Classifications

• • 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 non-invasive measurement device.
• Raman spectroscopy blood glucose measurement is a non-invasive method that uses light to selectively detect the specific chemical structure of glucose.
• the measurement principle is to detect light generated by the Raman scattering process, and the glucose concentration is estimated by the intensity of the light, but the intensity obtained is very weak, which is a major factor that prevents glucose measurement in interstitial fluid deep in the skin.
• an excitation light source with a wavelength range of 700nm-1200nm, known as a biological window, has been used.
• 800nm-1000nm is a band with a deep light penetration depth, and a method has been adopted to capture glucose signals generated in the 900nm-1000nm band using 785nm, 830nm, or 860nm as an excitation light source.
• the blood measuring device used in the invention disclosed in Patent Document 1 irradiates a living body with 785 nm laser light and guides Raman scattered light from the living body to a spectroscope.
• the spectrum of the Raman scattered light is detected by a detector using light of each wavelength dispersed by the spectroscope, and the multiple detected spectra are integrated, and the blood glucose concentration in the blood is calculated from the integrated spectrum.
• the present invention has been made in consideration of the above, and aims to provide a measurement device suitable for non-invasive measurement that selectively excites interstitial fluid present in the dermis layer and does not capture autofluorescence generated in the melanin layer.
• the non-invasive measurement device comprises: A light source unit that emits excitation light; a probe for irradiating skin tissue with the excitation light and collecting Raman scattered light from the skin tissue; a spectrometer that disperses the Raman scattered light and outputs a spectroscopic signal; an analysis device for analyzing the spectroscopic signal; Equipped with The probe comprises: a transmission optical fiber that transmits the excitation light from the light source unit; a detection optical fiber provided around the transmission optical fiber and configured to collect the Raman scattered light; a ball lens provided at a tip of the transmission optical fiber and the detection optical fiber, the ball lens abutting against the skin tissue to irradiate the dermis layer with the excitation light and to collect Raman scattered light from the dermis layer; Equipped with The detection optical fiber is provided at a position where the Raman scattered light is collected by the ball lens, but where autofluorescence from the melanin layer is not collected.
• excitation light is irradiated onto the dermis layer by a ball lens, and the detection optical fiber is disposed at a position where the Raman scattered light is collected by the ball lens, but where the autofluorescence from the melanin layer is not collected.
• 1 is a diagram illustrating a configuration of a non-invasive measurement device according to an embodiment of the present invention.
• 2A to 2C are diagrams illustrating both ends of a probe of a non-invasive measuring device according to an embodiment of the present invention 1 is a cross-sectional view of a tip of a probe of a non-invasive measurement device according to an embodiment of the present invention.
• the non-invasive measurement device selectively excites interstitial fluid present in the dermis layer by using a near-lens illumination method with a ball lens, and acquires signals with high efficiency. Furthermore, in addition to the ball lens, it is combined with a spatial offset detection method that creates a distance between the excitation position and the signal detection position. This makes it possible to remove autofluorescence from deep within the skin from the collected light, and selectively detect signals only from the dermis layer without significantly distorting the waveform of the Raman scattering signal.
• FIG. 1 is a diagram showing the configuration of a non-invasive measurement device 1.
• the non-invasive measurement device 1 analyzes the concentration of a substance contained in skin tissue 2 based on Raman scattered light generated in skin tissue 2 by irradiation with excitation light.
• the non-invasive measurement device 1 includes a light source unit 10, a probe 11, a spectroscope 12, and an analysis device 13.
• the light source unit 10 is a light source that emits excitation light. Since the Raman scattering light generated in the skin tissue 2 by irradiation with excitation light tends to be weak, it is preferable that the light source unit 10 be a light source that emits high-intensity excitation light. Furthermore, since the concentration of glucose contained in the skin tissue 2 is calculated based on the wavelength of the excitation light, it is preferable that the light source unit 10 be a light source that emits excitation light of a single wavelength. Examples of such light sources include semiconductor lasers and solid-state lasers. Furthermore, the light source unit 10 may be an LED (Light Emitting Diode). The wavelength of the excitation light is a single wavelength selected from, for example, 785 nm, 830 nm, and 860 nm.
• the probe 11 is a spectroscopic probe used in spectroscopic analysis equipment, and is a fiber probe using multiple optical fibers.
• a ball lens 110 is attached to the tip of the probe 11. When measuring blood glucose in interstitial fluid, the ball lens 110 attached to the tip of the probe 11 is placed in contact with the surface of the skin tissue 2.
• the spectroscope 12 has a spectroscopic element that separates the incident light into wavelengths, and a photodetector 120.
• the spectroscopic element separates the Raman scattered light supplied from the skin tissue 2 through the probe 11 into wavelengths, and guides the light to the light receiving surface of the photodetector 120.
• Methods for separating light into wavelengths include, for example, a dispersive spectrometer that uses the diffraction of light, and a Fourier transform spectrometer that uses the coherence of light.
• a dispersive spectrometer is composed of a collimating mirror, a collecting mirror, and a diffraction grating, and disperses light by using the diffraction and interference caused by the diffraction grating.
• a Fourier transform spectrometer uses an interferometer to measure the interference waveform of light.
• the measured interference waveform is Fourier transformed to measure the spectrum of light for each wavelength.
• an interferometer a Michelson interferometer composed of a reference mirror, a sample mirror, and an optical branching filter is used.
• the photodetector 120 has a plurality of light receiving elements on its light receiving surface. Raman scattered light is incident on the light receiving surface of the photodetector 120. When the photodetector 120 receives the Raman scattered light from the spectroscopic element, the light receiving elements convert the light of each wavelength into an electrical signal and output a light detection signal indicating the intensity distribution for each wavelength. For example, a photodiode, a CCD (Charge Coupled Device), a CMOS (Complementary Metal Oxide Semiconductor), etc. may be used as the photodetector 120. The spectroscopic signal output from the photodetector 120 is input to the analysis device 13.
• the analysis device 13 is a computer such as a personal computer, and includes a processor that processes data according to a control program, a main memory that functions as a work area for the processor, and an auxiliary memory for storing data for a long period of time.
• the analysis device calculates the concentration of glucose contained in the skin tissue 2 based on the spectroscopic signal input from the photodetector 120 of the spectrometer.
• FIG. 2 is a diagram showing the details of both ends of the probe 11, with the middle part of the probe 11 omitted by a wavy line.
• One end of the probe 11 is the tip of the probe 11 that contacts the detection target to irradiate and collect light, and shows the state in which the tip of the probe 11 is in contact with the surface of the skin tissue 2.
• a ball lens 110 is provided at the tip of the probe 11 as a condensing lens that focuses the light emitted from the light source unit 10 from the excitation channel within the skin tissue 2 and directs the scattered light from the skin tissue 2 to the detection channel within the probe 11.
• the other end of the probe 11 is the rear end of the probe 11 that is connected to the light source unit 10 and the spectrometer 12, and receives the light emitted from the light source unit 10 and outputs the detection light from the detection target to the spectrometer 12.
• the probe 11 is composed of a bundle of multiple optical fibers.
• Figure 3 shows a cross-sectional view of the tip of the probe 11.
• one transmission optical fiber 111 is provided at the center as an excitation channel.
• eight detection optical fibers 112 are provided in a ring shape at a predetermined radius around the excitation channel as detection channels, with the transmission optical fiber 111 at the center.
• the light source unit 10 such as a laser
• the transmission optical fiber 111 that constitutes the excitation channel, and excitation light from the light source unit 10 is transmitted.
• a band-pass filter 113 is coupled to the rear end of the transmission optical fiber 111. This band-pass filter 113 is a filter that selectively transmits light of a specific wavelength.
• the excitation light output from the light source unit 10 is band-passed by the band-pass filter 113 and introduced into the transmission optical fiber 111, which is the excitation channel of the probe 11.
• the detection optical fiber 112 constituting the detection channel is positioned a predetermined radial distance away from the transmission optical fiber 111 so as to selectively detect signals only from the dermis layer 21 in the skin tissue 2.
• the distance between the excitation position and the detection position i.e., the distance between the transmission optical fiber 111 and the detection optical fiber 112 is set to 100 ⁇ m-2000 ⁇ m.
• An edge filter 114 is coupled to the rear end of the detection optical fiber 112. This edge filter 114 is a filter that removes Rayleigh scattered light. The light detected from the skin tissue 2 is collected, and the Raman scattered light from which the Rayleigh scattered light has been removed by the edge filter 114 is output to the spectroscope.
• a ball lens 110 is attached to the tip of the probe 11.
• the ball lens 110 has a shorter focal length than a convex lens and collects light over a large angle.
• the ball lens 110 is abutted against the surface of the skin tissue 2 to focus the excitation light from the excitation channel and irradiate it into the skin tissue 2, while outputting the Raman scattered light from the skin tissue 2 toward the detection channel.
• the diameter of the ball lens 110 is set to 3-15 mm in order to predominantly illuminate the dermis layer 21.
• the skin tissue 2 of the living body with which the ball lens 110 abuts has an epidermis layer 20 on the surface, and a dermis layer 21 below the epidermis layer 20.
• the epidermis layer 20 is about 0.1-0.3 mm thick, and does not contain nerves or blood vessels.
• the dermis layer 21 is about 1-2 mm thick, and contains capillaries, nerves, and lymphatic vessels.
• the dermis layer 21 contains interstitial fluid, which is a bodily fluid between cells. Glucose in the blood diffuses into the interstitial fluid through the capillary walls, and is transported from the interstitial fluid to the cells of the tissue. The blood glucose level can be determined by measuring the glucose contained in this interstitial fluid.
• a melanin layer 22 that produces melanin pigment.
• the excitation light output from transmission optical fiber 111 which is the excitation light channel of probe 11, is incident on skin tissue 2 via ball lens 110.
• the incident excitation light is focused on dermis layer 21 in skin tissue 2 by ball lens 110.
• dermis layer 21 components contained in interstitial fluid generate Raman scattered light with a wavelength different from that of the excitation light, and generate Rayleigh scattered light with the same wavelength as that of the excitation light.
• the scattered light travels while diffusing inside the skin tissue 2, and returns to the surface of the skin tissue 2.
• the light scattered to a deeper position in the skin tissue 2 returns to a position on the circumference of the surface of the skin tissue 2, a certain radius away on the surface of the skin tissue 2, which is a plane perpendicular to the incident direction with the incident position of the excitation light on the surface of the skin tissue 2 as its center.
• the scattered light generated by interaction with components contained in the interstitial fluid of the dermis layer 21 is indicated by a solid arrow.
• the scattered light generated by interaction with components contained in the interstitial fluid is emitted at a position away from the incident position of the excitation light in the x-axis direction.
• the excitation light is irradiated to the dermis layer 21, but since the melanin layer 22 is provided immediately above the dermis layer 21, the excitation light is also irradiated to the melanin layer 22.
• the melanin layer 22 absorbs the excitation light and generates autofluorescence.
• the autofluorescence from the melanin layer 22 travels through the skin tissue 2 and is emitted from the surface of the skin tissue 2.
• the autofluorescence from the melanin layer 22 is emitted from a position on the circumference of the surface of the skin tissue 2, which is a plane perpendicular to the incident direction with the incident position of the excitation light on the surface of the skin tissue 2 as the center, and is a predetermined radius away from the surface of the skin tissue 2.
• the melanin layer 22 is located at a shallower position in the skin tissue 2 than the dermis layer 21, the circumference radius is shorter than that of the scattered light generated by interaction with the components contained in the interstitial fluid, and the excitation light is emitted from near the incident position.
• the autofluorescence from the melanin layer 22 is indicated by a dashed arrow.
• the autofluorescence from the melanin layer 22 is emitted from a position in the x-axis direction closer to the incident position of the excitation light than the scattered light generated by interaction with components contained in the interstitial fluid.
• Light emitted from the surface of the skin tissue 2 is incident on the ball lens 110.
• the incident light passes through the ball lens 110 and is focused toward the end of the probe 11.
• the position of the light incident on the end of the probe 11 changes depending on the position of the light emitted from the surface of the skin tissue 2.
• the scattered light generated by interaction with the components contained in the interstitial fluid is incident on the ball lens 110 from the surface of the skin tissue 2, where it is focused by the ball lens 110 and incident on the detection optical fiber 112 in the probe 11.
• the distance between the position of the transmission optical fiber 111, which is the excitation position, and the position of the detection optical fiber 112, which is the detection position is set so that the scattered light is incident on the detection optical fiber 112.
• the autofluorescence from the melanin layer 22 is emitted from a position on the surface of the skin tissue 2 closer to the incident position of the excitation light than the scattered light, and is incident on the ball lens 110 as shown by the optical path indicated by the dashed line in FIG. 2. Because the incident position of the autofluorescence on the ball lens 110 is inside the incident position of the scattered light, the autofluorescence focused by the ball lens 110 is directed inside the detection optical fiber 112 and is not incident on the detection optical fiber 112. In other words, the distance between the position of the transmission optical fiber 111, which is the excitation position, and the position of the detection optical fiber 112, which is the detection position, is set so that the autofluorescence does not enter the detection optical fiber 112. Therefore, the autofluorescence from the melanin layer 22 is removed from the collected light.
• the scattered light incident on the detection optical fiber 112 has Rayleigh scattered light removed by an edge filter 114 connected to the rear end of the detection optical fiber 112, and only the Raman scattered light is input to the spectrometer 12.
• the spectrometer 12 separates the supplied Raman scattered light by wavelength, guides it to the light receiving surface of the photodetector 120, and outputs a light detection signal indicating the intensity distribution for each wavelength.
• the signal output from the photodetector 120 is input to the analysis device 13.
• the analyzer 13 When the analyzer 13 receives a spectrum from the photodetector 120, it performs a determination process to determine whether or not the spectrum is a waveform specific to glucose based on the waveform pattern in the spectrum. If the determination process determines that the waveform is that of glucose, it acquires the glucose peak. It measures the glucose concentration based on the glucose peak in the acquired Raman spectrum.
• the present invention can be widely applied to non-invasive measurement devices that irradiate a living body with excitation light and detect the transmitted light that passes through the body.
• Non-invasive measurement device 2 Skin tissue, 10 Light source unit, 11 Probe, 12 Spectrometer, 13 Analysis device, 20 Epidermis layer, 21 Dermis layer, 22 Melanin layer, 110 Ball lens, 111 Transmission optical fiber, 112 Detection optical fiber, 113 Band pass filter, 114 Edge filter, 120 Photodetector.

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Citations (7)

• 2024
  • 2024-02-21 JP JP2025505214A patent/JPWO2024185521A1/ja active Pending
  • 2024-02-21 WO PCT/JP2024/006358 patent/WO2024185521A1/ja not_active Ceased

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