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WO2008086191A1 - Dispositif de spectroscopie raman à sélection temporelle - Google Patents

Dispositif de spectroscopie raman à sélection temporelle Download PDF

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Publication number
WO2008086191A1
WO2008086191A1 PCT/US2008/050248 US2008050248W WO2008086191A1 WO 2008086191 A1 WO2008086191 A1 WO 2008086191A1 US 2008050248 W US2008050248 W US 2008050248W WO 2008086191 A1 WO2008086191 A1 WO 2008086191A1
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WO
WIPO (PCT)
Prior art keywords
optic signal
coherent light
raman spectroscopy
temporally
raman
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/US2008/050248
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English (en)
Inventor
Sebastian Wachsmann-Hogiu
Daniel L. Farkas
Andreas G. Nowatzyk
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cedars Sinai Medical Center
Original Assignee
Cedars Sinai Medical Center
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.)
Filing date
Publication date
Application filed by Cedars Sinai Medical Center filed Critical Cedars Sinai Medical Center
Publication of WO2008086191A1 publication Critical patent/WO2008086191A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01J—MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
    • G01J3/00—Spectrometry; Spectrophotometry; Monochromators; Measuring colours
    • G01J3/28—Investigating the spectrum
    • G01J3/44—Raman spectrometry; Scattering spectrometry ; Fluorescence spectrometry
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01J—MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
    • G01J3/00—Spectrometry; Spectrophotometry; Monochromators; Measuring colours
    • G01J3/02—Details
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01J—MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
    • G01J3/00—Spectrometry; Spectrophotometry; Monochromators; Measuring colours
    • G01J3/02—Details
    • G01J3/0205—Optical elements not provided otherwise, e.g. optical manifolds, diffusers, windows
    • G01J3/0218—Optical elements not provided otherwise, e.g. optical manifolds, diffusers, windows using optical fibers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01J—MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
    • G01J3/00—Spectrometry; Spectrophotometry; Monochromators; Measuring colours
    • G01J3/02—Details
    • G01J3/0205—Optical elements not provided otherwise, e.g. optical manifolds, diffusers, windows
    • G01J3/0224—Optical elements not provided otherwise, e.g. optical manifolds, diffusers, windows using polarising or depolarising elements
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01J—MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
    • G01J3/00—Spectrometry; Spectrophotometry; Monochromators; Measuring colours
    • G01J3/02—Details
    • G01J3/0297—Constructional arrangements for removing other types of optical noise or for performing calibration
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01J—MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
    • G01J3/00—Spectrometry; Spectrophotometry; Monochromators; Measuring colours
    • G01J3/28—Investigating the spectrum
    • G01J3/45—Interferometric spectrometry
    • G01J3/453—Interferometric spectrometry by correlation of the amplitudes
    • G01J3/4531—Devices without moving parts
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01J—MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
    • G01J3/00—Spectrometry; Spectrophotometry; Monochromators; Measuring colours
    • G01J3/28—Investigating the spectrum
    • G01J3/44—Raman spectrometry; Scattering spectrometry ; Fluorescence spectrometry
    • G01J2003/4424—Fluorescence correction for Raman spectrometry

Definitions

  • the invention relates to the field of Raman Spectroscopy, and particularly to a method, device and system for time-gated Raman Spectroscopy that enhances the ratio of Raman signal to fluorescence noise.
  • Raman Spectroscopy probes the chemistry of molecules, or monitors changes in molecular structures, through the measurement of inelastically scattered light.
  • photons are elastically scattered when they come in contact with a molecule, meaning that the frequency of the scattered photons is the same as that of the incident photons.
  • a small fraction of photons are inelastically scattered, meaning that their frequency is different from that of the incident photons.
  • a sample is repeatedly illuminated with a monochromatic light source, such as a laser in the visible, near infrared or near ultraviolet range.
  • a monochromatic light source such as a laser in the visible, near infrared or near ultraviolet range.
  • NIR near-infrared
  • Light from the illuminated spot is collected with a lens and sent through a monochromator. Wavelengths close to the laser line (due to elastic Rayleigh scattering) are filtered out and those in a certain spectral window away from the laser line are dispersed onto a detector.
  • Raman spectrometers To filter out higher energy Rayleigh scattered laser light, Raman spectrometers typically use holographic diffraction gratings and multiple dispersion stages to achieve a high degree of laser rejection. A photon-counting photomultiplier tube (PMT) or, more commonly, a CCD camera is used to detect the Raman scattered light. Detection of Raman signals using current technology is difficult, however, because the signals are usually weak and overlap with the stronger fluorescence signals from the sample.
  • PMT photon-counting photomultiplier tube
  • CCD camera CCD camera
  • the current invention seeks to address this limitation of Raman spectroscopy, by providing a novel device which temporally separates Raman signals from background fluorescence noise. As a result, the device can be used in any circumstance where background fluorescence would interfere with measurement of the Raman signal.
  • the current invention relates to a time gated Raman spectroscopy device, system and method.
  • weaker Raman signals are often undetectable due to stronger background fluorescent noise.
  • the current invention seeks to overcome this problem by separating Raman signals, which are emitted within picoseconds of sample excitation, from fluorescent signals which occurs several nanoseconds after sample excitation.
  • the invention provides a device, system and method that preserve Raman signals while eliminating background fluorescence through interference.
  • One promising application of the inventive technology relates to optical biopsy procedures, solving many of the shortcomings of traditional tissue biopsies. Because tissue biopsies are often used to diagnose, or confirm a diagnosis, of cancer or other tissue pathology, biopsies are one of the most commonly performed medical procedures.
  • a tissue sample may easily be retrieved by fine needle aspiration biopsy.
  • a thin needle is inserted into a mass or lump to extract cells that will be examined under a microscope.
  • an imaging exam may be required to locate the tissue mass, tumor, or pathological tissue, and guide the needle to obtain the biopsy.
  • a surgical biopsy is required to retrieve an adequate tissue sample to make a diagnosis of the suspect tumor or tissue mass.
  • tissue biopsies Despite being the preferred means of diagnosing cancer or other tissue pathology, or confirming such a diagnosis, tissue biopsies have several limitations. Namely, tissue biopsies cannot make an in vivo diagnosis or confirmation of cancer or other medical conditions. Rather a tissue sample must be removed from the patient for analysis in a lab. As a result, traditional biopsy procedures introduce a greater risk of contamination because the tissue sample must be removed and transported for analysis. Traditional biopsies also cannot diagnose or confirm a
  • the results of a traditional biopsy are usually not available until two to five days after the biopsy procedure. During this time period a patient may undergo significant mental stress due to the possibility they may have a serious medical condition.
  • traditional biopsies are necessarily invasive, particularly where surgical biopsies are required. Although fine needle aspiration biopsies are minimally invasive, they still require removal of a tissue sample from the patient's body.
  • fluorescence spectroscopy can be used to identify neoplastic transformations in cells, and pre-cancer and cancer in organ tissues.
  • the diagnostic efficacy of fluorescence spectroscopy is limited, however, because the fluorescence spectra of pre-cancerous lesions in certain tissues are similar to benign abnormalities.
  • tissue fluorescence such as flavins, porphyrins, and certain structural and enzymatic proteins, and most have overlapping broadband emissions.
  • many biological molecules are Raman active with unique spectral characteristics. These unique spectra can be used to identify markers for disease, such as cancer, in cells and organ tissues.
  • the inventive Raman spectroscopy device/system filters Raman signals from background fluorescence by exploiting the different time scales over which fluorescence and Raman processes take place. Raman scattering occurs in less than a picosecond from the time a sample is excited by incident photons. In contrast, fluorescence requires the excitation of a molecule and the subsequent emission of a fluorescence photon which occurs over several nano-seconds after excitation of the sample — a time scale at least three orders of magnitude greater than that of Raman processes. To filter out fluorescent noise, the inventive Raman device/system creates a temporal gate, which removes signals after the first few picoseconds of sample excitation. As a result, the inventive Raman spectrometer is capable of detecting Raman signals that would ordinarily be undetectable due to overlapping background fluorescence.
  • LAX 510134v3 0067789-000876 - Although there have been attempts in the art to create a time gate capable of operating on a picosecond time scale, such as through electronic switches or optoelectronic switches, these attempts have resulted in technologies that are either very costly and complex, or do not provide adequate resolution for use in capturing Raman signals.
  • the inventive Raman spectroscopy device/system provides an all optical switch providing a resolution of two to four picoseconds.
  • inventive Raman device/system has an estimated fabrication cost far lower than the aforementioned systems. Accordingly, the current inventive Raman spectroscopy device/system provides an elegant and cost effective solution to the problem of filtering Raman signals from the fluorescence background of a sample.
  • Figure 1 illustrates a Raman spectroscopy device and/or system according to an embodiment of the present invention.
  • Figure 2 illustrates an input signal interacting with a Sagnac interferometer according to an embodiment of the present invention.
  • Figure 3 illustrates a plurality of signals such as those observed in a device and/or system in an embodiment of the present invention.
  • a signal 1 in response to laser excitation, or other coherent light source, of a sample is received at a signal port 2 of the inventive Raman spectroscopy device/system shown in FIG. 1.
  • the signal including both the Raman scatter and fluorescence background, is received at the signal port 2, it is
  • the beam splitter 3 can be constructed from two triangular prisms. In alternate embodiments, the beam splitter 3 can be a half-silvered mirror. After the signal passes through the beam splitter 3, one half of the signal propagates around a Sagnac interferometer 4 in a clockwise direction, while the other half of the signal propagates counterclockwise.
  • the Sagnac Interferometer 4 is tuned according to techniques known in the art such that if the signals are allowed to propagate uninterrupted, the signals will destructively interfere with each other. In other words, if the signals are uninterrupted, they will cancel each other out and nothing will be detected by the spectrometer detector 5.
  • the half of the signal 1 propagating clockwise is temporally overlapped with a stronger, vertically polarized laser pulse 7.
  • the wavelength of the laser pulse 7 can be the same as the wavelength used for Raman excitation.
  • the duration of this injected temporally overlapped laser pulse 7 determines the portion of the signal 1 that will be detected by the spectrometer detector 5.
  • the combined signal 8 enters a portion of the Sagnac interferometer 4 composed of non-linear fiber optic cable 9 at 10.
  • the half of the signal 1 propagating counterclockwise propagates through the non-linear fiber 9 starting at 11.
  • non-linear fiber 9 optical signals interact with the material of the fiber based on their intensity.
  • the induced polarization is directly proportional to the electric field of the applied optical signal resulting in constant fiber properties.
  • the induced polarization is no longer directly proportional to the electric field.
  • the refractive index of the nonlinear fiber becomes intensity dependent. Because the phase and envelope velocity of an optical signal are dependent on the refractive index of the medium in which it travels, a change in the refractive index of the nonlinear fiber will change an optical signal's propagation through the non-linear fiber. As a result, when the high intensity laser pulse 7 overlaps a portion of the combined signal 8, the refractive index of the non-linear fiber 9 will change as that temporally overlapped portion of the optic signal 8 propagates through the non-linear fiber 9.
  • This change in the refractive index results in a phase change for the temporally overlapped portion of the combined signal 8.
  • the system can be tuned such that phase change places the overlapped portion of the combined signal 8 in
  • the portion of the combined signal 8 that does not overlap with the higher intensity laser pulse 7 propagates under the ordinary tuned conditions of the Sagnac Interferometer 4.
  • the non-overlapped portion of the signal propagating clockwise destructively interferes with the same portion of the signal propagating counterclockwise, eliminating the non-overlapped portion of the signal 1.
  • the input signal 1 is split in half at the beam splitter 3, with one half propagating around the Sagnac interferometer clockwise 20 and the other half of the signal propagating counterclockwise 21.
  • a portion 22 of the half signal 20 is temporally overlapped with a higher intensity vertically polarized laser pulse 7 produced by the same laser as the excitation pulse of the sample.
  • the overlapped portion 22 of the signal 20 is phase shifted such that it will constructively interfere with the half signal propagating counterclockwise 21.
  • the remaining portion of the signal 23, however, is not phase shifted, and this portion of the signals 20 and 21 will destructively interfere with each other.
  • the output of the interferometer going to the spectrometer detector 5 is the portion of the signal 1 that is overlapped by the injected laser impulse 7.
  • the waves shown in Figures 1 and 2 are made up of a plurality of signals such as those shown in FIG. 3.
  • the signals making up the overall signal are also phase shifted.
  • the inventive system is tuned such that the phase shift caused by the injected laser pulse 7 will result in constructive interference with the corresponding portion of the signal propagating counter clockwise.
  • the system is tuned such that without a phase shift the signal propagating clockwise 20 and counterclockwise 21 will destructively interfere with each other.
  • the signals within the overlapped portion 31 of the signal 22 are phase shifted such they constructively interfere with each other.
  • the signals 32 within the remaining portion of the signal 23 will destructively interfere with one another.
  • a delay line 12 can be used to temporally overlap the laser pulse 7 at the first few picoseconds of the excitation response signal.
  • the same laser that provides excitation pulses to the sample is used to inject the laser pulse 7, with the delay line 12 delaying the pulse such that it temporally overlaps with a desired portion of the signal 1. It is not necessary that the laser pulse 7 and the excitation pulse have the same wavelength because the excitation beam can readily be converted to other wavelengths by nonlinear processes such as second harmonic generation.
  • a pair of coordinated lasers may be used.
  • the spectrometer 16 can use holographic diffraction gratings and multiple dispersion stages to achieve a high degree of laser rejection. This process leaves a portion 15 of the signal 1 that was overlapped by the laser pulse 7 to be processed by the spectrometer 16 and detector 5. In one embodiment, this portion 15 corresponds to the first few picoseconds of the signal 1 , which contains the Raman signal from the pulsed sample. This process is repeated rapidly as the excitation light source repeatedly pulses the sample.
  • the senor 5 is a photon-counting photomultiplier tube (PMT). In an alternate embodiment, the sensor 5 is a CCD photosensor.
  • the detected Raman signal can be processed into full spectrum for the analyzed sample. In one embodiment, this may be used to create a unique Raman spectrum or fingerprint for the sample, such as healthy or diseased cells.
  • Raman spectra can be used to identify markers for disease, such as cancer, in cells and organ tissues.
  • the inventive Raman spectroscopy device/system can be used to excite a sample and receive the corresponding optic scatter in vivo through a fiber optic endoscope.
  • the excitation pulse can be delivered through a fiber optic cable in the endoscope, and the response signal 1 can also be received by optics in the endoscope.
  • the endoscope is then connected to the signal port 2 of the inventive Raman spectroscopy device/system.
  • the inventive Raman spectroscopy device/system can be used to analyze material, chemical or biologic samples in vitro. The identification of spectra unique to a specific disease may take on the order of seconds, rather then the several days it may take to process a tissue biopsy.
  • Raman spectroscopy can also be applied to monitor the distribution of drugs on the cellular and tissue level.
  • the use of Raman spectroscopy to monitor drug distribution is advantageous because no external markers are required, which simplifies monitoring procedure and minimizes interference between the monitoring and drug action.
  • Raman spectroscopy has also been shown to be effective for the in vivo characterization of drug metabolizing enzymes, which may allow individualized dosing regimens based on a patient's phenotype. By incorporating the current invention into an endoscope, or other fiber optic probe, in vivo and real time monitoring of drug distribution may be possible.

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  • Physics & Mathematics (AREA)
  • Spectroscopy & Molecular Physics (AREA)
  • General Physics & Mathematics (AREA)
  • Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)

Abstract

L'invention concerne le domaine de la spectroscopie RAMAN à sélection temporelle. Sont prévus des dispositifs, des systèmes et des procédés qui améliorent les signaux RAMAN par élimination par filtrage des signaux fluorescents de fond. Des applications dans les diagnostics médicaux sont décrites.
PCT/US2008/050248 2007-01-04 2008-01-04 Dispositif de spectroscopie raman à sélection temporelle Ceased WO2008086191A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US88341707P 2007-01-04 2007-01-04
US60/883,417 2007-01-04

Publications (1)

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WO2008086191A1 true WO2008086191A1 (fr) 2008-07-17

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101464166B (zh) * 2009-01-08 2012-05-02 北京航空航天大学 光纤分布式扰动传感器及其实现扰动定位的方法
EP2389568A4 (fr) * 2009-01-21 2013-11-20 Rare Light Inc Procédés, dispositifs et systèmes interférométriques à corrélation pour spectroscopie robuste et à bas coût
CN104568150A (zh) * 2013-10-15 2015-04-29 南京理工大学 基于微偏振阵列的干涉成像全偏振光谱探测装置及方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4529313A (en) * 1980-12-24 1985-07-16 Licentia Patent-Verwaltung-Gmbh Ring interferometer
US6485413B1 (en) * 1991-04-29 2002-11-26 The General Hospital Corporation Methods and apparatus for forward-directed optical scanning instruments
US20030025917A1 (en) * 2001-07-18 2003-02-06 Avraham Suhami Method and apparatus for dispersion compensated reflected time-of-flight tomography
US20060022145A1 (en) * 2003-01-23 2006-02-02 Mcloskey David Solid state multi frequency fluorometric measurements system and method
US20060192969A1 (en) * 2005-02-28 2006-08-31 Marks Daniel L Distinguishing non-resonant four-wave-mixing noise in coherent stokes and anti-stokes Raman scattering

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4529313A (en) * 1980-12-24 1985-07-16 Licentia Patent-Verwaltung-Gmbh Ring interferometer
US4529313B1 (en) * 1980-12-24 1994-09-13 Telefunken Systemtechnik Ring interferometer
US6485413B1 (en) * 1991-04-29 2002-11-26 The General Hospital Corporation Methods and apparatus for forward-directed optical scanning instruments
US20030025917A1 (en) * 2001-07-18 2003-02-06 Avraham Suhami Method and apparatus for dispersion compensated reflected time-of-flight tomography
US20060022145A1 (en) * 2003-01-23 2006-02-02 Mcloskey David Solid state multi frequency fluorometric measurements system and method
US20060192969A1 (en) * 2005-02-28 2006-08-31 Marks Daniel L Distinguishing non-resonant four-wave-mixing noise in coherent stokes and anti-stokes Raman scattering

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101464166B (zh) * 2009-01-08 2012-05-02 北京航空航天大学 光纤分布式扰动传感器及其实现扰动定位的方法
EP2389568A4 (fr) * 2009-01-21 2013-11-20 Rare Light Inc Procédés, dispositifs et systèmes interférométriques à corrélation pour spectroscopie robuste et à bas coût
US9157804B2 (en) 2009-01-21 2015-10-13 Rare Light, Inc. Correlation interferometric methods, devices and systems for low cost and rugged spectroscopy
CN104568150A (zh) * 2013-10-15 2015-04-29 南京理工大学 基于微偏振阵列的干涉成像全偏振光谱探测装置及方法

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