WO2008024288A2 - Procédés non invasifs pour l'utilisation d'informations spectrales dans la détérmination de concentrations d'analytes - Google Patents

Procédés non invasifs pour l'utilisation d'informations spectrales dans la détérmination de concentrations d'analytes Download PDF

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Publication number
WO2008024288A2
WO2008024288A2 PCT/US2007/018310 US2007018310W WO2008024288A2 WO 2008024288 A2 WO2008024288 A2 WO 2008024288A2 US 2007018310 W US2007018310 W US 2007018310W WO 2008024288 A2 WO2008024288 A2 WO 2008024288A2
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WIPO (PCT)
Prior art keywords
skin tissue
raman
fluorescence
intensity light
determining
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PCT/US2007/018310
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English (en)
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WO2008024288A3 (fr
Inventor
Mihailo V. Rebec
Michael P. Houlne
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Bayer Healthcare Llc
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Priority to JP2009525575A priority Critical patent/JP2010501252A/ja
Priority to EP07837020A priority patent/EP2056716A2/fr
Priority to CA002661952A priority patent/CA2661952A1/fr
Publication of WO2008024288A2 publication Critical patent/WO2008024288A2/fr
Publication of WO2008024288A3 publication Critical patent/WO2008024288A3/fr

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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
    • A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
    • 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, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
    • 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, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1455—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, 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
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • 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 generally relates to a method of determining the concentration of an analyte. More specifically, the present invention is directed to a noninvasive method of determining the concentration of an analyte using spectral information (e.g., Raman or fluorescence).
  • spectral information e.g., Raman or fluorescence
  • Determining the analyte concentration of, for example, glucose is typically performed by invasive methods. It would be desirable to determine analyte concentrations by using a non-invasive method.
  • Non-invasive methods may incorporate the use of different types of signals to determine the analyte concentration.
  • One type of signal is a Raman spectral signal.
  • the use of Raman spectral information has had limited application in determining noninvasive analyte concentrations because the signals tend to be very weak.
  • There a number of factors that contribute to the very weak Raman signal collected from the skin One factor is the limited amount of high-intensity energy that one can safely deliver into tissue without causing photo-damage to the tissue.
  • a second factor is the limited Raman scattering efficiency inherent to most molecules of analytical and physiological interest.
  • a third factor is the scattering and absorbance characteristics of the tissue that limit the amount of energy that can be effectively delivered into the tissue and the amount of Raman spectral information that can be collected from the tissue.
  • Fluorescence signals are more general in nature than Raman signals. Fluorescence molecules of interest may be of a smaller number than desired. The scattering and absorbance characteristics of the tissue limit the amount of energy that can be effectively delivered into the tissue and the amount of fluorescence spectral information that can be collected from the tissue.
  • Optical absorbance and tissue scattering which are two fundamental optical properties of tissue, can be transient during non-invasive detection of an analyte such as glucose. Optical absorbance and tissue scattering can affect the glucose concentration measurement.
  • the concentration of an analyte is determined using Raman spectral information.
  • a high-intensity, narrow band of light is applied to a first side of skin tissue.
  • the high-intensity light enters the skin tissue and generates a Raman signal.
  • a Raman-generating material is placed in a location nearest a second side of the skin tissue. The second side is located generally opposite of the first side.
  • the high-intensity light is reflected from the Raman-generating material so as to produce additional Raman signal that passes through the skin tissue towards the first side of the skin tissue.
  • the Raman signal generated from the high-intensity light entering the skin tissue is reflected towards the first side of the skin tissue via the Raman-generating material.
  • the Raman signal generated from the high-intensity light entering the skin tissue and the additional Raman signal generated from the Raman-generating material is collected.
  • the analyte concentration using information from the collected Raman signals is determined.
  • a diagnosis using Raman spectral information is determined.
  • a high-intensity, narrow band of light is applied to a first side of skin tissue.
  • the high-intensity light enters the skin tissue and generates a Raman signal.
  • a Raman-generating material is placed in a location nearest a second side of the skin tissue. The second side is located generally opposite of the first side.
  • the high-intensity light is reflected from the Raman-generating material so as to produce additional Raman signal that passes through the skin tissue towards the first side of the skin tissue.
  • the Raman signal generated from the high-intensity light entering the skin tissue is reflected towards the first side of the skin tissue via the Raman-generating material.
  • the Raman signal generated from the high-intensity light entering the skin tissue and the additional Raman signal generated from the Raman-generating material is collected. Information from the collected Raman signals is used to perform a general diagnosis.
  • the concentration of an analyte using Raman spectral information is determined.
  • An area of the skin tissue is pinched.
  • a Raman-generating material is placed near or around the pinched skin tissue.
  • the Raman- generating material forms at least one opening therethrough.
  • a high-intensity, narrow band of light is applied to the skin tissue through the at least one opening.
  • the high-intensity light enters the skin tissue and generates a Raman signal.
  • the high-intensity light and Raman signal that pass through the pinched skin tissue is reflected back into the pinched skin tissue via the Raman-generating material.
  • the Raman signal generated from the high-intensity light entering the skin tissue and the additional Raman signal generated from the Raman- generating material is collected.
  • the analyte concentration is determined using the collected Raman signals.
  • the concentration of an analyte using fluorescence spectral information is determined.
  • a high-intensity, narrow band of light is applied to a first side of skin tissue.
  • the high-intensity light enters the skin tissue and generates a fluorescence signal.
  • a fluorescence-generating material is placed in a location nearest a second side of the skin tissue. The second side is located generally opposite of the first side.
  • the high-intensity light is reflected from the fluorescence- generating material so as to produce additional fluorescence signal that passes through the skin tissue towards the first side of the skin tissue.
  • the fluorescence signal generated from the high-intensity light entering the skin tissue is reflected towards the first side of the skin tissue via the fluorescence-generating material.
  • the fluorescence signal generated from the high-intensity light entering the skin tissue and the additional fluorescence signal generated from the fluorescence-generating material is collected.
  • the analyte concentration using information from the collected fluorescence signals is determined.
  • a diagnosis using fluorescence spectral information is performed.
  • a high-intensity light is applied to a first side of skin tissue.
  • the high-intensity light enters the skin tissue and generates a fluorescence signal.
  • a fluorescence-generating material is placed in a location nearest a second side of the skin tissue. The second side is located generally opposite of the first side.
  • the high-intensity light is reflected from the fluorescence-generating material so as to produce additional fluorescence signal that passes through the skin tissue towards the first side of the skin tissue.
  • the fluorescence signal generated from the high-intensity light entering the skin tissue is reflected towards the first side of the skin tissue via the fluorescence-generating material.
  • the fluorescence signal generated from the high-intensity light entering the skin tissue and the additional fluorescence signal generated from the fluorescence-generating material is collected. Information from the collected fluorescence signals is used to perform a general diagnosis.
  • the concentration of an analyte using fluorescence spectral information is determined.
  • An area of the skin tissue is pinched.
  • a fluorescence-generating material is placed near or around the pinched skin tissue.
  • the fluorescence-generating material forms at least one opening therethrough.
  • a high-intensity, narrow band of light is applied to the skin tissue through the at least one opening.
  • the high- intensity light enters the skin tissue and generates a fluorescence signal.
  • the high-intensity light and fluorescence signal that pass through the pinched skin tissue back is reflected into the pinched skin tissue via the fluorescence-generating material.
  • the fluorescence signal generated from the high-intensity light entering the skin tissue and the additional fluorescence signal generated from the fluorescence-generating material is collected.
  • the analyte concentration using the collected fluorescence signals is determined.
  • FIG. 1 is an illustration used in determining the concentration of an analyte using Raman spectral information according to one embodiment.
  • FIG. 2a is an illustration further detailing the spatial filter used in determining the analyte concentration of FIG. 1.
  • FIG. 2b, 2c depicts positions of a movable spatial filter according to one embodiment.
  • FIG. 3 is an illustration used in determining the analyte concentration using Raman spectral information according to another embodiment.
  • FIG. 4 is an illustration used in determining the analyte concentration using Raman spectral information according to another embodiment.
  • FIG. 5a is an illustration used in determining the analyte concentration using Raman spectral information according to a further embodiment.
  • FIG. 5b is an illustration used in determining the analyte concentration using Raman spectral information according to a further embodiment.
  • FIG. 6a is an illustration used in determining the concentration of an analyte using fluorescence spectral information according to another embodiment.
  • FIG. 6b is an illustration further detailing the spatial filter used in determining the analyte concentration of FIG. 6a.
  • FIG. 7 is an illustration used in determining the analyte concentration using fluorescence spectral information according to a further embodiment.
  • FIG. 8 is an illustration used in determining the analyte concentration using fluorescence spectral information according to yet another embodiment.
  • FIG. 9a is an illustration used in determining the analyte concentration using fluorescence spectral information according to a further embodiment.
  • FIG. 9b is an illustration used in determining the analyte concentration using fluorescence spectral information according to a further embodiment.
  • the invention is directed to non-invasive methods for determining the concentration of an analyte uses Raman spectral information.
  • the invention is adapted to increase optical throughput in these methods using spectral information.
  • Analytes that may be measured using the Raman spectral information include glucose, lipid profiles (e.g., cholesterol, triglycerides, LDL and HDL), microalbumin, hemoglobin Aic, fructose, lactate, or bilirubin.
  • the present invention is not limited, however, to these specific analytes and it is contemplated that other analyte concentrations may be determined.
  • the analytes may be in, for example, a whole blood sample, a blood serum sample, a blood plasma sample, and other body fluids like ISF (interstitial fluid) and urine.
  • the present invention assists in providing a method of correcting for optical absorbance and/or tissue scattering that can be transient during non-invasive analyte (e.g., glucose) detection.
  • the Raman signature of analytes such as glucose can be corrected based on the optical absorbance and tissue scattering occurring in the tissue.
  • the absorption of the skin tissue and tissue scattering may vary in the short term, as well as the long term. For example, one non-limiting short-term situation could be increased blood flow or changes in the tissue hydration. One non-limiting long-term condition could be an individual's skin being tan or even burned.
  • the absorption of the skin tissue and tissue scattering may vary under other short-term and long-term conditions such as localized hematocrit, tissue deformity (e.g., scar or melanoma), temperature, pH or skin morphology.
  • the concentration of an analyte is determined using Raman spectral information.
  • a high-intensity, narrow band of light is applied to a first side of skin tissue.
  • the high-intensity light enters the skin tissue and generates a Raman signal.
  • a Raman-generating material is placed in a location nearest a second side of skin tissue. The second side is located generally opposite of the first side.
  • the high-intensity light from the Raman-generating material is reflected so as to produce additional Raman signal that passes through the skin tissue towards the first side of the skin tissue.
  • the Raman signal generated from the high-intensity light entering the skin tissue is reflected towards the first side of the skin tissue via the Raman-generating material.
  • the Raman signal generated from the high-intensity light entering the skin tissue and the additional Raman signal generated from the Raman-generating material are collected.
  • the analyte concentration is determined using information from the collected Raman signals.
  • High-intensity light 10 is applied to skin tissue 12 such as pinched skin tissue or a finger.
  • the high-intensity light 10 is shown in FIG. 1 as coming from a high-intensity light source 10a.
  • the high-intensity light source may be a variety of light sources.
  • the high-intensity light source may come from a monochromatic light source that is delivered in a narrow band.
  • a monochromatic light source is a laser-diode source.
  • light sources may be used such as a light-emitting diode and incoherent lamps.
  • the light sources may be filtered to provide a more clearly defined (i.e., narrow) band of light.
  • the high-intensity light may be a dye laser, gas laser, ion laser or a pumped laser.
  • the wavelength of the light source may vary but is generally from about 300 to about 10,000 nm.
  • the light source may be an ultraviolet light source, a near-infrared light source, an infrared light source, or visible light source with appropriate filtering.
  • the light source to be used would be a high-intensity, narrow band of light.
  • the Raman spectral information in one method may be collected in the wavelength range from about 300 nm to about 12,000 nm.
  • several wavelength-dependent characteristics unique to tissue optics and to the Raman effect can significantly impact the ability to successfully employ the Raman technique for the non-invasive determination of analytes in tissue.
  • tissue autofluorescence is also relatively strong, which may overwhelm and complicate detecting the Raman signal in the tissue.
  • tissue autofluorescence and the inherent Raman signal decrease.
  • the choice of the light source would be made based on a balance of the Raman signal power and the autofluorescence interference at the wavelengths of interest for the analyte of interest. Therefore, for glucose analysis, it is desirable to employ a high-intensity, narrow band light source centered at or near 830 nm and collect the Raman spectral information in the wavelength range of from above 830 run to about 1030 nm where the strength of the Raman signal is optimized verses the tissue autofluorescence.
  • the glucose-related Raman spectral information may be collected from Raman scattered light shifted from 100 cm '1 to 10,000 cm '1 away from the light source. More specifically, the glucose-related Raman spectral information may be collected from Raman scattered light shifted from 100 cm “1 to 1600 cm “1 away from the light source since the strongest glucose peaks occur at Raman shifts of about 1340 cm “1 and about 1125 cm “1 . It is contemplated that the Raman spectral information may be collected in different ranges, especially if the analyte concentration to be determined is not glucose.
  • One specific example is an 830 nm laser-diode source.
  • One example of a commercially available 830 nm laser-diode source is InvictusTM NIR 830 nm diode laser, which is marketed by Kaiser Optical Systems, Inc. of Ann Arbor, Michigan.
  • Another example is a PI-ECL-830-300 diode laser, which is marketed by Process Instruments of Salt Lake City, Utah.
  • the laser light is delivered to the skin tissue in about a 1 mm beam diameter. It is contemplated that other laser-diode sources may be employed.
  • the high-intensity, narrow band of light may be adjusted so that a higher resolution Raman spectrum is generated.
  • the high-intensity narrow band of light may be limited, resulting in less light being exposed and a higher resolution Raman signal being obtained.
  • the strength of the Raman signal and the exposure may be optimized depending on the analyte of interest.
  • the high-intensity light 10 enters on a first side 12a of the skin tissue 12.
  • the thickness of the skin tissue that may be used in determining the analyte concentration may vary.
  • the skin tissue is generally from about 1 to about 5 mm in thickness. More specifically, the skin is generally from about 1 to about 3 mm in thickness.
  • the skin tissue may be pinched when the high-intensity light. enters the skin tissue.
  • the high-intensity light 10 enters the skin tissue 12 at point A. After the high-intensity light 10 enters the skin tissue 12, a Raman signal is generated and scatters in all directions. A portion of the high-intensity light may contact the skin without entering the skin and scatter in all directions.
  • a portion 16 of the Raman signal is redirected back towards collection optics 18 after entering the skin tissue 12.
  • Some of the Raman signal exits the skin tissue 12, however, and is reflected back using a Raman- generating material 22.
  • the Raman-generating material 22 reflects back Raman signals towards the collection optics 18 that would otherwise have been lost exiting the other side 12b of the skin tissue 12, which is opposite of the collection optics 18.
  • an increased fraction of the Raman signal will be redirected to the collection optics 18. It is contemplated that an increased fraction of the Raman signal may be redirected using a reflective surface such as a mirror.
  • a portion of the Raman signal created by the Raman-generating material is scattered at oblique angles and will not be detected or may also be absorbed before being detected.
  • the Raman-generating material 22 is placed in a location nearest the other side 12b of the skin tissue 12.
  • the Raman-generating material is located generally opposite of the entry of the applied high-intensity light. As shown in FIG. 1 , the Raman-generating material 22 is located opposite of the entry of the high-intensity light 10 at point A in FlG. 1. It is contemplated that the Raman-generating material may be a single reflector as shown in FIG. 1 or a plurality of reflectors.
  • the Raman-generating material 22 also receives the high-intensity light 10 and generates additional Raman signal therefrom. To the extent that the Raman-generating material does not create Raman signals from the high-intensity light 10, the Raman-generating material 22 reflects back the remaining portion of the high-intensity light back through the skin tissue 12. These Raman signals will typically envelop a larger volume of skin tissue because the Raman signals will originate and scatter outwardly from every point in the skin tissue. After this high-intensity light is reflected back into the skin tissue 12 via the Raman-generating material 22, additional Raman signals may be generated. Thus, the optical pathlength is increased by passing the source light through the skin tissue twice. By increasing the optical pathlength, the resulting analytical signal is also increased.
  • a measure of optical absorption can be obtained. Absorption is generally proportional to the total quantity of Raman signal from the Raman-generating material 22 that passes through the sample. In the case where the entire Raman signal can be integrated, then the analytical signal can be further corrected for changes in tissue absorbance and tissue scattering. Changes in tissue absorbance and scattering may be caused by, for example, increased blood flow or changes in tissue hydration.
  • the intensity of the Raman signals from the Raman-generating material using only the high-intensity light can be compared to the intensity of the Raman signals using the Raman-generating material and the body tissue using the high-intensity light. A comparison of these intensities can determine and quantify the level of optical absorbance by the tissue.
  • the level of optical absorbance can be done on an absolute basis or a relative basis. If done on an absolute basis, the high-intensity light will typically need to be adjusted to have a similar intensity level when contacting the Raman-generating material 22.
  • the Raman-generating material 22 (a) reflects back Raman signal created on the initial pass through the skin tissue that otherwise would have been lost; (b) creates Raman signal from the high-intensity light 10; and (c) reflects back the light source that did not create a Raman signal back into the skin tissue with the possibility of forming an additional Raman signal.
  • These Raman signals are designated generally in FIG. 1 as Raman signals 20.
  • the Raman-generating material may be formed from a variety of materials.
  • the Raman-generating material may include a polymeric material such as SpectralonTM polymeric lining.
  • SpectralonTM polymeric lining is a thermoplastic resin with a very high diffuse reflectance.
  • SpectralonTM polymeric lining is available through Labsphere Inc. of North Sutton, New Hampshire.
  • the Raman-generating material may include other polymeric materials.
  • the Raman-generating material may include a polystyrene surface or polycarbonate surface.
  • the Raman-generating material to be used needs to generate a unique Raman signal.
  • the Raman-generating material may be a thin coating or layer on a thicker substrate, which is not a Raman-generating material.
  • the substrate may be formed entirely of the Raman-generating material.
  • an analyte e.g., glucose
  • concentration of an analyte requires a measure proportional to the quantity of the analyte and a measure of the volume in which that quantity analyte resides.
  • Employing a measure of optical scattering allows the analyte concentration calculation to be corrected should the optical probe volume change over the course of several measurements.
  • a spatial filter is provided that measures the optical scattering of the Raman signals in the tissue. The amount of scattering affects the probe volume of the body tissue. The use of a spatial filter differentiates scattering from absorbance and further approximates the relative changes in absorbance and scattering in a skin tissue sample of fixed thickness.
  • a spatial filter is placed to block a fraction of the Raman signals emerging from the skin tissue and to allow the remaining fraction of the Raman signals to strike the at least one detector.
  • a spatial filter blocks light in one portion and allows light through in another portion.
  • FIG. 1 depicts a spatial filter 80, which is shown in more detail in FIG. 2a.
  • the spatial filter 80 includes a plurality of apertures 82, 84, 86 being formed. Sections 80a, 80b of the spatial filter 80 block a fraction of the Raman signals.
  • the intensity (I) of the Raman signal at the middle aperture 84 would likely be significantly higher than the intensities of the Raman signals at outer apertures 82, 86 since a small fraction of the Raman signals would take a lateral trajectory through the skin tissue.
  • the spatial pattern of the Raman signals from the Raman-generating material would also subsequently change.
  • the analyte signal is normalized against optical probe volume and, thus, increases the accuracy of the calculated analyte concentration.
  • a spatial filter 90 includes sections 90a and 90b.
  • the sections 90a, 90b are movable along a generally horizontal direction in either direction (see arrow A).
  • FIG. 2b depicts the sections 90a, 90b in a more open position such that the distance therebetween is represented by distance Dl .
  • FIG. 2c depicts the sections 90a, 90b in a more closed position such that the distance therebetween is represented by distance D2.
  • the spatial filter itself may be movable so as to better determine and characterize the scattered light.
  • the spatial filter may be moved to determine where the light propagates through the sample and/or to selectively measure multiple scattered or transmitted non-scattered light. If you excite a first point and measure at a second point with an aperture, then you have some idea of pathlength. By having a better idea of the pathlength, the tissue volume can be adjusted, if necessary, with respect to the analyte signal, which results in a more accurate analyte concentration.
  • the collection optics 18 collect the returned Raman signals 16, 20. It is contemplated that the collection optics may collect the Raman signals before they pass through the spatial filter.
  • the spatial filter 80 in this method needs to be located before the Raman signals are passed to a detector.
  • the collected Raman signals are then passed to a detector 30.
  • the detector 30 assists in determining the analyte concentration (e.g., glucose) from the collected Raman signals.
  • analyte concentration e.g., glucose
  • a detector that may be used is a silicon detector.
  • Other examples of detectors include an extended InGaAs detector, a germanium detector, a lead selenide (PbSe) detector, or a lead sulfide (PbS) detector. It is contemplated that other detectors may be employed to assist in determining the analyte concentration (e.g., glucose) from the collected Raman signals.
  • a plurality of detectors and a plurality of apertures may be used.
  • the plurality of apertures and detectors may approximate a direct-imaging arrangement, which likely would provide a more accurate measure of scattering and absorption.
  • the corrections for Raman absorption and/or scattering properties of the body tissue related to quantifying analytes that have weak Raman signals may be accomplished by several methods.
  • a calibration algorithm that incorporates absorption and/or scattering properties of the tissue to correct for the analyte concentration reading.
  • the collection times are automatically adjusted so that the appropriate signal-to-noise ratio is achieved, which assists in obtaining a more accurate analyte reading. For example, the collection times may be increased to increase the total amount of signals, which generally translates to better signals, especially with smaller signals.
  • the Raman signature of glucose can be quantitatively determined in a more accurate manner.
  • this method provides an optical solution to correct quantitative, analytical signals for changes in the tissue optical properties.
  • FIG. 3 depicts an illustration similar to FIG. 1 that includes a parabolic mirror 40 in which the high-intensity light 10 passes through an opening 42 formed therein.
  • the high-intensity light 10 enters the tissue and generates Raman signals, which scatter in all directions.
  • the scattered Raman signals 46 are directed back to the parabolic mirror 40 after passing between or around the spatial filter sections 80a, 80b.
  • the Raman signals are further reflected by the parabolic mirror to a detector 50 where the analyte concentration is determined from the collected Raman signals.
  • the analyte concentration in this method may be corrected in a similar manner as discussed in connection with FIGs. 1 and 2.
  • the collection optics may be other mirrors with curvatures that deliver focused laser light back into the tissue.
  • the collection optics may be other mirrors with curvatures that are shaped to deliver parallel light back into the tissue depending on the Raman signal collection optics.
  • the spatial distribution of the Raman signals may also be achieved by using an optical design based on spatial imaging.
  • a spatial filter is unnecessary.
  • FIG. 4 shows the high-intensity light source 10a, the skin issue 12, and the Raman-generating material 22.
  • Raman signals 100 are collected by imaging optics 110 and then are directed to an array detector 112.
  • the array detector 112 is an array of individuals detectors (pixels) that each measure a portion of Raman signal.
  • the imaging optics and the detector use the Raman signals to correct for both absorption and scattering caused by the tissue.
  • a non-invasive method of determining the concentration of an analyte using Raman spectral information includes pinching an area of the skin tissue. An area of the skin tissue is pinched. A Raman-generating material is placed near or around the pinched skin tissue. The Raman-generating material forms at least one opening therethrough. A high-intensity, narrow band of light is applied to the skin tissue through the at least one opening. The high-intensity light enters the skin tissue and generates a Raman signal. The high-intensity light and Raman signal that pass through the pinched skin tissue are reflected back into the pinched skin tissue via the Raman-generating material. The Raman signal generated from the high-intensity light entering the skin tissue and the additional Raman signal generated from the Raman-generating material is collected. The analyte concentration is determined using the collected Raman signals.
  • a Raman-generating material 170 is placed near or around a pinched skin tissue 180.
  • the width of the pinched skin tissue is generally from about 1 to about 2 mm.
  • the Raman-generating material 170 forms at least one opening 172 in which the high-intensity light 174 is applied through the at least one opening 172.
  • the high-intensity light 174 enters the pinched skin tissue 180 and generates a Raman signal.
  • the high-intensity light and Raman signal that pass through the pinched skin tissue are reflected back into the pinched skin tissue via the Raman-generating material 170. Additionally, the Raman-generating material 170 generates an additional Raman signal.
  • the Raman signals are collected and the analyte concentration is determined using the collected Raman signals.
  • the Raman signals may be collected via high NA (numerical aperture) optics or NA fiber(s) 190.
  • the high NA (numerical aperture) optics or NA fiber(s) 190 transmit the collected Raman signals to a spectrometer 192. It is contemplated that the collected signals may be transmitted to a single detector with a filter, a CCD (cathode- coupled detector), a diode array, or other devices that detect a specific signal. It is contemplated that the Raman signals may be collected on the same side as the high-intensity light entering the pinched skin tissue such as shown, for example, in FIG. 5b.
  • the Raman spectral information may be used in other methods.
  • information from the collected Raman signals may be used to perform a general diagnosis.
  • the general diagnosis may include identifying (a) the presence of a particular analyte; (b) a particular molecule or (c) tissue morphology.
  • the general diagnosis can be directed to several beneficial applications. For example, potential cancerous skin lesions may be identified in one application. By identifying potential cancerous cells, the tissue removal can be minimized. In another application, the stage of cancerous cells may be identified. In a further application, the effectiveness of cancer photodynamic therapy may be tracked. It is contemplated that other diagnosis may be performed using the inventive methods.
  • a non-invasive method for determining the concentration of an analyte uses fluorescence spectral information.
  • Analytes that may be measured using fluorescence spectral information include glucose, lipid profiles (e.g., cholesterol, triglycerides, LDL and HDL), microalbumin, hemoglobin Aic, or bilirubin.
  • the present invention is not limited, however, to these specific analytes and it is contemplated that other analyte concentrations may be determined.
  • the analytes may be in, for example, a whole blood sample, a blood serum sample, a blood plasma sample, and other body fluids like ISF (interstitial fluid) and urine.
  • ISF interstitial fluid
  • the present invention assists in providing a method of correcting for optical absorbance and/or tissue scattering that can be transient during non-invasive analyte (e.g., glucose) detection.
  • the fluorescence signature of analytes such as glucose can be corrected based on the optical absorbance and tissue scattering occurring in the tissue.
  • the absorption of the skin tissue and tissue scattering may vary in the short term, as well as the long term as discussed above.
  • the analyte concentration is determined using fluorescence spectral information.
  • a high-intensity band of light is applied to a first side of skin tissue. The high-intensity light enters the skin tissue and generates a fluorescence signal.
  • a fluorescence-generating material is placed in a location nearest a second side of skin tissue.
  • the second side is located generally opposite of the first side.
  • the high-intensity light from the fluorescence-generating material is reflected so as to produce additional fluorescence signal that passes through the skin tissue towards the first side of the skin tissue.
  • the fluorescence signal generated from the high-intensity light entering the skin tissue is reflected towards the first side of the skin tissue via the fluorescence-generating material.
  • the fluorescence signal generated from the high-intensity light entering the skin tissue and the additional fluorescence signal generated from the fluorescence-generating material are collected.
  • the analyte concentration is determined using information from the collected fluorescence signals.
  • High-intensity light 210 is applied to the skin tissue 12 such as pinched skin tissue or a finger.
  • the high-intensity light 210 is shown in FIG. 6a as coming from a high-intensity light source 210a.
  • the high-intensity light 210 may be a narrow band of light, but does not necessarily have to be a narrow band of light.
  • the high-intensity light source may come from a monochromatic light source. It is contemplated that other light sources may be used such as a light-emitting diode, incoherent lamps, a dye laser, gas laser, ion laser or a pumped laser.
  • the wavelength of the light source may vary but is generally between 300 and 10,000 run.
  • the fluorescence spectral information in one method may be collected in the wavelength range from about 300 nm to about 12,000 nm. It is contemplated that the fluorescence spectral information may be collected in different ranges depending on the analyte concentration to be determined.
  • the high-intensity light 210 enters on the first side 12a of the skin tissue 12. As shown in FIG. 6a, the high-intensity light 210 enters the skin tissue 12 at point A. After the high-intensity light 210 enters the skin tissue 12, a fluorescence signal is generated and scatters in all directions. A portion of the high-intensity light may contact the skin without entering the skin and scatter in all directions. A portion 216 of the fluorescence signal is redirected back towards the collection optics 18 after entering the skin tissue 12. Some of the fluorescence signal exits the skin tissue 12, however, and is reflected back using a fluorescence-generating material 222.
  • the fluorescence-generating material 222 reflects back fluorescence signals towards the collection optics 18 that would otherwise have been lost exiting the other side 12b of the skin tissue 12, which is opposite of the collection optics 18. Thus, an increased fraction of the fluorescence signal will be redirected to the collection optics 18. It is contemplated that an increased fraction of the fluorescence signal may be redirected using a reflective surface such as a mirror. A portion of the fluorescence signal created by the fluorescence-generating material is scattered at oblique angles and will not be detected or may also be absorbed before being detected.
  • the fluorescence-generating material 222 is placed in a location nearest the other side 12b of the skin tissue 12.
  • the fluorescence-generating material is located generally opposite of the entry of the applied high-intensity light. As shown in FIG. 6a, the fluorescence-generating material 222 is located opposite of the entry of the high-intensity light 210 at point A in FIG. 6a. It is contemplated that the fluorescence-generating material may be a single reflector as shown in FIG. 6a or a plurality of reflectors.
  • the fluorescence-generating material 222 also receives the high-intensity light 210 and generates additional fluorescence signal therefrom. To the extent that the fluorescence-generating material does not create fluorescence signals from the high-intensity light 210, the fluorescence-generating material 222 reflects back the remaining portion of the high-intensity light back through the skin tissue 12. These fluorescence signals will typically envelop a larger volume of skin tissue because the fluorescence signals will originate and scatter outwardly from every point in the skin tissue. After this high-intensity light is reflected back into the skin tissue 12 via the fluorescence-generating material 222, additional fluorescence signals may be generated. Thus, the optical pathlength is increased by passing the source light through the skin tissue twice. By increasing the optical pathlength, the resulting analytical signal is also increased.
  • a measure of optical absorption can be obtained. Absorption is generally proportional to the total quantity of fluorescence signal from the fluorescence-generating material 222 that passes through the sample.
  • the analytical signal can be further corrected for changes in tissue absorbance and tissue scattering.
  • the analytical signal can be further corrected for changes in tissue absorbance and scattering. Changes in tissue absorbance and scattering may be caused by, for example, increased blood flow or changes in tissue hydration.
  • the intensity of the fluorescence signals from the fluorescence- generating material using only the high-intensity light can be compared to the intensity of the fluorescence signals using the fluorescence-generating material and the body tissue using the high-intensity light. A comparison of these intensities can determine and quantify the level of optical absorbance by the tissue.
  • the fluorescence-generating material 222 (a) reflects back fluorescence signal created on the initial pass through the skin tissue that otherwise would have been lost; (b) creates fluorescence signal from the high-intensity light 210; and (c) reflects back the light source that did not create a fluorescence signal back into the skin tissue with the possibility of forming an additional fluorescence signal.
  • fluorescence signals 220 are designated generally in FIG. 6a as fluorescence signals 220.
  • the fluorescence-generating material may function under a fluorescence mechanism where light of a shorter wavelength excites the molecule and then the molecule fluoresces, giving off light of a longer wavelength.
  • the fluorescence-generating material may be formed from a variety of materials such fluorescence dyes.
  • the fluorescence dyes may be near-infrared (NIR) dyes, IR dyes and visible dyes.
  • NIR fluorescent dyes include derivatives from cyanine dyes (Cy5.5) or the clinically-approved indocyanine green (ICG). Such dyes are typically used as a coating since they are usually aqueous in nature.
  • the dyes may be mobilized or impregnated in the fluorescence-generating material. It is contemplated that other materials may be used as a fluorescence-generating material that function in a similar manner.
  • the material used in the NIR card functions on "photon upconversion" where light of a longer wavelength is absorbed by a first molecule and the energy is transferred to a second molecule that fluoresces at a shorter wavelength. This process is referred to upconversion since the excitation light is of lower energy than the emission light.
  • One example is the use of quantum dots. Quantum dots are small metallic materials whose fluorescence is size dependent. It is contemplated that other materials may be used as a fluorescence-generating material that function in a similar manner.
  • fluorescence-generating material that fluoresce in a different manner and in a different spectrum.
  • the fluorescence-generating material to be used generates a unique fluorescence signal.
  • the fluorescence-generating material may be a thin coating or layer on a thicker substrate, which is not a fluorescence-generating material.
  • the substrate may be formed entirely of the fluorescence-generating material.
  • an analyte e.g., glucose
  • concentration of an analyte requires a measure proportional to the quantity of the analyte and a measure of the volume in which that quantity analyte resides.
  • Employing a measure of optical scattering allows the analyte concentration calculation to be corrected should the optical probe volume change over the course of several measurements.
  • a spatial filter before collecting the fluorescence signals, a spatial filter is provided that measures the optical scattering of the fluorescence signals in the tissue.
  • a spatial filter is placed to block a fraction of the fluorescence signals emerging from the skin tissue and to allow the remaining fraction of the fluorescence signals to strike the at least one detector.
  • a spatial filter blocks light in one portion and allows light through in another portion.
  • FIG. 6a depicts a spatial filter 280, which is shown in more detail in FIG. 6b.
  • the spatial filter 280 includes a plurality of apertures 282, 284, 286 being formed. Sections 280a, 280b of the spatial filter 280 block a fraction of the fluorescence signals. If the optical scattering is low, the intensity (I) of the fluorescence signal at the middle aperture IS
  • the spatial filter may be adjustable to adjust the size of the aperture openings as, for example, described above in the spatial filter 90. It is also contemplated that the spatial filter itself may be movable so as to better determine and locate the scatter.
  • the returned fluorescence signals 216, 220 are collected by the collection optics 18.
  • the collected fluorescence signals are then passed to a detector 230.
  • the detector 230 assists in determining the analyte concentration (e.g., glucose) from the collected fluorescence signals.
  • analyte concentration e.g., glucose
  • One example of a detector of fluorescence signals that may be used is a silicon detector.
  • Other examples of detectors include an extended InGaAs detector, a germanium detector, a lead selenide (PbSe) detector, or a lead (PbS) detector. It is contemplated that other detectors may be employed to assist in determining the analyte concentration (e.g., glucose) from the collected fluorescence signal.
  • a plurality of detectors and a plurality of apertures may be used.
  • the plurality of apertures and detectors may approximate a direct-imaging arrangement, which likely would provide a more accurate measure of scattering and absorption.
  • the corrections for fluorescence absorption and/or scattering properties of the body tissue related to quantifying analytes that have weak fluorescence signals may be accomplished by several methods.
  • a calibration algorithm that incorporates absorption and/or scattering properties of the tissue to correct for the analyte concentration reading.
  • the collection times are automatically adjusted so that the appropriate signal-to-noise ratio is achieved, which assists in obtaining a more accurate analyte reading.
  • the collection times may be increased to increase the total amount of signals, which generally translates to better signals, especially with smaller signals.
  • the fluorescence signature of glucose can be quantitatively determined in a more accurate manner.
  • this method provides an optical solution to correct quantitative, analytical signals for changes in the tissue optical properties.
  • FIG. 7 depicts an illustration similar to FIG. 6a that includes a parabolic mirror 240 in which the high-intensity light 210 passes through an opening 242 formed therein.
  • the high-intensity light 210 enters the tissue and generates fluorescence signals, which scatter in all directions.
  • the scattered fluorescence signals 246 are- directed back to the parabolic mirror 240 after passing through the spatial filter sections 280a, 280b.
  • the fluorescence signals are further reflected by the parabolic mirror to the detector 250 where the analyte concentration is determined from the collected fluorescence signals.
  • the analyte concentration in this method may be corrected in a similar manner as discussed in connection with FIGs. 6a, 6b.
  • the collection optics may be other mirrors with curvatures that deliver focused laser light back into the tissue.
  • the collection optics may be other mirrors with curvatures that are shaped to deliver parallel light back into the tissue depending on the fluorescence-signal collection optics.
  • the spatial distribution of the fluorescence signals may also be achieved by using an optical design based on spatial imaging.
  • a spatial filter is unnecessary.
  • FIG. 8 shows the high-intensity light source 210a, the skin issue 12, and the fluorescence- generating material 222.
  • Fluorescence signals 300 are collected by imaging optics 310 and then are directed to the array detector 312.
  • the array detector 312 is an array of individuals detectors (pixels) that each measure a portion of fluorescence signal.
  • the imaging optics and the detector in one method, use the fluorescence signals to correct for both absorption and scattering caused by the tissue.
  • a fluorescence-generating material 370 is placed near or around a pinched skin tissue 380.
  • the width of the pinched skin tissue is generally from about 1 to about 2 mm.
  • the fluorescence-generating material 370 forms at least one opening 372 in which the high-intensity light 374 is applied through the at least one opening 372.
  • the high-intensity light 374 enters the pinched skin tissue 380 and generates a fluorescence signal.
  • the high-intensity light and fluorescence signal that pass through the pinched skin tissue are reflected back into the pinched skin tissue via the fluorescence-generating material 370.
  • the fluorescence-generating material 370 generates an additional fluorescence signal.
  • the fluorescence signals are collected and the analyte concentration is determined using the collected fluorescence signals.
  • the fluorescence signals may be collected via high NA (numerical aperture) optics or NA fiber(s) 390.
  • the high NA (numerical aperture) optics or NA fiber(s) 390 transmit the collected fluorescence signals to a spectrometer 392. It is contemplated that the collected signals may be transmitted to a single detector with a filter, a CCD (cathode- coupled detector), a diode array, or other devices that detect a specific signal. It is contemplated that the fluorescence signals may be collected on the same side as the high- intensity light entering the pinched skin tissue such as shown, for example, in FIG. 9b.
  • the fluorescence spectral information may be used in other methods.
  • information from the collected fluorescence signals may be used to perform a general diagnosis.
  • the general diagnosis may include identifying (a) the presence of a particular analyte; (b) a particular molecule or (c) tissue morphology.
  • the general diagnosis can be directed to several beneficial applications. For example, potential cancerous skin lesions may be identified in one application. By identifying potential cancerous cells, the tissue removal can be minimized. In another application, the stage of cancerous cells may be identified. In a further application, the effectiveness of cancer photodynamic therapy may be tracked. It is contemplated that other diagnosis may be performed using the inventive methods.
  • a non-invasive method of determining the concentration of an analyte using Raman spectral information comprising the acts of: applying a high-intensity, narrow band of light to a first side of skin tissue, the high- intensity light entering the skin tissue and generating a Raman signal; placing a Raman-generating material in a location nearest a second side of the skin tissue, the second side being located generally opposite of the first side; reflecting the high-intensity light from the Raman-generating material so as to produce additional Raman signal that passes through the skin tissue towards the first side of the skin tissue; reflecting the Raman signal generated from the high-intensity light entering the skin tissue towards the first side of the skin tissue via the Raman-generating material; collecting the Raman signal generated from the high-intensity light entering the skin tissue and the additional Raman signal generated from the Raman-generating material; and determining the analyte concentration using information from the collected Raman signals.
  • Process A further including a detector that assists in determining the analyte concentration.
  • Process A further including providing a spatial filter to assist in determining the level of absorbance of the skin tissue.
  • a non-invasive method of diagnosis using Raman spectral information comprising the acts of: applying a high-intensity, narrow band of light to a first side of skin tissue, the high- intensity light entering the skin tissue and generating a Raman signal; placing a Raman-generating material in a location nearest a second side of the skin tissue, the second side being located generally opposite of the first side; reflecting the high-intensity light from the Raman-generating material so as to produce additional Raman signal that passes through the skin tissue towards the first side of the skin tissue; reflecting the Raman signal generated from the high-intensity light entering the skin tissue towards the first side of the skin tissue via the Raman-generating material; collecting the Raman signal generated from the high-intensity light entering the skin tissue and the additional Raman signal generated from the Raman-generating material; and using information from the collected Raman signals to perform a general diagnosis.
  • the method of Process V wherein performing the general diagnosis includes identifying the presence of a particular analyte.
  • Process V further including a detector that assists in performing the general diagnosis.
  • Process V further including providing a spatial filter to assist in determining the level of absorbance of the skin tissue.
  • Process V further including an array detector and imaging optics.
  • a non-invasive method of determining the concentration of an analyte using Raman spectral information comprising the acts of: pinching an area of the skin tissue; placing a Raman-generating material near or around the pinched skin tissue, the Raman-generating material forming at least one opening therethrough; applying a high-intensity, narrow band of light to the skin tissue through the at least one opening, the high-intensity light entering the skin tissue and generating a Raman signal; reflecting the high-intensity light and Raman signal that pass through the pinched skin tissue back into the pinched skin tissue via the Raman-generating material; collecting the Raman signal generated from the high-intensity light entering the skin tissue and the additional Raman signal generated from the Raman-generating material; and determining the analyte concentration using the collected Raman signals.
  • a non-invasive method of determining the concentration of an analyte using fluorescence spectral information comprising the acts of: applying a high-intensity, narrow band of light to a first side of skin tissue, the high- intensity light entering the skin tissue and generating a fluorescence signal; placing a fluorescence-generating material in a location nearest a second side of the skin tissue, the second side being located generally opposite of the first side; reflecting the high-intensity light from the fluorescence-generating material so as to produce additional fluorescence signal that passes through the skin tissue towards the first side of the skin tissue; reflecting the fluorescence signal generated from the high-intensity light entering the skin tissue towards the first side of the skin tissue via the fluorescence-generating material; collecting the fluorescence signal generated from the high-intensity light entering the skin tissue and the additional fluorescence signal generated from the fluorescence-generating material; and determining the analyte concentration using information from the collected fluorescence signals.
  • Process XX further including a detector that assists in determining the analyte concentration.
  • Process XX further including providing a spatial filter to assist in determining the level of absorbance of the skin tissue.
  • Process XX further including an array detector and imaging optics.
  • a non-invasive method of diagnosis using fluorescence spectral information comprising the acts of: applying a high-intensity light to a first side of skin tissue, the high-intensity light entering the skin tissue and generating a fluorescence signal; placing a fluorescence-generating material in a location nearest a second side of the skin tissue, the second side being located generally opposite of the first side; reflecting the high-intensity light from the fluorescence-generating material so as to produce additional fluorescence signal that passes through the skin tissue towards the first side of the skin tissue; reflecting the fluorescence signal generated from the high-intensity light entering the skin tissue towards the first side of the skin tissue via the fluorescence-generating material; collecting the fluorescence signal generated from the high-intensity light entering the skin tissue and the additional fluorescence signal generated from the fluorescence-generating material; and using information from the collected fluorescence signals to perform a general diagnosis.
  • the method of Process SSS wherein performing the general diagnosis includes identifying the presence of a particular analyte.
  • Process SSS further including a detector that assists in determining the analyte concentration.
  • Process SSS further including providing a spatial filter to assist in determining the level of absorbance of the skin tissue.
  • Process SSS further including an array detector and imaging optics.
  • a non-invasive method of determining the concentration of an analyte using fluorescence spectral information comprising the acts of: pinching an area of the skin tissue; placing a fluorescence-generating material near or around the pinched skin tissue, the fluorescence-generating material forming at least one opening therethrough; applying a high-intensity, narrow band of light to the skin tissue through the at least one opening, the high-intensity light entering the skin tissue and generating a fluorescence signal; reflecting the high-intensity light and fluorescence signal that pass through the pinched skin tissue back into the pinched skin tissue via the fluorescence-generating material; collecting the fluorescence signal generated from the high-intensity light entering the skin tissue and the additional fluorescence signal generated from the fluorescence-generating material; and determining the analyte concentration using the collected fluorescence signals.

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Abstract

L'invention concerne un procédé non invasif pour la détermination de la concentration d'un analyte à l'aide d'informations spectrales Raman ou de fluorescence. Une bande de lumière de haute intensité est appliquée sur un côté du tissu de la peau. La lumière de haute intensité pénètre dans le tissu cutané et génère un signal Raman ou de fluorescence. Une matière de génération de Raman ou une matière de génération de fluorescence est placée à un endroit aussi proche que possible, de l'autre côté du tissu cutané. La matière de génération de Raman ou de fluorescence est située en général à l'opposé de l'entrée de la lumière de haute intensité appliquée. Le signal Raman ou de fluorescence est recueilli et la concentration d'analyte est déterminée à l'aide du signal Raman collecté.
PCT/US2007/018310 2006-08-22 2007-08-17 Procédés non invasifs pour l'utilisation d'informations spectrales dans la détérmination de concentrations d'analytes WO2008024288A2 (fr)

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JP2009525575A JP2010501252A (ja) 2006-08-22 2007-08-17 スペクトル情報を使用して、分析対象物の濃度を決定する、非侵襲的方法
EP07837020A EP2056716A2 (fr) 2006-08-22 2007-08-17 Procédés non invasifs pour l'utilisation d'informations spectrales dans la détérmination de concentrations d'analytes
CA002661952A CA2661952A1 (fr) 2006-08-22 2007-08-17 Procedes non invasifs pour l'utilisation d'informations spectrales dans la determination de concentrations d'analytes

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WO2012019102A3 (fr) * 2010-08-05 2012-10-18 Massachusetts Institute Of Technology Système de diagnostic raman portable
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KR101207695B1 (ko) * 2010-08-11 2012-12-03 서울대학교산학협력단 형광 및 라만 신호 표적에 대한 형광 및 라만 신호 동시검출방법 및 이를 이용한 표적 동시검출용 의학영상장치
CN102821688A (zh) * 2011-04-12 2012-12-12 松下电器产业株式会社 对生物体中所含有的生物体成分的浓度进行测定的方法
JP6212303B2 (ja) * 2013-06-28 2017-10-11 景博 内田 糖尿病マーカーの測定方法
CN103529013A (zh) * 2013-10-18 2014-01-22 福建师范大学 一种基于dcdr光谱技术的精浆果糖快速检测的方法
KR101651659B1 (ko) * 2015-02-12 2016-08-30 한국광기술원 광 간섭 단층촬영을 이용한 색소 병변의 정량화 시스템 및 방법
CN114295522B (zh) * 2021-12-28 2024-03-29 华东理工大学 基于振动光谱成像的渗透深度及空间浓度分布的分析方法

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WO2006127766A1 (fr) * 2005-05-25 2006-11-30 Bayer Healthcare Llc Procedes d'utilisation de l'information de spectre raman dans la determination des concentrations d'une substance a analyser

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WO2006127766A1 (fr) * 2005-05-25 2006-11-30 Bayer Healthcare Llc Procedes d'utilisation de l'information de spectre raman dans la determination des concentrations d'une substance a analyser

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US7911604B2 (en) 2005-11-25 2011-03-22 The Science And Technology Facilities Council Security screening using raman analysis
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WO2012019102A3 (fr) * 2010-08-05 2012-10-18 Massachusetts Institute Of Technology Système de diagnostic raman portable
US8509868B2 (en) 2011-04-12 2013-08-13 Panasonic Corporation Method for measuring a concentration of a biogenic substance contained in a living body

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CA2661952A1 (fr) 2008-02-28

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