WO2012141300A1 - Circular dichroism measuring device for living body, circular dichroism measuring method for living body, noninvasive blood sugar level measuring device and noninvasive blood sugar level measuring method - Google Patents

Abstract

The objective of the present invention is to provide a novel measuring device and measuring method for estimating, easily, noninvasively and with high precision, blood sugar level of a person where conventionally blood had to be drawn to measure the blood sugar level, for treatment or prevention of diabetes. To achieve this objective, a method was adopted in which a wavelength of a variable wavelength laser light or a length of an excitation polarization maintaining optical fiber (PMF) is changed in synchronization with the pulse, a left and right circularly polarized light state of an output light thereof is made to change periodically, and the light is entered into the living body via the PMF.

Description

Biological circular dichroism measuring device, biological circular dichroism measuring method, noninvasive blood sugar level measuring device, and noninvasive blood sugar level measuring method

The present invention relates to a living body circular dichroism measuring device and method and a living body non-invasive blood sugar level measuring device and method, for example, capable of measuring the concentration of carbohydrates in a living body and applied to a human finger, ear or skin. The present invention relates to a low-cost non-invasive blood glucose level measuring apparatus and method that can measure the glucose concentration of a subject with high measurement accuracy without irradiating laser light, measuring the transmitted light or reflected light, and collecting blood.

Currently, it is said that there are about 200 million people in the world and 20 million people with diabetes or their reserves in Japan. A conventional blood sugar level measuring method measures glucose in blood collected by a needle by a chemical reaction. However, the blood collection method has problems such as pain, needle processing, and the cost of one measurement. From such a background, a method for optically measuring the glucose concentration in blood without depending on blood collection has been studied, and development of a measuring device has been attempted.

A first known method for measuring carbohydrates is to irradiate a part of a living body such as a finger with infrared laser light, as described in Patent Document 1, so that scattered light or transmission from the living body. It is intended to measure light contained in blood and subcutaneous interstitial fluid by measuring light. This method utilizes the fact that scattered light decreases in proportion to the glucose concentration. However, this method has a problem that the light intensity of scattered light depends on temperature, moisture of the skin, an oil component, etc., and is not widely used.

The second measurement method, as described in Non-Patent Document 1 and Patent Document 2, etc., propagates a polarization component orthogonal to glucose and measures its birefringence in an open loop. However, this method has a large error when a sample having a blood glucose level of about 0.1 g / dL, which is a blood glucose level of a healthy person, is measured with a sample (glucose) having a length of about 10 mm. In particular, it cannot be measured in a living body having a very large light scattering loss.

The third measurement method is a method of measuring with a birefringence measuring device described in Patent Document 3. In this method, a nonreciprocal optical system is provided in the ring optical path of the interferometer, and the sample is placed inside thereof to measure the optical rotation of the sample. In this method, a blood glucose level of 0.1 g / dL, which is a healthy subject's blood glucose level, can be measured with sufficient accuracy using a specimen having a thickness of about 10 mm. In non-invasive measurement of a living body such as a 0.1 mm blood vessel, sufficient measurement accuracy is not obtained.

The fourth measurement method is a method of measuring the circular dichroism of the specimen with the spatial optical system described in Patent Document 4. In this method, when the specimen is a light scatterer such as a living body, the transmitted light from the living body cannot be efficiently collected on the light receiver. That is, a so-called non-invasive blood sugar level measuring device that measures the glucose concentration of a living body without collecting blood has not been put to practical use.

The reason is that the scattering generated when laser light is incident on the living body is so large that the detected light receiving power is very small, due to the effects of water and oil contained in the living body and on the surface, and slight changes in body temperature. It was because it was buried in noise and the glucose concentration of the specimen could not be measured with high accuracy.

Various attempts have been made to develop optical measuring devices that can measure the glucose concentration of blood or living blood collected with high accuracy, but it is extremely difficult to measure the glucose concentration of blood or living blood collected with high accuracy. Although it can be used to measure the sugar content of fruits, vegetables, etc., a measuring device that can be used to measure the glucose concentration of collected blood and living organisms has not yet been put into practical use. The current situation is that we have to rely on the technique using. Collecting blood every time for measuring the glucose concentration is very painful especially for diabetic patients, and the development of a measuring device that can measure the glucose concentration non-invasively is eagerly desired.

JP 2004-313554 A JP 2007-093289 A JP 2005-274380 A International Publication No. 2007/029652

The present invention has been made in view of the above problems, and the object of the present invention is to reduce the blood glucose level of humans, which had conventionally had to be collected for blood glucose measurement for the treatment or prevention of diabetes. A novel biological circular dichroism measuring device, biological dichroic measuring method, non-invasive blood sugar level measuring device, and non-invasive blood sugar level measuring method that can be estimated non-invasively and with high accuracy by a simple method There is to do.

In order to solve the above-mentioned problems, the present inventor can estimate human blood glucose level with high accuracy in a non-invasive manner, or with high accuracy circular dichroism related to optical rotation of polarized light based on human glucose. Inexpensive means that can be measured were studied extensively. As a result, we have improved the circular dichroism measurement technology, which was previously thought to be unusable due to insufficient measurement accuracy for non-invasive estimation of human blood glucose levels. We found that we can make an estimate.

The feature of the technology that can obtain measurement information that can be used for estimating the blood glucose level of the living body according to the present invention made to solve the above-mentioned problems with a simple operation at low cost and with high accuracy is mainly: In the measurement method, the wavelength of the light source or the polarization-maintaining optical fiber for excitation (hereinafter also referred to as “PMF”) is changed in synchronization with the pulse of the living body, and the polarization of the output of the PMF is synchronized with the pulse. The method of irradiating the living body through the PMF so that the left and right circularly polarized light changes periodically is employed. Hereinafter, embodiments of the present invention will be specifically described.

In a first embodiment according to the present invention (hereinafter referred to as a first embodiment) made to solve the above problems, the emission wavelength from the light source is in a region where the circular dichroism of the specimen is maximized, and Linearly polarized laser light that changes continuously or discretely in synchronism with an external trigger is incident on a polarization-maintaining optical fiber (PMF) with the polarization direction limited, and the output light from the PMF is in its polarization state Irradiates a living body as signal light so that left circularly polarized light and right circularly polarized light change periodically, receives the transmitted light and / or reflected light with a light receiver, and measures the wavelength characteristics of the received light intensity. It is a biological dichroism measuring method of a living body characterized by having a process.

A second embodiment (hereinafter referred to as embodiment 2) according to the present invention developed from embodiment 1 is the azimuth of the polarized light in the method for measuring circular dichroism of a living body described in embodiment 1. Is the azimuth of 45 degrees with respect to the intrinsic polarization axis of the polarization-maintaining optical fiber (PMF), the length of the PMF is L (mm), and the amount of change in wavelength of the light source that changes with time T (seconds) is Λ (Nm), when the light source wavelength is λ (nm) and the beat length of the PMF is B (mm), the wavelength of the light source is such that the period of the polarization state of the light emitted from the PMF is synchronized with the pulse. A method for measuring circular dichroism of a living body, comprising a step of measuring a change rate Λ / T (nm / second) as calculated by the following equation (4).
(Equation 1)
Λ / T = N (p) λB / 2L (4)

A third exemplary embodiment of the present invention (hereinafter referred to as exemplary embodiment 3) made to solve the above-described problem is that the wavelength of the light source is from the light source in the region where the circular dichroism of the specimen is maximum. And narrowing the spectrum of the light with a grating, linearly polarizing it with a polarizer, limiting the direction of polarization and entering the polarization-maintaining optical fiber (PMF), and continuously or discretely in synchronization with an external trigger. Expanding and contracting the length of the PMF so that the polarization state of the output light from the PMF periodically changes between left circularly polarized light and right circularly polarized light; and irradiating the living body as a specimen with the output light from the PMF The process and the transmitted light of the living body or the reflected light from the living body are directly or the core is subjected to a TEC (core expanded processed expanded core) treatment. A biological circle, comprising: a step of receiving light by a light receiver through a single-mode optical fiber, a multi-mode optical fiber or a multi-mode optical fiber bundle; and a measuring step of measuring a relationship between the received light intensity and the length of the optical fiber It is a dichroism measurement method.

A fourth embodiment of the present invention (hereinafter referred to as “embodiment example 4”) developed by expanding the embodiment example 3 is the narrow-spectrum narrowing in the biological circular dichroism measurement method described in the embodiment example 3. In an optical system in which linearly polarized laser light is incident at an angle of 45 degrees with respect to the intrinsic polarization axis of the PMF and the living body is irradiated with the output light, the beat length of the PMF is B and the pulse rate / second is When N (p) is set, the temporal change rate ΔL / T (mm / second) of the optical fiber length of the telescopic device attached to the PMF is changed as calculated by the following equation (7) and measured. It is a biological dichroism measuring method of a living body characterized by having a process.
[Equation 2]
ΔL / T = N (p) B (7)

A fifth embodiment according to the present invention (hereinafter referred to as a fifth embodiment) developed by developing the first to fourth embodiments is a circular dichroism measurement of a living body according to any one of the first to fourth embodiments. In the method, the laser light emitted from the light source is set to a value at which the light emitted from the PMF becomes a linearly polarized state having a 45-degree azimuth, and the change in optical power received by the light receiver is synchronized with the pulse. A method of measuring circular dichroism of a living body, wherein the incident position on the living body is adjusted.

A sixth embodiment according to the present invention (hereinafter referred to as a sixth embodiment) developed by developing the first to fifth embodiments is a circular dichroism measurement of a living body according to any one of the first to fifth embodiments. The method includes the step of measuring the wavelength characteristic of the received light intensity by receiving the transmitted light or reflected light directly or through a multimode optical fiber or a multimode optical fiber bundle with a light receiver. This is a method for measuring circular dichroism of a living body.

The seventh embodiment (hereinafter referred to as embodiment 7) according to the present invention developed by developing embodiments 1 to 6 is the circular dichroism measurement of a living body according to any of embodiments 1 to 6. In the method, the larger and smaller losses of left and right circularly polarized light are defined as C (M) and C (m), respectively, and the attenuation amounts of C (M) and C (m) are respectively α (M) and α ( m), the wavelength characteristic of the optical power received by the light receiver is measured under two conditions: when the blood vessel is dilated and when synchronized with C (M) and when synchronized with C (m). And a circular dichroism measurement method for a living body, comprising a step of measuring an amount proportional to (α (M) −α (m)) by calculation.

The eighth embodiment of the present invention (hereinafter referred to as embodiment 8) made by developing embodiments 1 to 7 is the circular dichroism measurement of a living body according to any of embodiments 1 to 7. In the method, when the emitted light of the PMF is coupled to a living body with a lens, the method includes a step of setting the emitting end of the PMF closer to the lens than the focal point of the lens. It is.

The ninth embodiment (hereinafter referred to as embodiment 9) according to the present invention developed by expanding embodiments 1 to 8 is the circular dichroism measurement of a living body according to any of embodiments 1 to 8. In the method, when the outgoing light of the PMF is coupled to a living body with a lens, the outgoing end of the PMF is subjected to TEC (core expanded processing, ie, thermally diffused expanded core) processing, and the core diameter is 2 times the core diameter of the original PMF. It is a method for measuring circular dichroism of a living body, characterized in that it is enlarged more than twice.

A tenth embodiment of the present invention (hereinafter referred to as a tenth embodiment) made by developing the first to ninth embodiments is a circular dichroism measurement of a living body according to any one of the first to ninth embodiments. In the method, the PMF is an elliptical jacket type fiber whose core is pure quartz and whose cladding is fluorine-doped, and is a biological circular dichroism measuring method characterized in that

An eleventh embodiment according to the present invention (hereinafter referred to as “embodiment 11”) obtained by developing Embodiments 1 to 10 is the circular dichroism measurement of a living body according to any one of Embodiments 1 to 10. Using the method, the larger and smaller losses of left and right circularly polarized light measured for the subject are defined as C (M) and C (m), respectively, and the attenuation of C (M) and C (m) is defined as When α (M) and α (m) are set, respectively, when the blood vessel is dilated, it is received by the light receiver in the case of two conditions of synchronizing with C (M) and synchronizing with C (m). A non-invasive blood glucose level comprising a step of measuring a wavelength characteristic of the optical power and estimating a blood glucose level of the subject from an amount proportional to (α (M) −α (m)) by calculation This is a measurement method.

A twelfth embodiment (hereinafter referred to as a morphological example 12) according to the present invention, which was developed by developing the morphological example 11, was measured with respect to the subject in the non-invasive blood sugar level measuring method according to the eleventh example. A correlation table between an amount proportional to (α (M) −α (m)) and a blood glucose level measured in advance by the subject's existing blood sampling method was prepared and measured (α (M) A non-invasive blood sugar level measuring method comprising a step of estimating a blood sugar level of the subject from an amount proportional to -α (m)).

In a thirteenth embodiment according to the present invention (hereinafter referred to as a thirteenth embodiment) made to solve the above-mentioned problem, the emission wavelength from the light source is in a region where the circular dichroism of the specimen is maximized, and Means for injecting linearly polarized laser light, which changes continuously or discretely in synchronization with an external trigger, into a polarization-maintaining optical fiber (PMF) by limiting the direction of polarization; and output light from the PMF Means for irradiating a living body as signal light so that left circularly polarized light and right circularly polarized light periodically change, means for receiving the transmitted light and / or reflected light with a light receiver, and It is a biological circular dichroism measuring apparatus characterized by having a means for measuring wavelength characteristics.

A fourteenth embodiment (hereinafter referred to as a fourteenth embodiment) according to the present invention developed by developing the thirteenth embodiment is the azimuth of the polarization in the biological circular dichroism measuring device according to the thirteenth embodiment. Is the azimuth of 45 degrees with respect to the intrinsic polarization axis of the polarization-maintaining optical fiber (PMF), the length of the PMF is L (mm), and the amount of change in wavelength of the light source that changes with time T (seconds) is Λ (Nm), when the light source wavelength is λ (nm) and the beat length of the PMF is B (mm), the wavelength of the light source is such that the period of the polarization state of the light emitted from the PMF is synchronized with the pulse. An apparatus for measuring circular dichroism of a living body, comprising a step of measuring a change rate Λ / T (nm / second) as calculated by the following equation (4).
[Equation 3]
Λ / T = N (p) λB / 2L (4)

The fifteenth embodiment according to the present invention (hereinafter referred to as embodiment 15) made to solve the above-described problems is obtained from a light source whose wavelength of the light source is in a region where the circular dichroism of the specimen is maximum. Means for narrowing the spectrum of light by a grating, linearly polarizing it by a polarizer, limiting the direction of polarization and entering the polarization-maintaining optical fiber (PMF), and continuously or discretely in synchronism with an external trigger Means for expanding and contracting the length so that the polarization state of the output light from the PMF periodically changes between left circularly polarized light and right circularly polarized light; and means for irradiating the living body as the specimen with the output light from the PMF; , The transmitted light of the living body and / or the reflected light from the living body, or the core was subjected to TEC (core expanded processing, ie, Thermally Expanded Core) processing Biological circle 2 characterized by having means for receiving light by a light receiver via a single-mode optical fiber, a multi-mode optical fiber or a multi-mode optical fiber bundle, and a means for measuring the relationship between the received light intensity and the length of the optical fiber This is a color measuring device.

A sixteenth embodiment (hereinafter referred to as a sixteenth embodiment) according to the present invention developed by developing the fifteenth embodiment is the narrow-spectrum in the biological circular dichroism measuring device according to the fifteenth embodiment. In an optical system in which linearly polarized laser light is incident at an angle of 45 degrees with respect to the intrinsic polarization axis of the PMF and the living body is irradiated with the output light, the beat length of the PMF is B and the pulse rate / second is When N (p) is set, the temporal change rate ΔL / T (mm / second) of the optical fiber length of the telescopic device attached to the PMF is changed as calculated by the following equation (7) and measured. This is a living body circular dichroism measuring device.
[Equation 4]
ΔL / T = N (p) B (7)

The seventeenth embodiment of the present invention (hereinafter referred to as the seventeenth embodiment) developed by developing the thirteenth to thirteenth embodiments is a circular dichroism measurement of a living body according to any one of the thirteenth to thirteenth embodiments. In the apparatus, the laser beam emitted from the light source is set to a value at which the emitted light from the PMF becomes a linearly polarized state with a 45 degree azimuth, and the change in the optical power received by the light receiver is synchronized with the pulse. An apparatus for measuring circular dichroism of a living body having means for adjusting an incident position on the living body.

An eighteenth embodiment according to the present invention (hereinafter referred to as embodiment 18) developed by developing embodiments 13 to 17 is a circular dichroism measurement of a living body according to any of embodiments 13 to 17. In the apparatus, the transmitted light or the reflected light is received by a light receiver directly or via a multimode optical fiber or a multimode optical fiber bundle in which the core is subjected to a TEC (core diffused expanded core) process. An apparatus for measuring circular dichroism of a living body having means for measuring wavelength characteristics of received light intensity.

The nineteenth embodiment according to the present invention developed from the thirteenth to thirteenth embodiments (hereinafter referred to as the thirteenth embodiment) is a circular dichroism measurement of a living body according to any one of the thirteenth to thirteenth embodiments. In the apparatus, the larger and smaller losses of left and right circularly polarized light are defined as C (M) and C (m), respectively, and the attenuation amounts of C (M) and C (m) are respectively α (M) and α ( m), the wavelength characteristic of the optical power received by the light receiver is measured under two conditions: when the blood vessel is dilated and when synchronized with C (M) and when synchronized with C (m). The biological dichroism measuring device for a living body is characterized in that an amount proportional to (α (M) −α (m)) is obtained by calculation.

A twentieth embodiment (hereinafter referred to as a morphological example 20) according to the present invention developed by developing the morphological examples 13 to 19 is the circular dichroism measurement of a living body according to any of the morphological examples 13 to 19. In the apparatus, when the emitted light of the PMF is coupled to a living body with a lens, the both end emitting ends of the PMF are located closer to the lens than the focal point of the lens. .

A twenty-first embodiment according to the present invention developed from the thirteenth to thirteenth embodiments (hereinafter referred to as a thirteenth embodiment) is a circular dichroism measurement of a living body according to any one of the thirteenth to thirteenth embodiments. In the apparatus, when the light emitted from the PMF is coupled to a living body with a lens, both ends of the PMF are subjected to TEC (core expanded processing, ie, thermally diffused expanded core) processing, and the core diameter is twice the core diameter of the original PMF. This is a biological circular dichroism measuring device that is enlarged as described above.

A twenty-second embodiment according to the present invention developed from the thirteenth to thirteenth embodiments (hereinafter referred to as a thirty-second embodiment) is a circular dichroism measurement of a living body according to any one of the thirteenth to thirteenth embodiments. In the apparatus, the PMF is an elliptical jacket type fiber whose core is pure quartz and whose cladding is fluorine-doped.

A twenty-third embodiment (referred to as a twenty-third embodiment) according to the present invention developed by developing the thirteenth to thirteenth embodiments includes the biological circular dichroism measuring device according to any one of the thirteenth to thirteenth embodiments. In the optical path of the signal light, a Peltier element and / or a temperature detection part as a temperature control element is incorporated into a part that sandwiches the measurement position for circular dichroism measurement or a part that contacts the measurement position. A non-invasive blood sugar level measuring device comprising means for controlling the temperature of a measurement site and / or measuring the temperature.

A twenty-fourth embodiment (hereinafter referred to as a twenty-fourth embodiment) according to the present invention developed by developing the twenty-third embodiment was measured with respect to the subject in the non-invasive blood sugar level measuring device described in the twenty-third embodiment. The larger and smaller losses of left and right circularly polarized light are defined as C (M) and C (m), respectively, and the attenuation amounts of C (M) and C (m) are α (M) and α (m), respectively. When measuring the wavelength characteristics of the optical power received by the light receiver for the two conditions of when the blood vessel is dilated and synchronized with C (M) and when synchronized with C (m), the calculation is performed. A non-invasive blood sugar level measuring apparatus comprising means for estimating the blood sugar level of the subject from an amount proportional to (α (M) −α (m)).

A twenty-fifth embodiment (hereinafter referred to as a twenty-fifth embodiment) according to the present invention developed by developing the twenty-third or twenty-fourth embodiment is a non-invasive blood sugar level measuring apparatus according to the twenty-third or twenty-fourth embodiment. , The larger and smaller loss of left and right circularly polarized light measured for the subject is defined as C (M) and C (m), respectively, and the attenuation of C (M) and C (m) is α ( M) and α (m), the optical power received by the light receiver when the blood vessel is dilated is synchronized with C (M) and when synchronized with C (m). A correlation table between an amount proportional to (α (M) −α (m)) and a blood glucose level measured in advance by the subject's existing blood sampling method is created by calculation. From the amount proportional to the measured (α (M) −α (m)) Is a non-invasive blood sugar level apparatus characterized by comprising means for estimating the sugar level.

According to the biological circular dichroism measuring device and method and the non-invasive blood sugar level measuring device and method of the present invention, the blood glucose concentration related to the blood glucose level can be measured without blood collection.

1 is a basic configuration diagram of a biological circular dichroism measuring device according to an embodiment of the present invention. FIG. It is a block diagram of the biological circular dichroism measuring apparatus in the other embodiment according to the present invention. It is a block diagram of the biological circular dichroism measuring apparatus in the further another example of embodiment which concerns on this invention. It is a conceptual diagram of the wavelength characteristic of the light receiver output in the embodiment according to the present invention. It is a conceptual diagram of the relationship between the wavelength characteristic of the light receiver output and the pulse signal in the embodiment according to the present invention. It is another conceptual diagram of the relationship between the wavelength characteristic of the light receiver output and the pulse signal in the embodiment according to the present invention. It is a basic lineblock diagram of a living body circular dichroism measuring device as an example of an embodiment concerning the present invention.

It is a block diagram of the circular dichroism measuring device of the living body without the light receiving fiber as another embodiment according to the present invention. It is a block diagram of the biological circular dichroism measuring apparatus at the time of using the optical fiber bundle as another example of embodiment which concerns on this invention. It is a block diagram of the example of a reflection type of the biological circular dichroism measuring device as an embodiment according to the present invention. It is experimental data of the insertion loss of the opposing optical fiber collimator which pinches | interposes the biological body used as the back data of this invention. It is a conceptual diagram explaining the relationship between the light receiver output as an example of embodiment according to the present invention, the incident side polarization plane preserving optical fiber length, and the pulse signal. It is another conceptual diagram explaining the relationship between the light receiver output as an embodiment according to the present invention, the incident-side polarization plane preserving optical fiber length, and the pulse signal.

Hereinafter, an embodiment of an invention according to the present invention will be described with reference to the drawings. The drawings used in the following description schematically show the dimensions, shapes, arrangement relationships, and the like of each component so that the embodiment of the present invention can be understood. For the convenience of the following explanation, there may be cases where the enlargement ratio is partially changed for illustration, and the drawings used for explanation of the embodiment of the present invention may not necessarily be similar to the actual thing or description such as the embodiment. is there. Moreover, in each figure, about the same component, it attaches and shows the same number, and the overlapping description may be abbreviate | omitted. Further, in the following description, overlapping descriptions of the biological circular dichroism measuring device, the biological circular dichroism measuring method, the non-invasive blood sugar level measuring device, and the non-invasive blood sugar level measuring method according to the embodiment of the present invention. There are many parts. Therefore, in order to avoid duplication of explanation, there is a case where any one of the explanations is combined with another explanation without particularly mentioning it while avoiding misunderstanding.

The present inventor has proposed the use of circular dichroism measurement for measuring glucose. However, it seemed difficult to use the circular dichroism measurement for measuring glucose and was given up. Accordingly, the fundamental principle of circular dichroism measurement has been reviewed and various studies have been made. As a result, the present invention has been achieved. Hereinafter, an embodiment of an invention according to the present invention will be described in detail with reference to experimental results leading to the present invention. In addition, the following description may be demonstrated only with wording, without necessarily using a figure.

FIG. 1 is a basic configuration diagram of a living body circular dichroism measuring apparatus according to an embodiment of the present invention. The light source 1 is a tunable light source or a coherent light source whose wavelength can be discretely changed to two or more wavelengths. The coherent light source includes a light source whose spectral width is limited by a grating or the like for diffused light from a laser or a broadband light source. The light source 1 includes a condenser lens for an optical fiber.

Linearly polarized laser light as signal light emitted from the light source 1 is incident at an angle of 45 degrees with respect to the intrinsic polarization axis of the PMF 2, collimated by the lens 3 disposed at the emission end, and incident on a living body 4 such as a finger. Is done. As the PMF2, an elliptical jacket type of a silica core fluorine-doped clad having NA = 0.05, a clad diameter of 30 μm, and a coating outer diameter of 150 μm was used. The core diameter was 2.5 μm. In this fiber, a preform designed for a cladding diameter of 125 μm for the 800 nm band was drawn with an outer diameter of 30 μm. The laser light propagated through the living body 4 is received by the light receiver 7, converted into an electrical signal, and guided to the signal processing unit 8. Reference numeral 9 denotes a pulse sensor. A signal from the pulse sensor 9 is sent to a signal processing unit (microcomputer) 8, and the signal is also transmitted to the light source drive control unit 10 of the light source drive control device, so that the wavelength of the light source is swept. Controlled. As the light receiver, an electronically cooled APD (avalanche photodiode) covering the light source wavelength is used, but a photomultiplier tube can also be used.

Here, the refractive index difference between the core and the clad or the numerical aperture NA is designed so that the PMF 2 becomes a single mode in the light source wavelength region. As a result of experiment, when the NA of the PMF 2 is reduced and the output end of the PMF 2 is shifted from the collimated state and defocused to the lens side instead of the focal point of the lens 3, the transmitted light of the living body 4 can be efficiently guided to the light receiver. did it. In this respect, the NA of PMF2 is desirably 0.05 or less. By doing so, the insertion loss can be reduced and the measurement accuracy can be increased.

As shown in Non-Patent Document 2, when polarized light is transmitted through a living body, the thickness of the living body where the polarized light is stored is about 1.2 mm. In addition, it was experimentally confirmed that it is effective to make the beam diameter as small as possible and to keep the incident angle small in order to reduce the light scattering loss in the living body. If light is received by a light receiver having a large light receiving diameter without considering the incident angle to the living body, a large optical power can be received, but the polarization component is lost.

FIG. 2 is a basic configuration diagram for explaining a biological circular dichroism measuring apparatus according to another embodiment of the present invention. The output light of the biological body 4 in FIG. 1 is collected via the multimode optical fiber bundle 5. In this example, the optical lens 6 leads to the light receiver 7. FIG. 3 is a basic configuration diagram for explaining a biological circular dichroism measuring apparatus according to still another embodiment of the present invention. A multi-mode optical fiber bundle 5 is arranged around the signal light irradiation PMF 2 to perform irradiation. It is a figure which shows the structure which received the reflected light from the biological body 4 irradiated with the light from PMF2, condensed the emitted light of the multimode optical fiber bundle 5 with the lens 6, and guide | induced to the light receiver 7. FIG. FIG. 2 is the same as FIG. 1 in principle. As the bundle optical fiber, a 7-core silica-based multimode optical fiber having a core / clad diameter of 200/220 μm was used.

1 to 3, when the wavelength λ of the light source 1 is scanned, the polarization state of the emitted light repeats right circular polarization and left circular polarization in the vicinity of the wavelength λ with a period determined by the beat length B and the length L of the PMF 2. . If the period is Δλ, Δλ is given by the following equation.
[Equation 5]
Δλ = λB / 2L (1)
Further, when the light source wavelength is changed by Λ at time T (seconds), the polarization state change frequency f is expressed by the following equation.
[Equation 6]
f = Λ / (ΔλT) (2)
Substituting equation (1) [Equation 7]
f = 2ΛL / (λBT) (3)
It becomes.
When the pulse frequency is N (p) and f = N (p), the wavelength change rate of the light source is given by the following equation.
[Equation 8]
Λ / T = N (p) λB / 2L (4)
Here, if the wavelength λ = 182 nm, B = 0.35 mm, and L = 0.5 m, Δλ in the equation (1) is approximately 0.064 nm. Further, the expression (4) becomes the following expression.
[Equation 9]
Λ / T = 0.064N (p) (nm) (5)

A method for changing the wavelength of the light source in the vicinity of 182 nm, which is the circular dichroism peak of glucose, will be described. That is, the wavelength of the light source was changed via a grating from a deuterium lamp or a laser-excited broadband light source commercialized by Energetic in 2010. The light transmitted through the grating was linearly polarized by a lotion prism, and incident at 45 degrees with respect to the intrinsic polarization axis of PMF2 by a lens. In this way, the wavelength characteristics of the output polarization state of the PMF 2 were measured in advance.

FIG. 4 is a conceptual diagram of the wavelength characteristic of the light receiver output in the embodiment of the invention according to the present invention. The vertical axis represents the receiver output, and the horizontal axis represents the wavelength of the light source. When the wavelength of the light source is changed in the vicinity of 182 nm, the optical power of the light receiver shows a maximum value P (M) at the wavelength λ1 and an intermediate value P (0) at the wavelength λ2, as shown in FIG. The minimum value P (m) is shown at λ3, and thereafter, the intermediate value P (0), the maximum value P (M), the intermediate value P (0), and the minimum value P (m) are sequentially shown as the wavelength changes. Change. As described above, the period is approximately 0.064 nm. In FIG. 4, reference numerals 11-1 and 11-2 are points where the receiver output is a maximum value P (M) when right (or left) circularly polarized light is incident on the graph, and reference numeral 12 is left (or right) circularly polarized light incident. In this case, the light receiver output has a minimum value P (m), and reference numerals 13-1 and 13-2 indicate points at which the light receiver output has an intermediate value P (0) when linearly polarized light is incident. Here, the wavelength of the left circularly polarized light is shifted by 0.032 nm from the output wavelength of the linearly polarized light, but the wavelength change width is extremely small compared to 182 nm, so the loss of the left circularly polarized light is almost the same at the wavelength near 182 nm that becomes the left circularly polarized light. It can be assumed that they are equal. Similarly, it can be assumed that the loss of right-handed circularly polarized light is substantially equal at a wavelength near 182 nm that is right-handed circularly polarized light.

5 and 6 are conceptual diagrams for explaining the relationship between the wavelength characteristic of the light receiver output and the pulse signal in the embodiment of the present invention. 5 and 6, the upper graph is the wavelength characteristic graph of the receiver output, where the vertical axis represents the receiver output and the horizontal axis represents the wavelength of the light source, and the lower graph represents the pulse signal intensity and the horizontal axis. It is a graph of the pulse signal which expressed the axis with respect to time.

In the upper graph of FIG. 5, that is, the wavelength characteristic graph of the receiver output, the receiver output has a maximum value (position 11-1) P (M) at the wavelength λ1, and an intermediate value (reference 13-1) at the wavelength λ2. Position) P (0), a minimum value (position 12-1) P (m) at wavelength λ3, and an intermediate value (position 13-2) P (0) at wavelength λ4. The change is such that the maximum value (position of reference numeral 11-2) P (M) is reached at the wavelength λ3. In the lower graph of FIG. 5, the pulse 14 is generated at the time when the wavelength is λ1 in the upper graph, and the next pulse 14 is generated at the time when the wavelength is λ5.

In the upper graph of FIG. 6, that is, the wavelength characteristic graph of the receiver output, the receiver output has a maximum value (position of reference numeral 11-1) P ′ (M) at the wavelength λ1, and an intermediate value (reference numeral 13− at the wavelength λ2). 1) P ′ (0), a minimum value (position 12-1) P ′ (m) at the wavelength λ3, and an intermediate value (position 13-2) P ′ (0) at the wavelength λ4. And the maximum value (position of reference numeral 11-2) P ′ (M) is changed at the wavelength λ3. In the lower graph of FIG. 6, the pulse 14 is generated at the time when the wavelength is λ3 in the upper graph, and the next pulse 14 is generated at the time when the wavelength is λ6.

Pulse measurement can be appropriately performed at a site where the pulse of a living body can be detected. However, when the pulse is measured near the measurement site of the light receiver output, the pulse signal measurement time is used as it is for sweep synchronization of the light source wavelength. However, if the pulse signal measurement part is performed at a part far from the receiver output measurement part, the pulse signal generation time at the pulse signal measurement part and the pulse generation time at the receiver output measurement part are shifted. If there is, the measurement accuracy is measured by measuring the deviation amount in advance, correcting the actual pulse generation time to the pulse generation time at the measurement site of the receiver output, and performing sweep synchronization of the light source wavelength. Can be increased.

Here, the larger and smaller losses when passing through the left and right circularly polarized light are defined as C (M) and C (m), respectively, and the attenuation amounts of C (M) and C (m) are expressed as α ( M) and α (m). When defined in this way, reference numerals 11-1 and 11-2 in FIGS. 4, 5, and 6 correspond to C (m), and reference numerals 12, 12-1, and 12-2 correspond to C (M).

Here, if the pulse rate N (p) per second is measured and set to the wavelength change rate of the light source given by equation (5), the polarization period and pulse of the PMF output as shown in FIGS. Can be synchronized. In FIG. 5, when the light source wavelength on the horizontal axis is swept so as to change the polarization of the PMF so that the wavelength λ1 corresponds to the first pulse 14 and the wavelength λ5 corresponds to the next pulse 14, the receiver output is measured. The graph of FIG. 5 can be obtained. Similarly, in FIG. 6, the light source wavelength on the horizontal axis is swept so as to change the polarization of the PMF so that the wavelength λ 3 corresponds to the first pulse 14 and the wavelength λ 6 corresponds to the next pulse 14. Is measured, the graph of FIG. 6 can be obtained. In FIG. 5, when the blood vessel expands, it corresponds to C (m), and when the blood vessel contracts, it corresponds to C (M). In FIG. 6, contrary to FIG. 5, when the blood vessel expands, it corresponds to C (M), and when the blood vessel contracts, it corresponds to C (m).

In order to obtain data as shown in FIGS. 5 and 6, the wavelength of the light source is a wavelength that does not affect the difference in attenuation due to the circular dichroism of the living body, that is, reference numeral 13-1 (λ2) in FIGS. Alternatively, the wavelength of 13-2 (λ4) is set, and the position of the output end of the PMF 2 is finely adjusted in the plane perpendicular to the beam (X and Y directions), and the folds of the base of the living body, here, the thumb and the index finger The signal light beam is incident on the blood vessel of the part and transmitted. That is, the position of the output end of the PMF 2 is determined at a position where the output of the light receiver changes in synchronization with the pulse.

Here, when the inner diameters when the blood vessel is expanded and contracted are D (M) and D (m), respectively, the transmission loss due to the signal light corresponding to P (M) in FIG. The transmission loss due to the signal light corresponding to P (m) passing through the blood vessel in (m) D (M) corresponds to α (M) D (m). Further, the transmission loss due to transmission of the signal light corresponding to P ′ (M) in FIG. 6 through the blood vessel is α (m) D (m), and the signal light corresponding to P ′ (m) is transmitted through the blood vessel. The transmission loss due to corresponds to α (M) D (M). The difference between P (M) and P ′ (m) is proportional to D (M) (α (M) −α (m)). Similarly, the difference between P ′ (M) and P (m) is proportional to D (m) (α (M) −α (m)). Taking these differences, data proportional to (α (M) −α (m)) (D (M) −D (m)) can be measured.

Here, (D (M) −D (m)) is a difference in the inner diameter of the blood vessel at the time of dilatation and contraction of the blood vessel, so there are individual differences, but it is constant for the same subject. Further, (α (M) −α (m)) is circular dichroism. Accordingly, the circular dichroism and the blood vessel contraction when the blood vessel is expanded in two cases, when the sweep is started from the wavelength λ1 in synchronization with the pulse (FIG. 5) and when the sweep is started from the wavelength λ3 (FIG. 6). By measuring the circular dichroism at this time, an amount proportional to the circular dichroism near the wavelength of 182 nm can be measured.

Here, there is a method in which left and right circularly polarized light is incident on a living body, and there is a method in which a wave plate is placed on the output side of the polarization preserving fiber 2 and rotated. However, in this method, the angle of incident light slightly changes. This becomes an error in detecting a minute difference in the attenuation amount of left and right circularly polarized light. In this regard, in the present invention, the optical system at the tip of the incident optical fiber is fixed.

The reflective biological circular dichroism measuring device of FIG. 3 as another embodiment according to the present invention is configured to detect reflected light from a biological body as described above. In general, left and right circularly polarized light are reversed by transmission and reflection, so that they are generally canceled out so that circular dichroism cannot be observed. However, since the scattering in the living body is not uniform, circular dichroism can be observed although it is slight. Since the reflection type biological circular dichroism measuring device only needs to irradiate the skin with laser light, the sensor can be easily mounted and used.

The result of repeating measurement by determining the measurement site of the subject using the biological circular dichroism measuring apparatus of the present embodiment as described above and the blood glucose level by the conventional blood sampling method are compared, and the circle 2 A non-invasive blood glucose level using the measurement method according to the embodiment of the present invention by creating a calibration table based on the comparison between the measurement value obtained by the color measuring device and the blood glucose level measured by the conventional blood sampling method A measuring device was realized. Using the circular dichroism measurement method, a non-invasive blood sugar level measurement system was constructed, and the blood sugar level of the living body could be estimated.

FIG. 7 is a basic configuration diagram of a biological circular dichroism measuring apparatus according to an embodiment of the present invention. The light source 101 is a broadband light source covering the vicinity of 182 nm where the circular dichroism of glucose peaks. A deuterium lamp or a light-excited incoherent light source. For example, there is a laser-excited broadband light source that was commercialized by Energygetq in 2010. The diffused light emitted from the broadband light source 101 is collimated by the lens 102-1 and connected to the PMF 107 via the grating 103 and the polarizer 104 and the lens 102-2 via the polarization plane preserving coupler 105 and the 45-degree splicing 106. . Note that a broadband light source such as a mercury lamp may be used as a light source, and a predetermined wavelength component may be cut out by a spectroscope and incident on the PMF.

The output light of the PMF 107 is irradiated to the living body 108 as the specimen by the lens 102-3, and the output from the specimen 108 is condensed on the light receiver 110-1 through the lens 102-104 and the light receiving optical fiber 109. The electrical output from the light receiver 110-1 is input to a signal processing circuit (microcomputer) 111. A pulse detection device 112 is attached to the specimen 108, and an electrical output from the pulse detection device 112 is input to the signal processing circuit 111. The electrical signal tapped by the coupler 105 and detected by the light receiver 110-2 is input to the signal processing circuit 111. The signal processing circuit 111 drives the optical fiber telescopic device 113 attached to the PMF 107 by a signal synchronized with the pulse. Reference numeral 123 denotes an optical fiber expansion / contraction control signal issued from the optical fiber expansion / contraction device 113. The above is the optical system necessary for the circular dichroism measurement method as an embodiment of the present invention.

Here, a lotion prism was used as the polarizer 104. As the PMF, an elliptical jacket type of a silica core fluorine-doped clad having NA = 0.05, a clad diameter of 30 μm, and a coating outer diameter of 150 μm was used. The core diameter was 2.5 μm. The transmission loss near 182 nm was 20,000 dB / km, that is, 20 dB / m. In the experiment, an optical fiber having a length of 20 cm was wound around a telescopic device 113 made of cylindrical PZT. A grating with a resolution of about 0.02 nm was used. For the light receiver, an electronically cooled APD (avalanche photodiode) covering the light source wavelength is used, but a photomultiplier tube can also be used. In addition, the polarizer can be an optical fiber type. By doing so, the apparatus can be further miniaturized and the cost can be further reduced.

FIG. 8 is a block diagram of a living body circular dichroism measuring apparatus without a light receiving fiber as another embodiment according to the present invention. FIG. 9 is a configuration diagram of a biological circular dichroism measuring apparatus using an optical fiber bundle as another embodiment according to the present invention. In these apparatus configurations, the light emitted from the specimen 108 is detected directly by the light receiver 110-1 without using the light receiving fiber 109 of FIG. 7 (FIG. 8) and when detected using the optical fiber bundle 114 (FIG. 8). 9), and basically the same principle as that of FIG. In the case of FIG. 7, the same type of PMF as the excitation fiber 107 is used for the light receiving fiber 109. In this case, however, it is possible to receive relatively paraxial light rays while avoiding multiple scattered light in the living body, and aim the blood vessel. There is a merit that it is easy to match. In the case of a bundle optical fiber, a 7-core silica-based multimode optical fiber having a core / clad diameter of 200/220 μm was used.

FIG. 10 is a configuration diagram of a reflection type example of a biological circular dichroism measuring apparatus as still another embodiment according to the present invention. In the example of FIG. 10, the diffused light emitted from the light source 101 is collimated by the lens 102-1 on the input side of the living body 108, and the polarization plane preserving coupler 105 is obtained by the lens 102-2 via the grating 103 and the polarizer 104. The optical fiber expansion / contraction device 113 connected to the PMF 107 via the 45-degree splicing 106 and attached to the PMF 107 is driven by a signal synchronized with the pulse by the signal processing circuit 111, and the polarization state of the output light of the PMF 107 is as described later. The right circularly polarized light and the left circularly polarized light are periodically repeated, and the output light of the PMF 107 is irradiated to the living body 108 as the specimen through the lens 102-3, and is tapped by the coupler 105 and detected by the light receiver 110-2. The inputted electric signal is input to the signal processing circuit 111 as in the case of FIG. On the input side of the living body 108, the reflected light from the living body 108 is collected on the light receiver 110-1 through the optical fiber bundle 114 and the lens 102-4, and the electrical output is input to the signal processing circuit 111.

FIG. 11 is experimental data of the insertion loss of the opposed optical fiber collimator that sandwiches the living body as back data of the present invention. The output light of the optical fiber 107 is collected by the lens 102-3 and received by the lens 102-4 through the living body. This is an experimental value of the relationship between the total insertion loss and the distance between the lenses 102-3 and 102-4 when the optical fiber 109 receives light. The wavelength used in the experiment was 1064 nm for reference. In FIG. 11, reference numeral 115 is data when using a PM980 manufactured by Nufern, a core diameter of 8 μm, and a polarization-preserving (PM) optical fiber with NA = 0.14. Reference numeral 116 is data when a multimode fiber having a core diameter of 50 μm is used. Reference numeral 117 denotes data of measurement results showing the relationship between the insertion loss (vertical axis, unit dB) and the inter-lens distance (horizontal axis, unit mm) in the case of a low NA (˜0.075) double clad PMF.

Here, the transmitting and receiving fibers are of the same type. In all experiments, the insertion loss was smaller when the tip of the optical fiber deviated from the focus of the lens, that is, when it was defocused. The light scattered in the living body is incident on the light receiving fiber at an angle. In this case, it is considered that the defocusing in advance has a smaller beam angle dependency of the coupling loss to the light receiving fiber. Moreover, if defocusing is performed, the beam diameter in the living body is reduced, and the influence of scattering of the living body is reduced.

FIG. 11 shows that the smaller the NA of the fiber, the smaller the insertion loss, and even when the distance between the lenses is increased, the loss is small. In addition, so-called TEC (Thermally diffused Expanded Core), which was expanded about 3 times by heating the core, had almost the same characteristics as a fiber having a core diameter of double clad PMF117 of 30 μm.

Based on this data, in the embodiment according to the present invention, a PMF of NA to 0.05 for a wavelength of 180 nm was used. As a result of detailed examination of the NA of the PMF used by this inventor by the present inventor, it was found that NA of 0.07 or less is preferable, and NA of 0.05 or less is particularly preferable. Even with PMF having a core NA of 0.1 or more, if the TEC processing is performed, the core at the tip is enlarged and the NA is reduced at the same time, so that the present embodiment can be applied.

Since the core diameter of the single-mode fiber having a wavelength of 180 nm is smaller than that of the infrared single-mode fiber, light from the light source can be efficiently coupled by TEC processing both ends of the polarization-preserving fiber. .
By making the core diameter of the TEC treatment more than twice the core diameter of the original optical fiber, a great effect is exhibited.

If there is a margin in the light-receiving S / N ratio of the measurement system, the accuracy of the embodiment is sufficiently practical with the configuration of the present embodiment even if the end face of the optical fiber is arranged at the focal position of the lens. Such a configuration is also included in the present invention.

In addition, by adopting a configuration in which the lens is integrally fixed with the optical fiber at or near the end face of the optical fiber, it is possible to realize a small and inexpensive example apparatus of the present embodiment with little variation in measurement. it can.

7 to 9, when the length of the PMF 107 is changed, the polarization state of the emitted light repeats right circular polarization and left circular polarization at a cycle determined by the beat length B of the PMF 107. When the length of the PMF 107 is changed by the length ΔL at time T (seconds), the polarization state change frequency f is expressed by the following equation (6).
[Equation 10]
f = ΔL / BT (6)
Here, in order to make this cycle equal to the pulse N (p) / second, the time change of the length may be controlled to an amount determined by the following equation.

[Equation 11]
ΔL / T = BN (p) (7)
When B = 0.35 mm and N (p) = 1, the rate of change of the length of the PMF 107 is 0.35 mm / second.
In the experiment, a PMF with a length of 200 mm was used, so that it was sufficient to expand and contract at a rate of 0.175% per second.

12 and 13 are conceptual diagrams for explaining the relationship between the light receiver output, the incident-side polarization plane preserving optical fiber length to the specimen 108, and the pulse signal as an embodiment according to the present invention. 12 and 13, the vertical axis represents the output of the light receiver, the horizontal axis represents the length of the polarization-maintaining optical fiber on the incident side with respect to the specimen 108, the vertical axis in the figure shown below represents the pulse signal intensity, and the horizontal axis represents the pulse signal light. This is the position (timing) corresponding to the fiber length. When the wavelength of the light source is fixed to around 182 nm and the length of the PMF 107 is changed, the optical power of the light receiver changes as shown in FIGS. As described above, the period is about 0.35 mm. That is, L3-L1 = 0.35 mm and L4-L2 = 0.35 mm in FIGS.

12 and 13, reference numerals 118-1 and 118-2 are points at which the light receiver output has a minimum value P (m) when the right (or left) circularly polarized light is incident on the graph, and reference numerals 119-1 and 119. -2 is a point where the light receiver output at the left (or right) circularly polarized light is at the maximum value P (M), and reference numerals 120-1 and 120-2 are the light receiver outputs at the linearly polarized light incident at the intermediate value P ( Point 0) is shown.

In the upper graphs in FIGS. 12 and 13, that is, the optical receiver output graph, when the optical fiber length is changed, the optical receiver output becomes the minimum value P (m) at the optical fiber length L1 (position 118-1). ), An intermediate value P (0) between the optical fiber lengths L1 and L2 (position 120-1), and a maximum value P (M) at the optical fiber length L2 (position 119-1). The optical fiber length L3 becomes the minimum value P (m) (position of reference numeral 118-2), and becomes the median value P (0) between the optical fiber lengths L3 and L4 (position of reference numeral 120-2). The change is such that the maximum value P (M) is reached at the length L4 (the position indicated by reference numeral 119-1). In the lower graph of FIG. 12, the pulse 121 is generated at the time when the optical fiber length is L1 in the upper graph, and the next pulse 121 is generated at the time when the optical fiber length is L3. In the lower graph of FIG. 13, the pulse 121 occurs at the time when the optical fiber length is L2 in the upper graph, and the next pulse 121 occurs at the time when the optical fiber length is L4.

In FIG. 12 and FIG. 13, the larger and smaller losses when passing through the left and right circularly polarized blood vessels are defined as C (M) and C (m), respectively, and attenuation amounts of C (M) and C (m) are defined. Are α (M) and α (m), respectively. When defined in this way, reference numerals 118-1 and 118-2 in FIGS. 12 and 13 correspond to C (M), and 119-1 and 119-2 correspond to C (m).

Here, if the pulse rate N (p) per second is measured and the expansion / contraction rate of the optical fiber is set to be given by the equation (7), the polarization period of the output of the PMF and the period shown in FIGS. The pulse can be synchronized. In FIG. 12, when the blood vessel expands, it corresponds to C (M), and when the blood vessel contracts, it corresponds to C (m). In FIG. 13, in contrast to FIG. 12, when the blood vessel expands, it corresponds to C (m), and when the blood vessel contracts, it corresponds to C (M).

In order to obtain data as shown in FIGS. 12 and 13, the length of the PMF is the optical fiber length that does not affect the difference in attenuation due to the circular dichroism of the living body, that is, 120-1 in FIGS. Alternatively, it is set to 120-2, and the position of the output end of the PMF 107 is finely adjusted in a plane (X and Y directions) orthogonal to the beam, and the beam is applied to the blood vessel of the living body, here, the fold of the base of the thumb and index finger. It was made to permeate. That is, the position of the output end of the PMF 107 was determined at a position where the output of the light receiver changes in synchronization with the pulse.

Here, when the inner diameters when the blood vessel is expanded and contracted are D (M) and D (m), respectively, the transmission loss due to the transmission of the signal light corresponding to P (M) in FIG. The transmission loss due to the signal light corresponding to P (m) passing through the blood vessel in (m) D (m) corresponds to α (M) D (M).

Further, transmission loss due to transmission of signal light corresponding to P (M) in FIG. 13 through the blood vessel is α (m) D (M), and transmission due to transmission of signal light corresponding to P (m) through the blood vessel. The loss corresponds to α (M) D (m).

The difference between P (M) in FIG. 12 and P (m) in FIG. 13 is proportional to D (m) (α (M) −α (m)). Similarly, the difference between P (M) in FIG. 13 and P (m) in FIG. 12 is proportional to D (M) (α (M) −α (m)). Taking these differences, data proportional to (α (M) −α (m)) (D (M) −D (m)) can be measured.

Here, (D (M) −D (m)) is a difference in the inner diameter of the blood vessel when the blood vessel is expanded and contracted, so there is an individual difference, but it is constant in the same subject. Further, (α (M) −α (m)) is circular dichroism. Accordingly, when the optical fiber length starts to sweep from L1 in synchronization with the pulse (FIG. 12) and when the optical fiber length starts to sweep from L2 (FIG. 13), the circle when the blood vessel expands is shown. By measuring the dichroism and the circular dichroism when the blood vessel contracts, an amount proportional to the circular dichroism near the wavelength of 182 nm can be measured.

FIG. 10 is a configuration diagram of a reflection type example of the biological circular dichroism measuring apparatus as an embodiment of the invention according to the present invention, and is configured to detect reflected light from the biological body. As described above, since the left and right circularly polarized light are generally reversed by transmission and reflection, they are generally canceled out and the circular dichroism cannot be observed. However, even in the case of the present embodiment, since the scattering in the living body is not uniform, the circular dichroism can be observed slightly. Since the reflection type biological circular dichroism measuring device only needs to irradiate the skin with laser light, the sensor can be easily mounted and used.

The optical system on the side of light incident on the living body 108 in the embodiment shown in FIGS. 7 to 10 is provided with a spatial light path corresponding to the focal length of the lens between the optical fiber 107 and the lens 102-3 as in the prior art. Unlike the idea of an optical system in which a spatial light path is also provided between the living body 108 and the living body 108, the optical fiber 107 is disposed at a position closer to the lens than the focal position of the lens 102-3.

Furthermore, the spatial optical path between the lens and the living body 108 is not essential, and by making the optical system defined as an all-optical fiber type, for example, by closely contacting the end of the incident optical system with the fold of the finger, the circle 2 The chromaticity measurement accuracy can be greatly increased.

Further, as in the examples of FIGS. 7, 8, 9, and 10, the all-optical fiber type absorption measurement optical system of the present embodiment is configured so that the light receiving side is also an optical fiber, and the specimen 108 is sandwiched in the optical path, so that the measurement accuracy is achieved. And usability can be improved.
In addition, when a refractive index matching agent was applied to the skin or a refractive index matching sheet was applied, the biological transmission loss was improved by about 3 dB.

Next, the necessary conditions for the resolution of the grating 103 shown in FIGS. 7 to 10 will be described. The beat length of the PMF 107 used in the embodiment is 0.35 mm at a wavelength of 182 nm. Accordingly, when propagating 500 mm, the optical path difference in the orthogonal polarization mode is ˜0.26 mm at (500 / 0.35) × 182 nm. Therefore, the coherence length of the light source needs to be sufficiently longer than 0.26 mm in order to ensure the degree of polarization at the emission end of the PM 107. When the coherence length of the light source is 0.26 mm, the wavelength width of the light source is about 0.12 nm. Therefore, in the embodiment of the present invention, the resolution of the grating 103 is set to 0.02 nm with a sufficient margin.

In the present embodiment, the polarization plane preserving optical fiber length is changed in synchronization with the pulse so that the polarization state of the output light of the PMF that irradiates the living body with the signal light changes periodically in the left and right circular polarization state. In another embodiment, the blood glucose level is determined by comparing the circular dichroism when the blood sample is removed while strongly suppressing the specimen portion of the living body and the circular dichroism when the blood flow is present while suppressing the blood flow gently. Could be estimated. Furthermore, in another embodiment, instead of synchronizing with the pulse, an external signal as an electrical and / or mechanical trigger signal is given to the specimen and used as a trigger signal instead of the pulse for measurement. The blood glucose level could be estimated.

Conventionally, a circular dichroism measurement technique has already been known, but it has never been expected that a human blood glucose level can be estimated using a circular dichroism measurement technique. However, as described above, according to the present embodiment, the optical system is devised, the wavelength of the light source is selected, that is, the wavelength in the region where the circular dichroism of the specimen is maximized, the use of the pulse, etc. As a result of the improvement, it was possible to realize glucose measurement with high accuracy capable of sufficiently estimating human blood glucose levels.

Calibration based on the result of repeating the measurement by determining the measurement site of the subject using the circular dichroism measuring device of the living body of the present embodiment and the result of repeating the measurement of the blood glucose level by the conventional blood sampling method By creating the table, the blood glucose level can be estimated non-invasively by referring to the calibration table based on the measurement result of the present embodiment.

That is, from the above description, it is possible to configure a living body non-invasive blood sugar level measuring device and a non-invasive blood sugar level measuring method using a living body circular dichroism measurement example as an embodiment of the present invention. Obviously.

In this embodiment, the temperature detection component is incorporated into a component that sandwiches the measurement position for circular dichroism measurement or contacts the measurement position in the optical path of the signal light, thereby improving the reliability of the measurement result. be able to. The temperature detection circuit or the temperature display means may be provided on a part that sandwiches the measurement position or contacts the measurement position for the circular dichroism measurement, or may be provided on the apparatus main body.

Further, in the present embodiment, a Peltier element as a temperature control element is incorporated in a component that sandwiches a measurement position for circular dichroism measurement or contacts the measurement position in the optical path of the signal light, By controlling the temperature of the specimen, the reliability of the measurement result can be increased. In this case, conventionally used temperature control means can be widely used. The temperature control circuit or the temperature control means may be provided on a part that sandwiches the measurement position or contacts the measurement position for the circular dichroism measurement, or may be provided on the apparatus main body.

Although the present embodiment has been described with some examples, the present invention is not limited to the above examples, and many variations are possible according to the technical idea of the present invention. Is.

As described above, according to the living body circular dichroism measuring device and method and the non-invasive blood sugar level measuring device and method of the present embodiment, the blood glucose concentration related to the blood sugar level can be measured without blood collection. .

According to the embodiment described above, for example, the following five effects can be expected. That is, first, it is freed from the annoyance and pain associated with blood collection with a needle. Secondly, the disposal of the blood collection needle is unnecessary and it is hygienic. Thirdly, since a reagent that reacts with glucose used at the time of blood collection is unnecessary, a running cost of, for example, 100,000 yen or more per year is unnecessary in Japan, which is economical.

Fourth, since it is easy to measure and the running cost can be kept low, blood glucose level monitoring (blood glucose level measurement) can be performed as many times a day as possible. It can provide easy-to-use items for health management. Fifth, it is possible to exert significant effects such as the medical expenses borne by the medical treatment country can be significantly reduced. Then, if the biological circular dichroism measuring device and the non-invasive blood sugar level measuring device of the present embodiment are used in a general household, the cost required for the treatment can be greatly reduced. It can also reduce the number of diabetic patients that are increasing.

In particular, if the biological circular dichroism measuring device and the non-invasive blood sugar level measuring device of the present embodiment are used in general households, the number of diabetic patients that are increasing worldwide can be reduced. Costs required for treatment can be greatly reduced. The present invention is also used for high-accuracy measurement of collected blood, and has a great effect in terms of measurement efficiency and cost as compared with conventional chemical methods.

As described above, according to the present invention, blood glucose level can be measured in a non-invasive manner, which has been considered impossible to realize. As a result, diabetic patients are freed from the pain and annoyance of blood sampling several times a day.

In addition, by utilizing the non-invasive blood sugar level measuring apparatus and / or method of the present invention for preventive maintenance of diabetes, it is possible to significantly reduce the number of diabetic patients that are currently increasing worldwide, and to treat it. Subject costs and public costs can be significantly reduced.

The non-invasive blood sugar level measuring apparatus and measuring method according to the present invention can be widely used as medical equipment, health equipment, etc., and the present invention can greatly contribute to the development of medical equipment, health equipment fields including nursing care. It can be done.

1: Tunable light source 2,107: Polarization plane maintaining optical fiber (PMF)
3, 6, 102-1, 102-2, 102-3, 102-4: Lens 4, 108: Sample (living body)
5, 114: Multimode optical fiber bundle 7, 110-1, 110-2: Light receiver 8, 111: Signal processing circuit 9: Pulse sensor 10: Light source drive controller 11-1, 11-2: Right (left) Receiver output maximum value for circularly polarized light input 12, 12-1, 12-2: Left (right) receiver output minimum value for circularly polarized light input 13-1, 13-2: Linearly polarized light input Light receiver output intermediate values 14, 121, 122: Pulse signal 101: Fixed wavelength light source 103: Grating 104: Polarizing plate 105: Fiber coupler 106: Splicing 45 degrees 109: Optical fiber for light reception 112: Pulse detection circuit 113: Optical fiber expansion / contraction Control unit 115: Data for PM980 116: Data for multimode fiber 117: Data for low NA double clad 118-1,1 8-2: high loss circle data in the case of the polarization 119-1 and 119-2: the data in the case of low-loss circular polarization 120-1, 120-2: output for the linear polarization 123: optical fiber stretch signal

Claims (25)

1. The polarization plane of the linearly polarized laser light whose emission wavelength from the light source is in a region where the circular dichroism of the specimen is maximized and which changes continuously or discretely in synchronization with an external trigger is limited to the direction of polarization. The incident light enters the storage optical fiber (PMF), and the output light from the polarization plane storage optical fiber (PMF) is irradiated to the living body as signal light so that the polarization state periodically changes between left circular polarization and right circular polarization. And measuring the wavelength characteristic of the received light intensity by receiving the transmitted light and / or reflected light with a light receiver, and measuring the circular dichroism of a living body.
2. The method for measuring circular dichroism of a living body according to claim 1,
   The direction of the polarization is set to 45 degrees with respect to the intrinsic polarization axis of the polarization-maintaining optical fiber (PMF), the length of the PMF is L (mm), and the wavelength of the light source is changed with time T (seconds). When the change amount is Λ (nm), the light source wavelength is λ (nm), and the beat length of the PMF is B (mm), the period of the polarization state of the light emitted from the PMF is synchronized with the pulse. A method for measuring circular dichroism of a living body, comprising a step of changing the wavelength change rate Λ / T (nm / second) of the light source so as to be calculated by the following equation (4).
   (Equation 12)
   Λ / T = N (p) λB / 2L (4)
3. The light from the light source whose wavelength is in the region where the circular dichroism of the specimen is maximum is narrowed by a grating, linearly polarized by a polarizer, and the direction of polarization is limited to a polarization-maintaining optical fiber (PMF). Increasing the length of the PMF continuously or discretely in synchronization with an incident step and an external trigger so that the polarization state of the output light from the PMF periodically changes between left circularly polarized light and right circularly polarized light A step of irradiating a living body as a specimen with the output light from the PMF, a transmitted light of the living body or a reflected light from the living body, or a TEC (Thermally Diffused Expanded Core) treatment directly or on the core Receiving light with a light receiver via a single mode optical fiber or a multimode optical fiber or a multimode optical fiber bundle; Circular dichroism measuring method of biological characterized by having a step of measuring the relationship between the optical fiber length of the light-receiving intensity of.
4. The biological circular dichroism measurement method according to claim 3,
   In the optical system in which the narrow spectrum and linearly polarized laser light is incident at an orientation of 45 degrees with respect to the intrinsic polarization axis of the PMF, and the living body is irradiated with the output light.
   When the beat length of the PMF is B and the pulse rate / second is N (p), the temporal change rate ΔL / T (mm / second) of the optical fiber length of the telescopic device attached to the PMF is expressed by the following (7 The method of measuring circular dichroism of a living body, comprising a step of changing the measurement so as to be calculated by the formula.
   [Equation 13]
   ΔL / T = N (p) B (7)
5. The method for measuring circular dichroism of a living body according to any one of claims 1 to 4,
   The laser light emitted from the light source is set to a value at which the light emitted from the PMF becomes a linearly polarized state with a 45-degree azimuth, and the change in optical power received by the light receiver is synchronized with the pulse so that the PMF is applied to the living body. A method for measuring circular dichroism of a living body, wherein the incident position is adjusted.
6. The biological dichroism measurement method for a living body according to any one of claims 1 to 5,
   A biological circle comprising a measuring step of receiving the transmitted light or reflected light directly or via a multimode optical fiber or a multimode optical fiber bundle with a light receiver and measuring the wavelength characteristic of the received light intensity. Dichroism measurement method.
7. The biological circular dichroism measurement method according to any one of claims 1 to 6,
   The larger and smaller losses of left and right circularly polarized light are defined as C (M) and C (m), respectively, and the attenuation amounts of C (M) and C (m) are α (M) and α (m), respectively. When measuring the wavelength characteristics of the optical power received by the light receiver for the two conditions of when the blood vessel is dilated and synchronized with C (M) and when synchronized with C (m), the calculation is performed. And measuring the amount proportional to (α (M) −α (m)) by the method for measuring circular dichroism of a living body.
8. The biological circular dichroism measuring method according to any one of claims 1 to 7,
   A method for measuring a circular dichroism of a living body, comprising the step of setting the emitting end of the PMF closer to the lens than the focal point of the lens when the emitted light of the PMF is coupled to the living body with a lens.
9. The biological circular dichroism measurement method according to any one of claims 1 to 8,
   A method for measuring circular dichroism of a living body, wherein both ends of the PMF are subjected to TEC (Thermally Diffused Expanded Core) processing, and the core diameter is expanded to more than twice the core diameter of the original PMF.
10. The biological circular dichroism measuring method according to any one of claims 1 to 9,
    The method of measuring circular dichroism of a living body, wherein the PMF is an elliptical jacket type fiber having a pure quartz core and a fluorine-doped cladding.
11. Using the biological circular dichroism measurement method according to any one of claims 1 to 10,
    The larger and smaller losses of left and right circularly polarized light measured for the subject are defined as C (M) and C (m), respectively, and the attenuation amounts of C (M) and C (m) are respectively α (M). , Α (m), the wavelength of the optical power received by the light receiver in the case of two conditions when the blood vessel is dilated is synchronized with C (M) and when synchronized with C (m) A non-invasive blood sugar level measuring method comprising a step of measuring a characteristic and estimating a blood sugar level of the subject from an amount proportional to (α (M) −α (m)) by calculation.
12. 12. The non-invasive blood sugar level measuring method according to claim 11, wherein an amount proportional to (α (M) −α (m)) measured for the subject and the subject's pre-existing blood sampling method are used. A step of preparing a correlation table with blood glucose level and estimating the blood glucose level of the subject from an amount proportional to the measured (α (M) −α (m)) is provided. Invasive blood glucose level measurement method.
13. The polarization plane of the linearly polarized laser light whose emission wavelength from the light source is in a region where the circular dichroism of the specimen is maximized and which changes continuously or discretely in synchronization with an external trigger is limited to the direction of polarization. Means for injecting into a storage optical fiber (PMF), means for irradiating the living body as signal light so that the polarization state of the output light from the PMF periodically changes between left circular polarization and right circular polarization, and An apparatus for measuring circular dichroism of a living body, comprising: means for receiving transmitted light and / or reflected light with a light receiver; and means for measuring a wavelength characteristic of the received light intensity.
14. The biological circular dichroism measuring device according to claim 13,
    The direction of the polarization is set to 45 degrees with respect to the intrinsic polarization axis of the polarization-maintaining optical fiber (PMF), the length of the PMF is L (mm), and the wavelength of the light source is changed with time T (seconds). When the change amount is Λ (nm), the light source wavelength is λ (nm), and the beat length of the PMF is B (mm), the period of the polarization state of the light emitted from the PMF is synchronized with the pulse. An apparatus for measuring circular dichroism of a living body, characterized by comprising means for changing the wavelength change rate Λ / T (nm / second) of the light source as calculated by the following equation (4).
    [Formula 14]
    Λ / T = N (p) λB / 2L (4)
15. Light from the light source in the region where the wavelength of the light source has the maximum circular dichroism of the specimen is narrowed by a grating, linearly polarized by a polarizer, and the direction of polarization is limited and incident on a polarization-maintaining optical fiber (PMF). And the length of the PMF is expanded or contracted continuously or discretely in synchronization with an external trigger so that the polarization state of the output light from the PMF periodically changes between left circularly polarized light and right circularly polarized light. Means for irradiating the living body as the specimen with the output light from the PMF, the transmitted light of the living body and / or the reflected light from the living body, or the core is subjected to a TEC (Thermally Diffused Expanded Core) process. Means for receiving light by a light receiver through a single mode optical fiber, a multimode optical fiber or a multimode optical fiber bundle; Circular dichroism measuring apparatus of the living body, characterized in that it comprises means for measuring the relationship between the optical fiber length of the received light intensity.
16. The biological circular dichroism measuring device according to claim 15,
    In the optical system in which the narrow spectrum and linearly polarized laser light is incident at an orientation of 45 degrees with respect to the intrinsic polarization axis of the PMF, and the living body is irradiated with the output light.
    When the beat length of the PMF is B and the pulse rate / second is N (p), the temporal change rate ΔL / T (mm / second) of the optical fiber length of the telescopic device attached to the PMF is expressed by the following (7 ) An apparatus for measuring circular dichroism of a living body, wherein the measurement is performed by changing the calculation so as to be calculated by the equation (1).
    [Equation 15]
    ΔL / T = N (p) B (7)
17. The biological circular dichroism measuring device according to any one of claims 13 to 16,
    The laser light emitted from the light source is set to a value at which the light emitted from the PMF becomes a linearly polarized state with a 45-degree azimuth, and the change in optical power received by the light receiver is synchronized with the pulse so that the PMF is applied to the living body. An apparatus for measuring a circular dichroism of a living body, comprising means for adjusting an incident position.
18. The biological circular dichroism measuring device according to any one of claims 13 to 17,
    The transmitted light or reflected light is received by a light receiver directly or via a multi-mode optical fiber or multi-mode optical fiber bundle whose core is subjected to TEC (core diffused expanded core) processing. An apparatus for measuring circular dichroism of a living body comprising means for measuring wavelength characteristics.
19. The biological circular dichroism measuring device according to any one of claims 13 to 18,
    The larger and smaller losses of left and right circularly polarized light are defined as C (M) and C (m), respectively, and the attenuation amounts of C (M) and C (m) are α (M) and α (m), respectively. When measuring the wavelength characteristics of the optical power received by the light receiver for the two conditions of when the blood vessel is dilated and synchronized with C (M) and when synchronized with C (m), the calculation is performed. An apparatus for measuring circular dichroism of a living body, characterized in that an amount proportional to (α (M) −α (m)) is obtained by:
20. The biological circular dichroism measuring device according to any one of claims 13 to 19,
    An apparatus for measuring circular dichroism of a living body, wherein when the emitted light of the PMF is coupled to a living body with a lens, the emitting end of the PMF is located closer to the lens than the focal point of the lens.
21. The biological circular dichroism measuring device according to any one of claims 13 to 20,
    When the emitted light of the PMF is coupled to a living body with a lens, both ends of the PMF are subjected to TEC (Thermally Diffused Expanded Core) processing, and the core diameter is expanded to more than twice the core diameter of the original PMF. An apparatus for measuring circular dichroism of a living body, characterized by:
22. The biological circular dichroism measuring device according to any one of claims 13 to 21,
    An apparatus for measuring circular dichroism of a living body, wherein the PMF is an elliptical jacket type fiber having a pure quartz core and a fluorine-doped cladding.
23. Using the biological circular dichroism measuring device according to any one of claims 13 to 22,
    In the optical path of the signal light, a Peltier element and / or a temperature detection part as a temperature control element is incorporated into a part that sandwiches the measurement position for circular dichroism measurement or a part that contacts the measurement position. A non-invasive blood sugar level measuring apparatus comprising means for controlling temperature and / or measuring temperature.
24. The non-invasive blood sugar level measuring apparatus according to claim 23,
    The larger and smaller losses of left and right circularly polarized light measured for the subject are defined as C (M) and C (m), respectively, and the attenuation amounts of C (M) and C (m) are respectively α (M). , Α (m), the wavelength of the optical power received by the light receiver when the blood vessel is dilated is synchronized with C (M) and when synchronized with C (m). A non-invasive blood sugar level measuring apparatus comprising means for measuring a characteristic and estimating a blood sugar level of the subject from an amount proportional to (α (M) −α (m)) by calculation.
25. The non-invasive blood sugar level measuring apparatus according to claim 23 or claim 24,
    The larger and smaller losses of left and right circularly polarized light measured for the subject are defined as C (M) and C (m), respectively, and the attenuation amounts of C (M) and C (m) are respectively α (M). , Α (m), the wavelength of the optical power received by the light receiver in the case of two conditions when the blood vessel is dilated is synchronized with C (M) and when synchronized with C (m) Measure the characteristics, create a correlation table between the amount proportional to (α (M) -α (m)) and the blood glucose level measured by the subject's existing blood sampling method in advance by measurement A non-invasive blood sugar level measuring apparatus comprising means for estimating a blood sugar level of the subject from an amount proportional to (α (M) −α (m)).

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