An imaging device and method for in vivo quantitative research on tumor hypoxia

Abstract

The present invention provides an imaging device and method for in vivo quantitative research on tumor hypoxia. The present invention provides a rapid photoacoustic excitation light source for multispectral photoacoustic and photoacoustic lifetime imaging, and excites to form photoacoustic signals for photoacoustic imaging; constructs a magnetic field-free line and an excitation short pulse waveform, measures the concentration distribution of magnetic nanoparticles in the tumor to be measured, and realizes magnetoacoustic imaging; collects the photoacoustic signals of photoacoustic imaging and the magnetoacoustic signals of magnetoacoustic imaging to provide raw data for rapid three-dimensional reconstruction; receives the photoacoustic signals of photoacoustic imaging and the magnetoacoustic signals of magnetoacoustic imaging for photo-magnetoacoustic image reconstruction, and intelligent spectral separation and quantitative analysis of multispectral photoacoustic images. Through the present invention, the comprehensive and accurate description of tumor hypoxia characteristics is realized, the heterogeneity of tumor hypoxia in physiology and pathology is analyzed, and an accurate and reliable imaging tool is provided for the basic research of tumor hypoxia.

Description

Technical Field

[0001] The present invention relates to the field of medical imaging technology, and particularly to an imaging device and method for in vivo quantitative research on tumor hypoxia. Background Art

[0002] Existing imaging devices for in vivo quantitative research on tumor hypoxia usually adopt two imaging modalities: photoacoustic and magnetoacoustic. Photoacoustic imaging and magnetoacoustic imaging often use different imaging devices. During actual research, it is necessary to switch devices for imaging work, and it is impossible to obtain quantitative information on the oxygenation level, molecular response, and vascular structure and function of tumor tissues. The description of tumor hypoxia characteristics is not comprehensive and accurate enough, and it is impossible to analyze the physiological and pathological heterogeneity of tumor hypoxia, providing an accurate and reliable imaging tool for basic research on tumor hypoxia. Summary of the Invention

[0003] The present invention provides an imaging device and method for in vivo quantitative research on tumor hypoxia, aiming to organically integrate the two imaging modalities of photoacoustic - magnetoacoustic, realize the acquisition of quantitative information on the oxygenation level, molecular response, and vascular structure and function of tumor tissues, and through the fusion and registration of hypoxia - related structural and functional images, achieve a comprehensive and accurate description of tumor hypoxia characteristics, analyze the physiological and pathological heterogeneity of tumor hypoxia, and provide an accurate and reliable imaging tool for basic research on tumor hypoxia.

[0004] To this end, the first object of the present invention is to propose an imaging device for in vivo quantitative research on tumor hypoxia, including:

[0005] A dual - light - source broadband laser excitation module, which is used to provide a fast photoacoustic excitation light source for multispectral photoacoustic and photoacoustic lifetime imaging, and excite to form a photoacoustic signal for photoacoustic imaging;

[0006] A regional magnetic field constraint and radio - frequency magnetoacoustic excitation module, which is used to construct a magnetic - field - free line and an excitation short - pulse waveform, measure the concentration distribution of magnetic nanoparticles in the tumor to be measured, and realize magnetoacoustic imaging;

[0007] A dual - center - frequency hemispherical acoustic ultrasonic detection module, which is used to collect the photoacoustic signal of photoacoustic imaging and the magnetoacoustic signal of magnetoacoustic imaging, and provide raw data for fast three - dimensional reconstruction;

[0008] An imaging module, which is used to receive the photoacoustic signal of photoacoustic imaging and the magnetoacoustic signal of magnetoacoustic imaging for photo - magnetic - acoustic image reconstruction, and intelligent spectral separation and quantitative analysis of multispectral photoacoustic images.

[0009] Among them, the dual - light - source broadband laser excitation module includes:

[0010] An optical parametric oscillator, a multimode optical fiber, a reflective collimator, and an engineering diffuser; among them,

[0011] The excitation light source generates pulsed light with rapid frequency modulation through an optical parametric oscillator; the pulsed light forms a photoacoustic excitation region with uniform light intensity distribution in the sample imaging region through a multimode optical fiber, a reflective collimator, and an engineering diffuser, thereby realizing uniform excitation of photoacoustic signals in the imaging region, and visualizing tumor hypoxia-related molecules through frequency modulation and timing control of the excitation light.

[0012] Among them, the regional magnetic field constraint and radiofrequency magnetoacoustic excitation module includes:

[0013] a design unit, a data acquisition unit, a power amplification unit, a low-pass filtering unit, and a unilateral magnetoacoustic excitation unit; among them,

[0014] the design unit is used to design the magnetic field free line and the excitation short pulse waveform;

[0015] the data acquisition unit is used to generate the required excitation short pulse waveform;

[0016] the power amplification unit is used to generate alternating current;

[0017] the low-pass filtering unit is used to filter out the interference caused by high-frequency excitation;

[0018] the unilateral magnetoacoustic excitation unit includes two pairs of unilateral coils; one pair of unilateral coils is a unilateral selection coil, which is used to generate a magnetic field free line with controllable magnitude and position, and form a zero magnetic region in the tumor region; the unilateral selection coil generates a magnetic field free line in the direction orthogonal to the coil plane, and the change in the distance between the magnetic field free line and the coil surface is realized by changing the magnitude of the offset current of the excitation coil; the lateral movement of the magnetic field free line in the tumor is realized by changing the current difference between the two selection coils; the other pair of unilateral coils is a unilateral excitation coil, which is used to generate a low-noise alternating magnetic field to excite the magnetic nanoparticles in the tumor region.

[0019] Among them, the unilateral selection coil is composed of 8 layers of coil units connected in parallel, and the unilateral excitation coil is composed of 6 layers of coil units connected in parallel; each coil unit is formed by a rectangular copper wire with a cross-sectional area of 1 mm to form 26 windings; the resistance of the unilateral selection coil is 124 mΩ and the inductance is 396 μH; the resistance of the unilateral excitation coil is 119 mΩ and the inductance is 377 μH; the maximum magnetic field on the surface of the coil unit is 0.62 mT / A.

[0020] Among them, the dual-center frequency hemispherical acoustic ultrasonic detection module includes:

[0021] a piezoelectric ultrasonic detector array with 2n high-density hemispherical arrangements on a hemispherical device, n preamplifiers, a data acquisition card with n parallel channels, and a mechanical fixing unit; among them,

[0022] Photoacoustic and magnetoacoustic signals are excited in the field of view near the center of the sphere. The excited signals are transmitted through ultrapure water or D2O as the medium to the piezoelectric ultrasonic detector array on the inner surface of the hemispherical device, and are detected by the piezoelectric ultrasonic detector array densely arranged on the inner surface of the real-time hemispherical device.

[0023] The ultrasonic detector array is divided into two groups. The central receiving frequency of n piezoelectric ultrasonic detectors in one group is 5 MHz, which is used to receive low-frequency magnetoacoustic signals. The central receiving frequency of n piezoelectric ultrasonic detectors in the other group is 10 MHz, which is used to receive photoacoustic signals. The two groups of piezoelectric ultrasonic detectors are evenly and staggeredly distributed in the hemispherical device to achieve high-density acquisition of photoacoustic and magnetoacoustic signals on the inner surface of the hemisphere. One of the two groups of n electro-ultrasonic detector arrays is respectively connected to one of the n preamplifiers. Each of the n preamplifiers is respectively connected to one of the n parallel-channel data acquisition cards. After selecting the photoacoustic or magnetoacoustic imaging modality, the corresponding n electro-ultrasonic detector signals are amplified one by one by a high-gain pre-signal amplifier for the measured signals, and data acquisition is performed through the corresponding data acquisition card.

[0024] The mechanical fixing unit includes a mechanical support mechanism and a mechanical rotation mechanism. The mechanical support mechanism is used to support the piezoelectric ultrasonic detector array, n preamplifiers, n parallel-channel data acquisition cards, and the hemispherical device. The mechanical rotation mechanism is used to support the hemispherical device and drive the hemispherical device to rotate.

[0025] The second object of the present invention is to propose an imaging method for in vivo quantitative research on tumor hypoxia, including:

[0026] Provide a fast photoacoustic excitation light source for multispectral photoacoustic and photoacoustic lifetime imaging, and excite to form photoacoustic signals for photoacoustic imaging.

[0027] Construct a magnetic field-free line and an excitation short pulse waveform, measure the concentration distribution of magnetic nanoparticles in the tumor to be measured, and realize magnetoacoustic imaging.

[0028] Collect the photoacoustic signals of photoacoustic imaging and the magnetoacoustic signals of magnetoacoustic imaging to provide raw data for fast three-dimensional reconstruction.

[0029] Receive the photoacoustic signals of photoacoustic imaging and the magnetoacoustic signals of magnetoacoustic imaging for photo-magnetoacoustic image reconstruction, and intelligent spectral separation and quantitative analysis of multispectral photoacoustic images.

[0030] Among them, in the step of providing a fast photoacoustic excitation light source for multispectral photoacoustic and photoacoustic lifetime imaging and exciting to form a photoacoustic signal for photoacoustic imaging, a pulsed light with fast frequency modulation is generated by an excitation light source through an optical parametric oscillator; the pulsed light forms a photoacoustic excitation region with uniform light intensity distribution in the sample imaging region through a multimode optical fiber, a reflective collimator and an engineered diffuser, so as to realize uniform excitation of the photoacoustic signal in the imaging region, and visualize tumor hypoxia-related molecules through frequency modulation and timing control of the excitation light.

[0031] Among them, in the step of constructing a magnetic field-free line and an excitation short pulse waveform, measuring the concentration distribution of magnetic nanoparticles in a tumor to be measured, and realizing magnetic acoustic imaging, it includes:

[0032] Designing a magnetic field-free line and an excitation short pulse waveform;

[0033] Generating the required excitation short pulse waveform;

[0034] Generating an alternating current;

[0035] Filtering the interference caused by high-frequency excitation;

[0036] Performing single-sided magnetoacoustic excitation through two pairs of single-sided coils; one pair of single-sided coils is a single-sided selection coil, which is used to generate a magnetic field-free line with controllable magnitude and position, and form a zero magnetic region in the tumor region; the single-sided selection coil generates a magnetic field-free line in the direction orthogonal to the coil plane, and the change in the distance between the magnetic field-free line and the coil surface is realized by changing the magnitude of the offset current of the excitation coil; the lateral movement of the magnetic field-free line in the tumor is realized by changing the current difference between the two selection coils; the other pair of single-sided coils is a single-sided excitation coil, which is used to generate a low-noise alternating magnetic field to excite the magnetic nanoparticles in the tumor region.

[0037] Among them, the single-sided selection coil is composed of 8 layers of coil units connected in parallel, and the single-sided excitation coil is composed of 6 layers of coil units connected in parallel; each coil unit is formed by a rectangular copper wire with a cross-sectional area of 1 mm to form 26 windings; the resistance of the single-sided selection coil is 124 mΩ and the inductance is 396 μH; the resistance of the single-sided excitation coil is 119 mΩ and the inductance is 377 μH; the maximum magnetic field on the surface of the coil unit is 0.62 mT / A.

[0038] Among them, the photoacoustic and magnetoacoustic signals are excited in the field of view near the center of the sphere, and the excitation signals are transmitted to the piezoelectric ultrasonic detector array on the inner surface of the hemispherical device through ultrapure water or D2O as the medium, and are detected by the piezoelectric ultrasonic detector array arranged in a high-density manner on the inner surface of the real-time hemispherical device.

[0039] A data acquisition card with n preamplifiers and n parallel channels is provided; the ultrasonic detector array is divided into two groups. Among them, the central receiving frequency of the n piezoelectric ultrasonic detectors in one group is 5 MHz, which is used to receive low-frequency magnetoacoustic signals, and the central receiving frequency of the n piezoelectric ultrasonic detectors in the other group is 10 MHz, which is used to receive photoacoustic signals; the two groups of piezoelectric ultrasonic detectors are evenly and staggeredly distributed on the hemispherical device to achieve high-density acquisition of photoacoustic and magnetoacoustic signals on the inner surface of the hemisphere; one of the two groups of n electro-ultrasonic detector arrays is respectively connected to one of the n preamplifiers; each of the n preamplifiers is respectively connected to one of the n parallel-channel data acquisition cards; after selecting the photoacoustic or magnetoacoustic imaging modality, the corresponding n electro-ultrasonic detector signals are amplified one by one by a high-gain pre-signal amplifier for the measured signals, and data acquisition is performed through the corresponding data acquisition card.

[0040] Different from the prior art, the imaging device provided by the present invention for in vivo quantitative research on tumor hypoxia provides a fast photoacoustic excitation light source for multispectral photoacoustic and photoacoustic lifetime imaging, and excites and forms photoacoustic signals for photoacoustic imaging; constructs a magnetic field free line and an excitation short pulse waveform to measure the concentration distribution of magnetic nanoparticles in the tumor to be measured, and realizes magnetoacoustic imaging; collects the photoacoustic signals of photoacoustic imaging and the magnetoacoustic signals of magnetoacoustic imaging to provide raw data for fast three-dimensional reconstruction; receives the photoacoustic signals of photoacoustic imaging and the magnetoacoustic signals of magnetoacoustic imaging for photo-magnetoacoustic image reconstruction, and intelligent spectral separation and quantitative analysis of multispectral photoacoustic images. Through the present invention, a comprehensive and accurate description of tumor hypoxia characteristics is carried out, the heterogeneity of tumor hypoxia in physiology and pathology is analyzed, and an accurate and reliable imaging tool is provided for the basic research of tumor hypoxia. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] The above and / or additional aspects and advantages of the present invention will become apparent and be readily understood from the following description of the embodiments in conjunction with the drawings, where:

[0042] Figure 1 is a schematic flow chart of an imaging method for in vivo quantitative research on tumor hypoxia provided by the present invention.

[0043] Figure 2 is a schematic structural diagram of a dual-light-source broadband laser excitation module in an imaging device for in vivo quantitative research on tumor hypoxia provided by the present invention.

[0044] Figure 3 is a schematic structural diagram of a regional magnetic field constraint and radiofrequency magnetoacoustic excitation module in an imaging device for in vivo quantitative research on tumor hypoxia provided by the present invention.

[0045] Figure 4It is a schematic structural diagram of a dual - center - frequency hemispherical acoustic ultrasonic detection module in an imaging device for in - vivo quantitative research on tumor hypoxia provided by the present invention.

[0046] Figure 5 It is a schematic process diagram of a reconstruction algorithm in an imaging method for in - vivo quantitative research on tumor hypoxia provided by the present invention.

[0047] Figure 6 It is a schematic diagram of the interpolation weight assignment of H(r) in an imaging method for in - vivo quantitative research on tumor hypoxia provided by the present invention.

[0048] Figure 7 It is a schematic algorithm flow diagram of a light - magneto - acoustic finite - projection reconstruction imaging method based on deep learning in an imaging method for in - vivo quantitative research on tumor hypoxia provided by the present invention.

[0049] Figure 8 It is a schematic algorithm flow diagram of an intelligent spectral separation and quantitative analysis method based on multi - spectral photoacoustic imaging in an imaging method for in - vivo quantitative research on tumor hypoxia provided by the present invention.

[0050] Figure 9 It is a schematic logical diagram of an algorithm for fusing the vascular structure and perfusion imaging of photo - magneto - acoustic imaging in an imaging method for in - vivo quantitative research on tumor hypoxia provided by the present invention.

[0051] Figure 10 It is a schematic diagram of measuring the perfusion characteristics of a measurement probe in tumor microvessels in an imaging method for in - vivo quantitative research on tumor hypoxia provided by the present invention. Detailed implementation manners

[0052] The following details the embodiments of the present invention. The examples of the embodiments are shown in the drawings, where the same or similar reference numerals represent the same or similar elements or elements with the same or similar functions throughout. The embodiments described below by referring to the drawings are exemplary and are intended to explain the present invention, and should not be construed as limiting the present invention.

[0053] As Figure 1 shown, an imaging method for in - vivo quantitative research on tumor hypoxia provided by an embodiment of the present invention includes:

[0054] S110: Provide a fast photoacoustic excitation light source for multi - spectral photoacoustic and photoacoustic lifetime imaging, and excite to form photoacoustic signals for photoacoustic imaging.

[0055] The technical objective of the present invention is to achieve in-vivo quantitative imaging of tumor hypoxia-related structural and functional information by integrating two modalities of photoacoustics and magnetoacoustics. Among them, photoacoustic lifetime imaging asynchronously excites in-vivo probes with dual light sources, and obtains the oxygen partial pressure distribution inside tumor tissues through the lifetime information of the probes; multispectral photoacoustic imaging obtains high spectral resolution of the photoacoustic signals of in-vivo tumor tissues, and accurately separates the signals of endogenous and exogenous chromophores in the tissues through an intelligent spectral separation algorithm, so as to obtain the oxygenation degree information of tumor tissues and the concentration quantitative information of hypoxia-related molecular probes; the magnetoacoustic imaging system relies on the deep tissue penetration ability of radiofrequency excitation and the ultrasonic signals generated by magnetic nanoparticles under radiofrequency excitation, targets and excites magnetic nanoparticles in the tumor site under the constraint of a spatial magnetic field, combines super-resolution imaging to accurately locate the spatial position of in-vivo magnetic nanoparticles, obtains the vascular network and blood flow information of tumor tissues by tracking the trajectories of magnetic nanoparticles, and fuses with photoacoustic vascular structure imaging to form a deeply complementary tumor vascular network and perfusion imaging. This project quantitatively images and intelligently analyzes the structural and functional information such as the oxygenation state of tumor tissues, hypoxia-related molecular responses, tumor vascular structure and blood perfusion by integrating three imaging technologies of photoacoustic lifetime, multispectral photoacoustics and magnetoacoustics in the same machine, so as to achieve an overall assessment of tumor hypoxia.

[0056] In terms of photo-magnetoacoustic excitation, the present invention focuses on the high-precision control of photoacoustic and magnetoacoustic excitation signals and the integrated acquisition of photo-magnetoacoustic signals. At the hardware level, by adopting a dual-light-source design, it not only meets the requirements of dual-wavelength excitation light for photoacoustic lifetime imaging, but also can improve the switching speed of the excitation light wavelength of multispectral photoacoustic imaging and enhance the imaging speed of multispectral photoacoustics. In terms of photo-magnetoacoustic integration reception, by designing a single-sided rectangular coil, the magnetic field excitation module only occupies the unilateral space of small animals and does not interfere with other modules of the imaging system. At the same time, a dual-center frequency detection array is designed and used according to the different frequency characteristics of photoacoustics and magnetoacoustics to achieve the integration of photo-magnetoacoustic reception devices.

[0057] Specifically, a broadband spectral tunable light source and an optical path design are adopted in the present invention to form photoacoustic excitation. Pulse laser in the wavelength range of 650 - 1100 nm is emitted to excite photoacoustic signals. As Figure 2As shown, the excitation light source generates pulsed light with rapid frequency modulation through an optical parametric oscillator; the pulsed light forms a photoacoustic excitation region with uniform light intensity distribution in the sample imaging region through a multimode optical fiber, a reflective collimator, and an engineered diffuser, thereby achieving uniform excitation of photoacoustic signals in the imaging region; then, visualization of tumor hypoxia-related molecules is achieved through frequency modulation and timing control of the excitation light, including: using pulsed lasers at 694 nm and 1064 nm to visualize deoxyhemoglobin and oxyhemoglobin in the human body respectively; using pulsed lasers at 650 nm and 920 nm to co-excite the phosphorescent probe in the tumor region with precise timing control to measure the photoacoustic lifetime of the phosphorescent probe, thereby achieving detection and visualization of the oxygen partial pressure in the tumor microenvironment; using pulsed lasers at other frequencies to excite various photoacoustic probes (for example, pulsed lasers at 774 nm, 780 nm, and 830 nm to excite IRDye 800CW, ICG, and IC-5-T respectively) to detect and visualize the hypoxia-related molecules they label, providing support for multi-channel simultaneous visualization of tumor hypoxia-related multi-molecular events.

[0058] S120: Construct a magnetic field-free line and an excitation short pulse waveform, measure the concentration distribution of magnetic nanoparticles in the tumor to be measured, and achieve magnetoacoustic imaging.

[0059] As Figure 3 , in this step, a design unit, a data acquisition unit, a power amplification unit, a low-pass filter unit, and a unilateral magnetoacoustic excitation unit are constructed; among them,

[0060] The design unit is used to design a magnetic field-free line and an excitation short pulse waveform;

[0061] The data acquisition unit is used to generate the required excitation short pulse waveform;

[0062] The power amplification unit is used to generate an alternating current;

[0063] The low-pass filter unit is used to filter out the interference caused by high-frequency excitation;

[0064] The unilateral magnetoacoustic excitation unit includes two pairs of unilateral coils; one pair of unilateral coils is a unilateral selection coil, which is used to generate a magnetic field-free line with controllable magnitude and position, forming a zero magnetic region in the tumor region; the unilateral selection coil generates a magnetic field-free line in the direction orthogonal to the coil plane, and the change in the distance between the magnetic field-free line and the coil surface is achieved by changing the magnitude of the offset current of the excitation coil; the lateral movement of the magnetic field-free line in the tumor is achieved by changing the current difference between the two selection coils; the other pair of unilateral coils is a unilateral excitation coil, which is used to generate a low-noise alternating magnetic field to excite the magnetic nanoparticles in the tumor region.

[0065] The design of the single-sided coil is simulated by COMSOL multi-physics software. Through the coil design with low impedance and low inductance, a large current and magnetic field are ensured at the operating frequency. The requirement for the coil hardware design is a maximum current density of 10 A / mm2. The size of each rectangular coil is 30 cm long and 6 cm wide. The spacing between the two selection coils is 11 mm, and the distance from the system surface is 4 mm. The spacing between the single-sided excitation coil and the single-sided selection coil is 5 mm.

[0066] The single-sided selection coil is composed of 8 layers of coil units in parallel, and the single-sided excitation coil is composed of 6 layers of coil units in parallel; each coil unit is formed by a rectangular copper wire with a cross-section of 1 mm to form 26 windings; the resistance of the single-sided selection coil is 124 mΩ and the inductance is 396 μH; the resistance of the single-sided excitation coil is 119 mΩ and the inductance is 377 μH; the maximum magnetic field on the surface of the coil unit is 0.62 mT / A.

[0067] The purpose of the single-sided selection coil is to generate a magnetic field free line with controllable size and position, forming a zero magnetic region in the tumor area. The single-sided excitation coil generates a low-noise alternating magnetic field to excite the magnetic nanoparticles in the tumor area. The single-sided selection coil generates a magnetic field free line in the direction orthogonal to the coil plane. The change in the distance between the magnetic field free line and the coil surface is achieved by changing the magnitude of the offset current of the excitation coil; the lateral movement of the magnetic field free line in the tumor is achieved by changing the current difference between the two selection coils.

[0068] The excitation coil generates a near-field, narrow-band radio frequency excitation magnetic field with an excitation frequency of 2.5 MHz, a short pulse duration of 4 - 12 μs, containing 10 - 30 radio frequency cycles, and a repetition rate of 1 - 50 Hz. The short pulse cosine excitation waveform with a frequency of 2.5 MHz is designed by computer software and input into the power amplifier through the digital-to-analog conversion module. The impedance matching circuit is used to reduce the power loss at the operating frequency. The excitation coil uses a high-voltage capacitor for resonant impedance matching to ensure the operating frequency of 2.5 MHz. The low-pass filter filters out the high-frequency harmonic signals generated during the excitation of the magnetic particles to prevent interference with the excitation coil.

[0069] S130: Collect the photoacoustic signals of photoacoustic imaging and the magnetoacoustic signals of magnetoacoustic imaging to provide the original data for rapid three-dimensional reconstruction.

[0070] As Figure 4 shown, in this step, 2n high-density hemispherical piezoelectric ultrasonic detector arrays, n preamplifiers, n parallel-channel data acquisition cards, and mechanical fixing units are arranged on a hemispherical device; among them,

[0071] Photoacoustic and magnetoacoustic signals are excited in the field of view near the center of the sphere. The excited signals are propagated through ultrapure water or D2O as the medium to the piezoelectric ultrasonic detector array on the inner surface of the hemispherical device, and are detected by the piezoelectric ultrasonic detector array arranged in a high-density manner on the inner surface of the real-time hemispherical device.

[0072] The ultrasonic detector array is divided into two groups. The central receiving frequency of n piezoelectric ultrasonic detectors in one group is 5 MHz, which is used to receive low-frequency magnetoacoustic signals. The central receiving frequency of n piezoelectric ultrasonic detectors in the other group is 10 MHz, which is used to receive photoacoustic signals. The two groups of piezoelectric ultrasonic detectors are evenly and staggeredly distributed on the hemispherical device to achieve high-density acquisition of photoacoustic and magnetoacoustic signals on the inner surface of the hemisphere. One of the two groups of n electro-ultrasonic detector arrays is respectively connected to one of the n preamplifiers. Each of the n preamplifiers is respectively connected to one of the n parallel-channel data acquisition cards. After selecting the photoacoustic or magnetoacoustic imaging mode, the corresponding n electro-ultrasonic detector signals are amplified one-to-one by the high-gain pre-signal amplifier for the measured signals, and data acquisition is performed through the corresponding data acquisition card.

[0073] The mechanical fixing unit includes a mechanical support mechanism and a mechanical rotation mechanism. The mechanical support mechanism is used to support the piezoelectric ultrasonic detector array, n preamplifiers, n parallel-channel data acquisition cards and the hemispherical device. The mechanical rotation mechanism is used to support the hemispherical device and drive the hemispherical device to rotate. Specifically, in this embodiment, n is 512.

[0074] Furthermore, the present invention can achieve high-time-precision synchronous control of the excitation light. The high-time-precision control of the excitation light is used to cooperate with the precise time delay control between the excitation laser and the imaging laser in photoacoustic lifetime imaging. The control sequence is designed through the control platform to control the digital delay generator. The digital delay generator is used to synchronize the internal clocks of the two laser light sources and send trigger signals to the two laser light sources at a given moment as control commands, so as to achieve high-precision synchronous control of the excitation light. The photoacoustic lifetime quantitative detection in the present invention is intended to be realized by short-time excitation of the in-vivo probe by two-band lasers successively. The two laser light sources are respectively adjusted to the excitation wavelength and the imaging wavelength. First, the in-vivo probe in the living tumor area is excited to the triplet state using the excitation wavelength. After the probe enters the triplet state, its electronic energy will decay exponentially. During the energy decay of the probe, the imaging wavelength laser is used to irradiate the probe at a short interval. The imaging wavelength excitation signal is obtained through the photoacoustic signal, and the photoacoustic lifetime curve is obtained through the fitting method. In the multi-spectral photoacoustic imaging mode, the excitation light wavelengths of the two laser sources are synergistically controlled, so as to double the wavelength adjustment time and further improve the photoacoustic signal sampling of high-density excitation wavelengths in the wide spectral range.

[0075] S140: Receive the photoacoustic signals of photoacoustic imaging and the magnetoacoustic signals of magnetoacoustic imaging for photo-magnetoacoustic image reconstruction, as well as intelligent spectral separation and quantitative analysis of multispectral photoacoustic images.

[0076] Based on the integrated photo-magnetoacoustic reception, conduct research on the integrated reconstruction algorithm for photo-magnetoacoustic images; use deep learning technology to enhance the limited projection reconstructed images to further improve the spatial resolution of photo-magnetoacoustic imaging; use the deep spectral separation technology to quantitatively obtain the information of various exogenous and endogenous chromophores from multispectral photoacoustic signals; finally, fuse the advantages of magnetoacoustic-photoacoustic imaging in imaging depth to achieve full-size and high-precision vascular structure and perfusion imaging of in vivo tumors.

[0077] 1. Model-based three-dimensional fast reconstruction algorithm under a hemispherical array

[0078] The model-based photo-magnetoacoustic image reconstruction method is based on the discretized description of the forward acoustic wave propagation problem. According to the physical relationship between the measured sound field signal and the sound source, establish a matrix equation between the measured sound signal and the excitation energy absorption density of the tissue to be solved, and finally solve the initial distribution of the sound field.

[0079] Assume that at the spatial position r, the solution of the sound wave equation can be approximately expressed as:

[0080]

[0081] Among them, Γ is the Grüneisen coefficient, which reflects the acoustic properties of biological tissues; S′(t) is the spherical integral path at time t. Considering that the sound speed vs is constant, r - r′ = vst; H(r) represents the excitation energy absorption conversion function. For photoacoustic signals, H(r) is related to the optical properties of tissues and information such as chromophore concentration. For magnetoacoustic signals, H(r) is jointly determined by the magnetic field strength and magnetization.

[0082] For the photoacoustic and magnetoacoustic signals received by the ultrasonic probe, according to the time difference method, equation (1) can be approximated as:

[0083]

[0084] Among them, I(t) is:

[0085]

[0086] The integral in equation (3) can be realized by discrete summation. Considering the spherical coordinate system centered on r, the spherical discrete surface element can be expressed as:

[0087]

[0088] Then I(r, t) can be obtained from the following formula:

[0089]

[0090] The above formula can be discretized. Considering that the spherical surface S′(r, t) is discretized into unit points uniformly distributed in the longitude angle l ′ and the latitude angle θ directions with a radius of r ′, then:

[0091]

[0092] In the calculation, for simplicity, when estimating the sound pressure of any unit, the fixed value can be ignored

[0093] During reconstruction, a discrete region of interest (ROI) is defined, which consists of a regular grid of points covering this region ( Figure 5 The solid circles in represent). The grid consists of nxy points at intervals of △xxxx in the x and y directions, and nz points at intervals of △zz in the z direction. The points corresponding to the discretized integral in Equation (6) are Figure 5 described as hollow circles in. Each discrete H(r′) on the discretized integral path needs to be interpolated using the values at the reconstruction grid points, and it can be represented as an H interpolation function of eight adjacent points in the grid through trilinear interpolation. H(r′) is distributed to the eight neighboring points with a certain weight ratio (as Figure 6 shown), that is:

[0094]

[0095] where Δx′ a =(x′ - x′ a ) / Δxy, Δy′ a =(y′ - y′ a ) / Δxy, Δz′ a =(z′ - z′ a ) / Δxy, H k =(x′ k , y′ k , z′ k ).

[0096] Combining Equations (2), (6), and (7), a model matrix A can be constructed to establish a linear relationship between the transient photoacoustic signal p(t) received at a detection position r at time t and the light energy absorption density distribution to be reconstructed. Using the column vector P to represent the photoacoustic signal sequence formed by arranging the transient p(t) received at each detection point at each time in sequence; using the column vector H as the vector representation of the excitation light or magnetic field energy absorption density distribution to be solved; then there is the following relationship:

[0097] P = AH (8)

[0098] The inverse process of the model - based three - dimensional image reconstruction method is to solve the above - mentioned linear equation by using certain mathematical means to obtain the energy absorption density (initial acoustic pressure) distribution that can reflect the structural and functional information of biological tissue. The inverse process of Equation (8) is ill - posed mathematically. To improve the stability of the solution, a regularization method is usually adopted, that is, by using some prior information, the solution of a set of well - posed problems adjacent to the original ill - posed problem is used to approximate the solution of the original problem. At the same time, the establishment process of the model matrix A can be accelerated by using a parallel computing strategy.

[0099] In addition, the Tikhonov regularization reconstruction algorithm and the total variation (TV) regularization reconstruction algorithm are widely used. The Tikhonov method adds the L2 - norm term of the solution in the original reconstruction process, thus forming a new optimization problem:

[0100]

[0101] where λ is the regularization parameter, and its selection can use the L - curve method. The solution of the above formula usually adopts the truncated singular value decomposition (TSVD) algorithm. The total variation (TV) - based regularization method takes the total variation value of the image as the regularization term in the inverse calculation process, and regards the image with the minimum total variation value as the solution approximating the true situation of the image reconstruction problem:

[0102]

[0103] 2. Photo - magneto - acoustic limited - projection reconstruction imaging method based on deep learning

[0104] At the hardware level, the present invention realizes the integrated acquisition of in - vivo tumor photo - acoustic and magneto - acoustic signals through a dual - center - frequency hemispherical acoustic detection array. In order to take into account the different frequency characteristics of photo - acoustic and magneto - acoustic signals, the acoustic signal detection array uses acoustic sensors with two different center frequencies. Its advantage is that it can realize the co - machine acquisition of photo - acoustic and magneto - acoustic signals. Its disadvantage is that when performing photo - acoustic and magneto - acoustic signal imaging, the detection distances of two acoustic sensors with the same center frequency are relatively large, reducing the spatial sampling of the imaging field of view. Therefore, in order to further improve the spatial resolution of the system imaging, the present invention intends to achieve sparse reconstruction under limited - angle projection data through a deep - learning algorithm. The specific algorithm flow is as Figure 7 shown.

[0105] With the turntable system of the system hardware, in the photoacoustic and magnetoacoustic working modes, by rotating the acquisition array, high-spatial high-density sampling of the imaging area is achieved. In order to obtain spatial sampling with the highest possible resolution for constructing training data, considering that the diameter of each detector in the present invention does not exceed 5 mm, the sampling array is rotated by a high-precision turntable to improve the spatial sampling accuracy of the ultrasonic signals in the imaging area.

[0106] In order to form the training data of the deep learning network, we use the image obtained by reconstruction through 512-channel data as the network input. The supervision signal of the network is the residual image between the spatially upsampled reconstructed image and the 512-channel reconstructed image. Fully considering the target information of different sizes in the imaging space, by fusing the layer-by-layer spatial attention module and the U-Net structure, the modeling of the residual image is realized. When used in normal imaging, the signals reconstructed from 512 channels at a fixed angle are input into the network to obtain the residual image. By fusing the input image and the residual image, the reconstructed image in the high-spatial sampling state is obtained, further improving the spatial resolution of the imaging.

[0107] 3. Intelligent spectral separation and quantitative analysis method based on multispectral photoacoustic imaging

[0108] The photoacoustic signals of exogenous chromophores composed of molecular probes and tissue endogenous chromophores obtained by multispectral photoacoustic imaging in the excitation wavelength range covering 650 nm to 1100 nm are the basis for obtaining vascular structure and tumor hypoxia-related molecular response information based on photoacoustic imaging. However, the absorption spectra of endogenous and exogenous chromophores are not only distributed at their peak positions. Each chromophore absorbs energy and releases acoustic signals in a relatively wide spectral space. The spectral aliasing between different chromophores directly causes the decline of the quantitative ability of the imaging system when multiple chromophores are present in vivo, and this decline becomes more serious as the number of chromophores increases. Therefore, separating the multispectral photoacoustic signals is the core technology for realizing vascular imaging, oxygen saturation quantification, and multimolecular photoacoustic quantitative imaging. Based on this goal, this project plans to adopt a spectral separation technology based on deep learning to achieve the precise separation of multispectral photoacoustic signals and estimate the intensity information of the corresponding chromophores.

[0109] With the help of the acoustic detection array, for the three-dimensional multispectral photoacoustic image obtained through the reconstruction algorithm, the initial sound pressure intensity at each voxel position in the image can be described by the following formula:

[0110] p0(r, λ) = Γ(r)Φ(r, λ)μ a (r, λ) (11)

[0111] In the above formula, \(p_0(r, \lambda)\) is the acoustic pressure information at spatial position \(r\) under the excitation wavelength \(\lambda\), and this value is related to the Gruneisen coefficient \(\Gamma(r)\), the optical flux \(\varPhi(r, \lambda)\) and the tissue absorption coefficient \(\mu_a\). At the same time, assuming that the main chromophores in the imaging group are oxyhemoglobin, deoxyhemoglobin, and other photoacoustic probes for labeling in-vivo molecules, the absorption coefficient of the tissue can be written as the following formula:

[0112]

[0113] In the above formula, \(c\) i (r, \lambda) is the concentration of the \(i\)-th chromophore, and \(\xi\) i (\lambda) is the standard spectrum of the \(i\)-th chromophore at the excitation wavelength \(\lambda\).

[0114] The purpose of in-vivo quantitative photoacoustic imaging is to restore the optical absorption parameters of chromophores at spatial position \(r\) through the acoustic pressure information \(p_0\) obtained by the acoustic detection array at different excitation wavelengths, so as to further obtain the concentration information of chromophores. The core difficulty in solving this problem is that the optical flux \(\varPhi(r, \lambda)\) of the tissue under laser excitation also has a strong coupling relationship with the tissue optical parameters, making the estimation of the optical parameters and concentrations of different chromophores a highly nonlinear and highly coupled optimization problem. In the present invention, drawing on the core idea of the feature multispectral imaging algorithm, the feature multispectral imaging is extended from the estimation method of the concentrations of two chromophores to the photoacoustic quantitative problem of complex exogenous and endogenous chromophores in-vivo simultaneously. Specifically, we assume that the complex optical flux information in the tissue can be obtained by the superposition of a finite number of characteristic spectra, that is:

[0115]

[0116] where \(\varPhi\) AVG (·) is the mean optical flux, \(\varPhi\) i (·) is the \(i\)-th characteristic spectrum, and \(\theta\) i is the coefficient matching the \(i\)-th characteristic spectrum. Thus, the initial acoustic pressure signal of the tissue can be decomposed into:

[0117]

[0118] where the concentrations of \(m\) chromophores and the coefficients of \(k\) characteristic spectra are unknowns. In order to solve the \((m + k)\) unknowns, the multi-spectral photoacoustic system designed in the present invention needs to satisfy the use of at least \((m + k)\) wavelengths of excitation lasers, and this requirement can be determined by determining the number of in-vivo probes and the number of endogenous chromophores of interest.

[0119] In order to obtain accurate quantitative information of different in-vivo chromophores, the present invention intends to adopt an estimation method based on a deep learning algorithm to realize the reconstruction of the concentration information of different chromophores. The algorithm block diagram is as Figure 8 shown.

[0120] Specifically, photoacoustic simulation data is generated using tissue optical parameters determined through in vitro experiments and standard spectra of various probes to be measured and endogenous chromophores for training a deep model. The acoustic pressure signals at each pixel point at different excitation light wavelengths are acquired, and the characteristic spectral coefficients are solved, so that only the chromophore concentration remains as an unknown parameter in the solved spectrum. In the case where the characteristic spectral values are determined, proportional quantification is used to achieve proportional quantification imaging of oxygen saturation and the ratio of exogenous probes to total hemoglobin concentration or oxyhemoglobin concentration.

[0121] 4. Vascular Structure and Perfusion Imaging Algorithm for Integrated Photo-Magnetoacoustic Imaging

[0122] In the present invention, magnetoacoustic signals are collected through a 512-channel acoustic detection array, jitter correction is performed on the magnetoacoustic signals from the surface of the ultrasonic transducer element, and a pressure distribution map of the tumor region is reconstructed through a back-projection algorithm. The reconstructed bipolar image is converted into a monopolar image through a Frangi vascular feature filter based on the Hessian. The present invention will collect dynamic temporal microvascular images inside the tumor at a collection rate of 20 Hz. The collection starts from injecting magnetic nanoparticles into the tail vein of small animals and lasts for 10 minutes, obtaining 12,000 sets of microvascular images of the tumor region. The present invention will accurately locate a single probe in each frame of the image, such as Figure 9 as shown.

[0123] Reference Figure 9 is made, and a two-dimensional adaptive denoising filter is used for the denoising method in the dynamic image. Adjacent frame images are subtracted to highlight the flowing single probe. To accurately locate a single probe, 1 / 4 of the maximum pixel value of the entire image is used as the threshold, and the differential grayscale image is converted into a binary image. Bright spots within the range of 16 to 64 pixels in the binary image are considered regions containing probes. Any bright spots with a roundness less than 0.7 (such as probe clusters and artifacts) are removed. The centroid of each bright spot in the binary image is calculated to roughly locate a single probe in the grayscale image. Furthermore, a region of interest centered on its centroid with a size of 11×11 pixels is separated from the grayscale image. A two-dimensional Gaussian function is used for fitting to achieve more accurate probe positioning. Each probe is represented by a two-dimensional Gaussian distribution point located at its center, and its radius is equal to the uncertainty of its positioning. By combining all the probe images, a microvascular contour image with a spatial resolution exceeding the acoustic diffraction limit is obtained.

[0124] The present invention will measure the perfusion characteristics of the probe in the tumor microvasculature. Such as Figure 10As shown, the sequential microvascular contour images are combined into spatio-temporal domain images, and two-dimensional Fourier transform is performed on these images. Blood vessels with the same slope are mapped to a line through the origin of the spatio-temporal frequency domain, and the flow direction of the probe is estimated according to the blood vessel direction, so as to extract the probe flow velocity along the blood vessel direction. Combining with the microvascular density, the blood flow, blood volume and mean transit time inside the tumor are obtained, and a perfusion pseudo-color image of the tumor region is generated to study the relationship between the blood perfusion and the hypoxic microenvironment in the tumor region.

[0125] The present invention will describe the heterogeneity of the tumor hypoxic environment according to the perfusion information of each pixel in the tumor region. The whole tumor tissue is divided into a vascular-rich region (high blood flow and high blood volume), a tumor cell growth region (low blood flow and high blood volume), and a necrotic region (low blood flow and low blood volume) by k-means clustering, and the relative proportion of each region in the whole tumor is determined to study the mechanism of action of perfusion in hypoxia. During tumor treatment, the dynamic changes in the proportion of each region are monitored as biomarkers to predict the therapeutic effect against the hypoxic microenvironment and evaluate the accuracy, sensitivity and specificity of efficacy prediction.

[0126] In addition, the present invention provides an imaging device for in vivo quantitative research on tumor hypoxia, including:

[0127] A dual-light-source broadband laser excitation module, which is used to provide a fast photoacoustic excitation light source for multispectral photoacoustic and photoacoustic lifetime imaging and excite a photoacoustic signal for photoacoustic imaging;

[0128] A regional magnetic field constraint and radiofrequency magnetoacoustic excitation module, which is used to construct a magnetic field free line and an excitation short pulse waveform, measure the concentration distribution of magnetic nanoparticles in the tumor to be measured, and realize magnetoacoustic imaging;

[0129] A dual-center-frequency hemispherical acoustic ultrasound detection module, which is used to collect the photoacoustic signal of photoacoustic imaging and the magnetoacoustic signal of magnetoacoustic imaging and provide raw data for fast three-dimensional reconstruction;

[0130] An imaging module, which is used to receive the photoacoustic signal of photoacoustic imaging and the magnetoacoustic signal of magnetoacoustic imaging for photo-magnetoacoustic image reconstruction, and intelligent spectral separation and quantitative analysis of multispectral photoacoustic images.

[0131] Among them, the dual-light-source broadband laser excitation module includes:

[0132] An optical parametric oscillator, a multimode optical fiber, a reflective collimator and an engineered diffuser; among them,

[0133] The excitation light source generates pulsed light with fast frequency modulation through an optical parametric oscillator; the pulsed light forms a photoacoustic excitation region with uniform light intensity distribution in the sample imaging area through a multimode optical fiber, a reflective collimator, and an engineering diffuser, thereby achieving uniform excitation of photoacoustic signals in the imaging area, and realizing visualization of tumor hypoxia-related molecules through frequency modulation and timing control of the excitation light.

[0134] Among them, the regional magnetic field constraint and radiofrequency magnetoacoustic excitation module includes:

[0135] a design unit, a data acquisition unit, a power amplification unit, a low-pass filtering unit, and a unilateral magnetoacoustic excitation unit; among them,

[0136] The design unit is used to design the magnetic field free line and the excitation short pulse waveform;

[0137] The data acquisition unit is used to generate the required excitation short pulse waveform;

[0138] The power amplification unit is used to generate alternating current;

[0139] The low-pass filtering unit is used to filter out the interference caused by high-frequency excitation;

[0140] The unilateral magnetoacoustic excitation unit includes two pairs of unilateral coils; one pair of unilateral coils is a unilateral selection coil, which is used to generate a magnetic field free line with controllable magnitude and position, and form a zero magnetic region in the tumor area; the unilateral selection coil generates a magnetic field free line in the direction orthogonal to the coil plane, and the change in the distance between the magnetic field free line and the coil surface is realized by changing the magnitude of the offset current of the excitation coil; the lateral movement of the magnetic field free line in the tumor is realized by changing the current difference between the two selection coils; the other pair of unilateral coils is a unilateral excitation coil, which is used to generate a low-noise alternating magnetic field to excite the magnetic nanoparticles in the tumor area.

[0141] Among them, the unilateral selection coil is composed of 8 layers of coil units connected in parallel, and the unilateral excitation coil is composed of 6 layers of coil units connected in parallel; each coil unit is formed by a rectangular copper wire with a cross-sectional area of 1 mm to form 26 windings; the resistance of the unilateral selection coil is 124 mΩ and the inductance is 396 μH; the resistance of the unilateral excitation coil is 119 mΩ and the inductance is 377 μH; the maximum magnetic field on the surface of the coil unit is 0.62 mT / A.

[0142] Among them, the dual-center frequency hemispherical acoustic ultrasonic detection module includes:

[0143] a piezoelectric ultrasonic detector array with 2n high-density hemispherical arrangements on a hemispherical device, n preamplifiers, a data acquisition card with n parallel channels, and a mechanical fixing unit; among them,

[0144] Photoacoustic and magnetoacoustic signals are excited in the field of view near the center of the sphere. The excited signals are transmitted as a medium of ultrapure water or D2O to the piezoelectric ultrasonic detector array on the inner surface of the hemispherical device and detected by the piezoelectric ultrasonic detector array densely arranged on the inner surface of the real-time hemispherical device.

[0145] The ultrasonic detector array is divided into two groups. The central receiving frequency of n piezoelectric ultrasonic detectors in one group is 5 MHz, which is used to receive low-frequency magnetoacoustic signals. The central receiving frequency of n piezoelectric ultrasonic detectors in the other group is 10 MHz, which is used to receive photoacoustic signals. The two groups of piezoelectric ultrasonic detectors are evenly and staggeredly distributed in the hemispherical device to achieve high-density acquisition of photoacoustic and magnetoacoustic signals on the inner surface of the hemisphere. One of the two groups of n electro-ultrasonic detector arrays is respectively connected to one of the n preamplifiers. Each of the n preamplifiers is respectively connected to one of the n parallel-channel data acquisition cards. After selecting the photoacoustic or magnetoacoustic imaging modality, the corresponding n electro-ultrasonic detector signals are amplified one by one by the high-gain pre-signal amplifier for the measured signals and data is collected by the corresponding data acquisition card.

[0146] The mechanical fixing unit includes a mechanical support mechanism and a mechanical rotation mechanism. The mechanical support mechanism is used to support the piezoelectric ultrasonic detector array, n preamplifiers, n parallel-channel data acquisition cards, and the hemispherical device. The mechanical rotation mechanism is used to support the hemispherical device and drive the hemispherical device to rotate.

[0147] In the description of this specification, the description with reference to terms such as "one embodiment", "some embodiments", "example", "specific example", or "some examples" means that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic expression of the terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described can be combined in a suitable manner in any one or more embodiments or examples. In addition, without contradiction, those skilled in the art can combine and combine the different embodiments or examples described in this specification and the features of different embodiments or examples.

[0148] In addition, the terms "first" and "second" are only used for descriptive purposes and cannot be understood as indicating or implying relative importance or implicitly indicating the quantity of the indicated technical features. Thus, the features defined with "first" and "second" can explicitly or implicitly include at least one of the features. In the description of the present invention, "a plurality" means at least two, such as two, three, etc., unless otherwise clearly and specifically defined.

[0149] Any process or method description represented in a flowchart or otherwise described herein can be understood to represent a module, segment, or portion of code including one or more executable instructions for implementing a customized logical function or process, and the scope of the preferred embodiments of the present invention includes additional implementations, where functions may be executed in a substantially simultaneous manner or in a reverse order according to the functions involved, rather than in the order shown or discussed, which should be understood by those skilled in the art to which the embodiments of the present invention pertain.

[0150] The logic and / or steps represented in a flowchart or otherwise described herein, for example, can be considered as a sequenced list of executable instructions for implementing a logical function, and can be specifically implemented in any computer-readable medium for use by an instruction execution system, apparatus, or device (such as a computer-based system, a system including a processor, or other systems that can fetch and execute instructions from the instruction execution system, apparatus, or device), or in conjunction with these instruction execution systems, apparatuses, or devices. For the purposes of this specification, a "computer-readable medium" can be any device that can contain, store, communicate, propagate, or transport a program for use by or in conjunction with an instruction execution system, apparatus, or device. More specific examples (a non-exhaustive list) of computer-readable media include the following: an electrical connection portion with one or more wirings (electronic device), a portable computer diskette (magnetic device), a random access memory (RAM), a read-only memory (ROM), an erasable programmable read-only memory (EPROM or flash memory), an optical fiber device, and a portable compact disc read-only memory (CDROM). Additionally, the computer-readable medium can even be paper or other suitable media on which the program can be printed, because the program can be obtained electronically, for example, by optically scanning the paper or other media, followed by editing, interpretation, or otherwise processing as appropriate, and then storing it in a computer memory.

[0151] It should be understood that various parts of the present invention can be implemented by hardware, software, firmware, or a combination thereof. In the described embodiments, multiple steps or methods can be implemented by software or firmware stored in a memory and executed by a suitable instruction execution system. For example, if implemented in hardware, as in another embodiment, any one or a combination of the following techniques well known in the art can be used: discrete logic circuits having logic gate circuits for implementing logical functions on data signals, application specific integrated circuits having appropriate combinational logic gate circuits, programmable gate arrays (PGAs), field programmable gate arrays (FPGAs), etc.

[0152] Those of ordinary skill in the art can understand that all or part of the steps carried out in implementing the method of the embodiment can be completed by instructing relevant hardware through a program. The program can be stored in a computer-readable storage medium. When the program is executed, it includes one or a combination of the steps of the method embodiment.

[0153] In addition, each functional unit in various embodiments of the present invention can be integrated into a processing module, or each unit can exist physically alone, or two or more units can be integrated into one module. The integrated module can be implemented in the form of hardware or in the form of a software functional module. When the integrated module is implemented in the form of a software functional module and sold or used as an independent product, it can also be stored in a computer-readable storage medium.

[0154] The storage medium mentioned above can be a read-only memory, a magnetic disk, an optical disc, etc. Although the embodiments of the present invention have been shown and described above, it can be understood that the embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions, and variations to the embodiments within the scope of the present invention.

Claims

1. An imaging device for in vivo quantitative research on tumor hypoxia, characterized in that, Comprising: A dual-light-source broadband laser excitation module, which is used to provide a fast photoacoustic excitation light source for multispectral photoacoustic and photoacoustic lifetime imaging, and excite a photoacoustic signal for photoacoustic imaging; A regional magnetic field constraint and radiofrequency magnetoacoustic excitation module, which is used to construct a magnetic field free line and an excitation short pulse waveform, measure the concentration distribution of magnetic nanoparticles in the tumor to be measured, and realize magnetoacoustic imaging; wherein, The regional magnetic field constraint and radiofrequency magnetoacoustic excitation module includes: A design unit, a data acquisition unit, a power amplification unit, a low-pass filtering unit and a unilateral magnetoacoustic excitation unit; wherein, The design unit is used to design the magnetic field free line and the excitation short pulse waveform; The data acquisition unit is used to generate the required excitation short pulse waveform; The power amplification unit is used to generate an alternating current; The low-pass filtering unit is used to filter out the interference caused by high-frequency excitation; The unilateral magnetoacoustic excitation unit includes two pairs of unilateral coils: one pair of unilateral coils is a unilateral selection coil, which is used to generate a magnetic field free line with controllable size and position, and form a zero magnetic field area in the tumor area; the unilateral selection coil generates a magnetic field free line in the direction orthogonal to the coil plane, and the change in the distance between the magnetic field free line and the coil surface is realized by changing the offset current of the excitation coil to generate a magnetic field free line with controllable size and position, and form a zero magnetic field area in the tumor area: the unilateral selection coil generates a magnetic field free line in the direction orthogonal to the coil plane, and the change in the distance between the magnetic field free line and the coil surface is realized by changing the magnitude of the offset current of the excitation coil: the lateral movement of the magnetic field free line in the tumor is realized by changing the current difference between the two selection coils; the other pair of unilateral coils is a unilateral excitation coil, which is used to generate a low-noise alternating magnetic field to excite the magnetic nanoparticles in the tumor area; A dual-center-frequency hemispherical acoustic ultrasonic detection module, which is used to collect the photoacoustic signal of photoacoustic imaging and the magnetoacoustic signal of magnetoacoustic imaging, and provide raw data for fast three-dimensional reconstruction; wherein, The dual-center-frequency hemispherical acoustic ultrasonic detection module includes: A piezoelectric ultrasonic detector array with 2n high-density hemispherical arrangements on a hemispherical device, n preamplifiers, a data acquisition card with n parallel channels and a mechanical fixing unit; wherein, The photoacoustic and magnetoacoustic signals are excited in the field of view near the center of the sphere, and the excitation signals are propagated to the piezoelectric ultrasonic detector array on the inner surface of the hemispherical device with ultrapure water or D20 as the medium, and are detected by the piezoelectric ultrasonic detector array with high-density arrangement on the inner surface of the real-time hemispherical device; The ultrasonic detector array is divided into two groups. Among them, the central receiving frequencies of the n piezoelectric ultrasonic detectors in one group are 5 MHz and are used to receive low-frequency magnetoacoustic signals, and the central receiving frequencies of the n piezoelectric ultrasonic detectors in the other group are 10 MHz and are used to receive photoacoustic signals. The two groups of piezoelectric ultrasonic detectors are evenly and staggeredly distributed on the hemispherical device to achieve high-density acquisition of photoacoustic and magnetoacoustic signals on the inner surface of the hemisphere. One of the two groups of n electro-ultrasonic detector arrays is respectively connected to one of the n preamplifiers. Each of the n preamplifiers is respectively connected to one of the n parallel-channel data acquisition cards. After selecting the photoacoustic or magnetoacoustic imaging modality, the corresponding n electro-ultrasonic detector signals are amplified one by one by a high-gain pre-signal amplifier for the measured signals, and data acquisition is performed by the corresponding data acquisition card. The mechanical fixing unit includes a mechanical support mechanism and a mechanical rotation mechanism. The mechanical support mechanism is used to support the piezoelectric ultrasonic detector array, the n preamplifiers, the n parallel-channel data acquisition cards, and the hemispherical device. The mechanical rotation mechanism is used to support the hemispherical device and drive the hemispherical device to rotate. An imaging module, which is used to receive the photoacoustic signals of photoacoustic imaging and the magnetoacoustic signals of magnetoacoustic imaging for photoacoustic and magnetoacoustic image reconstruction, and intelligent spectral separation and quantitative analysis of multispectral photoacoustic images.

2. The imaging device for in-vivo quantitative research on tumor hypoxia according to claim 1, wherein The dual-light-source broadband laser excitation module includes: An optical parametric oscillator, a multimode optical fiber, a reflective collimator, and an engineered diffuser. Among them, The excitation light source generates pulsed light with fast frequency modulation through the optical parametric oscillator. The pulsed light forms a photoacoustic excitation region with uniform light intensity distribution in the sample imaging region through the multimode optical fiber, the reflective collimator, and the engineered diffuser, so as to achieve uniform excitation of photoacoustic signals in the imaging region. Visualization of tumor hypoxia-related molecules is achieved through frequency modulation and timing control of the excitation light.

3. The imaging device for in vivo quantitative research on tumor hypoxia according to claim 1, wherein, The single-sided selection coil is composed of 8 layers of coil units connected in parallel, and the single-sided excitation coil is composed of 6 layers of coil units connected in parallel. Each coil unit is formed by a rectangular copper wire with a cross-sectional area of 1 mm to form 26 windings. The resistance of the single-sided selection coil is 124 mΩ and the inductance is 396 μH. The resistance of the single-sided excitation coil is 119 mΩ and the inductance is 377 μH. The maximum magnetic field on the surface of the coil unit is 0.62 mT / A.

4. An imaging method for in vivo quantitative research on tumor hypoxia, characterized in that, It includes: Provide a fast photoacoustic excitation light source for multispectral photoacoustic and photoacoustic lifetime imaging, and excite to form photoacoustic signals for photoacoustic imaging. Construct a magnetic field-free line and an excitation short pulse waveform, measure the concentration distribution of magnetic nanoparticles in the tumor to be measured, and achieve magnetoacoustic imaging. It includes: Construct a design unit for designing the magnetic field-free line and the excitation short pulse waveform; Construct a data acquisition unit for generating the required excitation short pulse waveform; Construct a power amplification unit for generating an alternating current; Construct a low-pass filtering unit for filtering out interference caused by high-frequency excitation; Construct a unilateral magnetoacoustic excitation unit, including two pairs of unilateral coils: One pair of unilateral coils is a unilateral selection coil, which is used to generate a magnetic field free line with controllable magnitude and position, and form a zero magnetic field area in the tumor area; The unilateral selection coil generates a magnetic field free line in the direction orthogonal to the coil plane. The change in the distance between the magnetic field free line and the coil surface is achieved by changing the offset current magnitude of the excitation coil to generate a magnetic field free line with controllable magnitude and position, and form a zero magnetic field area in the tumor area: The unilateral selection coil generates a magnetic field free line in the direction orthogonal to the coil plane. The change in the distance between the magnetic field free line and the coil surface is achieved by changing the offset current magnitude of the excitation coil; The lateral movement of the magnetic field free line in the tumor is achieved by changing the current difference between the two selection coils; The other pair of unilateral coils is a unilateral excitation coil, which is used to generate a low-noise alternating magnetic field to excite the magnetic nanoparticles in the tumor area. Collect the photoacoustic signals of photoacoustic imaging and the magnetoacoustic signals of magnetoacoustic imaging to provide raw data for fast three-dimensional reconstruction; including: Design a piezoelectric ultrasonic detector array with 2n high-density hemispherical arrangements on a hemispherical device, n preamplifiers, a data acquisition card with n parallel channels, and a mechanical fixing unit; where, The photoacoustic and magnetoacoustic signals are excited in the field of view near the center of the sphere. The excitation signals are transmitted as a medium of ultrapure water or D20 to the piezoelectric ultrasonic detector array on the inner surface of the hemispherical device and detected by the piezoelectric ultrasonic detector array with high-density arrangement on the inner surface of the real-time hemispherical device. The ultrasonic detector array is divided into two groups. The central receiving frequency of the n piezoelectric ultrasonic detectors in one group is 5 MHz and is used to receive low-frequency magnetoacoustic signals. The central receiving frequency of the n piezoelectric ultrasonic detectors in the other group is 10 MHz and is used to receive photoacoustic signals: The two groups of piezoelectric ultrasonic detectors are evenly and staggeredly distributed on the hemispherical device to achieve high-density acquisition of photoacoustic and magnetoacoustic signals on the inner surface of the hemisphere; One of the two groups of n electro-ultrasonic detector arrays is respectively connected to one of the n preamplifiers: Each of the n preamplifiers is respectively connected to one of the n parallel-channel data acquisition cards; After selecting the photoacoustic or magnetoacoustic imaging modality, the corresponding n electro-ultrasonic detector signals are amplified one-to-one by a high-gain pre-signal amplifier for the measured signals, and data acquisition is performed through the corresponding data acquisition card. The mechanical fixing unit includes a mechanical support mechanism and a mechanical rotation mechanism; The mechanical support mechanism is used to support the piezoelectric ultrasonic detector array, n preamplifiers, the data acquisition card with n parallel channels, and the hemispherical device; The mechanical rotation mechanism is used to support the hemispherical device and drive the hemispherical device to rotate. Receive the photoacoustic signals of the photoacoustic imaging and the magnetoacoustic signals of the magnetoacoustic imaging for photoacoustic and magnetic acoustic image reconstruction, and intelligent spectral separation and quantitative analysis of multi-spectral photoacoustic images.

5. The imaging method for in vivo quantitative research on tumor hypoxia according to claim 4, characterized in that, In the step of providing a fast photoacoustic excitation light source for multispectral photoacoustic and photoacoustic lifetime imaging and exciting to form a photoacoustic signal for photoacoustic imaging, a pulsed light that can be rapidly frequency modulated is generated by an optical parametric oscillator through an excitation light source; the pulsed light forms a photoacoustic excitation region with uniform light intensity distribution in the sample imaging region through a multimode optical fiber, a reflective collimator, and an engineered diffuser, so as to realize the uniform excitation of the photoacoustic signal in the imaging region, and the visualization of tumor hypoxia-related molecules is realized through the frequency modulation and timing control of the excitation light.

6. The imaging method for in vivo quantitative research on tumor hypoxia according to claim 4, wherein The unilateral selection coil is composed of 8 layers of coil units connected in parallel, and the unilateral excitation coil is composed of 6 layers of coil units connected in parallel; each coil unit is formed by a rectangular copper wire with a cross-section of 1 mm to form 26 windings; the resistance of the unilateral selection coil is 124 mΩ and the inductance is 396 μH; the resistance of the unilateral excitation coil is 119 mΩ and the inductance is 377 μH; the maximum magnetic field on the surface of the coil unit is 0.62 mT / A.

Images