent years, various non-invasive (non-invasive) measurement methods without pain have been proposed in place of the invasive (invasive) measurement having such disadvantages.

[0006] Mostly, the glucose concentration in the aqueous humor, which fills the anterior chamber between the cornea and the lens of the human eyeball, has a very high correlation with the blood glucose concentration, although there are individual differences. This is a non-invasive measurement of the glucose concentration in the aqueous humor.

For example, JP-A-51-75498 (US Pat. No. 3,955)
No. 8,560), by obtaining the optical rotation of infrared light incident on the aqueous humor, a glucose concentration related to this optical rotation is obtained.

According to Japanese Patent Publication No. Hei 6-503245, stimulated Raman light of glucose is measured.

Further, Japanese Patent Application Laid-Open No. Hei 6-237898 discloses a device for measuring an optical property of light reflected by a crystalline lens. In addition, U.S. Pat. No. 5,433,197 also describes a method for measuring glucose concentration in aqueous humor.

However, the invention described in Japanese Patent Application Laid-Open No. Hei 6-237898 cannot remove the reflected light at the boundary between the cornea and the aqueous humor, and also detects the absorption information at the cornea. Therefore, the accuracy of determining the glucose concentration in the aqueous humor is reduced.

Further, there is no practical method for measuring a minute change in absorbance by any specific technical means, so that there is a practical problem.

On the other hand, according to US Pat. No. 3,958,560,
Many compounds other than glucose in aqueous humor are optically active and involved in rotation of the plane of polarization. In addition, the cornea causes birefringence, causing rotation of the deflecting surface. Therefore, measuring the glucose concentration in the aqueous humor based on the optical rotation has a problem in securing the measurement accuracy.

According to Japanese Patent Publication No. 6-503245, a pump laser beam having a large output is introduced into the anterior chamber of the anterior chamber perpendicularly to the line of sight for measuring stimulated Raman light of glucose. It is difficult to configure a simple measurement system.

Therefore, the applicant of the present application has determined the glucose concentration in the aqueous humor based on the absorbance of the reflected light by the light irradiated to the eyeball for the purpose of noninvasively and accurately measuring the glucose concentration in the aqueous humor. As a method and apparatus for measuring glucose, a glucose concentration measuring method and a measuring apparatus have been proposed in which only the reflected light that has transmitted through the aqueous humor among the reflected light is accurately detected by an optical heterodyne detection method. No. 8-121790).

According to this method / apparatus, of the light detected as the reflected light from the eyeball, the reflected light at the boundary between the cornea and the air and the cornea and the anterior chamber, which are noises for the measurement of the absorbance by the aqueous humor, become noise. It is possible to accurately remove the reflected light due to the boundary surface with, so that the absorbance due to glucose in the aqueous humor can be accurately measured, and the glucose concentration can be accurately obtained based on this absorbance. .

[0016]

By the way, in order to make the glucose concentration in the aqueous humor correspond to the blood glucose concentration, and to use this aqueous humor glucose concentration measurement as an alternative to the blood glucose concentration measurement, It is required to measure the absorbance of the aqueous humor with an accuracy of 0.0001 Abs. This means that the accuracy of the measurement of glucose concentration in the aqueous humor is ± 10 mg /
It is equivalent to dl.

Here, the eyeball has a temperature distribution of about 1.5 to 6.0 ° C. from the corneal surface to the retina, and this temperature distribution depends on the outside air temperature and the core body temperature (approximately, the depth from the corneal surface). Temperature depending on the temperature). On the other hand, the absorbance is greatly affected by the temperature of the medium depending on the wavelength of the light, and the absorbance may vary by about 0.01 Abs even in a normal range of the outside air temperature.

For this reason, the method and apparatus for measuring glucose concentration in the aqueous humor according to Japanese Patent Application No. 8-121790 may not be able to sufficiently secure the desired measurement accuracy.

The present invention has been made in view of the above circumstances, and has as its object to provide a method and apparatus for measuring glucose concentration in aqueous humor with high measurement accuracy in consideration of the temperature distribution of the eyeball. It is.

[0020]

The glucose concentration measuring method and measuring apparatus of the present invention correct the absorbance of aqueous humor obtained from the reflected light of the light irradiating the eyeball according to the temperature distribution of aqueous humor. The above is applied to the calculation of the glucose concentration.

That is, according to the glucose concentration measuring method of the present invention, the eye is irradiated with light, and the light absorption characteristic of the aqueous humor component that fills the anterior chamber of the eye with the light is determined. Similarly, the light absorption characteristics of the aqueous humor component are determined by a plurality of other different lights, and the glucose concentration measurement method for determining the glucose concentration in the aqueous humor component based on the obtained multiple light absorption characteristics, Determine the temperature distribution of the aqueous humor in the anterior chamber, correct each of the light absorption characteristics according to the determined temperature distribution, and, based on each of the corrected light absorption characteristics, It is characterized in that the glucose concentration in the component is determined.

Further, the glucose concentration measuring apparatus of the present invention
In the apparatus for performing the glucose concentration measurement method of the present invention, the eye is irradiated with light, the light absorption characteristics of the aqueous humor component that fills the anterior chamber of the eye by the light is determined, and the light is A light absorption characteristic detecting means for similarly obtaining the light absorption characteristic of the aqueous humor component by using a plurality of other lights having different wavelength bands; and the eye based on the plurality of light absorption characteristics obtained by the light absorption characteristic detection means. In a glucose concentration measuring device comprising: a glucose concentration calculating means for obtaining a glucose concentration in an aqueous humor component, a temperature distribution detecting means for obtaining a temperature distribution of the aqueous humor in the anterior chamber, and the temperature distribution detecting means Correction means for correcting each of the light absorption characteristics in accordance with the determined temperature distribution, wherein the glucose concentration calculation means performs a correction based on each of the light absorption characteristics corrected by the correction means. It is characterized in that those determining glucose concentration in aqueous humor component.

Here, the method of obtaining the temperature distribution of the aqueous humor in the anterior chamber includes, specifically, (1) measuring the outside air temperature and the corneal surface temperature, and A method of obtaining the temperature distribution of the aqueous humor based on a plurality of types of temperature distributions of the eyeballs set in advance and the measured outside air temperature and corneal surface temperature, (2) outside air temperature, corneal surface temperature and By measuring the deep body temperature of the anterior chamber, based on the three measured temperatures, for example, by a finite element method,
A method of obtaining a temperature distribution of aqueous humor can be applied.

In the above method (1) for obtaining the temperature distribution, “a plurality of types of temperature distribution of the eyeball preset for each of the deep body temperature and the outside air temperature of the anterior chamber of the eye” is, for example, shown in FIG. Show. That is, FIG. 8 shows that when the core body temperature (fundus temperature) is 36.5 ° C., the outside air temperature is 10 ° C., 15 ° C., 20 ° C., 25 ° C.
It shows the temperature distribution (correspondence between the distance (horizontal axis) from the outer surface of the cornea and the temperature (vertical axis)) of the eyeball for each ° C and 30 ° C, and is set experimentally or theoretically. . And core body temperature 35.0 ℃, 35.5 ℃ different from 36.5 ℃, 36.0 ℃
℃, 37.0 ℃, 37.5 ℃, 38.0 ℃, etc. are set in advance in the same way, from the measured outside air temperature and corneal surface temperature, corresponding to these figures (preset temperature distribution) The temperature distribution may be selected or extrapolated (extrapolated) based on each of these temperature distributions.

The temperature and the light absorption characteristic (absorbance) have, for example, the correspondence shown in FIG. That is, FIG.
The absorbance at 35 ° C. (Abs) and the absorbance at 32 ° C. (Abs) are shown for each light wavelength as a difference from the absorbance at 34 ° C. (Abs). The temperature and the absorbance difference at each wavelength correspond linearly.

In order to determine the corresponding light absorption characteristics by using a plurality of lights, the aqueous humor is not only glucose but also sodium.
Since a plurality of components including Cl are included, by repeatedly performing light of wavelengths corresponding to these multiple components and applying a known near-infrared spectroscopic analysis method including multivariate analysis, This is for specifying the concentration of only glucose in water.

The method for obtaining the plurality of light absorption characteristics is as follows.
Specifically, for example, the following three methods can be applied.

That is, as a first method, low-coherence light emitted from a predetermined light source is transmitted to two different light sources.
Into a signal light and a reference light, which travel separately along one optical path, and modulate at least one of the two lights so that a slight frequency difference occurs between the signal light and the reference light. Irradiating the arranged eyeball with the signal light, the signal light emitted to the eyeball, the first backscattered light by the interface between the cornea and the anterior chamber, and the reference light, the reference light, Interfering by adjusting the optical path length, measuring the intensity of the first interference light obtained by the interference, obtaining the intensity of the first backscattered light based on the intensity of the first interference light, The signal light emitted to the eyeball causes the second backscattered light by the interface between the anterior chamber and the crystalline lens to interfere with the reference light by adjusting the optical path length of the reference light. The intensity of the obtained second interference light is measured, and the intensity of the second interference light is measured based on the intensity of the second interference light. Obtains the intensity of the backscattered light, wherein the first
Based on the intensity of the second backscattered light and the intensity of the aqueous humor component that fills the anterior chamber, the light absorption characteristics before the temperature correction is determined, and the other low-coherence light and another wavelength band different Similarly, for a plurality of low-coherence lights,
A plurality of light absorption characteristics before the temperature correction are obtained.

Here, the low coherence light includes:
For example, SLD (Super
Luminescent Diode), LED and the like are used. In practice, it is desirable to use an SLD having higher directivity.

The measurement of the intensity of the interference light is as follows.
This means that the intensity of a beat signal (interference light) that repeats strength at the difference frequency between the backscattered light (signal light) and the reference light is measured. The same applies to the following inventions.

In the first method, each of the low-coherence lights may be light selected as a part of light in an emission wavelength band wider than the wavelength band of each of the low-coherence lights. Alternatively, the light may be emitted separately from a plurality of different light sources.

When a plurality of light sources are used, low-coherence light is sequentially emitted from a plurality of light sources having different wavelength bands, and each of the corresponding interference lights is used by one photodetector. Alternatively, a plurality of low-coherence lights may be emitted at the same time, and the combined light may be analyzed and detected.

As a second method, the coherent light emitted from a predetermined light source and frequency-swept in a time sawtooth shape is divided into a signal light and a reference light which respectively travel along two different optical paths. Then, irradiating the signal light to an eyeball previously arranged at a predetermined position, the first backscattered light of the signal light by the interface between the cornea of the eyeball and the anterior chamber, the signal light and the second The first backscattered light emitted from the light source with a time difference based on the optical path length difference between the backscattered light of No. 1 and the reference light interferes with the reference light of coherent light having a frequency difference from the first backscattered light, And the intensity of the first backscattered light is determined based on the intensity of the first interference light, and the interface between the anterior chamber of the eyeball and the crystalline lens is determined. The second of the signal light
Back scattered light, the signal light (meaning the signal light from being split from the reference light to reaching the interface between the anterior chamber of the eye and the lens) and the second back scattered light (before the eye) From the interface between the eye chamber and the lens until it interferes with the reference beam)
The second backscattered light emitted from the light source with a time difference based on the optical path length difference between the reference light (being split from the signal light and interfering with the second backscattered light). The coherent light having the difference causes interference with the reference light, the intensity of the second interference light obtained by the interference is measured, and the intensity of the second backscattered light is measured based on the intensity of the second interference light. Determining the light intensity of the aqueous humor component that fills the anterior chamber, based on the intensity of the first and second backscattered light, before the temperature correction. Similarly, a plurality of light absorption characteristics before the temperature correction are obtained for the other plurality of coherent lights having different light absorption characteristics.

The reason why the reference light that interferes with the first backscattered light has "a frequency difference from the first backscattered light" is as follows.

A difference is provided between the sum of the optical path length of the signal light and the optical path length of the first backscattered light and the optical path length of the reference light (the optical path length of the reference light). It is of course possible to set the optical path length of the reference light longer as well as the case where the optical path length is shorter.)
For example, when the optical path length of the reference light is shorter, the reference light arrives at the position where the wavefront matching (interference) is performed earlier than the first backscattered light.

That is, when the first backscattered light arrives at that position, the signal light that caused the first backscattered light and the divided reference light have already passed through this position, and this signal light The reference light which is a part of the coherent light emitted at a time later than the time when the light is emitted from the light source arrives.

The coherent light emitted at the later time has a slight frequency difference from the first backscattered light because the frequency is temporally swept.

The reference light that interferes with the second backscattered light has a different frequency from the reference light that interferes with the first backscattered light. This is because the first backscattered light is the scattered light due to the boundary between the cornea and the anterior chamber, while the second backscattered light is the anterior chamber that is deeper than the boundary and the lens. Since the light is scattered light due to the boundary between the two, a time difference corresponding to the optical path length difference (twice the thickness of the anterior chamber) occurs, and as a result, the reference light that interferes with the second backscattered light is This is due to the coherent light emitted from the light source at a time later than the reference light that interferes with the first backscattered light.

In the second method, each of the coherent lights may be light selectively emitted from a single light source, or may be individually emitted from a plurality of light sources different from each other. It may be light.

As a third method, the eyeball is irradiated with ultrashort pulsed light emitted from a predetermined light source, and the first backscatter of the ultrashort pulsed light by the boundary between the cornea and the anterior chamber of the eyeball. The intensity of light and the intensity of the second backscattered light by the interface between the anterior chamber and the lens are measured separately, and the first and second
Based on the intensity of the backscattered light of the aqueous humor component that fills the anterior chamber, the light absorption characteristics before the temperature correction is determined, and a plurality of other ultrashort wavelengths having different wavelengths from the ultrashort pulsed light. Similarly, a plurality of light absorption characteristics before the temperature correction are obtained for the pulsed light.

Here, the ultrashort pulse light is obtained by temporally separating at least the intensity of the first backscattered light and the intensity of the second backscattered light at the interface between the anterior chamber and the crystalline lens. Pulsed light that emits for a very short time (for example, on the order of femtoseconds to picoseconds) that can be measured separately.
For example, mode lock Ti means sapphire laser or the like. By using such ultrashort pulse light, the second backscattered light delayed by a time corresponding to the distance to and fro the anterior chamber from the first backscattered light can be time-resolved by a streak camera or the like. Using a possible photodetector,
It can be detected separately from the first backscattered light.

Also in this third method, each ultrashort pulse light may be light selectively emitted from a single light source, or may be individually emitted from a plurality of light sources different from each other. Light may be used.

Further, for each glucose concentration in the aqueous humor component determined by the glucose concentration measuring method of the present invention, the corresponding blood glucose concentration is determined invasively separately, and the eye concentration determined by the method is determined. The correlation between the glucose concentration in the aqueous humor component and the blood glucose concentration obtained invasively was determined in advance, and after this correlation was determined, the glucose concentration in the aqueous humor component determined by each glucose concentration measurement method described above. And the correlation may be used to non-invasively determine the blood glucose concentration.

Further, as the light absorption characteristic detecting means of the glucose concentration measuring apparatus of the present invention, a configuration corresponding to each of the above-described methods for obtaining a plurality of light absorption characteristic methods can be applied.

That is, as the light absorption characteristic detecting means corresponding to the first method, a light source device for emitting a plurality of low coherence lights having different emission wavelength bands from each other, and a low coherence light emitted from the light source device Optical path splitting means for splitting the signal light into a reference light and a signal light incident on an eyeball, respectively, traveling along two different optical paths, and the two lights so that a slight frequency difference occurs between the signal light and the reference light. Modulating at least one of the, the modulation means provided on the at least one light path, light path length adjustment means to adjust the length of the light path in which the reference light travels, and the cornea and anterior chamber of the eyeball The first backscattering of the signal light by the boundary surface and the reference light, and the second backscattering light and the reference light of the signal light by the boundary surface between the anterior chamber of the eyeball and the crystalline lens, respectively. Wavefront matching Wavefront matching means, and a first interference light by wavefront matching between the reference light and the first backscattered light and a second interference light by wavefront matching between the reference light and the second backscattered light. A photodetector for photoelectrically detecting the intensity, a heterodyne calculating means for obtaining the intensity of the first and second backscattered light based on the intensity of each interference light, and the first and second backscattered light Light absorption characteristic analyzing means for determining the light absorption characteristics of the aqueous humor component that fills the anterior chamber based on the intensity of the light.

Here, the light source device comprises a single light source that emits low-coherence light in an emission wavelength band wider than the wavelength band of each coherence light, and a low-coherence light having a wide emission wavelength range. The low coherence light may be constituted by a plurality of light sources that individually emit the low coherence light. Is also good.

As a light absorption characteristic detecting means corresponding to the second method, as shown in FIG. 6, a light source device for emitting a plurality of coherent light beams having different wavelengths, which are frequency-swept temporally in a sawtooth shape. Optical path splitting means for splitting the frequency-swept coherent light emitted from the light source device into reference light and signal light incident on the eyeball which travel separately along two different optical paths, and a cornea of the eyeball A first backscattered light of the signal light due to a boundary surface between the light source and the anterior chamber, and emitted from the light source with a time difference based on an optical path length difference between the signal light and the first backscattered light and the reference light. The first backscattered light and the reference light by coherent light having a frequency difference, and, the second backscattered light of the signal light by the interface between the anterior chamber of the eyeball and the crystalline lens, Said The second backscattered light emitted from the light source with a time difference based on the optical path length difference between the reference light and the second backscattered light, and the reference light by coherent light having a frequency difference with the second backscattered light. Wavefront matching means for performing wavefront matching, first interference light obtained by wavefront matching between the first backscattered light and reference light having a slight frequency difference with respect to the first backscattered light, And light detection for photoelectrically detecting the intensity of the second interference light obtained by wavefront matching between the second backscattered light and the reference light having a slight frequency difference with respect to the second backscattered light. A heterodyne calculating means for obtaining the intensities of the first and second backscattered lights based on the intensities of the respective interference lights; and the anterior chamber based on the intensities of the first and second backscattered lights. Absorption characteristics of aqueous humor components that satisfy the conditions That a light absorption characteristics analyzing means for obtaining.

Also in this glucose concentration measuring device,
The light source device is a single light source that can selectively emit any one of the plurality of coherent lights, and selectively emits any one of the plurality of coherent lights to the light source. It may be constituted by a control means for performing the control for causing the light source to emit light, or may be constituted by a plurality of light sources which individually emit the coherent light.

As a light absorption characteristic detecting means corresponding to the third method, a light source device for emitting a plurality of ultrashort pulsed lights having different wavelengths from each other, the ultrashort pulsed light is made to enter the eyeball, and the cornea of the eyeball is emitted. The intensity of the first backscattered light of the ultrashort pulsed light due to the interface between the anterior chamber and the anterior chamber, and the intensity of the second backscattered light of the ultrashort pulsed light due to the interface between the anterior chamber and the lens. An optical time domain backscattering measuring means separately obtained in time series, and a light absorption characteristic for obtaining a light absorption characteristic of an aqueous humor component filling the anterior chamber based on the intensities of the first and second backscattered lights. With analysis means.

Further, the light source device comprises: a single light source capable of selectively emitting any one of the plurality of ultrashort pulse lights; It may be constituted by control means for performing control to selectively emit any one of the light sources, or may be constituted by a plurality of light sources which individually emit the ultrashort pulse lights. It may be something.

A table showing the correlation between the glucose concentration in the aqueous humor component determined by the glucose concentration measuring apparatus of the present invention and the blood glucose concentration obtained in advance, for example, invasively is provided. The blood glucose concentration may be determined non-invasively based on the determined glucose concentration in the aqueous humor component and the table.

[0052]

According to the glucose concentration measuring method of the present invention and the glucose concentration measuring device of the present invention, the temperature distribution of the aqueous humor is detected, and the aqueous humor obtained from the reflected light of the light applied to the eyeball is detected. After correcting the absorbance according to the temperature distribution of the aqueous humor and applying it to the calculation of glucose concentration, errors in glucose concentration measurement due to fluctuations in outside air temperature and body temperature are reduced, and measurement accuracy is improved to a practical level. Can be done.

As described above, the temperature distribution of the aqueous humor is determined by (1) measuring the outside air temperature and the corneal surface temperature,
A plurality of types of temperature distribution of the eyeball set in advance for each of the deep body temperature of the anterior chamber and the outside air temperature, and the method of obtaining the temperature distribution of the aqueous humor based on the measured outside air temperature and corneal surface temperature, Or (2) a method of measuring the outside air temperature, the corneal surface temperature, and the deep body temperature of the anterior chamber of the eye, and obtaining a temperature distribution of the aqueous humor based on the three measured temperatures, for example, by a finite element method. Can be applied,
By applying (2), a more accurate temperature distribution can be obtained.

As a method for obtaining a plurality of light absorption characteristics, the method and apparatus of the present invention to which the above-described first method, that is, a method using low-coherence light, and the above-described second method are used.
According to the method and apparatus according to the present invention, in which the method of using the frequency-swept coherent light is applied,
By using the optical heterodyne backscattering measurement method, first, the weak first backscattered light IR2 of the incident light due to the interface between the cornea and the anterior chamber and the weak first light backscattered light _IR2 due to the interface between the anterior chamber and the lens. The second backscattered light I _R3 can be detected separately and accurately.

As shown in FIG. 2, the intensity of the light incident on the eyeball 200 is I ₀ , and the reflectance between the air 300 and the cornea 210 is R.
1. The reflectance between the cornea 210 and the anterior chamber 220 is R2, and the anterior chamber 220
The reflectance between the lens 230 and the lens 230 is R3, the optical absorptance of one light path of the incident light by the cornea 210 is α ₁ , and the optical absorptivity of one light path of the incident light by the anterior chamber (aqueous humor) 220 is α ₂ Then, the intensity I _{R2 of} the first backscattered light and the intensity I _R2 of the second backscattered light
_R3 can be represented by the following formulas (1) and (2).
Here, the intensity of the backscattered light
The temperature distribution of the aqueous humor 220 is not considered in order to explain only the principle of obtaining the optical absorptivity α ₂ of one optical path of the incident light by the 220.

I _R2 = I ₀ (1-R1) ² R ₂ (1-α ₁ ) ² (1) _{IR 3} = I ₀ (1-R 2) ² (1-R 2) ² R 3 (1-α ₁ ) ² (1−α ₂ ) ² (2) When calculating the ratio ( _IR3 / _IR2 ) of each of the backscattered light _IR2 and _IR3 detected with high accuracy, _IR3 / _IR2 = (R3 / R2) (1−R2) ² (1−α ₂ ) ² (3) Since I _R3 , I _R2 , R ₃ , and R ₂ are known, the optical absorptivity α ₂ of one optical path of the incident light by the aqueous humor can be obtained.

The optical absorptivity α thus obtained
₂ is based on the assumption that the temperature distribution of the eyeball 200 is constant, so that the eyeball obtained by the method or means described above is used.
According to the temperature distribution of 200, the optical absorption α ₂ is corrected.

Here, the aqueous humor includes not only glucose but also NaCl.
Since a plurality of components are included, the above-described action is repeatedly performed on incident light of a plurality of wavelengths, and by applying a known near-infrared spectroscopic analysis method including a multivariate analysis, the aqueous humor in the aqueous humor is The concentration of glucose alone can be specified with higher accuracy than before.

The correlation between the non-invasively obtained glucose concentration in the aqueous humor and the conventional invasively obtained blood glucose concentration is prepared in advance for each patient as a conversion table or the like. By doing so, the glucose concentration in the aqueous humor may be measured thereafter without measuring the blood glucose concentration, and the measurement can be repeatedly performed with high accuracy without causing any pain to the patient.

As a method for obtaining a plurality of light absorption characteristics,
According to the method and apparatus of the present invention to which the above-described third method, that is, a method using ultrashort pulse light, is applied, the intensity of the first backscattered light and the intensity of the second backscattered light are reduced as shown in FIG.
Can be measured separately to each temporally separated as shown in, the light intensity, i.e. I _R2 and formula shown in the formula (1) by integrating the waveform shown in FIG. 9 with respect to time (2) it can be obtained I _R3 shown.

Therefore, the optical absorptivity α ₂ of one optical path of the incident light due to the aqueous humor can be obtained from the equation (3).

The optical absorptivity α thus obtained
₂ is based on the assumption that the temperature distribution of the eyeball 200 is constant, so that the eyeball obtained by the method or means described above is used.
According to the temperature distribution of 200, the optical absorption α ₂ is corrected.

Then, similarly to the case of the above-mentioned invention of the present application, the glucose concentration in the aqueous humor is more accurately determined by a known near-infrared spectroscopic method including multivariate analysis by repeating the process for incident light having a plurality of wavelengths. Can be identified.

[0064]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, specific embodiments of the present invention will be described with reference to the drawings.

FIG. 1 is a diagram showing a basic device configuration for implementing the glucose concentration measuring method of the present invention.

The glucose concentration measuring device shown in FIG.
Illuminate the anterior chamber 220 of the eyeball 200 with this light.
(See FIG. 2) Determine the light absorption characteristics (specifically, absorbance) of the aqueous humor component that satisfies the conditions, and sequentially or simultaneously irradiate a plurality of other lights having different wavelength bands from the irradiated light, and Similarly, a light absorption characteristic detecting means 10 for obtaining light absorption characteristics for each wavelength of light of the aqueous humor component, and a temperature for obtaining the temperature distribution of the eyeball 200 by measuring the outside air temperature, the outer surface temperature of the cornea and the inside temperature of the eardrum. Distribution detecting means 70, a correcting means 80 for correcting each of the plurality of light absorption characteristics obtained by the light absorption characteristic detecting means 10 according to the temperature distribution obtained by the temperature distribution detecting means 70, and a correcting means 80 A glucose concentration calculating means 90 for determining the glucose concentration in the aqueous humor component based on the corrected light absorption characteristics.

Here, the light absorption characteristic detecting means 10 is connected to the eyeball 2
2, the boundary surface R ₃ between the anterior chamber 220 and the crystalline lens 230 of the irradiated light (intensity I ₀ ) shown in FIG.
The light absorbance of the aqueous humor that fills the anterior chamber 220 is obtained from the intensity of the reflected light (intensity I _R3 ) due to the light reflected by the boundary surface R ₃ and the cornea 210 out of the reflected light from the eyeball 200. The reflected light (intensity I _R2 ) at the boundary surface R ₂ with the anterior chamber 220 is detected separately. More specifically, a detection method using optical heterodyne or a separation detection method on a time axis can be applied.

FIG. 3 shows a glucose concentration measuring apparatus according to an embodiment in which optical heterodyne is used as the light absorption characteristic detecting means 10. This embodiment will be described below.

The illustrated glucose concentration measuring apparatus 101 includes a light source device, a propagation means for transmitting light emitted from the light source device, light for irradiating the propagating light to the eyeball 200, and reference light for optical heterodyne detection. A polarization plane preserving coupler 18 as a multiplexing means for multiplexing the reflected light of the sky with the reference light, and a frequency modulator for shifting the frequency of the light applied to the eyeball 200 19, a moving table 25 as an optical path length adjusting means for changing the optical path length of the reference light, a photodetector 28a to 28e for detecting the light multiplexed by the polarization plane preserving coupler 18, an outside air temperature, Cornea210
Based on the radiation thermometer 30 that measures the outer surface temperature and the body temperature inside the eardrum (deep body temperature) and the light intensity detected by the photodetectors 28a to 28e, the absorbance of the aqueous humor component is determined for each wavelength of the irradiation light. Determined, and according to the temperature distribution determined by the radiation thermometer 30, to correct the absorbance of the aqueous humor, respectively,
Further, based on each of the corrected light absorption characteristics, a signal processing circuit 31 for calculating the glucose concentration in the aqueous humor component,
And a display device 32 for displaying the calculation result.

Here, for the light source device, the center wavelength is λ.
SLD11a which emits low-coherence light having a wide wavelength band of 1 and SLD11b which emits low-coherence light having a central wavelength of λ2 and a wide wavelength band,... Has a central wavelength of λe and has a wide wavelength band It consists of five light sources, SLD11e, which emit low-coherence light, one of which has a strong correlation with the physical length of the anterior chamber 220 along the optical axis (for example, a wavelength of 1790-1820 nm or 2230 nm).
~ 2250nm light). Further, a light source that emits light having a wavelength independent of the temperature of the aqueous humor is also included.

As the propagation means, each of the light sources 11a,.
Multiplexed mirror 12 and dichroic mirrors 13b to 13e that reflect the respective lights emitted from the multiplexed light, mirror 14 that changes the traveling direction of multiplexed light (hereinafter, multiplexed light), and multiplexed light as linearly polarized light. A half-wave plate (hereinafter referred to as a λ / 2 plate) 15, a lens 16 for allowing this linearly polarized light to enter a first polarization-maintaining fiber 17 a, and an incident light connected to a polarization-maintaining coupler 18. First to fourth polarization maintaining fibers 17a to 17d for preserving and propagating the polarization plane, a lens 20 for collimating light (signal light) emitted from the second polarization maintaining fiber 17b, A quarter-wave plate (hereinafter, λ / 4 plate) 21 that converts light into circularly polarized light, a lens 22 that irradiates circularly polarized light to the eyeball 200, and light emitted from the third polarization-maintaining fiber 17c A lens 20 that collimates light (reference light) and a circularly polarized reference light that is linearly polarized And of light λ /
Four plates 21, a reference mirror 24 for reflecting reference light, a lens 23 for irradiating the reference mirror 24 with circularly polarized reference light, and a lens for collimating light emitted from the fourth polarization-maintaining fiber 17d.
16, a λ / 2 plate 15, and a mirror 14 for changing the traveling direction of light
, Dichroic mirrors 26b to 26e for dividing the optical path for each wavelength band and the mirror 12, and each of the lights whose optical paths have been split by the dichroic mirror are converted to photodetectors 28a,.
, 27e for converging the light beams respectively.

As the name implies, the polarization plane preserving coupler 18 has a function of preserving the plane of polarization of the incident light to split or combine the light and to emit the same.

The frequency modulator 19 is provided in the second polarization maintaining fiber 17b, and shifts the frequency of light propagating through the fiber 17b by 1 Hz (the modulation frequency is not limited to 1 Hz).

Moving table on which reference mirror 24 and lens are installed
Numeral 25 is movable in these optical axis directions.

The radiation thermometer 30 measures the body temperature (deep body temperature) inside the eardrum, and based on the light obtained by spectrally separating the light reflected from the eyeball by a beam splitter disposed on the optical path, the temperature of the outer surface of the cornea is measured. Is measured.

Here, in the glucose concentration measuring apparatus 101 of the embodiment shown in FIG. 3, the signal processing circuit 31 includes a part of the function of the light absorption characteristic detecting means 10 shown in FIG. It has the function of the calculating means 90.

Next, the glucose concentration measuring apparatus of the present embodiment
The operation of 101 will be described.

First, each low coherence light source 11a (wavelength λ
1) to 11e (low wavelength coherence light) emitted from the mirror 12 and the dichroic mirrors 13b to 13e
Are multiplexed.

The traveling direction of the multiplexed light is changed by the mirror 14, and the multiplexed light is incident on the λ / 2 plate 15 to be linearly polarized. The linearly polarized light is converted by a lens 16 into a first polarization-maintaining fiber.
It is incident on 17a. The incident light propagates through the fiber while maintaining the polarization plane, and enters the polarization-maintaining coupler 18.

The polarization preserving coupler 18 divides the incident light into light traveling to the reference mirror 24 (reference light) and light traveling to the eyeball 200 (signal light) while preserving the polarization plane of the incident light. That is, the signal light is incident on the second polarization maintaining fiber 17b, while the reference light is incident on the third polarization maintaining fiber 17c.

The light incident on the second polarization-maintaining fiber 17b is modulated by a frequency modulator 19 provided on the optical path, and its frequency is shifted by 1 Hz.

The frequency-modulated linearly polarized light is emitted from the second polarization preserving fiber 17a, converted into parallel light by the lens 20, converted into circularly polarized light by the λ / 4 plate 21, and converted into the cornea 210 and the eye by the lens 22. It is focused on the boundary surface R ₃ of the boundary surface R ₂ and aqueous humor 220 and the lens 230 of the aqueous humor 220. Focused light is reflected as a first backward scattered light beam at the boundary surface R _2, on the other hand, is reflected at the boundary surface R ₃ as a second backward scattered light beam.

The two back-scattered lights are re-illuminated by the lens 22, the λ / 4 plate 21
And a second polarization maintaining fiber passing through the lens 20
It is incident on 17b.

Since the two backscattered lights are polarized in the opposite directions by reflection, after passing through the λ / 4 plate 21, they are rotated by 90 degrees with respect to the original polarization plane.

The reference light that has proceeded to the reference mirror 24 is emitted from the third polarization plane preserving fiber 17c and is converted into parallel light by the lens 20. Further, this reference light is circularly polarized by the λ / 4 plate 21,
The lens 23 focuses on the reference mirror 24. The light reflected by the reference mirror 24 passes through the lens 23 and the λ / 4 plate 21 again.

Since the reflected light has a polarization plane in the opposite direction due to reflection, after passing through the λ / 4 plate 21, the reflected light
It will be rotated 90 degrees. And this reflected light is lens 20
As a result, the light enters the third polarization preserving fiber 17c.

The first and second backscattered lights returning to the second polarization-maintaining fiber 17b and the reference light returning to the third polarization-maintaining fiber 17c are the detection-side fiber by the polarization-maintaining coupler 18. Fourth polarization maintaining fiber
It is incident on 17d and multiplexed.

The light propagating through the fourth polarization preserving fiber 17d is emitted from the fiber 17d and is converted into parallel light by the lens 16. This light has a polarization direction rotated by 90 degrees, and λ / 2
Passing through plate 15. On the other hand, the first polarization-maintaining fiber 17
Irradiation light incident from a has a polarization plane that does not match.
It does not pass through the two plates 15.

The traveling direction of the light passing through the λ / 2 plate 15 is changed by the mirror 14, and the dichroic mirrors 26e to 26e
b and split by the mirror 12, and the respective lenses 27a to 27e
Thus, the light is focused on each of the photodetectors 28a to 28e.

The intensity of the incident light is output from each of the photodetectors 28a to 28e as a DC signal.

Here, the first boundary R ₂ of the eyeball 200 is used.
AC of the second backward scattered light beam of the back-scattered light or boundary surface R _3, the reference light is reflected from the reference mirror 24, the optical path length from the light source is matched, the detector frequency 1Hz
A signal (interference signal) is detected.

The reference mirror 24 and the lens 23 can be moved in the direction of the optical axis by the moving table 25, and the movement makes the optical path length of the reference light variable. Therefore, by moving the position of the movable table 25 and adjusting the optical path length on the reference light side,
Backscattered light that interferes with the reference light can be selected.

That is, if the optical path length on the reference light side is made to match the optical path length of the first backscattered light, the reference light interferes only with the first backscattered light, and the interference light is detected as an AC signal. On the other hand, if the optical path length on the reference light side is made to match the optical path length of the second backscattered light, the reference light interferes only with the second backscattered light, and the interference light is detected as an AC signal.

The optical path length of the aqueous humor at each wavelength is obtained based on the moving distance of the moving table 25 during this time. That is, since the refractive index of aqueous humor differs for each wavelength of light, the optical path length also differs for each wavelength.

A signal processing circuit 31 is provided based on the AC signals for each wavelength detected by the photodetectors 28a to 28e.
Performs the optical heterodyne detection process, thereby obtaining the absorbance of the aqueous humor for each wavelength.

Next, the radiation thermometer 30 measures the outer surface temperature of the cornea 210 or the skin surface temperature near the eyeball 200 and the eardrum temperature. Based on the measured temperatures, the signal processing circuit 31 calculates the temperature distribution of the eyeball 200 by a finite element method or the like.

Next, the physical length of the aqueous humor is determined based on the absorbance at a wavelength that has a strong correlation with the physical length of the anterior chamber (aqueous humor). At this time, the influence of the change in the absorbance of the light having the wavelength used in the calculation and the composition of the aqueous humor is small.

The signal processing circuit 31 calculates the refractive index of the aqueous humor for each wavelength based on the obtained physical length and optical path length. The calculated refractive index is equal to the average value of the temperature distribution present in the aqueous humor.

(Refractive index) = (Optical optical path length) / (Object burying length) Since the refractive index changes substantially linearly in a temperature range of several degrees, the signal processing circuit 31 converts the calculated refractive index into The correction is performed based on the temperatures at the boundary surfaces R ₂ and R ₃ obtained from the temperature distribution of the eyeball 200. The correction coefficient at this time is set in advance.

Next, by applying the temperature-corrected refractive index for each wavelength, the signal processing circuit 31 determines each boundary surface (between air 300 / cornea 210, cornea 210 / anterior chamber 220) at each wavelength. Between the anterior chamber 220 / lens 230), R1, R2, R3
Is calculated, and the reflectance corresponding to the reflectance is subtracted from the absorbance already measured. Since the obtained absorbance includes a temperature change, the signal processing circuit 31 performs temperature correction.

The temperature dependence of the absorbance is linear in the assumed temperature range. Therefore, the obtained refractive index is corrected by the temperature at each of the boundary surfaces R ₂ and R ₃ . The temperature coefficient is a look-up table or function corresponding to the temperature and the absorbance for each wavelength (for example, see FIG. 4: a graph showing the difference between the absorbance at a temperature of 34 degrees and the temperature of 32 degrees and 36 degrees).
Is stored in the signal processing circuit 31 in advance, and is obtained by referring to this.

The signal processing circuit is based on the absorbances of the temperature-compensated light of the respective wavelengths thus obtained.
31 calculates the aqueous humor component glucose concentration with reference to the preset correspondence between the absorbance and the glucose concentration.

The calculated glucose concentration is output to the display device 32 and displayed on the display device 32.

As described above, according to the glucose concentration measuring apparatus of the present embodiment, the glucose concentration in the aqueous humor can be non-invasively measured, and the correction processing following the fluctuation of the outside air temperature or the body temperature can be performed. Accordingly, the glucose concentration can be accurately obtained even if there is a change in the outside air temperature or the body temperature.

The glucose concentration in the aqueous humor obtained in this manner is obtained by comparing the glucose concentration in the aqueous humor obtained in advance by the above-mentioned apparatus for each patient with the blood glucose concentration obtained in a conventional invasive manner. The correlation is stored in the signal processing circuit 31 as, for example, a conversion table, and when the glucose concentration in the aqueous humor of the patient is calculated, the blood is stored based on the correlation with the stored blood glucose concentration. The medium glucose concentration may be calculated.

FIG. 5 is a view showing a second embodiment of the glucose concentration measuring apparatus according to the present invention.

The illustrated glucose concentration measuring apparatus is also an embodiment in which optical heterodyne detection processing is applied as the light absorption characteristic detecting means 10 in the basic configuration of the apparatus for implementing the glucose concentration measuring method of the present invention shown in FIG. Hereinafter, this embodiment will be described.

The illustrated glucose concentration measuring apparatus 102 is composed of a light source device, a propagation means for propagating light emitted from the light source device, a polarization preserving coupler 18 ', and a λ / 4 plate 21 constituting the propagation means. A photodetector 28 for detecting the waved light; and a temperature distribution detecting means 70 for measuring the outside air temperature, the cornea 210 outer surface temperature of the eyeball 200 and the body temperature (deep body temperature) inside the eardrum to detect the temperature distribution of the eyeball 200. And, based on the light intensity detected by the photodetector 28, determine the absorbance of the aqueous humor component for each wavelength of the irradiation light, and according to the temperature distribution determined by the temperature distribution detecting means 70, Each of the water absorbance is corrected, and based on each of the corrected light absorption characteristics,
Signal processing circuit for calculating glucose concentration in aqueous humor component
40 and a display device 32 for displaying the calculation result.

Here, as the light source device, as shown in FIG. 6, a frequency-swept laser light source 11 which sweeps and emits a laser beam having a frequency fn in a constant frequency band in a saw-tooth manner over time.
A to 11E apply. The frequency bands of the laser beams sequentially emitted from the light sources 11A to 11E are different from each other.

In this embodiment, a description will be given of a case in which laser light is applied as one form of coherent light. However, in the glucose concentration measuring apparatus of this embodiment, any coherent light is not particularly limited to laser light. Absent.

As the propagation means, each of the light sources 11A,.
A mirror 12 and a dichroic mirror 13B to 13E for reflecting or transmitting each light sequentially emitted from the mirror, a mirror 14 for changing the traveling direction of the light, a λ / 2 plate 15 for converting the light into linearly polarized light, A lens 16 for allowing linearly polarized light to enter the first polarization-maintaining fiber 17a, and first to third polarization-maintaining planes connected to a polarization-maintaining coupler 18 for preserving and propagating the polarization plane of the incident light. Fiber 17A-17C
A lens 20 for collimating the light emitted from the second polarization-maintaining fiber 17B, and a λ / 4 plate for passing linearly polarized light as circularly polarized light and reflecting a part thereof.
21, a lens 22 for irradiating the eyeball 200 with circularly polarized light, a lens 16 for collimating the light emitted from the third polarization preserving fiber 17C, a λ / 2 plate 15, and This configuration includes two mirrors 14 and a lens 27 that focuses the light whose traveling direction has been changed on a photodetector 28.

Here, in the glucose concentration measuring apparatus 102 of the embodiment shown in FIG. 5, the signal processing circuit 40 includes a part of the function of the light absorption characteristic detecting means 10 shown in FIG. It has the function of the calculating means 90.

Next, the glucose concentration measuring device of the present embodiment
The operation of 102 will be described.

First, at the time t ₀ from the light source 11A, FIG.
As shown in the figure, irradiation light (frequency f ₀ at the time of emission) whose frequency is swept with respect to time is emitted.

This light is reflected by the mirror 12, passes through the dichroic mirrors 13B, 13C, 13D, and 13E sequentially, is reflected by the mirror 14, passes through the λ / 2 plate 15, and passes through the lens 16 to the first polarization plane. The light enters the storage fiber 17A.

The light that has propagated through the first polarization-maintaining fiber 17A is incident on the second polarization-maintaining fiber 17B via the polarization-maintaining coupler 18 ', and propagates through the fiber 17B.

The light emitted from the second polarization preserving fiber 17B is collimated by the lens 20, and
Pass through. At this time, a part of the light is reflected by the λ / 4 plate 21 and is guided again by the lens 20 to the second polarization maintaining fiber 17B.

On the other hand, the light that has passed through the λ / 4 plate 21
At 22 the interface R ₂ between the cornea 210 and the aqueous humor 220 and the aqueous humor
It is focused on the boundary surface R ₃ and 220 and the lens 230.
Focused light is reflected as a first backward scattered light beam at the boundary surface R _2, on the other hand, is reflected at the boundary surface R ₃ as a second backward scattered light beam.

The two backscattered lights are re-illuminated by the lens 22, the λ / 4 plate 21
And a second polarization maintaining fiber passing through the lens 20
It is incident on 17b.

Considering the situation when each backscattered light passes through the λ / 4 plate 21, the first backscattered light has a frequency f ₀ emitted from the light source 11 A at time t ₀ .
, The frequency is also f ₀ .

On the other hand, the frequency-swept laser light is continuously emitted from the light source 11A, and when the first backscattered light having the frequency f ₀ passes through the λ / 4 plate 21, the boundary light is emitted from the λ / 4 plate 21. surface R ₂ to a distance of 2 times the light emitted from the light source 11A with a delay from the time t ₀ by the time Delta] t that passes through the optical path length (time t ₁ (= light emitted to t ₀ + Delta] t): frequency f ₁₎ Arrives at the λ / 4 plate 21. The light (frequency f ₁ ) reflected by the λ / 4 plate 21 and the first backscattered light (frequency f ₀ ) of the light that arrived after the delay are λ / 4
Interference at plate 21.

The interference light has a frequency difference (f ₁ −
f ₀ ) is a beat signal having a repetition frequency.

Similarly, since the second backscattered light is also due to the light of frequency f ₀ emitted from the light source 11A at time t ₀ , the frequency is also f ₀ while the second back scattered light is The reference light that interferes when the light passes through the λ / 4 plate 21 is delayed from the time t ₀ by a time Δt ′ that passes through an optical path length twice the distance from the λ / 4 plate 21 to the boundary surface R _3. Light emitted from the light source 11A (time t ₂ (= t ₀ + Δ
Since the light emitted at t ′) is the frequency f ₂ ), the frequency of the beat signal of the interference light is (f ₂ −f ₀ ).

The interference light enters the second polarization preserving fiber 17b through the lens 20, and is output from the third polarization preserving fiber 17c via the coupler 18.

The interference light emitted from the fiber 17c is collimated by the lens 16, passes through the λ / 2 plate 15, and
The light is reflected by the mirror 14 and condensed by the lens 27 on the photodetector 28 to be detected.

The photodetector 28 detects the AC of the detected interference light intensity.
The signal is input to the signal processing circuit 40, and the signal processing circuit 40 analyzes the strong and weak repetition frequencies and, based on the frequency difference,
The respective intensities of the first backscattered light and the second backscattered light are calculated.

The same operation as described above is sequentially performed for laser beams having different frequency bands emitted from the respective light sources 11B to 11E to obtain a plurality of backscattered light intensities. The signal processing circuit 40 determines the absorbance of the aqueous humor with respect to.

On the other hand, the temperature distribution detecting means 70 detects the temperature distribution of the eyeball 200 by measuring the outside air temperature, the outer surface temperature of the cornea 210 of the eyeball 200 and the body temperature (deep body temperature) inside the eardrum.

Then, the signal processing circuit 40 corrects the absorbance of the aqueous humor with respect to the light of each frequency according to the temperature distribution obtained by the temperature distribution detecting means 70, and based on the obtained corrected absorbance. Thus, the glucose concentration in the aqueous humor component is calculated. The calculated glucose concentration is output to the display device 32 and displayed on the display device 32. As described above, according to the glucose concentration measuring device of the present embodiment, the glucose concentration in the aqueous humor can be non-invasively measured, and the correction process that follows a change in the outside air temperature or the body temperature can be performed. It is possible to accurately determine the glucose concentration even if there is a change in air temperature or body temperature.

The glucose concentration in the aqueous humor obtained in this manner was calculated by comparing the glucose concentration in the aqueous humor obtained in advance by the above-mentioned apparatus for each patient with the blood glucose concentration obtained by the conventional invasive method. The correlation is stored in the signal processing circuit 40 as, for example, a conversion table, and when the glucose concentration in the aqueous humor of the patient is calculated, the blood concentration is calculated based on the correlation with the stored blood glucose concentration. The medium glucose concentration may be calculated.

FIG. 7 is a diagram showing a third specific embodiment of the glucose concentration measuring device of the present invention.

The glucose concentration measuring apparatus shown in the figure has the basic configuration of the apparatus for implementing the glucose concentration measuring method of the present invention shown in FIG. 2 is an embodiment to which an optical time domain backscatter measurement process is applied, in which the light absorption characteristics of the aqueous humor are detected by separately detecting the backscattered light on the time axis using ultrashort pulse light, Hereinafter, this embodiment will be described.

[0133] The illustrated glucose concentration measuring device 103 includes a light source device for emitting ultra-short pulse light, a propagation means for propagating light emitted from the light source device, and an ultra-short pulse reflected on each boundary surface of the eyeball 200. Photodetector 50 that detects reflected light
The external temperature and the cornea 210 external surface temperature of the eyeball 200 were measured, and the temperature distribution as shown in FIG. 8 of a plurality of types of eyeballs preset for each of the deep body temperature of the anterior chamber 220 and the external temperature were measured. A temperature distribution detecting means 70 'for obtaining a temperature distribution of the aqueous humor based on the outside air temperature and the corneal surface temperature, and an absorbance of the aqueous humor component based on the light intensity detected by the photodetector 50. The absorbance of the aqueous humor is corrected for each wavelength and according to the temperature distribution obtained by the temperature distribution detecting means 70 ', and the aqueous humor component is further corrected based on the corrected light absorption characteristics. This is a configuration including a signal processing circuit 60 for calculating the glucose concentration therein, and a display device 32 for displaying the calculation result.

Here, as the light source device, a Ti: sapphire laser light source (hereinafter simply referred to as a light source) 11a 'for emitting ultrashort pulse light of wavelength λ1, a light source 11b' for emitting ultrashort pulse light of wavelength λ2, .., And a light source 11e 'for emitting ultrashort pulse light of wavelength λ5. What is ultrashort pulse light?
For example, it means pulsed light that emits light for a very short time such as femtosecond to picosecond.

As the propagation means, each light source 11a ',.
e ′ mirror 12 and dichroic mirrors 13 b to 13 e for reflecting or transmitting each light sequentially emitted, a mirror 14 for changing the traveling direction of the light, a lens 16 for collimating the light, and an eyeball for collimating the light. The lens 20 that irradiates the light 200, the beam splitter 33 that reflects the light reflected from the eyeball 200, and the dichroic mirror 26b that separates the light reflected by the beam splitter 33 for each wavelength
, 26e, the mirror 12, and lenses 27a,..., 27e for condensing each split light on the photodetector 50.

Here, in the glucose concentration measuring apparatus 103 of the embodiment shown in FIG. 7, the signal processing circuit 60 includes a part of the function of the light absorption characteristic detecting means 10 shown in FIG. It has the function of the calculating means 90.

The temperature distribution detecting means 70 'includes experimentally
As empirically or theoretically determined, as shown in FIG.
The temperature distribution (correspondence between the distance from the outer surface of the cornea (horizontal axis) and the temperature (vertical axis)) of the deep body temperature (fundus temperature) and the outside air temperature is stored. FIG. 8 shows the case where the outside air temperature is 10 ° C., 15 ° C., and 20 ° C. when the core body temperature is 36.5 ° C.
℃, 25 ℃, shows the temperature distribution of the eyeball for each 30 ℃, in addition to the core body temperature 35.0 ℃, 35.5 ℃, 36.0 ℃, 3
Those at 7.0 ° C., 37.5 ° C., and 38.0 ° C. are similarly set and stored in advance. Then, from the measured outside air temperature and corneal surface temperature, a corresponding temperature distribution is selected from these temperature distributions, or extrapolated (extrapolated) based on each of these temperature distributions to obtain a temperature distribution.

As the photodetector 50, a streak camera or the like capable of temporally separating condensed light as shown in FIG. 9 and separately measuring the light is applied. The intensity of each detected backscattered light is determined by a signal processing circuit 60.
Is integrated over time to calculate the amount of light.

Next, the operation of the glucose concentration measuring apparatus according to the present embodiment will be described.

First, an ultrashort pulse light having a wavelength λ1 is emitted from the light source 11a '. The emitted ultrashort pulse light having the wavelength λ1 is reflected by the mirrors 12 and 14, converted into parallel light by the lens 16 and incident on the beam splitter 33, and is interposed by the lens 20 between the cornea 210 and the aqueous humor 220. R ₂ and the interface R ₃ between the aqueous humor 220 and the lens 230 are focused. Focused light is reflected as a first backward scattered light beam at the boundary surface R _2, on the other hand, is reflected at the boundary surface R ₃ as a second backward scattered light beam.

The two backscattered lights enter the re-lens 20 and are made into parallel lights, reflected by the beam splitter 33, transmitted through the dichroic mirrors 26e,.
And is detected by the photodetector 50 by the lens 27a.

Here, the light incident on the eyeball 200 is an ultrashort pulse light, and the light emission time thereof is sufficiently shorter than the time required for the light to reciprocate through the cornea 210. And the second backscattered light sequentially reach the photodetectors 50 with a sufficient time difference with respect to the light emission time.

The photodetector 50 detects the time-resolved first backscattered light and second backscattered light that arrive sequentially. FIG. 9 shows the state of the intensity of the reference light and the intensity of each backscattered light which are time-resolved by the photodetector 50 and detected in time series. Note that the backscattered light by the eyeball 200 includes the light due to the interface between the air 300 and the cornea 210 as shown in FIG. 9, but the description is omitted here.

The photodetector 50 inputs the intensities of the respective lights detected in such a time-separated manner to the signal processing circuit 60, and the signal processing circuit 60 integrates the detected intensities with respect to time, thereby obtaining each backward light. The amount of scattered light is calculated.

The same operation as described above is performed for each of the light sources 11b 'to 11e.
′ Are sequentially performed on the ultrashort pulsed lights having different frequency bands to obtain the intensities of the plurality of backscattered lights. Based on the intensities, the signal processing circuit 60 determines the absorbance of the aqueous humor for the lights of the respective frequencies. Ask.

On the other hand, the temperature distribution detecting means 70 'measures the outside air temperature and the outer surface temperature of the cornea 210 of the eyeball 200, and stores the temperature distribution of the eyeball 200 for each of the deep body temperature and the outside air temperature which is stored in advance. The temperature distribution of the eyeball 200 is calculated based on the outside temperature and the outer surface temperature of the cornea 210.

Then, the signal processing circuit 60 determines the absorbance of the aqueous humor for the light of each of the above-mentioned frequencies by the temperature distribution detecting means 70 '.
And the glucose concentration in the aqueous humor component is calculated based on the corrected absorbance obtained.

Then, the calculated glucose concentration is output to the display device 32 and displayed on the display device 32.

As described above, according to the glucose concentration measuring apparatus of the present embodiment, the glucose concentration in the aqueous humor can be non-invasively measured, and the correction processing for following the fluctuation of the outside air temperature or the body temperature can be performed. Accordingly, the glucose concentration can be accurately obtained even if there is a change in the outside air temperature or the body temperature.

The glucose concentration in the aqueous humor obtained in this manner was calculated by comparing the glucose concentration in the aqueous humor obtained in advance by the above-mentioned apparatus for each patient with the blood glucose concentration obtained in a conventional invasive manner. The correlation is stored in the signal processing circuit 40 as, for example, a conversion table, and when the glucose concentration in the aqueous humor of the patient is calculated, the blood concentration is calculated based on the correlation with the stored blood glucose concentration. The medium glucose concentration may be calculated.

[Brief description of the drawings]

FIG. 1 is a diagram showing a basic apparatus configuration for implementing a glucose concentration measuring method of the present invention.

FIG. 2 is a diagram showing a relationship between light incident on an eyeball and backscattered light.

FIG. 3 is a diagram showing a more specific embodiment of the glucose concentration measuring device shown in FIG. 1;

FIG. 4 is a diagram showing an example of the temperature dependence of the absorbance of light of each wavelength.

FIG. 5 is a diagram showing a second more specific embodiment of the glucose concentration measuring device shown in FIG. 1;

FIG. 6 is a graph showing a state of a frequency sweep.

FIG. 7 is a diagram showing a third more specific embodiment of the glucose concentration measuring device shown in FIG. 1;

[Fig. 8] When the core body temperature is 36.5 ° C, the outside air temperature is 10 ° C and 15 ° C.
Shows the temperature distribution of the eyeball for each of ℃, 20 ℃, 25 ℃ and 30 ℃

FIG. 9 is a graph showing the concept of the intensity of each light detected by a time-resolvable photodetector.

[Explanation of symbols]

 10 Light absorption characteristic detecting means 70 Temperature distribution detecting means 80 Correcting means 90 Glucose concentration calculating means 100 Glucose concentration measuring device 200 Eyeball

──────────────────────────────────────────────────の Continued on front page (51) Int.Cl. ⁶ Identification code FI G01N 33/66 A61B 3/10 R

Claims (12)

[Claims] 1. An eyeball is irradiated with light, and the light absorption characteristics of an aqueous humor component that fills the anterior chamber of the eyeball with the light are determined. Determining the light absorption characteristics of the aqueous humor component, and determining the glucose concentration in the aqueous humor component based on the plurality of obtained light absorption characteristics. Determining a temperature distribution of water, correcting the respective light absorption characteristics according to the determined temperature distribution, and obtaining a glucose concentration in the aqueous humor component based on the corrected respective light absorption characteristics. A glucose concentration measuring method characterized by the above-mentioned. 2. An external air temperature and a corneal surface temperature are measured, a plurality of kinds of temperature distributions of an eyeball preset for each of the deep body temperature of the anterior chamber and the external air temperature, and the measured external air temperature and corneal surface temperature 2. The glucose concentration measuring method according to claim 1, wherein the temperature distribution of the aqueous humor is obtained based on the following. 3. The temperature distribution of the aqueous humor is determined based on the measured outside temperature, corneal surface temperature, and deep body temperature of the anterior chamber of the eye, based on the measured three temperatures. 2. The method for measuring glucose concentration according to 1. 4. A low-coherence light emitted from a predetermined light source is divided into signal light and reference light that travel separately along two different optical paths, and the signal light and the reference light slightly Modulating at least one of the two lights so that a frequency difference is generated, irradiating the signal light to an eyeball arranged in advance at a predetermined position, of the signal light applied to the eyeball, between the cornea and the anterior chamber. The first backscattered light by the interface and the reference light interfere with each other by adjusting the optical path length of the reference light, and the intensity of the first interference light obtained by the interference is measured. The intensity of the first backscattered light is obtained based on the intensity of the interference light of the above. The signal light emitted to the eyeball, the second backscattered light by the interface between the anterior chamber and the lens, and the reference Light and interference by adjusting the optical path length of the reference light; Measuring the intensity of the second interference light obtained from the above, obtaining the intensity of the second backscattered light based on the intensity of the second interference light, and determining the intensity of the first and second backscattered light. Based on the aqueous humor component that satisfies the anterior chamber, determine the light absorption characteristics before the temperature correction.The same applies to the other low-coherence light having a different wavelength band from the low-coherence light. 4. The glucose concentration measuring method according to claim 1, wherein a plurality of light absorption characteristics before the temperature correction are obtained. 5. A coherent light emitted from a predetermined light source and frequency-swept in a time sawtooth shape is divided into a signal light and a reference light which respectively travel along two different optical paths, and Irradiating the signal light to an eyeball previously arranged at a position, a first backscattered light of the signal light by an interface between a cornea and an anterior chamber of the eyeball, and the signal light and the first backscattered light. The first backscattered light emitted from the light source with a time difference based on the optical path length difference between the light and the reference light interferes with the reference light by coherent light having a frequency difference with the first backscattered light, and is obtained by the interference. Measuring the intensity of the first interference light; obtaining the intensity of the first backscattered light based on the intensity of the first interference light; the signal light due to the interface between the anterior chamber of the eye and the crystalline lens The second backscattered light, and the signal light and The second backscattered light emitted from the light source with a time difference based on the optical path length difference between the second backscattered light and the reference light, the second backscattered light interferes with the reference light by coherent light having a frequency difference, Measuring the intensity of the second interference light obtained by the interference; obtaining the intensity of the second backscattered light based on the intensity of the second interference light; Based on the intensity of the aqueous humor component filling the anterior chamber, determine the light absorption characteristics before the temperature correction, the coherent light and other coherent light having a different wavelength in the same manner. 4. A plurality of light absorption characteristics before the temperature correction are obtained.
The glucose concentration measuring method according to any one of the above. 6. An eyeball is irradiated with ultrashort pulsed light emitted from a predetermined light source, the intensity of the first backscattered light of the ultrashort pulsed light at the boundary between the cornea and the anterior chamber of the eyeball and The intensity of the second backscattered light by the interface between the anterior chamber and the lens is measured separately, and the aqueous humor filling the anterior chamber based on the intensities of the first and second backscattered lights. The light absorption characteristics of the component before the temperature correction are obtained, and the plurality of light absorption characteristics before the temperature correction are obtained in the same manner for the other plurality of ultrashort pulse lights having different wavelengths from the ultrashort pulse light. The glucose concentration measuring method according to any one of claims 1 to 3, wherein: 7. An eyeball is irradiated with light, and a light absorption characteristic of an aqueous humor component filling the anterior chamber of the eyeball with the light is obtained. A light absorption characteristic detecting means for determining the light absorption characteristic of the aqueous humor component; and a glucose concentration for determining the glucose concentration in the aqueous humor component based on the plurality of light absorption characteristics obtained by the light absorption characteristic detecting means. A glucose concentration measuring device comprising a calculating means, a temperature distribution detecting means for obtaining a temperature distribution of the aqueous humor in the anterior chamber, and a temperature distribution obtained by the temperature distribution detecting means. Correction means for correcting light absorption characteristics, wherein the glucose concentration calculation means obtains a glucose concentration in the aqueous humor component based on each light absorption characteristic corrected by the correction means. A glucose concentration measuring device, comprising: 8. The temperature distribution detecting means measures an outside air temperature and a corneal surface temperature, and a plurality of kinds of temperature distributions of an eyeball preset for each of the deep body temperature and the outside air temperature of the anterior chamber of the eye and the measured temperature distribution. The glucose concentration measuring device according to claim 7, wherein the temperature distribution of the aqueous humor is determined based on the outside air temperature and the corneal surface temperature. 9. The temperature distribution detecting means measures an outside air temperature, a corneal surface temperature, and a deep body temperature of the anterior chamber of the eye, and obtains a temperature distribution of the aqueous humor based on the three measured temperatures. The glucose concentration measuring device according to claim 7, wherein 10. A light source device that emits a plurality of low-coherence lights having different emission wavelength bands from each other, and the low-coherence light emitted from the light source device is transmitted to two different optical paths. Optical path splitting means for splitting the signal light into the reference light and the signal light incident on the eyeball, and modulating at least one of the two lights so that a slight frequency difference occurs between the signal light and the reference light A modulator provided on the at least one optical path, an optical path length adjuster for adjusting a length of an optical path along which the reference light travels, First
Backscattering and the reference light, and wavefront matching means for respectively wavefront matching the second backscattered light and the reference light of the signal light due to the interface between the anterior chamber of the eyeball and the lens, The intensity of the first interference light based on the wavefront matching between the reference light and the first backscattered light and the intensity of the second interference light based on the wavefront matching between the reference light and the second backscattered light are photoelectrically detected. A photodetector; heterodyne calculating means for obtaining the intensities of the first and second backscattered lights based on the intensities of the respective interference lights; The glucose concentration measuring device according to any one of claims 7 to 9, further comprising light absorption characteristic analysis means for determining light absorption characteristics of an aqueous humor component that fills the eye chamber. 11. A light source device for emitting a plurality of coherent light beams having different wavelengths from each other, wherein said light absorption characteristic detecting means emits a plurality of coherent light beams having different wavelengths in a time-sweep frequency-sweep manner. Optical path splitting means for splitting the coherent light into reference light and signal light incident on the eyeball, each of which travels separately along two different optical paths, and the signal light at the interface between the cornea and the anterior chamber of the eyeball And the first backscattered light emitted from the light source with a time difference based on the optical path length difference between the signal light and the first backscattered light and the reference light. And the reference light by coherent light having
And a time difference based on a second backscattered light of the signal light due to a boundary surface between the anterior chamber of the eyeball and the crystalline lens, and an optical path length difference between the signal light, the second backscattered light, and the reference light. A wavefront matching means for respectively wavefront matching the reference light by coherent light having a frequency difference with the second backscattered light emitted from the light source; and the first backscattered light and the first backscattered light. The first interference light obtained by wavefront matching with the reference light having a slight frequency difference with respect to the backscattered light, and the second backscattered light and the second interference light;
A photodetector that photoelectrically detects the intensity of the second interference light obtained by wavefront matching with the reference light having a slight frequency difference with respect to the backscattered light, based on the intensity of each interference light Heterodyne calculating means for obtaining the first and second backscattered light intensities; and obtaining light absorption characteristics of an aqueous humor component filling the anterior chamber based on the first and second backscattered light intensities. The glucose concentration measuring device according to any one of claims 7 to 9, further comprising a light absorption characteristic analyzing means. 12. A light source device for emitting a plurality of ultrashort pulse lights having different wavelengths from each other, a light source device for causing the ultrashort pulse light to enter an eyeball, and a cornea and an anterior chamber of the eyeball. The intensity of the first backscattered light of the ultrashort pulsed light due to the boundary surface and the intensity of the second backscattered light of the ultrashort pulsed light due to the boundary surface between the anterior chamber and the crystalline lens are time-series. A light time domain backscattering measuring means separately obtained; and a light absorption characteristic analyzing means for obtaining a light absorption characteristic of an aqueous humor component filling the anterior chamber based on the intensities of the first and second backscattered lights. The glucose concentration measuring device according to any one of claims 7 to 9, wherein the glucose concentration is measured.