Non-invasive measurement device for separating venous and arterial blood biochemical components.

Abstract

This invention provides technology for the practical application of a non-invasive photoacoustic measuring instrument that offers high precision and separates and measures the biochemical components of venous and arterial blood. [Solution] The blood biochemical component photoacoustic vascular separation analyzer of the present invention comprises a light emitter 17 that emits light of specific wavelengths corresponding to blood biochemical components such as glucose, water, and blood components in veins and arteries, a vibration detector 18 that detects acoustic waves from the living body when the light from the light emitter 17 is irradiated onto the living body at specific wavelengths, and a control unit 11 that processes the signals from the vibration detector 18 for each of the specific wavelengths and outputs the result.

Description

Technical Field

[0001] The present invention relates to a photoacoustic measuring device for non-invasively separating and measuring the blood biochemical components of veins and arteries.

Background Art

[0002] Although measuring devices using the photoacoustic effect have been reported conventionally, for example, non-invasive blood glucose meters have not yet been put into practical use. The reason is that the influence due to the variation in the mixing ratio of the mixed body fluid of arterial and venous blood by non-blood collection could not be separated and measured.

[0003] Also, there are still problems in terms of measurement accuracy. In order to solve the problems of measurement accuracy, the inventor has invented a non-invasive blood glucose value measuring device using a resonance type vibration detector and a correlation detector to increase the sensitivity and the signal-to-noise ratio by the photoacoustic resonance method, and to obtain depth analysis, and has filed a patent application (Patent Document 1). However, in Patent Document 1, since the details of the configuration such as the detector and the control procedure were not clarified, it was difficult to put it into practical use.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0005] Taking blood glucose measurement as an example, venous blood and arterial blood are often mixed and detected, resulting in poor accuracy. Also, as described above, at present, devices for non-invasively measuring blood biochemical components such as blood glucose have not yet been put into practical use, and furthermore, technologies for non-invasively separating and measuring the vascular components of veins and arteries have not been reported.

[0006] The present invention aims to provide technology for the practical application of a non-invasive separation and measurement device that can accurately separate and measure the biochemical components of venous and arterial blood. [Means for solving the problem]

[0007] The present invention is a photoacoustic blood vessel separation analyzer for blood biochemical components, comprising: a light emitter that emits light of specific wavelengths corresponding to blood biochemical components, water, and blood components in veins and arteries; a vibration detector that irradiates a living body with light from the light emitter at each of the specified wavelengths and detects a group of spherical acoustic waves from the living body as longitudinal vibrations; and a control unit that processes the signals from the vibration detector at each of the specified wavelengths and outputs the result.

[0008] The inventors have diligently conducted research and completed the present invention based on the findings detailed below. Photoacoustic signals generated within soft tissue are weak, and in order to separately measure venous and arterial vascular components, it is necessary to increase detection sensitivity and obtain data that is dependent on the depth of the body. Furthermore, impedance mismatch, i.e., boundary reflection of acoustic waves, occurs at the skin surface with the vibration detector, and fluctuations in the connection pressure of each operation of the detector sensor unit occur, causing measurement variability. For this reason, the inventors have devised a control algorithm to correct measurement errors caused by fluctuations in the connection pressure of each operation of the detector sensor unit for each measurement. In addition, the photoacoustic intermittent light source used in the light emitter generates synchronization noise that cannot be eliminated by correlation detection to increase detection sensitivity, so a detector with a structure that shields the light source from thermal expansion vibration, photoacoustic vibration, electromagnetically, optically, and thermally is necessary. Furthermore, in order to separately measure venous and arterial vascular components, positive feedback is applied to the resonant longitudinal oscillator type detector to increase Q, thereby improving depth-direction position resolution and detection sensitivity.

[0009] Specifically, the resonant transducer of the vibration detector requires impedance matching to avoid attenuation of acoustic waves with the skin surface, and also serves as electromagnetic shielding. It is enclosed in a metal enclosure, such as aluminum, which has a low acoustic impedance matched to the low acoustic impedance of muscles and has a high electromagnetic shielding effect. To mitigate thermal noise from intermittent light sources such as light-emitting diodes that generate synchronization noise that cannot be suppressed by synchronous detection, the transducer is arranged concentrically within a cylindrical flange of a metal with a high specific heat, such as brass or copper. To prevent thermal synchronization noise, an air gap is provided between the light-emitting element (such as a light-emitting diode) and the cylindrical flange. The cylindrical enclosure of the vibration detector is connected to the center of the cylindrical flange surface with a pseudo-elastic material such as a rubber membrane. The measuring surface of the cylindrical enclosure of the transducer is coplanar with the cylindrical flange surface. The circular surface of the cylindrical flange serves as a planar contact guide for the vibration detector on the surface of the human body being measured, and the vibration detector is made to make uniform soft-pressure reproducible contact with the human body surface by the pseudo-elastic material such as a rubber membrane. The light-emitting diodes of the intermittent light source are mounted with a gap around the flange, shorter than the height of the flange which serves as a contact guide for the vibration detector, and the light-emitting diodes are mounted so as not to come into contact with the surface of the human body being measured, thereby preventing heat transfer vibrations and other issues, and ensuring that they do not come into direct contact with the human body being measured. [Effects of the Invention]

[0010] The present invention provides a photoacoustic blood vessel separation and measurement device for blood biochemical components that can separate and measure venous and arterial blood biochemical components with high accuracy and in a non-invasive manner. By putting this into practical use, it becomes possible to continuously record the changes in blood biochemical components, preferably blood glucose levels, and, by increasing the number of light emitters of specific wavelengths, triglycerides, total protein, creatinine, urea, etc., without pain, without the need for blood collection needles or other waste, and without requiring qualified medical personnel. Furthermore, by transferring measurement data to smartphones or PCs, self-medication can reduce medical costs, enable telemedicine, and pave the way for home-based medical care in an aging society. Blood biochemical components, such as blood glucose levels, and other desired blood concentrations, such as triglycerides, total protein, creatinine, and urea, can be measured in real time separately for venous and arterial blood, benefiting research in blood metabolic physiology. [Brief explanation of the drawing]

[0011] [Figure 1] This is a block diagram of a photoacoustic blood glucose meter. [Figure 2] (a) is a top view and (b) is a cross-sectional view of the light emitter and vibration detector in a photoacoustic blood glucose meter. [Figure 3] This graph shows the measurement results of photoacoustic signals in the direction of deep body tissue using characteristic wavelengths (760 nm and 570 nm) for deoxyhemoglobin and oxyhemoglobin. The vertical axis represents signal intensity, and the horizontal axis represents frequency and its value converted to deep body depth. [Figure 4] This graph shows the measurement results of the photoacoustic signal in the direction of body depth using the characteristic wavelength of water (1450 nm). The vertical axis represents the signal intensity, and the horizontal axis represents the frequency and its value converted to body depth. [Figure 5] This graph shows the measurement results of the photoacoustic signal in the direction of deep body tissue using the characteristic wavelength (1200 nm) of glucose. The vertical axis represents the signal intensity, and the horizontal axis represents the frequency and its value converted to deep body depth. [Modes for carrying out the invention]

[0012] The photoacoustic blood vessel separation and measurement device for blood biochemical components of this embodiment will be described with reference to Figure 1. In the following description, blood glucose will be used as an example of a blood biochemical component, and a blood glucose meter for measuring blood glucose levels will be described, but the present invention is not limited to this. The photoacoustic blood glucose meter in Figure 1 consists of a light emitter 17, a vibration detector 18, and a control unit 11.

[0013] The light emitter 17 is composed of a diode with a variable illumination period that emits light of specific wavelengths corresponding to glucose, water, and blood components in veins and arteries, respectively, as blood biochemical components, but is not limited to this, and may be composed of a semiconductor laser or the like. Furthermore, the blood components in veins and arteries may be any blood components unique to veins and arteries, for example, deoxyhemoglobin and oxyhemoglobin. In this case, a diode that emits light with absorption wavelengths of 760 nm and 570 nm can be used as the light emitter 17.

[0014] In Figure 1, the vibration detector 18 is composed of, for example, a PZT, and light from the light emitter 17 is irradiated onto the living body, i.e., the human body to be measured 113, at specific wavelengths, and acoustic waves from the human body to be measured 113 are detected.

[0015] In Figure 1, the control unit 11 processes the signal from the vibration detector 18 for each specific wavelength and outputs it. Specifically, the acoustic wave signal from the vibration detector 18 is amplified by the tuning amplifier 19, input to the correlation detector 110, passes through the A / D converter 112, and is processed by the CPU 13 to control the display.

[0016] The CPU 13 controls the synthesizer 14, the diode light emission power controller 15, and the diode array switch 16. Specifically, the CPU 13 controls the timing synthesizer 14 that causes the light emitter 17 to emit light, outputs a timing reference signal 111 to the correlation detector 110, and the correlation detector 110 detects an acoustic wave signal based on this reference signal 111, enabling deep body depth exploration by specifying frequency undermodulation. Furthermore, the CPU 13 sets a measurement frequency ft for the synthesizer 14 to determine the subcutaneous depth measurement point. Based on this signal, the CPU 13 controls the diode light emission power controller 15 to specify a specific light emission power and wavelength. The light emission pulse width is set to 1 / 4 of the emission period, which is determined by the photoacoustic generation high efficiency width and correlation detection, enabling a narrow high-power pulse period derived from the load transient breakdown characteristics of the diode. Here, the light emission pulse width can be 1 / 3 to 1 / 100 of the pulse width, with a 1 / 4 emission period being more preferable. Furthermore, the CPU 13 controls the switching of the light emission power control signal from the diode light emission power controller 15 using the diode array switch 16, thereby switching the light emission wavelength of the light emitter 17.

[0017] Figure 2(a) is a top view of the light emitter 17 and vibration detector 18 in the photoacoustic blood glucose leveling device of Figure 1, and Figure 2(b) is a cross-sectional view thereof. In Figures 2(a) and (b), the light emitters 22 are diodes that emit light of specific wavelengths corresponding to glucose, water, and blood components in veins and arteries, respectively, and the light emitter 17 of Figure 1 is composed of these diodes and a diode support 24 that supports these diodes. The light emitters 22 only need to have at least these four, but may also include light emitters that emit light of specific wavelengths corresponding to two or more substances selected from the group consisting of glucose, triglycerides, total protein, creatinine, and urea. By including these, the amount of these blood biochemical components, represented by blood glucose levels, in the blood can be measured in veins and arteries, respectively. Note that these wavelengths may be any specific wavelengths absorbed by those substances, and commercially available diodes corresponding to these wavelengths can be used.

[0018] The vibration detector 18 in FIG. 1 is composed of a resonant vibrator (not shown) and an enclosure case 21 that surrounds the vibrator. The enclosure case 21 in FIG. 2 requires impedance matching to avoid acoustic wave connection attenuation with the skin surface, and also serves as electromagnetic shielding. A metal with a low acoustic impedance and a high electromagnetic shielding effect is selected to match the muscle, and it is preferably made of aluminum. The shape may be cylindrical or conical.

[0019] The enclosure case 21 in FIG. 2 places the synchronous noise that cannot be suppressed by synchronous detection in the concentric cylindrical flange 23 with a large specific heat that relaxes the intermittent light source thermal noise of the light emitter 22. To prevent heat transfer synchronous noise, a gap is provided between the cylindrical flange 23 and the enclosure case 21. The flange 23 has an elastic body 25 such as a rubber film on its upper surface, and the enclosure case 21 of the vibration detector 18 is connected to lead wires such as copper and platinum through the elastic body 25 at its center. The lower surface of the enclosure case 21 of the vibration detector 18 has the same surface structure as the lower surface of the cylindrical flange 23 and contacts the measured human body 113. The lower surface of the cylindrical flange 23 serves as a contact guide for the vibration detector 18 on the surface of the measured human body 113, and the vibration detector 18 is made to achieve uniform soft surface pressure reproducibility contact with the human body surface by an elastic body 25 such as a rubber film. The light emitting diode 22 of the intermittent light source is provided on the outer periphery of the flange 23 by a diode support 24, with a gap provided between it and the flange 23. Also, it is shorter than the height of the flange 23 and is spaced apart so that the light emitter 22 does not directly contact the surface of the measured human body to prevent heat transfer vibration, etc. Further, the flange 23 is a housing that surrounds the vibration detector 18 and the elastic body 25 that supports it. The shape is preferably cylindrical, and a conical shape similar to this may also be used. Also, at least the periphery of the vibration detector 25 is preferably made of a metal such as brass or copper with a large specific heat. The upper part 27 of the housing may be made of a different material from the flange 23, but considering assembling them integrally, it is preferable that the flange 23 and the upper part 27 of the housing are made of the same metal material such as aluminum. A control unit 11 including a synchronous amplifier 19 that amplifies the signal detected by the vibration detector 18 can be arranged on the upper part 27 of the housing.

[0020] The results of actual measurements using the photoacoustic blood glucose meters of FIGS. 1 and 2 are shown in FIGS. 3 to 5. Specifically, FIG. 3 shows the characteristic wavelengths (760 nm, 570 nm) of deoxygenated hemoglobin and oxygenated hemoglobin, FIG. 4 shows the characteristic wavelength (1450 nm) of water, and FIG. 5 shows the characteristic wavelength (1200 nm) of glucose. These are graphs showing the measurement results of photoacoustic signals in the body depth direction. The vertical axis represents the signal intensity, and the horizontal axis represents the frequency and the value converted to the body depth.

[0021] The measurement target was the thigh of a 23-year-old male. The measurement was performed by switching on four light-emitting diodes corresponding to deoxygenated hemoglobin, oxygenated hemoglobin, water, and glucose, respectively, at one frequency, and then repeatedly measuring by switching the four light-emitting diodes while decreasing the frequency by 5 Hz. In this embodiment, the measurement was performed by switching the diodes for each frequency, but it may also be possible to measure by switching the frequency for each diode of a specific wavelength. Also, the width of the frequency to be measured, the light emission time of the diode, etc. can be appropriately changed.

[0022] In this embodiment, in order to search for the body depth of blood vessels, the frequency is decreased in the body depth direction from the oscillator natural frequency indicating the body surface to form a continuous wave with the vibration detector 18 for a specific intermittent light frequency, and a certain data band is searched. For this purpose, a deep direction search function is used as described in Japanese Patent Application Laid-Open No. 2004-249025 for blood vessel search. Here, when the sound speed of the human body is V, the resonance frequency of the longitudinal vibration detector is fr, and the assumed longitudinal wave correlation detection frequency between the vibration detector and the wave source at a depth of ΔL is ft, ΔL = V(fr - ft) / frft is represented by.

[0023] Here, the sound speed V of the human body is measured in advance on the human body surface, and it is assumed to be equivalent to the sound speed in the human body depth direction (V in the above formula). The sound speed on the human body surface can be measured by using the diodes and the vibration detector in FIG. 1 and changing these distances along the body surface. Therefore, in FIGS. 3 to 5, the conversion to the body depth ΔL can be performed by the above formula.

[0024] Figure 3 shows measurements taken to separate venous and arterial blood glucose levels and to explore the arrangement of arterial and venous vessels in the depth direction. Figure 4 shows measurements taken to display blood glucose levels as a ratio to water. Figure 5 shows measurements taken using depth-dependent photoacoustic signals to separate and measure blood glucose levels in arterial and venous vessels.

[0025] In other words, in order to separately measure veins and arteries, blood vessels are primarily composed of water, exhibit lower acoustic signal attenuation compared to muscles, have a finite geometric size, and, because they are capillaries distributed parallel to the body surface, a constant data region is assumed for signal magnitude in the direction of deeper tissue.

[0026] Capillaries, where veins and arteries exist alternately in parallel, have a constant concentration aqueous solution medium within their diameter, and because aqueous solutions have low ultrasonic attenuation, they possess a constant intensity signal band in the direction of deeper tissue. Therefore, by measuring the photoacoustic signals of specific wavelengths in overlapping veins and arteries, the relatively dominant high signal bands of veins and arteries, which alternate in diameter and have a constant width and depth beneath the body surface, can be observed separately at different depths. By measuring the photoacoustic signals of specific substances at different wavelengths for the relatively high signal bands of veins and arteries, the blood components of venous and arterial blood can be separated and measured.

[0027] In other words, since deoxidized hemoglobin is abundant in veins and oxyhemoglobin is abundant in arteries, blood glucose levels in veins and arteries can be separated and measured based on the signal output from the vibration detector 18 (Figure 3) when light of a specific wavelength corresponding to these blood components in veins and arteries is irradiated, respectively. Specifically, by measuring the signal output value for a person whose blood glucose level is known from simultaneous vein blood sampling and then calibrating, the actual blood glucose level can be obtained. The sum of the photoacoustic signals of arterial and venous blood vessels in Figure 3 matches the shape of the photoacoustic signal data that depends on the depth of the body due to the characteristic wavelength of water in Figure 4, which is consistent with the localization of water in both blood vessels.

[0028] In the same manner as in Figure 3, among the photoacoustic signal data at a glucose absorption wavelength of 1200 nm measured in Figure 5, the glucose photoacoustic signal data in the same high-signal band as the venous high-signal band and the water photoacoustic signal data in the same band can be used to obtain the venous blood glucose level. Conversely, arterial blood glucose levels can be obtained by dividing the deep-band glucose data of the artery by the water data in the same deep-band, although the arterial signal is generally stronger than the venous acoustic signal. Furthermore, individual connection pressure fluctuation errors for each measurement and installation operation of the detector sensor can be automatically corrected. It should be noted that although this explanation describes the case of dividing glucose signal data by water signal data, the same applies based on the ratio of signal intensities.

[0029] Furthermore, by dividing the depth-direction signal intensity measured in the depth direction of the living organism by the signal intensity of the living organism measured at the natural frequency of the vibration detector 18, i.e., the signal intensity at a frequency of 40 kHz (i.e., corresponding to a depth of 0 mm), it is possible to prevent variations in depth-direction signal intensity caused by differences in diode power, etc., for each specific wavelength. However, Figures 3 to 5 are measurement data, and this normalization process for preventing variations has not been performed.

[0030] In Figure 1, the CPU 13 processes the measurement data as described above, and the obtained data can be displayed in real time as numerical values ​​for both venous and arterial blood glucose levels. Furthermore, for continuous measurements over a certain period, a graph display may be used. These display devices may be integrated into the photoacoustic blood glucose meter of this embodiment, or they may be attached externally. Additionally, a transmission device such as Bluetooth® can be incorporated into the photoacoustic blood glucose meter of this embodiment to transfer data to a smartphone or PC, allowing this data to be shared with a doctor and contributing to telemedicine and home healthcare.

[0031] In the above-described embodiment, blood glucose levels, which have absorption characteristics in the near-infrared region, were used as an example. Similarly, for biochemical components in the blood such as triglycerides, total protein, creatinine, and urea, the blood concentrations in both veins and arteries can be measured in real time by using a light emitter that emits light at wavelengths that have absorption characteristics for one or more types of substances. For example, glucose was exemplified at 1200 nm above, but other infrared absorption wavelengths may also be used. Light emitters with infrared absorption wavelengths such as 1740 nm for triglycerides, 1650 nm for total protein, 1500 nm for creatinine, and 1460 nm for urea can be used.

[0032] In the above-described embodiment, the light emitter 17 is configured by arranging a plurality of light-emitting diodes 22 on a circle at a certain distance from the detector 18. However, from the viewpoint of miniaturizing the device, an integrated light emitter incorporating elements of multiple wavelengths may be used, or the detector 18 may be integrated with this integrated unit. [Industrial applicability]

[0033] The present invention provides a photoacoustic blood vessel separation and measurement device for blood biochemical components, enabling highly accurate and non-invasive separation and measurement of blood biochemical components such as blood glucose levels in venous and arterial blood. By putting this into practical use, it will be possible to continuously record blood biochemical components without pain, without the use of blood collection needles or other waste, and without requiring qualified medical professionals. Furthermore, by transferring measurement data to smartphones or PCs, it will enable self-medication, reduce medical costs, facilitate telemedicine, and pave the way for home-based medical care in an aging society. [Explanation of symbols]

[0034] 11 Control Unit 13 CPU 14 Synthesizers 15 Diode Power Controller 16 Diode Array Switch 17 Light-emitting device 18. Vibration detector 19 Tuning Amplifier 21 Enclosed Case 22 Light-emitting element (diode) 23 Cylindrical flange 24 Diode Support 25 Pseudoelastic body 27 Top of the casing 110 Correlation detector 112 A / D converters

Claims

1. Light emitters that emit light of specific wavelengths corresponding to blood biochemical components, water, and blood components in veins and arteries, respectively. A vibration detector that detects acoustic waves from the living body as vibrations, and irradiates the living body with light from the light emitter at specific wavelengths, and A control unit that processes the signal from the vibration detector for each specific wavelength and outputs the signal, Equipped with, A metal flange is provided between the vibration detector and the light emitter. An elastic body is provided on the flange, and the vibration detector is positioned via the elastic body. A photoacoustic blood biochemical component vascular separation analyzer in which the vibration detector and the flange end face are in contact with the living body, but the light emitter is positioned at a distance.

2. The photoacoustic blood biochemical component vascular separation analyzer according to claim 1, wherein the vibration detector comprises an oscillator and a metal case surrounding the oscillator.

3. The blood biochemical component photoacoustic vascular separation analyzer according to Claim 1, wherein the signal processing in the control unit involves dividing the depth direction signal intensity measured in the depth direction of the living body by the signal intensity of the living body surface measured at the natural frequency of the vibration detector.

4. The blood biochemical component photoacoustic vascular separation analyzer according to claim 1 or 3, wherein the control unit separates and measures blood biochemical components in veins and arteries based on signals from vibration detectors when light of a specific wavelength corresponding to blood components in veins and arteries is irradiated, respectively.

5. The blood biochemical component photoacoustic vascular separation measuring instrument according to claim 4, wherein the control unit calculates the amount of blood biochemical components corresponding to the positions of veins and arteries based on the signal intensity from the vibration detector when light of a specific wavelength corresponding to water and blood biochemical components is irradiated, respectively.

6. The photoacoustic blood biochemical component vascular separation analyzer according to claim 1 or 2, wherein the light emitter outputs a light pulse with a pulse width of 1 / 3 to 1 / 100 of the light emission period.

7. The blood biochemical component photoacoustic blood vessel separation analyzer according to claim 1 or 2, wherein the blood biochemical component is at least one selected from the group consisting of glucose, triglycerides, total protein, creatinine, and urea, and the light emitter comprises a light emitter that emits light of a specific wavelength corresponding to the blood biochemical component.

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