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WO2024262621A1 - Système et procédé utilisant une lumière diffusée par effet raman - Google Patents

Système et procédé utilisant une lumière diffusée par effet raman Download PDF

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Publication number
WO2024262621A1
WO2024262621A1 PCT/JP2024/022648 JP2024022648W WO2024262621A1 WO 2024262621 A1 WO2024262621 A1 WO 2024262621A1 JP 2024022648 W JP2024022648 W JP 2024022648W WO 2024262621 A1 WO2024262621 A1 WO 2024262621A1
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Prior art keywords
interference
scattered light
light
interference pattern
raman scattered
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Japanese (ja)
Inventor
昭彦 中島
理花 村井
直幸 福島
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Atonarp Inc
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Atonarp Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/1455—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using optical sensors, e.g. spectral photometrical oximeters
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/65—Raman scattering

Definitions

  • the present invention relates to a system and method using Raman scattered light.
  • JP Patent Publication 2013-517516 discloses an apparatus and method for reducing laser speckle by using stimulated Raman scattering in optical fibers.
  • the fiber core diameter and length are selected to obtain the desired output light, and tunable despeckle is formed by combining two optical fibers in parallel and adjusting the amount of light in each path with the aid of a rotatable waveplate and polarizer as a beam splitter.
  • JP Patent Publication No. 2010-532699 discloses a laser speckle imaging system and method.
  • This document provides an apparatus and method for measuring perfusion in tissue, the method including the steps of recording images of the tissue under laser light, calculating a plurality of contrast images from the plurality of images of the tissue, determining a power spectrum of the scattered light from the plurality of contrast images, and determining the perfusion from the power spectrum.
  • Body fluids from a living organism such as blood, contain blood cells and plasma as their main components, with blood cells including red blood cells, white blood cells, and platelets. Furthermore, in order to check the health of a living organism, it is necessary to measure glucose, hemoglobin A1c, creatinine, albumin, and other components in the blood in addition to the main components, and plasma glucose level is required as the measurement standard for blood glucose level. Therefore, for example, even if information on glucose concentration is obtained from a living organism, the value or evaluation of the information as information may differ depending on whether it is possible to determine the origin of the information.
  • Raman spectroscopy is a method of evaluating materials using Raman scattered light.
  • the light interacts with the material to emit Raman scattered light with a different wavelength from the incident light, and a spectrum is obtained that shows the intensity as a function of frequency or wavelength.
  • Chemical bond information can be obtained from the peak positions in the spectrum, and molecular structure information can be obtained from the waveform of the entire spectrum.
  • it is not easy to simultaneously obtain dynamic or spatial information about the source of Raman scattered light, and when the source (target) moves or fluctuates over time, it is not easy to identify the source or perform an analysis that takes into account the displacement of the source.
  • One aspect of the present invention is a system, for example a monitoring system, having a first information acquisition device that acquires first interference information including temporal fluctuations in an interference pattern of Raman scattered light from an object, and a first analysis device that analyzes the first interference information.
  • the interference pattern is typically two-dimensional, but may be three-dimensional.
  • the first analysis device may include a behavior analysis device that analyzes the behavior of a specific component or an object related thereto in the object based on the first interference information.
  • behavior refers to a phenomenon including fluctuations or displacements such as movement, shading, and pulsation of a specific component or an object related thereto. For example, the movement of an object flowing in a flow channel and the accompanying change in concentration of a component (fluctuations in content (content)).
  • the first analysis device includes a first pattern analysis device configured to analyze the temporal behavior of a specific component that causes Raman scattered light in the object or an object related thereto (source) based on the asymmetric intensity distribution of the interference pattern.
  • first interference information is obtained, which includes two-dimensional or three-dimensional temporal fluctuations of an interference pattern, typically speckles, which were required to be removed or reduced as noise in conventional Raman spectroscopy.
  • the interference pattern is generated by the interference and diffraction properties of Raman scattered light, and includes information on the order of wavelength from the source of the Raman scattered light to a sensor (detector, for example, an image element or an image element array) that acquires the interference pattern.
  • the Raman scattered light includes information on a specific component that is the cause of the Raman scattered light.
  • the inventors of the present application found that the interference pattern has an asymmetric intensity distribution, and that the asymmetric intensity distribution suggests various behaviors of the specific component or an object related to the specific component (for example, an object containing more of the specific component, an object containing less of the specific component, an object in which the specific component fluctuates in association with the behavior, etc.). Therefore, in this system, the behavior of the specific component or an object related to the specific component in the target can be analyzed by analyzing the fluctuations in the asymmetric intensity distribution of the interference pattern of the Raman scattered light over time using the first pattern analysis device.
  • the first information acquisition device may be configured to acquire first interference information including an interference pattern of one or more monochromatic Raman scattered lights. Coherent broadband Raman scattered light including one or more peaks reflecting the components contained in the object is generated, and the interference pattern can be acquired. On the other hand, by irradiating the object with laser light of a specific wavelength so as to obtain narrowband Raman scattered light of a specific wavelength of a specific component, it is possible to acquire an interference pattern of monochromatic Raman scattered light of a specific wavelength, and by analyzing this, the behavior of a specific component or an object containing it can be analyzed with greater precision.
  • the first pattern analysis device may be configured to analyze the behavior of a specific component or an object related to the component in the target object based on the intensity difference between multiple symmetrical regions (e.g., regions to the left and right, above and below the center of the interference pattern) included in the interference pattern.
  • multiple symmetrical regions e.g., regions to the left and right, above and below the center of the interference pattern
  • the first analysis device may include a second pattern analysis device configured to determine the concentration of a predetermined component or an object associated with the behavior in the object based on the intensity of the center of the interference pattern and a central region around it. This second pattern analysis device may be configured to determine the concentration of a predetermined component or an object associated with the behavior in the object based on the intensity difference in the central region of the interference pattern of the multiple monochromatic Raman scattered lights included in the first interference information.
  • the first analysis device may include a third pattern analysis device configured to obtain physical property values (e.g., pulse rate, flow rate, hematocrit value, etc.) associated with the behavior of the predetermined component or an object associated with the behavior in the object.
  • the first analysis device can analyze the change in intensity over time in a specific area of the interference pattern to obtain information about the source of Raman scattered light and its surroundings over time. For example, information such as the movement of the source or an object that includes the source, and changes in concentration of a specific component contained in the source can be obtained.
  • the first information acquisition device may be configured to acquire first interference information including an interference pattern of Raman scattered light by at least two laser lights. For example, by irradiating Stokes light and pump light, Raman scattered light can be induced, and the first information including the interference pattern can be acquired efficiently. Furthermore, the location in the depth direction where the spot is formed by at least two laser lights can be controlled. Therefore, an interference pattern that reflects the state of the depth where the spot is formed can be acquired, rather than an interference pattern that mainly reflects the state of the surface of the object.
  • the temporal behavior can be analyzed from the first interference information including the interference pattern to identify the source of the interference pattern, and the specific component can be qualitatively analyzed because it is Raman scattered light from that source.
  • the first information acquisition device may acquire first interference information including an interference pattern of scattered light of any of stimulated Raman scattering (SRS), Raman amplification, inverse Raman, coherent anti-Stokes Raman scattering (CARS), coherent Stokes Raman scattering (CSRS), and hyper-Raman scattering.
  • SRS stimulated Raman scattering
  • Raman amplification Raman amplification
  • inverse Raman coherent anti-Stokes Raman scattering
  • CARS coherent anti-Stokes Raman scattering
  • CSRS coherent Stokes Raman scattering
  • hyper-Raman scattering hyper-Raman scattering
  • the system may have a second information acquisition device configured to acquire second interference information including temporal fluctuations in an interference pattern from the object of a monochromatic laser light that is irradiated onto the object to generate Raman scattered light, and a second analysis device configured to analyze the behavior of the object based on the second interference information.
  • the interference pattern of the laser light may be two-dimensional or three-dimensional. An interference pattern of the laser light (laser speckle) can be obtained together with the interference pattern of the Raman scattered light (Raman speckle), and interference information including a wider range of information including the surface of the object can be obtained regardless of the source of the Raman scattered light.
  • the system may have a third information acquisition device configured to acquire an image of the surface of the object irradiated with the laser light to generate Raman scattered light, and an image analysis device configured to analyze the irradiation position of the laser light from the image.
  • the system may have a generation device configured to generate first interference information including an interference pattern by irradiating the object with the laser light to generate Raman scattered light and receiving the Raman scattered light from the object.
  • An example of a generation device is one that irradiates at least two laser lights onto blood in a blood vessel of a living body as the object, and generates first interference information including an interference pattern of the Raman scattered light.
  • the first information acquisition device may acquire first interference information including an interference pattern of Raman scattered light in which at least two laser lights are irradiated onto blood in a blood vessel of a living body as the object.
  • the predetermined component that is the source of the Raman scattered light may include at least one of glucose, hemoglobin A0, hemoglobin A1c, glycoalbumin, albumin, anhydroglucitol, fructosamine, insulin, glucagon, creatinine, and albumin.
  • the first analytical device may analyze the temporal behavior of plasma components and/or blood cell components in blood.
  • the system may also have an injection device that injects a drug into the living body based on the state of the living body obtained by the first analytical device.
  • the monitoring system includes an information acquisition device that acquires information about Raman scattered light from an object, and an analysis device that analyzes first interference information.
  • the method includes the information acquisition device acquiring first interference information including temporal fluctuations in an interference pattern of the Raman scattered light, and the analysis device analyzing the temporal behavior of a predetermined component that causes Raman scattered light in the object or an object related thereto, based on the asymmetric intensity distribution of the interference pattern.
  • Acquiring the first interference information may include acquiring first interference information including an interference pattern of at least one monochromatic Raman scattered light.
  • Acquiring the first interference information may include acquiring first interference information including an interference pattern of Raman scattered light caused by at least two laser lights.
  • the analyzing may include analyzing the behavior of a predetermined component or an object related thereto in the object over time based on the intensity difference of a predetermined region included in the interference pattern included in the first interference information.
  • the analyzing may include analyzing the behavior of a predetermined component or an object containing the predetermined component in the object over time based on the intensity difference of a plurality of regions included in the interference pattern included in the first interference information.
  • the analyzing may include analyzing the behavior of a predetermined component or an object related thereto in the object based on the intensity difference of a plurality of symmetrical regions included in the interference pattern.
  • the analyzing may determine the concentration of the predetermined component or an object related thereto in the object associated with the behavior based on the intensity of the center and its periphery of the interference pattern.
  • the determining the concentration may include determining the concentration of the predetermined component or an object related thereto in the object based on the intensity difference of the central region included in the interference pattern of a plurality of monochromatic Raman scattered lights included in the first interference information.
  • the method may include an information acquisition device acquiring second interference information including temporal fluctuations in an interference pattern from the object of monochromatic laser light irradiated to the object to generate Raman scattered light, and an analysis device analyzing the behavior of the object based on the second interference information.
  • Acquiring the first interference information may include acquiring first interference information including an interference pattern of Raman scattered light when blood in a blood vessel of a living organism is irradiated with at least two laser lights as the object.
  • the method may further include injecting a drug into the living organism based on the state of the living organism obtained by the analysis.
  • a system having a first information acquisition device that acquires first interference information including an interference pattern and a first analysis device that analyzes the first interference information may be implemented in a computer, and a program (program product) including instructions for causing a computer to function as the above-mentioned system or the first analysis device is included in the present invention, and the program may be provided recorded on an appropriate computer-readable recording medium.
  • FIG. 11 shows an example in which the estimated blood glucose value obtained in this example is compared with the actual measured value using a consensus error grid.
  • FIG. 12 shows a different example of an image element device.
  • FIG. 13 shows an overview of different examples of systems for acquiring CARS speckle.
  • FIG. 14 shows an example of a monitoring system.
  • FIG. 15 shows an example of measurement using a monitoring system.
  • FIG. 16 is a flowchart showing a process of measurement using the monitoring system.
  • This system 1 shows an overview of a system (biological monitoring system, monitoring system) 1 that acquires Raman scattered light and analyzes information contained in the Raman scattered light in relation to the present invention.
  • This system 1 includes a generating device (detecting device) 10 that irradiates a target with laser light to generate Raman scattered light, receives the Raman scattered light, and generates and provides information (first interference information) 81 that includes an interference pattern (scattering pattern, Raman speckle) 81p of the Raman scattered light, and a management device (monitor) 50 that acquires and analyzes the first interference information 81 and monitors and/or manages the living body 5.
  • a generating device (detecting device) 10 that irradiates a target with laser light to generate Raman scattered light, receives the Raman scattered light, and generates and provides information (first interference information) 81 that includes an interference pattern (scattering pattern, Raman speckle) 81p of the Raman scattered light
  • a management device (monitor) 50 that
  • This system 1 has blood 7 flowing through a blood vessel 6 of a sample (living body) 5 as an observation target (target, monitoring target), and acquires an interference pattern 81p of Raman scattered light 31 derived from blood.
  • the generating device (optical device, inspection device) 10 in this example acquires CARS (Coherent Anti-Stokes Raman Scattering) light 31 as Raman scattered light.
  • the biological monitoring system 1 may also include a medication system (injection device) 90 that injects medicine to maintain the health of the living body 5.
  • An example of a biomonitoring system 1 is a wearable mobile terminal with built-in communication functions and a user interface, such as a smart watch.
  • An example of a biomonitoring system 1 may be a desktop or laptop type terminal with built-in communication functions and a user interface.
  • An example of a medication system 90 is a system that injects a drug through the skin 5a of a living body 5, and may include an injector 91, a supply device (supply unit) 92 that supplies a specific drug to the injector 91, and a controller 93 that controls them.
  • a biological monitoring system (biological management system) 1 is a measurement system (blood glucose measurement device) that measures blood glucose levels.
  • the biological monitoring system 1 includes a generating device 10 that includes a Raman optical device (optical system) 19 that irradiates blood 7 flowing through a blood vessel 6 with laser light to generate CARS light 31.
  • the generating device 10 shown in FIG. 1 is an example, and shows a generating device that observes a part of a finger of a living body (patient, user) 5, for example, blood 7 flowing through a blood vessel 6 in a nail bed as shown in image 83 in FIG. 2.
  • the generating device 10 is not limited to this example as long as it can non-invasively irradiate blood 7 flowing through a blood vessel 6 through the skin of the living body 5 with laser light to generate information including Raman scattered light (CARS light) 31.
  • the generating device 10 may be equipped with a minimally invasive method such as controlling the light path with an implant embedded in the living body or forming a blood flow just under the skin by embedding an artificial blood vessel (bioport) in the living body.
  • the example generating device 10 includes a laser source 11 for generating (generating) pump light (first laser light) 35 and Stokes light (second laser light) 36.
  • An example of the pump light 35 is a monochromatic laser (narrowband laser) with a wavelength of 1030 nm.
  • An example of the Stokes light 36 is one or more monochromatic lasers (narrowband lasers) with a predetermined wavelength within the wavelength range of 1100-1300 nm.
  • the Stokes light 36 may be generated by a tunable laser, or a laser with a desired wavelength may be selected from broadband lasers with wavelengths of about 1100-1300 nm using a bandpass filter (BP).
  • BP bandpass filter
  • the wavelength bands of the pump light 35 and Stokes light 36 irradiated to the target to generate the Raman scattered light 31 are not limited to the above.
  • a probe light may be irradiated to the target, for example, a blood vessel 6 of a living body 5, to generate the Raman scattered light 31.
  • FIG 3 shows an example of a generating device 10 that generates CARS light 31 by irradiating a target with pump light 35 and Stokes light 36 from a laser source 11.
  • monochromatic pump light 35 of 1030 nm and two types of monochromatic Stokes light 36 with wavelengths of 1155 nm and 1159 nm selected from broadband laser light 36b are supplied.
  • These pump lights 35 and Stokes lights 36 are irradiated onto blood 7 in a blood vessel 6, which is the target, to generate CARS light 31 whose source is blood 7, which is detected (acquired) by the generating device 10.
  • CARS light 31 with a wavelength of 928.7 nm corresponding to the Stokes light 36 with a wavelength of 1155 nm and CARS light 31 with a wavelength of 925.8 nm corresponding to the Stokes light 36 with a wavelength of 1159 nm are generated and are received by the two-dimensional image sensor array (EMCCD) 13 in a time-division manner.
  • the method of acquiring a plurality of monochromatic CARS lights 31 is not limited to time-division, and as described later, the image sensor array 13 may be divided to simultaneously acquire CARS lights 31 with different wavelengths (in parallel, in parallel).
  • the image sensor array 13 of the generating device 10 generates the first interference information 81 including the interference pattern 81p of the CARS light 31 of each wavelength.
  • the interference pattern 81p includes the laser speckle of the CARS light 31 of each wavelength.
  • the interference pattern 81p including the laser speckle (Raman speckle, CARS speckle) of the CARS light 31 is generated by the interference and diffraction of the CARS light 31, which is Raman scattered light, and includes information on the order of wavelength from the source of the CARS light 31 to the image sensor array 13, which is a sensor that acquires the interference pattern 81p.
  • an example of the source of the CARS light 31 is a component contained in the blood 7 in the blood vessel 6.
  • the source (location of generation) of the CARS light 31 is inside the living body. Therefore, the interference pattern 81p obtained from the CARS light 31 can be used as one of those called biospeckles.
  • the first interference information 81 including the interference pattern 81p of the CARS light 31 will be referred to as CARS speckle 81.
  • the CARS speckle 81 may include information on the interference pattern 81p as a speckle image, or may be information converted or compressed into data such as the average brightness (average intensity) of a predetermined area (e.g., the central area) of the speckle image (interference pattern) 81p, or the brightness difference (intensity difference) of multiple predetermined areas (e.g., multiple areas symmetrical around the center, left and right, top and bottom) of the speckle image 81p.
  • a predetermined area e.g., the central area
  • the speckle image (interference pattern) 81p the brightness difference (intensity difference) of multiple predetermined areas (e.g., multiple areas symmetrical around the center, left and right, top and bottom) of the speckle image 81p.
  • FIG 4 shows an example of a spectrum (CARS spectrum) 84 obtained by dispersing CARS scattered light 31 obtained using broadband Stokes light.
  • the CARS spectrum shown in Figure 4(a) is an example of a CARS spectrum 84a of a glucose solution (20% solution) and a CARS spectrum 84b of water.
  • the CARS spectrum 84a of the glucose solution has a peak Pg specific to glucose that has a top near a wavelength of 928.7 nm and a bottom near a wavelength of 925.8 nm.
  • the wavelength of the Stokes light 36 for generating the CARS light 31a with a wavelength of 928.7 nm is 1155 nm
  • the wavelength of the Stokes light 36 for generating the CARS light 31b with a wavelength of 925.8 nm is 1159 nm.
  • the generating device 10 of the monitoring system 1 shown in FIG. 1 irradiates the pump light 35 and Stokes light 36 supplied from the laser source 11 onto the object, in this example, the skin 5a of a living body (finger) 5 in which blood vessels 6 exist, and focuses the pump light 35 and Stokes light 36 on the blood vessels 6 through the skin 5a.
  • the generating device 10 receives the CARS light (Raman scattered light) 31 generated by the blood 7 in the blood vessels 6 with the image sensor 13, and is configured to generate CARS speckles 81.
  • the generating device 10 includes a supply optical system (laser light supply optical path, fifth optical path) 25 that guides the pump light 35 and Stokes light 36 supplied from the laser source 11 to a lens (objective lens) 12 facing the object, and a first optical path (first interference pattern acquisition optical system) 21 that guides the CARS light 31 generated by the object and input through the objective lens 12 to a first image sensor array (EMCCD) 13.
  • a supply optical system laser light supply optical path, fifth optical path
  • first optical path first interference pattern acquisition optical system
  • An example of the objective lens 12 is an immersion objective lens, such as a silicone immersion objective lens (silicone oil immersion objective lens), which allows for a larger numerical aperture and a finer resolution to be obtained.
  • the objective lens 12 may also be an air immersion lens (air objective lens), which allows for a higher intensity signal to be obtained.
  • the generating device 10 further includes a second optical path (second interference pattern acquisition optical system) 22 that guides reflected light (scattered light, second scattered light) 32 of the pump light 35 reflected from the skin 5a (at or near the surface of the skin 5a) via the objective lens 12 to a second image sensor array (CCD) 14, and a third optical path (image acquisition optical system) 23 that guides visible light 33 reflected from the surface of the skin 5a where the object is present via the objective lens 12 to a camera 15.
  • the generating device 10 may also include a fourth optical path (spectrum acquisition optical system) 24 that guides the CARS light 34 to a spectroscope (spectrometer) 16 for spectroscopic analysis.
  • Each of the optical paths 21 to 25 may include an appropriate optical element corresponding to the purpose, such as a prism, a mirror, or a filter.
  • a dichroic mirror 25a that reflects light with a wavelength of 980 nm or less may be provided upstream of the objective lens 12 to separate the short-wavelength CARS light 31 and the visible light image 33 input from the objective lens 12 into the first optical path 21 and the third optical path 23.
  • a dichroic mirror 21a that reflects light with a wavelength of 805 nm or less may be provided at the branch point between the first optical path 21 and the third optical path 23 to separate the visible light image 33 into the third optical path 23.
  • a filter group 21b that allows light with a wavelength of 900 to 960 nm to pass may be provided upstream of the image sensor array 13 that captures the CARS speckles 81.
  • the optical path 25 that guides the pump light 35 and the Stokes light 36 to the objective lens 12 may be provided with a beam splitter 25b for guiding the scattered light 32 of the pump light 35 input from the objective lens 12 to the second optical path 22.
  • the generating device 10 may be equipped with a scanning device (scanner) 17 that can adjust the spot positions (irradiation positions) of the pump light 35 and the Stokes light 36 in three dimensions by manipulating the objective lens 12.
  • the scanner 17 may include a function of automatic control based on the visible light image 33 obtained by the camera 15. It may also be controlled based on the analysis results of the management device 50 described below or an automatic sequence (protocol) for measurement.
  • the scanner 17 may also be equipped with a function of scanning in the depth direction (Z direction) so that the spot positions of the pump light 35 and the Stokes light 36 can be adjusted to the position of the blood vessel 6 under the skin.
  • an interference pattern of CARS light (CARS speckle) 81p is generated in the first image sensor array 13 of the first optical path 21 to which the CARS light 31 is guided.
  • the first interference information 81 including the interference pattern 81p generated by the generating device 10 is sent to the management device (management device, monitor device) 50.
  • the scattered light 32 of the pump light 35 from the skin 5a passes through the dichroic mirror 25a and is guided to the second optical path 22, and an interference pattern of the pump light (laser speckle, pump laser speckle) 82p is generated in the second image sensor array 14.
  • the second interference information 82 including the interference pattern 82p generated by the generating device 10 is sent to the management device 50.
  • a filter 22a for separating light of a wavelength other than the scattered light 32 of the pump light, for example, the Stokes light 36, may be provided upstream of the second image sensor array 14.
  • the image (image information) 83 obtained by the visible light camera 15 and the spectral information 84 obtained by the spectrometer 16 generated by the generation device 10 may also be sent to the management device 50.
  • FIG. 5 shows examples of some information obtained by the generating device 10.
  • FIG. 5(a) shows an example of a visible light image 83, in which a blood vessel 6 and pump light 35 and Stokes light 36 irradiated in accordance with the position of the blood vessel 6 are shown.
  • the visible light image 83 it can be confirmed that the pump light 35 and Stokes light 36 are irradiated to form a spot on the blood vessel 6 or in its vicinity.
  • FIG. 5(b) shows an example of second interference information (hereinafter, pump laser speckle) 82 including an interference pattern 82p of the scattered light 32 of the pump light 35.
  • pump laser speckle second interference information
  • the scattered light 32 of the pump light 35 includes information on the surface structure of the skin 5a irradiated with the pump light 35 and the movement of the skin 5a, i.e., information on the relative minute three-dimensional movement (displacement) between the living body (finger) 5 and the pump light 35, and such information is reflected in the pump laser speckle 82. Therefore, by referring to the temporal displacement of the pump laser speckle 82, the relative behavior (movement, displacement) of the source of the CARS light 31, i.e., the spots (irradiation positions) of the pump light 35 and the Stokes light 36, and the finger 5 can be grasped in three dimensions, and this can be one factor in determining whether the spots are being maintained in the desired location.
  • Figure 5(c) shows an example of an interference pattern 85 of CARS light obtained by broadband Stokes light.
  • Figure 5(d) shows an example of an interference pattern 81p of CARS speckle 81 (81a) obtained by narrowband Stokes light 36 with a wavelength of 1155 nm
  • Figure 5(e) shows an example of an interference pattern 81p of CARS speckle 81 (81b) obtained by narrowband Stokes light 36 with a wavelength of 1159 nm.
  • the interference pattern 81p in this example was acquired by an EMCCD (1024 x 1024 pixels) at a frame rate of 4.9 ms (202.55 Hz), but the frame rate etc. are not limited to this example.
  • the bandwidth of CARS light 31 obtained by narrowband Stokes light 36 is narrow, the interference or diffraction pattern of the CARS speckle 81 appears clearly. Therefore, by referring to the CARS speckle 81 of the CARS light 31 generated by the narrowband Stokes light (monochromatic Stokes light) 36, the behavior of the source of the CARS light 31, in this example the behavior of the composition components in the blood 7 in the blood vessel 6, can be grasped with greater accuracy.
  • the CARS speckle 81a shown in FIG. 5(d) corresponds to an interference pattern 81p of CARS light 31 at 928.7 nm, which is the top of the glucose peak in the CARS spectrum
  • the CARS speckle 81b shown in FIG. 5(e) corresponds to an interference pattern 81p of CARS light 31 at 925.8 nm, which is the bottom of the glucose peak in the CARS spectrum. Therefore, by obtaining the intensity difference between these CARS speckles 81a and 81b, for example, the difference in the average brightness of a predetermined region (the center and the central region around it) 88 including the center 89 of the interference pattern 81p as shown in FIG. 5(f), information corresponding to the glucose concentration (content rate, amount) can be obtained.
  • the inventors of the present application found that the interference pattern 81p shown in this example has an asymmetric intensity distribution, and that the asymmetric intensity distribution suggests various behaviors of a specific component or an object related to that specific component (e.g., an object containing more of the specific component, an object containing less of the specific component, an object whose specific component fluctuates with its behavior, etc.). For example, even if the intensity of the interference pattern 81p is the same, the intensity difference between the left and right regions 87a and 87b may be reversed, which allows information to be obtained regarding the situation of the movement of the source.
  • One example is thought to include information regarding the entry and exit of constituent components such as plasma or blood cells in blood vessels into and out of the spot (irradiation position, focus) of the laser that generates Raman scattering light. That is, the movement of blood cells (red blood cells, white blood cells, etc.) and plasma in blood vessels, and their behavior is reflected in the interference pattern 81p, and the behavior of a specific component or an object related to it in the target object can be analyzed by analyzing the fluctuations in the asymmetric intensity distribution of the interference pattern over time.
  • constituent components such as plasma or blood cells in blood vessels into and out of the spot (irradiation position, focus) of the laser that generates Raman scattering light. That is, the movement of blood cells (red blood cells, white blood cells, etc.) and plasma in blood vessels, and their behavior is reflected in the interference pattern 81p, and the behavior of a specific component or an object related to it in the target object can be analyzed by analyzing the fluctuations in the asymmetric intensity distribution of the interference pattern over time.
  • the system may be configured to analyze the behavior of a specific component in an object or an object related thereto based on the intensity difference between multiple symmetrical regions 87a and 87b (in this example, regions to the left and right of the center 89 of the interference pattern 81p) contained in the interference pattern 81p.
  • the multiple symmetrical regions may be upper and lower regions, and the shape of the region may be a square, or may be another polygon, semicircle, sector, etc.
  • the size and shape of the region for which the intensity (brightness) of the interference pattern 81p is to be determined may be determined according to the application.
  • the management device 50 of the biological monitoring system 1 shown in FIG. 1 may include a laser control device 51 that controls the laser source 11 of the generating device 10, an information acquisition device (input device, input interface) 52 that acquires information such as CARS speckles 81 from the generating device 10, an analysis device 53 that analyzes the acquired information, a database (library) 54 that stores the acquired information, information for analysis, and further programs 54p, a medication control device 95 that controls the medication system 90, and an input/output interface 60 that controls a user interface 61 such as a display or touch panel.
  • a laser control device 51 that controls the laser source 11 of the generating device 10
  • an information acquisition device (input device, input interface) 52 that acquires information such as CARS speckles 81 from the generating device 10
  • an analysis device 53 that analyzes the acquired information
  • a database (library) 54 that stores the acquired information, information for analysis, and further programs 54p
  • a medication control device 95 that controls the medication system 90
  • an input/output interface 60 that controls
  • the input/output interface 60 may include a function 60a for communicating with an external device wirelessly or via a wire, and an alarm function 60b for reporting the results of the analysis device 53 and/or an alarm resulting therefrom to the user interface 61 or a predetermined institution (such as a hospital or security service provider).
  • An example of the management device 50 is an information processing device such as a computer or server equipped with computer resources such as a CPU and memory, and performs a predetermined function by downloading a program 54p recorded in an appropriate computer-readable recording medium such as a database 54.
  • the information acquisition device (input device) 52 includes a first information acquisition device (first information acquisition function, information acquisition unit) 52a that acquires first interference information (CARS speckle) 81 including temporal fluctuations in a two-dimensional or three-dimensional interference pattern 81p of Raman scattered light from an object, a second information acquisition device (second information acquisition function, information acquisition unit) 52b that acquires second interference information (pump laser speckle) 82 including temporal fluctuations in a two-dimensional or three-dimensional interference pattern 82p from an object of monochromatic laser light (pump light in this example) 35 that is irradiated to the object to generate Raman scattered light, a third information acquisition device (third information acquisition function, information acquisition unit) 52c that acquires image information 83 of the surface of the object to which the laser light is irradiated to generate Raman scattered light, and a fourth information acquisition device (fourth information acquisition function, information acquisition unit) 52d that acquires a Raman spectrum 84 obtained by dispersing the Raman scattered light.
  • first information acquisition device
  • the first interference information 81 in this example may include interference patterns 81a and 81b of two monochromatic Raman scattered lights 31 generated by two monochromatic Stokes lights 36, respectively, as described above.
  • the first interference information 81 may include only an interference pattern 81p of one monochromatic Raman scattered light 31.
  • it is possible to estimate the glucose concentration by only acquiring an interference pattern 81p of Raman scattered light 31 of a wavelength corresponding to the top of the glucose peak.
  • an interference pattern 81p of Raman scattered light 31 of multiple wavelengths, such as the top and bottom of the peak may be acquired.
  • the first interference information 81 in this example is a CARS speckle, and includes an interference pattern 81p of Raman scattered light (CARS light) 31 caused by at least two laser lights, the pump light 35 and the Stokes light 36.
  • the CARS light 31 may be generated by irradiating a probe light having a wavelength of, for example, about 780 nm in addition to the pump light 35 and the Stokes light 36, or may be TD-CARS light (time-dependent CARS light) generated by a probe light delayed with respect to the pump light 35 and the Stokes light 36.
  • TD-CARS light time-dependent CARS light
  • CARS speckles 81 are acquired, but the method is not limited to inverse Raman and coherent anti-Stokes Raman scattering (CARS), and may be an interference pattern of Raman scattered light obtained by stimulated Raman scattering (SRS), Raman amplification, coherent Stokes Raman scattering (CSRS), hyper-Raman scattering, etc.
  • the interference pattern is generated by a two-dimensional image sensor array such as a CCD, but since the scattered light is not completely collimated light, a three-dimensional interference pattern may be obtained, for example, the scattered light may be split by a beam splitter or the like to acquire multiple interference patterns at different depths. More information related to the interference and/or diffraction contained in the scattered light can be acquired with even greater precision.
  • the analysis device 53 includes a first analysis device (CARS speckle analysis device) 56 that analyzes the behavior of a specific component or an object containing the same in an object such as blood based on CARS speckle 81, which is the first interference information; a second analysis device (pump laser speckle analysis device) 57 that analyzes the behavior (relative behavior) of the object based on pump laser speckle 82, which is the second interference information; a third analysis device (image analysis device) 58 that analyzes image information 83; a fourth analysis device (spectrum analysis device) 59 that analyzes CARS spectrum 84; and an automatic analysis device 55 for automatically performing these analyses by the analysis device 53.
  • CARS speckle analysis device CARS speckle analysis device
  • the first analysis device 56 includes a first pattern analysis device (first behavior analysis device, first pattern analysis function, analysis unit) 56a configured to analyze the temporal behavior of a specific component that causes Raman scattered light in the object or an object related to the specific component, based on the asymmetric intensity distribution of the interference pattern 81p included in the first interference information (CARS speckle) 81.
  • the first pattern analysis device 56a may be configured to analyze the behavior of a specific component in the object or an object related to the specific component, based on the intensity difference between multiple symmetrical regions (e.g., left and right regions 87a and 87b) included in the interference pattern 81p.
  • the first analysis device 56 may further include a second pattern analysis device 56b (second behavior analysis device, analysis function, analysis unit) configured to determine the concentration of a predetermined component in the object associated with the behavior based on the intensity of the center of the interference pattern 81p and a central region 88 around it.
  • the second pattern analysis device 56b may be configured to determine the concentration of a predetermined component in the object or an object associated therewith based on the intensity difference of the central region 88 of the interference patterns 81a and 81b of the multiple monochromatic Raman scattering lights included in the first interference information 81.
  • the first analysis device 56 may further include a third pattern analysis device (third behavior analysis device) 56c configured to obtain physical property values related to the behavior of a predetermined component in the object or an object associated therewith.
  • FIGS. 6 and 7 show an example of a two-dimensional CARS speckle 81 obtained from a living body using pump light 35 and narrowband Stokes light 36 with a wavelength of 1155 nm.
  • An example of a CARS speckle 81 is a bundle of frames each including an interference pattern 81p along the time at which the frames were acquired.
  • the frame rate may be in the range of several tens of microseconds to several hundreds of milliseconds, or several hundred microseconds to several tens of milliseconds.
  • the frame rate needs to be sufficiently shorter than the movement (displacement) speed of the object whose behavior is to be obtained, and needs to be such that an interference pattern 81p of a measurable intensity can be obtained.
  • Figure 6 shows the time change (vertical direction) of intensity (brightness) in the horizontal direction (X-axis, center line) passing through the center of a CARS speckle 81 containing multiple frames.
  • Figure 7 shows an enlarged portion of the CARS speckle 81.
  • the source the component that appears as a characteristic
  • the CARS speckles 81 reflect the temporal behavior and concentration of glucose as a component in the living body and objects related to it, such as tissues, cells, blood cells and/or plasma in blood, and lymphocytes and/or plasma in lymph.
  • 6(a) and 7(a) show CARS speckles 81 obtained from subcutaneous tissue, and almost no change in intensity over time is observed.
  • 6(b) and 7(b) show CARS speckles 81 obtained from within a blood vessel 6, and it can be seen that the intensity (intensity and brightness) repeatedly changes at regular intervals. Therefore, by obtaining the intensity difference in frame units (over time) of a specified area including the center of the CARS speckle 81 using the first analysis device 56, it is possible to grasp physical properties associated with the behavior (flow) of the blood 7 in the blood vessel 6, which is the subject of this example, such as pulse rate and blood flow velocity.
  • the first analysis device 56 which is a CARS speckle analysis device, may include a fourth pattern analysis device 56d that determines whether or not the CARS speckle 81 is a signal from a blood vessel 6 by performing a comprehensive analysis of the CARS speckle 81.
  • Figure 8 shows the intensity on the X-axis of CARS speckles 81 derived from glucose in blood.
  • Figure 8(a) shows the intensity change on the X-axis of high-intensity frames included in the course of CARS speckles 81 (dynamic speckle image, speckle video, speckle flow), i.e., the intensity change on the X-axis of interference pattern 81p.
  • Figure 8(b) shows the intensity change on the X-axis of low-intensity frames included in the course of CARS speckles 81, i.e., the intensity change on the X-axis of interference pattern 81p.
  • FIG. 9 shows an example of the results of analyzing CARS speckles 81 derived from glucose in blood in the time direction.
  • the vertical axis (Y axis) shows the results of calculating the intensity difference (difference in brightness) by dividing a predetermined region from the center of the CARS speckle 81 into multiple regions, in this example, the left and right regions 87a and 87b shown in FIG. 5(f)
  • the horizontal axis (X axis) shows the average intensity of a predetermined region corresponding to almost the entire CARS speckle 81, for example the intensity (brightness) of the central region 88
  • the Z axis shows the time elapse (number of frames), showing the results calculated for each frame plotted.
  • the information contained in the CARS speckle 81 fluctuates in a spiral manner over time by processing it as described above. This is assumed to indicate that blood 7 flows through the blood vessel 6 forming the spot (focus) of the pump light 35 and the Stokes light 36, and red blood cells enter and leave the spot.
  • the first pattern analyzer 56a can therefore analyze the behavior of red blood cells in blood 7 based on the intensity difference between multiple regions of the CARS speckle 81.
  • the second pattern analyzer 56b can extract CARS speckle 81 of the plasma portion suitable for measuring blood glucose levels from the blood-derived CARS speckle 81 and obtain the intensity of its central region 88 to obtain the glucose concentration mainly reflected in the CARS speckle 81.
  • the third pattern analyzer 56c can extract frames to which red blood cells are the main contributor and frames to which plasma is the main contributor from among the many frames of the CARS speckle 81, making it possible to obtain, for example, the hematocrit value, which is the ratio of red blood cells to plasma, as a physical property value related to the behavior of red blood cells.
  • FIG. 10 shows an example in which CARS speckles 81a and 81b are obtained in sequence, for example, in 3-second intervals (3-second intervals, 3-second time divisions), from narrowband Stokes light 36 with a wavelength of 1155 nm and narrowband Stokes light 36 with a wavelength of 1159 nm.
  • the second pattern analyzer 56b extracts a frame reflecting an interference pattern 81p of a plurality of monochromatic Raman scattering lights contained in the CARS speckle 81, in this example, an interference pattern 81p of two-color CARS speckles 81a and 81b at 928.7 nm, which is the top of the glucose peak in the CARS spectrum, and 925.8 nm, which is the bottom of the peak, due to the narrowband Stokes light 36 of each of the above wavelengths, and obtains the intensity difference of each predetermined region, for example, a region 88 including the center.
  • This intensity difference corresponds to the glucose concentration in the plasma portion of the blood 7, so that it is possible to obtain quantitative and highly accurate information on the blood glucose level, including changes over time.
  • the CARS speckle of the frame corresponding to the plasma portion of the 3D profile shown in FIG. 9 may be selected.
  • Figure 11 shows the estimated blood glucose level obtained by the above process using the system 1 of this example, compared with the actual measured value (reference) obtained by a glucose meter (Glucometer (SMBG) Nipro Freestyle Freedom Lite) using a consensus error grid.
  • Glucometer Glucometer
  • the system 1 of this example can provide a function as a sensor that constantly measures blood glucose levels in real time, a function as a blood glucose monitor, and a function to manage the human body based on blood glucose levels.
  • the system 1 can also provide a function to constantly monitor other physical properties (parameters) in the blood, not just blood glucose levels, in real time.
  • Figure 12 shows different examples of an image sensor array (image generating device, image sensor) 13 for generating an interference pattern.
  • image sensor array image generating device, image sensor
  • the image sensor array 13 shown in Figure 12 has a Bayer pattern (Bayer pattern, Bayer arrangement, Bayer filter) as shown in Figure 12 (a), and as shown in Figure 12 (b), three types of pixels or filters 13a to 13c sensitive to three types of light with different wavelengths are arranged in a checkerboard pattern.
  • this image sensor array 13 multiple, for example, three types of monochromatic interference patterns can be acquired in parallel.
  • the original interference pattern obtained by the image sensor array 13 is a mosaic image.
  • an image (interference pattern) for each color can be obtained as shown in Figure 12 (c).
  • FIG. 13 shows another example of a generating device 10 that generates CARS light 31 by irradiating a target with pump light 35 and Stokes light 36 from a laser source 11.
  • this generating device 10 monochromatic pump light 35 and monochromatic (narrowband) Stokes light 36 of four different wavelengths selected from broadband laser light 36b are irradiated to blood 7 in a blood vessel 6, which is a target, to generate CARS light 31 of four different wavelengths originating from blood 7.
  • These CARS lights 31 of different wavelengths are spatially separated by a beam splitter 18 and guided to one or more imaging element arrays (image sensors) 13, and interference patterns of CARS light 31 of each wavelength are generated in parallel (simultaneously).
  • the beam splitter 18 may be adjusted so that interference patterns of CARS light 31 of different wavelengths are generated in different areas of one image sensor 13, or may be adjusted so that interference patterns of CARS light 31 of different wavelengths are generated in different image sensors 13.
  • the narrowband Stokes light 36 may be generated from the broadband Stokes light 36b using a bandpass filter, a diffraction grating, or the like.
  • the narrowband 6 may be generated using a tunable laser.
  • FIGS. 14 and 15 show an example of a biomonitoring system (monitoring system, monitor) 1 that measures the blood glucose level in the blood flowing through the blood vessels in the human wrist (more specifically, the inside of the wrist (palm side)) 5.
  • this monitoring system 1 is a portable desktop-type device that is approximately 250 mm in length and width and 120 mm in height, and includes a housing 66 that incorporates the generating device 10 and the management device 50, and a cover 65 that also serves as a user interface 61.
  • a display 61 with a touch panel function appears as a user interface
  • a mechanism 64 for setting the user's wrist 5 appears on the top surface of the housing 66.
  • the top surface of the housing 66 includes an arm mounting section 67 that is recessed in the shape of a hand so that the hand (arm) can be placed on it and the wrist can be easily aligned to a predetermined position, a palm rest 68 for holding the wrist in front of the objective lens 12 of the generating device 10, and a wrist strap (wristband) 69 for holding the wrist.
  • the user opens the cover 65 of the biomedical management system 1 and places the inside of the wrist 5 on the top surface of the housing 66 facing the objective lens 12 of the generating device 10, thereby enabling the blood glucose level to be measured non-invasively and in real time and displayed on the display 61.
  • the biomedical management system 1 may include a medication device 90 in addition to the management device 50 in the housing 66, and may be configured to automatically receive processing according to the measurement results.
  • step 101 the management system 1 is installed at a predetermined location on the human body and measurement is started.
  • the inside of the wrist 5 is set to face the objective lens 12 of the generation device 10, and then the start button of the management system 1 is clicked.
  • step 102 the blood vessel 6 to be measured is automatically selected. This process may be performed automatically (autonomously) by the scanning device 17 of the generation device 10 using the image information 83 obtained by the generation device 10, or may be performed by the image analysis device 58 of the management device 50.
  • An example of a blood vessel 6 selected based on the image information 83 is a capillary vessel with a blood vessel diameter of 6 ⁇ m or less and a blood flow velocity of 300 ⁇ m/sec or less that can be observed from a flat portion of the wrist 5.
  • step 103 detailed alignment of the laser (laser spot, irradiation position) to be irradiated onto the selected blood vessel 6 is performed.
  • This process may also be performed automatically (autonomously) by the scanning device 17 of the generating device 10 using the image information 83, or may be performed by the image analysis device 58 of the management device 50.
  • Image information 83 of the pump light 35 and Stokes light 36 actually irradiated onto the skin 5a of the wrist 5 may be obtained, and the laser spot may be aligned with the blood vessel 6.
  • step 104 the generating device 10 irradiates the skin 5a of the wrist 5 with pump light 35 and Stokes light 36, generates CARS light 31, and acquires interference information (CARS speckle) 81 including an interference pattern 81p.
  • the generating device 10 generates pump laser speckle 82 and image information 83 together with the CARS speckle 81, and supplies them to the managing device 50.
  • step 105 the managing device 50 analyzes this information (data) acquired via the acquiring device 52 with the analyzing device 53 to verify the accuracy of the information. Items to be verified include (1) whether the signal (data) is derived from blood, (2) whether any signals other than blood are mixed in, and (3) whether there is positional stability.
  • Whether or not a signal is derived from blood may be determined, for example, by the fourth pattern analyzer 56d of the first analyzer 56 comparing the intensity (average intensity) of the central region 88 of the interference pattern 81p contained in the CARS speckle 81 with that observed when tissue is observed, and determining whether or not there is an oscillatory increase or decrease in brightness intensity on a time scale of 10-100 ms.
  • Whether or not a signal other than blood is mixed in may be determined, for example, by the first pattern analyzer 56a of the first analyzer 56, by determining whether or not a stable spiral structure is observed in the 3D plot image shown in FIG. 9 after a predetermined time (predetermined number of frames) has elapsed.
  • the criterion may be whether or not a stable spiral structure is observed for 1 second or more, at about 10 times/second.
  • the positional stability may be determined based on the behavior of the object (skin 5a or human body (wrist)) 5 obtained by analyzing the second interference information (pump laser speckle) 82, which includes temporal fluctuations in the interference pattern 82p from the object (skin 5a) of the monochromatic laser light (pump light 35 in this example) irradiated to the object to generate Raman scattered light, acquired by the information acquisition device 52, using the second analysis device 57. For example, if a fluctuation of 10% or more is observed in the brightness (intensity) of the central region of the interference pattern 82, it may be determined that the object's position is unstable.
  • the image information 83 may be analyzed by the image analysis device 58, and it may be determined that the object's position is unstable because vibrations or shifts are observed in the relative positions of the spots of the pump light 35 and/or Stokes light 36 and the blood vessel 6.
  • the fourth analyzer (spectral analyzer) 59 of the first analyzer 53 may intermittently or periodically analyze the CARS spectrum 84 to determine whether a predetermined CARS signal, for example a peak or trough corresponding to glucose, has been obtained.
  • a predetermined CARS signal for example a peak or trough corresponding to glucose
  • the analysis device 53 performs data processing.
  • the first analysis device 56 analyzes the first interference information (CARS speckle) 81 including the temporal fluctuation of the interference pattern 81p of the Raman scattered light acquired by the information acquisition device 52.
  • the first pattern analysis device 56a analyzes the temporal behavior of objects (blood cells (red blood cells) and plasma in this example) related to a specific component (glucose in this example) that causes Raman scattered light in the blood vessel 6, which is the target, based on the asymmetric intensity distribution of the interference pattern 81p. More specifically, the first pattern analysis device 56a analyzes the behavior of the blood cells and plasma in the blood vessel based on the intensity difference between multiple symmetrical regions (left and right regions) 87a and 87b included in the interference pattern 81p.
  • the second pattern analyzer 56b determines the concentration of a predetermined component or an object related to the behavior in the object based on the intensity of the center of the interference pattern 81p and the surrounding region 88.
  • the second pattern analyzer 56b determines the value of glucose in the plasma (plasma blood glucose level), which is one of the objects whose behavior has been confirmed in the blood 7, which is the object. More specifically, a frame corresponding to the bottom (the part where the intensity difference between the left and right regions 87a and 87b is small) of the spiral pattern of the 3D plot image shown in FIG. 9 generated by the first pattern analyzer 56a is selected from the CARS speckle 81, and the plasma blood glucose level is determined based on the intensity of the central region 88.
  • the second pattern analyzer 56b can determine the plasma blood glucose level based on the intensity difference of the central region 88 included in the interference pattern 81p of multiple monochromatic Raman scattering lights (in this example, the interference pattern of one peak wavelength of glucose and the interference pattern of the bottom wavelength) of CARS speckle 81.
  • the second pattern analysis device 56b is not limited to obtaining plasma glucose levels, but can also obtain blood glucose levels of blood cells (red blood cells), and may select multiple frames that are most suitable for calculating the glucose level from the CARS speckles 81 obtained from the generation device (detection device) 10, and obtain the desired glucose level based on those frames.
  • the third pattern analyzer 56c of the first analyzer 56 may obtain a physical property value related to the behavior of a predetermined component or an object related thereto in the object, for example, a hematocrit value indicating the ratio of red blood cells to plasma.
  • the first analyzer 56 may obtain information on components other than glucose that cause CARS scattered light, that is, components that have a large effect on CARS scattering or substances related thereto, using the interference pattern 81p of multiple monochromatic CARS scattered lights.
  • hemoglobin A0, hemoglobin A1c, glycoalbumin, albumin, anhydroglucitol, fructosamine, insulin, and glucagon can be listed as targets (components) for which abnormalities in the body can be detected in relation to blood glucose levels.
  • targets (components) for which abnormalities in renal function can be detected include creatinine and albumin.
  • Other blood components may be measured and monitored using this management system 1. Additionally, the management system 1 may acquire other information regarding blood vessels or blood, such as blood flow and pulsation (beats), and these may also be subject to monitoring.
  • the input/output interface 60 displays the various measured results on the user interface 61.
  • the input/output interface 60 may provide the measured results to a specified external system.
  • the medication control device 95 determines whether or not medication is required based on the measured results. If the medication control device 95 determines that medication, for example, injection of insulin, is required, in step 109, it causes the medication system 90 to perform a procedure to inject a specified drug into the user.
  • the system 1 of this example has a generating device (detecting device) 10 that irradiates at least two laser beams 35 and 36 onto blood 7 in a blood vessel 6 of a living body 5 as an object, and generates first interference information (CARS speckle) 81 including an interference pattern of the Raman scattered light.
  • the first analyzing device 56 can also analyze the temporal behavior of plasma components and/or blood cell components in the blood, and in the above example, calculates the blood glucose level from the glucose concentration contained in the plasma components.
  • the first analyzing device 56 can analyze the quantitative behavior of components other than glucose, for example, components including at least one of hemoglobin A1c, creatinine, and albumin.
  • components contained in other bodily fluids can also be measured in a similar manner.
  • the main components are not limited to plasma components and red blood cells, but may also include other blood cell components, for example, white blood cells and/or platelets.
  • the target component whose concentration is to be measured may include any of the components that are the subject of testing for bodily fluids such as blood.
  • the subject of measurement may be any chemical, molecule, compound, composition, microorganism, or aggregate, including, but not limited to, blood cells, amino acids, peptides, polypeptides, proteins, glycoproteins, lipoproteins, nucleosides, nucleotides, oligonucleotides, nucleic acids, sugars, carbohydrates, oligosaccharides, polysaccharides, fatty acids, lipids, hormones, metabolites, cytokines, chemokines, receptors, neurotransmitters, antigens, allergens, antibodies, substrates, cofactors, inhibitors, drugs, pharmaceuticals, nutrients, prions, toxins, poisons, explosives, pesticides, chemical warfare agents, biological hazards, radioisotopes, vitamins, heterocyclic aromatic compounds, carcinogens, mutagens, narcotics, amphetamines, barbiturates, hallucinogens, waste products, and/or pollutants.
  • Microorganisms include, but are not limited
  • the Raman scattered light is not limited to CARS light, but may be scattered light obtained using other known methods such as stimulated Raman scattering (SAS) and surface enhanced Raman scattering (SERS), and it is possible to obtain information including their interference patterns.
  • SAS stimulated Raman scattering
  • SERS surface enhanced Raman scattering
  • the system 1 of this example has a first information acquisition device that acquires first interference information including temporal fluctuations in a two-dimensional or three-dimensional interference pattern of Raman scattered light from an object, and a first analysis device that analyzes the behavior of a specific component in the object or an object containing the same based on the first interference information.
  • the first analysis device may include a behavior analysis device that analyzes the temporal behavior of a specific component in the object or an object containing the same based on the intensity difference in a specific two-dimensional or three-dimensional region included in the interference pattern included in the first interference information.
  • the first analysis device may include a behavior analysis device that analyzes the temporal behavior of a specific component in the target object or an object containing the same, based on the intensity differences between multiple two-dimensional or three-dimensional regions included in the interference pattern contained in the first interference information. For example, even if the intensity of the interference pattern is the same, the intensity difference between the left and right regions may be reversed, thereby making it possible to obtain information on the status of the movement of the source.
  • One example is the discovery that information can be obtained on the entry and exit of constituent components such as plasma or blood cells in blood vessels into and out of the laser spot that generates Raman scattered light.
  • the first analysis device may include a behavior analysis device that analyzes the quantitative behavior of a specific component in the target or an object containing the same based on the intensity difference in a specific region included in the interference pattern of multiple monochromatic Raman scattered lights included in the first interference information.
  • the concentration of the specific component and its fluctuation can be obtained quantitatively with greater accuracy.
  • One example is obtaining an interference pattern of Raman scattered light at the wavelengths of the top and bottom of the peak of the specific component included in the Raman spectrum.

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Abstract

L'invention concerne un système de surveillance (1) qui comprend : un premier dispositif d'acquisition d'informations (52a) configuré pour acquérir des premières informations d'interférence (81) comprenant une variation temporelle d'un motif d'interférence (81p) de lumière diffusée par effet Raman provenant d'un objet (6) ; et un premier dispositif d'analyse (56) pour l'analyse des premières informations d'interférence. Le premier dispositif d'analyse comprend un premier dispositif d'analyse de motif (56a) configuré pour analyser le comportement temporel d'un composant prescrit ou d'un objet associé à celui-ci qui est la cause de la génération de la lumière diffusée par effet Raman dans l'objet sur la base de la distribution d'intensité asymétrique du motif d'interférence.
PCT/JP2024/022648 2023-06-22 2024-06-21 Système et procédé utilisant une lumière diffusée par effet raman Pending WO2024262621A1 (fr)

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