WO2019062844A1 - 一种飞秒激光多模态分子影像系统 - Google Patents

一种飞秒激光多模态分子影像系统 Download PDF

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WO2019062844A1
WO2019062844A1 PCT/CN2018/108303 CN2018108303W WO2019062844A1 WO 2019062844 A1 WO2019062844 A1 WO 2019062844A1 CN 2018108303 W CN2018108303 W CN 2018108303W WO 2019062844 A1 WO2019062844 A1 WO 2019062844A1
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femtosecond laser
pulse
dispersion
signal
function
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PCT/CN2018/108303
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French (fr)
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徐炳蔚
朱欣
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飞秒激光研究中心（广州）有限公司
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Priority to ES18863004T priority Critical patent/ES2904649T3/es
Priority to EP18863004.0A priority patent/EP3667273B1/en
Priority to US16/644,517 priority patent/US11128096B2/en
Priority to JP2020537834A priority patent/JP7117794B2/ja
Priority to DK18863004.0T priority patent/DK3667273T3/da
Publication of WO2019062844A1 publication Critical patent/WO2019062844A1/zh

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    • G—PHYSICS
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    • G01J—MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
    • G01J11/00—Measuring the characteristics of individual optical pulses or of optical pulse trains
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    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
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    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • G01N21/6456—Spatial resolved fluorescence measurements; Imaging
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    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
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    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
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    • H01S3/00—Lasers, i.e. devices using stimulated emission of electromagnetic radiation in the infrared, visible or ultraviolet wave range
    • H01S3/05—Construction or shape of optical resonators; Accommodation of active medium therein; Shape of active medium
    • H01S3/06—Construction or shape of active medium
    • H01S3/063—Waveguide lasers, i.e. whereby the dimensions of the waveguide are of the order of the light wavelength
    • H01S3/067—Fibre lasers
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    • H01S3/00—Lasers, i.e. devices using stimulated emission of electromagnetic radiation in the infrared, visible or ultraviolet wave range
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    • H01S—DEVICES USING THE PROCESS OF LIGHT AMPLIFICATION BY STIMULATED EMISSION OF RADIATION [LASER] TO AMPLIFY OR GENERATE LIGHT; DEVICES USING STIMULATED EMISSION OF ELECTROMAGNETIC RADIATION IN WAVE RANGES OTHER THAN OPTICAL
    • H01S3/00—Lasers, i.e. devices using stimulated emission of electromagnetic radiation in the infrared, visible or ultraviolet wave range
    • H01S3/14—Lasers, i.e. devices using stimulated emission of electromagnetic radiation in the infrared, visible or ultraviolet wave range characterised by the material used as the active medium
    • H01S3/16—Solid materials
    • H01S3/1601—Solid materials characterised by an active (lasing) ion
    • H01S3/1603—Solid materials characterised by an active (lasing) ion rare earth
    • H01S3/1618—Solid materials characterised by an active (lasing) ion rare earth ytterbium
    • G—PHYSICS
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    • 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
    • G01N21/6408—Fluorescence; Phosphorescence with measurement of decay time, time resolved fluorescence
    • G01N2021/6415—Fluorescence; Phosphorescence with measurement of decay time, time resolved fluorescence with two excitations, e.g. strong pump/probe flash
    • 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
    • G01N2021/6417—Spectrofluorimetric devices
    • G01N2021/6419—Excitation at two or more wavelengths
    • 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
    • G01N2021/6417—Spectrofluorimetric devices
    • G01N2021/6421—Measuring at two or more wavelengths
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2201/00—Features of devices classified in G01N21/00
    • G01N2201/12—Circuits of general importance; Signal processing
    • G01N2201/127—Calibration; base line adjustment; drift compensation
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01S—DEVICES USING THE PROCESS OF LIGHT AMPLIFICATION BY STIMULATED EMISSION OF RADIATION [LASER] TO AMPLIFY OR GENERATE LIGHT; DEVICES USING STIMULATED EMISSION OF ELECTROMAGNETIC RADIATION IN WAVE RANGES OTHER THAN OPTICAL
    • H01S3/00—Lasers, i.e. devices using stimulated emission of electromagnetic radiation in the infrared, visible or ultraviolet wave range
    • H01S3/005—Optical devices external to the laser cavity, specially adapted for lasers, e.g. for homogenisation of the beam or for manipulating laser pulses, e.g. pulse shaping
    • H01S3/0057—Temporal shaping, e.g. pulse compression, frequency chirping

Definitions

  • the invention relates to the technical field of femtosecond laser devices, in particular to a femtosecond laser multi-modal molecular imaging system.
  • the traditional supercontinuum generation method uses 50 femtosecond low-power pulses (pulse energy less than 3nJ) to excite photonic crystal fibers with a length of less than 10 mm, while ensuring that the zero-dispersion wavelength of the photonic crystal fibers used is generated.
  • the supercontinuum range for example, to produce a supercontinuum of 600-900 nm, the zero dispersion wavelength of the photonic crystal fiber must be in the range of 600-900 nm, but the supercontinuum optical pulse produced by this method is lower, power Low, poor optical path stability, unable to excite all nonlinear molecular image modes.
  • the femtosecond laser pulse produces a "time-domain broadening" effect when passing through the optical path, that is, due to the dispersion in the optical path, especially the presence of higher-order dispersions of the second order and above, the width of the femtosecond pulse on the time axis will As the propagation in the optical path increases, the peak power of the femtosecond pulse is greatly reduced, so that the nonlinear effect between the pulse and the sample is weakened or even disappeared.
  • the object of the present invention is to provide a femtosecond laser multi-mode molecule for the problem that the average power of the femtosecond laser pulse generated by the supercontinuum generation method in the prior art is low and the femtosecond pulse peak power is reduced due to dispersion.
  • the imaging system is capable of providing femtosecond pulses of greater power and effectively eliminating dispersion effects.
  • a femtosecond laser multi-modal molecular imaging system comprising a supercontinuum generation module, a pulse measurement compression control module, and an optical microscopy module;
  • the supercontinuum generation module includes a near-infrared band generating device for providing pulses in a near-infrared band, and an optical medium having a strong nonlinearity for use in a Generating a femtosecond laser pulse by pulse excitation in the near-infrared band; the center wavelength of the pulse in the near-infrared band is 1010 nm to 1100 nm, and the spectral width is less than 25 nm;
  • the pulse measurement compression control module includes a first optical component for receiving the femtosecond laser pulse, and a measurement module for measuring dispersion in a system optical path and adjusting according to the measurement result
  • the first optical component parameter performs dispersion compensation on the femtosecond laser pulse to obtain a compressed femtosecond laser pulse;
  • the optical microscopy module includes a second optical component, a sample platform, and a first signal acquisition device, the compressed femtosecond laser pulse passing through the second optical component to reach the sample platform, and interacting with a tissue sample on the sample platform A multi-modal signal is generated, and the first signal acquisition device is configured to acquire the multi-modal signal.
  • the near-infrared band generating device is a germanium-containing fiber laser or a pulsed laser, and the pulse width of the near-infrared band generating device is less than 1500 femtoseconds;
  • the femtosecond laser pulse generated by the optical medium having strong nonlinearity has a spectral range of 750 nm to 1300 nm;
  • the optical medium having strong nonlinearity is a birefringent photonic crystal fiber having a length greater than 45 mm, a birefringence of at least 5*10 -6 , and a positive dispersion in the transmittable band.
  • the first optical component is a pulse shaper including active adaptive optics
  • the pulse shaper includes a first grating, a first convex lens, a liquid crystal spatial light modulator, a second convex lens, and a second, which are sequentially disposed.
  • a grating the first grating is located at a focus position of the first convex lens, a distance between the first convex lens and the liquid crystal spatial light modulator is a focal length, the liquid crystal spatial light modulator and the first The distance between the two convex lenses is one focal length, and the distance between the second convex lens and the second grating is one focal length.
  • the measurement module includes a control device, a second signal acquisition device, and a nonlinear crystal disposed on the sample platform;
  • the femtosecond laser pulse is focused by the pulse measurement compression control module and the optical microscopy module to the nonlinear crystal to generate a nonlinear spectrum
  • the second signal acquisition device is configured to acquire a nonlinear spectral signal and send the signal to the Control device
  • the control device is configured to control a parameter of the liquid crystal spatial light modulator to introduce a known reference spectral phase function, measure a dispersion function of the optical path of the system by changing the known reference spectral phase function, and adjust the dispersion according to the dispersion function
  • the parameters of the liquid crystal spatial light modulator control the phase of each wavelength spectrum of the femtosecond laser pulse to cancel the dispersion.
  • the nonlinear crystal is a BBO crystal or a KDP crystal, and the nonlinear crystal has a thickness of 10 micrometers to 300 micrometers.
  • the known reference spectral phase function includes a parabolic function and a sine function; the nonlinear spectrum is a second harmonic;
  • the control device is further configured to perform maximum value analysis on the second harmonic each time the phase function of the known reference spectrum is changed, obtain a second derivative of the dispersion to be measured, and perform second integration on the second derivative , obtain the dispersion function of the system optical path.
  • control device is further configured to change a parameter of the pulse shaper to introduce a negative function of the dispersion function, and control a phase of each wavelength spectrum of the femtosecond laser pulse to cancel the dispersion;
  • the control device is further configured to determine whether the femtosecond laser pulse has approached the Fourier transform limit, and if not, measure the dispersion function again.
  • the first optical component is a passive optical device, and a known reference spectral phase function is introduced by adjusting a relative distance and a relative angle between the passive optical devices, and a dispersion function of the optical path of the system is measured, and adjusted according to the dispersion function.
  • the femtosecond laser pulses are dispersion compensated by the relative distance and relative angle between the passive optics.
  • the second optical component includes a first mirror, a scanning galvanometer module, a second mirror, a dichroic mirror, an optical microscope objective, and a plurality of filters;
  • the first signal acquisition device includes a plurality of photodetectors corresponding to the plurality of filters, the plurality of photodetectors being coupled to the control device;
  • the compressed femtosecond laser pulse enters the scanning galvanometer module through the first mirror, and sequentially passes through the second mirror, the dichroic mirror and the optical microscope objective to focus on the sample platform;
  • the compressed femtosecond laser pulse interacts with a tissue sample on the sample platform to generate a multimodal signal, and the multimodal signal is reflected by the dichroic mirror to the plurality of filters for separation and The plurality of photodetectors are collected and sent to the control device.
  • the multi-modal signal comprises: a second harmonic signal with a spectral range of 570 nm to 630 nm, a third harmonic signal with a spectral range of 343 nm to 405 nm, and a dual range of 510 nm to 565 nm.
  • the second harmonic signal is used to identify cholesterol in a tissue sample;
  • the third harmonic signal is used to identify cytoplasm, melanin, and intercellular vesicles produced by the tumor in the tissue sample;
  • the two-photon fluorescence spectral signal is used for Identifying elastin, flavin adenine dinucleotide, and a basement membrane;
  • the three-photon fluorescence spectral signal is used to identify a distribution of a reduced coenzyme in a tissue sample;
  • the nonlinear Raman signal is used to identify a lipid compound and blood cells;
  • the second harmonic signal, the third harmonic signal, and the non-linear Raman signal are coincident for identifying a collagen fiber network and myosin; the nonlinear Raman signal and the second harmonic signal are coincident for identification DNA, blood vessels, and lymphatic vessels.
  • the near-infrared band generating device to provide a near-infrared band pulse having a center wavelength of 1010 nm to 1100 nm and a spectral width of less than 25 nm, the near-infrared band pulse exciting an optical medium having a strong nonlinearity to produce an ultra-wide spectrum Femtosecond laser pulse, through the pulse measurement compression control module to measure and compensate the dispersion of the femtosecond laser pulse reaching the tissue sample, to minimize the "time domain broadening" effect, the shortest pulse can be combined with the tissue sample to generate a variety of different modes Spectral signals to provide a variety of nonlinear molecular image modes;
  • the birefringent photonic crystal fiber used does not have a zero-dispersion wavelength in the spectral range of the generated femtosecond laser pulse, and has a high light-passing efficiency, and can generate a femtosecond laser pulse of more than 500 mW.
  • the femtosecond laser pulse spectrum can be adjusted by optimizing the polarization, power and incident angle of the incident light;
  • the negative function of the dispersion function can be introduced into the system optical path, thereby canceling the system dispersion, and generating a compressed femtosecond laser pulse when the sample reaches the sample position, the dispersion is 0 or close.
  • the Fourier transform limit pulse is obtained, so that the pulse peak power is maximized at the sample position, thereby maximizing the nonlinear signal generation efficiency of different molecules of the tissue sample and improving the signal to noise ratio;
  • the spectral intensity and spectral phase of a nonlinear signal can be further optimized to achieve selective excitation and improve multi-modal signals.
  • FIG. 1 is a schematic structural view of an embodiment of a femtosecond laser multi-modal molecular imaging system provided by the present invention.
  • FIG. 2 is a schematic structural view of an embodiment of a pulse measurement compression control module in a femtosecond laser multi-modal molecular imaging system according to the present invention.
  • FIG. 3 is a flow chart of an embodiment of a dispersion measurement and compensation method in a femtosecond laser multi-modal molecular imaging system provided by the present invention.
  • FIG. 4 is a schematic structural view of an embodiment of an optical microscopy module in a femtosecond laser multi-modal molecular imaging system according to the present invention.
  • this embodiment provides a femtosecond laser multi-modal molecular imaging system, including a supercontinuum generation module 101, a pulse measurement compression control module 102, and an optical microscopy module 103;
  • the supercontinuum generation module 101 includes a near-infrared band generating device 1011 and an optical medium 1012 having strong nonlinearity, a near-infrared band generating device 1011 for providing pulses in the near-infrared band, and a highly nonlinear optical medium 1012 for passing near-infrared.
  • the pulse excitation of the band generates a femtosecond laser pulse; the center wavelength of the pulse in the near-infrared band is 1010 nm to 1100 nm, and the spectral width is less than 25 nm;
  • the pulse measurement compression control module 102 includes a first optical component 1021 for receiving femtosecond laser pulses, and a measurement module 1022 for measuring dispersion in the optical path of the system, and adjusting the first optical according to the measurement result.
  • the component 1021 parameter performs dispersion compensation on the femtosecond laser pulse to obtain a compressed femtosecond laser pulse;
  • the optical microscopy module 103 includes a second optical component 1031, a sample platform 1032, and a first signal acquisition device 1033.
  • the compressed femtosecond laser pulse passes through the second optical component 1031 and reaches the sample platform 1032, and acts on the tissue sample on the sample platform 1032.
  • a multi-modal signal is generated, and the first signal acquisition device 1033 is configured to acquire the multi-modal signal.
  • the femtosecond laser multi-modal molecular imaging system provides a near-infrared band pulse with a center wavelength of 1010 nm to 1100 nm and a spectral width of less than 25 nm using a near-infrared band generating device, and the near-infrared band pulse can be excited.
  • the highly nonlinear optical medium produces a femtosecond laser pulse with an ultra-wide spectrum.
  • the pulse measurement compression control module measures and compensates for the dispersion of the femtosecond laser pulse reaching the tissue sample, minimizing the "time domain broadening" effect, and obtaining the shortest Pulses can interact with tissue samples to generate spectral signals from a variety of different modalities, providing a variety of nonlinear molecular image modalities.
  • the near-infrared band generating device is a germanium-containing fiber laser, or other pulsed laser that can generate a desired wavelength, a spectral width, and a pulse width, and may be a commercial laser or a full positive dispersion.
  • the pulsed laser of the fiber laser architecture can be an all-fiber architecture or a hybrid architecture of optical fibers and open optics when using a full-positive dispersion-containing fiber laser architecture.
  • the pulse width of the near-infrared band generating device is less than 1500 femtoseconds; the femtosecond laser pulse generated by the strongly nonlinear optical medium has a spectral range of 750 nm to 1300 nm; as a preferred embodiment, the optical with strong nonlinearity
  • the medium is a birefringent photonic crystal fiber having a length greater than 45 mm, a birefringence of at least 5*10 -6 , and a positive dispersion in the transmittable band with a polarization greater than 15:1.
  • the birefringent photonic crystal fiber used in this embodiment does not have a zero dispersion wavelength in the spectral range of the generated femtosecond laser pulse, and has a high light-passing efficiency, and can generate a femtosecond laser pulse of more than 500 mW. With better polarization, it is also possible to adjust the resulting femtosecond laser pulse spectrum by optimizing the polarization, power and angle of incidence of the incident light.
  • the first optical component 1021 is a pulse shaper including active adaptive optics, and the pulse shaper includes a first grating G1, a first convex lens L1, and a liquid crystal which are sequentially disposed.
  • the spatial light modulator SLM, the second convex lens L2, and the second grating G2 the first grating G1 is located at a focus position of the first convex lens L1, and the distance between the first convex lens L1 and the liquid crystal spatial light modulator SLM is one focal length, and the liquid crystal
  • the distance between the spatial light modulator SLM and the second convex lens L2 is one focal length
  • the distance between the second convex lens L2 and the second grating G2 is one focal length.
  • the femtosecond laser pulse generated by the supercontinuum generation module 101 includes a plurality of spectral wavelengths. After passing through the first grating G1, the spectrum is scattered in the space, and after being focused by the first convex lens, all the spectral wavelengths are At a focal length position on the other side of the convex lens, a uniform distribution is formed, and the Fourier transform of the femtosecond laser pulse from the time domain to the frequency domain is completed, the plane is also referred to as a Fourier plane, and the liquid crystal spatial light modulator SLM is located. On the Fourier plane.
  • the optical path and optics after the Fourier plane are mirror images of the previous optical path, and all spectral wavelengths are recombined after passing through the second convex lens and the second grating to complete the transformation of the pulse from the frequency domain back to the time domain.
  • the liquid crystal of the liquid crystal spatial light modulator SLM has a one-to-one correspondence with the spectral wavelength.
  • the liquid crystal spatial light modulator SLM can control the relative spectral phase between different wavelengths by controlling the refractive indices of different pixels of different spectral wavelengths.
  • Active adaptive optics include, but are not limited to, liquid crystal spatial light modulators, acousto-optic crystals, deformable mirrors, and the like.
  • the measurement module 1022 includes a control device 1023, a second signal acquisition device 1024, and a nonlinear crystal 1025 disposed on the sample platform;
  • the femtosecond laser pulse is focused by the pulse measurement compression control module 102 and the optical microscopy module 103 to the nonlinear crystal 1025 to generate a nonlinear spectrum, and the second signal acquisition device 1024 is configured to acquire the nonlinear spectral signal and send it to the control device 1023;
  • the control device 1023 is configured to control a parameter of the liquid crystal spatial light modulator to introduce a known reference spectral phase function, measure a dispersion function of the optical path of the system by changing the known reference spectral phase function, and adjust the liquid crystal space according to the dispersion function
  • the parameters of the light modulator control the phase of each wavelength spectrum of the femtosecond laser pulse to cancel the dispersion.
  • the refractive index of each pixel of the liquid crystal spatial light modulator can be adjusted to control the phase of each wavelength of the femtosecond laser pulse.
  • the nonlinear crystal is a BBO crystal or a KDP crystal
  • the nonlinear crystal has a thickness of 10 micrometers to 300 micrometers, and within this thickness range, phase matching conditions can be effectively ensured in all laser spectral ranges.
  • one or a series of known reference spectral phase functions are introduced into the system by changes in the parameters of the liquid crystal spatial light modulator, each of which is a different known reference.
  • the spectral phase function causes a change in the total spectral phase of the system, which causes a change in the nonlinear expression of the femtosecond laser pulse.
  • the known reference spectral phase function includes, but is not limited to, a parabolic function and a sine function;
  • the nonlinear spectrum includes, but is not limited to, a second harmonic;
  • the control device is further configured to perform maximum value analysis on the second harmonic each time the phase function of the known reference spectrum is changed, obtain a second derivative of the dispersion to be measured, and perform second integration on the second derivative to obtain The dispersion function of the system light path.
  • a second harmonic signal is generated, which is collected by the second signal acquisition device and sent to the control device, and each time the known reference spectral phase function is changed, After measuring the nonlinear spectrum of a second harmonic, after changing the phase function of the known reference spectrum multiple times, the control device collects the three-dimensional graph with the wavelength or frequency as the X-axis, the reference phase function as the Y-axis, and the signal intensity as the Z-axis.
  • the second derivative of the system to be measured can be directly measured, and the obtained second derivative can be calculated by the two times, and the total dispersion accumulated by the femtosecond laser pulse at the sample position can be calculated. That is, the dispersion function of the system optical path.
  • control device is further configured to change a parameter of the pulse shaper to introduce a negative function of the dispersion function, and control a phase of each wavelength spectrum of the femtosecond laser pulse to cancel the dispersion ;
  • control device takes a negative function of the dispersion function and introduces a spatial light modulator to adjust the refractive index of each pixel to control the phase of each wavelength of the femtosecond laser pulse.
  • the control device is further configured to determine whether the femtosecond laser pulse has approached the Fourier transform limit, and if not, measure the dispersion function again.
  • the total dispersion of the femtosecond laser pulse after canceling the dispersion is 0 or approaches zero, that is, the compressed femtosecond laser pulse.
  • the expression of the femtosecond laser pulse generated by the supercontinuum generation module 101 is:
  • E(t) is the expression of the femtosecond pulse in the time domain
  • E( ⁇ ) is the spectral intensity term
  • e -i ⁇ t is the phase term
  • t is the time
  • ⁇ is the frequency
  • ⁇ ( ⁇ ) is the femtosecond pulse Initial dispersion.
  • the transmittance function of the control spectral intensity introduced into the system by the liquid crystal spatial light modulator controlled by the control device is T( ⁇ )
  • the function of controlling the phase of the spectrum is ⁇ ( ⁇ )
  • the femtosecond laser exiting after passing through the first optical component The mathematical expression of the pulse is:
  • the nonlinear crystal reaching the sample position After the femtosecond laser pulse passes through the first optical component and the optical microscopy module, the nonlinear crystal reaching the sample position generates a second harmonic, wherein the dispersion function to be measured is ⁇ ( ⁇ ) (including the initial dispersion of the femtosecond laser pulse, After the pulse measurement compression control module and the dispersion introduced by the optical microscopy module, and the phase introduced by the control device, the introduced reference spectral phase function is f( ⁇ ), and the spectral phase of the femtosecond laser pulse at the nonlinear crystal That is the sum of the two:
  • I SHG (2 ⁇ ) is the signal strength of the second harmonic signal at the 2 ⁇ frequency
  • ⁇ is the fundamental frequency
  • ⁇ is the frequency difference between the frequency at which the photon pair of the second harmonic is generated and the center frequency ⁇
  • E 0 ( ⁇ + ⁇ ) and E 0 ( ⁇ + ⁇ ) are the strengths of the femtosecond laser pulses at frequencies ⁇ + ⁇ and ⁇ + ⁇
  • exponential terms For the sum of the phases of the photon pairs that can generate the second harmonic signal at 2 ⁇ , when the term approaches 0, the exponential term is 1, and the integral reaches the maximum, and this is done as a Taylor polynomial expansion ( ⁇ ):
  • the second harmonic signal is generated at 2 ⁇ to the maximum, and the known reference spectral phase function is a parabolic function.
  • the scanning parameter is parabolic intensity ⁇
  • the second derivative is equal to the scanning parameter ⁇ .
  • the control device will collect three-dimensional graphics with the wavelength and frequency as the X-axis, the scanning parameter ⁇ as the Y-axis, and the second harmonic signal strength as the Z-axis, for any frequency ⁇ 1 It is very intuitive to obtain a position Z ( ⁇ 1 , ⁇ ) with the highest signal strength. This position is satisfied. Approaching the position of 0, and the value of f (2) ( ⁇ 1 ) is the scan parameter value ⁇ 1 corresponding to this position, that is, the second derivative of the dispersion to be measured By repeating the above steps for each spectral wavelength in the measurement range, the function of the dispersion to be measured relative to the wavelength or frequency can be measured. After two integrations, the total dispersion accumulated by the pulse at the sample position can be calculated.
  • the negative function of the dispersion function can be introduced into the system optical path, thereby canceling the system dispersion, and generating a compressed femtosecond laser pulse to a sample position with a dispersion of 0 or close to zero.
  • the Fourier transform limit pulse is obtained, so that the pulse peak power is maximized at the sample position, thereby maximizing the nonlinear signal generation efficiency of different molecules of the tissue sample and improving the signal to noise ratio.
  • the active adaptive optics can be used to further optimize the spectral intensity and spectral phase of a nonlinear signal based on the Fourier transform limit pulse to achieve selective excitation and improve multi-modal signals. Specificity.
  • the first optical component is a passive optical device, including but not limited to a series of second-order dispersion spectral phase functions of the passive optics, such as a grating pair, a prism pair, a prism grating, etc., by adjusting each passive optical
  • the relative distance and relative angle between the devices introduce a known reference spectral phase function, measure the dispersion function of the optical path of the system, complete the total dispersion measurement of the pulse at the sample position, and adjust the relative distance and relative angle between the passive optics.
  • the femtosecond laser pulse is used for dispersion compensation.
  • second- and third-order dispersion data can be extracted from the measured system dispersion function by linear fitting, and then the distance and relative angle between the devices can be adjusted by manual or automatic control devices to maximize the degree.
  • the second and third order dispersions are cancelled, so that the pulse is as close as possible to the Fourier transform limit at the sample position, and the signal to noise ratio is optimized.
  • the second optical component includes a first mirror M1, a scanning galvanometer module G, a second mirror M2, a dichroic mirror DM, an optical microscope objective O, and a plurality of filters F1-F (n-1). );
  • the first signal acquisition device includes a plurality of photodetectors PMT1-PMT(n-1) corresponding to the plurality of filters, and a plurality of photodetectors are connected to the control device;
  • the compressed femtosecond laser pulse enters the scanning galvanometer module G through the first mirror M1, and is sequentially focused to the sample platform 1032 through the second mirror M2, the dichroic mirror DM, and the optical microscope objective O.
  • the scanning galvanometer module G includes an X-axis galvanometer GMx and a Y-axis galvanometer GMy, and performs scanning of the XY axis by controlling the scanning galvanometer module, and performs Z-axis scanning by controlling the optical platform piezoelectric scanner or optical microscope to organize samples without Prepare and place directly on the sample platform.
  • the control device analyzes the multimodal signal.
  • the multi-modal signal includes: a second harmonic signal with a spectral range of 570 nm to 630 nm, a third harmonic signal with a spectral range of 343 nm to 405 nm, and a two-photon fluorescence with a spectral range of 510 nm to 565 nm.
  • the second harmonic signal is used to identify cholesterol in a tissue sample;
  • the third harmonic signal is used to identify cytoplasm, melanin, and intercellular vesicles produced by the tumor in the tissue sample;
  • the two-photon fluorescence spectral signal is used for Identifying elastin, flavin adenine dinucleotide, and a basement membrane;
  • the three-photon fluorescence spectral signal is used to identify a distribution of a reduced coenzyme in a tissue sample;
  • the nonlinear Raman signal is used to identify a lipid compound and blood cells;
  • the femtosecond laser multi-modal molecular imaging system provided by the embodiment can generate a wide range of multi-modal signals, and the multi-modal signal can identify various components in the tissue sample, thereby improving the diversity of the femtosecond laser imaging device recognition.
  • the femtosecond laser multi-modal molecular imaging system includes at least the following
  • the near-infrared band generating device to provide a near-infrared band pulse having a center wavelength of 1010 nm to 1100 nm and a spectral width of less than 25 nm, the near-infrared band pulse exciting an optical medium having a strong nonlinearity to produce an ultra-wide spectrum Femtosecond laser pulse, through the pulse measurement compression control module to measure and compensate the dispersion of the femtosecond laser pulse reaching the tissue sample, to minimize the "time domain broadening" effect, the shortest pulse can be combined with the tissue sample to generate a variety of different modes Spectral signals to provide a variety of nonlinear molecular image modes;
  • the birefringent photonic crystal fiber used has no zero-dispersion wavelength in the spectral range of the femtosecond laser pulse generated, has high light-passing efficiency, and can generate femtosecond laser pulses of more than 500 mW, and has Better polarization, and can also adjust the femtosecond laser pulse spectrum generated by optimizing the polarization, power and incident angle of the incident light;
  • the negative function of the dispersion function can be introduced into the system optical path to cancel the system dispersion, and the dispersion can be 0 or close when the compressed femtosecond laser pulse reaches the sample position.
  • the Fourier transform limit pulse is obtained, so that the pulse peak power is maximized at the sample position, thereby maximizing the nonlinear signal generation efficiency of different molecules of the tissue sample and improving the signal to noise ratio;
  • the spectral intensity and spectral phase of a nonlinear signal can be further optimized to achieve selective excitation and improve multi-modal signals.

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Abstract

一种飞秒激光多模态分子影像系统，采用近红外波段生成装置（1011）提供中心波长为1010纳米至1100纳米、谱宽小于25纳米的近红外波段脉冲，近红外波段脉冲可激发具有强非线性的光学媒介（1012）产生具有超宽光谱的飞秒激光脉冲，通过脉冲测量压缩控制模块（102）测量并补偿飞秒激光脉冲到达组织样品积累的色散，最大限度消除时域展宽效应，得到的最短脉冲可以与组织样品作用生成多种不同模态的光谱信号，从而提供多种非线性分子影像模态。

Description

一种飞秒激光多模态分子影像系统 技术领域
本发明涉及飞秒激光设备技术领域，尤其涉及一种飞秒激光多模态分子影像系统。
背景技术
传统的超连续谱产生方式是使用50飞秒的低功率脉冲(脉冲能量小于3nJ)，激发长度小于10毫米的光子晶体纤维，同时保证所使用的光子晶体纤维的零色散波长处在所产生的超连续谱范围内，例如产生600-900纳米的超连续谱，光子晶体纤维的零色散波长必须处在600-900纳米的范围内，但此种方式产生的超连续谱光学脉冲较低，功率低，光路稳定性差，无法激发所有非线性分子影像模态。此外，由于飞秒激光脉冲在通过光路时会产生“时域展宽”效应，即由于光路中的色散，特别是二阶及以上的高阶色散的存在，飞秒脉冲在时间轴上的宽度会随着在光路中的传播增大，导致飞秒脉冲的峰值功率大幅度降低，以致脉冲和样品之间的非线性效应减弱甚至消失。
发明内容
本发明的目的在于针对上述现有技术中的超连续谱产生方式产生的飞秒激光脉冲平均功率低、色散带来的飞秒脉冲峰值功率降低等问题，提出一种飞秒激光多模态分子影像系统，能够提供较大功率的飞秒脉冲，并有效消除色散影响。
一种飞秒激光多模态分子影像系统，包括超连续谱生成模块、脉冲测 量压缩控制模块以及光学显微模块；
所述超连续谱生成模块包括近红外波段生成装置以及具有强非线性的光学媒介，所述近红外波段生成装置用于提供近红外波段脉冲，所述具有强非线性的光学媒介用于经所述近红外波段脉冲激发生成飞秒激光脉冲；所述近红外波段脉冲的中心波长为1010纳米至1100纳米、谱宽小于25纳米；
所述脉冲测量压缩控制模块包括第一光学组件和测量模块，所述第一光学组件用于接收所述飞秒激光脉冲，所述测量模块用于测量系统光路中的色散，并根据测量结果调节第一光学组件参数对所述飞秒激光脉冲进行色散补偿，获得压缩飞秒激光脉冲；
所述光学显微模块包括第二光学组件、样品平台以及第一信号采集装置，所述压缩飞秒激光脉冲经所述第二光学组件后到达所述样品平台，与样品平台上的组织样品作用后生成多模态信号，所述第一信号采集装置用于采集所述多模态信号。
进一步地，所述近红外波段生成装置为含镱光纤激光器或者脉冲激光器，所述近红外波段生成装置的脉宽小于1500飞秒；
所述具有强非线性的光学媒介生成的飞秒激光脉冲的光谱范围为750纳米至1300纳米；
所述具有强非线性的光学媒介为双折射光子晶体光纤，所述双折射光子晶体光纤的长度大于45毫米，具有至少5*10 -6的双折射率，并且在可透射波段具有正色散。
进一步地，所述第一光学组件为包含主动自适应光学器件的脉冲整形器，所述脉冲整形器包括依次设置的第一光栅、第一凸透镜、液晶空间光调制器、第二凸透镜以及第二光栅，所述第一光栅位于所述第一凸透镜的焦点位置，所述第一凸透镜和所述液晶空间光调制器之间的距离为一倍焦距，所述液晶空间光调制器和所述第二凸透镜之间的距离为一倍焦距，所 述第二凸透镜与所述第二光栅之间的距离为一倍焦距。
进一步地，所述测量模块包括控制装置、第二信号采集装置以及设置在所述样品平台上的非线性晶体；
所述飞秒激光脉冲经所述脉冲测量压缩控制模块和光学显微模块聚焦至所述非线性晶体产生非线性光谱，所述第二信号采集装置用于采集非线性光谱信号并发送至所述控制装置；
所述控制装置用于控制所述液晶空间光调制器的参数引入已知参考光谱相位函数，通过改变所述已知参考光谱相位函数，测量系统光路的色散函数，并根据所述色散函数调节所述液晶空间光调制器的参数，控制所述飞秒激光脉冲各个波长光谱的相位，以抵消色散。
进一步地，所述非线性晶体为BBO晶体或者KDP晶体，所述非线性晶体的厚度为10微米至300微米。
进一步地，所述已知参考光谱相位函数包括抛物线函数和正弦函数；所述非线性光谱为二次谐波；
所述控制装置还用于每次改变所述已知参考光谱相位函数时对所述二次谐波进行最大值分析，获得待测色散的二阶导数，对所述二阶导数进行二次积分，获得系统光路的色散函数。
进一步地，所述控制装置还用于改变所述脉冲整形器的参数以引入所述色散函数的负函数，控制所述飞秒激光脉冲各个波长光谱的相位，以抵消色散；
所述控制装置还用于判断所述飞秒激光脉冲是否已经接近傅里叶变换极限，如果不是，则再次测量色散函数。
进一步地，所述第一光学组件为被动式光学器件，通过调整各被动式光学器件之间的相对距离和相对角度引入已知参考光谱相位函数，测量系统光路的色散函数，并根据所述色散函数调整各被动式光学器件之间的相对距离和相对角度对所述飞秒激光脉冲进行色散补偿。
进一步地，所述第二光学组件包括第一反射镜、扫描振镜模块、第二反射镜、二向色镜、光学显微物镜以及多个滤片；
所述第一信号采集装置包括与所述多个滤片对应的多个光电探测器，所述多个光电探测器与所述控制装置连接；
所述压缩飞秒激光脉冲经过所述第一反射镜进入所述扫描振镜模块，并依次通过所述第二反射镜、二向色镜和光学显微物镜，聚焦至所述样品平台；
所述压缩飞秒激光脉冲与所述样品平台上的组织样品作用后生成多模态信号，所述多模态信号经所述二向色镜反射至所述多个滤片进行分离，并被所述多个光电探测器采集后发送至所述控制装置。
进一步地，所述多模态信号包括：光谱范围为570纳米至630纳米的二次谐波信号、光谱范围为343纳米至405纳米的三次谐波信号、光谱范围为510纳米至565纳米的双光子荧光光谱信号、光谱范围为410纳米至490纳米的三光子荧光光谱信号以及光谱范围为640纳米至723纳米的非线性拉曼信号；
所述二次谐波信号用于识别组织样品中的胆固醇；所述三次谐波信号用于识别组织样品中的细胞质、黑色素及肿瘤产生的细胞间囊泡；所述双光子荧光光谱信号用于识别弹性蛋白、黄素腺嘌呤二核苷酸和基膜；所述三光子荧光光谱信号用于识别还原性辅酶在组织样品中的分布；所述非线性拉曼信号用于识别类脂化合物和血细胞；
所述二次谐波信号、三次谐波信号以及非线性拉曼信号重合用于识别胶原纤维网络和肌浆球蛋白；所述非线性拉曼信号和所述二次谐波信号重合用于识别DNA、血管以及淋巴管。
本发明提供的飞秒激光多模态分子影像系统，至少包括如下有益效果：
(1)采用近红外波段生成装置提供中心波长为1010纳米至1100纳米、谱宽小于25纳米的近红外波段脉冲，该近红外波段脉冲可激发具有强非线 性的光学媒介产生具有超宽光谱的飞秒激光脉冲，通过脉冲测量压缩控制模块测量并补偿飞秒激光脉冲到达组织样品积累的色散，最大限度消除“时域展宽”效应，得到的最短脉冲可以与组织样品作用生成多种不同模态的光谱信号，从而提供多种非线性分子影像模态；
(2)采用的双折射光子晶体光纤，在所产生的飞秒激光脉冲的光谱范围内不存在零色散波长，具有较高的通光效率，可产生大于500毫瓦的飞秒激光脉冲，同时具有较好的偏振性，还可以通过优化入射光的偏振性、功率和入射角度调整产生的飞秒激光脉冲光谱；
(3)采用主动自适应光学器件，在测量出色散函数后，可以把该色散函数的负函数引入系统光路，从而抵消系统色散，生成压缩飞秒激光脉冲到达样品位置时色散为0或趋近于0，得到傅里叶变换极限脉冲，使得脉冲峰值功率在样品位置达到最大化，从而最大限度的提高组织样品不同分子的非线性信号产生效率，提高信噪比；
(4)采用主动自适应光学器件，可以在得到傅里叶变换极限脉冲的基础上，进行进一步针对某种非线性信号的光谱强度和光谱相位的优化，实现选择性激发，提高多模态信号的特异性；
(5)能够生成宽范围的多模态信号，多模态信号可识别组织样品中的多种成分，提高飞秒激光影像设备识别的多样性。
附图说明
图1为本发明提供的飞秒激光多模态分子影像系统一种实施例的结构示意图。
图2为本发明提供的飞秒激光多模态分子影像系统中脉冲测量压缩控制模块一种实施例的结构示意图。
图3为本发明提供的飞秒激光多模态分子影像系统中色散测量和补偿方法一种实施例的流程图。
图4为本发明提供的飞秒激光多模态分子影像系统中光学显微模块一种实施例的结构示意图。
具体实施方式
为使本发明的目的、技术方案及效果更加清楚、明确，以下参照附图并举实施例对本发明进一步详细说明。应当理解，此处所描述的具体实施例仅用以解释本发明，并不用于限定本发明。
参考图1，本实施例提供一种飞秒激光多模态分子影像系统，包括超连续谱生成模块101、脉冲测量压缩控制模块102以及光学显微模块103；
超连续谱生成模块101包括近红外波段生成装置1011以及具有强非线性的光学媒介1012，近红外波段生成装置1011用于提供近红外波段脉冲，具有强非线性的光学媒介1012用于经近红外波段脉冲激发生成飞秒激光脉冲；近红外波段脉冲的中心波长为1010纳米至1100纳米、谱宽小于25纳米；
脉冲测量压缩控制模块102包括第一光学组件1021和测量模块1022，第一光学组件1021用于接收飞秒激光脉冲，测量模块1022用于测量系统光路中的色散，并根据测量结果调节第一光学组件1021参数对飞秒激光脉冲进行色散补偿，获得压缩飞秒激光脉冲；
光学显微模块103包括第二光学组件1031、样品平台1032以及第一信号采集装置1033，压缩飞秒激光脉冲经第二光学组件1031后到达样品平台1032，与样品平台1032上的组织样品作用后生成多模态信号，第一信号采集装置1033用于采集所述多模态信号。
本实施例提供的飞秒激光多模态分子影像系统，采用近红外波段生成装置提供中心波长为1010纳米至1100纳米、谱宽小于25纳米的近红外波段脉冲，该近红外波段脉冲可激发具有强非线性的光学媒介产生具有超宽光谱的飞秒激光脉冲，通过脉冲测量压缩控制模块测量并补偿飞秒激光脉 冲到达组织样品积累的色散，最大限度消除“时域展宽”效应，得到的最短脉冲可以与组织样品作用生成多种不同模态的光谱信号，从而提供多种非线性分子影像模态。
作为一种优选的实施方式，近红外波段生成装置为含镱光纤激光器，或者其他可以产生所需波长、谱宽和脉宽的脉冲激光器，可以是商用激光器、也可以是采用全正色散含镱光纤激光架构的脉冲激光器，采用全正色散含镱光纤激光架构时，可以是全光纤架构，也可以是光纤和开放式光学器件的混合架构。
近红外波段生成装置的脉宽小于1500飞秒；具有强非线性的光学媒介生成的飞秒激光脉冲的光谱范围为750纳米至1300纳米；作为一种优选的实施方式，具有强非线性的光学媒介为双折射光子晶体光纤，双折射光子晶体光纤的长度大于45毫米，具有至少5*10 -6的双折射率，并且在可透射波段具有正色散，偏振大于15:1。
本实施例采用的双折射光子晶体光纤，在所产生的飞秒激光脉冲的光谱范围内不存在零色散波长，具有较高的通光效率，可产生大于500毫瓦的飞秒激光脉冲，同时具有较好的偏振性，还可以通过优化入射光的偏振性、功率和入射角度调整产生的飞秒激光脉冲光谱。
进一步地，参考图2，作为一种优选的实施方式，第一光学组件1021为包含主动自适应光学器件的脉冲整形器，脉冲整形器包括依次设置的第一光栅G1、第一凸透镜L1、液晶空间光调制器SLM、第二凸透镜L2以及第二光栅G2，第一光栅G1位于第一凸透镜L1的焦点位置，第一凸透镜L1和液晶空间光调制器SLM之间的距离为一倍焦距，液晶空间光调制器SLM和第二凸透镜L2之间的距离为一倍焦距，第二凸透镜L2与第二光栅G2之间的距离为一倍焦距。
具体地，由超连续谱生成模块101生成的飞秒激光脉冲，包含多个光谱波长，通过第一光栅G1后，光谱被散射在空间中，再经过第一凸透镜聚 焦后，所有的光谱波长会在凸透镜另一侧的一倍焦距位置，形成均匀分布，完成飞秒激光脉冲从时域变换为频率域的傅里叶变换，该平面也被成为傅里叶平面，液晶空间光调制器SLM位于所述傅里叶平面上。傅里叶平面之后的光路和光学器件为之前光路的镜像，所有的光谱波长再经过第二凸透镜和第二光栅后重新结合，完成脉冲从频率域回到时域的变换。液晶空间光调制器SLM的液晶与光谱波长一一对应，通过液晶空间光调制器SLM对应不同光谱波长的不同像素的折射率的控制，就可以达到控制不同波长之间相对光谱相位的目的。
主动自适应光学器件包括但不限于液晶空间光调制器、声光晶体、可形变反射镜等。
进一步地，测量模块1022包括控制装置1023、第二信号采集装置1024以及设置在样品平台上的非线性晶体1025；
飞秒激光脉冲经脉冲测量压缩控制模块102和光学显微模块103聚焦至非线性晶体1025产生非线性光谱，第二信号采集装置1024用于采集非线性光谱信号并发送至控制装置1023；
控制装置1023用于控制液晶空间光调制器的参数引入已知参考光谱相位函数，通过改变所述已知参考光谱相位函数，测量系统光路的色散函数，并根据所述色散函数调节所述液晶空间光调制器的参数，控制所述飞秒激光脉冲各个波长光谱的相位，以抵消色散。
具体地，可调节液晶空间光调制器每个像素的折射率控制飞秒激光脉冲各个波长的相位。
作为一种优选的实施方式，非线性晶体为BBO晶体或者KDP晶体，非线性晶体的厚度为10微米至300微米，在此厚度范围内，能够有效保证在全部激光光谱范围内满足相位匹配条件。
具体地，进行系统色散测量时，通过液晶空间光调制器参数的改变，向系统引入一个或一系列的已知参考光谱相位函数(例如抛物线函数、正 弦函数等)，每一个不同的已知参考光谱相位函数，都会引起系统总光谱相位的改变，从而引发飞秒激光脉冲的非线性表达的改变。此时如果在脉冲测量压缩控制模块之后任意位置放置非线性晶体，收集产生的非线性光谱信号，就可以测量出该位置所积累的总色散。
作为一种优选的实施方式，所述已知参考光谱相位函数包括但不限于抛物线函数和正弦函数；所述非线性光谱包括但不限于二次谐波；
控制装置还用于每次改变所述已知参考光谱相位函数时对所述二次谐波进行最大值分析，获得待测色散的二阶导数，对所述二阶导数进行二次积分，获得系统光路的色散函数。
具体地，参考图3，当飞秒激光脉冲到达非线性晶体时，产生二次谐波信号，通过第二信号采集装置采集后发送至控制装置，每改变一次已知参考光谱相位函数，就可以测量一个二次谐波的非线性光谱，多次改变已知参考光谱相位函数后，控制装置会收集到以波长或频率为X轴，参考相位函数为Y轴，信号强度为Z轴的三维图形，通过对三维图形的最大值分析，可以直接测量出系统待测色散的二阶导数，得到的二阶导数通过两次积分后，可以计算出飞秒激光脉冲在样品位置所积累的总色散，即系统光路的色散函数。
进一步地，测量出色散函数后，所述控制装置还用于改变所述脉冲整形器的参数以引入所述色散函数的负函数，控制所述飞秒激光脉冲各个波长光谱的相位，以抵消色散；
具体地，控制装置取色散函数的负函数引入空间光调制器调节每个像素的折射率，控制飞秒激光脉冲各个波长的相位。
所述控制装置还用于判断所述飞秒激光脉冲是否已经接近傅里叶变换极限，如果不是，则再次测量色散函数。
抵消色散后的飞秒激光脉冲的总色散为0或趋近于0，即压缩飞秒激光脉冲。
具体地，超连续谱生成模块101生成的飞秒激光脉冲表达式为：
Figure PCTCN2018108303-appb-000001
其中，其中E(t)为飞秒脉冲在时域的表达，E(ω)为光谱强度项，e -iωt为相位项，t为时间，ω为频率，θ(ω)为生成飞秒脉冲的初始色散。
通过控制装置控制的液晶空间光调制器引入系统的控制光谱强度的透光率函数为T(ω)，控制光谱相位的函数为ε(ω)，则经过第一光学组件后出射的飞秒激光脉冲的数学表达式为：
Figure PCTCN2018108303-appb-000002
其中，
Figure PCTCN2018108303-appb-000003
飞秒激光脉冲通过第一光学组件和光学显微模块后，到达样品位置上的非线性晶体产生二次谐波，其中待测色散函数为φ(ω)(包含飞秒激光脉冲的初始色散，经过脉冲测量压缩控制模块以及光学显微模块引入的色散，以及控制装置引入的相位)，引入的已知参考光谱相位函数为f(ω)，飞秒激光脉冲在非线性晶体处的光谱相位
Figure PCTCN2018108303-appb-000004
即为二者之和：
Figure PCTCN2018108303-appb-000005
二次谐波的数学表达式为：
Figure PCTCN2018108303-appb-000006
其中，I SHG(2ω)为二次谐波信号在2ω频率处的信号强度，ω为基频频率，Ω为产生二次谐波的光子对所在频率和中心频率ω的频率差，E 0(ω+Ω)和E 0(ω+Ω)项为飞秒激光脉冲在频率ω+Ω和ω+Ω的强度，指数项
Figure PCTCN2018108303-appb-000007
为可在2ω处产生二次谐波信号的光子对的相位之和，当此项趋近于0时，指数项为1，积分达到最大，把此项做一个泰勒多项式展开(Ω＜＜ω)：
Figure PCTCN2018108303-appb-000008
并做一次略去高阶项的近似，即可得到当
Figure PCTCN2018108303-appb-000009
为0，即
Figure PCTCN2018108303-appb-000010
趋近于0时，在2ω处产生二次谐波信号为最大，以已知参考光谱相位函数为抛物线函数
Figure PCTCN2018108303-appb-000011
为例，扫描参数为抛物线强度β，其二阶导数等于扫描参数β，对于每一个不同的扫描参数β，都会采集到一个相应的二次谐波光谱。因此，在不同的参数β被扫描后，控制装置将会收集到以波长和频率为X轴，扫描参数β为Y轴，二次谐波信号强度为Z轴的三维图形，对于任意频率ω 1可以很直观的得到一个信号强度最大的位置Z(ω 1，β)，这个位置就是满足
Figure PCTCN2018108303-appb-000012
趋近于0的位置，而f (2)(ω 1)的值就是此位置对应的扫描参数值β1，即待测色散的二阶导数
Figure PCTCN2018108303-appb-000013
对待测范围内每一个光谱波长重复上述步骤，即可测量待测色散相对波长或频率的函数，两次积分后，可以计算出脉冲在样品位置所积累的总色散。
采用主动自适应光学器件，在测量处色散函数后，可以把该色散函数的负函数引入系统光路，从而抵消系统色散，生成压缩飞秒激光脉冲到达样品位置时色散为0或趋近于0，得到傅里叶变换极限脉冲，使得脉冲峰值功率在样品位置达到最大化，从而最大限度的提高组织样品不同分子的非线性信号产生效率，提高信噪比。
此外，采用主动自适应光学器件，可以在得到傅里叶变换极限脉冲的基础上，进行进一步针对某种非线性信号的光谱强度和光谱相位的优化，实现选择性激发，提高多模态信号的特异性。
作为另外一种可选的实施方式，第一光学组件为被动式光学器件，包括但不限于光栅对、棱镜对、棱镜光栅等一系列二阶色散光谱相位函数的被动光学器件，通过调整各被动式光学器件之间的相对距离和相对角度引 入已知参考光谱相位函数，测量系统光路的色散函数，完成脉冲在样品位置的总色散测量，通过调整各被动式光学器件之间的相对距离和相对角度对所述飞秒激光脉冲进行色散补偿。
采用被动式光学器件，可以通过线性拟合、从测量的系统色散函数中提取二阶和三阶色散数据，之后通过手动或自动控制设备调节各器件之间的距离和相对角度，从而达到最大程度上抵消二阶和三阶色散，使脉冲在样品位置尽量接近傅里叶变换极限，优化信噪比。
参考图4，第二光学组件包括第一反射镜M1、扫描振镜模块G、第二反射镜M2、二向色镜DM、光学显微物镜O以及多个滤片F1-F(n-1)；
第一信号采集装置包括与所述多个滤片对应的多个光电探测器PMT1-PMT(n-1)，多个光电探测器与所述控制装置连接；
压缩飞秒激光脉冲经过第一反射镜M1进入扫描振镜模块G，并依次通过第二反射镜M2、二向色镜DM和光学显微物镜O，聚焦至样品平台1032。
其中扫描振镜模块G包括X轴振镜GMx和Y轴振镜GMy，通过控制扫描振镜模块进行XY轴的扫描，通过控制光学平台压电扫描仪或光学显微镜做Z轴扫描，组织样品无需做准备，直接放置在样品平台。
压缩飞秒激光脉冲与所述样品平台上的组织样品作用后生成多模态信号，所述多模态信号经所述二向色镜反射至所述多个滤片进行分离，并被所述多个光电探测器采集后发送至控制装置。
控制装置对多模态信号进行分析。
进一步地，多模态信号包括：光谱范围为570纳米至630纳米的二次谐波信号、光谱范围为343纳米至405纳米的三次谐波信号、光谱范围为510纳米至565纳米的双光子荧光光谱信号、光谱范围为410纳米至490纳米的三光子荧光光谱信号以及光谱范围为640纳米至723纳米的非线性拉曼信号；
所述二次谐波信号用于识别组织样品中的胆固醇；所述三次谐波信号 用于识别组织样品中的细胞质、黑色素及肿瘤产生的细胞间囊泡；所述双光子荧光光谱信号用于识别弹性蛋白、黄素腺嘌呤二核苷酸和基膜；所述三光子荧光光谱信号用于识别还原性辅酶在组织样品中的分布；所述非线性拉曼信号用于识别类脂化合物和血细胞；
二次谐波信号、三次谐波信号以及非线性拉曼信号重合用于识别胶原纤维网络和肌浆球蛋白；所述非线性拉曼信号和所述二次谐波信号重合用于识别DNA、血管以及淋巴管。
本实施例提供的飞秒激光多模态分子影像系统，能够生成宽范围的多模态信号，多模态信号可识别组织样品中的多种成分，提高飞秒激光影像设备识别的多样性。
综上，本实施例提供的飞秒激光多模态分子影像系统，至少包括如下
有益效果：
(1)采用近红外波段生成装置提供中心波长为1010纳米至1100纳米、谱宽小于25纳米的近红外波段脉冲，该近红外波段脉冲可激发具有强非线性的光学媒介产生具有超宽光谱的飞秒激光脉冲，通过脉冲测量压缩控制模块测量并补偿飞秒激光脉冲到达组织样品积累的色散，最大限度消除“时域展宽”效应，得到的最短脉冲可以与组织样品作用生成多种不同模态的光谱信号，从而提供多种非线性分子影像模态；
(2)采用的双折射光子晶体光纤，所产生的飞秒激光脉冲的光谱范围内不存在零色散波长，具有较高的通光效率，可产生大于500毫瓦的飞秒激光脉冲，同时具有较好的偏振性，还可以通过优化入射光的偏振性、功率和入射角度调整产生的飞秒激光脉冲光谱；
(3)采用主动自适应光学器件，在测量处色散函数后，可以把该色散函数的负函数引入系统光路，从而抵消系统色散，生成压缩飞秒激光脉冲到达样品位置时色散为0或趋近于0，得到傅里叶变换极限脉冲，使得脉冲峰值功率在样品位置达到最大化，从而最大限度的提高组织样品不同分子 的非线性信号产生效率，提高信噪比；
(4)采用主动自适应光学器件，可以在得到傅里叶变换极限脉冲的基础上，进行进一步针对某种非线性信号的光谱强度和光谱相位的优化，实现选择性激发，提高多模态信号的特异性；
(5)能够生成宽范围的多模态信号，多模态信号可识别组织样品中的多种成分，提高飞秒激光影像设备识别的多样性。
应当理解的是，对本领域普通技术人员来说，可以根据上述说明加以改进或变换，而所有这些改进和变换都应属于本发明所附权利要求的保护范围。

Claims (15)

  1. 一种飞秒激光多模态分子影像系统，其特征在于，包括超连续谱生成模块、脉冲测量压缩控制模块以及光学显微模块；
    所述超连续谱生成模块包括近红外波段生成装置以及具有强非线性的光学媒介，所述近红外波段生成装置用于提供近红外波段脉冲，所述具有强非线性的光学媒介用于经所述近红外波段脉冲激发生成飞秒激光脉冲；所述近红外波段脉冲的中心波长为1010纳米至1100纳米、谱宽小于25纳米；
    所述脉冲测量压缩控制模块包括第一光学组件和测量模块，所述第一光学组件用于接收所述飞秒激光脉冲，所述测量模块用于测量系统光路中的色散，并根据测量结果调节第一光学组件参数对所述飞秒激光脉冲进行色散补偿，获得压缩飞秒激光脉冲；
    所述光学显微模块包括第二光学组件、样品平台以及第一信号采集装置，所述压缩飞秒激光脉冲经所述第二光学组件后到达所述样品平台，与样品平台上的组织样品作用后生成多模态信号，所述第一信号采集装置用于采集所述多模态信号。
  2. 根据权利要求1所述的飞秒激光多模态分子影像系统，其特征在于，所述近红外波段生成装置为含镱光纤激光器或者脉冲激光器，所述近红外波段生成装置的脉宽小于1500飞秒；
    所述具有强非线性的光学媒介生成的飞秒激光脉冲的光谱范围为750纳米至1300纳米；
    所述具有强非线性的光学媒介为双折射光子晶体光纤，所述双折射光子晶体光纤的长度大于45毫米，具有至少5*10-6的双折射率，并且在可透射波段具有正色散。
  3. 根据权利要求1所述的飞秒激光多模态分子影像系统，其特征在于， 所述第一光学组件为包含主动自适应光学器件的脉冲整形器，所述脉冲整形器包括依次设置的第一光栅、第一凸透镜、液晶空间光调制器、第二凸透镜以及第二光栅，所述第一光栅位于所述第一凸透镜的焦点位置，所述第一凸透镜和所述液晶空间光调制器之间的距离为一倍焦距，所述液晶空间光调制器和所述第二凸透镜之间的距离为一倍焦距，所述第二凸透镜与所述第二光栅之间的距离为一倍焦距。
  4. 根据权利要求2所述的飞秒激光多模态分子影像系统，其特征在于，所述第一光学组件为包含主动自适应光学器件的脉冲整形器，所述脉冲整形器包括依次设置的第一光栅、第一凸透镜、液晶空间光调制器、第二凸透镜以及第二光栅，所述第一光栅位于所述第一凸透镜的焦点位置，所述第一凸透镜和所述液晶空间光调制器之间的距离为一倍焦距，所述液晶空间光调制器和所述第二凸透镜之间的距离为一倍焦距，所述第二凸透镜与所述第二光栅之间的距离为一倍焦距。
  5. 根据权利要求3所述的飞秒激光多模态分子影像系统，其特征在于，所述测量模块包括控制装置、第二信号采集装置以及设置在所述样品平台上的非线性晶体；
    所述飞秒激光脉冲经所述脉冲测量压缩控制模块和光学显微模块聚焦至所述非线性晶体产生非线性光谱，所述第二信号采集装置用于采集非线性光谱信号并发送至所述控制装置；
    所述控制装置用于控制所述液晶空间光调制器的参数引入已知参考光谱相位函数，通过改变所述已知参考光谱相位函数，测量系统光路的色散函数，并根据所述色散函数调节所述液晶空间光调制器的参数，控制所述飞秒激光脉冲各个波长光谱的相位，以抵消色散。
  6. 根据权利要求4所述的飞秒激光多模态分子影像系统，其特征在于，所述测量模块包括控制装置、第二信号采集装置以及设置在所述样品平台上的非线性晶体；
    所述飞秒激光脉冲经所述脉冲测量压缩控制模块和光学显微模块聚焦至所述非线性晶体产生非线性光谱，所述第二信号采集装置用于采集非线性光谱信号并发送至所述控制装置；
    所述控制装置用于控制所述液晶空间光调制器的参数引入已知参考光谱相位函数，通过改变所述已知参考光谱相位函数，测量系统光路的色散函数，并根据所述色散函数调节所述液晶空间光调制器的参数，控制所述飞秒激光脉冲各个波长光谱的相位，以抵消色散。
  7. 根据权利要求5所述的飞秒激光多模态分子影像系统，其特征在于，所述非线性晶体为BBO晶体或者KDP晶体，所述非线性晶体的厚度为10微米至300微米。
  8. 根据权利要求6所述的飞秒激光多模态分子影像系统，其特征在于，所述非线性晶体为BBO晶体或者KDP晶体，所述非线性晶体的厚度为10微米至300微米。
  9. 根据权利要求5所述的飞秒激光多模态分子影像系统，其特征在于，所述已知参考光谱相位函数包括抛物线函数和正弦函数；所述非线性光谱为二次谐波；
    所述控制装置还用于每次改变所述已知参考光谱相位函数时对所述二次谐波进行最大值分析，获得待测色散的二阶导数，对所述二阶导数进行二次积分，获得系统光路的色散函数。
  10. 根据权利要求6所述的飞秒激光多模态分子影像系统，其特征在于，所述已知参考光谱相位函数包括抛物线函数和正弦函数；所述非线性光谱为二次谐波；
    所述控制装置还用于每次改变所述已知参考光谱相位函数时对所述二次谐波进行最大值分析，获得待测色散的二阶导数，对所述二阶导数进行二次积分，获得系统光路的色散函数。
  11. 根据权利要求9所述的飞秒激光多模态分子影像系统，其特征在 于，所述控制装置还用于改变所述脉冲整形器的参数以引入所述色散函数的负函数，控制所述飞秒激光脉冲各个波长光谱的相位，以抵消色散；
    所述控制装置还用于判断所述飞秒激光脉冲是否已经接近傅里叶变换极限，如果不是，则再次测量色散函数。
  12. 根据权利要求10所述的飞秒激光多模态分子影像系统，其特征在于，所述控制装置还用于改变所述脉冲整形器的参数以引入所述色散函数的负函数，控制所述飞秒激光脉冲各个波长光谱的相位，以抵消色散；
    所述控制装置还用于判断所述飞秒激光脉冲是否已经接近傅里叶变换极限，如果不是，则再次测量色散函数。
  13. 根据权利要求1所述的飞秒激光多模态分子影像系统，其特征在于，所述第一光学组件为被动式光学器件，通过调整各被动式光学器件之间的相对距离和相对角度引入已知参考光谱相位函数，测量系统光路的色散函数，并根据所述色散函数调整各被动式光学器件之间的相对距离和相对角度对所述飞秒激光脉冲进行色散补偿。
  14. 根据权利要求5所述的飞秒激光多模态分子影像系统，其特征在于，所述第二光学组件包括第一反射镜、扫描振镜模块、第二反射镜、二向色镜、光学显微物镜以及多个滤片；
    所述第一信号采集装置包括与所述多个滤片对应的多个光电探测器，所述多个光电探测器与所述控制装置连接；
    所述压缩飞秒激光脉冲经过所述第一反射镜进入所述扫描振镜模块，并依次通过所述第二反射镜、二向色镜和光学显微物镜，聚焦至所述样品平台；
    所述压缩飞秒激光脉冲与所述样品平台上的组织样品作用后生成多模态信号，所述多模态信号经所述二向色镜反射至所述多个滤片进行分离，并被所述多个光电探测器采集后发送至所述控制装置。
  15. 根据权利要求14所述的飞秒激光多模态分子影像系统，其特征在 于，所述多模态信号包括：光谱范围为570纳米至630纳米的二次谐波信号、光谱范围为343纳米至405纳米的三次谐波信号、光谱范围为510纳米至565纳米的双光子荧光光谱信号、光谱范围为410纳米至490纳米的三光子荧光光谱信号以及光谱范围为640纳米至723纳米的非线性拉曼信号；
    所述二次谐波信号用于识别组织样品中的胆固醇；所述三次谐波信号用于识别组织样品中的细胞质、黑色素及肿瘤产生的细胞间囊泡；所述双光子荧光光谱信号用于识别弹性蛋白、黄素腺嘌呤二核苷酸和基膜；所述三光子荧光光谱信号用于识别还原性辅酶在组织样品中的分布；所述非线性拉曼信号用于识别类脂化合物和血细胞；
    所述二次谐波信号、三次谐波信号以及非线性拉曼信号重合用于识别胶原纤维网络和肌浆球蛋白；所述非线性拉曼信号和所述二次谐波信号重合用于识别DNA、血管以及淋巴管。
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JP7117794B2 (ja) 2022-08-15
ES2904649T3 (es) 2022-04-05
US11128096B2 (en) 2021-09-21
US20200295519A1 (en) 2020-09-17
DK3667273T3 (da) 2022-01-24
EP3667273B1 (en) 2021-11-10

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