JP3093871B2 - Optical blood glucose non-destructive measuring device - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for non-destructively measuring the glucose concentration (blood glucose level) in human blood in a short time by optical means, and to measure the optical blood glucose level mainly used for diabetic patients. It relates to a destruction measuring device.

[0002]

2. Description of the Related Art Diabetes is a disease in which glucose levels in blood, extracellular fluid and tissue fluid are chronically increased.
In a normal human body, the concentration of glucose dissolved in blood is 60
~ 120mg / dl and 140 ~ 200mg / d
The case where there is 1 or more is called diabetes. In diabetes, there is no complete cure for its cause, and when blood sugar levels rise, insulin, a hormone that lowers blood sugar levels, is administered to maintain blood sugar levels at appropriate levels.

[0003] There are two methods for measuring the blood sugar level: a blood sampling method (invasive method) and a bloodless method (non-invasive method). The blood collection method
The most commonly used method is to react the collected blood with a reagent as a simple method, usually by the glucose oxidase method, and to determine the blood glucose level from the reaction color using colorimetry.
Various methods have been reported for the blood-free method as described below, but have not yet been put to practical use. [Non-invasive blood glucose measurement method by infrared spectroscopy] This is a glucose determination method by oral spectrum analysis proposed by Kenichiro Kajiwara et al. (Kumamoto University School of Medicine). Absorption of mucosa collected from oral cavity instead of blood. The spectrum was measured by an attenuated total reflection method (ATR method) using a Fourier transform infrared spectrometer (FTIR), and was measured at 2920 cm ⁻¹ (3.42 μm).
With reference to m), the blood glucose level is quantified using the second derivative of the corrected absorbance at 1033 cm ⁻¹ (9.68 μm), which is the glucose absorption peak. [Percutaneous blood glucose measurement] Tsuneori Arai et al. (Defense Medical University group)
In this method, after removing the stratum corneum of the skin epidermis, the tissue fluid (aspiration exudate) is collected by attaching a vacuum suction device, and the glucose concentration of the tissue fluid is measured, whereby the blood glucose level is indirectly measured. Is what you want.

[0004] In addition, overseas, reports and proposals on the FTIR-ATR method have been made, but most are invasive methods.

[0005] Heise-HM et al. (USA)
It has been reported that the glucose concentration can be quantified by measuring the blood absorption spectrum at 0 to 750 cm ^-1 (6.67 to 13.33 μm) by the ATR method (Anal-Chem. 1989 Sep 15). .

[0006] Zeller-H et al. (Institut
fur PhysikalishMedizin, W
est-Germany), as the glucose absorption wavelength 1040cm ^-1 (9.62μm), 1085cm ^-1
(9.22 μm), 1109 cm ⁻¹ (9.02 μm),
1160 cm ^-1 (8.62 μm), 1365 cm
^-1 (7.33 μm), but the wave number unaffected by urea, protein, fat, etc. in blood was only 1040 cm ^-1, but 1109 cm ^-1 was also effective for quantifying glucose concentration. (Int-J-Artif-Or
gans. 1989 Feb. ).

Arnold-MA and the like (Departme
nt of ChemistryUniversity
of Iowa) is 4400 cm ⁻¹ (2.27 μm).
m) glucose absorption is present and 5000-4000c
m ^-1 (2.00 to 2.50 μm)
It has been reported that the glucose concentration in collected blood can be quantified by measuring with the TIR method (Anal-
Chem 1990 Jul).

[0008]

However, according to the blood sampling method, a diabetic patient must collect at least hundreds of blood samples per year (usually hundreds to 1,000 times or more) throughout his or her life. It is also dangerous for young and elderly people.

[0009] Even if an optical method is used, FTIR
If the measurement wavelength is in the infrared region or the near-infrared region of 1.4 μm or more, the device must be large, and since the signal intensity is extremely weak, it is difficult to measure the transmission absorption spectrum of the finger or earlobe. is there. Therefore, an object of the present invention is to provide a portable non-invasive blood glucose measurement method that is a complete non-invasive blood glucose measurement method that does not provide blood collection, and that enables one patient to use one device. It is an object of the present invention to provide a non-destructive optical blood glucose level measuring device.

[0010]

In order to achieve this object, the optical blood glucose level non-destructive measuring apparatus of the present invention has a wavelength of 0.1 mm.
Means for irradiating the human body with at least two wavelengths of near infrared light of 78 to 1.32 μm, means for detecting light radiated by the light irradiating means and transmitted through the human body, and performing photoelectric conversion; Information processing means for obtaining the glucose concentration in the human body based on the photoelectrically converted detection signal, wherein the information processing means refers to a detection signal based on one of the wavelengths, In determining the glucose concentration based on the optical blood glucose level non-destructive measuring device that excludes the influence of the optical path length when the light of the measurement wavelength passes through the human body, the information processing means, Based on the glucose concentration as a value corresponding to the glucose concentration determined from the difference absorbance, and the information processing means, based on the detection signal, the absorbance And characterized in that to determine the glucose concentration as a value corresponding to the glucose concentration obtained from the following differential value.

The glucose concentration is determined by, for example, converting the intensity of the transmitted light into a value corresponding to a theoretical glucose concentration obtained from a value obtained by converting the intensity of the transmitted light into an absorbance at the time of transmission through a human body. Also, in advance, through experiments, etc.
A correspondence chart between the transmitted light intensity and the glucose concentration at each measurement wavelength may be prepared and prepared, and the transmitted light intensity may be converted into the glucose concentration based on the chart.

When the theoretical glucose concentration is determined, it is preferable to standardize the absorbance at a certain wavelength as a reference and the absorbance as a specific absorbance. When the measured wavelength is 0.80 to 1.05 μm, The wavelength of the absorbance is preferably a wavelength near 0.96 μm which is a glucose absorption edge, a wavelength near 0.87 μm or 0.89 μm which is a glucose absorption peak, or a wavelength near 0.92 μm which is a glucose absorption valley. When the measurement wavelength is 1.05 to 1.32 μm, it is preferable to standardize the absorbance at each measurement wavelength as the specific absorbance with reference to the absorbance near 1.20 μm, which is the maximum glucose absorption peak. Further, the specific absorbance may be determined based on the difference absorbance.

FIG. 1 conceptually shows an apparatus according to the present invention for carrying out such a method. As shown in the figure, means 101 for irradiating a human body with at least one wavelength of near-infrared light having a wavelength of 0.78 to 1.32 μm,
A means 103 for detecting light irradiated by the light irradiating means 101 and transmitted through the human body and performing photoelectric conversion; a means 105 for obtaining a glucose concentration in the human body based on the photoelectrically converted signal
And The light irradiating means 101 includes, for example, a light source 1 and a grating 1 for dispersing light from the light source 1 and irradiating the human body with at least one wavelength of the near-infrared light.
07 and a mirror 109. Photoelectric conversion means 103
Are, for example, a light collecting unit (integrating sphere) 111 for collecting light transmitted through the human body and a detecting unit 113 for detecting the collected light.
Is provided. The means 105 for obtaining the glucose concentration is constituted by, for example, an arithmetic means for controlling the light irradiation means 101, the photoelectric conversion means 103 and the like, storing the detection data and performing a predetermined arithmetic processing.

[0014]

The absorption spectrum of a substance is likely to be fractal. That is, FIG. 2 shows the glucose absorption spectrum in the infrared region measured by the FTIR method, and the original absorption wavelength of glucose is changed from 1500 to 950 in the infrared region shown in FIG.
Assuming that cm ⁻¹ (6.61 to 10.5 μm), the wavelength range of the 2 ⁿ -order harmonic present in the ultraviolet to near-infrared region is as shown in Table 1.

[0015]

[Table 1]

The human body has several absorption bands in the visible region. This is mainly due to the absorption of pigment and red blood cells and water in the blood. On the other hand, in the near-infrared region and ultraviolet region, the influence of absorption of red blood cells is small, and mainly sugar and water (OH group)
Absorption is seen. However, in the ultraviolet region and 1.4
In the near-infrared region longer than μm, the transmittance to the human body is extremely small, and it is difficult to measure the transmission absorption spectrum in this region. Therefore, sugar and water (OH group)
To see a transmission method absorption by the human body is, 2 ³
The second harmonic region must be used.

The glucose absorption in this region is roughly divided into two zones as shown in FIG. Zone I is a weak absorption band having an absorption peak near 0.91 μm, and zone II is a strong absorption band having an absorption peak near 1.20 μm. In addition, water (OH group) near this region
Absorption peaks of 0.98 μm, 1.19 μm and 1.
45 μm. FIG. 4 shows the absorption spectrum of water. In order to measure the glucose concentration in blood, the influence of absorption by water must be reduced as much as possible.

Further, when light is applied to a finger or an earlobe and an absorption spectrum is measured by a transmission method, it is necessary to correct a difference in the length of a subject (transmitted optical path length). Generally, as shown in the following equation (1), the difference in the optical path length can be corrected by converting the absorbance at a certain wavelength into the specific absorbance using a reference.

[0019]

(Equation 1) In this case, the △ OD value (△ Op at two wavelengths λ1 and λ2)
Tickal Density) is defined by the following equation (2).

[0020]

(Equation 2) The glucose absorption spectrum in Zone I is shown in FIG. In this zone, the absorption peak of water, 0.1.
When the absorbance at a wavelength near 0.96 μm is used as a reference while avoiding 98 μm, the ratio to the measured wavelength around 0.83 to 0.96 μm, preferably 0.87, 0.89, 0.91, 0.94 μm is used. By calculating the absorbance, the difference between these specific absorbances, or the second derivative of the absorbance at these measurement wavelengths, or when the absorbance near 0.87 μm is used as a reference, 0.83 to 0.
87 μm, desirably specific absorbance around 0.86 μm,
The glucose concentration in blood can be determined by determining the difference absorbance between these specific absorbances or the second derivative of the absorbance at the measurement wavelength.

FIG. 6 shows the glucose absorption spectrum in zone II. 1.21 μm in this zone
When the absorbance in the vicinity is used as a reference, 1.06 to
1.21 μm, preferably 1.06, 1.08, 1.1
0, 1.13, 1.14, 1.16, 1.70, 1.1
By obtaining the specific absorbance around 9 μm or around 1.21 to 1.32 μm, desirably around 1.25 and 1.30 μm, the difference absorbance between these specific absorbances, or the second derivative of the absorbance at these measurement wavelengths, blood Can be determined.

According to this method, the concentration of glucose in the body is easily measured non-destructively from the outside without collecting blood or a blood substitute (oral mucus, skin tissue fluid, etc.), and there is no invasion to the human body. . Since the wavelength contributing to the measurement is 0.80 to 1.30 μm, it is 2.50 μm.
The signal intensity of transmitted light is higher than that of infrared light having a wavelength longer than m, so that the measurement device is configured to be small and measurement is performed in real time.

An important point when considering applications is that continuous blood glucose measurement is possible. That is, by taking the change in blood glucose level as a time-series change, it becomes possible to perform appropriate insulin administration to a diabetic patient based on a doctor's instruction. If such a judgment function is incorporated as a judgment unit in the device of the present invention, the device can inform the patient of the dose, administration time, etc. of insulin that has been subjectively judged by the doctor or the patient. . An artificial pancreas-like development by combining insulin administration with a micromachine is also expected.

[0024]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS In the case where blood glucose measurement is performed using absorbances of a maximum of four wavelengths, various embodiments can be considered as a miniaturized blood glucose measurement device. FIG. 7 is a schematic diagram showing the configuration of the one according to the embodiment.

This is a pre-spectroscopy system using an interference filter, and includes a light source unit 1 such as halogen, a rotary interference filter unit 2 that transmits light of a predetermined wavelength out of the light emitted from the light source unit 1, and a rotary interference filter unit 2. A light emitting fiber 5 for guiding the light, a measurement object such as an earlobe, a finger, and the like are fixed, and a measurement housing portion 6 for irradiating the light to be measured with the light guided by the light emitting fiber 5. A light-receiving fiber 7 for guiding the light transmitted through the object to be measured in the measurement housing portion 6; a detecting portion 8 including a light-receiving element for detecting light guided by the light-receiving fiber 7 and converting the light into an electric signal; It comprises an amplifying unit 9 for amplifying the output of the unit 8, and a calculating unit 10 for calculating a blood sugar level based on the output of the amplifying unit 9. The rotation interference filter unit 2 includes a rotation interference filter having four interference filters 3 each transmitting only light of four different wavelengths suitable for the above-described measurement, and a motor 4 for rotating the rotation interference filter. Are divided into monochromatic lights having a maximum of four wavelengths by the respective filters 3. Further, since the filter 3 rotates at a constant frequency, it also has a chopper function.

Similar to the above, there is a post-spectral system using an interference filter as shown in FIG. This is a type in which a rotary interference filter unit 2 is arranged in front of a light receiving element, and the other configuration is the same as that of FIG. 7, and the basic function is the same as that of the pre-spectroscopic method using the interference filter.

FIG. 9 shows four semiconductor lasers 91 that do not employ a spectroscopic method and output measurement lights of different wavelengths.
Is used as a light source, and the other components have the same configuration as that of FIG.

In order to verify the effectiveness of such a device,
The following measurements and considerations were made.

First, as an in vitro measurement, four types of plasma collected from different human bodies were respectively placed in a cell having a thickness of 10 mm, and the transmitted light path length was set to 1.
The transmission absorbance was determined in a wavelength range of 0.700 to 1.400 μm while keeping the distance constant at 0 mm. The glucose concentration of the collected plasma was 88, 144, 210, and 372 m, respectively.
g / dl (by the glucose oxidase method).

On the other hand, as an in vivo measurement, the transmission absorbance of the middle finger of the subject was measured seven times based on the time table shown in Table 2, and the blood glucose level of glucose (Maltos-T) added orally was measured. Time series changes were observed. For comparison, as soon as each measurement of the transmission absorption spectrum was completed, blood was collected and the blood glucose level was measured by the glucose oxidase method. The results of measurement by the glucose oxidase method are as shown in Table 2. The wavelength measured in vivo was 0.800 to 1.000 μm. The seven measurements were performed at almost the same site as much as possible, but the transmitted light path lengths were slightly different.

[0031]

[Table 2]

Applicability of Normalization Method by One-Wavelength Absorbance (In Vitro Test) Regarding transmission absorbance measured in vitro, standardization for each wavelength when the reference wavelength λR is set to 0.964 μm and 1.200 μm FIGS. 10 and 11 show single correlation coefficient distribution charts of absorbance (ABS (λ) / ABS (λR)) and glucose concentration.

As shown in FIG. 10, the reference wavelength λ
When R is 0.964 μm, 0.800 to 0.9
The single correlation coefficient shows about 0.9 in the range of 60 μm and 0.985 to 1.000 μm. The zone showing a negative correlation near 0.97 μm is a part affected by water absorption, not sugar.

As shown in FIG. 11, the reference wavelength λ
When R is 1.200 μm, a range showing a high positive correlation is found at 1.00 to 1.190 μm, and a range showing a high negative correlation is found at 1.280 to 1.4000 μm.

From the above, it is understood that even a slight difference in glucose concentration such as several tens of mg / dl is based on the principle of the present invention.
This suggests that measurement can be performed by absorption spectroscopy in the near infrared region, and that blood glucose levels of different subjects can be measured by the same principle.

(In Vivo Test) FIG. 12 shows the normalized absorbance (ABS (λ) / ABS (λR) between 0.800 and 1.000 μm when the reference wavelength λR is 0.964 μm (near the glucose absorption end). FIG. 4 is a simple correlation distribution diagram between the blood glucose level and the blood glucose level. 0.855-0.
A high positive correlation is stably observed in the range of 945 μm,
The vicinity of 0.945 μm shows the highest correlation. This tendency does not contradict the in vitro test results described above.

FIG. 13 shows that the reference wavelength λR is 0.87.
FIG. 4 is a single correlation distribution diagram in the case of 2 μm (near the peak of glucose absorption). In this case, there is a portion showing a high negative correlation near 0.89 μm, which is a valley of glucose absorption.

FIG. 14 shows that the reference wavelength λR is 0.89.
It is a single correlation distribution figure in case it is set to 2 micrometers (near a glucose absorption trough). 0.87μ which is the top of glucose absorption
Near m indicates a high positive correlation.

FIG. 15 shows that the reference wavelength λR is 0.91.
It is a single correlation distribution figure at the time of 5 micrometers (near a glucose absorption top). In this case, a portion showing a positive correlation near 0.87 μm, which is the top of glucose absorption, and a portion showing a negative correlation near 0.96 μm, which is the end of glucose absorption, are observed.

The above description indicates that even if there is a large absorption by an interfering substance such as water, attention is paid to the absorbances at wavelengths having characteristics such as peaks, saddles, and ends of the glucose absorption spectrum. This shows that it is possible to non-invasively measure the glucose concentration in the body by obtaining the specific absorbance.

As an example, FIG. 16 shows an in vitro scatter plot of the normalized absorbance at a measurement wavelength of 0.944 μm with the reference wavelength set to 0.964 μm and the blood glucose level, and FIG. 16 shows an in vivo scatter plot. 17 both show a high correlation coefficient of about 0.95.

Applicability of Second-Order Differentiation Method of Absorbance The second-order differentiation method is considered to be an effective method for reducing the influence of the background and extracting minute spectral changes. FIG. 18 shows the correlation distribution between the second derivative of the light absorption for each wavelength and the blood glucose level obtained in vivo. 0.93
There is a wavelength having a high correlation at ０．９0.97 μm. The second derivative of the light absorption at the wavelength λ _nm is a value defined by the following equation (3).

[0043]

(Equation 3)

[0044]

According to the present invention, the concentration of glucose in the body can be easily measured non-destructively from the outside without collecting blood or blood substitutes (such as oral mucus and skin tissue fluid). Also, because light is used,
No invasion of the human body.

The wavelength contributing to the measurement is 0.80 to 1.
Since it is 30 μm, the signal intensity of the transmitted light is higher than that of infrared light having a wavelength longer than 2.50 μm, so that the measuring device can be downsized and the measurement time can be performed in real time.

[Brief description of the drawings]

FIG. 1 is a conceptual diagram showing an apparatus of the present invention.

FIG. 2 is a graph showing a glucose absorption spectrum in an infrared region measured by the FTIR method.

3 is a graph showing the 2 ^third harmonic glucose absorption spectra in the near infrared region (0.80~1.40μm).

FIG. 4 is a graph showing an absorption spectrum of water (OH group) in a near infrared region (0.80 to 1.35 μm).

5 is a graph showing the 2 ^third harmonic glucose absorption spectra in the near infrared region (0.80~1.00μm).

6 is a graph showing the 2 ^third harmonic glucose absorption spectra in the near infrared region (1.00~1.40μm).

7 to 9 are schematic configuration diagrams showing a miniaturized measuring device according to an embodiment of the present invention.

FIG. 10: In vitro using plasma in a cell
o is a graph showing the results of the experiment, showing the simple correlation coefficient between the specific absorbance with reference to the absorbance at 0.964 μm and the glucose concentration in plasma for each wavelength (wavelength range 0.8 １．０1.0 μm).

FIG. 11: In vitro using plasma in a cell
o is a graph showing the results of the experiment, showing the simple correlation coefficient between the specific absorbance using the absorbance of 1.200 μm as a reference and the glucose concentration in plasma for each wavelength (wavelength range 1.0 １1.4 μm).

FIG. 12 is a graph showing the results of an in vivo experiment using a human finger according to one embodiment of the present invention, and is a graph showing 0.9 results.
It shows the single correlation coefficient between the specific absorbance using the absorbance of 64 μm as a reference and the glucose concentration in the collected blood for each wavelength (wavelength range 0.8 to 1.0 μm).
m).

FIG. 13 is a graph showing the results of an in vivo experiment using a human finger according to one embodiment of the present invention,
It shows the single correlation coefficient between the specific absorbance using the absorbance of 72 μm as a reference and the glucose concentration in the collected blood for each wavelength (wavelength range 0.8 to 1.0 μm).
m).

FIG. 14 is a graph showing the results of an in vivo experiment using a human finger according to one embodiment of the present invention, and is a graph showing 0.8 results.
It shows the single correlation coefficient between the specific absorbance using the absorbance of 92 μm as a reference and the glucose concentration in the collected blood for each wavelength (wavelength range 0.8 to 1.0 μm).
m).

FIG. 15 is a graph showing the results of an in vivo experiment using a human finger according to one example of the present invention, and is a graph showing 0.9 results.
It shows the simple correlation coefficient between the specific absorbance using the absorbance of 15 μm as a reference and the glucose concentration in the collected blood for each wavelength (wavelength range 0.8 to 1.0 μm).
m).

FIG. 16: In vitro using plasma in a cell
FIG. 9 is a scatter diagram of the specific absorbance of 0.944 μm with reference to the absorbance of 0.964 μm and the glucose concentration in plasma in Experiment o.

FIG. 17 is a graph showing the relationship between the specific absorbance of 0.944 μm with reference to the absorbance of 0.964 μm and the glucose concentration in the collected blood in an in vivo experiment using a human finger according to one embodiment of the present invention. FIG.

FIG. 18 is a graph showing the results of an in vivo experiment using a human finger according to one example of the present invention, wherein a single correlation coefficient between the second derivative of the absorbance and the glucose concentration in the collected blood is shown. Is shown for each wavelength (wavelength range 0.8 to 1.0 μm).

────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-2-191434 (JP, A) JP-A-1-131436 (JP, A) JP-A-57-115232 (JP, A) (58) Field (Int.Cl. ⁷ , DB name) A61B 5/145 G01N 21/35

Claims (2)

(57) [Claims] 1. A means for irradiating a human body with at least two wavelengths of near-infrared light having a wavelength of 0.78 to 1.32 μm, and detecting light radiated by the light irradiating means and transmitted through the human body. Means for performing photoelectric conversion, and information processing means for determining the glucose concentration in the human body based on the photoelectrically converted detection signal, wherein the information processing means refers to a detection signal based on one of the wavelengths, When determining the glucose concentration based on the detection signal by other measurement wavelength,
In the optical blood glucose level non-destructive measurement device that eliminates the effect of the optical path length when light of the measurement wavelength passes through the human body,
The optical blood glucose non-destructive measuring device, wherein the information processing means calculates a glucose concentration as a value corresponding to a glucose concentration determined from a difference absorbance based on the detection signal. 2. A means for irradiating a human body with at least two wavelengths of near-infrared light having a wavelength of 0.78 to 1.32 μm, and detecting light emitted by the light irradiating means and transmitted through the human body. Means for performing photoelectric conversion, and information processing means for obtaining the glucose concentration in the human body based on the photoelectrically converted detection signal, the information processing means refers to a detection signal by one of the wavelengths, When determining the glucose concentration based on the detection signal by other measurement wavelength,
In the optical blood glucose level non-destructive measurement device that eliminates the effect of the optical path length when light of the measurement wavelength passes through the human body,
The optical blood glucose nondestructive measuring device, wherein the information processing means calculates a glucose concentration as a value corresponding to a glucose concentration determined from a second derivative of absorbance based on the detection signal.