WO2012062306A2 - Utilisation d'une combinaison de méthodes d'évaluation dans un dispositif de détection de tumeurs et dispositif de détection de tumeurs - Google Patents

Utilisation d'une combinaison de méthodes d'évaluation dans un dispositif de détection de tumeurs et dispositif de détection de tumeurs Download PDF

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Publication number
WO2012062306A2
WO2012062306A2 PCT/DE2011/075240 DE2011075240W WO2012062306A2 WO 2012062306 A2 WO2012062306 A2 WO 2012062306A2 DE 2011075240 W DE2011075240 W DE 2011075240W WO 2012062306 A2 WO2012062306 A2 WO 2012062306A2
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WO
WIPO (PCT)
Prior art keywords
evaluation method
oscillator
combination
signals
stokes
Prior art date
Application number
PCT/DE2011/075240
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German (de)
English (en)
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WO2012062306A3 (fr
Inventor
Karsten KÖNIG
Hans Georg Breunig
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Jenlab Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Jenlab Gmbh filed Critical Jenlab Gmbh
Priority to EP11813772.8A priority Critical patent/EP2624743A2/fr
Publication of WO2012062306A2 publication Critical patent/WO2012062306A2/fr
Publication of WO2012062306A3 publication Critical patent/WO2012062306A3/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • 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
    • A61B5/0071—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence by measuring fluorescence emission
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54366—Apparatus specially adapted for solid-phase testing
    • G01N33/54373—Apparatus specially adapted for solid-phase testing involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
    • 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
    • G01N2021/653—Coherent methods [CARS]
    • 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
    • G01N2021/653—Coherent methods [CARS]
    • G01N2021/655—Stimulated Raman

Definitions

  • the present invention relates to a use of a combination of evaluation methods in a device for detecting tumors according to claim 1 and a device for detecting tumors according to claim 2 or 3.
  • the present invention is based on the object to improve the safety in the detection of tumors.
  • Claim 1 relates to the use of a combination of evaluation methods in a device for detecting tumors, wherein the combination of the evaluation methods comprises the multiphoton excitation evaluation method and / or the second harmonic generation method, and furthermore either the evaluation method of the coherent anti-Stokes-Raman Scattering or the evaluation method of stimulated Raman scattering includes.
  • Claim 2 relates to a device for the detection of tumors using a combination of evaluation methods, wherein the combination of the evaluation method, the evaluation method of multiphoton excitation and / or the evaluation method the generation of the second harmonic and further comprises the method of evaluation of coherent anti-Stokes Raman scattering.
  • the device comprises a femtosecond oscillator or a picosecond oscillator whose output signals are supplied to an optical parametric oscillator, wherein the output signals of the optical parametric Oscillator be projected by means of a focusing on the skin of a person to be examined, wherein scattered signals with a frequency which results as a frequency due to the coherent anti-Stokes-Raman scattering from the two frequencies of the optical parametric oscillator, are analyzed in terms of their intensity
  • the apparatus further comprises means for masking one of the output signals of the optical parametric oscillator for performing the multiphoton excitation evaluation method and the second harmonic generation evaluation method.
  • Said device is suitable when using the evaluation method of the coherent anti-Stokes Raman scattering.
  • Claim 3 relates to a device for the detection of tumors using a combination of evaluation methods, wherein the combination of the evaluation method comprises the multiphoton excitation evaluation method and / or the second harmonic generation method and further the Raman scattering evaluation method; Femtose III- oscillator or a picosecond oscillator whose output signals are supplied to an optical parametric oscillator, wherein the output signals of the optical parametric oscillator are projected by means of a focusing on the skin of a person to be examined, wherein scattered signals of the frequency of Pumpfeldes and / or the Frequency of the Stokes E-field, are analyzed in terms of their intensity, the apparatus further comprising means for masking one of the output signals of the optical parametric oscillator for carrying out the multiphoton excitation evaluation method and the second harmonic generation evaluation method. It also proves to be advantageous that several components can be used together to carry out the different evaluation methods. Said device is suitable when using the evaluation method of the stimulated Raman scattering.
  • the output signals of the optical parametric oscillator and the backscattered signals are distinguished by the polarization planes of the signals are rotated in the path of the signals.
  • This embodiment again relates to the stimulated Raman scattering, because in this case the frequencies of the scattered radiation coincide with the frequencies of the introduced radiation.
  • the evaluation takes place in this case in that the scattered radiation amplifies the radiation introduced with respect to one frequency and is weakened with respect to the other frequency. In order to distinguish the scattered radiation from the introduced radiation, these radiations are polarized differently.
  • the object of the present invention is therefore an apparatus for performing optical tomography of the skin, wherein the imaging signals by generation and detection of multiphoton fluorescence, coherent anti-Stokes Raman scattering (CARS) or the second harmonic (SHG) of the incident light arise.
  • CARS coherent anti-Stokes Raman scattering
  • SHG second harmonic
  • Coherent anti-Stokes Raman microscopy allows imaging of chemical or biological samples using molecular vibration transitions as a contrasting mechanism.
  • an electromagnetic pump field with a central frequency (Dp and an electromagnetic Stokes field with central frequency w s are used.
  • CARS microscopy (as well as SHG microscopy) does not require fluorophores, since the imaging mechanism is based on vibrational excitation of chemical and biological samples, and provides significantly higher coherence properties due to CARS microscopy Sensitivity as the spontaneous Raman microscopy, whereby a clear H lower average excitation power can be used or a shorter measurement time is necessary.
  • US Patent No. 6108081 deals with an apparatus and method for microscopically imaging molecular vibrations using CARS with a collinear excitation geometry.
  • collinear pump and Stokes beams are focused onto the sample with the aid of a high numerical aperture objective. Due to the nonlinear dependence of the signal on the excitation intensity, only in The small focus volume generates signals so that a three-dimensional scanning of the sample is possible. The signals are detected only in the beam direction.
  • US Patent No. 6934020 deals with an apparatus in which the signal is detected from the sample in the reverse direction (opposite to the beam direction, Epi-CARS).
  • This reverse signal typically has a higher signal-to-noise ratio, but is weaker in many applications than the signal simultaneously generated in the forward direction.
  • US Patent 7414729 describes an endoscopy system in which at least two stimulating electromagnetic fields and the generated signal are transmitted through an optical fiber system.
  • the signal is again generated by the non-linear interaction of the exciting electromagnetic fields with the sample volume and passed through the same fiber as the exciting fields to the detector.
  • the subject matter of the present invention is a tomograph which generates and detects signals in a spatially resolved manner by non-linear optical excitation.
  • the image signals are generated by pixel-by-pixel detection of the signal intensities.
  • the spatial resolution is generated by minimizing the focus volume, since only in this volume signals arise.
  • the signals to be detected are multiphoton autofluorescence, the second harmonics of the incident light and CARS light.
  • CARS signals For the generation of CARS signals, at least two collinear laser beams of different wavelengths must be focused through a microscope objective onto the sample in a common focus volume.
  • the signal light must be collected and (spectrally) separated from the incident radiation and detected.
  • an oscillator in combination with an optical parametric oscillator can be used.
  • the laser beams can be moved over the skin with the aid of scanner mirrors and the collected signal can be detected with a photomultiplier.
  • OPO optical parametric oscillator
  • the use of a single laser beam is sufficient, the second laser beam can be blocked in this mode of operation.
  • different excitation wavelengths and filters must generally be used. Exemplary embodiments of the tomograph for carrying out optical skin examinations on the basis of multiphoton excitations, the generation of the second harmonic and coherent anti-Stokes-Raman scattering are described below.
  • FIG. 1 shows an embodiment of the combined multiphoton excitation CARS tomograph.
  • the excitation is carried out by a femtosecond oscillator and an optical parametric oscillator.
  • the pulses of a femtosecond oscillator (a) (eg MaiTai HP Spectra Physics) are directed via deflecting mirrors located under a cover (b) into an optical parametric oscillator (OPO) (c) (eg Chameleon APE Berlin)
  • OPO generates sig- naled signal and idler pulses that emerge through an opening on the side, in addition to which the OPO has an output opening for the oscillator pulses, which are spatially and temporally superimposed on oscillator and Stokes pulse trains by means of a delay path and a dichroic mirror.
  • the pulses are then focused on the skin to be examined via a scanner-detector module (e) and a mirror arm with focusing optics.
  • the (mirror) scanner is used for pixel-by-pixel scanning of the sample with the stimulating pulses.
  • the generated signals (depending on the configuration CARS, autofluorescence, SHG) are collected by the same focusing optics and passed through the mirror arm (f) back into the scan detector module (e).
  • stimulating radiation and signal are separated by a dichroic mirror and the signal is detected.
  • the beam path of the exciting laser pulses and the generated signal is shown in FIG.
  • a single beam is sufficient.
  • either the oscillator, signal or Idlerpulse be used and blocked the other beams each.
  • suitable filters are introduced into the signal beam path, for example by sliding tabs, eg color glass filters BG 39 for the detection of SHG and autofluorescence, and suitable bandpass filters for the exclusive detection of SHG or CARS signals.
  • the superimposed Stokes and oscillator pulses are used for the excitation of CARS signals, for example of water (eg central wavelength of the oscillator pulses: 810 nm, signal pulses: 1105 nm, CARS signal at 639 nm, filter used: bandpass 624/40) or the CH 2 Stretching vibration used, which occurs in lipid molecules (eg oscillator pulses: 810 nm, signal pulses: 1052 nm, CARS signal at 658 nm, bandpass filter 660/10).
  • an oscillator another laser is conceivable that can generate pulses in the fs range.
  • a picosecond oscillator may be used in the described construction.
  • the pulse duration of the OPO pulses is then also in the picosecond range. With these pulses, CARS can achieve higher spectral accuracy of excitation, but the pulse intensities available to excite autofluorescence are lower.
  • one of the previously described possibilities is used to generate the exciting electromagnetic fields and to generate autofluorescence / SHG signals.
  • another non-linear Raman technique is used.
  • One such technique is stimulated Raman scattering (SRS).
  • SRS stimulated Raman scattering
  • Two E fields (pump and Stokes) of different wavelengths are simultaneously irradiated onto the sample and spatially superimposed. If the energy difference of pump and Stokes E fields corresponds to the energy of a vibration transition, then the molecule can be excited to vibrate.
  • the Stokes E field is amplified by stimulated emission and the pump field is attenuated. The intensity of this increase in intensity or attenuation is used as a signal for imaging.
  • SRS measurement in epi-geometry does not allow spectral separation of stimulating rays and backscattered signal.
  • a beam splitter can be used for a separation, which either lets pass or reflects differently polarized light.
  • a quarter-wave plate is introduced into the excitation / signal beam path, which circularly polarizes the linearly polarized exciting radiation.
  • the amplified or attenuated signal light passes through the quarter-wave plate a second time on the way to the detector and is thus linearly polarized with a plane of polarization shifted by 90 ° with respect to the exciting radiation.
  • Exciting light and signal light are then spatially separated by a polarization beam splitter and the signal light is detected.
  • the lock-in technique is used.
  • the intensity of the Stokes beam is modulated at high frequency and the intensity of the pump beam at the modulation frequency detected with a lock-in amplifier.
  • the pump beam can also be modulated and the intensity of the Stokes beam can be detected.
  • SHG / Autofluoreszenzsignalen is converted to the configuration shown in Figure 2 by the detector and filter and beam splitters are mounted on slidable riders.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Biomedical Technology (AREA)
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  • Physics & Mathematics (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
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  • Urology & Nephrology (AREA)
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  • Spectroscopy & Molecular Physics (AREA)
  • Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)

Abstract

La présente invention concerne une combinaison de méthodes d'évaluation dans un dispositif de détection de tumeurs, la combinaison des méthodes d'évaluation comprenant la méthode d'évaluation par excitation multiphoton et/ou la méthode d'évaluation par production de la seconde harmonique, ainsi que soit la méthode d'évaluation par diffusion Raman anti-Stokes cohérente soit la méthode d'évaluation par diffusion Raman stimulée. Selon l'invention, afin d'améliorer la sécurité lors de la détection de tumeurs, les méthodes d'évaluation mentionnées sont combinées.
PCT/DE2011/075240 2010-10-07 2011-10-05 Utilisation d'une combinaison de méthodes d'évaluation dans un dispositif de détection de tumeurs et dispositif de détection de tumeurs WO2012062306A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP11813772.8A EP2624743A2 (fr) 2010-10-07 2011-10-05 Utilisation d'une combinaison de méthodes d'évaluation dans un dispositif de détection de tumeurs et dispositif de détection de tumeurs

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102010047578.5 2010-10-07
DE102010047578A DE102010047578A1 (de) 2010-10-07 2010-10-07 Verwendung einer Kombination von Auswertungsverfahren in einer Vorrichtung zur Detektion von Tumoren sowie Vorrichtung zur Detektion von Tumoren

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WO2012062306A2 true WO2012062306A2 (fr) 2012-05-18
WO2012062306A3 WO2012062306A3 (fr) 2012-07-12

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104382557A (zh) * 2014-11-20 2015-03-04 西安邮电大学 基于红外谱分析的肿瘤细胞预警方法和系统
US9176309B2 (en) 2011-10-08 2015-11-03 Jenlab Gmbh Flexible nonlinear laser scanning microscope for noninvasive three-dimensional detection
CN113390850A (zh) * 2021-06-02 2021-09-14 复旦大学 基于u型卷积神经网络的胃拉曼飞秒皮秒图像映射方法

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102012213600A1 (de) * 2012-08-01 2014-02-06 Leica Microsystems Cms Gmbh Scanner für die Abtastung von Schnellschnitt-Proben
EP3542710A1 (fr) 2018-03-23 2019-09-25 JenLab GmbH Système d'imagerie multimodale et procédé d'examen non invasif d'un objet d'examen

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4405237A (en) 1981-02-04 1983-09-20 The United States Of America As Represented By The Secretary Of The Navy Coherent anti-Stokes Raman device
US6108081A (en) 1998-07-20 2000-08-22 Battelle Memorial Institute Nonlinear vibrational microscopy
US6934020B2 (en) 2001-07-03 2005-08-23 Olympus Optical Co., Ltd. Laser microscope
US7414729B2 (en) 2005-10-13 2008-08-19 President And Fellows Of Harvard College System and method for coherent anti-Stokes Raman scattering endoscopy

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5208825B2 (ja) * 2008-09-12 2013-06-12 オリンパス株式会社 光学顕微鏡
WO2010071682A2 (fr) * 2008-12-20 2010-06-24 Purdue Research Foundation Plate-forme multimodale pour microscopie et microspectroscopie optiques non linéaires
US9285575B2 (en) * 2009-01-26 2016-03-15 President And Fellows Of Harvard College Systems and methods for selective detection and imaging in coherent Raman microscopy by spectral excitation shaping

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4405237A (en) 1981-02-04 1983-09-20 The United States Of America As Represented By The Secretary Of The Navy Coherent anti-Stokes Raman device
US6108081A (en) 1998-07-20 2000-08-22 Battelle Memorial Institute Nonlinear vibrational microscopy
US6934020B2 (en) 2001-07-03 2005-08-23 Olympus Optical Co., Ltd. Laser microscope
US7414729B2 (en) 2005-10-13 2008-08-19 President And Fellows Of Harvard College System and method for coherent anti-Stokes Raman scattering endoscopy

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9176309B2 (en) 2011-10-08 2015-11-03 Jenlab Gmbh Flexible nonlinear laser scanning microscope for noninvasive three-dimensional detection
CN104382557A (zh) * 2014-11-20 2015-03-04 西安邮电大学 基于红外谱分析的肿瘤细胞预警方法和系统
CN113390850A (zh) * 2021-06-02 2021-09-14 复旦大学 基于u型卷积神经网络的胃拉曼飞秒皮秒图像映射方法

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WO2012062306A3 (fr) 2012-07-12
EP2624743A2 (fr) 2013-08-14
DE102010047578A1 (de) 2012-04-12

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