A method for high intensity focused ultrasound ablation efficacy monitoring and dose control

Abstract

The application provides a high intensity focused ultrasound (HIFU) ablation effect monitoring and dose control method, and belongs to the field of biomedical ultrasound. The method uses a double-frequency multiplexing technology to excite a single focusing transducer to construct a double-frequency HIFU ablation treatment system, and carries out orthogonal detection of tissue scattering difference frequency sound pressure outside the HIFU treatment sound field; the dynamic change of tissue parameters caused by temperature rise is introduced to correct the sound pressure distribution of the focal region in real time, and the accuracy of tissue temperature rise and effect monitoring is improved; the critical point of the change of the difference frequency sound pressure is selected as the effect monitoring standard and dose control parameter of the HIFU ablation. The double-frequency excitation of the single transducer improves the treatment efficiency and positioning accuracy of the HIFU ablation; the difference frequency sound pressure is generated in real time by the treatment focal region, is not affected by the tissue parameters of other parts, is accurate in measurement, is not interfered by the excitation sound field in the orthogonal difference frequency detection outside the HIFU treatment sound field, and is stable and reliable in synchronous measurement; the application is completely compatible with the existing commercial HIFU treatment system, and does not need to be additionally equipped with other detection equipment.

Description

Technical Field

[0001] This invention relates to the fields of biomedical ultrasound and high-intensity focused ultrasound therapy, specifically to methods for monitoring the efficacy and controlling the dosage of high-intensity focused ultrasound ablation. Background Technology

[0002] High-intensity focused ultrasound (HIFU) is a non-invasive tumor treatment method that significantly reduces surgical risks and recovery time. It utilizes ultrasound energy focused on the target tissue, converting acoustic energy into heat energy to rapidly increase the target area temperature, leading to coagulative necrosis of tumor cells and achieving early tumor treatment. HIFU ablation focuses on two aspects: acoustic field modulation and efficacy monitoring. One aspect is HIFU acoustic field modulation and optimization, such as precise focal zone localization under MRI guidance, the influence of HIFU acoustic parameters, tissue characteristic parameters, and nonlinearity on efficacy, and the enhancement of efficacy through multi-frequency excitation. The other aspect is temperature monitoring and dose control based on changes in tissue morphology or physical parameters, using electrical, magnetic, and acoustic methods.

[0003] Currently, common methods for evaluating the efficacy of HIFU ablation include MRI imaging, ultrasound imaging, electrical impedance tomography (EIT), and magnetoacoustic-electrical detection (MEAD). MRI imaging reflects the effectiveness of tumor tissue killing by detecting protein denaturation and aggregation, cell membrane and nuclear membrane damage, and tissue metabolic cessation. It has high spatial resolution but poor real-time performance and is expensive. Ultrasound imaging monitors the thermal damage state of tissues by utilizing the differences in sound velocity, density, or elastic modulus of tissues with temperature changes. It has unique system fusion advantages, but requires an additional ultrasound system, and the accuracy of ultrasound echo measurement is severely affected by the HIFU signal and the environment. Electrical impedance tomography and MEAD detect the difference in conductivity of human tissue before and after denaturation to evaluate the efficacy of HIFU. It can reconstruct high-resolution images, but requires an additional current or magnetic field excitation system and cannot achieve real-time monitoring of tissue characteristics.

[0004] Studies have shown that dual-frequency excitation of the HIFU focal zone with higher sound pressure levels can significantly improve the efficacy of HIFU treatment. However, when the energy reaches the MPa level, the nonlinearity generated by the propagation of sound waves in tissues cannot be ignored. The changes in tissue nonlinear acoustic parameters are closely related to temperature, especially showing significant changes before and after tissue thermal damage. For example, with the same temperature change, the tissue nonlinear acoustic parameter B... AThe rate of change of sound is four times higher than the speed of sound, making it more sensitive to the therapeutic effect of HIFU. Furthermore, in dual-frequency HIFU treatment, the parametric array effect of the interaction between sound waves and tissue generates a difference-frequency signal. The magnitude of this sound pressure varies with the nonlinear characteristics of the tissue, providing more useful information for monitoring tissue temperature and denaturation, and possessing the absolute advantages of low attenuation and high sensitivity. The difference-frequency sound pressure is generated by tissue nonlinearity during dual-frequency HIFU ablation, and its magnitude is determined by the focal zone sound pressure, tissue temperature and density, and nonlinear acoustic parameters, providing a physical basis for real-time monitoring of the therapeutic effect of HIFU ablation. However, previous experimental studies considered the difference-frequency signal to be a low-frequency envelope generated by the superposition of dual-frequency excitation signals acting on biological tissue, and its amplitude could reflect the degree of ablation in the target area to some extent. However, these studies did not fundamentally study the physical mechanism of the difference-frequency sound pressure generation, neglecting the influence of temperature-varying tissue physical parameters and nonlinear characteristics on the sound field, temperature field, and difference-frequency sound pressure. Consequently, a quantitative monitoring method for HIFU ablation based on difference-frequency sound pressure has not been developed, and precise dose control cannot be achieved. Summary of the Invention

[0005] To address the common problems in current HIFU ablation temperature monitoring and efficacy assessment, such as complex measurement systems, low sensitivity, slow speed, low resolution, and non-real-time performance, this invention proposes a differential frequency sound pressure generation and measurement model based on the temperature distribution of the HIFU focal zone and considering the influence of tissue parameters and nonlinear characteristics on the sound field. It determines the variation characteristics of differential frequency sound pressure with treatment time in dual-frequency HIFU ablation and proposes a method for high-intensity focused ultrasound ablation efficacy monitoring and dose control. The differential frequency sound pressure of this invention is generated in real-time by the dual-frequency HIFU sound field in the treatment focal zone, unaffected by tissue parameters from other sites, ensuring accurate measurement. Furthermore, it requires no additional excitation, and its orthogonal measurement exhibits good anti-interference capabilities, making it easy to implement real-time efficacy monitoring and dose control based on existing HIFU systems.

[0006] A method for monitoring the efficacy and controlling the dosage of high-intensity focused ultrasound ablation, comprising the following steps:

[0007] S1. Based on the nonlinear propagation theory of sound waves in biological tissues, this study investigates the generation mechanism of difference-frequency sound waves excited by dual-frequency HIFU. Considering the real-time influence of temperature distribution on tissue density, sound velocity, and nonlinear acoustic parameters, the theoretical formula of difference-frequency sound pressure is derived, and a method for real-time efficacy monitoring and dose control of HIFU ablation based on difference-frequency sound pressure is proposed.

[0008] S2. Based on a single dual-frequency multiplexed signal excitation with a transducer, the acoustic field distribution in the focal domain of HIFU was studied, and the temperature field distribution in the acoustic field focal domain at different treatment times under different acoustic power was investigated.

[0009] S3. Based on the relationship between tissue temperature and physical parameters, parameters such as tissue density, sound velocity, and nonlinear acoustic parameters caused by temperature are introduced into the sound field calculation. The sound wave transmission coefficient is corrected, and a closed-loop feedback calculation model of "focal temperature-tissue parameters-sound pressure distribution-difference frequency sound pressure" is established to obtain the real-time difference frequency sound pressure during HIFU treatment.

[0010] S4. By changing the output acoustic power of the transducer, the real-time differential frequency sound pressure distribution in HIFU treatment is simulated. The magnitude and occurrence time of the peak differential frequency sound pressure are studied, and the focal temperature distribution at the inflection point of the differential frequency sound pressure is analyzed. A therapeutic efficacy monitoring standard is proposed, which uses the inflection point of the differential frequency sound pressure as the starting point for thermal damage in the focal center.

[0011] S5. After the differential frequency sound pressure inflection point appears, HIFU treatment continues. The thermal damage area in the focal zone center gradually increases, while the real-time differential frequency sound pressure decreases monotonically. Analyzing the focal zone temperature distribution during the differential frequency sound pressure decrease process, it was found that when the differential frequency sound pressure decays by 6dB from the peak, the axial length of the HIFU focal zone reaching 67℃ is basically the same under different sound power, generally 8-15mm, which is determined by the transducer frequency, radius, and focal length. Therefore, a method of using a 6dB decay of the differential frequency sound pressure as an effective dose control parameter for HIFU ablation is proposed.

[0012] S6. By using dual-frequency multiplexing technology to excite single-focus transducers of different sizes, a dual-frequency HIFU treatment and differential frequency real-time monitoring system was established. The differential frequency sound pressure change under different sound power was measured in real time. The inflection point of the differential frequency sound pressure and the size of the focal thermal ablation area at the 6dB decay time were measured. This proved the correctness and feasibility of using the differential frequency sound pressure inflection point and 6dB decay as HIFU ablation efficacy monitoring standards and dose control parameters.

[0013] Furthermore, in step S1, based on the nonlinear characteristics of tissues and the theory of acoustic parametric arrays, a principle and method for real-time monitoring of difference frequency sound pressure based on dual-frequency excitation HIFU are constructed, as follows:

[0014] A dual-frequency signal is constructed using multiplexing technology, and after power amplification, it excites a concave spherical focusing transducer to build a confocal dual-frequency HIFU sound field. The transducer radius a = 1–30 cm, and its focal length F is greater than the radius. Based on the transducer's center (angular) frequency ω0 and relative bandwidth B... W If the difference frequency signal frequency Δω is set to (-3dB), then the dual-frequency signal frequency is ω0±Δω, where Δω≤(B w ω0) / 2. The acoustic attenuation coefficient of biological tissue increases with increasing frequency, which can be expressed as α=α0×(f / f0). yWhere α0 represents the acoustic attenuation coefficient corresponding to f0 = 1MHz, and the y-value of biological tissue is between 1.1 and 1.7, which needs to be determined based on actual tissue measurements. Two sound waves of different frequencies propagating coaxially in biological tissue will produce a nonlinear interaction. Based on the parametric array effect, the difference-frequency sound wave excited when the coaxially propagating dual-frequency sound waves travel a distance z is:

[0015]

[0016] Where c is the speed of sound in the medium, and ρ is the density of the medium. and Here, Δω represents the sound pressure level of the dual-frequency sound wave, Δω is the frequency difference, z is the sound propagation distance, and γ = B. A +1 represents the ratio of isobaric specific heat to isovolumetric specific heat, B A It is a nonlinear acoustic parameter. Thus, the difference frequency sound pressure is obtained, which is determined by the dual-frequency excitation sound pressure, the medium acoustic impedance, the nonlinear acoustic parameter, and the propagation distance.

[0017] Further, in step S2, a study of the acoustic field focal temperature field is conducted, as detailed below:

[0018] In dual-frequency HIFU treatment, the amount of heat absorbed by the tissue in the focal region of the sound field can be approximated as Q≈2α(I ω1 +I ω2 ), where I ω1 and I ω2 The sound intensity of the dual-frequency sound wave is approximately equal in terms of attenuation coefficient α when Δω < ω0 / 10. Since the metabolic heat of biological tissues is extremely small, the Pennes equation for heat conduction in biological tissues is used without considering the influence of blood perfusion rate. Predict the temperature distribution in the focal region of the tissue, where ρ(T) and C p K(T) and K(T) represent the density, specific heat, and thermal conductivity of the tissue at temperature T, respectively. Since the temperature rise distribution of the focal zone tissue is uneven, the tissue density and sound velocity distribution will differ due to temperature differences. Therefore, based on the change in acoustic impedance of the focal zone tissue caused by temperature distribution, a transmission coefficient is introduced to correct the sound pressure distribution of the HIFU focal zone.

[0019] Further, step S3, the real-time sound field construction based on tissue parameters and the real-time calculation of difference frequency sound pressure, is as follows:

[0020] Under dual-frequency HIFU excitation, the sound pressure, density, sound velocity, and nonlinear acoustic parameter distribution of the ellipsoidal focal region tissue change in real time with treatment time. Since the axial length of the focal region is greater than its radial width, the difference-frequency sound pressure generated by the HIFU focal region can be obtained by the one-dimensional sound pressure distribution along the z-axis sound propagation.

[0021]

[0022] Where dz is the axial length of the infinitesimal element at position z. and B represents the dual-frequency sound pressure level at that location. A (T,z), ρ(T,z), and c(T,z) represent the nonlinear acoustic parameters, density, and sound velocity at temperature T. Due to variations in tissue parameters, the acoustic impedance differs at different locations within the focal region, causing changes in the sound wave transmission coefficient during propagation. Therefore, the acoustic transmission coefficient tp(z) resulting from the acoustic impedance change is introduced at z and applied to the dual-frequency signal to further correct the sound pressure distribution of the sound field. A simplified layered model is established along the propagation z direction; the transmission coefficient at the propagation distance z can be obtained by multiplying the transmission coefficients between different layers within the focal region. To calculate, where The input impedance is the total impedance of all layers before point z, k = 2π / λ, where λ is the wavelength of the acoustic wave. The axial calculation range of the focal region of the focusing transducer is [F–L / 2, F+L / 2], where F is the focal length of the focusing transducer, and L = 4λF. 2 / a 2 For the axial focal length of , dz is generally required to be less than L / 1000 in order to ensure calculation accuracy.

[0023] Further, in step S4, the relationship between difference frequency sound pressure and treatment time is studied to determine the relationship between the peak sound pressure inflection point and the therapeutic effect, as detailed below:

[0024] Based on the proposed differential frequency sound pressure theory formula, differential frequency sound pressure simulations were performed on HIFU devices with different power levels. The relationship between the simulation and treatment time was analyzed, and experimental verification was conducted. The results show that the temperature in the HIFU focal zone increases with the extension of treatment time, and the nonlinear acoustic parameter B in the focal zone tissue... A The temperature gradient of the increased tissue in the focal zone increases the acoustic impedance difference, reduces the acoustic transmission system, and decreases the real-time sound pressure in the HIFU focal zone. When the temperature reaches 67°C, tissue denaturation occurs, and the tissue nonlinear acoustic parameters hardly increase, remaining approximately constant. This causes the differential frequency sound pressure to peak when the therapeutic effect is achieved at the center of the focal zone, and then begins to decline as the treatment time increases, forming an inflection point. Therefore, the differential frequency sound pressure inflection point can be used as the standard for monitoring the therapeutic effect when tissue denaturation begins to appear in the center of the HIFU focal zone.

[0025] Further, in step S5, the relationship between difference frequency sound pressure and the size of the tissue ablation area is studied to determine the dose control method for sound pressure attenuation, as follows:

[0026] Theoretical and experimental results demonstrate that as the acoustic power of HIFU increases, the peak value of the differential frequency sound pressure increases, but the treatment time to reach the inflection point decreases. Therefore, the inflection point of the differential frequency sound pressure only indicates that the tissue in the center of the focal zone begins to degenerate, but it cannot determine the extent of the degeneration. However, when the differential frequency sound pressure decreases by 6 dB from its peak value, ablation focal zones (temperatures exceeding 67°C) with approximately the same axial length (approximately 10 mm for the transducer used in the example) are produced under different acoustic powers. These can serve as effective treatment areas of approximately the same size. Therefore, a 6 dB decrease in the peak value of the differential frequency sound pressure can be used as an effective dose control parameter to obtain therapeutic focal zones of the same size.

[0027] Furthermore, in step S6, the system's hardware system and experimental plan are as follows:

[0028] This experimental system consists of a computer, a function generator, a power amplifier, a focusing transducer, a difference frequency detection transducer, a digital oscilloscope, a tissue phantom, and a camera. The focusing transducer is connected to the power amplifier, the signal generator, and the computer in sequence. Dual-frequency multiplexed signal waveform data is obtained through computer programming, output by the function generator, amplified by the power amplifier, and then drives the focusing transducer to form a dual-frequency HIFU sound field acting on the tissue phantom. To avoid interference from the dual-frequency HIFU sound field on the difference frequency sound pressure detection, a planar piston transducer with a center angular frequency of Δω is placed outside the HIFU treatment sound field at a fixed position perpendicular to the sound beam propagation axis. The difference frequency detection transducer is connected to the digital oscilloscope and the computer in sequence. The detected focal-area scattered difference frequency signal is acquired by the digital oscilloscope and transmitted in real time to the computer for calculating the difference frequency sound pressure. A camera can be placed above the focal area to record the HIFU ablation and denaturation process of the tissue phantom in real time.

[0029] In step S6, the dual-frequency excitation of a single focusing transducer within its bandwidth effectively improves the treatment efficiency and positioning accuracy of HIFU ablation. The difference-frequency sound pressure is generated in real-time by the treatment focal zone, unaffected by tissue parameters from other sites, ensuring accurate measurement. Orthogonal difference-frequency sound pressure detection located outside the HIFU treatment sound field is unaffected by the excitation sound field. The high difference-frequency sound pressure generated by tissue nonlinearity under HIFU excitation allows for direct synchronous measurement without a preamplifier, resulting in a stable and reliable waveform. This facilitates real-time efficacy monitoring and dose control of HIFU ablation through direct measurement of the difference-frequency sound pressure peak and its attenuation. This orthogonal difference-frequency sound pressure detection method is fully compatible with existing commercial HIFU treatment systems, facilitating system integration and development. It achieves real-time, high-precision efficacy monitoring and dose control without requiring additional temperature or efficacy detection equipment.

[0030] The beneficial effects of this invention are as follows: This invention combines real-time differential frequency sound pressure monitoring with dual-frequency HIFU ablation technology. By orthogonally detecting the differential frequency signal scattered by the focal zone tissue, the efficacy monitoring of HIFU ablation is directly carried out using the amplitude change of the differential frequency sound pressure. Furthermore, the 6dB attenuation of the differential frequency sound pressure is used as a precise control parameter for ultrasound dosage. This invention has the advantages of simple system, direct measurement, strong anti-interference ability, and high measurement accuracy. It is easy to integrate and apply in existing HIFU treatment systems, providing a stable and reliable new method for efficacy monitoring and dosage control of HIFU ablation technology. Attached Figure Description

[0031] Figure 1 System block diagram of the present invention.

[0032] A: Computer B: Signal generator C: Power amplifier D: Oscilloscope

[0033] Figure 2 When the surface vibration velocity u0 = 50 mm / s, the (a) axial and (b) focal plane of the dual-frequency HIFU focal domain.

[0034] Radial sound pressure distribution within the plane.

[0035] Figure 3 Under the condition of u0=50mm / s, (a) axial profile of the HIFU focal zone, (b) axial and (c) radial temperature distributions through the focal point; (d) axial profile temperature distributions of the tissue within the 10mm axial and 1.6mm radial range of the HIFU focal zone at different acoustic power levels when the tissue temperature exceeds 67℃.

[0036] Figure 4 (a) Axial sound pressure distribution at different times after parameter correction under u0=50mm / s condition, (b) Curve of difference frequency sound pressure change with treatment time, (c) Focus temperature and (d) Distribution curves of axial length and radial width of the modified focal domain with treatment time.

[0037] Figure 5 Under different HIFU sound power, (a) the curve of difference frequency sound pressure change with time, and (b) the relationship between the treatment time and sound power required to reach the inflection point and the therapeutic effect.

[0038] Figure 6 Experimental results under different HIFU sound power: (a) the curve of difference frequency sound pressure change over time; (b) the relationship between the treatment time and sound power required to reach the inflection point and the therapeutic effect; (c) gel denaturation photograph at the inflection point of difference frequency sound pressure; (d) gel denaturation photograph at 6 dB decay of difference frequency sound pressure. Detailed Implementation

[0039] The present invention will be further illustrated below with reference to the accompanying drawings and specific embodiments. It should be understood that the following specific embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. It should be noted that the terms "front," "rear," "left," "right," "up," and "down" used in the following description refer to directions in the accompanying drawings, and the terms "inner" and "outer" refer to directions toward or away from the geometric center of a specific component, respectively.

[0040] like Figure 1 As shown, this embodiment uses dual-frequency signals A0cos(2πf1t) + A0cos(2πf2t) to excite the focusing transducer and construct a dual-frequency HIFU sound field. The specific parameters of the focusing transducer used are: radius a = 50mm, focal length F = 130mm, center frequency f0 = 1.15MHz, and relative bandwidth B. W The focal length range is 40%, with an axial range of [115, 148] mm. The dual-frequency signals are f1 = 1.13 MHz and f2 = 1.17 MHz, with Δf = 40 kHz. Due to the small frequency difference, the surface sound pressure of the transducer can be approximated as p1 ≈ p2 = ρcu0 (where u0 is the surface vibration velocity of the transducer, ranging from 50 to 100 mm / s). The sound power of the HIFU is adjusted by adjusting u0. A planar piston transducer with a center frequency of 40 kHz is vertically mounted on the side of the focal length for orthogonal detection of the difference frequency sound pressure.

[0041] Using the aforementioned transducer, the HIFU sound field distribution was simulated, and the focal zone tissue temperature distribution at different treatment times was calculated. The relationship between tissue parameters and temperature was introduced, and the acoustic impedance difference and nonlinear parameter distribution caused by temperature in the focal zone were considered to correct the sound field distribution at different times. The real-time difference frequency sound pressure was calculated using the derived formula to obtain the distribution of difference frequency sound pressure with treatment time. Through calculations under different vibration velocities u0, the relationship between the peak inflection point of difference frequency sound pressure, the focal zone temperature distribution, and the therapeutic effect during HIFU ablation was analyzed. The relationship between difference frequency sound pressure attenuation and the therapeutic area was determined, and finally, a difference frequency sound pressure monitoring standard and dosage control method for tissue ablation were constructed. An experimental system was established, and dual-frequency HIFU ablation of a gel phantom was performed using the transducer with the above parameters. The distribution of difference frequency sound pressure over time was measured in real time to verify the therapeutic efficacy of the difference frequency sound pressure inflection point and its 6dB attenuation.

[0042] The specific implementation steps are as follows:

[0043] (1) Using the COMSOL pressure acoustics module, the focusing sound field at two frequencies was calculated based on the homogeneous Helmholtz equation. The initial water temperature T0 = 30℃, and the effects of cavitation and organization parameters on the sound field were ignored. The relevant parameters are shown in Table 1.

[0044] Table 1 Simulation parameters of tissue and water at an ambient temperature of 30℃

[0045]

[0046]

[0047] When u0 = 50 mm / s, the axial and radial sound pressure distributions at the focal region of the HIFU under two frequency excitations are as follows: Figure 2 As shown, since the two frequencies are similar, their sound pressure distributions are basically the same, with the peak sound pressure level remaining at z = 128.5 mm. Due to tissue attenuation and absorption, the axial width of -3 dB near the transducer side is slightly smaller. The radial sound pressure distribution exhibits obvious axisymmetric characteristics and has certain side lobes, with a main lobe width of approximately 1.66 mm. When u0 = 50 mm / s, the surface sound pressure of the transducer is p1 ≈ p2 = 75 kPa, corresponding to a single-frequency sound power of approximately 15.71 W. Therefore, the equivalent heat source for dual-frequency excitation is Q ≈ 2α(I ω1 +I ω2 The value is 5.91 × 10 7 W / m 3 Furthermore, the calculated surface acoustic pressures for u0 = 60, 70, 80, 90, and 100 mm / s are 90, 105, 120, 135, and 150 kPa, respectively, with corresponding single-frequency acoustic powers of 21.34, 27.53, 34.26, 41.53, and 49.31 W, and a corresponding Q = 8.51 × 10⁻⁶. 7 1.16×10 8 1.51×10 8 1.92×10 8 and 2.36×10 8 W / m 3 .

[0048] (2) Based on the sound field heat source distribution and the Pennes equation, the temperature distribution of the tissue focal region is calculated at 5ms time intervals. The tissue density, constant pressure heat capacity, and thermal conductivity change with temperature as follows:

[0049]

[0050]

[0051]

[0052] With p1≈p2=75kPa, the temperature distribution at different treatment times was calculated, and the results are as follows: Figure 3As shown in (a), with the extension of treatment time, the focal temperature continuously increases, heat diffuses to the surrounding tissue, and the focal area continuously increases, gradually forming an elliptical focal spot on the axial section. When t = 5.2 s, the tissue temperature within the axial range of 1.06 mm and radial range of 0.13 mm of the ellipsoidal focal area reaches 67 °C, resulting in tissue ablation and coagulation. With further extension of treatment time, the temperature at the focal area continues to rise, and the ablation area further expands. At t = 9.6 s, the focal temperature increases from 67 °C to 80 °C, the axial length of the focal area achieving therapeutic effect increases from 1.06 mm to approximately 10 mm, and the radial width increases from 0.13 mm to 1.6 mm. At this point, the ablated tissue size reaches the conventional size for HIFU treatment. The axial and radial temperature distribution of the focal area at different treatment times is shown in the figure. Figure 3 (b) and Figure 3 As shown in (c). Furthermore, to ensure therapeutic efficacy (temperature exceeding 67°C) within a 10mm axial and 1.6mm radial range of the HIFU focal zone, the treatment times required for different HIFU acoustic powers were approximately 9.6, 4.6, 2.77, 1.88, 1.39, and 1.05 seconds, respectively. The corresponding axial profile temperature distributions are shown below. Figure 3 As shown in (d). However, due to the many factors that affect actual acoustic power, it is difficult to achieve precise dosage control solely through treatment time.

[0053] (3) Furthermore, consider the relationship between the nonlinear acoustic parameters, sound velocity, and density of the tissue and temperature:

[0054]

[0055]

[0056]

[0057] Within the focal axial range of [115, 148] mm, the sound field was layered at intervals of dz = 5 μm. Tissue acoustic impedance and nonlinear acoustic parameters were introduced into the sound field to correct the acoustic transmission coefficient at different locations in real time, resulting in... Figure 4 (a) shows the focal axial sound pressure distribution at different treatment times. It can be seen that the sound pressure distribution decreases due to the decrease in the transmission coefficient, and the degree of decrease increases with the extension of treatment time.

[0058] Based on the tissue physical parameters and nonlinear coefficients at different times, the following calculations were obtained: Figure 4(b) shows the curve of difference frequency sound pressure as a function of treatment time. The results indicate that with prolonged treatment time, the focal zone temperature increases, the tissue nonlinear coefficient increases, leading to an increase in difference frequency sound pressure. Increased temperature causes an increase in acoustic impedance difference and a decrease in transmission coefficient, resulting in a decrease in focal zone sound pressure and, to some extent, reducing the rate of increase in difference frequency sound pressure. When the focal zone center temperature reaches 67℃, the tissue gradually coagulates and denatures, and the increase in its nonlinear acoustic parameters tends to level off, remaining essentially unchanged after exceeding 75℃. This leads to a decreasing trend in difference frequency sound pressure. Therefore, under the condition of u0 = 50 mm / s, if... Figure 4 (c) As shown, at t=5.2s, the highest focal temperature is approximately 67℃, reaching the tissue coagulation and denaturation threshold. Further increasing the treatment time increases the focal temperature. At this point, the rate of increase in the nonlinear acoustic parameter is much smaller than the decrease in sound pressure caused by the increase in the transmission coefficient, causing the difference frequency sound pressure to decrease from its peak (0.636MPa). When t=9.6s, the difference frequency sound pressure attenuates by 6dB. Figure 4 (d) shows that the axial length of the focal zone coagulation and denaturation region increases to 10 mm, and the radial width increases to 1.6 mm accordingly, which meets the needs of conventional HIFU treatment.

[0059] (4) With a fixed focal zone axial ablation length of 10 mm (reaching 67℃), the following calculations were performed: Figure 5 (a) shows the curves of difference frequency sound pressure as a function of treatment time under different sound power. It can be seen that the difference frequency sound pressure initially increases and then decreases with increasing treatment time; as shown in (a). Figure 5 As shown in (b), while the inflection point of the differential frequency sound pressure level (DSF) appears more quickly with increasing acoustic power, the time required to achieve the therapeutic effect (6 dB attenuation of DSF) also decreases accordingly. Therefore, the time to achieve the therapeutic effect can be estimated based on acoustic power, and the efficacy monitoring and dosage control of HIFU ablation can be achieved through the inflection point and 6 dB attenuation of the DSF.

[0060] (5) An experimental measurement system with the same simulation parameters was established. The focusing transducer and gel were fixed on a support and placed in degassed water. A dual-frequency multiplexed signal was generated using cos(2πf1t) + cos(2πf2t), and waveform data was obtained through computer programming, where f1 = 1.13MHz and f2 = 1.17MHz. The signal was output by a function generator, amplified by a power amplifier, and used to drive the focusing transducer to form a dual-frequency HIFU sound field acting on the gel phantom. To avoid interference from the HIFU sound field on the difference frequency, a planar transducer with a center frequency of 40kHz was placed perpendicular to the sound beam propagation axis to receive orthogonal difference frequency sound pressure. Data was acquired at 100ms intervals using a computer-controlled digital oscilloscope, and the difference frequency sound pressure was calculated in real time by the computer. At the same time, a camera was placed in the vertical direction to record the solidification and denaturation process of the gel phantom in real time.

[0061] In the experiment, a laser vibrometer was used to measure the vibration velocity on the transducer surface. The vibration velocity was adjusted by adjusting the signal amplitude to satisfy u0 = 50, 60, and 70 mm / s. The distribution measurements were as follows: Figure 6 The experimental results of the difference frequency sound pressure as a function of treatment time shown in (a) exhibit a trend of first increasing and then decreasing. The corresponding inflection point and the relationship between the treatment time required to achieve the therapeutic effect and the sound power are as follows: Figure 6 As shown in (b), the experimental results and Figure 6 The simulation results in (b) are consistent.

[0062] like Figure 6 (c) Displaying tissue ablation images at different acoustic power levels, showing the differential frequency sound pressure inflection point and the point at which therapeutic effect is achieved. At the corresponding differential frequency sound pressure inflection point, a small amount of white coagulation with an axial length of approximately 1 mm is present in the focal center; Figure 6 As shown in (d), when the differential frequency sound pressure attenuation is 6dB, a white coagulation area appears within 10mm of the focal axis. The experimental measurement results are highly consistent with the theoretical simulation results, proving the feasibility of using the inflection point of the differential frequency sound pressure and 6dB attenuation to achieve highly sensitive and accurate real-time efficacy monitoring and dose control in dual-frequency HIFU ablation.

[0063] The technical means disclosed in this invention are not limited to those disclosed in the above embodiments, but also include technical solutions composed of any combination of the above technical features.

Claims

1. A dual-frequency HIFU ablation and differential frequency sound pressure real-time monitoring system, characterized in that, The system includes a computer, a function signal generator, a power amplifier, a focusing transducer, a difference frequency detection transducer, a digital oscilloscope, a tissue phantom, and a camera. The focusing transducer is connected to the power amplifier, the signal generator, and the computer in sequence, and the difference frequency detection transducer is connected to the digital oscilloscope and the computer in sequence. The dual-frequency multiplexed signal waveform data is obtained through computer programming, output by the function signal generator, amplified by the power amplifier, and then drives the focusing transducer to form a dual-frequency HIFU sound field that acts on the tissue. The difference frequency receiving transducer is placed vertically outside the HIFU treatment sound field. The detected focal-area scattered difference frequency signal is acquired by the digital oscilloscope and transmitted to the computer in real time to calculate the difference frequency sound pressure. A camera is placed above the focal area to record the HIFU ablation and denaturation process of the tissue phantom in real time. This system implements a high-intensity focused ultrasound ablation efficacy monitoring and dose control method, including the following steps: S1. A confocal ellipsoidal HIFU focal domain is constructed by using a dual-frequency multiplexed signal to excite a single spherical focusing transducer. Considering the nonlinear interaction of dual-frequency sound waves propagating along the same path in biological tissue, a difference-frequency sound pressure model based on focal domain tissue scattering is constructed according to the principle of acoustic parametric array. The theoretical formula of difference-frequency sound pressure is derived using parameters such as dual-frequency excitation sound pressure, medium acoustic impedance, nonlinear acoustic parameters and propagation distance. S2. Calculate the sound pressure distribution of the dual-frequency excited HIFU sound field, use the Pennes biological tissue heat conduction equation to calculate the temperature field distribution of the HIFU focal domain at different times during the treatment process, further consider the changes in tissue parameters caused by tissue temperature rise, and introduce the transmission coefficient to correct the real-time sound pressure distribution of the HIFU focal domain. S3. For each treatment moment, a closed-loop model of "sound pressure distribution - temperature rise - tissue parameter change - sound field sound pressure correction" is constructed, and the relationship between difference frequency sound pressure and treatment time is obtained through theoretical calculation based on the sound pressure, density, sound velocity and nonlinear acoustic parameter distribution in the focal domain tissue. S4. In HIFU treatments with different acoustic powers, the difference-frequency sound pressure level first increases and then decreases with increasing treatment time, until the ablation temperature at the focal center reaches... When the differential frequency sound pressure reaches its peak, the inflection point of the differential frequency sound pressure is used as an effective monitoring standard for HIFU ablation therapy. S5. After the differential frequency sound pressure reaches its peak value, HIFU ablation is performed. The attenuation characteristics of the differential frequency sound pressure are studied under the condition of fixed size of the ablation area to achieve therapeutic effect. The 6 dB attenuation of the peak value of the differential frequency sound pressure is used as the dose control parameter for HIFU ablation. S6. A dual-frequency HIFU treatment and differential frequency real-time monitoring system is constructed using dual-frequency excitation of a single focusing transducer. At the same time, the orthogonal differential frequency signal outside the HIFU sound field is detected, and the real-time efficacy monitoring and dosage control of HIFU ablation are achieved by detecting the peak value and attenuation of the differential frequency sound pressure.

2. The dual-frequency HIFU ablation and differential frequency sound pressure real-time monitoring system according to claim 1, characterized in that, Step S1 also includes constructing a dual-frequency signal using multiplexing technology, amplifying it, and then exciting a focusing transducer to build a confocal dual-frequency HIFU sound field. The transducer radius 'a' is 1–30 cm, and its focal length 'F' is greater than the radius. The signal is then calculated based on the transducer's center angular frequency. and relative bandwidth B W To set the difference frequency signal frequency The frequencies of the dual-frequency signals are respectively ,in The acoustic attenuation coefficient of biological tissues increases with increasing frequency. It means that, among them, The y-value represents the acoustic attenuation coefficient corresponding to f0=1MHz. The y-value for biological tissue is 1.1 to 1.7, which is determined based on the tissue measurement results.

3. The dual-frequency HIFU ablation and differential frequency sound pressure real-time monitoring system according to claim 1, characterized in that, Step S2 also includes the heat absorbed by the focal zone organization of the dual-frequency HIFU sound field. ,in and For the sound intensity of a dual-frequency sound wave, in < / 10 attenuation coefficient They are approximately equal.

4. The dual-frequency HIFU ablation and differential frequency sound pressure real-time monitoring system according to claim 1, characterized in that, Step S3 also includes calculating the variation of difference frequency sound pressure with treatment time using the derived theoretical formula, constructing a closed-loop model of "sound pressure distribution - temperature rise - tissue parameter change - sound field sound pressure correction", and based on the sound pressure, density, sound velocity, and nonlinear acoustic parameter distribution of the focal domain tissue; the sound pressure, density, sound velocity, and nonlinear acoustic parameter distribution of the HIFU ellipsoidal focal domain tissue change with treatment time, resulting in real-time difference frequency sound pressure changes; since the axial length of the focal domain is significantly greater than its radial width, the difference frequency sound pressure generated by the HIFU focal domain is calculated through the one-dimensional sound pressure distribution along the z-axis sound propagation: Where dz is the axial length of the infinitesimal element at the propagation distance z. and This represents the dual-frequency sound pressure level at point z. , and This represents the nonlinear acoustic parameters, density, and sound velocity at temperature T at point z. Let be the acoustic transmission coefficient at point z caused by the change in acoustic impedance; a simplified layered structure model is established along the z-direction, and the transmission coefficient at the propagation distance z can be obtained by multiplying the transmission coefficients of different layers in the focal domain. To calculate, where It is the input impedance formed by all the layers preceding z. , The wavelength of the sound wave; In the calculation of difference frequency sound pressure, the focal axial calculation range is [F–L / 2, F+L / 2], where F is the focal length of the focusing transducer. The axial length of the focal region is dz; the layer length dz is less than L / 1000.

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