CN110243454B - Micro-bubble synergy dynamics experiment system and method based on dual-frequency superposed ultrasonic pulses in viscoelastic medium - Google Patents
Micro-bubble synergy dynamics experiment system and method based on dual-frequency superposed ultrasonic pulses in viscoelastic medium Download PDFInfo
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Abstract
The invention discloses a micro-bubble synergy dynamics experiment system and method based on dual-frequency superposition in viscoelastic medium, wherein the experiment method comprises the following steps: 1) setting KZK equation parameters to construct a microbubble nonlinear excitation waveform according to the actual waveform of the focal zone sound field measured by the hydrophone; 2) constructing an HIFU synergistic model according to the viscoelasticity of biological tissues and the vibration characteristics of micro-bubbles in a compressible fluid; 3) establishing a microbubble synergy dynamics method based on double-frequency superposition; 4) and determining the phase, sound pressure and frequency parameters of the HIFU waveform by combining the simulation results of the steps to perform a thermal ablation or tissue damage experiment. The invention fully utilizes the dynamic characteristics of the micro-bubbles in the biological tissue, designs the acoustic waveform and the phase parameter, causes the maximum vibration of the micro-bubbles in the focal region, enhances the cavitation effect, and improves the safety and the efficiency of HIFU thermal ablation and tissue damage.
Description
Technical Field
The invention belongs to the technical field of ultrasound, and particularly relates to a system and a method for a micro-bubble synergy dynamics experiment in viscoelastic media.
Background
High Intensity Focused Ultrasound (HIFU) has become a hot spot in the field of therapeutic Ultrasound due to its non-invasive, strongly Focused nature. At present, the action mechanism of the high-intensity focused ultrasound is of two types: thermal ablation mechanisms and tissue destruction mechanisms. The traditional HIFU thermal ablation mode mainly utilizes the thermal effect of ultrasound, and locally ablates tissues by high-intensity ultrasonic energy focused to a target area from the outside of a body, so that the tissues of the target area generate coagulative necrosis due to instant high temperature; the tissue destruction (Histotripsy) mode mainly utilizes the cavitation mechanical effect of HIFU to break up target tissue into micron-sized fragments.
The cavitation effect refers to the dynamic process of oscillation, stretching, contraction and rupture of micro bubbles in liquid under the action of positive and negative alternating ultrasonic waves, and is considered as a most potential mechanism for improving the HIFU effect, so that the cavitation effect is widely researched. In vitro and in vivo experiments of Kawabata and other scholars, the fact that the directional diffusion in a single period is enhanced by superimposing second harmonic on fundamental frequency is found, and the cavitation effect is obviously enhanced. International patent WO2,015,138,781A 1, inventor Kuang-Wei Lin, entitled "Frequency compounded ultrasonic pulses for imaging and therapy" proposes a method for tissue destruction by simultaneously applying low-Frequency (100 kHz-1 MHz) sound waves and high-Frequency (2-10 MHz) sound waves (non-harmonic waves) to target tissues and controlling pulse time delay of the two frequencies to form unipolar pulses. Iernetti in "enhancement of high-frequency cavitation effects by a low frequency simulation" ultrasound diagnostics, vol.4, pp.263-268,1997, investigated the use of high frequency 700kHz and low frequency 20kHz ultrasound to enhance cavitation: the low frequency ultrasound is used to amplify the cavitation of the high frequency ultrasound at different cavitation stages in the target tissue region. The method of superposing KHz as a low frequency on a high frequency sound wave has the defects that the focal region has larger volume, the target tissue cannot be accurately damaged, the amplitude of the focal region sound wave is lower, and the target tissue cannot be efficiently damaged.
The microbubble dynamics model is an RPNNP model in the classical incompressible fluid, but the model cannot adapt to the compressible fluid, and the cavitation effect occurs in the compressible fluid such as biological tissue. The latest Zener model can better simulate the mechanical properties of compressible fluids such as biological tissues, is more suitable for the actual conditions of the tissues, and has deeper application in the research of micro-bubble dynamic models. Whether it is thermal ablation or tissue destruction, the energy released during the oscillation and collapse of the microbubbles plays a role therein, and thus exploring the dynamics of microbubbles in tissue helps to perfect a thermal ablation and tissue destruction control method to improve treatment efficiency.
The existing methods of thermal ablation and tissue destruction still suffer from the following drawbacks: biological tissues are a kind of compressible fluid with viscoelasticity, the development of an HIFU process is guided by a micro-bubble model in RPNNP incompressible fluid, the theoretical deficiency exists, at present, no viscoelasticity model in the compressible fluid is used for simulating and guiding the HIFU process, and the nonlinear effect is not considered in the previous excitation waveform, so that the thermal ablation and tissue damage parameter setting is inaccurate, the cavitation activity of a focal region in a single-frequency mode is not severe enough, the cavitation threshold is too high, the required peak sound pressure is too high, and the single focus volume is only a few mm3。
Disclosure of Invention
The invention aims to provide a micro-bubble synergy dynamics experiment system and method based on dual-frequency superposition ultrasonic pulses in viscoelastic media, so as to solve the technical problem. The method comprises the steps of firstly determining KZK equation parameter setting to construct micro-bubble vibration excitation nonlinear waveform according to actual sound field nonlinear waveform of a focal region measured by an optical fiber hydrophone, ensuring that sound waves of each frequency can generate nonlinear distortion, then solving a Zener model and a Keller-Miksis equation to construct a micro-bubble synergy model according to viscoelasticity of biological tissues and vibration characteristics of micro-bubbles in compressible fluid, then constructing a micro-bubble synergy dynamic method based on double-frequency superposition of ultrasonic pulses in viscoelastic media, performing simulation calculation to select proper tissue viscoelasticity parameters and HIFU waveform, frequency, sound pressure and phase parameters, and finally combining simulation results to guide experiment development, so that the safety and efficiency of the HIFU are improved, and the effectiveness is enhanced.
The HIFU mainly acts in the field of ultrasonic treatment, but the invention does not directly relate to the treatment of human pathological tissues, but determines the control method by taking acrylamide gel mimetibodies as media, takes in-vitro organs with higher morbidity, such as pig liver, kidney and the like, and the like as research objects, and explores the effects of a microbubble synergistic dynamic method based on dual-frequency superposed ultrasonic pulses in viscoelastic media on improving the efficiency, the safety and the like.
In order to achieve the purpose, the invention adopts the following technical scheme:
the micro-bubble synergy dynamics experiment system based on the double-frequency superposed ultrasonic pulse in the viscoelastic medium comprises an ultrasonic excitation system, a monitoring guide system, a sound field measurement system and a control system;
an ultrasound excitation system comprising: the device comprises an arbitrary waveform generator, a radio frequency power amplifier, an impedance matching network and a HIFU transducer;
the monitoring guide system comprises a light source, a high-speed camera, a PCD probe and digital ultrasound;
the control system comprises a computer;
the arbitrary waveform generator, the radio frequency power amplifier, the impedance matching network and the HIFU transducer are connected in sequence;
the gel phantom or the in vitro sample is placed in a constant temperature device, and the HIFU transducer is arranged on the constant temperature device; the light source is arranged outside the constant temperature device and used for providing illumination;
the sound field measuring system comprises an optical fiber hydrophone and a data acquisition card; the sound field measurement system is used for detecting the pressure waveform of the sound field in the focal region of the fundamental frequency sound wave and the frequency doubling sound wave of the HIFU transducer by matching the optical fiber hydrophone with the data acquisition card;
the computer is connected with the arbitrary waveform generator, the high-speed camera, the PCD probe, the digital ultrasound and data acquisition card and is used for controlling the arbitrary waveform generator to send out a set waveform and controlling the high-speed camera and the PCD probe to acquire experimental data.
Further, any waveform generator generates a driving signal, the driving signal is amplified by a power amplifier and then passes through an impedance matching network to drive the HIFU transducer to work, and a waveform is applied to a focal zone of the gel phantom or the in vitro sample; the high-speed camera monitors the cavitation activity of the focal region under the assistance of a light source, the PCD probe is used for receiving a passive cavitation signal generated in the cavitation activity, and the digital ultrasound is used for positioning the gel phantom or the in-vitro sample at the focal position; the computer is responsible for receiving the drive signal from the signal generator, and the high-speed camera of synchronous control shoots.
Furthermore, the HIFU transducer is an annular array transducer, and the working range of a base frequency array element of the HIFU transducer is 1-3 MHz; the working range of the frequency multiplication array element is 2-10 MHz.
Furthermore, the middle of the HIFU transducer is provided with a hole for installing the digital ultrasonic probe.
The microbubble synergy dynamics experimental method based on the dual-frequency superposed ultrasonic pulse in the viscoelastic medium comprises the following steps:
step one, constructing a microbubble vibration enhanced excitation waveform;
1.1) detecting the focus sound field pressure waveform of fundamental frequency sound waves and frequency doubling sound waves of the HIFU transducer by using a fiber hydrophone;
1.2) constructing a model for generating a micro-bubble vibration excitation waveform, and solving a KZK equation to obtain a focal zone sound field pressure simulation waveform;
1.3) comparing the simulation waveform with an actual pressure waveform measured by a hydrophone, optimizing model parameters to ensure that the simulation waveform is consistent with the actual measured pressure waveform, and taking the simulation pressure waveform as a driving waveform condition of micro-bubble vibration;
secondly, constructing a HIFU synergistic model according to the viscoelasticity of the biological tissue of the tested gel phantom or the in vitro sample and the vibration characteristic of the micro-bubbles in the compressible fluid;
step three: establishing a micro-bubble synergy dynamic method based on dual-frequency superposition ultrasonic pulses in viscoelastic medium of the tested gel phantom or in-vitro sample and carrying out simulation calculation;
3.1) establishing a micro-bubble vibration model in a viscoelastic medium under a single sine wave excitation condition, selecting tissue viscoelastic parameters and simulating;
3.2) establishing a micro-bubble vibration model in the viscoelastic medium under the condition of continuous sine wave excitation, selecting tissue viscoelastic parameters and simulating;
step four: determining the waveform parameters of the arbitrary waveform generator according to the results of the first to third steps: and adjusting the power of a power amplifier according to the sound field measurement result of the step one until the sound pressure of a focal region generates nonlinear distortion, adjusting the waveform frequency of any waveform generator according to the vibration characteristics of microbubbles in the biological tissue, and controlling the HIFU transducer to perform HIFU thermal ablation or tissue damage experiments on the gel phantom or the in-vitro sample to be tested according to the waveform parameters.
Further, the KZK sound field model constructed in the step 1.2) is as follows:
wherein c is0Is the speed of sound; p is sound pressure;
is the nonlinear coefficient of the propagation medium;
mu is the volume viscosity in a fluid medium, u' is the shear viscosity, kappa is the thermal conductivity, and delta is the attenuation parameter of the acoustic wave in the propagation medium⊥Is the laplacian, z is the axial distance, and t is time.
Further, the constructed HIFU synergistic microbubble model is as follows:
wherein R is the radius of the microbubble;
the derivative of the microbubble radius with time; c0Is the speed of sound; σ is the surrounding liquid surface tension; μ is the viscosity coefficient of the surrounding liquid; pvIs the saturated vapor pressure of the surrounding liquid; tau is a gas polytropic index of 1.4;
reaction tissue relaxation time, wherein lambda is Poisson's ratio;
reflecting the elasticity of the tissue;
reflecting tissue surface tension;
reflecting the tissue viscosity.
The invention provides a micro-bubble synergy dynamics experiment system and method based on dual-frequency superposition ultrasonic pulses in viscoelastic media according to a micro-bubble dynamics model in biological tissues and a nonlinear effect caused by HIFU high-intensity focused ultrasound.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a micro-bubble synergy dynamics experiment system and method based on dual-frequency superimposed ultrasonic pulses in viscoelastic medium for overcoming the defects of the existing HIFU method; the invention uses the optical fiber hydrophone to measure the sound field of the fundamental frequency and frequency doubling transducer, ensures that the sound wave generates nonlinear distortion, fully utilizes the dynamic characteristics of the microbubbles in the compressible fluid such as biological tissue, has a Zener model closer to the actual condition than a classical RPNNP model, and uses two superposed sound waves to ensure that the microbubbles in the tissue vibrate more violently, thereby enhancing the cavitation effect and realizing high-efficiency thermal ablation and tissue damage.
Furthermore, the invention adopts a double-frequency superposition mode to act on the gel phantom or the in-vitro sample, and the negative sound pressure peak value is enhanced by controlling the interference of the fundamental wave and the harmonic amplitude and phase in the focal region, thereby being more beneficial to cavitation; the fundamental wave and the harmonic wave can not generate interference enhancement outside the focal region, thereby reducing the pressure on the adjacent parts around and further improving the safety.
Based on the two points, the invention can further improve the efficiency and the safety of HIFU thermal ablation and tissue damage through experiments.
Drawings
The present invention will be described in further detail with reference to the accompanying drawings and specific embodiments.
Fig. 1 is a block diagram of an implementation system of an experimental system of the present invention, where 1 is a synchronous signal control system, 1 is an arbitrary waveform generator, 2 is a signal power amplifier, 3 is an impedance matching network, 4 is a light source, 5 is an HIFU transducer, 6 is a gel phantom or an in vitro sample, 7 is a thermostat, 8 is a high-speed camera, 9 is a Passive Cavitation Detection (PCD) probe, 10 is a computer, and 11 is an organic glass container.
FIG. 2 is a schematic diagram of a system constructed by a fiber optic hydrophone FOPH2000 used in the present invention.
Fig. 3 is a schematic diagram of a HIFU transducer used in the present invention. Fig. 3(a) is a concave spherical annular split array transducer with a hole in the middle, fig. 3(b) is a confocal fan-shaped split array transducer, fig. 3(c) is a confocal volute split array transducer, and fig. 3(d) is a spherical shell type phased array transducer.
FIG. 4 is a flow chart of the method of the present invention.
FIG. 5 is a waveform simulation diagram obtained by using hydrophone measured focus area sound field pressure waveform diagram and solving KZK equation.
FIG. 6 is a graph of microbubble vibration in biological tissue under different hydrodynamic parameters.
Fig. 7 is a calculation of the microbubble vibration characteristics in the biological tissue when the two array elements are controlled to have phase differences of 135 ° and 60 °. Wherein, fig. 7(a) is a schematic diagram of a waveform superposition curve when the phase difference of two array elements is 135 °; FIG. 7(b) is a schematic diagram of a waveform superposition curve when the phase difference between two array elements is 60 °; FIG. 7(c) is a schematic diagram of the R-t vibration curve when the phase difference between two array elements is 135 °; FIG. 7(d) is a schematic diagram of the R-t vibration curve when the phase difference between two array elements is 60 °.
FIG. 8 is a typical result of monitoring using high-speed video when the method of the present invention is performed in a bovine serum albumin acrylamide mimetic; in fig. 8: (a) fig. d to (d) are typical results of the first-stage operation with a relatively high duty ratio pulse, and fig. e to (h) are typical results of the second-stage operation with a low duty ratio pulse.
FIG. 9 is a pictorial view of the physical anatomy of a method of the invention when applied to ex vivo porcine liver.
FIG. 10 is a graph of H & E staining results when the method of the invention is applied in ex vivo porcine liver; in fig. 10: (a) the images (a), (b) and (c) are the images around the lesion boundary in the image (a), and (d) are the images of H & E staining of normal tissues.
FIG. 11 is a diagram of waveforms generated by an arbitrary waveform generator in the method of the present invention.
Detailed Description
The present invention will be described in detail below with reference to the accompanying drawings and examples.
Based on research and application current situations of an HIFU technology, the invention provides a microbubble synergistic dynamics experiment system and method based on dual-frequency superposed ultrasonic pulses in a viscoelastic medium, the HIFU is guided to be developed and tissue viscoelastic parameters, waveforms and phase parameters are continuously optimized according to viscoelasticity of biological tissues and vibration characteristics of microbubbles in compressible fluid, and finally two superposed sound waves with a certain phase difference are used to enable the vibrations of the microbubbles in the tissues to be more severe, and cavitation effect is enhanced to improve the efficiency of the HIFU.
Referring to fig. 1, the invention provides a micro-bubble synergy dynamics experiment system based on dual-frequency superimposed ultrasonic pulses in viscoelastic media, which includes an ultrasonic excitation system, a monitoring guidance system, a control system and an acoustic field measurement system.
The ultrasonic excitation system mainly comprises the following devices: an arbitrary waveform generator 1, a radio frequency power amplifier 2, an impedance matching network 3, and a HIFU transducer 5.
The monitoring guidance system mainly comprises a light source 4, a high-speed camera 8, a passive cavitation detection probe (PCD probe) 9 and digital ultrasound.
The control system is formed by a computer 10.
The sound field measurement system comprises an optical fiber hydrophone FOPH2000 and a data acquisition card. The computer 10 is connected with a data acquisition card and an optical fiber hydrophone FOPH 2000.
The arbitrary waveform generator 1, the radio frequency power amplifier 2, the impedance matching network 3 and the HIFU transducer 5 are connected in sequence. The computer 10 is connected with the control end of the arbitrary waveform generator 1 and the high-speed camera 8 and is used for controlling the arbitrary waveform generator 1 to send out a specific waveform and controlling the high-speed camera 8 to shoot. The gel phantom or in-vitro sample 6 is placed in a constant temperature device 7, and the HIFU transducer 5, the passive cavitation detection probe (PCD probe) 9 and the digital ultrasound are arranged on the constant temperature device 7; a passive cavitation detection probe (PCD probe) 9 and a connection computer 10, which are used for feeding back monitoring information; the light source 4 is disposed outside the thermostat 7 for providing illumination. Digital ultrasound is used to locate the gel mimic or ex vivo sample at the focal position.
The invention provides a micro-bubble synergy dynamics experimental system based on dual-frequency superposed ultrasonic pulses in viscoelastic media, which is characterized in that firstly, a required driving signal is generated by an arbitrary waveform generator 1, and then the driving signal is amplified to specified power by a power amplifier 2 and then passes through an impedance matching network 3 to drive a HIFU transducer 5 to work. The high-speed camera 8 monitors the cavitation activity of the focal region under the assistance of the light source 4, the PCD probe is used for receiving a passive cavitation signal generated in the cavitation activity, and the digital ultrasonic system is used for positioning the gel phantom or the in-vitro sample at the focal position. The computer 10 is responsible for receiving the drive signal from the signal generator, and the high-speed camera of synchronous control shoots, accurate control time sequence.
The invention provides a micro-bubble synergy dynamics experimental method based on dual-frequency superposition ultrasonic pulses in viscoelastic media, which comprises the following steps:
the method comprises the following steps: a microbubble vibration-enhanced excitation waveform is constructed.
(1) The method comprises the steps of detecting pressure waveforms of a focal zone sound field of fundamental frequency sound waves and frequency doubling sound waves of the HIFU transducer 5 by using an optical fiber hydrophone, wherein the measurement system is as shown in figure 2, the optical fiber hydrophone needs to be calibrated before measurement, and the light scattering coefficient and the polarization light scattering coefficient of the hydrophone are ensured to be within an instrument specified range. During measurement, the three-dimensional moving device is adjusted to enable the optical fiber hydrophone probe to scan in a focus area in a certain step length. The transducer driving unit drives the HIFU transducer to emit focused ultrasonic waves, the data acquisition card is triggered to acquire the sound pressure of a focal region at the same time, and the optical fiber probe of the optical fiber hydrophone is moved until the maximum value appears according to the signal-to-noise ratio and the sound pressure amplitude of an acquired signal. The sound pressure calculation formula is as follows:
As shown in fig. 5, when a single-frequency acoustic wave with a large amplitude propagates in a medium due to a nonlinear effect, the waveform of the acoustic wave is gradually distorted due to the interaction with the medium, and a shock wave is formed.
(2) And constructing a model for generating a micro-bubble vibration excitation waveform, and solving a KZK equation to obtain a focal zone sound field pressure simulation waveform.
Wherein c is0Is the speed of sound; p is sound pressure;
is the nonlinear coefficient of the propagation medium;
for the attenuation parameter of the acoustic wave in the propagation medium, μ is the bulk viscosity in the fluid medium, u' is the shear (shear) viscosity, κ is the thermal conductivity, Δ⊥Is the laplacian, z is the axial distance, and t is time.
The KZK equation is to do axial approximate transformation to the Westervelt equation, which accords with the actual condition of small opening focusing sound source. The first term on the right represents the diffraction effect of the sound field, the second term represents the attenuation effect of the sound wave, and the third term represents the nonlinear effect of sound propagation.
Considering that in practical application, the ultrasonic wave needs to pass through a coupling mediumThe ultrasonic wave enters organism tissues to avoid unnecessary loss of acoustic wave energy, so that 5cm of water medium is simulated firstly, and then tissue parameters and characteristic parameters of the ultrasonic transducer are set according to the actual condition as far as possible. Acoustic velocity c in aqueous medium11482 m/s; density p1＝1000kg/m3A non-linear parameter β13.5, tissue absorption coefficient η 12. Taking the speed of sound c in biological tissue21629 m/s; density p2＝1000kg/m3A non-linear parameter β14.5, tissue absorption coefficient η 11. Inner diameter R of transducer 11 cm; outer diameter R22.5 cm; the focusing depth d is 8 cm; the central frequency f is 1-5 MHz; the sound power P is 40-200W.
As shown in fig. 5, the simulated waveform obtained by solving the KZK equation is consistent with the sound field pressure waveform actually measured by the hydrophone, which indicates that the constructed excitation waveform can well meet the nonlinear distortion of the actual situation, and can be used as the driving waveform condition of the microbubble vibration.
(3) And comparing the simulated waveform with the actual pressure waveform measured by the hydrophone, changing the acoustic power and frequency parameters of the waveform to make the simulated waveform consistent with the actual measured waveform, and taking the simulated pressure waveform as the driving waveform condition of the micro-bubble vibration.
Step two: and constructing a HIFU synergistic model according to the viscoelasticity of the tissues and the vibration characteristics of the micro-bubbles in the compressible fluid.
Combining a Zener mechanical model and a Keller-Miksis equation to obtain the following HIFU synergy model:
wherein R is the radius of the microbubble;
the derivative of the microbubble radius with time; c0Is the speed of sound; σ is the surrounding liquid surface tension; μ is the viscosity coefficient of the surrounding liquid; pvIs the saturated vapor pressure of the surrounding liquid; τ is gas polytropic index, 1.4.
Response to tissue relaxation time, λ is Poisson's ratio (λ)<0.5), the Poisson's ratio of water is 0.5;
reflecting the elasticity of the tissue;
reflecting tissue surface tension;
reflecting the tissue viscosity.
Because the elastic modulus G of the biological tissue is within the range of 0-10 MPa and the viscosity mu is within the range of 0.004-0.03 Pa.s, the simulation parameters are set as follows when the biological tissue model is constructed: 0.01-5% of Ca; de is 0-1; we is 1-20; re is 0 to 10. The parameters are different in different biological tissues, resulting in differences in the oscillation characteristics of the microbubbles in different biological tissues.
Step three: establishing a micro-bubble synergy dynamics method based on dual-frequency superposition ultrasonic pulses in viscoelastic media (gel phantom or in vitro samples (6)) and carrying out simulation calculation.
(1) Establishing a micro-bubble vibration model in the viscoelastic medium under a single sine wave excitation condition according to the formulas (3), (4) and (5): taking Ca as 0.01-1 as a simulation parameter; de is 0-0.5; we is 1-10; re is 0 to 5.
As a result, as shown in FIG. 6, the elasticity, viscosity, relaxation time and surface tension of the biological tissue all affect the oscillation amplitude, equilibrium radius and the rupture process of the microbubbles. Therefore, the conditions of acoustic pressure, frequency phase and the like of the sound waves are changed according to the viscoelastic property of the biological tissue, so that the vibration amplitude of the micro-bubbles in the biological tissue can be increased, the cavitation effect is enhanced, and the development of HIFU thermal ablation and tissue damage is efficiently guided.
(2) Establishing a micro-bubble vibration model in a viscoelastic medium under a continuous sine wave excitation condition: during actual HIFU thermal ablation and tissue destruction, the microbubbles are under constant excitation. Under the condition of double-frequency superposition, the two groups of ultrasonic pulses have certain phase difference. Taking Ca as 0.01-1 as a simulation parameter; de is 0-0.5; we is 1-10; re is 0 to 5.
The obtained microbubble vibration characteristics under the continuous excitation double-frequency superposition are shown in fig. 7, when the phase difference is 135 degrees in the fundamental frequency and 2 frequency multiplication modes, the negative pressures of the two frequencies are just superposed together, the vibration radius of the microbubble reaches the maximum amplitude, the cavitation effect is enhanced, and the HIFU thermal ablation and tissue damage efficiency is improved.
Step four: and determining waveform parameters to perform HIFU thermal ablation or tissue damage by combining simulation results of the synergy method.
The arbitrary waveform generator 1 emits the waveform in fig. 11, and after passing through the power amplifier, drives the HIFU transducer through the impedance matching network, and performs thermal ablation or tissue destruction on the gel phantom or the ex vivo sample 6 under the monitoring of the monitoring guidance system. Driving an HIFU transducer by using two groups of ultrasonic pulses, wherein an excitation pulse sent by an arbitrary waveform generator drives a base frequency array element after power amplification, and the working range of the base frequency array element is 1-3 MHz; and the excitation pulse emitted by the other arbitrary waveform generator drives a harmonic frequency array element after power amplification, and the working range of the harmonic frequency array element is 2-10 MHz. The pulse focusing ultrasonic wave can generate boiling bubbles, shock waves and the like to form a loose local structure, and various mechanical actions such as inertial cavitation, shock waves and the like further homogenize the damaged interior and form a large number of cavitation nuclei. The phase difference between the two groups of excitation pulses is 135 degrees, the microbubble can reach the maximum vibration radius in a focal region, the cavitation effect is enhanced, and the time required by HIFU thermal ablation and tissue damage is shortened.
When the test object is a gel phantom, the process of lesion formation and the final morphology are observed by high-speed imaging.
When the experimental object is the ex vivo pig kidney, the damage form is observed by incision, and the change of the cell form is observed by staining.
FIG. 4 is a flow chart of the present invention, which includes determining KZK equation parameter settings to construct enhanced microbubble vibration excitation waveforms according to actual sound field waveforms of a fundamental frequency and frequency doubling sound wave focal regions measured by a hydrophone, then solving a Keller-Miksis equation to construct a microbubble synergy model according to viscoelasticity of tissues and vibration characteristics of microbubbles in compressible fluid, then establishing a microbubble synergy dynamics method based on dual-frequency superimposed ultrasonic pulses in viscoelastic media, performing simulation calculation to select appropriate tissue viscoelasticity parameters, HIFU waveforms and phase parameters, and finally combining simulation results to guide experiment development and continuously optimize the parameters.
FIG. 5 shows the focus area sound field simulation waveform obtained by resolving the KZK equation from the focus area sound field waveform of the fundamental frequency sound wave and the frequency doubling sound wave measured by the hydrophone. As shown in fig. 5(a) and fig. 4(c), the actual waveforms of the sound field in the focal region measured by the hydrophone, the high-intensity sound waves have nonlinear effects in the propagation process, and are distorted into shock waves from standard sine waves, and the formation of the shock waves is beneficial to cavitation effects. Fig. 5(b) and 5(d) show simulated waveforms of the sound field in the focal region obtained by solving the KZK equation. By comparing the two, the simulation waveform and the actual waveform can be seen to be in good agreement, and the simulation waveform is taken as the excitation waveform.
FIG. 6 is a simulation diagram of micro-bubble vibration of biological tissue under different fluid mechanics parameters. As shown in fig. 6, it can be seen that in the biological tissue, the final equilibrium radius of the microbubble increases with the decrease of the Ca value (elasticity decreases), the amplitude of the oscillation decreases, the decreased elasticity increases the damping, and limits the oscillation of the microbubble, the value De (relaxation time) increases, the equilibrium radius of the microbubble pulsation remains constant, and the value De (relaxation time) plays a major role in the oscillation characteristic of the microbubble in the low-elasticity medium (low Ca value), and governs the magnitude of the damping. In a high-elasticity medium (high Ca value), the value of Re (viscosity) plays a main role in the pulsation characteristic of the microbubbles. As the pressure increases, the amplitude and frequency of the microbubble pulsations increase (i.e., the oscillations are fast and severe); the time taken to reach equilibrium is reduced.
FIG. 7 is a simulation diagram of the micro-bubble vibration when the phase difference between the fundamental frequency array element and the frequency multiplication array element is 135 DEG and 60 deg. When the phase difference between the fundamental frequency and the frequency multiplication is 135 degrees, the negative pressures of the two frequencies are just superposed together to reach the maximum amplitude, the maximum radius of the microbubble vibration is also maximized, the cavitation effect is enhanced, and the HIFU efficiency is greatly improved. When the phase difference is 60 °, the maximum radius of the microbubble oscillation decreases, and a significant resonance occurs.
Example 1:
1) bovine Serum Albumin (BSA) polyacrylamide gel mimetibody with a mass fraction of 7% was prepared, and bovine serum albumin was added as a temperature change indicator. The density of the gel phantom was 1.06g/cm3The sound velocity in the finished gel imitation is 1477 +/-5 m/s, and the sound attenuation coefficient is 0.42 +/-0.01 dB/cm.
2) The annular HIFU transducer 5, the B-ultrasonic probe, and the like are placed and fixed as shown in fig. 1, a proper amount of deaerated water is injected into the reaction vessel, and the thermostat 7 is opened. And starting the ultrasonic imaging equipment, and guiding and adjusting the point needing to be damaged in the gel phantom to the focus of the transducer according to the image.
3) The signal waveforms to be generated by the arbitrary waveform generator are programmed according to fig. 11.
4) The computer 10 controls the timing sequence of the signal excitation module and the monitoring guide module, so that the damage and the monitoring of the gel phantom or the in-vitro sample are triggered simultaneously.
And (3) analysis results:
as shown in fig. 8, the time of the boiling bubbles appearing at the center of the focal region for the first time is 1.29s, and the speed of the boiling bubbles appearing at the first time is increased by 417.05% compared with the single frequency result of 1.06MHz, i.e., 6.67s, as shown in fig. 8(b), the microbubbles which are randomly distributed in the axial direction are gathered and fused to form microbubbles with larger sizes at the two ends, as shown in fig. 8(c) and 8(d), it is shown that more and larger boiling bubbles appear in the focal region, and the size of the damage is gradually enlarged, and at this stage, a higher duty ratio pulse is used, the boiling bubbles are generated mainly by the HIFU thermal effect, and the boiling bubbles; fig. 8(e) - (h) show that with the time increase, the volume of the injury expands towards the end far away from the transducer, and the microbubbles move towards the end far away from the transducer under the action of the radiation force, which indicates that the inside of the injury is completely liquefied to form a fusiform cavity.
Example 2:
1) an acrylamide mimetic fluid was prepared. Selecting fresh pig kidney, cutting into 5mm × 3mm × 30mm, fixing in simulated body fluid, and coagulating at room temperature.
2) Fixing the annular array HIFU transducer 5, the B-ultrasonic probe and the like as shown in figure 1, injecting a proper amount of deaerated water into the reaction vessel, and opening the constant temperature device 7. And starting the ultrasonic imaging equipment, and guiding and adjusting the central position of the pig kidney to the focus of the transducer according to the image.
3) The signals to be generated by the arbitrary waveform generator are programmed according to fig. 11. Throughout the process, the acoustic power was set to 240W.
4) A channel 1 of an arbitrary waveform generator in a synchronous signal control system is connected with an ultrasonic excitation system, and a channel 2 is connected with a guide monitoring system. And starting each device, and manually triggering the synchronous signal control system. The channel 1 is connected with an external trigger end of an arbitrary waveform generator in the ultrasonic excitation system, and a signal sent out in the ultrasonic excitation system is triggered to pass through a radio frequency power amplifier and an impedance matching network and drive the HIFU transducer. And the channel 2 starts the high-speed camera equipment for real-time monitoring.
5) After the HIFU process is finished, the damage is observed through B-ultrasonic equipment, then the pig kidney is taken out, and the damage condition is carefully analyzed after the pig kidney is cut open. The damaged pig kidneys were stained with H & E and the histological results were observed using a high power microscope.
And (3) analysis results:
as shown in fig. 9, the actual lesion volume was similar to that observed in the gel phantom experiment. The damaged boundary formed in the pig kidney tissue is smooth and clear without obvious white thermal damage, a obvious boundary appears between the damaged area tissue and the normal area tissue in fig. 10(a), and after the boundary is enlarged, the boundary can be obviously seen in fig. 10(b) and fig. 10 (c): the damaged area inside the boundary is completely homogenized, and the cell structure of the normal area outside the boundary is kept complete, which shows that the micro-bubble synergy dynamics method based on the dual-frequency superposition ultrasonic pulse of the viscoelastic medium has excellent effect. In addition, when the isolated tissue is dissected and the internal injury is checked, the injury can be seen to be completely emulsified inside, the fluidity is enhanced, and the injury becomes liquid which can be directly absorbed by surrounding groups.
It will be appreciated by those skilled in the art that the invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The embodiments disclosed above are therefore to be considered in all respects as illustrative and not restrictive. All changes which come within the scope of or equivalence to the invention are intended to be embraced therein.
Claims (6)
1. The microbubble synergistic dynamics experimental method based on the dual-frequency superposed ultrasonic pulse in the viscoelastic medium is characterized by being based on a microbubble synergistic dynamics experimental system based on the dual-frequency superposed ultrasonic pulse in the viscoelastic medium; the micro-bubble synergy dynamics experiment system based on the dual-frequency superposed ultrasonic pulses in the viscoelastic medium comprises an ultrasonic excitation system, a monitoring guide system, a sound field measurement system and a control system; an ultrasound excitation system comprising: an arbitrary waveform generator (1), a radio frequency power amplifier (2), an impedance matching network (3) and a HIFU transducer (5); the monitoring and guiding system comprises a light source (4), a high-speed camera (8), a PCD probe (9) and digital ultrasound; the control system comprises a computer (10); the system comprises an arbitrary waveform generator (1), a radio frequency power amplifier (2), an impedance matching network (3) and a HIFU transducer (5) which are connected in sequence; the gel phantom or the in-vitro sample (6) is placed in a constant temperature device (7), and the HIFU transducer (5) is arranged on the constant temperature device (7); the light source (4) is arranged outside the constant temperature device (7) and used for providing illumination; the sound field measuring system comprises an optical fiber hydrophone and a data acquisition card; the sound field measuring system is used for detecting the pressure waveforms of the sound field of the focal region of the fundamental frequency sound wave and the frequency doubling sound wave of the HIFU transducer (5) through the cooperation of the optical fiber hydrophone and the data acquisition card; the computer (10) is connected with the arbitrary waveform generator (1), the high-speed camera (8), the PCD probe (9) and the digital ultrasonic and data acquisition card and is used for controlling the arbitrary waveform generator (1) to send out a set waveform and controlling the high-speed camera (8) and the PCD probe (9) to acquire experimental data;
the microbubble synergy kinetics experimental method comprises the following steps:
step one, constructing a microbubble vibration enhanced excitation waveform;
1.1) detecting the focus sound field pressure waveform of fundamental frequency sound waves and frequency doubling sound waves of the HIFU transducer by using a fiber hydrophone;
1.2) constructing a model for generating a micro-bubble vibration excitation waveform, and solving a KZK equation to obtain a focal zone sound field pressure simulation waveform;
1.3) comparing the simulation waveform with an actual pressure waveform measured by a hydrophone, optimizing model parameters to ensure that the simulation waveform is consistent with the actual measured pressure waveform, and taking the simulation pressure waveform as a driving waveform condition of micro-bubble vibration;
secondly, constructing a HIFU synergistic model according to the viscoelasticity of the biological tissue of the tested gel phantom or the in-vitro sample (6) and the vibration characteristics of the micro-bubbles in the compressible fluid;
step three: establishing a micro-bubble synergy dynamics method based on dual-frequency superimposed ultrasonic pulses in the viscoelastic medium of the gel phantom or the in-vitro sample (6) to be tested and carrying out simulation calculation;
3.1) establishing a micro-bubble vibration model in a viscoelastic medium under a single sine wave excitation condition, selecting tissue viscoelastic parameters and simulating;
3.2) establishing a micro-bubble vibration model in the viscoelastic medium under the condition of continuous sine wave excitation, selecting tissue viscoelastic parameters and simulating;
step four: and determining the waveform parameters of the arbitrary waveform generator (1) according to the results of the steps one to three, and controlling the HIFU transducer (5) to carry out HIFU thermal ablation or tissue damage experiments on the gel phantom or the in-vitro sample (6) to be tested according to the waveform parameters.
2. A method of dual-frequency superimposed ultrasound pulse based enhanced microbubble kinetics in a viscoelastic medium as set forth in claim 1, wherein the model constructed in step 1.2) is:
wherein c is0Is the speed of sound; p is sound pressure;
is the nonlinear coefficient of the propagation medium;
mu is the volume viscosity in a fluid medium, u' is the shear viscosity, kappa is the thermal conductivity, and delta is the attenuation parameter of the acoustic wave in the propagation medium⊥Is the laplacian, z is the axial distance, and t is time.
3. A method of dual-frequency superimposed ultrasound pulse based microbubble enhanced kinetics in a viscoelastic medium as set forth in claim 1, wherein the HIFU enhancement model is constructed by:
wherein R is the radius of the microbubble;
the derivative of the microbubble radius with time; c0Is the speed of sound; σ is the surrounding liquid surface tension; μ is the viscosity coefficient of the surrounding liquid; pvIs a peripheryThe saturated vapor pressure of the liquid; tau is a gas polytropic index of 1.4;
reaction tissue relaxation time, wherein lambda is Poisson's ratio;
reflecting the elasticity of the tissue;
reflecting tissue surface tension;
reflecting the tissue viscosity.
4. The method of dual-frequency superimposed ultrasound pulse-based microbubble-enhanced kinetics in a viscoelastic medium according to claim 1, wherein an arbitrary waveform generator (1) generates a driving signal, the driving signal is amplified by a power amplifier (2) and then passes through an impedance matching network (3) to drive a HIFU transducer (5) to work, and a waveform is applied to a focal region of a gel phantom or an ex vivo sample (6); the high-speed camera (8) monitors the cavitation activity of the focal region under the assistance of the light source (4), the PCD probe (9) is used for receiving a passive cavitation signal generated in the cavitation activity, and the digital ultrasound is used for positioning the gel phantom or the in-vitro sample at the focal position; the computer (10) is responsible for receiving the driving signal from the signal generator and synchronously controlling the high-speed camera to shoot.
5. The micro-bubble synergy dynamics method based on the dual-frequency superimposed ultrasonic pulse in the viscoelastic medium according to claim 1, characterized in that the HIFU transducer (5) is an annular array transducer, and the working range of the fundamental frequency array element is 1-3 MHz; the working range of the frequency multiplication array element is 2-10 MHz.
6. A method of dual-frequency superimposed ultrasound pulse based enhanced microbubble kinetics in a viscoelastic medium as set forth in claim 1 wherein the HIFU transducer has a hole in the middle for mounting a digital ultrasound probe.
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