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WO2025010030A1 - Agencement optique, dispositif et procédé non invasif d'analyse d'un échantillon de peau - Google Patents

Agencement optique, dispositif et procédé non invasif d'analyse d'un échantillon de peau Download PDF

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Publication number
WO2025010030A1
WO2025010030A1 PCT/SG2024/050437 SG2024050437W WO2025010030A1 WO 2025010030 A1 WO2025010030 A1 WO 2025010030A1 SG 2024050437 W SG2024050437 W SG 2024050437W WO 2025010030 A1 WO2025010030 A1 WO 2025010030A1
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WIPO (PCT)
Prior art keywords
skin sample
optical
fiber
spectra
optical arrangement
Prior art date
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Pending
Application number
PCT/SG2024/050437
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English (en)
Inventor
Xinhui Valerie TEO
Dinish Unnimadhava Kurup Soudamini Amma
Ghayathri BALASUNDARAM
Malini Carolene Devapiriyai OLIVO
Ruochong ZHANG
Mahesh Choolani
Susan Logan
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Agency for Science Technology and Research Singapore
National University of Singapore
National University Hospital Singapore Pte Ltd
Original Assignee
Agency for Science Technology and Research Singapore
National University of Singapore
National University Hospital Singapore Pte Ltd
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Publication date
Application filed by Agency for Science Technology and Research Singapore, National University of Singapore, National University Hospital Singapore Pte Ltd filed Critical Agency for Science Technology and Research Singapore
Publication of WO2025010030A1 publication Critical patent/WO2025010030A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B1/00—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor
    • A61B1/303—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor for the vagina, i.e. vaginoscopes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
    • A61B5/0082—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence adapted for particular medical purposes
    • A61B5/0084—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence adapted for particular medical purposes for introduction into the body, e.g. by catheters
    • 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
    • A61B5/14546—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 for measuring analytes not otherwise provided for, e.g. ions, cytochromes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/43—Detecting, measuring or recording for evaluating the reproductive systems
    • A61B5/4306—Detecting, measuring or recording for evaluating the reproductive systems for evaluating the female reproductive systems, e.g. gynaecological evaluations
    • A61B5/4318—Evaluation of the lower reproductive system
    • A61B5/4337—Evaluation of the lower reproductive system of the vagina
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/48—Other medical applications
    • A61B5/4869—Determining body composition
    • 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
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/47—Scattering, i.e. diffuse reflection
    • G01N21/4738—Diffuse reflection, e.g. also for testing fluids, fibrous materials
    • G01N21/474—Details of optical heads therefor, e.g. using optical fibres
    • 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
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/55—Specular reflectivity
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
    • A61B5/0075—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence by spectroscopy, i.e. measuring spectra, e.g. Raman spectroscopy, infrared absorption spectroscopy
    • 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
    • A61B5/14542—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 for measuring blood gases
    • 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
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/47—Scattering, i.e. diffuse reflection
    • G01N21/4738—Diffuse reflection, e.g. also for testing fluids, fibrous materials
    • G01N21/474—Details of optical heads therefor, e.g. using optical fibres
    • G01N2021/4742—Details of optical heads therefor, e.g. using optical fibres comprising optical fibres
    • 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
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/55—Specular reflectivity
    • G01N2021/555—Measuring total reflection power, i.e. scattering and specular

Definitions

  • Various embodiments relate to an optical arrangement, a device and a non-invasive method for analyzing a skin sample.
  • GSM refers to oestrogen deficiency associated genital, sexual, and urinary changes in the lower genital tract of menopausal women. Typical symptoms include vulvovaginal dryness, itch, irritation and burning, vaginal discharge; decreased lubrication; painful sex; dysorgasmia; postmenopausal bleeding; urinary frequency, urgency and urge incontinence, dysuria, nocturia and urinary tract infections. [0004] Without effective treatment, GSM and postmenopausal complications evolve chronically affecting both QoL as well as the functional and structural aspects of the urogenital tissue. As per a survey, vaginal dryness had a QoL index of 0.566, similar to that of stroke patients and patients with multiple comorbidities.
  • VMI Vaginal Maturation Index
  • estrogen therapy is prescribed as “one size fits all” approach for GSM patients, without available objective tech to compare the efficacy of treatment longitudinally, quantify the dosage and inter patient variation.
  • 60% of women aged 51-57 years have taken hormone replacement therapy (Br J Gen Pract. 2002; 52:835-837), with 45% having tried it by the time they are 50 (Br J Obstet Gynaecol. 1997; 104:923-933).
  • Br J Obstet Gynaecol. 1997; 104:923-933 In the US, about38% of postmenopausal women take hormone replacement therapy.
  • 46 million prescriptions were written for Premarin (conjugated equine estrogens), making it the second most frequently prescribed drug in the United States.
  • an optical arrangement may include a first fiber optic probe configured to measure Raman spectra of a skin sample; a second fiber optic probe configured to measure diffuse reflectance spectra of the skin sample; and an imaging camera configured to capture a reflectance image of the skin sample.
  • the first fiber optic probe, at least part of the second fiber optic probe and the imaging camera may be arranged adjacent to one another.
  • the optical arrangement may be configured to acquire at least one selected from the Raman spectra, the diffuse reflectance spectra, or the reflectance image in a location of the skin sample.
  • the optical arrangement may be configured to interrogate a predetermined depth below a surface of the skin sample at the location, or tissue chromophores of the skin sample at the pre-determined depth, or both.
  • a device may include an analytical unit; and an optical arrangement in communication with the analytical unit.
  • the optical arrangement may include a first fiber optic probe configured to measure Raman spectra of a skin sample; a second fiber optic probe configured to measure diffuse reflectance spectra of the skin sample; and an imaging camera configured to capture a reflectance image of the skin sample, the first fiber optic probe, at least part of the second fiber optic probe and the imaging camera being arranged adjacent to one another.
  • the optical arrangement may be configured to acquire at least one selected from the Raman spectra, the diffuse reflectance spectra, or the reflectance image in a location of the skin sample.
  • the optical arrangement may be configured to interrogate a pre- determined depth below a surface of the skin sample at the location, or tissue chromophores of the skin sample at the pre-determined depth, or both.
  • the analytical unit may be configured to assess data including the at least one selected from the acquired Raman spectra, the acquired diffuse reflectance spectra, or the acquired reflectance image, and the interrogated pre- determined depth and the interrogated tissue chromophores to determine a medical status and/or condition based on the skin sample.
  • a non-invasive method for analyzing a skin sample may include acquiring at least one selected from Raman spectra, diffuse reflectance spectra or a reflectance image of the skin sample in a location of the skin sample; based on the at least one selected from the acquired Raman spectra, the acquired diffuse reflectance spectra, and the acquired reflectance image, interrogating a pre-determined depth below a surface of the skin sample at the location, or tissue chromophores of the skin sample at the pre- determined depth, or both; assessing data including the at least one selected from the acquired Raman spectra, the acquired diffuse reflectance spectra, or the acquired reflectance image, and the interrogated pre-determined depth and the interrogated tissue chromophores to determine a medical status and/or condition based on the skin sample.
  • FIG. 1 shows a schematic cross-sectional view of an optical arrangement, according to various embodiments.
  • FIG. 2 shows a schematic cross-sectional view of a device for analyzing a skin sample, according to various embodiments.
  • FIG. 3 shows a flow chart illustrating a non-invasive method for analyzing a skin sample, according to various embodiments.
  • FIG. 4 shows a schematic cross-sectional view of the optical arrangement of FIG.
  • FIG. 5 shows an isolated view of a first fiber optic probe (e.g. a Raman probe) of FIG. 4.
  • a first fiber optic probe e.g. a Raman probe
  • FIG. 6 shows an isolated view of a second fiber optic probe (e.g. a DRS fiber probe) of FIG. 4.
  • a second fiber optic probe e.g. a DRS fiber probe
  • FIG. 7 shows an isolated view of a second fiber optic probe, according to different embodiments.
  • FIG. 8 shows a photograph of a MFO1S device/system, according to one example.
  • FIG. 9 shows an expanded view of an integrated probe of the MFOIS device/system of FIG 8, according to one example.
  • FIG. 10 shows a schematic cross-sectional view of the integrated probe of FIG. 9 with DRS, imaging and Raman fiber probe, according to one example.
  • FIG. 11 shows a plot illustrating the representative data of intervention experiments to capture the changes in blood fraction of human volunteers.
  • FIG. 12 shows a plot illustrating the representative data of intervention experiments to capture the changes in sO2 of the human volunteers.
  • FIG. 13 shows a plot illustrating the representative data of intervention experiments to capture the changes in water of the human volunteers.
  • FIG. 14 shows a plot illustrating the representative data of intervention experiments to capture the changes in lipid content of the human volunteers.
  • FIG. 15 shows a plot illustrating the correlation between DRS water index measurement and commercial moisture meter measurement, according to one example.
  • FIG. 16 shows a plot illustrating average DRS measurement indicating difference in water content among pre-menopausal, peri-menopausal, and post-menopausal women in six locations of the vulva region, according to various examples.
  • FIG. 17 shows a plot illustrating average DRS measurement indicating difference in lipid content among pre-menopausal, peri-menopausal, and post-menopausal women in the six locations of the vulva region, according to various examples.
  • FIG. 18 shows a plot illustrating average DRS measurement indicating difference in oxygen saturation among pre-menopausal, peri-menopausal, and post-menopausal women in the six locations of the vulva region, according to various examples.
  • FIG. 19 shows a plot illustrating average DRS measurement indicating difference in blood fraction among pre-menopausal, peri-menopausal, and post-menopausal women in the six locations of the vulva region, according to various examples.
  • Embodiments described in the context of one of the methods or devices are analogously valid for the other methods or devices Similarly, embodiments described in the context of a method are analogously valid for a device, and vice versa.
  • the articles “a”, “an” and “the” as used with regard to a feature or element include a reference to one or more of the features or elements.
  • the phrase “substantially” may include “exactly” and a reasonable variance.
  • the term “about” or “approximately” as applied to a numeric value encompasses the exact value and a reasonable variance.
  • phrase of the form of “at least one of A or B” may include A or B or both A and B.
  • phrase of the form of “at least one of A or B or C”, or including further listed items may include any and all combinations of one or more of the associated listed items.
  • Various embodiments may provide an optical spectroscopy device and a method for objective assessment of GSM.
  • the technology may involve a custom designed fiber optic probe and an imaging camera to measure the diffuse reflectance spectroscopy (DRS) and Raman spectroscopy (RS) spectra and high-resolution reflectance image from the vulva/vaginal skin non-invasively.
  • DRS diffuse reflectance spectroscopy
  • RS Raman spectroscopy
  • MFO1S Multifunctional Fiber Optical Imaging and Spectroscopy
  • These spectral and imaging data may be used to evaluate the relative changes in water, lipid, melanin, oxygen saturation, estrogen content, amongst others in the vulva and vaginal skin.
  • An objective scoring metrics may be developed based on these tissue chromophores.
  • FIG. 1 shows a schematic cross-sectional view of an optical arrangement 100, according to various embodiments.
  • the optical arrangement 100 includes a first fiber optic probe 102 configured to measure Raman spectra of a skin sample (not shown in FIG. 1); a second fiber optic probe 104 configured to measure diffuse reflectance spectra of the skin sample; and an imaging camera 106 configured to capture a reflectance image of the skin sample
  • the first fiber optic probe 102, at least part of the second fiber optic probe 104 and the imaging camera 106 may be arranged adjacent to one another, as denoted by a dotted circular path 108. Having the first fiber optic probe 102, and the at least part of the second fiber optic probe 104 arranged adjacent to each other may achieve high signal to noise ratio.
  • the order and/or formation shape, in which the first fiber optic probe 102, the at least part of the second fiber optic probe 104 and the imaging camera 106 may be arranged, may vary from that presented in FIG. 1 as long as the first fiber optic probe 102, the at least part of the second fiber optic probe 104 and the imaging camera 106 may be in close proximity to one another to perform measurements at a location of the skin sample.
  • the optical arrangement 100 may be configured to acquire at least one selected from the Raman spectra, the diffuse reflectance spectra, or the reflectance image in the location of the skin sample. Based on the at least one selected from the acquired Raman spectra (i.e. the Raman spectra measured by the first fiber optic probe 102), the acquired diffuse reflectance spectra (i.e. the diffuse reflectance spectra measured by the second fiber optic probe 104), or the acquired reflectance image (i.e.
  • the optical arrangement 100 may be configured to interrogate a pre-determined depth below a surface of the skin sample at the location, or tissue chromophores of the skin sample at the pre-determined depth, or both [0044] In one embodiment, the optical arrangement 100 may be configured to acquire a combination of at least two selected from the Raman spectra, the diffuse reflectance spectra, or the reflectance image sequentially in the location of the skin sample.
  • the term “acquire” may mean measure, obtain, detect, or capture.
  • the optical arrangement 100 may provide integrated optical spectroscopy techniques including reflectance imaging, DRS and/or RS techniques to measure endogenous tissue chromophores (such as water content, lipid, oxygen saturation, melanin, estrogen, amongst others) to objectively track the safety and efficacy of GSM treatment methodology.
  • endogenous tissue chromophores such as water content, lipid, oxygen saturation, melanin, estrogen, amongst others
  • the first fiber optic probe 102, the second fiber optic probe 104 and the imaging camera 106 may integrally form the optical arrangement 100 in a single probe, which may be interchangeably referred to as a MFOIS probe.
  • FIG. 4 shows a schematic cross-sectional view of the MFOIS probe 400, according to one example. It should be appreciated that other arrangements of the first fiber optic probe 102, the second fiber optic probe 104 and the imaging camera 106 are also possible, although not shown in the figures.
  • the first fiber optic probe 102 may include a first optical fiber 1022 configured to deliver laser energy to excite the skin sample; and a first plurality of optical fibers 1024 configured to detect and measure the Raman spectra of the skin sample.
  • the first optical fiber 1022 may be centrally arranged along the first fiber optic probe 102, and the first plurality of optical fibers 1024 may be arranged substantially surrounding the first optical fiber 1022. While such a concentric arrangement is preferred, other arrangements of the first optical fiber 1022 and the first plurality of optical fibers 1024 may also be possible.
  • Each optical fiber of the first plurality of optical fibers 1024 may be arranged adjacent to and spaced apart from a neighbouring optical fiber of the first plurality of optical fibers 1024.
  • the arrangement of each optical fiber of the first plurality of optical fibers 1024 may be based on the depth of interrogation.
  • illumination using the first optical fiber 1022 e g. interchangeably referred to as a laser source or an illumination source
  • the first plurality of optical fibers 1024 e.g. interchangeably referred to as collection/ detection fibers
  • the first optical fiber 1022 may include a first optical fiber bundle
  • each optical fiber of the first plurality of optical fibers 1024 may include an optical fiber bundle.
  • the first optical fiber 1022 or each of the first plurality of optical fibers 1024 may include a single mode fiber, or a multimode fiber, or a combination of a single mode fiber and a multimode fiber.
  • the first optical fiber 1022 has a core size ranging from 150-800 pm and a cladding size of 160-800 pm.
  • the first optical fiber 1022 may have a transmission range of 350 nm to 2400 nm.
  • the second fiber optic probe 104 may include a second optical fiber 1042 configured to deliver light to the skin sample, and a second plurality of optical fibers 1044 configured to detect and measure the diffuse reflectance spectra of the skin sample.
  • the second optical fiber 1042 may be centrally arranged along the second fiber optic probe 104, and the second plurality of optical fibers 1044 may be arranged substantially surrounding the second optical fiber 1042. While such a concentric arrangement is preferred, other arrangements of the second optical fiber 1042 and the second plurality of optical fibers 1044 may also be possible.
  • Each optical fiber of the second plurality of optical fibers 1044 may be arranged adjacent to and spaced apart from a neighbouring optical fiber of the second plurality of optical fibers 1044.
  • the arrangement of each optical fiber of the second plurality of optical fibers 1044 may be based on the depth of interrogation.
  • excitation using the second optical fiber 1042 being a single fiber
  • the second plurality of optical fibers 1044 e.g. interchangeably referred to as DRS collection fibers or DRS detectors
  • the second optical fiber 1042 may include a second optical fiber bundle
  • each optical fiber of the second plurality of optical fibers 1044 may include an optical fiber bundle.
  • the second optical fiber 1042 or each of the second plurality of optical fibers 1044 may include a single mode fiber, or a multimode fiber, or a combination of a single mode fiber and a multimode fiber.
  • the second optical fiber may have a core size ranging from 150-800 pm and a cladding size of 160-800 pm.
  • the second optical fiber may have a transmission range of 350 nm to 2400 nm.
  • each optical fiber of the second plurality of optical fibers 1044 may be arranged at a distance (DI of FIG. 6) ranging between 500 pm and 1000 pm from the second optical fiber 1042.
  • Such optical arrangement 100 may be configured to interrogate the pre-determined depth below the surface of the skin sample ranging between 250 pm and 2500 pm.
  • each optical fiber of the second plurality of optical fibers 1044 may be arranged at a distance (D2) ranging between 2700 pm and 6000 pm from the second optical fiber 1042.
  • Such optical arrangement 100 may be configured to interrogate the pre-determined depth below the surface of the skin sample ranging between 1300 pm and 3000 pm.
  • Various embodiments may provided the optical arrangement 100 configured to interrogate the pre-determined depth below the surface of the skin sample ranging between 25 pm and 1 mm.
  • the first fiber optic probe 102 and the imaging camera 106 may be integrated into the second fiber optic probe 104 such that the second plurality of optical fibers 1044 may be arranged substantially surrounding the second optical fiber 1042, the first fiber optic probe 102 and the imaging camera 106. Having the first fiber optic probe 102 integrated into the second fiber optic probe 104 may achieve high signal to noise ratio.
  • the second fiber optic probe 104 may further include a third optical fiber configured to deliver the light to the skin sample, the third optical fiber being arranged offset from the second optical fiber 1042 and substantially surrounded by the second plurality of optical fibers 1044.
  • the third optical fiber may be provided to enhance the excitation.
  • the first fiber optic probe 102 and the imaging camera 106 may be collectively arranged between the second optical fiber 1042 and the third optical fiber.
  • the optical arrangement 100 when in operation, may acquire DRS spectra only, or Raman spectra only, or a reflectance image only, or any combinations thereof, at a location of a sample area, depending on the applications and the requirements.
  • the combinations involve any two of the DRS spectra, the Raman spectra, or the reflectance image to be acquired, or all three of the DRS spectra, the Raman spectra, and the reflectance image to be acquired, the acquisitions may be performed in a sequential manner at a same location of the sample area.
  • a prior publication discloses a device capable of capturing digital images of a sample area using a CCD camera while measuring Raman, reflectance and/or fluorescence spectra mainly for skin assessment, specifically for lesions.
  • Various embodiments of the present invention may be vastly different as compared to state-of-the-art devices at least in the following aspects: • A multifunctional probe configured to interrogate various depths of the skin, specifically to capture tissue features of vulva/vaginal skin at various depths (from about 25 microns to about 1mm) is proposed. This may only be achieved by customizing and optimizing the source-detector fiber separation, size of the fiber, numerical aperture of the fiber, and collection features.
  • the probe may achieve reflectance imaging and sequential Raman spectroscopy measurement, and more specifically, may achieve spectral data from specific depth of skin.
  • the probe may be a handheld probe.
  • a device and probe may be customized to interrogate the vulva/vaginal skin to evaluate the GSM condition.
  • the Raman probe may include an excitation fiber and a plurality of collection fibers, wherein the plurality of collection fibers may be arranged surrounding the excitation fiber in a concentric manner.
  • the DRS probe may include an illumination fiber and a plurality of collection fibers, wherein the plurality of collection fibers may be arranged surrounding the illumination fiber in a concentric manner.
  • a general skin specific fiber optic probe is not suitable for GSM application as the vulva/vaginal skin is thin (much smaller epidennal thickness) and less affected by Melanin. Thus, signal collection and interpretation throw totally different challenges if a general skin specific fiber optic probe is used.
  • Analytics according to the present invention may quantify the lipid and oxygen saturation at various skin depths other than standard water measurements.
  • the diffused reflectance spectra in the present invention cover near-infrared regions up to 2000 nm, which are more effective for lipid, water analysis.
  • FIG. 2 shows a schematic cross-sectional view of a device 220, according to various embodiments.
  • the device 220 may include an analytical unit 222; and an optical arrangement 100 in communication with the analytical unit 222, as denoted by a line 224.
  • the optical arrangement 100 may include a first fiber optic probe 102 configured to measure Raman spectra of a skin sample; a second fiber optic probe 104 configured to measure diffuse reflectance spectra of the skin sample; and an imaging camera 106 configured to capture a reflectance image of the skin sample, wherein the first fiber optic probe 102, at least part of the second fiber optic probe 104 and the imaging camera 106 may be arranged adjacent to one another.
  • the optical arrangement 100 may be configured to acquire at least one selected from the Raman spectra, the diffuse reflectance spectra, or the reflectance image in a location of the skin sample. Based on the at least one selected from the acquired Raman spectra, the acquired diffuse reflectance spectra, or the acquired reflectance image, the optical arrangement 100 may be configured to interrogate a predetermined depth below a surface of the skin sample at the location, or tissue chromophores of the skin sample at the pre-determined depth, or both.
  • the optical arrangement 100 may be configured to acquire a combination of at least two selected from the Raman spectra, the diffuse reflectance spectra, or the reflectance image sequentially in the location of the skin sample.
  • the optical arrangement 100 may include the optical arrangement 100 of FIG. 1. More specifically, the optical arrangement 100 of FIG. 2 may include the same or like elements or components as those of the optical arrangement 100 of FIG. 1, and as such, the same numerals are assigned and the like elements may be as described in the context of the optical arrangement 100 of FIG. 1, and therefore the corresponding descriptions are omitted here.
  • the analytical unit 222 may be configured to assess data including the at least one selected from the acquired Raman spectra, the acquired diffuse reflectance spectra, or the acquired reflectance image, and the interrogated pre-determined depth and the interrogated tissue chromophores to determine a medical status and/or condition based on the skin sample.
  • the skin sample may be a vulva/vagina skin sample.
  • the medical status and/or condition may be associated with Genitourinary Syndrome of Menopause of a female subject providing the skin sample.
  • analytical unit 222 may include a receiving unit 226 configured to receive the data; a processor 228 configured to unmix the interrogated tissue chromophores and determine relative changes of tissue chromophores of the skin sample; and an output unit 230 configured to provide information based on the determined relative changes of tissue chromophores.
  • the receiving unit 226 may be in communication with the processor 228, as denoted by a dotted line 232, while the processor 228 may be in communication with the output unit 230, as denoted by a dotted line 234.
  • the phrase “in communication” may refer to direct connection or indirect connection, wired communication or wireless communication.
  • assert may mean analyze, examine, or calculate.
  • the processor 228 may further be configured to generate an objective index based on the determined relative changes of tissue chromophores, the objective index being used to monitor an efficacy of a course of treatment on the medical status and/or condition.
  • the device 220 may be for analyzing a skin sample and may be a multi-well surface- enhanced infrared spectroscopy (SEIRA) sensor chip that may include a custom designed portable multifunctional fiber optic probe capable of acquiring the reflectance image, DRS and RS sequentially e.g. in less than 1 minute in the location of the tissue; and interrogating the various depth in the skin to accurately deduce the concentration of tissue chromophores such as water, lipid, melanin, oxygen saturation, estrogen, amongst others.
  • SEIRA surface- enhanced infrared spectroscopy
  • the custom designed MFOIS point of care device may demonstrate associated data analytics for the objective assessment of the severity of GSM and way to monitor the effectiveness and dosage of their course of treatment, eventually leading to safer and improved result.
  • the MFOIS may measure the endogenous tissue parameters (tissue chromophores) non-invasively (via non-contact) and objectively from LGT of woman undergoing GSM treatment, and may provide custom designed spectral/data analytics capable of spectrally unmix various tissue chromophores and estimate their relative changes in the vulva/vaginal skm.
  • a new ‘objective index’, and optionally using tissue markers, may be developed based on the tissue chromophores to provide objective assessment of the severity of GSM, as well as objectively track treatment outcome and efficacy.
  • the device 220 and the methodology which will be further explained below may be suitable for in situ measurements and close to real-time continuous monitoring.
  • FIG. 3 shows a flow chart illustrating a non- invasive method 340 for analyzing a skin sample, according to various embodiments.
  • at least one selected from Raman spectra, diffuse reflectance spectra or a reflectance image of the skin sample may be acquired in a location of the skin sample.
  • Step 344 based on the at least one selected from the acquired Raman spectra, the acquired diffuse reflectance spectra, and the acquired reflectance image, a pre-determined depth below a surface of the skin sample at the location, or tissue chromophores of the skin sample at the pre-determined depth, or both may be interrogated.
  • data including the at least one selected from the acquired Raman spectra, the acquired diffuse reflectance spectra, or the acquired reflectance image, and the interrogated pre-determined depth and the interrogated tissue chromophores may be assessed to determine a medical status and/or condition based on the skin sample.
  • the pre-determined depth may be ranged between 25 gm and 1 mm, or between 1300 gm and 3000 gm, or between 250 gm and 2500 gm.
  • the skin sample may be a vulva/vagina skin sample.
  • the non-invasive method 340 may be performed by an optical arrangement 100 of FIG. 1 or a device 220 of FIG. 2. Since the optical arrangement 100 or the device 220 used in the non-invasive method 340 may include the same or like elements or components as those of the optical arrangement 100 of FIG. 1 or the device 220 of FIG. 2, the same numerals are assigned and the like elements may be as described in the context of the optical arrangement 100 of FIG. 1 or the device 220 of FIG. 2, and therefore the corresponding descriptions are omitted here
  • Step 342 of acquiring the at least one selected from the Raman spectra, the diffuse reflectance spectra or the reflectance image of the skin sample may include acquiring a combination of at least two selected from the Raman spectra, the diffuse reflectance spectra or the reflectance image of the skin sample sequentially in the location of the skin sample.
  • the step of acquiring the combination of the at least two selected from the Raman spectra, the diffuse reflectance spectra, or the reflectance image of the skin sample sequentially in the location of the skin sample may include at least two correspondingly selected from: delivering laser energy to excite the skin sample, and sequentially measuring the Raman spectra using a first fiber optic probe 102; delivering light to illuminate the skin sample, and sequentially measuring the diffuse reflectance spectra using a second fiber optic probe 104; or sequentially capturing the reflectance image using an imaging camera 106.
  • acquiring the combination of the at least two selected from the Raman spectra, the diffuse reflectance spectra or the reflectance image of the skin sample sequentially in the location of the skin sample may include acquiring the at least two selected from the Raman spectra, the diffuse reflectance spectra or the reflectance image of the skin sample sequentially in less than 1 minute in the location of the skin sample.
  • Step 342 of acquiring the at least one selected from the Raman spectra, the diffuse reflectance spectra or the reflectance image of the skm sample may include acquiring the Raman spectra, the diffuse reflectance spectra and the reflectance image of the skin sample sequentially in the location of the skin sample.
  • the step of acquiring the Raman spectra, the diffuse reflectance spectra, and the reflectance image of the skin sample sequentially in the location of the skin sample may include: delivering laser energy to excite the skin sample, and measuring the Raman spectra using a first fiber optic probe 102; delivering light to illuminate the skin sample, and sequentially measuring the diffuse reflectance spectra using a second fiber optic probe 104; and sequentially capturing the reflectance image using an imaging camera 106.
  • acquiring the Raman spectra, the diffuse reflectance spectra, and the reflectance image of the skin sample sequentially in the location of the skin sample may include acquiring the Raman spectra, the diffuse reflectance spectra and the reflectance image of the skin sample sequentially in less than 1 minute in the location of the skin sample
  • the laser energy may be emitted from a laser operable in a wavelength range of 500 nm to 950 nm.
  • the laser may include a single wavelength laser or a tunable laser.
  • the light may have a wavelength in a range of 300 nm to 2500 nm.
  • the first fiber optic probe 102, the second fiber optic probe 104 and the imaging camera 106 form a stable and non-revolving optical collection assemble.
  • each of the Raman spectra, the diffuse reflectance spectra and the reflectance image may be polarization-independent
  • Step 346 of assessing the data may include receiving the data, unmixing the interrogated tissue chromophores, determining relative changes of tissue chromophores of the skin sample, and providing information based on the determined relative changes of tissue chromophores.
  • the non-mvasive method 340 may further include generating an objective index based on the determined relative changes of tissue chromophores, wherein the objective index may be used to monitor an efficacy of a course of treatment on the medical status and/or condition.
  • the tissue chromophores may include endogenous tissue chromophores.
  • the tissue chromophores may include at least one of water contents, lipid contents, melanin contents, oxygen saturation levels, estrogen levels, and blood fraction levels.
  • the medical status and/or condition may be associated with Genitourinary Syndrome of Menopause of a female subject providing the skin sample.
  • the non-invasive method 340 may further be configured to assess a severity of the Genitourinary Syndrome of Menopause of the female subject.
  • the non-invasive method 340 may include an in situ non-invasive method conducted on the female subject.
  • the non-invasive method 340 may be performed in substantially real-time to provide continuous monitoring of the medical status and/or condition.
  • the method described above is illustrated and described as a series of steps or events, it will be appreciated that any ordering of such steps or events are not to be interpreted in a limiting sense. For example, some steps may occur in different orders and/or concurrently with other steps or events apart from those illustrated and/or described herein. In addition, not all illustrated steps may be required to implement one or more aspects or embodiments described herein. Also, one or more of the steps depicted herein may be carried out in one or more separate acts and/or phases.
  • FIG. 8 shows a photograph of a MFOIS device/system 820
  • FIG. 9 shows an expanded view of an integrated probe 800 of the MFOIS device/system 820, according to one example.
  • FIG. 10 shows a schematic cross-sectional view of the integrated probe 800 with DRS 804, imaging 806 and Raman 802 fiber probe.
  • the MFOIS device/system 820 and the integrated probe 800 may include the same or like elements or components as those of the device 220 of FIG. 2 and the optical arrangement 100 of FIG. 1, respectively, and thus, the same ending numerals are assigned and the like elements may be as described in the context of the device 220 of FIG. 2 and the optical arrangement 100 of FIG. 1 , respectively, and therefore the corresponding descriptions are omitted here.
  • the MFOIS system 820 includes special fiber optic probe (integrated probe 800) integrated for reflectance imaging, DRS and RS measurement.
  • the integrated probe 800 includes a Raman probe 802 (e.g. as described in similar context to the first fiber optic probe 102 of FIG. 5) arranged adjacent to a high-resolution reflectance imaging camera 806 and two separate optical fibers 8042 (e g. each described in similar context to the second optical fiber 1042 of FIGS 6 and 7) arranged between the Raman probe 802 and the imaging camera 806, where both the Raman probe 802 and the imaging camera 806 are arranged within a DRS probe 804. More specifically, a plurality of DRS collection fibers 8044 (e.g.
  • each DRS collection fiber 8044 may be spaced apart from a neighbouring DRS collection fiber 8044 to encircle the Raman probe 802, the imaging camera 806 and the two separate optical fibers 8042.
  • the DRS collection fiber 8044 (source detector) separation in the fiber 804a may be optimized to interrogate at various depth ( ⁇ 25 microns to ⁇ 1 mm) below the skin surface of vulva and vaginal skin.
  • One of the two separate optical fibers 8042 may be located opposite to the other separate optical fiber 8042 and both 8042 being strategically positioned to optimize illumination/excitation with respect to the imaging camera 806 and the plurality of DRS collection fibers 8044.
  • FIG. 11 shows a plot 1101 illustrating the representative data of intervention experiments to capture the changes in blood fraction.
  • FIG. 12 shows a plot 1201 illustrating the representative data of intervention experiments to capture the changes in sCh.
  • FIG. 13 shows a plot 1301 illustrating the representative data of intervention experiments to capture the changes in water.
  • FIG. 14 shows a plot 1401 illustrating the representative data of intervention experiments to capture the changes in lipid content.
  • FIG. 15 shows a plot 1501 illustrating the correlation between DRS water index measurement 1503 and commercial moisture meter measurement 1505.
  • FIGS. 16 to 19 show the relative change in water content, lipid content, oxygen saturation, and blood fraction measured at the vulva skin of pre-menopausal, peri- menopausal (reflected as “menopausal transition”), and post-menopausal women using DRS. More specifically, FIG. 16 shows a plot 1601 illustrating average DRS measurement indicating difference in water content among pre-menopausal, peri-menopausal, and postmenopausal women in six locations of the vulva region. FIG.
  • FIG. 17 shows a plot 1701 illustrating average DRS measurement indicating difference in lipid content among premenopausal, peri-menopausal, and post-menopausal women in the six locations of the vulva region.
  • FIG. 18 shows a plot 1801 illustrating average DRS measurement indicating difference in oxygen saturation among pre-menopausal, peri-menopausal, and postmenopausal women in the six locations of the vulva region.
  • FIG. 19 shows a plot 1901 illustrating average DRS measurement indicating difference in blood fraction among premenopausal, peri-menopausal, and post-menopausal women in the six locations of the vulva region.
  • FIG. 16 depicts that there is significant increase in the water content of postmenopausal women compared to pre-menopausal women. This could be due to different skin layer being examined with the 1.3 mm DRS probe i.e. epidermis in pre-menopausal and peri-menopausal women, and dermis in post-menopausal women.
  • postmenopausal women appear to have higher lipid content possibly indicating lipid and accumulation which occurs during estrogen deficiency.
  • FIGS. 18 and 19 respectively depict a slight decrease in oxygen saturation and a decrease in blood fraction of postmenopausal women which may stem from estrogen deficiency leading to vaginal atrophy.
  • MFOIS scan may be performed on site for the objective assessment of treatment monitoring and risk evaluation of therapy of GSM as a companion diagnostics device.

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Abstract

La présente invention, selon des modes de réalisation, concerne un agencement optique. L'agencement optique comprend une première sonde à fibre optique configurée pour mesurer des spectres Raman d'un échantillon de peau ; une seconde sonde à fibre optique configurée pour mesurer des spectres de réflectance diffuse de l'échantillon de peau ; et une caméra d'imagerie configurée pour capturer une image de réflectance de l'échantillon de peau. La première sonde à fibre optique, au moins une partie de la seconde sonde à fibre optique et la caméra d'imagerie sont disposées adjacentes l'une à l'autre. Sur la base d'au moins un spectre parmi les spectres Raman mesurés, les spectres de réflectance diffuse mesurés, ou l'image de réflectance capturée, l'agencement optique est configuré pour interroger une profondeur prédéterminée au-dessous d'une surface de l'échantillon de peau, et/ou des chromophores tissulaires de l'échantillon de peau à la profondeur prédéterminée. Selon d'autres modes de réalisation, l'invention concerne également un dispositif et un procédé non invasif pour analyser un échantillon de peau.
PCT/SG2024/050437 2023-07-06 2024-07-04 Agencement optique, dispositif et procédé non invasif d'analyse d'un échantillon de peau Pending WO2025010030A1 (fr)

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US20150335248A1 (en) * 2012-07-02 2015-11-26 National University Of Singapore Methods related to real-time cancer diagnostics at endoscopy utilizing fiber-optic raman spectroscopy
US20160038076A1 (en) * 2012-03-08 2016-02-11 Koninklijke Philips N.V Apparatus for determining a property of a tissue
US20170071509A1 (en) * 2015-09-15 2017-03-16 Massachusetts Institute Of Technology Systems and methods for diagnosis of middle ear conditions and detection of analytes in the tympanic membrane
US20210161388A1 (en) * 2017-05-18 2021-06-03 Vanderbilt University Method, system and speculum-free optical probe for optical assessment of cervix, and applications of same
US20230125467A1 (en) * 2017-12-29 2023-04-27 The Regents Of The University Of California Image-based health index scoring system for genitourinary tract

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080076985A1 (en) * 2004-12-09 2008-03-27 The Science And Technology Facilities Council Raman Spectral Analysis Of Sub-Surface Tissues And Fluids
US20070167836A1 (en) * 2005-07-25 2007-07-19 Massachusetts Institute Of Technology Multi modal spectroscopy
US20100016668A1 (en) * 2006-07-24 2010-01-21 Wave Group Ltd. Medical device for discreetly performing a routine vaginal examination
US20160038076A1 (en) * 2012-03-08 2016-02-11 Koninklijke Philips N.V Apparatus for determining a property of a tissue
US20150335248A1 (en) * 2012-07-02 2015-11-26 National University Of Singapore Methods related to real-time cancer diagnostics at endoscopy utilizing fiber-optic raman spectroscopy
US20170071509A1 (en) * 2015-09-15 2017-03-16 Massachusetts Institute Of Technology Systems and methods for diagnosis of middle ear conditions and detection of analytes in the tympanic membrane
US20210161388A1 (en) * 2017-05-18 2021-06-03 Vanderbilt University Method, system and speculum-free optical probe for optical assessment of cervix, and applications of same
US20230125467A1 (en) * 2017-12-29 2023-04-27 The Regents Of The University Of California Image-based health index scoring system for genitourinary tract

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