Multimodal imaging system based on radio frequency programmable GHz femtosecond pulse string

Abstract

The invention discloses a multi-mode imaging system based on a radio frequency programmable GHz femtosecond pulse string. The system comprises a femtosecond pulse laser light source, a pulse division module, a pulse amplification module, a pulse compression module, an imaging module, an optical signal acquisition part, an ultrasonic signal acquisition part and a data processing part. Monopulse laser generated by the femtosecond pulse laser light source enters the pulse division module, and femtosecond pulse strings generated by the pulse division module sequentially enter the pulse amplification module and the pulse compression module for energy amplification and pulse width compression and then enter the imaging module; the imaging module synchronously performs multi-photon imaging and photoacoustic imaging, and the images respectively enter the optical signal acquisition part and the ultrasonic signal acquisition part to form electric signals, and the electric signals are sent into the data processing part to be processed to generate an imaging result; according to the invention, multi-photon imaging and photoacoustic imaging are simultaneously carried out based on one femtosecond laser, multi-dimensional real-time observation is implemented, and compared with the prior art, the system has the advantages of system integration and low cost.

Description

Technical Field

[0001] The invention relates to the field of multimodal biomedical imaging and femtosecond laser technology, and in particular to a multimodal imaging system based on a radio frequency programmable GHz femtosecond pulse train. Background Art

[0002] Multiphoton imaging technology has become a powerful tool for current biomedical research due to its advantages such as low invasiveness, strong penetration, high spatial resolution, and high selectivity. It plays a huge role in the study of deep tissue structure and physiological function in the brain, neurological diseases, and cancer pathology. At present, the most widely used multiphoton imaging technology is two-photon excitation fluorescence microscopy. In recent years, three-photon excitation fluorescence microscopy has also been developing rapidly and has great application potential in the biomedical field.

[0003] As an emerging biomedical imaging method, photoacoustic imaging uses pulsed light to excite ultrasonic signals and has the advantages of being non-invasive, having a high penetration depth, and having high image contrast. It is an important means of studying cardiovascular and cerebrovascular diseases, drug metabolism, gene expression, and immunity. Its broad application prospects will bring about changes in the field of clinical medical imaging in the future.

[0004] Since only some biological tissues can effectively excite fluorescence, the information that can be obtained by multiphoton imaging without dye labeling is relatively limited, while photoacoustic imaging has the characteristic of not requiring labeling. Therefore, if multiphoton imaging and photoacoustic imaging can be performed simultaneously, more comprehensive information such as fluorescent labeled biological tissue structure based on multiphoton imaging and blood oxygen saturation and oxygen metabolism rate based on photoacoustic imaging can be collected simultaneously. This multimodal imaging system that combines multiphoton imaging and photoacoustic imaging can more comprehensively grasp the internal connections of biological tissues, more accurately analyze complex concurrent medical problems, and provide stronger technical support for biomedical research.

[0005] Due to the different requirements of multiphoton imaging and photoacoustic imaging for the required laser light sources, the hybrid imaging systems based on multiphoton imaging and photoacoustic imaging on the market are currently coupled by two different light sources (Rao, B. et al. Integrated photoacoustic, confocal, and two-photon microscope. J. Biomed. Opt 19, 036002) and then act simultaneously. They have the disadvantages of large size, high cost, complex system, etc., and are difficult to integrate (Song, W. et al. Fully integrated reflection-mode photoacoustic, two-photon and second harmonic generation microscopy in vivo. Sci Rep 6, 32240). Summary of the invention

[0006] The problem to be solved by the present invention is that the dimension of information obtained by a single imaging mode is limited.

[0007] A hybrid imaging system based on GHz repetition rate femtosecond pulse train proposed in the present invention will provide a solution to the above-mentioned problem. It can perform multi-photon imaging and photoacoustic imaging simultaneously based on a femtosecond laser and implement multi-dimensional real-time observation. Compared with the existing technology, it has the advantages of system integration and low cost.

[0008] The purpose of the present invention is achieved by at least one of the following technical solutions.

[0009] A multimodal imaging system based on a radio frequency programmable GHz femtosecond pulse train, comprising a femtosecond pulse laser light source, a pulse splitting module, a pulse amplification module, a pulse compression module, an imaging module, an optical signal acquisition component, an ultrasonic signal acquisition component and a data processing component;

[0010] The single-pulse laser generated by the femtosecond pulse laser light source enters the pulse splitting module through spatial optical coupling, and the femtosecond pulse train generated by the pulse splitting module enters the pulse amplification module and the pulse compression module in turn for energy amplification and pulse width compression before entering the imaging module; the imaging module synchronously performs multi-photon imaging and photoacoustic imaging, the output end of the imaging module is respectively connected to the input end of the optical signal acquisition component and the ultrasonic signal acquisition component, and the output end of the optical signal acquisition component and the ultrasonic signal acquisition component are respectively connected to the input end of the data processing component; the optical signal and ultrasonic signal generated by the imaging module enter the optical signal acquisition component and the ultrasonic signal acquisition component respectively to form an electrical signal that can be calculated and analyzed, and the electrical signal is sent to the data processing component for processing to generate an imaging result;

[0011] The femtosecond pulse laser light source is used to generate a single pulse laser with a repetition frequency of the megahertz level;

[0012] The pulse splitting module is used to evenly split a single femtosecond pulse into multiple femtosecond pulses to form a pulse train with an approximate nanosecond envelope, meeting the requirements of photoacoustic imaging;

[0013] The pulse amplification module is used to adjust the laser energy to reach the pulse energy required for imaging the sample;

[0014] The pulse compression module is used to compress the pulse width to meet the multi-photon imaging requirements;

[0015] The imaging module is used to perform multi-photon imaging and photoacoustic imaging simultaneously;

[0016] The optical signal acquisition component is used to receive the optical signal obtained by multi-photon imaging excitation and convert it into an electrical signal that can be calculated and analyzed;

[0017] The ultrasonic signal acquisition component is used to receive the ultrasonic signal obtained by the acoustic-optical imaging and convert it into an electrical signal that can be calculated and analyzed;

[0018] The data processing component is used to process the electrical signals generated by the optical signal acquisition component and the ultrasonic signal acquisition component to obtain imaging results;

[0019] The present invention generates a programmable GHz femtosecond pulse train, and realizes multi-photon imaging and photoacoustic imaging based on one femtosecond laser at the same time.

[0020] Furthermore, the femtosecond pulse laser light source is an all-fiber femtosecond pulse laser, which, as an initial light source, can emit pulse laser with a repetition frequency of megahertz level suitable for biological imaging.

[0021] Furthermore, in the pulse splitting module, the input femtosecond pulse laser is split into a pulse train including multiple femtosecond pulses. The nanosecond envelope of the pulse train formed by splitting a single femtosecond pulse laser can be used for photoacoustic imaging, and the several femtosecond pulses within its envelope can be used for multi-photon imaging.

[0022] Further, the pulse splitting module includes a radio frequency signal generating component, an angle deviation component, a beam splitting and combining component, a relay optical path component and a long mirror pair;

[0023] In the split pulse module, the signal of the radio frequency signal generating component acts on the angle deviation component, so that the input single femtosecond pulse laser is separated into multiple laser beams with different deflection angles, and then transmitted through the beam splitting and combining component to reach the relay optical path component. The relay optical path component relays the angle deviation generated by the angle deviation component to match the incident angle condition of the long mirror pair. After multiple reflections of the long mirror pair, the laser beams with different deflection angles return to the original optical path to the beam splitting and combining component for output. Due to the different optical path lengths of lasers with different deflection angles in the long mirror pair, a uniform time delay is generated, thereby achieving the effect of splitting the pulse; the number of deflection angles is consistent with the number of pulse splits. By programming the radio frequency signal loaded into the angle deviation component, the number of pulses and the pulse intensity of the GHz femtosecond pulse train can be set in real time without changing the optical path system design. Therefore, the performance of the pulse train can be adjusted according to different imaging requirements to achieve the best imaging effect.

[0024] Further, the radio frequency signal generating component includes a programmable terminal, an arbitrary waveform generator and a radio frequency signal amplifier;

[0025] The programmable terminal controls the arbitrary waveform generator to send the required radio frequency signal, which is amplified by the radio frequency signal amplifier and then loaded on the angle deviation component.

[0026] Furthermore, the angle deviation component is an acousto-optic deflector.

[0027] Furthermore, the beam splitting and combining component is a 50:50 beam splitter.

[0028] Furthermore, the pulse amplification module includes an all-fiber amplifier for amplifying the power of the split pulse train.

[0029] Furthermore, the pulse compression module is a dispersion compensating optical fiber, which compresses the pulse width by dispersion compensation.

[0030] Furthermore, the imaging module includes a lens, an objective lens, a dichroic mirror and a sample; the pulse light is collimated by the lens and then transmitted through the dichroic mirror into the objective lens and focused on the sample, and the light signal excited by the sample returns to the dichroic mirror and is reflected and output.

[0031] Compared with the prior art, the present invention has the following beneficial effects:

[0032] 1. The present invention utilizes pulse splitting technology to split a single femtosecond pulse into multiple femtosecond pulse trains and simulates nanosecond pulses through pulse envelopes. By adjusting the radio frequency signal loaded on the split pulse module, the number of pulses and pulse intensity of the GHz femtosecond pulse train can be designed in real time.

[0033] 2. The present invention uses one laser light source to simultaneously meet the requirements of photoacoustic imaging and multiphoton imaging, thereby realizing a multimodal imaging system that can simultaneously perform multiphoton imaging and photoacoustic imaging. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 Schematic diagram of the structure of a multi-modal imaging system based on a radio frequency programmable GHz femtosecond pulse train in an embodiment of the present invention;

[0035] Figure 2 This is a schematic diagram of the structure of the pulse splitting module in an embodiment of the present invention;

[0036] Figure 3 Schematic diagram of the pulse division principle in an embodiment of the present invention. DETAILED DESCRIPTION

[0037] The technical solutions in the embodiments of the present invention will be described clearly and completely below in conjunction with the accompanying drawings in the embodiments of the present invention.

[0038] Example:

[0039] A multimodal imaging system based on RF programmable GHz femtosecond pulse trains, such as Figure 1 As shown, it includes a femtosecond pulse laser light source 101, a pulse division module 102, a pulse amplification module 103, a pulse compression module 104, an imaging module 105, an optical signal acquisition component 106, an ultrasonic signal acquisition component 107 and a data processing component 108;

[0040] The single pulse laser generated by the femtosecond pulse laser light source 101 enters the pulse splitting module 102 through spatial optical coupling, and the femtosecond pulse train generated by the pulse splitting module 102 enters the pulse amplification module 103 and the pulse compression module 104 in turn for energy amplification and pulse width compression, and then enters the imaging module 105; the imaging module 105 performs multi-photon imaging and photoacoustic imaging simultaneously, and the output end of the imaging module 105 is respectively connected to the input end of the optical signal acquisition component 106 and the ultrasonic signal acquisition component 107, and the output end of the optical signal acquisition component 106 and the ultrasonic signal acquisition component 107 are respectively connected to the input end of the data processing component 110; the optical signal and the ultrasonic signal generated by the imaging module 105 enter the optical signal acquisition component 106 and the ultrasonic signal acquisition component 107 respectively to form an electrical signal that can be calculated and analyzed, and the electrical signal is sent to the data processing component 108 for processing to generate an imaging result;

[0041] The current mainstream multiphoton imaging includes two-photon imaging and three-photon imaging. According to the specific requirements of medical imaging, the two-photon-photoacoustic hybrid imaging mode or the three-photon-photoacoustic hybrid imaging mode can be selected by setting the working band of the laser.

[0042] In this embodiment, a three-photon-photoacoustic hybrid imaging mode is taken as an example.

[0043] The femtosecond pulse laser light source 101 is a 1700nm all-fiber femtosecond pulse laser with an output laser average power of up to 5W, a pulse repetition frequency of 1MHz, and a pulse width of 100fs. As an initial light source, it can emit a pulse laser with a repetition frequency of megahertz level suitable for biological imaging.

[0044] like Figure 2 As shown, in the pulse splitting module 102, the input femtosecond pulse laser is split into a pulse train including multiple femtosecond pulses. The nanosecond envelope of the pulse train formed by splitting a single femtosecond pulse laser can be used for photoacoustic imaging, and the several femtosecond pulses within the envelope can be used for multi-photon imaging.

[0045] like Figure 2 As shown, the pulse division module 102 includes a radio frequency signal generating component 201, an angle deviation component 202, a beam splitting and combining component 203, a relay optical path component 204 and a long mirror pair 205;

[0046] In the pulse splitting module 102, the signal of the radio frequency signal generating component 201 acts on the angle deviation component 202, so that the input single femtosecond pulse laser is separated into multiple laser beams with different deflection angles, and then transmitted through the beam splitting and combining component 203 to reach the relay optical path component 204. The relay optical path component 204 relays the angle deviation generated by the angle deviation component 202 to match the incident angle condition of the long mirror pair 205. After multiple reflections of the long mirror pair 205, the laser beams with different deflection angles return to the original optical path to the beam splitting and combining component 203 for output. Since the laser beams with different deflection angles have different optical paths in the long mirror pair 205, a uniform time delay is generated, thereby achieving the effect of splitting the pulse; the number of deflection angles is consistent with the number of pulse splits. By programming the radio frequency signal loaded into the angle deviation component 202, the number of pulses and the pulse intensity of the GHz femtosecond pulse train can be set in real time without changing the optical path system design, so the performance of the pulse train can be adjusted according to different imaging requirements to achieve the best imaging effect.

[0047] In one embodiment, the radio frequency signal generating component 201 includes a programmable terminal, an arbitrary waveform generator and a radio frequency signal amplifier;

[0048] The programmable terminal controls the arbitrary waveform generator to send the required radio frequency signal, which is amplified by the radio frequency signal amplifier and then loaded on the angle deviation component 202 .

[0049] In one embodiment, the angle deviation component 202 is an acousto-optic deflector.

[0050] In one embodiment, the beam splitting and combining component 203 is a 50:50 beam splitter.

[0051] In one embodiment, the relay optical path component 204 includes a relay lens and a reflector; the long mirror pair 205 is a free space angle linear frequency modulation pulse enhancement delay mirror pair. The pulse splitting module 102 splits a single laser pulse with a time interval of T1=1μs into 21 sub-pulses with a time interval of T2=0.5ns in the time domain, and the number of split sub-pulses can be designed to control and deflect the direction of the light beam by loading a radio frequency signal on the acousto-optic deflector.

[0052] The pulse splitting schematic diagram of this embodiment is as follows Figure 3 As shown, the radio frequency signal designed by the programmable terminal is amplified by the radio frequency signal amplifier and then loaded on the acousto-optic deflector, so that the light beam forms 21 sub-beams with different deflection angles after passing through the acousto-optic deflector, and the sub-beams pass through the 50:50 beam splitter, and 50% of the light passes through the relay optical path component to relay the angle deviation generated by the angle deviation component to match the incident angle condition of the long mirror pair, and the laser beams with different deflection angles are reflected by the long mirror pair for multiple times, and then return to the original optical path to the beam splitting and combining component for output. Due to the different optical paths of the laser beams with different deflection angles in the long mirror, a uniform time delay of T2=0.5ns is generated, thereby achieving the effect of splitting the pulse. When the light beam is reflected back to the beam splitter, 50% of the light is output, and a single pulse with a single pulse energy of E1=5μJ is split in the time domain after passing through the pulse splitting module 102 to form a pulse train consisting of 21 sub-pulses with a time interval of T2. The diffraction efficiency of the light beam after passing through the AOD is about 70%, and about 50% enters the relay module after passing through the beam splitter. The loss between the relay module and the high reflectivity long mirror pair is expected to be 2dB. Finally, about 50% is output through the beam splitter. The output optical power passes through the pulse amplification module (103) with a gain of 13dB. The single pulse energy E2 of the final output pulse train is about 520nJ, and the single envelope pulse energy E3 is about 11μJ.

[0053] In one embodiment, the envelope duration of the pulse train formed by 21 sub-pulses is 10ns, the sub-pulse repetition rate F1 = 2GHz, and the envelope pulse frequency F2 = 1MHz. The pulse energy E2 and repetition rate F1 of the sub-pulses under the envelope meet the light source requirements for three-photon imaging, and the pulse energy E3 and repetition rate F2 of the envelope pulse meet the light source requirements for acousto-optic imaging.

[0054] In one embodiment, the pulse amplification module 103 is an all-fiber amplifier, which is used to amplify the power of the split pulse train.

[0055] In one embodiment, the pulse compression module 104 is a dispersion compensating optical fiber, which is used to compensate for the dispersion caused by the gain optical fiber in the pulse amplifier, thereby achieving the effect of compressing the pulse width. After passing through the pulse compression module, the sub-pulse width in the envelope is 100fs, and the envelope pulse duration is 10ns, which meet the pulse width requirements of three-photon imaging and photoacoustic imaging respectively.

[0056] In one embodiment, the imaging module 105 includes a lens, an objective lens, a dichroic mirror, and a sample. The light collection component 106 is a photomultiplier tube, and the ultrasound collection component 107 includes an ultrasound detector, a signal amplifier, and an oscilloscope. The laser is beam-shaped by two lenses and then focused on the sample by the objective lens for imaging. The fluorescent signal light excited by three-photon absorption enters the photomultiplier tube through the dichroic mirror, thereby converting the optical signal into an electrical signal and sending it to the data processing component 108 for data analysis. The ultrasound signal generated by photoacoustic imaging is collected by the ultrasound detector, converted into an electrical signal by the oscilloscope, amplified by the signal amplifier, and sent to the data processing component for data analysis to obtain the final high-resolution, multi-contrast mechanism biological image.

[0057] The above embodiment is one of the implementation modes of the present invention, but the implementation modes of the present invention are not limited to the embodiments and test examples. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. A multimodal imaging system based on radio frequency programmable GHz femtosecond pulse train, characterized in that: It comprises a femtosecond pulse laser light source (101), a pulse splitting module (102), a pulse amplification module (103), a pulse compression module (104), an imaging module (105), an optical signal acquisition component (106), an ultrasonic signal acquisition component (107) and a data processing component (108). The single pulse laser generated by the femtosecond pulse laser light source (101) enters the pulse splitting module (102) through spatial optical coupling, and the femtosecond pulse train generated by the pulse splitting module (102) enters the pulse amplification module (103) and the pulse compression module (104) in sequence for energy amplification and pulse width compression before entering the imaging module (105); the imaging module (105) synchronously performs multi-photon imaging and photoacoustic imaging, the output end of the imaging module (105) is respectively connected to the input end of the optical signal acquisition component (106) and the ultrasonic signal acquisition component (107), and the output ends of the optical signal acquisition component (106) and the ultrasonic signal acquisition component (107) are respectively connected to the input end of the data processing component (110); the optical signal and the ultrasonic signal generated by the imaging module (105) enter the optical signal acquisition component (106) and the ultrasonic signal acquisition component (107) respectively to form electrical signals, and the electrical signals are sent to the data processing component (108) for processing to generate imaging results.

2. A multimodal imaging system based on radio frequency programmable GHz femtosecond pulse train according to claim 1, characterized in that: The femtosecond pulse laser light source (101) is an all-fiber femtosecond pulse laser, which, as an initial light source, can emit pulse laser with a repetition frequency of megahertz level suitable for biological imaging.

3. A multimodal imaging system based on radio frequency programmable GHz femtosecond pulse train according to claim 1, characterized in that: In the pulse splitting module (102), the input femtosecond pulse laser is split into a pulse train including multiple femtosecond pulses, and the nanosecond envelope of the pulse train formed by splitting a single femtosecond pulse laser is used for photoacoustic imaging, and the several femtosecond pulses in the envelope are used for multi-photon imaging.

4. A multimodal imaging system based on radio frequency programmable GHz femtosecond pulse train according to claim 3, characterized in that: The pulse splitting module (102) comprises a radio frequency signal generating component (201), an angle deviation component (202), a beam splitting and combining component (203), a relay optical path component (204) and a long mirror pair (205); In the pulse splitting module (102), a signal of a radio frequency signal generating component (201) acts on an angle deviation component (202), thereby separating an input single femtosecond pulse laser into a plurality of laser beams with different deflection angles, which are then transmitted through a beam splitting and combining component (203) to reach a relay optical path component (204). The relay optical path component (204) relays the angle deviation generated by the angle deviation component (202) to match the incident angle condition of a long mirror pair (205). After multiple reflections from the long mirror pair (205), the laser beams with different deflection angles return to the original optical path to the beam splitting and combining component (203) for output.

5. A multimodal imaging system based on radio frequency programmable GHz femtosecond pulse train according to claim 4, characterized in that: The radio frequency signal generating component (201) comprises a programmable terminal, an arbitrary waveform generator and a radio frequency signal amplifier; The programmable terminal controls the arbitrary waveform generator to send the required radio frequency signal, which is amplified by the radio frequency signal amplifier and then loaded on the angle deviation component (202).

6. A multimodal imaging system based on radio frequency programmable GHz femtosecond pulse train according to claim 4, characterized in that: The angle deviation component (202) is an acousto-optic deflector.

7. The multimodal imaging system based on radio frequency programmable GHz femtosecond pulse train according to claim 4, characterized in that: The beam splitting and combining component (203) is a 50:50 beam splitter.

8. The multimodal imaging system based on radio frequency programmable GHz femtosecond pulse train according to claim 1, characterized in that: The pulse amplification module (103) comprises an all-fiber amplifier, which is used to amplify the power of the split pulse train.

9. The multimodal imaging system based on radio frequency programmable GHz femtosecond pulse train according to claim 1, characterized in that: The pulse compression module (104) is a dispersion compensating optical fiber, which compresses the pulse width by means of dispersion compensation.

10. The multimodal imaging system based on radio frequency programmable GHz femtosecond pulse train according to claim 1, characterized in that: The imaging module (105) comprises a lens, an objective lens, a dichroic mirror and a sample; the pulse light is collimated by the lens and then transmitted through the dichroic mirror into the objective lens and focused on the sample; the light signal excited by the sample returns to the dichroic mirror and is reflected and output.

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