A molecular-specific label-free endoscopic imaging system

Abstract

The present invention discloses a molecular-specific label-free endoscopic imaging system. An infrared tunable pulsed light illumination device excites the photothermal signal of specific molecules in a sample. The photothermal signal interacts with the sample to generate a change in refractive index or volume, which is manifested as a change in the scattering signal of the sample under a visible light array detector and is recorded by an endoscopic imaging device in combination with the visible light array detector. A thermal frame and a cold frame are generated respectively according to the presence or absence of the infrared tunable pulsed light illumination. The finally obtained molecular-specific label-free signal is obtained by subtracting the thermal frame from the cold frame. By tuning the infrared wavelength, photothermal effects can be produced on different molecules, presenting the distribution maps of different molecules. The present invention can realize real-time display of specific photothermal images and normal visible light illumination endoscopic images on a computer split screen. It can achieve various functions such as distinguishing the boundaries of biological tissues, accurately diagnosing and identifying diseased areas, and simplifies the traditional endoscopic diagnosis process of sampling, sectioning, staining, and imaging.

Description

Technical Field

[0001] The present invention relates to the technical field of optical endoscopy imaging, and particularly to a molecular-specific label-free imaging endoscope system. Background Art

[0002] Medical endoscopes are commonly used medical devices in modern medicine. They enter the human body through natural orifice such as the oral cavity or surgically created orifices, helping doctors to observe the internal organs of the human body in real time, diagnose diseases and assist in surgeries. Traditional electronic endoscopy technology lacks the specificity and high-resolution imaging ability for biological tissues, and cannot perform component analysis on diseased tissues. It is necessary to collect biological tissue samples for microscopic section imaging and analysis. Therefore, its diagnostic process includes sampling, sectioning, staining, and microscopic imaging, which has problems such as complexity, low efficiency, long time, difficulty in real-time diagnosis, and easy misjudgment.

[0003] If molecular-specific label-free imaging can be performed during surgery, the above problems can be solved. Summary of the Invention

[0004] The object of the present invention is to provide a novel infrared photothermal endoscopy imaging system, which can simultaneously achieve traditional endoscopy imaging and molecular-specific label-free high-resolution imaging. Compared with traditional optical endoscopy imaging, it can bring molecular-specific information, thus simplifying the traditional endoscopy diagnosis process of sampling, sectioning, staining, and imaging.

[0005] The object of the present invention is achieved by the following technical solutions: A molecular-specific label-free endoscopy imaging system, which includes an infrared tunable pulsed light illumination device, an endoscopy imaging device, a visible light array detector, a visible light illumination device, an infrared detector, an optical switch, a signal synchronization system, and a computer;

[0006] The visible light array detector is connected to the endoscopy imaging device and is used to record endoscopy imaging; specifically: The infrared tunable pulsed light illumination device is used to excite the photothermal signal of specific molecules in biological tissues; the photothermal signal interacts with biological tissues to cause changes in refractive index or volume, which are manifested as changes in the scattering signal of biological tissues under the visible light array detector, and are recorded through the combination of the endoscopy imaging device and the visible light array detector; the visible light generated by the visible light illumination device is coupled into the endoscopy imaging device;

[0007] The optical switch is connected to the infrared tunable pulsed light illumination device and is used to perform switch modulation on the infrared tunable pulsed light illumination device, generating a thermal frame and a cold frame according to the presence or absence of the infrared tunable pulsed light respectively; the finally obtained molecular-specific label-free signal is obtained by subtracting the cold frame from the thermal frame; by tuning the infrared wavelength, photothermal effects are generated on different molecules, presenting the distribution maps of different molecules;

[0008] The computer is connected to the visible light array detector to realize the synthesis or split-screen display of the infrared photothermal signal and the normal visible light endoscope imaging;

[0009] The infrared detector is used to detect the pulse frequency of the infrared tunable pulsed light and calibrate the intensity of each wavelength of the infrared tunable pulsed light;

[0010] The signal synchronization system includes a timing pulse generator to synchronize the light beam emitted by the infrared tunable pulsed light illumination device, the light beam emitted by the visible light illumination device, and the visible light array detector.

[0011] Further, the specific process of the signal synchronization system synchronizing the light beam emitted by the infrared tunable pulsed light illumination device, the light beam emitted by the visible light illumination device, and the visible light array detector is as follows:

[0012] First, the infrared detector measures the frequency of the infrared tunable pulsed light as f, and generates a pulse signal of this frequency through the timing pulse generator to modulate the visible light illumination. At the same time, a pulse with a frequency of f / n is generated to perform chopping modulation on the infrared tunable pulsed light. Meanwhile, a pulse signal with a frequency of 2f / n is generated to synchronize the visible light array detector to record the scattered signal of the visible light; the photothermal signal distribution map is obtained from the difference in the intensity of each pixel between the thermal frame and the cold frame; where n is a positive integer, depending on the fastest imaging speed that the visible light array detector can achieve; assuming the highest imaging frame rate of the visible light array detector is f c , then according to the Nyquist sampling rate, n needs to satisfy:

[0013]

[0014] Among them, the larger n is, the more cumulative pulses of the photothermal signal, and the stronger the photothermal signal. However, at the same time, the imaging speed decreases, which is not conducive to real-time imaging; therefore, on the premise of satisfying the above formula, n is adjusted according to the actual requirements for imaging signal-to-noise ratio and imaging speed.

[0015] Further, the pulse frequencies of the visible light illumination and the infrared tunable pulsed light illumination are the same.

[0016] Further, the light beam emitted by the visible light illumination device, the light beam emitted by the infrared tunable pulsed light illumination device, and the endoscope imaging field region need to be adjusted to achieve spatial coincidence.

[0017] Further, the endoscope imaging device has the best imaging quality in the visible light band.

[0018] Further, the light beam emitted by the visible light illumination device is generated by a light-emitting diode (LED) or a laser with a spectral range of 380 nm to 780 nm.

[0019] Furthermore, the light beam emitted by the infrared tunable pulsed light illumination device is generated nonlinearly by a quantum cascade laser or a femtosecond laser, and its wavelength range is: 0.75 μm to 15 μm, and the pulse range is: ps to ns.

[0020] Furthermore, the visible light array detector is a charge-coupled device (CCD) detector or a complementary metal oxide semiconductor (CMOS) detector.

[0021] Furthermore, the optical switch is a chopper, an electro-optic / acousto-optic / magneto-optic modulator, or is composed of a microelectromechanical system (MEMS), a digital micromirror device (DMD), a spatial light modulator (SLM), a galvanometer and the corresponding optical path.

[0022] Furthermore, the timing pulse generator is a function generator or is generated by a designed circuit.

[0023] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0024] The label-free endoscopy imaging system can realize computer split-screen real-time display of specific optothermal images and normal visible light illumination endoscopy images. Among them, the visible light illumination endoscopy image can realize normal surgical guidance, while the optothermal image can provide a molecular specificity distribution map of the biological tissue sample area, and can also realize single-point infrared absorption spectroscopy, so as to realize various functions such as boundary distinction of biological tissues, accurate diagnosis and identification of lesion areas, and simplify the traditional endoscopic diagnosis process of sampling, sectioning, staining and imaging. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 is a system schematic diagram of an embodiment of the present invention. Wherein 1 is an infrared tunable pulsed light illumination device, 2 is an infrared beam splitter, 3 is an optical switch, 4 is a mirror, 5 is an infrared detector, 6 is an infrared fiber coupler, 7 is an optical fiber, 8 is a biological tissue sample, 9 is a timing pulse generator, 10 is a visible light illumination device, 11 is a computer, 12 is an endoscopy imaging device, and 13 is a visible light array detector.

[0026] Figure 2 is a schematic diagram of a synchronous pulse signal of an embodiment of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0027] To enable those skilled in the art to better understand the technical solutions of the present invention, the present invention will be described in detail below with reference to the embodiments and the drawings.

[0028] Embodiment 1

[0029] Embodiment 1 describes a composition and usage method of the system.

[0030] As Figure 1 shown, a novel molecular-specific label-free endoscopic imaging system provided by the present invention includes: an infrared tunable pulsed light illumination device 1, an infrared beam splitter 2, an optical switch 3, a mirror 4, an infrared detector 5, an infrared fiber coupler 6, an optical fiber 7, a biological tissue sample 8, a timing pulse generator 9, a visible light illumination device 10, a computer 11, an endoscopic imaging device 12, and a visible light array detector 13.

[0031] The infrared tunable pulsed light illumination device 1 can be a quantum cascade laser or generated by a femtosecond laser, with a tunable wavelength in the range of 0.75 μm to 15 μm and a pulse range of ps to ns. The beam emitted by the infrared tunable pulsed light illumination device 1 passes through the infrared beam splitter 2, and the infrared beam splitter 2 reflects part of the light to the infrared detector 5. The infrared detector 5 records the pulse frequency and the intensity at this wavelength of the infrared tunable pulsed light illumination device 1. For example, assume the intensity is I and the frequency is f at a wavelength of λ. The infrared tunable pulsed light is pulse-modulated by the optical switch 3 before irradiating the biological tissue sample 8. Its modulation frequency f m depends on the highest frequency f that the visible light array detector can detect c and needs to satisfy 2f m <f c . The infrared tunable pulsed light is reflected by the mirror 4 and focused and coupled into the optical fiber 7 by the infrared fiber coupler 6, thereby realizing the illumination of the biological tissue sample 8. The optical switch is a chopper, an electro-optic / acousto-optic / magneto-optic modulator, or composed of a microelectromechanical system (MEMS), a digital micromirror device (DMD), a spatial light modulator (SLM), a galvanometer, and the corresponding optical path.

[0032] The visible light illumination device 10 can be an LED or a laser, emitting a beam with a spectral range of 380 nm to 780 nm. Its switch can be modulated by a pulse signal loaded by the timing pulse generator 9 in the signal synchronization system, and its modulation frequency is the same as that of the infrared tunable pulsed light, which is f. The timing pulse generator is a function generator or generated by a designed circuit. The visible light generated by the visible light illumination device 10 is coupled into the endoscopic imaging device 12. The endoscopic imaging device 12 has the best imaging quality in the visible light band.

[0033] The pulsed illumination beam generated by the visible light illumination device 10 spatially coincides with the infrared pulsed illumination beam and also coincides with the imaging field of view of the endoscopic imaging system. The visible light array detector 13 is connected to the endoscopic imaging device 12 and is used to capture the visible light signals of the endoscopic imaging device 12. Specifically: The infrared tunable pulsed light illumination device 1 is used to excite the photothermal signals of specific molecules in the biological tissue sample 8; the photothermal signals interact with the biological tissue sample 8 to cause changes in refractive index or volume, which are manifested as changes in the scattering signals of the biological tissue sample 8 under the visible light array detector 13, and are recorded through the combination of the endoscopic imaging device 12 and the visible light array detector 13; the computer 11 is connected to the visible light array detector and is used to store the pictures captured by the visible light array detector 13 and perform calculations and displays. The visible light array detector is a charge-coupled device (CCD) detector or a complementary metal oxide semiconductor (CMOS) detector.

[0034] When the visible light array detector 13 detects the presence and absence of infrared light pumping, they are respectively the thermal frame and the cold frame. Finally, the molecular-specific imaging distribution map at this wavelength is as follows:

[0035] I λ = |I λ热 - I λ冷 |

[0036] By tuning the infrared wavelength λ, photothermal effects can be produced on different molecules, and photothermal distribution maps of different molecules can be presented. The computer 11 can control the display to output in real time the overlapping map of the infrared photothermal signals and the normal visible light endoscopy, or display the infrared photothermal signals and the normal visible light endoscopy in split screens.

[0037] Embodiment 2

[0038] Embodiment 2 is a supplement to Embodiment 1 and elaborates on the synchronization pulse signals of the signal synchronization system. The infrared pulsed light emitted by the infrared tunable pulsed light illumination device 1 is split by the infrared beam splitter 2 and then undergoes frequency detection and intensity calibration by the infrared detector 5. The specific process is as follows: First, the infrared detector measures the frequency of the infrared tunable pulsed light as f, and generates a pulse signal of this frequency through the timing pulse generator for modulating the visible light illumination. At the same time, a pulse with a frequency of f / n is generated to perform chopping modulation on the infrared tunable pulsed light. Meanwhile, a pulse signal with a frequency of 2f / n is generated to synchronize the visible light array detector and record the scattering signals of the visible light; the photothermal signal distribution map is obtained from the difference in the intensity of each pixel between the thermal frame and the cold frame; where n is a positive integer and depends on the fastest imaging speed that the visible light array detector can achieve; assuming the highest imaging frame rate of the visible light array detector is f c , then according to the Nyquist sampling rate, n needs to satisfy:

[0039]

[0040] Among them, the larger the n, the more cumulative pulses of the optothermal signal and the stronger the optothermal signal. However, the imaging speed decreases simultaneously, which is not conducive to real-time imaging. Therefore, on the premise of satisfying the above formula, n is adjusted according to the actual requirements for the imaging signal-to-noise ratio and imaging speed. Specific examples are as follows:

[0041] For example, at a wavelength of λ 1 with an intensity of I 1 and a frequency of f 1 . At the same time, the optical switch 3 modulates the infrared pulsed light at a frequency of f 1 / 16, as shown in the first row of Figure 2 . The timing pulse generator 9 emits rectangular pulses at a frequency of f 1 to pulse-modulate the visible light source 10, as shown in the second row of Figure 2 . The timing pulse generator 9 sends a pulse synchronization signal at a frequency of f 1 / 8 to the visible light array detector 13, as shown in the second row of 1 Figure 2 . Therefore, the adjacent two frames detected by the visible light array detector 13 respectively correspond to the thermal frame and the cold frame when the infrared pulsed light is on and off. Subtracting the corresponding pixel intensities of the adjacent two frames detected by the visible light array detector 13 gives the infrared optothermal distribution map of the molecules corresponding to that wavelength.

[0042] The above are only the preferred embodiments of the present invention and are not used to limit the present invention. Any modification of the structure, change in the proportional relationship, or adjustment of the size, without affecting the effects that the present invention can produce and the purposes that can be achieved, should still fall within the technology disclosed by the present invention.

Claims

1. A molecular-specific label-free endoscopic imaging system, characterized in that, the system includes an infrared tunable pulsed light illumination device, an endoscopic imaging device, a visible light array detector, a visible light illumination device, an infrared detector, an optical switch, a signal synchronization system, and a computer; the visible light array detector is connected to the endoscopic imaging device for recording endoscopic imaging; specifically: the infrared tunable pulsed light illumination device is used to excite the photothermal signal of specific molecules in biological tissues; the photothermal signal interacts with biological tissues to produce changes in refractive index or volume, which are manifested as changes in the scattering signal of biological tissues under the visible light array detector, and are recorded by combining the endoscopic imaging device and the visible light array detector; the visible light generated by the visible light illumination device is coupled into the endoscopic imaging device; the optical switch is connected to the infrared tunable pulsed light illumination device for switching modulation of the infrared tunable pulsed light illumination device, generating a thermal frame and a cold frame according to the presence or absence of the infrared tunable pulsed light respectively; the finally obtained molecular-specific label-free signal is obtained by subtracting the thermal frame from the cold frame; by tuning the infrared wavelength, photothermal effects are produced on different molecules, presenting the distribution maps of different molecules; the computer is connected to the visible light array detector to realize the synthesis or split-screen display of the infrared photothermal signal and the normal visible light endoscopic imaging; the infrared detector is used to detect the pulse frequency of the infrared tunable pulsed light and calibrate the intensity of each wavelength of the infrared tunable pulsed light; the signal synchronization system includes a timing pulse generator to synchronize the light beam emitted by the infrared tunable pulsed light illumination device with the light beam emitted by the visible light illumination device and the visible light array detector.

2. A molecular-specific label-free endoscopic imaging system according to claim 1, characterized in that, the specific process of the signal synchronization system synchronizing the light beam emitted by the infrared tunable pulsed light illumination device with the light beam emitted by the visible light illumination device and the visible light array detector is as follows: First, the infrared detector measures the frequency of the infrared tunable pulsed light as f, and a pulsed signal of this frequency is generated by the timing pulse generator for modulating the visible light illumination. At the same time, a pulsed signal with a frequency of f / n is generated to perform chopping modulation on the infrared tunable pulsed light. Meanwhile, a pulsed signal with a frequency of 2f / n is generated to synchronize the visible light array detector and record the scattered signal of the visible light. The optothermal signal distribution map is obtained from the difference in the intensity of each pixel between the thermal frame and the cold frame; where n is a positive integer, depending on the fastest speed at which the visible light array detector can image; assuming the highest imaging frame rate of the visible light array detector is f c , then according to the Nyquist sampling rate, n needs to satisfy: wherein, the larger n is, the more cumulative pulses of the photothermal signal and the stronger the photothermal signal are, but at the same time, the imaging speed decreases, which is not conducive to real-time imaging; therefore, on the premise of satisfying the above formula, n is adjusted according to the actual requirements for imaging signal-to-noise ratio and imaging speed.

3. A molecular-specific label-free endoscopic imaging system according to claim 1, characterized in that, the pulse frequencies of the visible light illumination and the infrared tunable pulsed light illumination are the same.

4. A molecular-specific label-free endoscopic imaging system according to claim 1, characterized in that, the light beam emitted by the visible light illumination device, the light beam emitted by the infrared tunable pulsed light illumination device, and the endoscopic imaging field region need to be adjusted to achieve spatial coincidence.

5. A molecular-specific label-free endoscopic imaging system according to claim 1, characterized in that, the endoscopic imaging device has the best imaging quality in the visible light band.

6. A molecular-specific label-free endoscopic imaging system according to claim 1, characterized in that, the light beam emitted by the visible light illumination device is generated by a light-emitting diode (LED) or a laser with a spectral range of 380 nm to 780 nm.

7. A molecular-specific label-free endoscopic imaging system according to claim 1, characterized in that, the light beam emitted by the infrared tunable pulsed light illumination device is generated by a quantum cascade laser or nonlinearly generated by a femtosecond laser, and its wavelength range is: 0.75 μm to 15 μm, and the pulse range is: ps to ns.

8. A molecular-specific label-free endoscopic imaging system according to claim 1, characterized in that, the visible light array detector is a charge-coupled device (CCD) detector or a complementary metal oxide semiconductor (CMOS) detector.

9. A molecular-specific label-free endoscopic imaging system according to claim 1, characterized in that, the optical switch is a chopper, an electro-optic / acousto-optic / magneto-optic modulator, or is composed of a microelectromechanical system (MEMS), a digital micromirror device (DMD), a spatial light modulator (SLM), a galvanometer and the corresponding optical path.

10. A molecular-specific label-free endoscopic imaging system according to claim 1, characterized in that, the timing pulse generator is a function generator or is generated by a designed circuit.

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