JP2017140159A - Non-invasive blood glucose level measuring method using infrared spectroscopy - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a non-invasive blood glucose level measuring method using infrared spectroscopy capable of measuring accurately a blood glucose level with little load on a subject without blood sampling.SOLUTION: In a non-invasive blood glucose level measuring method using infrared spectroscopy, a measuring method using an optical fiber and a multiplex reflection prism is provided, and an absorption spectrum including a wavenumber range of 990-1,150 cmin which an absorption peak group of glucose appears is measured, and a blood glucose level is measured based on an integral value of absorption intensity in the wavenumber range.SELECTED DRAWING: Figure 8

Description

  The present invention relates to a blood glucose level measurement method, and more particularly to a method for measuring an absorption spectrum of glucose in blood or body fluid using infrared spectroscopy and measuring the blood glucose level based on the result.

  As a technique for non-invasively measuring blood glucose levels, research has been conducted on measurement methods using near-infrared light having a wavelength of about 800-1500 nm. Because light in this wavelength range is not easily absorbed by water, it penetrates deep into the human body. Therefore, it is suitable for non-invasive measurement of the state of the body by irradiating light to the human body, and for optical communications. It is possible to construct a system that uses inexpensive semiconductor lasers and photodetectors, and some blood glucose measuring devices have been commercialized. However, the decisive thing that spreads to the market has not been realized. The main reason for this is that the absorption of blood sugar (glucose) in the near-infrared region is so weak that there are problems with its detection accuracy and reproducibility. The fundamental wave of the absorption peak caused by the molecular vibration of glucose exists in the mid-infrared region with a wavelength of about 10 microns, and its absorption is very weak because it appears in the near-infrared region as its 8-10th harmonic vibration. It becomes. Furthermore, in this region, there are many absorption peaks of substances constituting the living body such as water, hemoglobin, and protein, and it is extremely difficult to detect only glucose.

Therefore, a non-invasive system for measuring blood glucose level with high accuracy by detecting the fundamental vibration peak of glucose in the mid-infrared region has been proposed. This is a combination of a Fourier infrared spectrometer and an attenuated total reflection prism (hereinafter referred to as ATR prism), which irradiates infrared light from the body surface and measures the glucose concentration in body fluids or blood.
JP 2014-18478 A Table 2006/011487

For the method of measuring blood glucose level based on the glucose absorption peak intensity existing in the mid-infrared region, sufficient measurement accuracy has not been obtained so far. One reason for this is: Since mid-infrared light is absorbed on the very surface of the body tissue, the detected glucose absorption intensity is small, and the wave number 1080 cm ⁻¹ or 1035 cm ⁻ , which is large and relatively easy to detect among the absorption peak groups of glucose. ^This is because the blood glucose level was measured based on the intensity of the absorption peak near ¹ . These peaks are attributed to the binding energy between CH or C-OH elements of glucose molecules in aqueous solution. However, C-H and C contained in components taken from phosphoric acid and food in body fluids. Absorption occurs in the vicinity of the above wave number even with the structure of C-OH, which becomes a disturbance and the measurement accuracy decreases.

  The present invention has been devised in order to solve the above-mentioned problems of the conventional non-invasive blood glucose level measurement method using infrared spectroscopy, and can accurately measure the blood glucose level non-invasively. Therefore, the purpose of this study is to realize a blood glucose level measurement method that enables diagnosis with less burden on the subject without blood collection.

  In order to solve the above problems, a noninvasive blood glucose level measurement method using infrared spectroscopy provides a method for measuring blood glucose level using an optical fiber and a multiple reflection prism connected to the optical fiber.

  The blood glucose level measuring method may be characterized in that the optical fiber is a hollow optical fiber.

  Further, the blood glucose level measuring method may be characterized in that the multiple reflection prism is made of zinc sulfide.

In the noninvasive blood sugar level measuring method using infrared spectroscopy, an absorption spectrum including the entire wave number range of 990 to 1150 cm ⁻¹ including five different absorption peaks of glucose is measured, and the absorption intensity in the wave number range is measured. The blood glucose level may be measured based on the integral value of.

Further, in the noninvasive blood sugar level measuring method using infrared spectroscopy, the blood sugar level is calculated based on the intensity of the absorption peak of glucose appearing in the wave number range of 1140 to 1170 cm ⁻¹ or the integrated value of the intensity of the absorption peak. It may be a measurement method.

Further, in the noninvasive blood sugar level measurement method using infrared spectroscopy, the blood sugar level is determined based on the intensity of the absorption peak of glucose appearing in the wave number range of 1100 to 1140 cm ⁻¹ or the integrated value of the intensity of the absorption peak. It may be a measurement method.

Further, in the noninvasive blood sugar level measuring method using infrared spectroscopy, the blood sugar level is calculated based on the intensity of the absorption peak of glucose appearing in the wave number range of 1000 to 980 cm ⁻¹ or the integrated value of the intensity of the absorption peak. It may be a measurement method.

  In any one of the blood glucose level measurement methods described above, the blood glucose level measurement method may use a quantum cascade laser as a light source.

  Hereinafter, embodiments of the present invention will be described with reference to the drawings. FIG. 1 is a configuration diagram of a blood sugar level measuring apparatus showing an example of an embodiment of the present invention. The light is collected by the concave mirror 2 emitted from the Fourier infrared spectrometer 1 and introduced into the optical fiber 3. An ATR prism 5 in contact with the target sample 4 is attached to the tip of the optical fiber 3, and the light transmitted through the ATR prism 5 is received by the optical fiber 6 and guided to a detection device including a lens 7 and an infrared detector 8. .

The Fourier infrared spectrometer 1 is preferably one that can measure a wide region having a wave number of 800 to 5000 cm ⁻¹ , but may be a laser light source that generates only light of a specific wave number. In particular, a quantum cascade laser that is relatively small and can provide a large output is suitable as a light source for this measurement device. In that case, any one of the absorption peak groups of glucose appearing in the region of wave numbers 990 to 1150 cm ⁻¹ , or a plurality of wave numbers that match the wave numbers of a plurality of peaks and a wave number that is not affected by the absorption of glucose used as the background It is desirable to use a single laser device that generates a wave number of 1 or multiple laser devices that generate each wave number. A tunable infrared laser that can change the oscillation wavelength is also suitable as the light source of this device.

  Optical fibers 3 and 6 are preferably hollow optical fibers that can transmit infrared light with low loss and are flexible. In addition, broadband light sources used in Fourier infrared spectrometers and the like are difficult to focus on minute points, so the diameter of the hollow optical fiber should be 1 mm or more.

  FIG. 2 is an enlarged view of the ATR prism 5. This prism is an example assuming that it is connected to a hollow optical fiber with a diameter of 2 mm, and reflection occurs nine times in total at the upper and lower bases of the trapezoidal prism. The number of reflections in a normal ATR prism is about 1 to 2 times, but by increasing the number of reflections, it is possible to detect the absorption of the sample contacting the prism with higher sensitivity. The number of times is desirably 5 times or more. In addition, since the trapezoidal prism has a large contact area with the sample, it is possible to minimize fluctuations in the detection value due to changes in the pressing pressure of the prism. By connecting the trapezoidal prism to a flexible optical fiber, it is possible to measure in the shape of the lip. Unlike the skin covered with a thick stratum corneum, the mucous membrane such as the lips has only a very thin stratum corneum, so it is possible to detect glucose in body fluids or blood with higher sensitivity.

Further, the material of the ATR prism 5 is not toxic to the human body and needs to exhibit a high transmittance in the vicinity of a wave number of 1000 cm ^−1, which is the glucose absorption band to be measured. Materials that satisfy these conditions include diamond, germanium, silicon, and zinc sulfide. Of these, diamond or zinc sulfide is the preferred low-refractive index material that has a large light oozing from the prism and can be detected deeper, but a lower-cost zinc sulfide is preferred as the prism material. Unlike zinc selenide, which is commonly used as an infrared material, zinc sulfide has been shown to be non-carcinogenic and is also used in dental materials as a non-toxic dye (lithopon).

FIG. 3 is an infrared absorption spectrum of a glucose aqueous solution gel measured by bringing glucose gel having a concentration of 0 to 1% into contact with the upper and lower bottom surfaces of the multiple reflection type ATR prism. Note The spectra were obtained by the base correction between the 2 wave number of 1175cm ^-1 and 980 cm ^-1 which is both ends of a wave number region present absorption peaks of glucose. In FIG. 3, five absorption peaks of glucose appear in the vicinity of wave numbers 1155, 1100, 1080, 1035, and 990 cm ⁻¹ . Among these, the peaks at 1080 and 1035 cm ⁻¹ are due to the binding energy between the C—OH or C—H elements forming the glucose molecule, and the other peaks are mainly due to glucose in the aqueous solution. This is due to the C—C bond of the pyranose ring structure to be formed. It is confirmed that every peak increases as the concentration increases.

FIG. 4 shows an example of the absorption spectrum of the human lip mucosa measured with the upper and lower surfaces of the ATR prism 5 sandwiched between the lips. 3300 cm ^-1 O over H bond of water in the vicinity, a plurality of absorption peaks due to protein appears in the vicinity of 1150 cm ^-1. Moreover, although it is weak, the absorption peak group of glucose can be seen around 1000 cm- ¹ .

FIG. 5 is an enlarged view of the absorption region of glucose near 1000 cm ^{−1 in} the spectrum shown in FIG. Although absorption peaks near 1035 cm ⁻¹ and 1080 cm ⁻¹ are observed, the peaks do not appear as clearly as the absorption spectrum of the aqueous solution in FIG. This seems to be due to the superposition of absorption peaks caused by components such as phosphate and protein other than glucose contained in the lip mucosa.

  FIG. 6 shows the difference between the absorption spectrum when the blood glucose level rises and the absorption spectrum when fasting (blood glucose level 72 mg / dl) among the absorption spectra measured when the human oral glucose tolerance test was performed. . By taking the difference in absorption spectrum, the influence of tissue absorption such as protein is eliminated, and only the increase in glucose concentration in body fluids or blood appears, and five absorption peaks can be seen like the glucose aqueous solution in FIG. . These peak intensities increase with increasing blood glucose level.

FIG. 7 is a correlation diagram between the peak intensity of 1035 cm ⁻¹ and the blood glucose level measured by blood collection when the difference spectrum is measured in the same manner as in FIG. 6 at various blood glucose levels. Although the blood glucose and peak height correlation is the correlation coefficient R ² is not obtained very good correlation to about 0.6. When the evaluation was performed based on the peak intensity of 1080 cm ⁻¹ , almost the same result was obtained. These peaks are attributed to the binding energy between CH or C-OH elements of glucose molecules in aqueous solution. However, C-H and C contained in components taken from phosphoric acid and food in body fluids. It is thought that absorption is also observed in the vicinity of the above wavenumbers depending on the structure of C-OH, and these become disturbances and the measurement accuracy decreases.

The magnitude of these peak intensity fluctuations is considered to have no correlation between the peaks, so the effect can be suppressed by using the integrated value in the wavenumber range including the glucose absorption peaks. is there. FIG. 8 is a schematic diagram showing a method for obtaining an integral value of a region including a wave number range including a glucose absorption peak group. It performs baseline correction at two points 1170Cm ^-1 wave number 980 cm ^-1 on the spectrum, and integrating the absorption spectrum obtained as a result. FIG. 9 is a correlation diagram between the estimated blood glucose level obtained from the above integrated value and the blood glucose level measured by blood sampling. Good correlation with 0.82 degree correlation coefficient ^{R 2} is obtained.

In addition, by performing evaluation based on the peak intensity or area around wave numbers 1155, 1100, and 990 cm ⁻¹ that are not affected by C—H or C—OH contained in components taken from phosphoric acid or food in body fluids. However, highly accurate measurement is possible. FIG. 10 shows the change in the absorption peak intensity around 1155 cm ⁻¹ depending on the blood glucose level, and the intensity increases as the blood glucose level increases. FIG. 11 is a correlation diagram between a blood glucose level estimated based on a peak area near a wave number of 1155 cm ⁻¹ and a blood glucose level measured by blood collection, and a good correlation of about 0.78 is obtained with a correlation coefficient R ^2. ing. In addition, other values estimated based on the peak intensity or area near 1100,990 cm ⁻¹ also showed good correlation with blood glucose levels measured by blood sampling.

It is a block diagram of the blood glucose level measuring apparatus which shows an example of embodiment of this invention. It is an enlarged view of the ATR prism. It is an infrared absorption spectrum of a glucose aqueous solution gel measured by bringing a glucose gel having a concentration of 0 to 1% into contact with the upper and lower bottom surfaces of the ATR prism. It is an example of the absorption spectrum of the human lip mucosa, measured with the upper and lower surfaces of the ATR prism 5 sandwiched between the lips. It is an enlarged view of the absorption region of glucose in the vicinity of the wave number of 1000 cm ^{−1 of the} absorption spectrum shown in FIG. This is the difference between the absorption spectrum measured when the blood glucose level increased and the absorption spectrum during fasting (blood glucose level 72 mg / dl) among the absorption spectra measured during the human oral glucose tolerance test. FIG. 7 is a correlation diagram between the peak intensity at a wave number of 1035 cm ⁻¹ and the blood sugar level measured by blood collection when the difference spectrum was measured in the same manner as in FIG. 6 at various blood sugar levels. It is the schematic diagram which showed the method of calculating | requiring the integral value of the area | region containing the wave number range containing the absorption peak group of glucose. It is a correlation diagram between the estimated blood glucose level obtained from the integral value of the region including the wave number range including the glucose absorption peak group and the blood glucose level measured by blood sampling. It is the graph which showed the change by the blood glucose level of the absorption peak intensity of wave number around 1155cm- ¹ . It is a correlation diagram between the blood sugar level estimated based on the peak area near the wave number of 1155 cm ⁻¹ and the blood sugar level measured by blood sampling.

DESCRIPTION OF SYMBOLS 1 Fourier infrared spectrometer 2 Concave mirror 3 Optical fiber 4 Sample to be measured 5 ATR prism 6 Optical fiber 7 Receiving lens 8 Infrared detector

Claims (8)

In non-invasive blood glucose level measurement method using infrared spectroscopy,
A method for measuring a blood glucose level using an optical fiber and a multiple reflection prism connected to the optical fiber.   The blood glucose level measuring method according to claim 1, wherein the optical fiber is a hollow optical fiber.   The blood sugar level measuring method according to claim 1, wherein the multiple reflection prism is made of zinc sulfide. In non-invasive blood glucose level measurement method using infrared spectroscopy,
A method of measuring an absorption spectrum including the entire wave number range of 990 to 1150 cm ⁻¹ including five different absorption peaks of glucose and measuring a blood glucose level based on an integrated value of the absorption intensity in the wave number range. In non-invasive blood glucose level measurement method using infrared spectroscopy,
A method of measuring a blood glucose level based on an intensity of an absorption peak of glucose appearing in a wave number range of 1140 to 1170 cm ⁻¹ or an integrated value of the intensity of the absorption peak. In non-invasive blood glucose level measurement method using infrared spectroscopy,
A method for measuring a blood glucose level based on an intensity of an absorption peak of glucose appearing in a wave number range of 1100 to 1140 cm ⁻¹ or an integrated value of the intensity of the absorption peak. In non-invasive blood glucose level measurement method using infrared spectroscopy,
A method of measuring a blood glucose level based on an intensity of an absorption peak of glucose appearing in a wave number range of 1000 to 980 cm ⁻¹ or an integrated value of the intensity of the absorption peak.   The blood sugar level measuring method according to any one of claims 1 to 7, wherein a quantum cascade laser is used as a light source in the blood sugar level measuring method.

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