CN110243454B - Experimental system and method of microbubble synergy kinetics based on dual-frequency superimposed ultrasonic pulses in viscoelastic media - Google Patents

Abstract

The invention discloses an experimental system and method for microbubble synergy dynamics in viscoelastic medium based on double-frequency superposition. The experimental method includes: 1) according to the actual waveform of the focal area sound field measured by a hydrophone, setting KZK equation parameters to construct microbubbles nonlinear excitation waveform; 2) build a HIFU synergy model based on the viscoelasticity of biological tissues and the vibration characteristics of microbubbles in compressible fluids; 3) establish a dual-frequency superposition-based microbubble synergistic dynamic method; 4) combine the above The simulation results of the steps determine the HIFU waveform phase, sound pressure, and frequency parameters for thermal ablation or tissue damage experiments. The invention makes full use of the dynamic characteristics of microbubbles in biological tissue, designs sound wave waveform and phase parameters, induces the maximum vibration of microbubbles in the focal area, enhances cavitation effect, and improves the safety and efficiency of HIFU thermal ablation and tissue damage .

Description

Experimental system of microbubble synergy kinetics based on dual-frequency superimposed ultrasonic pulses in viscoelastic media systems and methods

technical field

The invention belongs to the field of ultrasonic technology, and in particular relates to an experimental system and method of microbubble synergy dynamics in a viscoelastic medium.

Background technique

High Intensity Focused Ultrasound (HIFU) has become a hot spot in the field of therapeutic ultrasound because of its non-invasive and strong focusing characteristics. At present, there are two mechanisms of action of high-intensity focused ultrasound: thermal ablation mechanism and tissue destruction mechanism. The traditional HIFU thermal ablation mode mainly uses the thermal effect of ultrasound, and the high-intensity ultrasonic energy focused from the outside to the target area locally ablates the tissue, causing the target tissue to undergo coagulation necrosis due to the instantaneous high temperature; the tissue destruction (Histotripsy) mode mainly uses The cavitational mechanical effect of HIFU smashes the target tissue into micron-sized fragments.

The cavitation effect refers to the dynamic process of oscillation, stretching, shrinkage and rupture of tiny bubbles in the liquid under the action of alternating positive and negative ultrasonic waves. It is considered to be the most potential mechanism to improve the HIFU effect. extensive research. Kawabata and other scholars have found in both in vitro and in vivo experiments that superimposing the second harmonic on the fundamental frequency can enhance the directional diffusion within a single cycle and significantly enhance the cavitation effect. International patent WO2,015,138,781 A1, inventor Kuang-Wei Lin, in the name of the invention "Frequency compounding ultrasound pulses for imaging and therapy" proposes the use of low-frequency (100kHz-1MHz) sound waves and high-frequency (2-10MHz) sound waves (anharmonics). A method of destroying tissue by controlling the pulse delay of two frequencies to form a monopolar pulse by acting on the target tissue at the same time. G. Iernetti, "Enhancement of high-frequency cavitation effects by a low frequency stimulation" Ultrasonics Sonochemistry, vol.4, pp.263-268, 1997. The use of high frequency 700kHz and low frequency 20kHz ultrasound to enhance cavitation effects: low frequency ultrasound It is used to amplify the cavitation effect of high frequency ultrasound in different cavitation stages in the target tissue area. This method of superimposing low frequency on high-frequency sound waves with KHz has the disadvantages of large focal volume, inability to accurately damage the target tissue, and low acoustic wave amplitude in the focal area, which cannot effectively damage the target tissue.

The microbubble dynamics model has the classical RPNNP model in incompressible fluids, but it cannot adapt to compressible fluids, and cavitation effects occur in compressible fluids such as biological tissues. The latest Zener model can better simulate the mechanical properties of compressible fluids such as biological tissues, which is more in line with the actual situation of tissues, and has a deeper application in the study of microbubble dynamics models. Whether it is thermal ablation or tissue damage, the vibration of microbubbles and the energy released when collapsing play a role in it. Therefore, exploring the dynamic characteristics of microbubbles in tissue can help improve thermal ablation and tissue damage control methods and improve treatment efficiency.

The existing thermal ablation and tissue destruction methods still have the following defects: biological tissue is a kind of compressible fluid with viscoelasticity, and there are theoretical deficiencies in the development of HIFU process guided by the microbubble model in the RPNNP incompressible fluid. There is no viscoelastic model in compressible fluids for simulation to guide the HIFU process, and the previous excitation waveforms did not consider nonlinear effects, resulting in inaccurate thermal ablation and tissue damage parameter settings, and insufficient cavitation activity in the focal zone in single-frequency mode. , so that the cavitation threshold is too high, the required peak sound pressure is too high, and the monofocal volume is only a few mm ³ .

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a microbubble synergy kinetics experimental system and method based on dual-frequency superimposed ultrasonic pulses in a viscoelastic medium, so as to solve the above-mentioned technical problems. The invention first measures the nonlinear waveform of the actual sound field in the focal area according to the optical fiber hydrophone, determines the parameter setting of the KZK equation to construct the nonlinear waveform of the microbubble vibration excitation, and ensures that the sound wave of each frequency can generate nonlinear distortion, and then according to the viscosity of the biological tissue Elasticity and vibration characteristics of microbubbles in compressible fluids, solve the Zener model and Keller-Miksis equation to build a microbubble synergy model, and then establish a microbubble synergy dynamics method based on dual-frequency superimposed ultrasonic pulses in viscoelastic media. The simulation calculation selects appropriate tissue viscoelastic parameters and HIFU waveform, frequency, sound pressure and phase parameters, and finally combines the simulation results to guide the experiment to improve the safety, efficiency and effectiveness of HIFU.

HIFU mainly acts on the field of ultrasonic therapy, but the present invention does not directly relate to the treatment of human diseased tissue, but uses acrylamide gel phantom as a medium to determine its control method, and uses pig liver, kidney and other isolated tissues with high incidence. Organs and other media are the research objects to explore the effects of the microbubble synergistic kinetic method based on dual-frequency superimposed ultrasonic pulses in improving efficiency and safety in viscoelastic media.

In order to achieve the above object, the present invention adopts the following technical solutions:

An experimental system of microbubble synergy dynamics in viscoelastic medium based on dual-frequency superimposed ultrasonic pulses, including ultrasonic excitation system, monitoring and guidance system, sound field measurement system and control system;

Ultrasonic excitation system includes: arbitrary waveform generator, RF power amplifier, impedance matching network and HIFU transducer;

The monitoring and guidance system includes light source, high-speed camera, PCD probe and digital ultrasound;

The control system includes a computer;

Arbitrary waveform generator, RF power amplifier, impedance matching network and HIFU transducer are connected in sequence;

The gel phantom or the isolated sample is placed in a constant temperature device, and the HIFU transducer is installed on the constant temperature device; the light source is set outside the constant temperature device to provide light;

The sound field measurement system includes a fiber optic hydrophone and a data acquisition card; the sound field measurement system is used to detect the sound field pressure waveform of the HIFU transducer fundamental frequency sound wave and octave sound wave focal zone through the cooperation of the fiber optic hydrophone and the data acquisition card;

The computer is connected to the arbitrary waveform generator, high-speed camera, PCD probe, digital ultrasound and data acquisition card, which is used to control the arbitrary waveform generator to send out the set waveform, and control the high-speed camera and the PCD probe to collect experimental data.

Further, the arbitrary waveform generator generates the driving signal, which is amplified by the power amplifier and then passed through the impedance matching network to drive the HIFU transducer to work, and apply waveform to the focal area of the gel phantom or the isolated sample; The cavitation activity in the focal area is monitored with the aid of the PCD probe. The PCD probe is used to receive the passive cavitation signal generated in the cavitation activity. The digital ultrasound is used to locate the gel phantom or the isolated sample at the focal position; the computer is responsible for receiving the signal from the cavitation. The driving signal of the generator controls the high-speed camera to shoot synchronously.

Further, the HIFU transducer is a ring array transducer, and the working range of the fundamental frequency array element is 1-3 MHz; the working range of the frequency-doubling array element is 2-10 MHz.

Further, there is a hole in the middle of the HIFU transducer for installing a digital ultrasound probe.

The experimental method of microbubble synergy kinetics based on dual-frequency superimposed ultrasonic pulses in viscoelastic media includes the following steps:

Step 1. Construct the vibration-enhanced excitation waveform of the microbubble;

1.1), use the fiber optic hydrophone to detect the sound field pressure waveform of the HIFU transducer fundamental frequency sound wave and double frequency sound wave focal area;

1.2), build a model for generating microbubble vibration excitation waveform, and solve the KZK equation to obtain the focal zone sound field pressure simulation waveform;

1.3), compare the simulated waveform with the actual pressure waveform measured by the hydrophone, optimize the model parameters so that the simulated waveform is consistent with the actual measured pressure waveform, and use the simulated pressure waveform as the driving waveform condition of the microbubble vibration;

Step 2: Construct 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 characteristics of the microbubbles in the compressible fluid;

Step 3: Establish a microbubble synergistic kinetic method based on dual-frequency superimposed ultrasonic pulses in the viscoelastic medium of the gel phantom or the ex vivo sample and carry out simulation calculation;

3.1), establish the microbubble vibration model in the viscoelastic medium under the condition of a single sine wave excitation, select the tissue viscoelastic parameters and simulate;

3.2), establish the microbubble vibration model in the viscoelastic medium under the condition of continuous sine wave excitation, select tissue viscoelastic parameters and simulate;

Step 4: Determine the waveform parameters of the arbitrary waveform generator according to the results of steps 1 to 3: adjust the power of the power amplifier according to the sound field measurement results of step 1 until nonlinear distortion of the sound pressure in the focal zone occurs, and according to the vibration characteristics of the microbubbles in the biological tissue The waveform frequency of the arbitrary waveform generator is adjusted, and the HIFU transducer is controlled to perform HIFU thermal ablation or tissue damage experiments on the gel phantoms or in vitro samples to be tested according to the waveform parameters.

Further, the KZK sound field model constructed in step 1.2) is:

为传播介质的非线性系数；

为声波在传播介质中的衰减参数，μ为流体介质中的体积黏性，u′为切边黏性，κ为热传导系数，Δ_⊥为拉普拉斯算子，z为轴向距离，t为时间。where c ₀ is the speed of sound; P is the sound pressure;

is the nonlinear coefficient of the propagation medium;

is the attenuation parameter of the sound wave in the propagation medium, μ is the volume viscosity in the fluid medium, u′ is the viscosity of the cutting edge, κ is the thermal conductivity, Δ _⊥ is the Laplace operator, z is the axial distance, t for time.

Further, the constructed HIFU synergistic microbubble model is:

为微泡半径随时间的导数；C₀为声速；σ为周围液体表面张力；μ为周围液体的粘滞系数；P_v为周围液体的饱和蒸气压；τ为气体多方指数，为1.4；

反应组织弛豫时间，λ为泊松比；

反应组织弹性；

反应组织表面张力；

反应组织粘性。where R is the radius of the microbubble;

is the derivative of the microbubble radius with time; C ₀ is the speed of sound; σ is the surface tension of the surrounding liquid; μ is the viscosity coefficient of the surrounding liquid; P _v is the saturated vapor pressure of the surrounding liquid; τ is the gas polytropic exponent, which is 1.4;

Reaction tissue relaxation time, λ is Poisson's ratio;

Responsive tissue elasticity;

Reactive tissue surface tension;

Reactive tissue stickiness.

According to the microbubble dynamics model in biological tissue and the nonlinear effect caused by HIFU high-intensity focused ultrasound, the present invention proposes a microbubble synergistic dynamic experiment system and method based on dual-frequency superimposed ultrasonic pulses in a viscoelastic medium.

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

In order to overcome the deficiencies in the existing HIFU method, the present invention proposes a microbubble synergistic dynamic experimental system and method based on dual-frequency superimposed ultrasonic pulses in a viscoelastic medium; The sound field of the frequency transducer is measured, which ensures the nonlinear distortion of the sound wave, and makes full use of the dynamic characteristics of microbubbles in compressible fluids such as biological tissues. The Zener model is closer to the actual situation than the classical RPNNP model, and then use The two superimposed acoustic waves make the vibration of the microbubbles in the tissue more intense and enhance the cavitation effect to achieve efficient thermal ablation and tissue damage.

Further, the present invention adopts the dual-frequency superposition mode to act on the gel phantom or the isolated sample, and by controlling the fundamental wave and the harmonic amplitude and phase to interfere in the focal region, the negative sound pressure peak is enhanced, which is more conducive to cavitation. ; The fundamental wave and harmonics will not interfere and strengthen outside the focal area, which reduces the pressure on the surrounding adjacent parts and further improves the safety.

Based on the above two points, the present invention can further improve the efficiency and safety of HIFU thermal ablation and tissue damage through experiments.

Description of drawings

The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments.

Fig. 1 is the realization system block diagram of the experimental system of the present invention, 1 is the synchronization signal control system, 1 is the arbitrary waveform generator, 2 is the signal power amplifier, 3 is the impedance matching network, 4 is the light source, 5 is the HIFU transducer, 6 7 is a constant temperature device, 8 is a high-speed camera, 9 is a passive cavitation detection (PCD) probe, 10 is a computer, and 11 is a plexiglass container.

FIG. 2 is a schematic diagram of a system constructed by the optical fiber hydrophone FOPH2000 adopted in the present invention.

FIG. 3 is a schematic diagram of the HIFU transducer used in the present invention. Among them, Fig. 3(a) is a concave spherical annular split-array transducer with a hole in the middle, Fig. 3(b) is a confocal sector-shaped split-array transducer, and Fig. 3(c) is a confocal vortex-shaped split-array transducer. Figure 3(d) is a spherical-shell phased array transducer.

Figure 4 is a flow chart of the method of the present invention.

5 is a waveform diagram of the sound field pressure in the focal zone measured by a hydrophone in the present invention and a waveform simulation diagram obtained by solving the KZK equation.

Figure 6 is a graph of the vibration of microbubbles in biological tissue under different hydrodynamic parameters.

Figure 7 is the calculation of the vibration characteristics of microbubbles in biological tissue when the phase difference between the two array elements is controlled to be 135° and 60°. Among them, Figure 7(a) is a schematic diagram of the waveform superposition curve when the phase difference between the two array elements is 135°; Figure 7(b) is a schematic diagram of the waveform superposition curve when the phase difference between the two array elements is 60°; Figure 7(c) Schematic diagram of the R-t vibration curve when the phase difference between the two array elements is 135°; Figure 7(d) is a schematic diagram of the R-t vibration curve when the phase difference between the two array elements is 60°.

Figure 8 is a typical result of monitoring by using high-speed camera when the method of the present invention is implemented in the bovine serum albumin acrylamide phantom; in Figure 8: (a) to (d) are relatively high duty cycle pulses in the first stage. The typical result graphs of , (e)~(h) are the typical result graphs when the second stage low duty cycle pulse acts.

Figure 9 is an anatomical diagram of the present invention when the method is applied in isolated pig liver.

Figure 10 is a diagram of the H&E staining results when the method of the present invention is applied to the isolated pig liver; in Figure 10: (a) is the injury boundary after the end, (b) and (c) are the images around the injury boundary in (a) Magnification of the image, (d) H&E stained image of normal tissue.

Fig. 11 is a waveform diagram generated by an arbitrary waveform generator in the method of the present invention.

Detailed ways

The present invention will be described in detail below with reference to the accompanying drawings and embodiments.

Based on the research and application status of HIFU technology, the present invention proposes a microbubble synergistic dynamic experimental system and method based on dual-frequency superimposed ultrasonic pulses in a viscoelastic medium. The vibration characteristics in the HIFU guide the development of HIFU and continuously optimize the tissue viscoelastic parameters, waveform and phase parameters. Finally, two superimposed acoustic waves with a certain phase difference are used to make the vibration of the microbubbles in the tissue more intense, enhancing the cavitation effect and improving the efficiency of HIFU. .

Referring to FIG. 1 , the present invention provides a microbubble synergy kinetics experimental system based on dual-frequency superimposed ultrasonic pulses in a viscoelastic medium, including an ultrasonic excitation system, a monitoring and guidance system, a control system and a sound field measurement system.

The ultrasonic excitation system is mainly composed of 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 and guidance system is mainly composed of a light source 4, a high-speed camera 8, a passive cavitation detection probe (PCD probe) 9 and digital ultrasound.

The control system is composed of a computer 10 .

The sound field measurement system includes a fiber optic hydrophone FOPH2000 and a data acquisition card. The computer 10 is connected to the data acquisition card and the optical fiber hydrophone FOPH2000.

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 to the control terminal of the arbitrary waveform generator 1 and the high-speed camera 8, and is used to control the arbitrary waveform generator 1 to emit a specific waveform and to control the high-speed camera 8 to shoot. The gel phantom or the isolated sample 6 is placed in the constant temperature device 7, and the HIFU transducer 5, the passive cavitation detection probe (PCD probe) 9 and the digital ultrasound are installed on the constant temperature device 7; the passive cavitation detection probe (PCD probe) ) 9 and connected to the computer 10 for feedback monitoring information; the light source 4 is arranged outside the constant temperature device 7 for providing illumination. Digital ultrasound is used to locate gel phantoms or ex vivo samples in focus.

The invention provides a microbubble synergy dynamics experimental system based on dual-frequency superimposed ultrasonic pulses in a viscoelastic medium. First, an arbitrary waveform generator 1 generates a required driving signal, and then a power amplifier 2 amplifies it to a specified power and then undergoes impedance matching. After the network 3, the HIFU transducer 5 is driven to work. The high-speed camera 8 monitors the cavitation activity in the focus area with the aid of the light source 4, the PCD probe is used to receive the passive cavitation signals generated in the cavitation activity, and the digital ultrasound system is used to locate the gel phantom or the isolated sample in the focus position. The computer 10 is responsible for receiving the driving signal from the signal generator, synchronously controlling the high-speed camera to shoot, and precisely controlling the timing.

The invention provides a microbubble synergistic kinetic experiment method based on dual-frequency superimposed ultrasonic pulses in a viscoelastic medium, comprising the following steps:

Step 1: Construct the vibration-enhanced excitation waveform of the microbubble.

(1) Use the optical fiber hydrophone to detect the sound field pressure waveform of the HIFU transducer 5 fundamental frequency sound wave and double frequency sound wave focal area. The light scattering coefficient and deviated light coefficient of the instrument are within the specified range of the instrument. During measurement, firstly adjust the three-dimensional moving device so that the fiber optic hydrophone probe scans with a certain step size in the focal area. The HIFU transducer is driven by the transducer drive unit to emit focused ultrasonic waves, and at the same time, the data acquisition card is triggered to collect the sound pressure in the focus area, and the fiber optic probe of the fiber optic hydrophone is moved according to the signal-to-noise ratio and sound pressure amplitude of the collected signal until it appears. maximum value. The sound pressure calculation formula is as follows:

其中α为光纤水听器的光散射系数；

为光纤水听器置于水中测得的光电压值；U_B为光纤水听器置于空气中测得的背景噪声光电压值；U_i为采集的测量光电压值。

where α is the light scattering coefficient of the fiber optic hydrophone;

is the photovoltage value measured by the fiber optic hydrophone placed in water; U _B is the background noise photovoltage value measured by the fiber optic hydrophone placed in the air; U _i is the collected measured photovoltage value.

The obtained results are shown in Figure 5. Due to the nonlinear effect, when a single-frequency sound wave with large amplitude propagates in the medium, the sound wave waveform is gradually distorted due to the interaction with the medium, forming a shock wave.

(2) Build a model to generate the vibration excitation waveform of the microbubble, and solve the KZK equation to obtain the simulation waveform of the sound field pressure in the focal area.

为传播介质的非线性系数；

为声波在传播介质中的衰减参数，μ为流体介质中的体积黏性，u′为切边(剪断)黏性，κ为热传导系数，Δ_⊥为拉普拉斯算子，z为轴向距离，t为时间。where c ₀ is the speed of sound; P is the sound pressure;

is the nonlinear coefficient of the propagation medium;

is the attenuation parameter of the sound wave in the propagating medium, μ is the volume viscosity in the fluid medium, u′ is the edge-cut (shear) viscosity, κ is the thermal conductivity, _Δ⊥ is the Laplace operator, and z is the axial direction distance, t is time.

The KZK equation is an axial approximation transformation of the Westervelt equation, which is in line with the actual situation of a small opening focused sound source. The first term on the right side 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 the sound propagation.

Considering that in practical applications, ultrasound needs to enter the biological tissue through the coupling medium to avoid the useless loss of acoustic energy, so first simulate a 5cm water medium, and then set the tissue parameters and the characteristic parameters of the ultrasonic transducer according to the real situation as much as possible. The sound velocity c ₁ =1482m/s in the water intake medium; the density ρ ₁ =1000kg/m ³ ; the nonlinear parameter β ₁ =3.5; the tissue absorption coefficient η ₁ =2. Take the sound velocity in biological tissue as c ₂ =1629m/s; density ρ ₂ =1000kg/m ³ ; nonlinear parameter β ₁ =4.5; tissue absorption coefficient η ₁ =1. The inner diameter of the transducer R ₁ =1cm; the outer diameter R ₂ =2.5cm; the focal depth d=8cm; the center frequency f=1～5MHz; the sound power P=40～200W.

As shown in Figure 5, the simulated waveform obtained by solving the KZK equation is consistent with the sound field pressure waveform actually measured by the hydrophone. drive waveform conditions.

(3) Compare the simulated waveform with the actual pressure waveform measured by the hydrophone, change the sound power and frequency parameters of the waveform to make the simulated waveform consistent with the actual measured waveform, and use the simulated pressure waveform as the driving waveform condition for microbubble vibration.

Step 2: Build a HIFU synergistic model based on the viscoelasticity of the tissue and the vibration characteristics of microbubbles in compressible fluids.

Combining the Zener mechanics model and the Keller-Miksis equation, the following HIFU synergy model is obtained:

为微泡半径随时间的导数；C₀为声速；σ为周围液体表面张力；μ为周围液体的粘滞系数；P_v为周围液体的饱和蒸气压；τ为气体多方指数，为1.4。

反应组织弛豫时间，λ为泊松比(λ<0.5)，水的泊松比为0.5；

反应组织弹性；

反应组织表面张力；

反应组织粘性。where R is the radius of the microbubble;

is the derivative of the microbubble radius with time; C ₀ is the speed of sound; σ is the surface tension of the surrounding liquid; μ is the viscosity coefficient of the surrounding liquid; P _v is the saturated vapor pressure of the surrounding liquid; τ is the gas polytropic exponent, which is 1.4.

Reaction tissue relaxation time, λ is Poisson's ratio (λ<0.5), and Poisson's ratio of water is 0.5;

Responsive tissue elasticity;

Reactive tissue surface tension;

Reactive tissue stickiness.

Since the elastic modulus G of biological tissue is in the range of 0-10MPa, and the viscosity μ is in the range of 0.004-0.03Pa.s, when constructing the biological tissue model, the simulation parameters are set as follows: Ca=0.01-5; De=0- 1; We=1～20; Re=0～10. Various parameters in different biological tissues are not the same, resulting in different vibration characteristics of microbubbles in different biological tissues.

Step 3: Establish a microbubble synergistic kinetic method based on dual-frequency superimposed ultrasonic pulses in a viscoelastic medium (gel phantom or in vitro sample (6)) and perform simulation calculation.

(1) The microbubble vibration model in the viscoelastic medium under the excitation of a single sine wave is established by formulas (3), (4) and (5): the simulation parameters are Ca=0.01～1; De=0～0.5; We= 1～10; Re=0～5.

The results are shown in Fig. 6. The elasticity, viscosity, relaxation time and surface tension of biological tissue all affect the vibration amplitude, equilibrium radius and rupture process of microbubbles. Therefore, changing the sound pressure and frequency phase of the acoustic wave according to the viscoelastic properties of the biological tissue can increase the vibration amplitude of the microbubbles in the biological tissue, enhance the cavitation effect, and effectively guide the development of HIFU thermal ablation and tissue damage.

(2) Establish the vibration model of microbubbles in viscoelastic media under the condition of continuous sine wave excitation: in the actual process of HIFU thermal ablation and tissue damage, the microbubbles are in a continuous excitation state. Under the condition of double-frequency superposition, the two groups of ultrasonic pulses have a certain phase difference. The simulation parameters take Ca=0.01-1; De=0-0.5; We=1-10; Re=0-5.

The obtained vibration characteristics of the microbubble under the continuous excitation double-frequency superposition are shown in Figure 7. In the fundamental frequency and the double-frequency mode, when the phase difference is 135°, the negative pressures of the two frequencies are just superimposed together, and the microbubble When the vibration radius reaches the maximum amplitude, the cavitation effect is enhanced, which improves the efficiency of HIFU thermal ablation and tissue damage.

Step 4: Determine the waveform parameters to perform HIFU thermal ablation or tissue damage in combination with the simulation results of the above-mentioned synergistic methods.

Arbitrary waveform generator 1 sends out the waveform shown in Figure 11. After passing through the power amplifier, it drives the HIFU transducer through the impedance matching network, and performs thermal ablation or tissue damage on the gel phantom or the isolated sample 6 under the monitoring of the monitoring and guidance system. . Two sets of ultrasonic pulses are used to drive the HIFU transducer. One of the excitation pulses sent by an arbitrary waveform generator is amplified by power to drive the fundamental frequency array element, and its working range is 1-3MHz; the excitation pulses sent by the other arbitrary waveform generator are After power amplification, the harmonic frequency array element is driven, and its working range is 2-10MHz. Pulse focused ultrasound will generate boiling bubbles and shock waves to form loose local structures, while inertial cavitation and shock waves and other mechanical effects will further homogenize the damage and form a large number of cavitation nuclei. The phase difference between the two sets of excitation pulses is 135°, which can make the microbubbles reach the maximum vibration radius in the focal zone, enhance the cavitation effect, and shorten the time required for HIFU thermal ablation and tissue damage.

When the experimental object is a gel phantom, the process and final shape of the damage formation are observed by high-speed videography.

When the experimental object is an isolated pig kidney, the damage morphology should be observed by incision, and the changes of cell morphology should be observed by staining.

Accompanying drawing 4 is the flow chart of the present invention, first according to the fundamental frequency that the hydrophone measures and obtains the actual sound field waveform of the frequency-octave sound wave focal area, determine the KZK equation parameter setting to construct the enhanced microbubble vibration excitation waveform, then according to the viscoelasticity of the tissue and Based on the vibration characteristics of microbubbles in compressible fluids, the Keller-Miksis equation was solved to build a microbubble synergy model, and then a microbubble synergy dynamics method based on dual-frequency superimposed ultrasonic pulses in viscoelastic media was established and simulated to select the appropriate model. Tissue viscoelastic parameters, HIFU waveform and phase parameters, and finally combined with the simulation results to guide the experiment and continuously optimize the parameters.

FIG. 5 is the focal area sound field waveforms of fundamental frequency sound wave and double frequency sound wave measured by the hydrophone and the focal area sound field simulation waveform obtained by solving the KZK equation. Figures 5(a) and 4(c) are the actual waveforms of the focal area sound field measured by the hydrophone. High-intensity sound waves will have nonlinear effects during the propagation process, and the standard sine waves will be distorted into shock waves. The formation is favorable for the cavitation effect. Figures 5(b) and 5(d) are the simulation waveforms of the focal area sound field obtained by solving the KZK equation. By comparing the two, it can be seen that the simulated waveform is in good agreement with the actual waveform, and it is used as the excitation waveform.

6 is a simulation diagram of microbubble vibration under different hydrodynamic parameters of biological tissue. As shown in Fig. 6, it can be found that in biological tissue, the final equilibrium radius of microbubbles increases with decreasing Ca value (reduced elasticity), and the amplitude of oscillation decreases, which is due to the decreased elasticity The damping is increased and the oscillation of the microbubble is limited. The value of De (relaxation time) increases, and the equilibrium radius of the microbubble pulsation remains constant. In a low elastic medium (low Ca value), the value of De ( The relaxation time) plays a major role in the oscillation characteristics of the microbubbles and dominates the magnitude of the damping. In highly elastic media (high Ca value), the value of Re (viscosity) plays a major role in the pulsatile properties of microbubbles. As the pressure increases, the amplitude and frequency of the microbubble pulsation increase (ie, the vibration is fast and intense); the time taken to reach equilibrium decreases.

FIG. 7 is a simulation diagram of the microbubble vibration when the phase difference between the fundamental frequency array element and the frequency-doubling array element is 135° and 60°. When the phase difference between the fundamental frequency and the doubling frequency is 135°, the negative pressures of the two frequencies are superimposed together and reach the maximum amplitude. At this time, the maximum radius of the microbubble vibration also reaches the maximum, and the cavitation effect is enhanced, greatly improving the the efficiency of HIFU. When the phase difference is 60°, the maximum radius of the microbubble vibration decreases, and obvious resonance occurs.

Example 1:

1) Prepare a bovine serum albumin (BSA) polyacrylamide gel replica with a mass fraction of 7%, and add bovine serum albumin as a temperature change indicator. The density of the gel phantom is 1.06g/cm ³ , the sound velocity in the finished gel phantom is 1477±5m/s, and the sound attenuation coefficient is 0.42±0.01dB/cm.

2) Place and fix the annular HIFU transducer 5 and the B-ultrasound probe as shown in FIG. 1 , inject an appropriate amount of degassed water into the reaction vessel, and open the thermostat 7 . Turn on the ultrasound imaging equipment and adjust the point to be damaged in the gel phantom to the focal point of the transducer according to the image guidance.

3) Write the signal waveform to be generated by the arbitrary waveform generator according to Figure 11.

4) The timing sequence of the signal excitation module and the monitoring and guiding module is controlled by the computer 10, so that the damage and monitoring of the gel phantom or the isolated sample are triggered at the same time.

Analysis results:

As shown in Fig. 8, the time for the first appearance of boiling bubbles in the center of the focal zone was 1.29s, which was 417.05% faster than the first appearance of boiling bubbles in the 1.06MHz single frequency result of 6.67s, as shown in Fig. 8(b). The randomly distributed microbubbles aggregate and fuse to form larger-sized microbubbles. Figure 8(c) and Figure 8(d) show that more and larger boiling bubbles appear in the focal area, and the size of the damage gradually expands. , this stage uses a higher duty cycle pulse, mainly using the HIFU thermal effect to generate boiling bubbles, and the boiling bubbles burst to generate more cavitation nuclei; after the cavitation bubbles burst, a mechanical effect occurs to smash the target area, Figure 8(e)～(h ) shows that with the extension of time, the damage volume expands towards the end away from the transducer, and the microbubbles swim towards the end away from the transducer under the action of radiation force, indicating that the interior of the injury has been completely liquefied, forming a fusiform cavity .

Example 2:

1) Preparation of acrylamide mimic body fluid. Select fresh pig kidneys, cut them into a size of 5mm×3mm×30mm, fix them in imitation body fluid, and coagulate them at room temperature.

2) Fix the annular array HIFU transducer 5 and the B-ultrasound probe as shown in Figure 1, inject an appropriate amount of degassed water into the reaction vessel, and open the thermostat 7. Turn on the ultrasound imaging equipment and adjust the center position of the porcine kidney to the focus of the transducer according to the image guidance.

3) Write the signal to be generated by the arbitrary waveform generator according to Figure 11. Throughout the process, the sound power was set to 240W.

4) Connect channel 1 of the arbitrary waveform generator in the synchronization signal control system to the ultrasonic excitation system, and channel 2 to the guidance monitoring system. Turn on each device and manually trigger the synchronization signal control system. Channel 1 is connected to the external trigger terminal of the arbitrary waveform generator in the ultrasonic excitation system, and the signal sent in the trigger ultrasonic excitation system passes through the RF power amplifier, the impedance matching network and drives the HIFU transducer. Channel 2 starts high-speed camera equipment for real-time monitoring.

5) When the HIFU process is over, first observe the damage through B-ultrasound equipment, then take out the pig kidney, cut it open, and then analyze the damage carefully. The damaged porcine kidneys were stained with H&E, and the histological results were observed under a high-power microscope.

Analysis results:

As shown in Figure 9, the actual damage volume is similar to that observed in the gel phantom experiments. The lesion boundary formed in pig kidney tissue is smooth and clear without obvious white thermal damage. Figure 10(a) shows that there is a clear boundary between the damaged area tissue and the normal area tissue, Figure 10(b) and Figure 10(c) After zooming in on the boundary, it can be clearly seen that the damaged area inside the boundary is completely homogenized, and the cell structure of the normal area outside the boundary remains intact. The effect is excellent. In addition, when we dissect the ex vivo tissue to look at the internal injury, we can see that the inside of the injury has been completely emulsified, the fluidity has been enhanced, and it has become a liquid that can be directly absorbed by the surrounding group.

It is known from the technical common sense that the present invention can be realized by other embodiments without departing from its spirit or essential characteristics. Accordingly, the above-disclosed embodiments are, in all respects, illustrative and not exclusive. All changes within the scope of the present invention or within the scope equivalent to the present invention are encompassed by the present invention.

Claims (6)

1. the microbubble synergy kinetics experimental method based on dual-frequency superimposed ultrasonic pulses in viscoelastic medium, is characterized in that, based on the microbubble synergistic kinetics experimental system based on dual-frequency superimposed ultrasonic pulses in a viscoelastic medium; The microbubble synergistic kinetics experimental system based on dual-frequency superimposed ultrasonic pulses in the viscoelastic medium includes an ultrasonic excitation system, a monitoring and guidance system, a sound field measurement system and a control system; the ultrasonic excitation system includes: an arbitrary waveform generator (1), A radio frequency power amplifier (2), an impedance matching network (3) and a HIFU transducer (5); the monitoring and guidance system includes a light source (4), a high-speed camera (8), a PCD probe (9) and a digital ultrasound; the control system includes a computer (10); 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 gel phantom or the isolated sample (6) is placed at a constant temperature In the device (7), the HIFU transducer (5) is installed on the constant temperature device (7); the light source (4) is arranged outside the constant temperature device (7) for providing illumination; the sound field measurement system includes an optical fiber hydrophone and a data acquisition card; the sound field measurement system is used to detect the sound field pressure waveform of the HIFU transducer (5) the fundamental frequency sound wave and the multiplied frequency sound wave focal zone through the cooperation of the optical fiber hydrophone and the data acquisition card; the computer (10) is connected to an arbitrary waveform to generate device (1), high-speed camera (8), PCD probe (9), digital ultrasound and data acquisition card, used to control the waveform generator (1) to send out the set waveform, control the high-speed camera (8) and the PCD probe (9) ) collect experimental data; The microbubble synergy kinetics experimental method comprises the following steps: Step 1. Construct the vibration-enhanced excitation waveform of the microbubble; 1.1), use the fiber optic hydrophone to detect the sound field pressure waveform of the HIFU transducer fundamental frequency sound wave and double frequency sound wave focal zone; 1.2), build a model for generating microbubble vibration excitation waveform, and solve the KZK equation to obtain the focal zone sound field pressure simulation waveform; 1.3), compare the simulated waveform with the actual pressure waveform measured by the hydrophone, optimize the model parameters so that the simulated waveform is consistent with the actual measured pressure waveform, and use the simulated pressure waveform as the driving waveform condition of the microbubble vibration; Step 2, 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 microbubbles in the compressible fluid; Step 3: establish a microbubble synergistic kinetic method based on dual-frequency superimposed ultrasonic pulses in the viscoelastic medium of the tested gel phantom or the in vitro sample (6), and perform simulation calculation; 3.1), establish the microbubble vibration model in the viscoelastic medium under the condition of a single sine wave excitation, select the tissue viscoelastic parameters and simulate; 3.2), establish the microbubble vibration model in the viscoelastic medium under the condition of continuous sine wave excitation, select tissue viscoelastic parameters and simulate; Step 4: Determine the waveform parameters of the arbitrary waveform generator (1) according to the results of steps 1 to 3, and control the HIFU transducer (5) to perform HIFU heating on the gel phantom or in vitro sample (6) to be tested according to the waveform parameters. Ablation or tissue destruction experiments. 2. in the viscoelastic medium according to claim 1, the microbubble synergy kinetics method based on dual-frequency superimposed ultrasonic pulse is characterized in that, step 1.2) built model is:

where c ₀ is the speed of sound; P is the sound pressure;

is the nonlinear coefficient of the propagation medium;

is the attenuation parameter of the sound wave in the propagation medium, μ is the volume viscosity in the fluid medium, u′ is the viscosity of the cutting edge, κ is the thermal conductivity, Δ _⊥ is the Laplace operator, z is the axial distance, t for time. 3. in the viscoelastic medium according to claim 1, based on the microbubble synergistic dynamics method of double-frequency superposition ultrasonic pulse, it is characterized in that, the built HIFU synergy model is:

where R is the radius of the microbubble;

is the derivative of the microbubble radius with time; C ₀ is the speed of sound; σ is the surface tension of the surrounding liquid; μ is the viscosity coefficient of the surrounding liquid; P _v is the saturated vapor pressure of the surrounding liquid; τ is the gas polytropic exponent, which is 1.4;

Reaction tissue relaxation time, λ is Poisson's ratio;

Responsive tissue elasticity;

Reactive tissue surface tension;

Reactive tissue stickiness. 4. The microbubble synergy dynamics method based on dual-frequency superimposed ultrasonic pulses in the viscoelastic medium according to claim 1, is characterized in that, the arbitrary waveform generator (1) generates a driving signal, and then the power amplifier (2) After zooming in, the HIFU transducer (5) is driven to work after passing through the impedance matching network (3), and a waveform is applied to the focal area of the gel phantom or the isolated sample (6). The cavitation activity in the focal area is monitored with the aid of the PCD probe (9) to receive the passive cavitation signal generated in the cavitation activity, and the digital ultrasound is used to locate the gel phantom or the isolated sample at the focal position; the computer ( 10) Responsible for receiving the driving signal from the signal generator, and synchronously controlling the high-speed camera for shooting. 5. in the viscoelastic medium according to claim 1, the microbubble synergistic dynamics method based on dual-frequency superimposed ultrasonic pulse is characterized in that, the HIFU transducer (5) is an annular array transducer, and its fundamental frequency array The working range of the element is 1~3MHz; the working range of the frequency doubling array element is 2~10MHz. 6 . The microbubble synergy kinetics method based on dual-frequency superimposed ultrasonic pulses in the viscoelastic medium according to claim 1 , wherein the HIFU transducer has a hole in the middle for installing a digital ultrasonic probe. 7 .

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