A dual frequency phased array complex pulse tissue ablation system and method

Abstract

The application discloses a double frequency phased array composite pulse tissue destruction system and method; comprising a double frequency phased array transducer, a drive control module, a focal point control module and a real-time monitoring module, the double frequency phased array transducer is a double frequency hundreds of array element phased array transducer or a double frequency split array transducer; the double frequency phased array transducer contains a fundamental frequency array element group and a frequency multiplication array element group, the drive control module is used for outputting drive signals of corresponding frequencies to the two groups of array elements, the focal point control module is used for regulating the focal point position and quantity, and the real-time monitoring module is used for tracking the effect; the double frequency phased array composite pulse tissue destruction system adopts four-stage composite pulse time sequence to cooperatively control the working states of the fundamental frequency array element group and the frequency multiplication array element group, and realizes the method in combination with a multi-focal point control strategy; the method overcomes the deficiencies of possible cavitation shielding in the front focal region of the double frequency millisecond long pulse tissue destruction and the slow bubble dissipation affecting the immediate B-ultrasonic monitoring at the end of treatment.

Description

Technical Field

[0001] This application belongs to the field of focused ultrasound technology and relates to a double-frequency phased array composite pulse tissue destruction system and method. Background Technology

[0002] Histotripsy is a non-invasive, non-ionizing, non-thermal (purely mechanical), ultrasound-guided ablation technique that breaks down (liquefies) the target tissue into cell-free fragments. Also known as HIFU mechanical ablation (m-HIFU), it is a new technology that is poised to replace HIFU thermal ablation (t-HIFU).

[0003] The advantages of tissue destruction are: (1) Precisely ablates the target tissue. The damage boundary of pure mechanical ablation is sharper than that of t-HIFU thermal ablation. The cavitation bubbles of tissue destruction are only a few micrometers, and the cutting boundary is only half a cell (the gap between the intact cell and the damaged liquefaction zone is about 5 micrometers). In contrast, the thermal ablation boundary is irregular due to the non-uniform heat transfer of the tissue and the boundary is greater than 1 mm.

[0004] (2) Real-time guidance and monitoring by ultrasound imaging: During treatment, due to cavitation and bubble activity in the target area, the ultrasound image shows a bright area, which can display the treatment target area in real time; after treatment irradiation, the liquefied area is displayed as a low echo (deep black) area in the ultrasound image, and the treatment results can be displayed immediately.

[0005] (3) Tissue destruction is selective: blood vessels larger than 300 micrometers remain intact, as do connective tissue and bile ducts; it can treat target tissues adjacent to large blood vessels, overcoming the "heatsink effect" that t-HIHU cannot treat tissues adjacent to large blood vessels. Tissue destruction breaks down the structure of the target tissue (cells), with fragments as small as 2 micrometers that are easily absorbed.

[0006] (4) The immune response to tumor treatment is better than that of thermal ablation, which enhances the tumor-specific immune response.

[0007] The mechanical ablation mechanism of tissue destruction utilizes shock wave sound pressure levels that are higher than, and extremely high than, those produced by thermal ablation, along with short-pulse bubble activity. Tissue destruction typically involves short pulses lasting a few microseconds or milliseconds. Recent classifications of tissue destruction based on pulse length include cavitation histotripsy (CH), boiling histotripsy (BH), and hybrid histotripsy (HH).

[0008] CH is further divided into shock scattering histotripsy and intrinsic threshold histotripsy. Shock scattering histotripsy was first invented in 2004 by Zhen Xu's research group at the University of Michigan. Shock scattering histotripsy uses pulse lengths of 3–20 cycles and 0.6–80 μs, with extremely high shock wave sound pressure: positive sound pressure P+ > 100 MPa, negative sound pressure P- = -(20–30) MPa; and a low duty cycle, less than 1%. Shock scattering ablation generates cavitation clouds in the focal region. The violent expansion and collapse of microbubbles mechanically pulverize tissue cells. Due to the multiple pulse cycles, the cavitation bubbles generated in the previous cycle are reflected back by the soft surface of the bubble when the leading edge of the subsequent positive shock wave arrives, resulting in a negative wave exceeding the inherent cavitation threshold. This negative wave is superimposed on the negative wave of the traveling wave, forming a cavitation bubble cluster (scattered towards the transducer end), hence the name shock scattering ablation. Because of the cavitation memory effect, the pulse repetition frequency (PRF) of shock scattering ablation cannot be too high; sufficient time must be allowed for the cavitation bubbles to dissipate before the next pulse arrives. Simultaneously, the duty cycle must be extremely small (<1%), thus it is considered pure mechanical ablation. In October 2023, the US Food and Drug Administration (FDA) approved ablation for the treatment of liver tumors, using shock scattering ablation. Shock scattering ablation is already undergoing preclinical trials for liver cancer, kidney cancer, pancreatic cancer, and benign prostatic hyperplasia.

[0009] Inherent threshold tissue ablation produces a smaller focal cavitation cloud (damage) than shock scattering tissue ablation. Ultrashort pulses (1–2 cycles, 0.2–4 μs) with only a single negative wave generate a negative sound pressure P- exceeding -30 MPa, significantly exceeding the inherent cavitation threshold. A duty cycle of <1% produces dense, small-sized cavitation clouds with no cavitation bubble scattering. The damage size is small (less than one wavelength, subwavelength), and the damage boundary is sharp. This smaller damage size is suitable for more precise treatment scenarios such as ablation of vascular emboli (without damaging the vessel wall). Shock scattering tissue ablation, on the other hand, produces a larger damage size, thus resulting in higher efficiency.

[0010] BH (boiling tissue ablation) has a longer pulse length (1-20 ms), with a negative sound pressure P- = - (10-15) MPa; the shock wave sound pressure is positive P+ > 60 MPa, and the duty cycle is less than 1-2%. According to the weak impact theory, tissue absorption is proportional to the cube of the shock wave amplitude. With a pulse duration of only a few milliseconds, the tissue temperature rises rapidly to boiling point in front of the shock wave. The boiling bubbles interact with the shock wave front (the bubble interface produces jet atomization), causing mechanical pulverization and liquefaction of the charred tissue. BH has the same mechanical liquefaction effect as CH, but the damage size of BH is larger due to millimeter-sized bubbles. However, the damage often presents as a "tadpole shape," with a "tadpole head" near the transducer end; a tadpole tail is undesirable. Because the shock wave is very narrow, less than 100 micrometers wide, the boiling point is limited to a very small local area (precise location) at the focal point. In addition, the low duty cycle is <2%, so the effect is mechanical ablation without heat accumulation or thermal damage. BH appeared later than CH technology, and BH is not yet used in clinical practice.

[0011] Some tissue ablation treatments require phased array transducer electronic focus scanning. On one hand, phased array transducer electronic focus scanning is faster than single-element, single-focus mechanical scanning, significantly shortening treatment time and improving efficiency. On the other hand, it allows for electronic deflection of the focus to areas inaccessible to single-element beams. Phased array transducer electronic focus scanning requires more than 32 elements. The element size of therapeutic phased array transducers is generally larger than half a wavelength, reaching several wavelengths, thus preventing full-area grating-free electronic focus deflection. However, the more elements a phased array transducer has, the larger the electronic focus scanning area (near the geometric focus). Current technology can support phased array transducers with hundreds of elements; for example, 128-element, 256-element, 512-element, and 1024-element phased array transducers can guarantee a certain range of grating-free focus scanning. Because each element of a phased array transducer requires an amplifier channel to drive it, a 256-element phased array transducer would require an amplifier with 256 channels, making the system more complex.

[0012] The double-frequency split array with several elements has two frequencies: a fundamental frequency and a harmonic frequency acting simultaneously. Due to the superposition of the double harmonics, the cavitation threshold is lowered, enhancing cavitation activity. Compared to single-frequency action, the addition of a low frequency (large focal area) increases the cavitation region, thus increasing the lesion size and improving treatment efficiency. Potential problems include: if the double-frequency is low, local cavitation clouds in front of the focal area may obstruct the beam; furthermore, the slow dissipation of cavitation clouds at the end of millisecond-long pulse treatment affects immediate ultrasound monitoring, as a hypoechoic liquefaction area can only be accurately assessed on ultrasound after the cavitation bubbles dissipate. Therefore, this application aims to solve these two problems and overcome these shortcomings using a special composite pulse waveform sequence.

[0013] Currently, there is no tissue destruction method for double-frequency phased array transducers with hundreds of elements. This application pre-discloses a new system and method for tissue destruction of double-frequency phased array transducers with hundreds of elements, aiming to significantly improve the efficiency of tissue destruction treatment using double-frequency phased array transducers with hundreds of elements. Summary of the Invention

[0014] This application proposes a double-frequency phased array composite pulse tissue ablation system and method. In addition to overcoming the shortcomings of possible cavitation obstruction in the front of the focal zone in double-frequency millisecond long pulse tissue ablation and the shortcomings of slow bubble dissipation at the end of treatment affecting immediate B-ultrasound monitoring, this method also provides an optimized phased array transducer and driving technology solution for efficient tissue ablation.

[0015] To achieve the above objectives, this application provides the following technical solution: In a first aspect, this application provides a double-frequency phased array composite pulse tissue destruction system, comprising: a double-frequency phased array transducer, a drive control module, a focus control module, and a real-time monitoring module. The double-frequency phased array transducer is a double-frequency phased array transducer with hundreds of array elements or a double-frequency split array transducer; the double-frequency phased array transducer includes a fundamental frequency array element group and a frequency-doubled array element group, the drive control module is used to output drive signals of corresponding frequencies to the two array elements, the focus control module is used to adjust the focus position and number, and the real-time monitoring module is used to track the effect. The double-frequency phased array composite pulse tissue destruction system adopts a four-stage composite pulse timing coordinated control of the working state of the fundamental frequency array element and the frequency doubling array element, combined with a multi-focus control strategy. Among them, the first three stages of the four-stage composite pulse timing sequence are millisecond-long pulses to achieve mechanical ablation, and the fourth stage is microsecond-long short pulses to dissipate cavitation clouds and enable immediate B-ultrasound image monitoring of the ablation effect. The sound pressure output by the frequency doubling array element in each stage is a shock wave and ensures that boiling bubbles are generated in each pulse in the first three stages. The output of the fundamental frequency array element does not require a shock wave. The multi-focus control strategy of the double-frequency phased array transducer with hundreds of elements uses a genetic optimization algorithm adapted to the double-frequency characteristics to inversely solve the driving vector corresponding to the multi-focus position, which is used to generate a 3D single-focus or multi-focus mode, thereby enabling 3D single-focus or multi-focus electronic scanning; the multi-focus control strategy of the double-frequency split array generates a single-focus (at the geometric focus) or multi-focus (geometric focus plane axisymmetric) mode by controlling several phase difference modes of adjacent array elements.

[0016] As a further improvement of this application, the double-frequency phased array transducer is a double-frequency phased array transducer with hundreds of elements or a double-frequency split array transducer with no more than 12 elements; the double-frequency split array transducer controls the forward synthesis of fixed multifocals (geometric focal plane axisymmetric) through phase difference control.

[0017] As a further improvement of this application, the double-frequency phased array transducer with hundreds of elements has 128, 256, 512, or 1024 elements; the elements are spherical rectangular elements with a projected square shape, arranged compactly in 2D array, and the elements are not aligned; when the elements are distributed in 2D, the focal point can be electronically scanned in 3D space; the dual-frequency of the double-frequency phased array transducer with hundreds of elements is 0.4 to 10 MHz; the dual frequency includes a fundamental frequency f1 and a harmonic frequency f2; f2 = nf1, n = 2 to 10; the double-frequency phased array transducer with hundreds of elements is divided into two annular regions, with the fundamental frequency elements distributed in the outer annular region and the harmonic frequency elements distributed in the inner annular region.

[0018] As a further improvement of this application, in the double-frequency phased array transducer with hundreds of elements, the element size of the fundamental frequency array element group is larger than the element size of the frequency-doubled array element group.

[0019] As a further improvement of this application, in the double-frequency phased array transducer with hundreds of elements, when the double frequency is double 2, the element size of the base frequency array element group is 1.5 to 2 times the element size of the frequency multiplication array element group; when the double frequency is double 3, the element size of the base frequency array element group is 2 to 3 times the element size of the frequency multiplication array element group.

[0020] As a further improvement of this application, in the double-frequency phased array transducer with hundreds of elements, the number of elements in the fundamental frequency array element group is less than the number of elements in the frequency-doubled array element group.

[0021] As a further improvement to this application, the double-frequency phased array composite pulse tissue destruction system also includes a driver for a phased array transducer with hundreds of channels; The driver for the hundreds of phased array transducers transmits element drive signals to the double-frequency phased array transducers through two sets of impedance matching networks for the hundreds of elements. The phased array transducers are divided into two groups: a fundamental frequency group and a frequency-harmonic group. The impedance matching networks are also divided into two groups: a fundamental frequency group and a frequency-harmonic group. The phased array transducer driver includes an arbitrary waveform generator module that controls a composite pulse sequence of two frequencies, using the fundamental frequency pulse sequence waveform and the frequency-harmonic pulse sequence waveform to control the timing of each channel of the fundamental and frequency harmonics, respectively. The phase and amplitude control of the hundreds of channels in the phased array transducer driver receives the multi-focal drive signal corresponding to each element from the double-frequency genetic algorithm. The phase and amplitude; hundreds of phased array transducers correspond to hundreds of phased array transducer channel amplifiers, each element corresponds to the power control of one channel, the power and phase of each channel in the phased array transducer driver are independently controlled, and the pulse timing of each frequency element is a composite pulse frequency pulse waveform timing.

[0022] As a further improvement of this application, in the control of the double-frequency phased array transducer with hundreds of elements, a genetic optimization algorithm adapted to the double-frequency characteristics is used to realize 3D single-focus and multi-focus, including axisymmetric multi-focus and off-axis multi-focus; relying on the double-frequency genetic optimization algorithm, 3D multi-focus can be distributed on the focal plane, and the distance between adjacent focal points on the focal plane is one fundamental frequency wavelength.

[0023] As a further improvement of this application, when the double-frequency genetic algorithm in the control of the double-frequency phased array transducer with hundreds of array elements reversely solves the driving vector, it can independently control the operation of the frequency-doubling array elements. The multi-focus negative pressure output by the frequency-doubling array elements all exceed 10 MPa of shock waves. The boiling time is calculated by the weak shock theory formula, and the millisecond-long pulse length PD value of the first three stages is designed based on the boiling time.

[0024] As a further improvement of this application, when the large-point damage formed by the multi-focus mode of the hundreds of phased array transducers is scanned electronically, the spacing between two adjacent large-point damages is 2 / 3 of the radial or axial dimension of the large-point damage, achieving a 1 / 3 coverage scanning effect.

[0025] As a further improvement of this application, the center of the double-frequency phased array transducer with hundreds of elements is provided with a through hole, and the B-ultrasound probe of the real-time monitoring module is coaxially installed in the through hole. The B-ultrasound probe can rotate 180 degrees in both directions to guide and track the focal point destruction process in 3D space with images.

[0026] As a further improvement of this application, the split array transducer is fixed and axisymmetric in single-focus, two-focus, four-focus, or six-focus modes by positively synthesizing the phase difference of adjacent array elements. The double frequency range is 0.4 to 10 MHz, and the double frequency is 2 to 10 times the fundamental frequency, with f-number less than 1.

[0027] As a further improvement of this application, the split array transducer is a spherical 2-element ring array, a 4- or 6-element rectangular split array, or a 4- or 6-element fan-shaped split array, and the maximum number of focal points of the split array transducer is equal to the number of array elements.

[0028] As a further improvement of this application, when the large point damage formed by the multi-focal mode of the split array transducer is mechanically scanned and destroyed, the spacing between two adjacent large point damages is 2 / 3 of the radial or axial dimension of the large point damage, achieving a 1 / 3 coverage scanning effect; when the split array transducer is a 2-element ring array, the phase difference between the two frequencies is set to 135 degrees of the fundamental frequency in the dual 2nd harmonic mode and 60 degrees in the dual 3rd harmonic mode, resulting in confocal enhanced acoustic pressure cavitation effect. The nonlinear acoustic pressure is quantitatively calculated using the nonlinear KZK equation to ensure the characteristics of the harmonic impulse wave.

[0029] As a further improvement of this application, the double frequency split array has no more than 12 elements; the focus of the double frequency split array is the phase difference controlled multi-focus positive synthesis of the split array; the composite ultrasonic pulse waveform of the two frequencies is controlled by the number of channels of an arbitrary waveform generator with the same number of elements as the split array.

[0030] As a further improvement of this application, the split array transducer is a spherical 2-element ring array, a 4- or 6-element rectangular split array, a 4- or 6-element fan-shaped split array, or a fan-shaped spiral split array. The maximum number of focal points of the split array transducer is equal to the number of array elements, and the adjacent spacing of the multiple focal points on the focal plane is one fundamental frequency wavelength.

[0031] As a further improvement of this application, the phase difference control of the split array transducer adopts a forward synthesis algorithm. By adjusting the phase difference combination of adjacent array elements, the switching of single focus, 2 focus, 4 focus or 6 focus (geometric focus plane axisymmetric) can be realized, and the sound pressure of the multi-focus all meet the mechanical ablation requirements.

[0032] As a further improvement of this application, the center of the split array transducer is provided with a through hole, and the B-ultrasound probe of the real-time monitoring module is coaxially installed in the through hole for real-time monitoring of the cavitation cloud dissipation state and liquefaction damage area. The B-ultrasound probe can also work with the 3D position control module to track the focal point damage process.

[0033] Secondly, this application provides a double-frequency phased array composite pulse tissue destruction method, based on the double-frequency phased array composite pulse tissue destruction system, including: a double-frequency phased array transducer with hundreds of elements adopts a four-stage composite pulse timing coordinated control of the working state of the fundamental frequency array elements and the frequency-doubled array elements, combined with a multi-focus control strategy of the multi-element phased array transducer. The four-stage composite pulse timing includes: Phase 1: Only frequency doubling is used for millisecond-long pulse tissue destruction, while the fundamental frequency is not used. The frequency doubling shock wave performs efficient tissue destruction, generating boiling bubbles with each pulse. Specific parameters: frequency doubling pulse duration PD = 1-20 ms and pulse repetition frequency PRF = 1-20 Hz, pulse repetition S1 = 5-30 times, followed by an off time of 0.1-0.5 s, with a duty cycle of 2-7%. Stage 2: Simultaneous millisecond-long pulse destruction using both fundamental and harmonic frequencies. Specific parameters: pulse duration PD = 1–20 ms and pulse repetition frequency PRF = 1–20 Hz, pulse repetition S2 = 20–60 times, duty cycle 2–7%. Phase 3: The fundamental frequency and harmonic frequency operate, with concentrated millisecond-long pulse trains followed by 1-4 s off time. These two segments form a pulse group that is repeated N times, making the average duty cycle as low as about 1%. Specific parameters: pulse duration PD = 1-20 ms and pulse repetition frequency PRF = 1-20 Hz, pulse repetition S3 = 3-10 times, followed by 1-4 s off time, pulse group repetition N = 2-15 times with an average duty cycle of about 1%. Phase 4: Fundamental and harmonic frequency microsecond long pulses, specific parameters: pulse duration PD = 5–80 μs, pulse repetition frequency PRF = 100–1000 Hz, pulse repetition S4 = 100–1000 times, duty cycle ~1%; The multi-focus control strategy for the double-frequency phased array transducer with hundreds of elements includes: Design the position of the focal plane multifocal points Monofocal, 2-focal, 4-focal, 6-focal, off-axis monofocal, off-axis multifocal; Using a double-frequency genetic algorithm to solve multifocal problems in reverse. corresponding drive signals ; A precise calculation program for a phased array transducer containing a dual-frequency spherical rectangular array element was used, along with the obtained... The 3D sound field focusing characteristics were obtained through simulation to verify whether they met the requirements. Only the double-frequency single-frequency drive was used, and the double-frequency sound pressure level had to exceed 10 MPa. The boiling time was calculated using the weak impact theory formula, and the millisecond-long pulse length PD value was designed based on the boiling time to ensure that boiling bubbles occurred with each pulse. use The composite pulse parameters are loaded into the phased array transducer driver with hundreds of channels and emitted to achieve the designed multifocal tissue destruction.

[0034] Thirdly, this application provides a double-frequency phased array composite pulse tissue destruction method. Based on the double-frequency phased array composite pulse tissue destruction system, the double-frequency split array transducer adopts a four-stage composite pulse timing coordinated control of the fundamental frequency array element and the frequency-doubling array element, combined with a split array multi-focus control strategy. The four-stage composite pulse timing includes: Phase 1: The fundamental frequency does not operate during the off-time; only the harmonic frequency operates. The pulse duration PD = 1–20 ms and the pulse repetition frequency PRF = 1–20 Hz are repeated 5–30 times, followed by an off-time of 0.1–0.5 s. The duty cycle is 2–7%. Phase 2: Dual-frequency operation, pulse duration PD = 1–20 ms and pulse repetition frequency PRF = 1–20 Hz, pulse repetition S2 = 20–60 times, duty cycle 2–7%; Phase 3: Dual-frequency operation, with concentrated millisecond-long pulse trains of duration PD=1~20 ms and pulse repetition frequency PRF=1~20 Hz, repeated 3~10 times, followed by an off time of 1~4 s. These two segments constitute a pulse group repeated N=2~15 times, with an average duty cycle of approximately 1%. Stage 4: Dual-frequency operation simultaneously, pulse duration PD = 5–40 μs, pulse repetition frequency PRF = 100–1000 Hz, pulse repetition S4 = 100–1000 times, duty cycle ~1%; The multi-focus control strategy for the split array includes: Based on the required split array and focal mode, the sound field distribution is obtained using the double-frequency split array sound field formula or nonlinear KZK, ensuring the frequency-doubled shock wave and obtaining experimental control parameters; The prepared sample is moved using 3D position control so that the focal point is located at a certain depth within the sample. At the same time, ultrasound positioning is used to emit short pulses with a lower intensity than the treatment pulse to cavitation the focal point. Use the composite pulse parameters to set the arbitrary waveform generator of the split array, and use the power settings of step 1 to set the power amplifier of the split array to emit tissue damage; monitor in real time with ultrasound; if multi-point irradiation is used, set the 3D position control movement path and the 2-focal distance to emit tissue damage.

[0035] This application has the following beneficial effects: Regarding the biharmonic phased array composite pulse tissue ablation technology, its beneficial effects can be observed from both temporal and spatial dimensions. Firstly, in terms of temporal efficiency, the four stages of the composite pulse are synchronized with the fundamental and harmonic pulse timings: the first three stages utilize highly efficient millisecond-long pulses for tissue ablation. In particular, the first stage only activates the harmonic pulse (high duty cycle 2-7%) with shock waves, while the fundamental pulse remains inactive. This reduces the potential for cavitation bubbles in the prefocal region to obstruct the beam, initiating the most powerful tissue fragmentation at precise locations. These three stages of efficient mechanical ablation produce "elongated ellipsoidal" (not "tadpole-shaped") or "spherical" (4-focal) damage. The size of these biharmonic damages is larger than that of single-frequency harmonic damage. Furthermore, the fourth stage (5-80 μs) pulse primarily aims to rapidly dissipate cavitation clouds and also has some CH (chondrogenic shock) effect. Its short duration allows for immediate ultrasound monitoring of the damage effect. In terms of spatial aspects, the double-frequency genetic algorithm obtains 3D spatial multifocal imaging with hundreds of double-frequency array elements. Double-frequency phased array transducers with hundreds of double-frequency array elements can achieve simultaneous multifocal tissue destruction through optimization algorithms. Simultaneous multifocal imaging can expand the treatment damage volume of a single irradiation. For example, a single irradiation damage from a 4-focal focal plane is a relatively large volume damage. The damage volume of a single 4-focal irradiation is the same as the damage volume obtained from at least 9 (times, double-frequency single-focal) positions of a double-frequency single-focal mechanical scan (3×3 adjacent focal points half-covering). In fact, due to the addition of the fundamental frequency, the single-focal region or cavitation region of double-frequency is larger than the frequency-doubled focal region, resulting in a larger double-frequency damage size than a frequency-doubled single-frequency damage size. A double-frequency 4-focal imaging is also approximately 3 times larger than a frequency-doubled 4-focal imaging alone, thus shortening the treatment time for large tumors and significantly improving efficiency. Furthermore, during multifocal imaging, the distance between two adjacent damages can be larger than that of a single-focal imaging, reducing the number of irradiations required to treat large tumors and further improving efficiency. Double-frequency phased array transducers with hundreds of elements can achieve simultaneous 3D single-focus and multi-focus scanning through optimized algorithms. This means they can generate axisymmetric multi-focus systems (single-focus, two-focus, four-focus, six-focus) and off-axis (non-axisymmetric) multi-focus systems (off-axis single-focus, off-axis two-focus, off-axis four-focus, off-axis six-focus). In other words, the single-focus and multi-focus systems can be located around the geometric focal point, enabling 3D single-focus and multi-focus electronic scanning. Electron-focus scanning is faster than mechanical-focus scanning, significantly reducing treatment time and making it highly efficient for treating large tumors.

[0036] This application provides a double-frequency phased array transducer (HIFU) with hundreds of elements and gives a method for accurately calculating the sound pressure of double-frequency phased array transducers by combining a genetic algorithm with a double-frequency spherical rectangular array element. This can achieve optimized control of a large scanning area in 3D multi-focus mode.

[0037] For the compound ultrasound pulse bifrequency split array tissue ablation technique: the bifrequency split array can generate fixed confocal single focal points, two focal points, and four focal points, but cannot generate focal deflection, that is, it cannot generate off-axis single focal points, off-axis two focal points, or off-axis four focal points, i.e., it cannot perform focal electronic scanning. Furthermore, a fourth stage uses even shorter pulses (5–40 μs).

[0038] The specific advantages are as follows: Firstly, regarding time efficiency, the four stages of the composite pulse synchronize the pulse timing of each fundamental and harmonic array element: the first three stages are highly efficient millisecond-long pulses for tissue destruction. In particular, the first stage only allows the harmonics (high duty cycle 2-7%) with shock waves to operate, while the fundamental frequency does not operate, reducing the possibility of cavitation bubbles blocking the beam in the prefocal region of the dual-frequency array and initiating the most favorable tissue fragmentation at the precise location. These three stages efficiently produce "long ellipsoidal" (not "tadpole-shaped") or "spherical" (4-focal) damage. The fourth stage, with even shorter pulses (5-40 μs), mainly aims to rapidly dissipate cavitation clouds and also has some CH effect. It is short-lived, allowing for immediate ultrasound monitoring of the damage effect. This technical solution specifically addresses the problem of cavitation clouds blocking the beam in the prefocal region of confocal dual-frequency arrays, as well as the problem of slow cavitation cloud dissipation at the end of treatment.

[0039] Then there's the spatial aspect, namely, the simultaneous multifocal design of a double-frequency split array: when double-frequency transmission occurs at millisecond long wavelengths, the two frequency waves can interfere to generate a focal plane with simultaneous multifocal design, such as a double-frequency split array with 4 array elements. This can produce fixed focal points such as single-focal, 2-focal, and 4-focal designs (i.e., 4-focal designs arranged symmetrically about the acoustic axis or about the geometric focal point). A 4-focal-focused tissue destruction at the focal plane forms a large-size lesion, equivalent to the lesion volume of 3×3=9 (times) single-focal tissue destruction mechanical scans, saving treatment time and thus improving treatment efficiency. The focus calculation for a double-frequency split array does not require parallel optimization (reverse) genetic algorithms, but rather forward synthesis; several phase differences between adjacent array elements can control single-focal, 2-focal, and 4-focal designs. Furthermore, during multifocal mechanical scanning, the distance between two adjacent lesions can be larger than that of a single-focal lesion, reducing the number of irradiations required to treat large tumors.

[0040] Furthermore, the number of elements in a double-frequency split array is as low as 2, 4, or less than 12; the double-frequency split array system is simpler and easier to implement than a phased array transducer system with hundreds of elements. Attached Figure Description

[0041] In order to clearly illustrate the technical solution and features of this application, and to better understand the specific implementation methods, this application will be further described in detail below with reference to the accompanying drawings.

[0042] Figure 1This is a schematic diagram of the composite pulse sequence of this application. The composite pulse has four stages: Stage 1: The fundamental frequency does not operate during off-time, only the harmonics operate, with pulse duration PD = 1-20 ms and pulse repetition frequency PRF = 1-20 Hz, repeating S1 = 5-30 times, followed by an off-time of 0.1-0.5 s, with a duty cycle of 2-7%. Stage 2: Both frequencies (fundamental frequency and harmonics) operate simultaneously, with pulse duration PD = 1-20 ms and pulse repetition frequency PRF = 1-20 Hz, repeating S2 = 20-60 times, with a duty cycle of 2-7%. Stage 3: Both frequencies (fundamental frequency and harmonics) operate simultaneously, a concentrated millisecond-long pulse train with pulse duration PD = 1-20 ms and pulse repetition frequency PRF = 1-20 Hz, repeating S3 = 3-10 times, followed by an off-time of 1-4 s. These two segments form a pulse group that repeats N = 2-15 times, with an average duty cycle of approximately 1%. Stage 4: Dual-frequency (fundamental frequency and harmonic frequency) operation, pulse duration PD = 5 ~ 80 μs, pulse repetition frequency PRF = 100 ~ 1000 Hz, pulse repetition S4 = 100 ~ 1000 times, duty cycle ~ 1%.

[0043] Figure 2 This is a schematic diagram of the array element structure of the phased array transducer with hundreds of elements in this application.

[0044] Figure 3 Design the multifocal positions of the focal plane, and use a double-frequency genetic algorithm to inversely solve for the driving signals corresponding to the multifocal positions. A flowchart of the process (a set of amplitude and phase parameters corresponding to the driving of each array element).

[0045] Figure 4 This is a schematic diagram of the drive control structure for a double-frequency phased array transducer with hundreds of elements, as described in this application.

[0046] Figure 5 The sound fields of the dual-frequency 256-element phased array transducer are obtained by reverse solving the dual-frequency genetic optimization algorithm in single-focus and dual-focus modes: single-focus (a) is the sound intensity distribution on the focal plane and (b) is the sound intensity contour map on the xy plane; dual-focus (c) is the sound intensity distribution on the focal plane and (d) is the sound intensity contour map on the xz plane.

[0047] Figure 6 The off-axis single-focus mode sound field and element driving signal of the dual-frequency 256-element phased array transducer are obtained by reverse solving the double-frequency genetic optimization algorithm: (a) is the focal plane sound intensity distribution and (b) is the xy plane sound intensity contour map, and (c) is the amplitude and (d) is the phase of the 256-element driving signal.

[0048] Figure 7The sound field of the axisymmetric 4-focal mode of the double-frequency 256-element phased array transducer is obtained by reverse solving the double-frequency genetic optimization algorithm: (a) is the sound intensity distribution on the focal plane, (b) is the sound intensity distribution on the y-projection plane and (c) is the sound intensity contour map on the xy plane.

[0049] Figure 8 The non-axisymmetric (off-axis) 4-focal mode sound field and element driving signals of the dual 2-harmonic 256-element phased array transducer are obtained by reverse solving the double-harmonic genetic optimization algorithm: (a) is the focal plane sound intensity distribution and (b) is the xy plane sound intensity contour map, and (c) is the amplitude and (d) is the phase of the 256-element driving signal.

[0050] Figure 9 The sound field of the non-axisymmetric (off-axis) 4-focal mode of the double-frequency 256-element phased array transducer using only the second harmonic (2nd harmonic) is obtained by reverse solving the double-frequency genetic optimization algorithm: (a) is the sound intensity distribution on the focal plane, (b) is the sound intensity contour map of the xy plane and (c) is the sound intensity distribution on the y projection plane.

[0051] Figure 10 The nonlinear sound pressure of the dual 2nd harmonic 256-element phased array transducer is as follows: (a) is a 2nd harmonic shock wave with a pressure of 114 MPa: positive pressure P+ = 96 MPa, negative pressure P- = -19 MPa; (b) is a 2nd harmonic positive pressure 2D distribution; (c) is a 2nd harmonic negative pressure 2D distribution; (d) is a fundamental frequency sound pressure wave, a nonlinear wave (without shock wave).

[0052] Figure 11 Several double-frequency split array transducers (f2=2f1 or f2=3f1, etc.) are shown: (a) is a 2-element ring array transducer, (b) is a 4-element rectangular split array, (c) is a 4-element fan-shaped split array, and (d) is a 6-element fan-shaped split array.

[0053] Figure 12 It is a double-frequency-doubled array with two elements and a ring array. Figure 11 (a) Nonlinear sound pressure: High-frequency (2nd harmonic f2) shock wave (solid line) 72 MPa, positive pressure P+ = 67 MPa, negative pressure P- = -10.5 MPa; Low-frequency sound pressure wave, nonlinear wave (no shock wave), positive pressure P+ = 13 MPa, negative pressure P- = -8 MPa; Under linear conditions, the negative wave peaks meet and superimpose, resulting in the largest negative peak (which is conducive to cavitation).

[0054] Figure 13 It is a double triple frequency 2-element ring array ( Figure 11(a) In the driving signal waveform with a 60-degree phase difference between the fundamental frequency (the fundamental frequency is represented by a short dashed line, and the third harmonic is represented by a long dashed line), under linear conditions, the positive and negative voltages superimposed at the focal point with a 60-degree phase difference between the two frequencies reach their maximum values ​​(solid line).

[0055] Figure 14 The sound field distribution of the dual 3rd harmonic 2-element ring array single focus is shown in (a) as the sound intensity distribution on the focal plane (geometric focal plane) and (b) as the sound intensity contour map on the xy plane (geometric focal plane).

[0056] Figure 15 It is a double triple frequency 2-element ring array ( Figure 11 (a) Nonlinear sound pressure: (a) shows the positive pressure nearing its maximum and the negative pressure reaching its maximum at the focal point, with the two frequencies 60 degrees out of phase. The third harmonic is a shock wave; there is no shock wave at the fundamental frequency. The positive pressure P+ = 40 MPa and the negative pressure P- = -17 MPa. (b) shows the third harmonic as a shock wave: the shock wave amplitude is 100 MPa, the positive pressure P+ = 87.3 MPa, and the negative pressure P- = -15.1 MPa. (c) shows the 2D distribution of the positive pressure at the third harmonic, and (d) shows the 2D distribution of the negative pressure at the third harmonic.

[0057] Figure 16 It is a double-frequency 4-element fan-shaped split array ( Figure 11 (c) ) ) 4-focal sound field distribution: (a) is the sound intensity distribution of the focal plane (geometric focal plane), and (b) is the sound intensity contour map of the xy plane (geometric focal plane).

[0058] Figure 17 The system for implementing this method consists of a main control computer 16 that primarily controls the split array arbitrary waveform transmitter (group) 15, the split array element power amplifier (group) 14, the split array element impedance matching circuit (group) 13, and the split array transducer 11 to transmit focused ultrasound to the sample 19 in a composite pulse sequence for tissue ablation. An ultrasound probe 12 is coaxially mounted in the central hole of the split array transducer, acquiring signals from the probe and transmitting them to the ultrasound imaging system. Thus, the ultrasound system completes the tasks of image guidance for tissue ablation and real-time ultrasound image monitoring. The main control computer 16 also controls a 3D position control 18 to move the sample so that the focus is on the sample. If a high-speed camera is used for monitoring, one of the split array arbitrary waveform generators (groups) triggers the high-speed camera 21 to capture images.

[0059] Figure 18 High-speed photographs of transparent BSA gel phantoms subjected to composite pulse tissue destruction using a 1.1 / 3.3 MHz (dual 3rd harmonic) 2-element ring array were selected, showing the tissue destruction process of the first three stages with millisecond-long pulses, revealing the boiling bubble activity mechanism; the first stage (only the 3rd harmonic (3.3 MHz) operates, the fundamental frequency (1.1 MHz) does not operate): (a iBefore the first pulse causes boiling, the narrow white area is the shock wave region, with the focal point in the middle. (a) ii The first pulse boiling bubble appears in the coke area, (a) iii In the first stage, the final pulse of boiling causes an increase in bubble size, appearing in the foreground of the coke zone. In the second stage, both frequencies operate: (b) i The first pulse initiates boiling at the focal point, increasing the cavitation region. (b) ii The second pulse of the second stage: The increasing size of the boiling bubbles is pushed towards the back-burn zone. (b) iii The second stage, the last pulse: increases the size of the boiling bubbles in the coke zone. The third stage involves both frequencies operating: (c) i The first pulse initiates boiling at the focal point. ii The final pulse of the third stage: boiling bubbles are pushed towards the back burner region, (c iii After treatment, the outline of the damage.

[0060] Figure 19 Tissue destruction by dual 3-fold frequency-harmonic 2-element ring array composite pulses: (a) Schematic diagram of single-focus elongated ellipsoidal lesion size, (b) Single-focus elongated ellipsoidal lesion, (c) 9-point (times) treatment pathway in mouse tumors, with a distance of d1 / 2 (half-coverage) between the two points, and (d) Large-sized lesions formed by 9-point (times) treatment in mouse tumors.

[0061] Figure 20 Illustrations of H&E-stained sections of mouse tumor single-focus injury tissue destroyed by 1.1 / 3.3 MHz (double 3rd harmonic) 2-element ring array composite pulse. (a) shows the lesion outline (dashed line division) on the section, and (b) shows the lesion boundary after magnification (dashed line division).

[0062] Figure 21 Composite pulse tissue destruction of a dual 2-fold frequency 4-element fan-shaped split array: (a) shows a large-sized lesion formed by the 4 focal plane, d2>= 2d1; (b) shows a photograph showing that the 4 focal plane formed a large-sized lesion in mouse tumors during treatment, with the radial size of the lesion being approximately 3 times that of a single-focal lesion.

[0063] Figure 22For tissue destruction by dual 2x frequency 4-element fan-shaped split array composite pulse: (a) radially enlarged lesion formed by 4 focal points in the focal plane; (b) large point lesion with increased radial size formed by 4 focal points in isolated porcine kidney; (c) larger lesion formed by 2 layers and 4 (large points) treatment paths of 4 focal points, with a distance of 2 / 3 radial or axial large point lesion size between adjacent 2 large points, and 1 / 3 lesion coverage (larger than the 1 / 2 coverage distance of single focal point, requiring fewer (points) treatments and being more efficient in treating large tumors); (d) larger lesion formed by 2 layers and 4 (large points) treatment paths of 4 focal points in isolated porcine kidney.

[0064] Figure 23 The following is a real-time ultrasound monitoring diagram of a rabbit kidney tissue destruction experiment using a compound pulse, mainly showing the results of bubble dissipation after the fourth stage pulse: (a) During treatment, the ultrasound shows a bright focal area, indicating boiling bubbles and cavitation clouds in the focal area (arrows point to the bright area); (b) Immediately after treatment (1-2 s), the liquefied damage area shows low echoes (arrows point to the dashed ellipsoid area). The low echoes indicate that the bubbles have dissipated and the target area has been liquefied. Detailed Implementation

[0065] To enable those skilled in the art to better understand the technical solutions in this application, the technical solutions in the embodiments of this application will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this application, and not all embodiments. Based on the embodiments of this application, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of this application.

[0066] Unless otherwise defined, all technical and scientific terms used in this application have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used in this application's specification is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. The term "and / or" as used in this application includes any and all combinations of one or more of the associated listed items.

[0067] The double-frequency phased array transducers provided in this application are of two types: a phased array transducer with hundreds of elements and a split array (with several elements); because the technical solutions contained in these two types of phased array transducers are different, the technical solutions are divided into "double-frequency phased array transducer with hundreds of elements and multi-focus composite ultrasonic pulse tissue destruction" and "double-frequency split array multi-focus composite ultrasonic pulse tissue destruction".

[0068] This application provides a double-frequency phased array composite pulse tissue destruction system, including a composite pulse timing suitable for enhancing the nonlinear mechanism of double-frequency phased array transducers to improve tissue destruction efficiency, a double-frequency phased array transducer structure with hundreds of elements that can guarantee 3D multi-focus, and a genetic optimization algorithm that can obtain the double-frequency characteristics of 3D multi-focus control of the double-frequency phased array transducer.

[0069] Timing characteristics of the four stages of a composite pulse (see) Figure 1 The first three stages consist of highly efficient millisecond-long pulses for tissue destruction; the fourth stage uses microsecond-long pulses primarily to rapidly dissipate cavitation clouds, enabling immediate ultrasound monitoring of the ablation results. The harmonic sound pressure level is a shock wave, ensuring boiling occurs with each millisecond-long pulse; the fundamental frequency does not require a shock wave. This composite pulse sequence controls the power drive of hundreds of array elements and hundreds of channels across two frequency groups.

[0070] Phase 1: Only frequency doubling is used for millisecond-long pulse tissue destruction, while the fundamental frequency is not used. This is to reduce the possible beam obstruction by cavitation clouds in the focal front area of ​​the dual-frequency system. The frequency doubling shock wave performs efficient tissue destruction (duty cycle 2-7% > conventional duty cycle 1%), ensuring that boiling bubbles are generated with each pulse. The initial powerful tissue breakage is initiated and strengthened by the generation of high-frequency boiling bubbles at precise locations. Specific parameters: frequency doubling pulse duration PD = 1-20 ms and pulse repetition frequency PRF = 1-20 Hz, pulse repetition S1 = 5-30 times, followed by an off time of 0.1-0.5 s, duty cycle 2-7%.

[0071] Stage 2: Simultaneous dual-frequency (fundamental and harmonic) millisecond-long pulses for efficient tissue destruction (duty cycle 2-7%). The addition of low frequency lowers the cavitation threshold, enhances cavitation activity, and expands the damage area (larger focal area with low frequency). Pulse number control ensures mechanical ablation without thermal loss, achieving homogenization of the target tissue. Specific parameters: Dual-frequency synchronous working pulse duration PD = 1-20 ms and pulse repetition frequency PRF = 1-20 Hz, pulse repetition S2 = 20-60 times, duty cycle 2-7%.

[0072] Phase 3: Dual-frequency (fundamental frequency and harmonics) operation, with concentrated millisecond-long pulse trains followed by 1-4 s off time. These two segments form pulse group N, which is repeated several times to reduce the average duty cycle to approximately 1%. Phase 3 millisecond-long pulses achieve complete mechanical fragmentation (complete homogenization or liquefaction) of the target tissue. Single-focal damage is elongated ellipsoidal, while four-focal damage is a larger, approximately spherical lesion (twice as large radially). Specific parameters: Pulse duration PD = 1-20 ms and pulse repetition frequency PRF = 1-20 Hz, pulse repetition S3 = 3-10 times, followed by 1-4 s off time, pulse group N = 2-15 times with an average duty cycle of approximately 1%.

[0073] Phase 4: Short, microsecond-long (5–80 μs) dual-frequency (fundamental and harmonic) pulses, similar to CH. This phase is very short, so its tissue-damaging effect is minimal. Its main function is to rapidly dissipate cavitation bubbles using the microsecond-long pulses, immediately making the liquefied area appear as a low-echo zone on ultrasound monitoring. Phased array transducers with off-axis single-focus and off-axis (non-axisymmetric) multi-focus transducers will select longer microsecond pulses. Specific parameters: Dual-frequency (fundamental and harmonic) operation simultaneously; pulse duration PD = 5–80 μs; pulse repetition frequency PRF = 100–1000 Hz; pulse repetition S4 = 100–1000 times; duty cycle ~1%.

[0074] The array element structure of a novel double-frequency phased array transducer with hundreds of elements (see...) Figure 2 The transducer can have hundreds of elements, including 128, 256, 512, and 1024 elements; spherical rectangular elements (projected squares); compact 2D array arrangement; non-aligned element arrangement; 2D element distribution; the focal point (multi-focal point) can be scanned in 3D space; dual-frequency range of 0.4–10 MHz; f1 is the fundamental frequency, f2 is the harmonic frequency; f2 = nf1, (n = (2–10)); f-number is less than 1. The transducer is divided into two annular regions, with the fundamental frequency elements distributed in the outer ring region and the harmonic frequency elements distributed in the inner ring region. 3D Multifocal Modes of a Double-Frequency Phased Array Transducer with Hundreds of Elements Based on a Double-Frequency Genetic Algorithm: Applying the newly constructed genetic algorithm for a double-frequency phased array transducer to the double-frequency phased array transducer with hundreds of elements in this application can achieve 3D spatial single-focal, 2-focal, 4-focal, and 6-focal mode control, i.e. (Multi-focus) corresponding driving vector (Complex vector, each component corresponds to the driving amplitude and phase of each array element; the driving includes dual frequencies), see [link / reference]. Figure 3It can generate 3D single-focus areas: acoustic axis single-focus areas; off-axis single-focus areas, meaning the focus can be located in the region surrounding the geometric focus, which means 3D single-focus electronic scanning is possible. It can also generate 3D multi-focus areas: axisymmetric multi-focus areas (2-focus, 4-focus, 6-focus, etc.); off-axis (non-axisymmetric) multi-focus areas (off-axis 2-focus, off-axis 4-focus, off-axis 6-focus, etc.), meaning the multi-focus area can be located in the region surrounding the geometric focus, which means 3D multi-focus electronic scanning is possible.

[0075] The double-frequency phased array transducer driver control structure (see Figure 4) for hundreds of elements: The driver transmits element drive signals to the double-frequency phased array transducer through two sets of impedance matching networks for the hundreds of elements. Because the composite pulse sequence contains both fundamental and harmonic frequency pulse sequences, the phased array transducer is also divided into two groups: a fundamental frequency group and a harmonic frequency group; the impedance matching network is also divided into two groups: a fundamental frequency group and a harmonic frequency group; the phased array transducer driver has an arbitrary waveform generator module to control the composite pulse sequence of two frequencies (divided into two channels), controlling the timing of each channel of the fundamental and harmonic frequencies respectively. The phased array transducer driver also includes hundreds of channels for phase and amplitude control, receiving the multi-focal drive signals corresponding to each element obtained by the double-frequency genetic algorithm. The phase and amplitude are controlled. Hundreds of phased array transducers correspond to hundreds of phased array transducer channel amplifiers. Each element corresponds to the power control of one channel. The power and phase of each channel in the phased array transducer driver are independently controlled. The pulse timing of each frequency element is a composite pulse frequency pulse waveform timing sequence. The ultrasound probe is connected to the ultrasound imaging system for real-time monitoring, monitoring the effect of the fourth stage of the composite pulse.

[0076] The steps for multi-focus composite pulse transmission using a double-frequency phased array transducer with hundreds of elements include: Step 1: Design the position of the focal plane multifocal points Monofocal, 2-focal, 4-focal, 6-focal, off-axis monofocal, off-axis multifocal.

[0077] Step 2: Reverse solve the multifocal problem using the double-frequency genetic algorithm (double-frequency genetic algorithm calculation flow) program. corresponding drive signals (A set of amplitude and phase corresponding to each element's drive) (See steps 1 and 2) Figure 3 process).

[0078] Step 3: Use the precise calculation program for the phased array transducer with dual-frequency spherical rectangular array elements and the result obtained in Step 2. The driving simulation yields the 3D sound field focusing characteristics, verifying whether they meet the requirements, such as the presence or absence of grating lobes. In particular, it is also possible to drive only the harmonic frequency, with the harmonic sound pressure exceeding 10 MPa (the harmonic frequency is a shock wave). The boiling time is calculated using the weak impact theory formula, and the millisecond-long pulse length PD value is designed based on the boiling time to ensure that boiling bubbles occur with each pulse.

[0079] Step 4: Use the method from step 2 The composite pulse parameters are loaded into the phased array transducer driver with hundreds of channels and emitted to achieve the designed multifocal tissue destruction.

[0080] The double-frequency phased array transducer with over 100 elements is characterized by the following structural features: the fundamental frequency element size is larger than the harmonic frequency element size. The double-frequency phased array transducer with over 100 elements is characterized by the following structural features: for a double 2nd harmonic phased array transducer, the fundamental frequency element size is 1.5 to 2 times the 2nd harmonic element size; for a double 3rd harmonic phased array transducer, the fundamental frequency element size is 2 to 3 times the 3rd harmonic element size. The double-frequency phased array transducer with over 100 elements is characterized by the following structural features: the number of fundamental frequency elements is less than the number of harmonic frequency elements. The double-frequency genetic algorithm is used to reverse-engineer multifocal solutions. corresponding drive signals Furthermore, it can utilize specialized control design features for frequency doubling drive. Each focal point of the frequency doubling multifocal transducer requires a negative sound pressure exceeding 10 MPa of shock wave. The boiling time is calculated using weak impact theory formulas, and the millisecond-long pulse length (PD) value is designed based on the boiling time to ensure boiling bubbles occur with each pulse. The maximum number of focal points for tissue destruction in a phased array transducer multifocal transducer is 6. Phased array transducer focal plane multifocal damage refers to radially expanding, large-sized damage, known as large-point damage. In multifocal (large-point) electronic scanning for tumor treatment, the distance between two adjacent large points is 2 / 3 of the radial or axial large-point damage size, with 1 / 3 of the damage covered (compared to 1 / 2 coverage in a single-focus transducer, and the adjacent distance being 1 / 2 of the single-focus damage size). The larger scanning interval allows for fewer scans (points) to treat large tumors, further improving treatment efficiency. In the structural features of a phased array transducer, a dual-frequency, hundred-element phased array transducer has a central aperture. An ultrasound probe is coaxially mounted in the central aperture, and the ultrasound probe rotates 180 degrees positively (negatively) to guide and track 3D focal tissue destruction.

[0081] The following is a description of the multi-focus composite ultrasound pulse tissue ablation technology using a double-frequency phased array transducer with over 100 elements. Currently, there are no double-frequency phased array transducers with hundreds of elements that can be damaged. This application provides a double-frequency phased array transducer with hundreds of elements, and gives the acoustic field calculation and multi-focus optimization algorithm of the phased array transducer.

[0082] First, the key scheme of the composite pulse sequence proposed in this application: the ultrasonic pulse wave sequence waveform scheme is crucial for enhancing the nonlinear mechanism and improving tissue destruction efficiency. It includes a composite pulse timing suitable for enhancing the nonlinear mechanism and improving tissue destruction efficiency of a double-frequency phased array transducer, a double-frequency phased array transducer structure with hundreds of elements that can guarantee 3D multi-focus control, and a genetic optimization algorithm capable of obtaining the double-frequency characteristics of 3D multi-focus control of the double-frequency phased array transducer.

[0083] The composite pulse of this application has four stages of synchronous control to control the timing of the dual-frequency base frequency array element and the frequency multiplier array element respectively. Figure 1 The first three stages of the pulse are highly efficient millisecond-long pulses for tissue destruction (BH); the fourth stage (5–80 μs) pulses primarily cause rapid dissipation of cavitation clouds, facilitating immediate ultrasound monitoring of the ablation results, and also have some effect on chemiluminescence (CH), taking approximately 1 second. The harmonic (2nd or 3rd harmonic) sound pressure is essentially a shock wave; each focal point (generated by the harmonic) of the multifocal array is a shock wave. The boiling time of the shock wave is estimated according to weak shock wave theory to ensure that boiling occurs with each millisecond-long pulse. The fundamental frequency does not require a shock wave. This composite pulse sequence controls the power drive of hundreds of array elements and hundreds of channels across two frequency groups.

[0084] Phase 1: The fundamental frequency is not active; only the harmonic frequency (HHF) delivers millisecond-long pulses for tissue destruction. This is to reduce the potential beam obstruction by cavitation bubbles in the focal front region from the dual-frequency system. The dual-frequency system has a low cavitation threshold, making cavitation more likely. If the HHF (with a high cavitation threshold) operates alone, there will be little or no cavitation. The HHF shock wave delivers highly efficient tissue destruction (duty cycle 2-7% > conventional duty cycle 1%, but the phase 1 duration is controlled). A higher duty cycle results in more pulses per unit time, with a pulse length of 1-20 ms and a pulse repetition frequency (PRF) of 1-20 Hz, ensuring that each pulse generates boiling bubbles. The initial, powerful tissue fragmentation is initiated and strengthened by the precise location of high-frequency boiling bubbles. Because the shock wave is precisely positioned in a small localized area (width less than 100 micrometers) at the focal point, boiling and a low duty cycle are generated, resulting in mechanical ablation and precise damage location. The phase 1 duration is controlled to 1-2 s, with an additional 0.1-0.5 s of off-frequency pulses. If the time is reached, the bubbles will dissipate, ensuring that boiling bubbles can occur at the focal point in the next stage.

[0085] Phase 2: Dual-frequency (fundamental and harmonic) simultaneous millisecond-long pulses for efficient tissue ablation, with pulses ranging from 1 to 20 ms and a pulse repetition frequency (PRF) of 1 to 20 Hz, and a duty cycle of 2 to 7% (greater than the conventional duty cycle of 1%). The addition of the fundamental frequency lowers the cavitation threshold, enhances cavitation activity, and expands the damage area (larger focal area at low frequencies). The number of pulse repetitions in Phase 2 is limited to 20 to 60 times to ensure mechanical ablation without thermal damage, achieving homogenization of the damage within the target tissue.

[0086] Phase 3: Dual-frequency (fundamental frequency and harmonic frequency) synchronous operation, concentrated millisecond-long pulse trains (1-20 ms pulses, pulse repetition frequency PRF of 1-20 Hz), followed by 1-4 s off time. These two segments form a pulse group that is repeated N times, making the average duty cycle as low as about 1%. The phase 3 millisecond-long pulse tissue destruction achieves complete mechanical pulverization (complete homogenization or liquefaction) of the target tissue. The 3D single-focal damage is an elongated ellipsoid, and the 3D four-focal damage is a larger approximately spherical damage (twice as large radially).

[0087] Phase 4: Dual-frequency (fundamental frequency and harmonic frequency) synchronous short microsecond-long (5-80 μs) pulses, similar to CH. This phase is controlled for a very short time, so the tissue damage effect is small. The main function is that the microsecond-long pulses cause cavitation bubbles to dissipate quickly, so that the liquefaction area monitored by ultrasound immediately shows low echo. The phased array transducer off-axis single focus and off-axis (non-axisymmetric) multifocus will select longer microsecond pulses.

[0088] The parameters for the four stages of the composite pulse are as follows: Stage 1: The fundamental frequency is not active (off time), only the harmonic frequency is active. The pulse duration PD = 1-20 ms and the pulse repetition frequency PRF = 1-20 Hz are repeated 5-30 times, followed by an off time of 0.1-0.5 s. The duty cycle is 2-7%. Stage 2: Both frequencies f1 and f2 are active simultaneously. The pulse duration PD = 1-20 ms and the pulse repetition frequency PRF = 1-20 Hz are repeated 20-60 times. The duty cycle is 2-7%. Stage 3: Both frequencies f1 and f2 are active simultaneously. The pulse duration PD = 1-20 ms and the pulse repetition frequency PRF = 1-20 Hz are repeated 3-10 times, followed by an off time of 1-4 s. The pulse group N is repeated 2-15 times with an average duty cycle of about 1%. Stage 4: Dual-frequency pulses f1 and f2 operate simultaneously, with pulse duration PD = 5–80 μs, pulse repetition frequency PRF = 100–1000 Hz, pulse repetition S4 = 100–1000 times, and duty cycle ~1%. Figure 1 ).

[0089] This application then provides a HIFU (High-Intensity Focused Ultrasonic Fusion) transducer with a double-frequency multi-element phased array structure that supports a wider range of 3D single-focus and multi-focus electronic scanning. In some treatments, such as liver tumor treatment, the phased array transducer needs to control the phase of the elements to shift the focus (away from the geometric focus) to a specific location on the tumor for treatment. A single-element transducer with a fixed focus cannot reach this specific location. Furthermore, treating a large tumor, such as one with a diameter of 3 cm, with a single-element transducer requires hundreds of mechanical scans; however, electronic focus scanning with a phased array transducer (scanning hundreds of points electronically) takes far less time than hundreds of mechanical scans, making phased array transducer electronic scanning highly efficient. Additionally, when encountering objects such as ribs that may obstruct the beam, the phased array transducer can shut off the drive of some of the obstructed elements. The high-efficiency electronic scanning and electron focus deflection (offset from geometric focus) advantages of phased array transducers necessitate their use, despite their greater complexity (e.g., a 256-element phased array transducer requires 256 channels of power control). Since there are currently no high-frequency harmonic optimization (HIFU) phased array transducers, this application will present a HIFU transducer element structure for a high-frequency harmonic optimization phased array transducer with hundreds of elements. This high-frequency harmonic optimization phased array transducer can not only perform single-focus deflection (offset from geometric focus, offset from acoustic axis) for high-efficiency electronic scanning, but also simultaneously perform multi-focus (2-focus, 4-focus, 6-focus) and multi-focus deflection (non-axisymmetric focus) for multi-focus electronic scanning.

[0090] The element arrangement of a double-frequency phased array transducer with hundreds of elements is crucial for achieving multi-focus tissue destruction, requiring sufficient multi-focus energy and adequate scanning range of multiple focal points in 3D space; a double-frequency phased array transducer with hundreds of elements ( Figure 2 ): Hundreds of array elements can be 128, 256, 512, or 1024 elements; spherical rectangular array elements (projected square), 2D array compactly arranged, array elements distributed in 2D, and the focal point can be scanned in 3D space; The dual-frequency range is 0.4–10 MHz; f1 is the low frequency (fundamental frequency), f2 is the high frequency (multiplication frequency), and f2 = nf. 1， (n=(2~10)); f-number is less than 1.

[0091] The transducer is divided into two annular regions. The f1 (fundamental frequency) array element is distributed in the outer annular region, and the f2 (hyperfrequency) array element is distributed in the inner annular region. The central hole is used to install the ultrasound probe. The ultrasound probe rotates 180 degrees positively (negatively) to track 3D focal tissue damage.

[0092] Array element misalignment: Due to the extremely high sound pressure required for tissue damage, the transducer surface area is large. Even with hundreds of array elements, each element's size is larger than one wavelength, thus the focus can only be shifted within a limited space around the geometric focus, without grating lobes. A reasonable arrangement of array elements can expand the grating-lobe-free focal three-dimensional scanning range. Therefore, adjacent array elements in the double-frequency phased array transducer of this application are misaligned (see...). Figure 2 This is to maximize the focal depth of the grating-free stereoscopic scanning range.

[0093] The size of the f1 (fundamental frequency) array element is larger than the size of the f2 (multiplier frequency) array element; Dual 2-harmonic phased array transducers: The size of the fundamental frequency array element is 1.5 to 2 times the size of the 2-harmonic frequency array element; Dual 3rd harmonic phased array transducer: The size of the fundamental frequency array element is 2 to 3 times the size of the 3rd harmonic array element; The number of elements in the fundamental frequency array is less than the number of elements in the frequency multiplier array.

[0094] Furthermore, this application presents a 3D spatial multifocal mode for a biharmonic phased array transducer with hundreds of elements based on a biharmonic genetic algorithm: the biharmonic phased array transducer can achieve simultaneous multifocal tissue destruction through optimization algorithms. Simultaneously, multifocality can expand the treatment damage volume of a single irradiation. For example, a single irradiation damage from a 4-focal focal plane is a relatively large volume damage. The single irradiation damage volume of a 4-focal transducer is the same as the damage volume obtained from at least 9 (times, biharmonic single-focal) mechanical scans (3×3 adjacent focal points half-covering). In fact, due to the addition of the fundamental frequency, the single-focal region or cavitation region of biharmonic is larger than the frequency-doubled focal region, resulting in a larger biharmonic damage size than a frequency-doubled damage size. A biharmonic 4-focal transducer is also approximately 3 times larger than a frequency-doubled 4-focal transducer, thereby shortening the treatment time for large tumors and significantly improving efficiency.

[0095] Simultaneously, multi-focal scanning aims to maximize the ultrasonic energy at multiple focal points, which is a parallel optimization problem. Therefore, achieving multi-focal electronic scanning in a phased array transducer with hundreds of elements relies on parallel optimization algorithms, such as genetic algorithms and particle swarm optimization. This application presents a method for accurately calculating the sound pressure level of a double-frequency phased array transducer by combining a genetic algorithm with a double-frequency spherical rectangular array element.

[0096] The genetic algorithm for the double-frequency phased array transducer in this application first sets the position of the 3D multifocal points, and the sound pressure level of these multifocal points is represented by a vector. (Complex vector) representation, Phase angles of each component Genetic algorithms for double-frequency phased array transducers The phase angles of each component are used as variables for parallel optimization. The genetic operation of the genetic algorithm for double-frequency phased array transducers is used to obtain the maximum multifocal energy through iterative evolution. Then, the corresponding maximum energy is obtained by inverse matrix method. driving vector (Complex vector, each component corresponding to the driving amplitude and phase of each array element; the driving includes dual frequencies); see Figure 3 .

[0097] use The amplitude and phase emission of each array element ( Figure 4 (System) Ultrasonic waves can be used to... The M points achieve multifocal focusing results.

[0098] The algorithm for the spherical rectangular array element of the multi-focus controlled double-frequency phased array transducer, as well as the genetic algorithm, will be described in detail in the later implementation method section.

[0099] The driver obtained using a genetic algorithm for a double-frequency phased array transducer The algorithm for the spherical rectangular array elements of the double-frequency phased array transducer can quantitatively simulate the 3D sound field distribution of the multifocal mode; it can also obtain the 3D sound field distribution of the multifocal mode with only the frequency-doubled f2 array element working. In order to make the applied sound power sufficient to generate a shock wave with a frequency-doubled negative pressure exceeding 10 MPa, this application can also achieve frequency-doubled driving to obtain the frequency-doubled multifocal sound pressure, so that the multifocal negative pressure is a shock wave exceeding 10 MPa. According to the weak shock theory, the boiling time of the shock wave can be calculated, thereby ensuring that boiling bubbles occur in each pulse of the millisecond long pulse therapy.

[0100] Using a genetic algorithm for a double-frequency phased array transducer, focal mode control can be obtained for 3D spatial single-focus, 2-focus, 4-focus, and 6-focus modes. 3D single-focus means that it can generate a single focus along the acoustic axis. Off-axis single-focus means that the focus can be located in the area around the geometric focus, which means that 3D single-focus electronic scanning is possible.

[0101] 3D multifocal: This means that it can generate axisymmetric multifocals (2-focal, 4-focal, 6-focal, etc.); off-axis (non-axisymmetric) multifocals (off-axis 2-focal, off-axis 4-focal, off-axis 6-focal, etc.) that means the multifocals can be located in the area around the geometric focus, which means that 3D multifocal electronic scanning is possible.

[0102] The single-shot irradiation damage volume of a 4-focal site is the damage volume obtained by mechanical scanning at least 9 positions of a single focal spot (3×3 adjacent focal spots half-covering). The larger single-shot irradiation damage volume reduces the number of 4-focal large focal area irradiations required to treat large tumors, significantly reducing the time required to treat a tumor and thus significantly improving treatment efficiency.

[0103] Because the sound pressure is extremely high due to tissue damage, and the number of multifocal points has an upper limit, generally not exceeding 6 focal points.

[0104] The multifocal design for tissue damage in this application generally involves distributing multiple focal points (2-focal, 4-focal, etc.) on the focal plane (see...). Figure 7The focal plane (with four focal points) is a plane perpendicular to the acoustic axis; the multiple focal points are distributed on the focal plane (rather than along the acoustic axis) to prevent acoustic blockage by the bubble. The distance between adjacent focal points on the focal plane is approximately one fundamental wavelength (see...). Figure 7 and 8 (Focal plane 4-focal). The damage volume of a 2-focal site is greater than the damage size obtained by at least 3 mechanical or electronic scans of a single-focal site. The damage volume of a 4-focal site is greater than the damage size obtained by at least 9 positional mechanical or electronic scans (3×3 adjacent focal points half-covering). The spacing between adjacent focal points in a multifocal site can be designed and is variable; generally, the spacing between adjacent focal points in a multifocal site is one fundamental frequency wavelength.

[0105] A relatively large tumor, such as one with a diameter of 3 cm, requires at least 100 single-focus scans to complete the treatment. The distance between two consecutive single-focus scans is d1 / 2 (d1 is the diameter of the single-focus lesion, i.e., half coverage). A 4-focus scan results in a lesion diameter d2 (d2>= 2d1), and the distance between two consecutive single-focus scans in a 4-focus scan is 2(d2) / 3 (2(d2) / 3 distance, i.e., one-third coverage). A larger distance between scan points further reduces the number of times the tumor needs to be irradiated, thus improving treatment efficiency.

[0106] The double-frequency phased array transducer structure with hundreds of elements provided in this application, along with the simultaneous multifocal approach combining double-frequency genetic algorithms, is also suitable for low-intensity treatments involving ultrasound contrast microbubbles, such as opening the blood-brain barrier to enhance large-area drug delivery; it is also suitable for other scenarios involving therapeutic ultrasound. If the double-frequency phased array transducer with hundreds of elements uses composite pulses or high-frequency focal points requiring shock waves, then it becomes a tissue destruction technique. Similarly, these treatments can also utilize the subarray method of the double-frequency phased array transducer structure with hundreds of elements provided in this application, combined with the simultaneous multifocal approach combining double-frequency genetic algorithms, including working with only high-frequency (single-frequency) elements.

[0107] The drive and control structure of the phased array transducer with hundreds of elements in this application is as follows: Figure 4 As shown, a phased array transducer driver with hundreds of channels transmits element drive signals to the double-frequency phased array transducer with hundreds of elements through two sets of impedance matching networks for hundreds of elements. Because the composite pulse sequence contains both a fundamental frequency and a harmonic frequency pulse sequence, the phased array transducer is also divided into two groups: a fundamental frequency group and a harmonic frequency group; the impedance matching network is also divided into two groups: a fundamental frequency group impedance matching network and a harmonic frequency group impedance matching network; the phased array transducer driver has an arbitrary waveform generator module that controls the composite pulse sequence of two frequencies (divided into two channels), and the fundamental frequency pulse sequence waveform and the harmonic frequency pulse sequence waveform control the timing of each channel of the fundamental frequency and harmonic frequency respectively. The phased array transducer driver also has hundreds of channels whose phase and amplitude control accepts the multi-focal drive of each element corresponding to a genetic algorithm. The phase and amplitude are controlled. Hundreds of phased array transducers correspond to hundreds of phased array transducer channel amplifiers. Each element corresponds to the power control of one channel. The power and phase of each channel in the phased array transducer driver are independently controlled. The pulse timing of each frequency element is a composite pulse frequency pulse waveform timing sequence. The ultrasound probe is connected to the ultrasound imaging system for real-time monitoring, monitoring the effect of the fourth stage of the composite pulse.

[0108] The drive and control of a phased array transducer with hundreds of elements specifically includes the following steps: Step 1: Design the position of the focal plane multifocal points Monofocal, 2-focal, 4-focal, 6-focal, off-axis monofocal, off-axis multifocal.

[0109] Step 2: Reverse solve the multifocal problem using the double-frequency genetic algorithm (double-frequency genetic algorithm calculation flow) program. corresponding drive signals (A set of amplitude and phase corresponding to each element drive).

[0110] Step 3: Use the precise calculation program for the phased array transducer with dual-frequency spherical rectangular array elements and the result obtained in Step 2. The 3D sound field focusing characteristics are obtained through simulation to verify whether they meet the requirements, such as the presence or absence of grating lobes. Alternatively, only the harmonic drive can be used, with the harmonic focus sound pressure exceeding 10 MPa (the harmonic is a shock wave). The boiling time is calculated using the weak impact theory formula, and the millisecond-long pulse length PD value is designed based on the boiling time to ensure that boiling bubbles occur with each pulse.

[0111] Step 4: Use the method from step 2 The composite pulse parameters are loaded into the phased array transducer driver with hundreds of channels and emitted to achieve the designed multifocal tissue destruction.

[0112] This application provides a double-frequency phased array composite pulse tissue destruction method, including split array multi-focus control, composite pulse timing to improve tissue destruction efficiency through enhanced nonlinear mechanisms, and verification of the double-frequency phased array composite pulse tissue destruction effect.

[0113] Biharmonic split arrays commonly use 2 or 4 elements, with a maximum of 12 elements. Biharmonic split arrays generate confocal single focal points, 2-focal points, and 4-focal points as fixed multifocal points (geometrically symmetric in the focal plane), but cannot produce focal deflection, i.e., cannot perform focal electronic scanning. The focal point calculation for biharmonic split arrays does not require parallel optimization (reverse) genetic algorithms; instead, the phase difference of the split array controls the forward synthesis of multifocal points. The composite ultrasonic pulse waveform of the two frequencies is controlled by the number of channels in an arbitrary waveform generator, which has the same number of elements as the split array.

[0114] The frequency of the double-frequency split array is 0.4–10 MHz; f1 is the fundamental frequency, f2 is the harmonic frequency, f2 = nf1, (n = (2–10); f-number is less than 1. Double-frequency split arrays are typically spherical 2-element ring arrays, 4- or 6-element rectangular split arrays, 4- or 6-element fan-shaped split arrays, and fan-shaped spiral split arrays. By controlling several phase difference modes of adjacent elements, multi-focal points on the focal plane of the double-frequency split array can be obtained, such as single-focal, 2-focal, and 4-focal points. To ensure that the applied acoustic power is sufficient to generate a shock wave with a negative pressure exceeding 10 MPa, the boiling time of the shock wave can be calculated according to the weak shock theory, thereby ensuring that boiling bubbles occur in each pulse of millisecond-long pulse therapy.

[0115] The composite pulse consists of four stages: The first three stages utilize highly efficient millisecond-long pulses for tissue ablation. In particular, the first stage only operates the harmonics (high duty cycle 2-7%) of the shock wave, while the fundamental frequency remains inactive. This reduces the potential for cavitation bubbles in the focal pre-focus region to obstruct the beam, initiating the most powerful tissue fragmentation at a precise location. Because the shock wave is precisely positioned in a small localized region (width less than 100 micrometers) at the focal point, boiling and a low duty cycle occur, resulting in mechanical ablation with precise damage location. The second stage employs dual-harmonic simultaneous millisecond-long pulses for highly efficient tissue ablation, with a duty cycle of 2-7% (greater than the conventional 1%). The addition of the fundamental frequency lowers the cavitation threshold, enhances cavitation activity, and expands the damage area, ensuring mechanical ablation and homogenization of the damage within the target tissue. Phase 3: Dual-frequency operation, with concentrated millisecond-long pulse trains followed by off-time. These two segments form pulse group N, which is repeated several times to reduce the average duty cycle to approximately 1%. This three-stage millisecond-long pulse ablation achieves complete mechanical fragmentation (complete homogenization or liquefaction). This highly efficient three-stage tissue ablation produces fixed-focus "elongated ellipsoidal" (not "tadpole-shaped") or "spherical" (four-focal) lesions. Phase 4, with even shorter pulses (5–40 μs), primarily aims to rapidly dissipate cavitation clouds and also has some CH (choic aspiration) effect. Its short duration allows for immediate ultrasound monitoring of the damage effect. This method specifically addresses the problem of cavitation clouds obscuring the beam in the anterior focal zone of confocal doubling frequency treatments, and the issue of slow cavitation cloud dissipation at the end of treatment.

[0116] Specific parameters: Stage 1: The fundamental frequency does not operate with an off-time; only the harmonic frequency operates. The pulse duration PD = 1–20 ms and the pulse repetition frequency PRF = 1–20 Hz, with pulse repetitions S1 = 5–30 times, followed by an off-time of 0.1–0.5 s. Duty cycle 2–7%. Stage 2: Both frequencies operate simultaneously. The pulse duration PD = 1–20 ms and the pulse repetition frequency PRF = 1–20 Hz, with pulse repetitions S2 = 20–60 times. Duty cycle 2–7%. Stage 3: Both frequencies operate simultaneously. A concentrated millisecond-long pulse train, with a pulse duration PD = 1–20 ms and a pulse repetition frequency PRF = 1–20 Hz, is repeated S3 = 3–10 times, followed by an off-time of 1–4 s. These two segments form a pulse group that repeats N = 2–15 times, with an average duty cycle of approximately 1%. Stage 4: Dual-frequency operation, pulse duration PD = 5 ~ 40 μs, pulse repetition frequency PRF = 100 ~ 1000 Hz, pulse repetition S4 = 100 ~ 1000 times, duty cycle ~ 1%.

[0117] System Implementation: The simple and easy-to-implement system consists of a main control computer that primarily controls the split-array arbitrary waveform transmitters (groups), split-array element power amplifiers (groups), split-array element impedance matching circuits (groups), and split-array transducers to emit focused ultrasound waves into the sample in a composite pulse sequence for tissue ablation. The ultrasound probe is coaxially mounted in the central hole of the split-array transducer, acquiring signals from the probe and transmitting them to the ultrasound imaging system. Thus, the ultrasound system performs image guidance for tissue ablation and real-time ultrasound image monitoring. The main control computer also controls 3D positioning to move the sample and focus it on the sample. If a high-speed camera is used for monitoring, one of the split-array arbitrary waveform transmitters (groups) triggers the high-speed camera to capture images.

[0118] The steps for implementing the focus mode of the split array system include: Step 1: Based on the required split array and focal mode (single focal, 2 focal, 4 focal), obtain the sound field distribution using the double-frequency split array sound field formula or nonlinear KZK to ensure the frequency-doubled shock wave and obtain experimental control parameters such as power, phase difference, and composite pulse parameters.

[0119] Step 2: Use 3D position control to move the prepared sample so that the focus is located at a certain depth within the sample. At the same time, use ultrasound for positioning. The system sends a short pulse lower than the treatment pulse to position the focus for cavitation (the highlighted area is the focus).

[0120] Step 3: Set the arbitrary waveform generator (group) of the split array using the composite pulse parameters from Step 1, and set the power amplifier (group) of the split array using the power parameters from Step 1, to induce tissue damage. Monitor in real-time using ultrasound. If multiple points (several) are irradiated, set the 3D position control movement path and the focal distance between the two (several) focal points to induce tissue damage.

[0121] Step 4: After treatment, the experimental sample is dissected, H&E stained, or subjected to relevant tests, and preserved by ultrasound or high-speed imaging.

[0122] Among them, multi-element fan-shaped split arrays or multi-element rectangular split arrays can generate simultaneous multifocal points (geometrically symmetric focal plane); the maximum number of multifocal points is equal to the number of elements in a double-frequency split array. Tissue damage characterized by radially expanding, large-sized lesions in multifocal lesions on the focal plane are called large-point lesions. In multifocal (large-point) mechanical scanning for tumor treatment, a distance of 2 / 3 radial or axial large-point lesion size between two adjacent large-point lesions, and 1 / 3 lesion coverage (compared to 1 / 2 coverage in a single-focus lesion, with an adjacent distance of 1 / 2 single-focus lesion size), and a larger scanning point spacing, further reduces the number of irradiation sessions on the tumor and improves treatment efficiency. The two-element ring array transducer has a single focal point. Nonlinear KZK (quantitative calculation of nonlinear sound pressure) can be used, with the harmonic frequency representing a shock wave. Based on weak shock theory, the boiling time of the shock wave can be accurately calculated, ensuring that boiling bubbles occur with every millisecond-long pulse. In a dual second-harmonic ring array, when the phase difference between the two frequencies is 135 degrees from the fundamental frequency, the negative pressure superposition at the focal point is maximized, which is beneficial for cavitation initiation and activity. In a dual third-harmonic ring array, when the phase difference between the two frequencies is 60 degrees, the superposition of positive and negative pressures at the focal point is close to maximum, which is beneficial for cavitation initiation and collapse, thus enhancing cavitation.

[0123] The following is a description of the bi-frequency split-array multifocal composite ultrasound pulse tissue ablation technique. The composite ultrasound pulse is a tissue ablation pulse waveform sequence tailored for biharmonic split arrays. This technology specifically addresses the problem of cavitation cloud obscuring the beam in front of the focal zone in biharmonic confocal arrays, and the issue of slow cavitation cloud dissipation at the end of treatment, thereby improving the efficiency of tissue ablation treatment. The biharmonic split array system is simple and easy to implement. Unlike biharmonic phased array transducers with hundreds of elements, biharmonic split arrays typically use 2 or 4 elements, generally not exceeding 12 elements. The confocal single focus, 2-focus, and 4-focus outputs of biharmonic split arrays are fixed (geometrically symmetrical focal plane), and cannot produce focus deflection, i.e., cannot produce off-axis single focus, off-axis 2-focus, or off-axis 4-focus, meaning it cannot perform focus electronic scanning. Focus calculation for biharmonic split arrays does not require parallel optimization (reverse) genetic algorithms; instead, it uses the phase difference of the split array to control the forward synthesis of multiple focuses, employing nonlinear quantitative methods and 3D dual-frequency sound field calculation. The composite ultrasonic pulse waveform at two frequencies is controlled by the number of channels of an arbitrary waveform generator, which is the same as the number of elements in the split array.

[0124] First, the ultrasonic pulse wave sequence waveform scheme is key to enhancing the nonlinear mechanism and improving tissue destruction efficiency. The composite pulse in this application has four stages that synchronously control the timing of the fundamental and harmonic array elements of the dual-frequency system: the first three stages are highly efficient millisecond-long pulse tissue destruction (BH); the fourth stage (5–40 μs) pulse mainly causes rapid dissipation of cavitation clouds and also has some CH effect, lasting only about 1 s. The harmonic sound pressure is essentially a shock wave, with each focal point (generated by the harmonic) being a shock wave; the boiling time of the shock wave is estimated according to weak shock wave theory to ensure that boiling occurs with each millisecond-long pulse. The fundamental frequency does not require a shock wave. The composite pulse sequence of the two frequencies controls the power drive of each channel of the arbitrary waveform generator (group) corresponding to the frequency of each split array element.

[0125] Phase 1: The fundamental frequency is not active; only the harmonic frequency (HHF) delivers millisecond-long pulses for tissue destruction. This reduces the possibility of cavitation bubbles blocking the beam in the focal front region due to the dual-frequency system. The dual-frequency system has a low cavitation threshold, making it prone to cavitation. If the harmonic frequency (with a high cavitation threshold) operates alone, there will be little or no cavitation. The harmonic shock wave delivers highly efficient tissue destruction (duty cycle 2-7% > conventional duty cycle 1%, but the duration of Phase 1 is controlled). A high duty cycle results in a higher number of pulses per unit time, ensuring high efficiency. The pulse duration is 1-20 ms, and the pulse repetition frequency (PRF) is 1-20 Hz, ensuring that each pulse generates boiling bubbles. The initial powerful tissue fragmentation is initiated by high-frequency boiling bubbles at precise locations. Because the shock wave is precisely positioned in a small local area (width less than 100 micrometers) at the focal point, boiling and a low duty cycle are generated, resulting in mechanical ablation and precise damage location. The duration of Phase 1 is controlled to 1-2 s. If an off time of 0.1-0.5 s is added, the bubbles dissipate, ensuring that boiling bubbles occur at the focal point in the next phase.

[0126] Phase 2: High-efficiency tissue ablation using double-frequency simultaneous millisecond-long pulses (1–20 ms pulses), with a pulse repetition frequency (PRF) of 1–20 Hz and a duty cycle of 2–7% (greater than the conventional duty cycle of 1%). The addition of the fundamental frequency lowers the cavitation threshold, enhances cavitation activity, and expands the damage area (larger focal zone due to the fundamental frequency). The number of pulse repetitions in Phase 2 is limited to 20–60 times to ensure mechanical ablation without thermal damage, achieving homogenization of the damage within the target tissue.

[0127] Phase 3: Dual-frequency operation, with concentrated millisecond-long pulse trains (1-20 ms pulses, pulse repetition frequency PRF of 1-20 Hz), followed by 1-4 s off time. These two segments form a pulse group that is repeated N times, making the average duty cycle as low as about 1%. The phase 3 millisecond-long pulse tissue destruction achieves complete mechanical pulverization (complete homogenization or liquefaction) of the target tissue. The fixed single-focal damage is an elongated ellipsoid, and the fixed four-focal damage is a larger approximately spherical damage (twice as large radially).

[0128] Phase 4: Dual-frequency short-duration microsecond-long (5-40 μs) pulses, similar to CH. This phase is controlled for a very short time, so the tissue damage is small. The main function is that the microsecond-long pulses cause the cavitation bubbles to dissipate quickly, so that the liquefaction area can be monitored as low echo on ultrasound immediately.

[0129] The composite pulse has four stages: Stage 1: The fundamental frequency is not active (off time), only the harmonic frequency is active, with pulse duration PD = 1-20 ms and pulse repetition frequency PRF = 1-20 Hz, repeating S1 = 5-30 times, followed by an off time of 0.1-0.5 s, with a duty cycle of 2-7%. Stage 2: Dual frequencies f1 and f2 are active simultaneously, with pulse duration PD = 1-20 ms and pulse repetition frequency PRF = 1-20 Hz, repeating S2 = 20-60 times, with a duty cycle of 2-7%. Stage 3: Dual frequencies f1 and f2 are active simultaneously, with pulse duration PD = 1-20 ms and pulse repetition frequency PRF = 1-20 Hz, repeating S3 = 3-10 times, followed by an off time of 1-4 s, with pulse groups repeating N = 2-15 times with an average duty cycle of approximately 1%. Stage 4: Dual-frequency pulses f1 and f2 operate simultaneously, with pulse duration PD = 5–40 μs, pulse repetition frequency PRF = 100–1000 Hz, pulse repetition S4 = 100–1000 times, and duty cycle ~1%. See also... Figure 1 .

[0130] The frequency of a double-frequency split array is 0.4–10 MHz; f1 is the low frequency (fundamental frequency), f2 is the high frequency (multiplication frequency), f2 = nf1, (n = (2–10); f-number is less than 1. Double-frequency split arrays are typically spherical 2-element ring arrays. Figure 11 (a)), 4-element rectangular split array ( Figure 11 (b)), 4-element fan-shaped split array ( Figure 11 (c) and fan-shaped split array.

[0131] Double-frequency splitting arrays commonly use 2 or 4 elements, and generally do not exceed 12 elements. If it is a multi-element fan-shaped splitting array or a multi-element rectangular splitting array, it can split into multiple focal planes simultaneously (geometrically symmetric focal planes); the maximum number of splitting focal points is equal to the number of elements in the double-frequency splitting array. For example, a 4-element fan-shaped double-frequency splitting array can produce single-focal, 2-focal, and 4-focal arrays.

[0132] When a double-frequency wave is emitted in millisecond long waves, the two frequency waves can interfere to generate a focal plane with multiple focal points, such as a double-frequency split array of a 4-element fan array: it can generate fixed focal points such as single focal points, 2 focal points, and 4 focal points (i.e., 4 focal points are arranged symmetrically about the acoustic axis or about the geometric focal point); the destruction of tissue at the focal plane of 4 focal points forms a large-size lesion, which is equivalent to the lesion volume of 3×3=9 (times) single-focal tissue destruction mechanical scans, saving treatment time and thus improving treatment efficiency.

[0133] A relatively large tumor, such as one with a diameter of 3 cm, requires at least 100 single-focus scans to complete the treatment. The distance between two consecutive single-focus scans is d1 / 2 (d1 is the diameter of the single-focus lesion, i.e., half coverage). A 4-focus scan results in a lesion diameter d2 (d2>= 2d1), and the distance between two consecutive single-focus scans in a 4-focus scan is 2(d2) / 3 (2(d2) / 3 distance, i.e., one-third coverage). A larger distance between scan points further reduces the number of times the tumor needs to be irradiated, thus improving treatment efficiency.

[0134] The confocal point of the two-element ring array transducer is a focal point, and the tissue destruction using the composite pulse of this application is an elongated ellipsoidal lesion located at the focal point.

[0135] The confocal point of the two-element ring array transducer is a single focal point. Nonlinear sound pressure can be quantitatively calculated using the nonlinear KZK (Khokhlov Zabolotskaya Kuznnetsov) method. The octave (high frequency) is considered a shock wave with a negative pressure exceeding 10 MPa. Based on weak shock theory, the boiling time of the shock wave can be calculated, ensuring that boiling bubbles occur in each pulse of millisecond-long pulse therapy. The fundamental frequency does not require a shock wave. In a dual 2nd harmonic ring array, when the phase difference between the two frequencies is 135 degrees from the fundamental frequency, the negative pressure superposition at the focal point is maximized, which is beneficial for cavitation initiation and activity. In a dual 3rd harmonic ring array, when the phase difference between the two frequencies is 60 degrees, the superposition of positive and negative pressures at the focal point is close to maximum, which is beneficial for cavitation initiation and collapse, thus enhancing cavitation.

[0136] If the geometric focal plane of the double-frequency split array is axisymmetric and multifocal, such as single-focal, 2-focal, and 4-focal control, only a few phase difference modes of adjacent array elements are needed. The 3D sound field distribution of the multifocal mode is obtained by calculating the double frequency. To ensure that the applied sound power is sufficient to generate a shock wave with a negative pressure exceeding 10 MPa, the boiling time of the shock wave can be calculated according to the weak shock theory, thereby ensuring that boiling bubbles occur in each pulse of the millisecond long pulse therapy.

[0137] The system implemented using this method is a simple and easy-to-implement double-frequency split array with few elements, suitable for performing multi-focus composite pulse tissue ablation. The main control computer controls the split array arbitrary waveform transmitters (groups), split array element power amplifiers (groups), split array element impedance matching circuits (groups), and split array transducers to emit focused ultrasound waves into the sample according to a composite pulse sequence for tissue ablation. An ultrasound probe is coaxially mounted in the center hole of the split array transducer, acquiring signals from the probe and transmitting them to the ultrasound imaging system. Thus, the ultrasound system performs image guidance and real-time ultrasound image monitoring for tissue ablation. The main control computer also controls 3D positioning to move the sample and focus it on. If a high-speed camera is used for monitoring, one of the split array arbitrary waveform transmitters (groups) triggers the high-speed camera to capture images. See [link to documentation]. Figure 17 .

[0138] Steps for implementing the focal mode of the system using a split array: Step 1: Based on the required split array and focus mode (single focus, 2 focus, 4 focus), use the double-frequency split array sound field formulas (8) and (9) or nonlinear KZK to obtain the sound field distribution, ensure the double-frequency shock wave, and obtain experimental control parameters such as power, phase difference, and composite pulse parameters.

[0139] Step 2: Implement the system using the above method ( Figure 17 The prepared sample is moved using 3D position control so that the focus is located at a certain depth within the sample. At the same time, the ultrasound is used for positioning, and the system sends a short pulse lower than the treatment pulse to position the focus for cavitation (the highlighted area is the focus).

[0140] Step 3: Set the arbitrary waveform generator (group) of the split array using the composite pulse parameters from Step 1, and set the power amplifier (group) of the split array using the power parameters from Step 1, to induce tissue damage. Monitor in real-time using ultrasound. If multiple points (several) are irradiated, set the 3D position control movement path and the focal distance between the two (several) focal points to induce tissue damage.

[0141] Step 4: After treatment, the experimental sample is dissected, H&E stained, or subjected to relevant tests, and preserved by ultrasound or high-speed imaging.

[0142] This application belongs to the field of ultrasound technology and does not involve related human experiments. This application uses phantom experiments for mechanism analysis and uses in vitro tissue and mouse tumor experiments for effectiveness verification.

[0143] 1) Boiling time calculation using the weak impact theory: First, both types of array element destruction require high-frequency (hyperfrequency) generation of shock waves, and the required boiling time for the shock wave is given here; according to the weak shock theory, the boiling time t reached by the shock wave can be obtained. b : (1) △T is the temperature difference between the ambient temperature and 100℃ (°C); As is the shock wave amplitude (Pa); f0 is the ultrasonic frequency (Hz); β is the nonlinear coefficient; c is the sound velocity in the medium. ; ρ Dielectric density C v Specific heat capacity .

[0144] 2) Specific implementation method of multi-focus composite ultrasound pulse tissue destruction using a double-frequency phased array transducer with hundreds of elements: A. Double-frequency phased array composite ultrasonic pulse The ultrasonic pulse wave sequence waveform scheme is key to enhancing the efficiency of tissue destruction through nonlinear mechanisms. The composite pulse in this application has four stages that synchronously control the timing of the fundamental and harmonic frequency array elements: the first three stages are highly efficient millisecond-long pulses for tissue destruction; the fourth stage (5–80 μs) pulses primarily cause rapid dissipation of cavitation clouds and also have some CH (hygroscopic effect), and its duration is very short. If the harmonic sound pressure is a shock wave, the boiling time of the shock wave is estimated according to weak shock wave theory to ensure that boiling occurs with each millisecond-long pulse. The fundamental frequency does not require a shock wave. This composite pulse sequence controls the power drive of hundreds of array elements and hundreds of channels across two frequency groups.

[0145] Phase 1: The fundamental frequency is not active; only the harmonic frequency delivers millisecond-long pulses for tissue destruction. This is to reduce the potential beam obstruction by cavitation bubbles in the focal pre-field region from dual-frequency operation; ensure that each pulse of the harmonic frequency generates boiling bubbles; achieve highly efficient tissue destruction (duty cycle 2-7% > conventional duty cycle 1%); initiate powerful tissue fragmentation; because the shock wave is precisely positioned in a small localized area (width less than 100 micrometers) at the focal point, boiling and a low duty cycle are generated, resulting in mechanical ablation and precise damage location. The pulse duration PD = 1-20 ms and the pulse repetition frequency PRF = 1-20 Hz are repeated 5-30 times, followed by an off-time of 0.1-0.5 s, with a duty cycle of 2-7%.

[0146] Phase 2: Simultaneous dual-frequency millisecond-long pulses for efficient tissue ablation. The addition of low frequency lowers the cavitation threshold, enhances cavitation activity, and expands the damage area (larger focal zone due to low frequency). Pulses range from 1 to 20 ms, with a pulse repetition frequency (PRF) of 1 to 20 Hz and a duty cycle of 2 to 7% (greater than the conventional duty cycle of 1%). The number of pulse repetitions in Phase 2 is limited to 20 to 60 times to ensure mechanical ablation without thermal damage, achieving homogenization of the damage to the target tissue.

[0147] Phase 3: Dual-frequency operation, consisting of concentrated millisecond-long pulse trains with pulse duration PD = 1–20 ms and pulse repetition frequency PRF = 1–20 Hz, repeated 3–10 times, followed by an off-time of 1–4 s. These two segments constitute a pulse group repeated N = 2–15 times, with an average duty cycle of approximately 1%. Phase 3 millisecond-long pulses achieve complete mechanical fragmentation (complete homogenization or liquefaction) of the target tissue. Single-focal damage is elongated ellipsoidal, while four-focal damage is a larger, approximately spherical lesion (twice as large radially).

[0148] Phase 4: Dual-frequency, short, microsecond-long (5–80 μs) pulses, similar to CH. This phase is very short, so its tissue-damaging effect is minimal. Its main function is to rapidly dissipate cavitation bubbles using the microsecond-long pulses, immediately making the liquefied area appear as a low-echo zone on ultrasound. Phased array transducers with off-axis single-focus and off-axis (non-axisymmetric) multi-focus transducers will select longer microsecond pulses. Pulse duration PD = 5–80 μs, pulse repetition frequency PRF = 100–1000 Hz, pulse repetition S4 = 100–1000 times, duty cycle ~1%.

[0149] B. Structure of a double-frequency phased array transducer with hundreds of elements The element distribution design of a double-frequency spherical phased array transducer needs to ensure that the single- and multi-focal electron scanning acoustic characteristics of the damaged tissue are within the largest possible range. Figure 2 This application presents a first-ever proposed element distribution for a double-frequency spherical 256-element phased array transducer; the spherical rectangular elements (projected squares) are arranged in a compact 2D array, with the elements distributed in 2D and the focal point capable of scanning in 3D space.

[0150] The double-frequency 256-element phased array transducer has a frequency range of 0.4–10 MHz, with f1 as the fundamental frequency and f2 as the harmonic (f2 = nf1, n = (2–10)); the f-number is less than 1. The transducer is divided into two annular regions: 64 fundamental frequency elements are distributed in the outer ring, and 192 harmonic elements are distributed in the inner ring. A central aperture is used to mount an ultrasound probe, which rotates 180 degrees positively (or negatively) to track 3D focal tissue damage. The number of fundamental frequency elements is less than the number of harmonic elements.

[0151] Array element misalignment: Due to the extremely high sound pressure required for tissue damage, the transducer surface area is large. Even with hundreds of array elements, each element's size is larger than one wavelength, resulting in a limited focal deflection within a grating-lobe-free space around the geometric focal point. A proper arrangement of the array elements can expand the grating-lobe-free focal three-dimensional scanning range. Therefore, adjacent array elements in the double-frequency phased array transducer of this application are misaligned.

[0152] The size of the fundamental frequency array element is larger than that of the frequency harmonic array element; for dual 2nd harmonics, the size of the fundamental frequency array element is 1.5 to 2 times the size of the 2nd harmonic array element; for dual 3rd harmonic phased array transducers, the size of the fundamental frequency array element is 2 to 3 times the size of the 3rd harmonic array element. C. Multifocal mode genetic algorithm for double-frequency spherical rectangular phased array transducer with hundreds of elements The spherical rectangular array structure of the double-frequency spherical rectangular phased array transducer is a 2D array. Theoretically, a 2D array can generate a 3D focal point, enabling 3D spatial focal electronic scanning. The control method of this application aims to provide a control method that can generate 3D single-focal and multi-focal forms, namely, a sound field calculation method for the double-frequency spherical rectangular phased array transducer and a double-frequency genetic algorithm multi-focal mode optimization method suitable for the design of multi-point focusing modes of any double-frequency phased array transducer.

[0153] (a) Sound field calculation method for a double-frequency spherical rectangular phased array transducer This application provides a concise method for calculating the double harmonic sound pressure level; assuming the array element width is... The array element height is The area of ​​the array element is The origin of the xyz coordinate system is at the vertex of the spherical cap, and the beam direction is the z-axis (acoustic axis). The sound pressure formula for the dual-frequency spherical phased array transducer is: (2) In the formula, the complex sound pressure P(x, y, z) , c and c represent the density of the medium and the speed of sound, respectively. and Here, f1 is the wave number, f2 is the fundamental frequency, and f2 is the harmonic frequency; N is the total number of array elements, where N1 are the array elements with frequency f1, and the remaining N-N1 are the array elements with frequency f2. The velocity of the surface particles of the nth array element is used as the element driving signal; the calculation of each parameter is as follows:

[0154]

[0155] ,and

[0156]

[0157] Equation (2) above was derived using three methods: converting the surface integral into a projected plane integral, establishing a translational coordinate system, and using a binomial expansion method. Equation (2) is suitable for calculating far-field sound pressure, that is, the distance between the calculated sound pressure point and the transducer is much larger than the element size. Each element can also be divided into smaller rectangular stacks.

[0158] (b) Genetic Algorithm for Multifocal Mode of Double-Frequency Phased Array Transducer with Hundreds of Elements Genetic algorithms (GA) are computational models that simulate Darwin's genetic selection and natural selection processes in biological evolution. They are a class of randomized search methods that draw inspiration from the mechanisms of natural selection and heredity in the biological world. Unlike traditional methods that search for solutions at a single point or along a single line, genetic algorithms search in parallel across the solution space, thus obtaining globally optimal solutions. Genetic algorithms have become an ideal tool for searching for optimal solutions in many fields, including science, engineering, and economics. Each generation of a genetic algorithm involves four steps: evaluation, propagation, recombination, and mutation.

[0159] The matrix expression of the sound field sound pressure of a phased array transducer is as follows: If the sound source consists of N array elements, the sound pressure at control point M (in this application, the M focal positions) is... p(r m ) If it can be set to known: (3) Where m=1, 2 M; and Here, f1 is the wave number, f2 is the fundamental frequency, and f2 is the harmonic frequency; N is the total number of array elements, where N1 are the array elements with frequency f1, and the remaining N-N1 are the array elements with frequency f2. Written in matrix form: (4) It is the complex driving vector of the array element. .vector It is the complex sound pressure vector of the set control points (M focal positions). , It is a forward transport operator, where the element .

[0160] The driving force can be obtained in reverse using matrix methods. : (5) Before describing the steps of a genetic algorithm, we first define two very important elements: chromosomes and the fitness function.

[0161] In genetic manipulation, chromosomes, also known as individuals, represent possible solutions. Chromosomes are typically represented as encoded gene strings. In the genetic construct of this application, chromosomes are composed of binary strings, where each gene bit is composed of a concatenation of encoded parameters or variables. Phase angles of the vector The gene fragment with a string length of 8 bits is selected (meeting the precision of digitally controlled phase). The total length of the phase angle is an 8×M bit binary string, which is used as the encoded individual (chromosome).

[0162] The fitness function is used to evaluate the quality of the current chromosome. In the evolutionary search of genetic algorithms, the fitness function is the most important and only metric for measuring the optimization degree of the solution. In the genetic optimization control of this application, sound intensity gain is used as the fitness function. Fit : (6) in It is the aforementioned vector The phase angle of each component vector. In genetic search, each phase angle... If it's a variable, then the maximum value of the fitness function is being searched. Fitmax The corresponding one That is, the optimal solution.

[0163] Used to obtain multifocal drive for double-frequency phased array transducers The process of the genetic algorithm is shown in Figure 3 Genetic algorithms begin with a randomly generated initial population, which is a set of chromosomes or individuals, and also a set of possible solutions. With each generation, the population evolves, and the solutions improve towards the optimal solution.

[0164] In the process of generating a new generation, the first step is to use the calculated fitness function. Assess the current chromosome, see Figure 3 Then, several individuals with the best fitness function are copied to the next generation.

[0165] The next few steps involve using appropriate genetic operations such as selection, crossover, and mutation to evolve into a new generation.

[0166] The operation of selecting superior individuals and eliminating inferior individuals from a population is called selection. In the selection steps of the genetic algorithm optimization control proposed in this application, the fitness proportional model method, also known as roulette wheel selection, is used. The selection probability of an individual in the population... It is proportional to its fitness, and is defined by the following formula: (7) Where L is the population size.

[0167] Crossover refers to the operation of partially recombinating two parent individuals to generate a row of individuals. The parallel search capability of genetics is reflected in the crossover operation. In the crossover sequence, the crossover point is randomly selected, and the number of offspring produced depends on the crossover probability.

[0168] A mutant individual is a randomly selected individual from the selection sequence, and the location (locus) of the mutation point in the individual string is randomly chosen. Mutation randomly injects new information into the population, maintaining population diversity and preventing premature convergence. The number of offspring produced by mutation depends on the mutation probability.

[0169] The new generation includes seeing Figure 3 The process involves: replicating several of the best individuals, selecting a certain number of individuals based on selection probability, generating a certain number of crossover offspring based on crossover probability, and generating several mutated offspring based on mutation probability. Reproduction continues generation after generation until a stopping criterion is met; the stopping criterion is finding the optimal solution or reaching the maximum generation limit. Optimal solution and the settings (M focal points) Amplitude composition The driving vector of the corresponding focal point can be obtained by reversing equation (5) using the vector. .

[0170] The double-frequency genetic algorithm of this application can be used to design the focal position and focal peak of any type of phased array transducer, and then the genetic algorithm can be used to obtain the driving vector for the corresponding focal point design. .

[0171] The sound field calculation method for a double-harmonic spherical rectangular phased array transducer and the genetic algorithm for a multi-point focusing mode of a double-harmonic phased array transducer, combined in this application, can design a three-dimensional spatial multi-focus mode for a double-harmonic spherical phased array transducer. The combination of the double-harmonic sound field calculation method and the phased array transducer genetic algorithm refers to the calculation of the fitness function Fit in the genetic algorithm process (see...). Figure 3 According to the definition of the fitness function (6), the sound pressure... and forward transport operator (Including double harmonic calculation). The sound field calculation formula (2) for the double harmonic spherical rectangular phased array transducer of this application is used.

[0172] To accommodate tumors of different sizes, phased array transducers can be designed with various focusing patterns on the focusing plane, also known as focal modes, including single-focus and multi-focus modes. Each mode, along with the corresponding set of drive signals based on position information, is used. The driving signal consists of a set of amplitude signals and a set of phase signals, with the amplitude signals corresponding to vectors. The amplitude and phase of the middle component, corresponding to the vector of the signal. The phase angle of the intermediate component. Drive signal used in the phased array transducer drive system. (Each component corresponds to the driving amplitude and phase of each array element; the driving includes dual frequencies), thus obtaining Multifocal focusing effect.

[0173] Double-frequency phased array transducers with hundreds of elements can achieve simultaneous 3D multi-focus by relying on optimization algorithms: that is, they can generate axisymmetric multi-focus (single focus, 2 focus, 4 focus, 6 focus, etc.); off-axis (non-axisymmetric) multi-focus (single focus, off-axis 2 focus, off-axis 4 focus, off-axis 6 focus, etc.), that is, the multi-focus can be located in the area around the geometric focus, which means that 3D multi-focus electronic scanning is possible.

[0174] D. The drive control structure for the phased array transducer with hundreds of elements in this application: A schematic diagram of the drive control structure for the phased array transducer with hundreds of elements in this application is shown below. Figure 4 The phased array transducer driver 5, with hundreds of channels, transmits element drive signals to the double-frequency phased array transducer 1, which has hundreds of elements, through two sets of impedance matching networks 4. Because the composite pulse sequence contains both fundamental and harmonic frequency pulse sequences, the phased array transducer is also divided into two groups: a fundamental frequency group and a harmonic frequency group; the impedance matching network is also divided into two groups: a fundamental frequency group impedance matching network and a harmonic frequency group impedance matching network; the phased array transducer driver 5 has an arbitrary waveform generator module 6 that controls the composite pulse sequence of two frequencies (divided into two channels), controlling the timing of each channel of the fundamental and harmonic frequencies respectively. The phased array transducer driver 5 also has a phase and amplitude control module 7 that receives the drive signals for each element corresponding to the multi-focus area of ​​the double-frequency genetic algorithm. The phase and amplitude. Hundreds of phased array transducers correspond to hundreds of phased array transducer channel amplifiers. Each element corresponds to the power control of one channel. The power and phase of each channel in the phased array transducer driver 5 are independently controlled. The pulse timing of each frequency element is a composite pulse frequency pulse waveform timing. The ultrasound probe 9 is connected to the ultrasound imaging system 10 for real-time monitoring.

[0175] The drive and control of a phased array transducer with hundreds of elements specifically includes the following steps: Step 1: Design the position of the focal plane multifocal points (Single focal length, dual focal length, quad focal length, six focal lengths, off-axis single focal length, off-axis multifocal).

[0176] Step 2: Reverse solve the multifocal problem using the double-frequency genetic algorithm. corresponding drive signals (A set of amplitude and phase corresponding to the drive of each array element) Figure 3 (Double frequency genetic algorithm calculation process) program.

[0177] Step 3: Use the program for accurate calculation (Formula (2)) of the phased array transducer with dual-frequency spherical rectangular array elements and the result obtained in Step 2. The 3D sound field focusing characteristics are obtained by driving simulation to check whether they meet the requirements, such as the presence or absence of grating lobes. Alternatively, only the frequency can be driven, and the frequency sound pressure must exceed 10 MPa (the frequency is a shock wave). The boiling time is calculated using the weak impact theory formula (1), and the millisecond pulse length PD value is designed based on the boiling time to ensure that boiling bubbles occur with each pulse.

[0178] Step 4: Use step 2 The composite pulse parameters are loaded into the phased array transducer driver with hundreds of channels and emitted to achieve the designed multifocal tissue destruction.

[0179] The corresponding driving force is obtained by using a double-frequency genetic algorithm to determine the position of each scanning point in the multifocal array. After the characteristics are confirmed to be qualified through sound field simulation, this series of drives are stored in the system and recalled one by one during scanning, which is the phased array transducer multi-focus electronic scanning.

[0180] E. Focus mode characteristics of a dual 2x frequency-harmonic 256-element phased array transducer the following Figures 5 to 10 Key characteristics of a dual 2x2 256-element phased array transducer: Figure 5 The sound fields of the single-focus and two-focus modes of the dual-frequency 256-element phased array transducer are obtained by inverse solving using a genetic optimization algorithm: for the single-focus mode, (a) is the focal plane sound intensity distribution and (b) is the xy-plane sound intensity contour map; for the two-focus mode, (c) is the focal plane sound intensity distribution and (d) is the xz-plane sound intensity contour map. The two focal points are arranged on the focal plane with a spacing of approximately one fundamental frequency wavelength. The tissue damage is larger than the damage size obtained by three (times) of the dual-frequency single-focus mode.

[0181] Figure 6 The off-axis single-focus mode sound field and element driving signals of a dual 2nd harmonic 256-element phased array transducer are obtained by inverse solving using a genetic optimization algorithm: (a) shows the focal plane sound intensity distribution and (b) shows the xy-plane sound intensity contour map; (c) shows the amplitude of the 256-element driving signal and (d) shows the phase. At the off-axis (9.5 mm off-axis) single focus, the sidelobes reach 1 / 10 of the peak value (cavitation region expands), the element driving amplitude remains unchanged, and the element driving phase varies within a 2π range. This off-axis single focus demonstrates that the phased array transducer can perform single-focus electronic scanning within a certain region.

[0182] Figure 7The acoustic field of the axisymmetric 4-focal mode of a dual 256-element phased array transducer obtained by inverse solving using a genetic optimization algorithm is shown in (a) as the focal plane acoustic intensity distribution, (b) as the y-projection plane acoustic intensity distribution, and (c) as the xy-plane acoustic intensity contour map. The focal plane has four focal points, with the distance between adjacent focal points approximately one fundamental wavelength. The sound pressure amplitude is sufficient to cause tissue damage. A single irradiation injury at the 4-focal-plane is a relatively large volume injury; the single irradiation injury volume at the 4-focal-plane is the volume obtained from at least nine (times) mechanical scans at a dual 256-element phased array transducer (3×3 adjacent focal points half-covering).

[0183] Figure 8 The acoustic field and element driving signals of a dual 2nd harmonic 256-element phased array transducer in a non-axisymmetric (off-axis) 4-focal mode are obtained by inverse solving using a genetic optimization algorithm: (a) shows the focal plane acoustic intensity distribution and (b) shows the xy-plane acoustic intensity contour map; (c) shows the amplitude and (d) shows the phase of the 256-element driving signals. The off-axis 4-focal mode has 4 focal planes, with an adjacent focal distance of approximately one fundamental wavelength. The element driving amplitude varies, and the element driving phase varies within a 2π range. The off-axis 4-focal mode demonstrates that the phased array transducer can perform multi-focal electronic scanning within a certain region.

[0184] Figure 8 A dual 2x frequency-doubled 256-element phased array transducer with four off-axis focal points. It can be driven by only the frequency multiplier (with the fundamental frequency disabled) to obtain... Figure 9 The off-axis 4-focal 3D sound field characteristics shown are octave frequency. Figure 9 The sound field of a dual 2nd harmonic 256-element phased array transducer using only high-frequency (2nd harmonic) non-axisymmetric (off-axis) 4-focal mode, obtained by reverse solving using a genetic optimization algorithm, is shown in (a) as the focal plane sound intensity distribution, (b) as the xy-plane sound intensity contour map, and (c) as the y-projection plane sound intensity distribution. Figure 9 A shock wave with a negative sound pressure exceeding 12 MPa at a harmonic frequency can be obtained. The boiling time can be calculated using the weak shock theory formula (1). Based on the boiling time, the millisecond-long pulse length (PD) value can be designed to ensure that boiling bubbles occur with each pulse. All multifocal modes of the double-harmonic phased array transducer can achieve the corresponding 3D sound field by driving only the fundamental frequency, only the harmonic frequency, or only the double harmonic frequency. Therefore, driving the sound field only at the harmonic frequency can be used to design the harmonic shock wave conditions and the millisecond-long pulse length.

[0185] This application can also obtain numerical solutions to the nonlinear KZK equations at the geometric focus for the harmonics or fundamental frequency: Figure 10The nonlinear sound pressure of the dual 2nd harmonic 256-element phased array transducer is as follows: (a) is a high-frequency (2nd harmonic) shock wave of 114 MPa: positive pressure P+ = 96 MPa, negative pressure P- = -19 MPa; (b) is a high-frequency (2nd harmonic) positive pressure 2D distribution; (c) is a high-frequency (2nd harmonic) negative pressure 2D distribution; (d) is a low-frequency sound pressure wave, a nonlinear wave (without shock wave). Figure 10 (b) To show that the positive pressure region of the second harmonic is very narrow (shock wave width is less than 100 μm), the sound pressure of the second harmonic shock wave can be accurately calculated using the weak shock theory formula (1).

[0186] 3) Specific implementation method of biharmonic split array multifocal composite ultrasound pulse tissue ablation Unlike double-frequency phased array transducers with hundreds of elements, double-frequency split arrays typically use 2 or 4 elements, generally not exceeding 12 elements. Double-frequency split array systems are simple and easy to implement; the embodiments in this application can be presented using a double-frequency split array system. Corresponding focal mode results, high-speed imaging revealing the composite pulse tissue damage mechanism, and monitoring results also support the effectiveness mechanism of the multi-focal phased array transducer.

[0187] The composite ultrasound pulse is a tissue ablation pulse waveform sequence tailored for biharmonic split arrays. This technique specifically addresses the problem of cavitation cloud obscuring the beam in the front of the focal zone in biharmonic confocal arrays, and the issue of slow cavitation cloud dissipation at the end of treatment, thereby improving the efficiency of tissue ablation therapy. The biharmonic split array generates fixed confocal single-focus, two-focus, and four-focus beams (at the geometric focus, axisymmetric multifocal), and cannot produce focus deflection, i.e., it cannot generate off-axis single-focus, off-axis two-focus, or off-axis four-focus beams, meaning it cannot perform focus electronic scanning; furthermore, a fourth stage uses even shorter pulses (5–40 μs). The focus calculation for the biharmonic split array does not require parallel optimization (inverse) genetic algorithms, but rather forward synthesis: nonlinear quantification, 3D dual-frequency acoustic field calculation, and focus mode control determined by the phase difference driven by adjacent array elements. The composite ultrasound pulse waveforms of the two frequencies are controlled by the number of channels of an arbitrary waveform generator, which is the same as the number of array elements in the split array.

[0188] A. The calculation process for the sound field of the double-frequency split array is as follows: For each element of the split array, the element m is first divided into NN squares with the same and sufficiently small projected area. Generally, the side length of the square needs to be less than one wavelength. The squares are joined together with zero gaps. The sound pressure at each point on the focal plane calculated by the following formula is superimposed to obtain the sound pressure P of the sector element at any point in space. m The expression: (8) Where the frequency is the fundamental frequency f1 or a harmonic f2, and the wave number is... or

[0189] The sound pressure of any point in space can be obtained by superimposing the sound pressure of all elements of the split array: (9) B. The pulse timing of each fundamental frequency array element and frequency multiplier array element is synchronized in four stages of the composite pulse; The composite pulse synchronously synchronizes the pulse timing of each fundamental and harmonic array element in four stages: The first three stages are highly efficient millisecond-long pulses for tissue destruction. In particular, the first stage only operates the harmonics (high duty cycle 2-7%) with shock waves, while the fundamental frequency is not active. This reduces the possible beam obstruction by cavitation bubbles in the focal pre-focus area of ​​the dual-frequency array, initiating the most powerful tissue fragmentation at a precise location. Because the precise location of the shock wave in the focal pre-focus area generates boiling and a low duty cycle in a small local area (width less than 100 micrometers), the damage is mechanical ablation, and the damage location is precise. The second stage: Simultaneous millisecond-long pulses with dual harmonics for highly efficient tissue destruction, 1-20 ms pulses, duty cycle 2-7% (greater than the conventional duty cycle of 1%); the addition of the fundamental frequency lowers the cavitation threshold, enhances cavitation activity, and expands the damage area (larger focal area at low frequencies); ensuring mechanical ablation without thermal loss, and achieving homogenization of the target tissue. Phase 3: Dual-frequency operation, featuring concentrated millisecond-long pulse trains (1–20 ms pulses, pulse repetition frequency PRF of 1–20 Hz), followed by a 1–4 s offtime. These two segments form pulse group N, which is repeated several times to reduce the average duty cycle to approximately 1%. This three-phase millisecond-long pulse achieves complete mechanical fragmentation (complete homogenization or liquefaction) of the tissue. This highly efficient phase produces fixed single-focus "elongated ellipsoidal" (not "tadpole-shaped") or "spherical" (four-focus) lesions. Phase 4, with even shorter pulses (5–40 μs), primarily aims to rapidly dissipate cavitation clouds and also has some CH (choic aspiration) effect. Its short duration allows for immediate ultrasound monitoring of the damage. This technical solution specifically addresses the problem of cavitation clouds obscuring the beam in the anterior focal zone of confocal doubly frequency treatments, and the issue of slow cavitation cloud dissipation at the end of treatment.

[0190] See details for specific parameters Figure 1The diagram below illustrates the composite pulse sequence of this application: The composite pulse consists of four stages. Stage 1: The fundamental frequency is not active during the off-time; only the harmonic frequencies are active. The pulse duration PD = 1–20 ms and the pulse repetition frequency PRF = 1–20 Hz are repeated 5–30 times, followed by an off-time of 0.1–0.5 s, with a duty cycle of 2–7%. Stage 2: Both frequencies operate simultaneously. The pulse duration PD = 1–20 ms and the pulse repetition frequency PRF = 1–20 Hz are repeated 20–60 times, with a duty cycle of 2–7%. Stage 3: Both frequencies operate simultaneously. A concentrated millisecond-long pulse train with a pulse duration PD = 1–20 ms and a pulse repetition frequency PRF = 1–20 Hz is repeated 3–10 times, followed by an off-time of 1–4 s. These two segments form a pulse group that repeats N = 2–15 times, with an average duty cycle of approximately 1%. Stage 4: Dual-frequency operation, pulse duration PD = 5~40μs, pulse repetition frequency PRF = 100~1000 Hz, pulse repetition S4 = 100~1000 times, duty cycle, ~1%.

[0191] Common types of double-frequency split array transducers include 2-element ring array transducers, 4- or 6-element rectangular split arrays, and 4- or 6-element sector split arrays (see...). Figure 11 (and fan-shaped split array, with no more than 12 array elements)

[0192] The maximum number of split-focus arrays is equal to the number of array elements. For example, a 4-element fan array double-frequency split array can produce single-focus, 2-focus, and 4-focus arrays. The 3D sound field of the focus mode is calculated using formulas (8) and (9); the focus sound pressure must be greater than 10 MPa (shock wave).

[0193] The confocal point of the two-element ring array transducer can be quantitatively calculated using nonlinear KZK (Khokhlov Zabolotskaya Kuznnetsov) methods. By using the harmonic frequency as a shock wave with a negative pressure exceeding 10 MPa, the boiling time of the shock wave can be calculated according to weak shock theory, thus ensuring that boiling bubbles occur in each pulse of millisecond-long pulse therapy. The fundamental frequency does not require a shock wave. In a dual second-harmonic ring array, when the phase difference between the two frequencies is 135 degrees from the fundamental frequency, the negative pressure superposition at the focal point is maximized, which is beneficial for cavitation initiation and activity. In a dual third-harmonic ring array, when the phase difference between the two frequencies is 60 degrees, the superposition of positive and negative pressures at the focal point is close to maximum, which is beneficial for cavitation initiation and collapse, thus enhancing cavitation.

[0194] Numerical simulation characteristics of a double-frequency-doubled 2-element ring array using nonlinear KZK are shown in [reference needed]. Figure 12 , Figure 12 It is a double-frequency-doubled array with two elements and a ring array. Figure 11(a) Nonlinear sound pressure: High frequency (2nd harmonic f2) shock wave (solid line) 72 MPa, positive pressure P+ = 67 MPa, negative pressure P- = -10.5 MPa; Low frequency sound pressure wave, nonlinear wave (no shock wave), positive pressure P+ = 13 MPa, negative pressure P- = -8 MPa; The negative peaks of the two frequencies with a phase difference of 135 degrees meet and superimpose under linear conditions, resulting in the largest negative peak (which is conducive to cavitation). Such shock waves can accurately calculate the boiling time using the weak shock theory formula (1), and design the millisecond pulse length PD value based on the boiling time to ensure that boiling bubbles occur with each pulse.

[0195] Figure 13 It is a double triple frequency 2-element ring array ( Figure 11 (a) is the waveform of the driving signal with a 60-degree phase difference between the fundamental frequency (the fundamental frequency is represented by a short dashed line, and the third harmonic is represented by a long dashed line). Under linear conditions, the positive and negative voltages superimposed at the focal point with a 60-degree phase difference between the two frequencies reach their maximum values ​​(solid line).

[0196] The sound field characteristics of a dual 3x2 octave ring array single-focus array are shown in [link to relevant documentation]. Figure 14 , Figure 14 The sound field distribution of a dual 3rd harmonic 2-element ring array with a single focal point is shown in (a) as the sound intensity distribution on the focal plane and (b) as the contour map of the sound intensity on the xy plane.

[0197] Figure 15 It is a double triple frequency 2-element ring array ( Figure 11 (a) shows the nonlinear sound pressure: (a) shows the positive pressure nearing its maximum and the negative pressure reaching its maximum at the focal point, with a 60-degree phase difference between the two frequencies, representing a third harmonic shock wave; the low-frequency fundamental frequency has no shock wave, with positive pressure P+ = 40 MPa and negative pressure P- = -17 MPa; (b) shows a third harmonic shock wave (Shockwave), with an amplitude of 100 MPa, positive pressure P+ = 87.3 MPa, and negative pressure P- = -15.1 MPa. (c) shows the 2D distribution of positive pressure at high frequency (third harmonic), and (d) shows the 2D distribution of negative pressure at third harmonic. Figure 15 (c) shows that the positive pressure region of the third harmonic is very narrow (shock wave width is less than 100 μm). The sound pressure of the third harmonic shock wave can be accurately calculated using the weak shock theory formula (1).

[0198] The four focal points produced by a dual-frequency-doubled 4-element fan-shaped split array are similar to those produced by a 256-element array. Figure 16 , Figure 16 It is a double-frequency 4-element fan-shaped split array ( Figure 11 (c) shows the sound field distribution at the four focal points: (a) shows the sound intensity distribution at the geometric focal plane, and (b) shows the sound intensity contour map at the xy plane (geometric focal plane). The negative pressure at the focal point reaches 27.9 MPa.

[0199] C. The system for implementing this method is as follows: The main control computer 16 primarily controls the split-array arbitrary waveform transmitter (group) 15, the split-array element power amplifier (group) 14, the split-array element impedance matching circuit (group) 13, and the split-array transducer 11 to transmit focused ultrasound to the sample 19 in a composite pulse sequence for tissue ablation. The ultrasound probe 12 is coaxially mounted in the central hole of the split-array transducer, acquiring signals from the probe and transmitting them to the ultrasound imaging system. Thus, the ultrasound system performs image guidance for tissue ablation and real-time ultrasound image monitoring. The main control computer 16 also controls the 3D position control 18 to move the sample so that the focus is on the sample. If a high-speed camera is used for monitoring, one of the split-array arbitrary waveform transmitters (groups) triggers the high-speed camera 21 to capture images. See [link to documentation]. Figure 17 The double-frequency split array has few elements, making the system simple and easy to implement. It can be used to complete multi-focus composite pulse tissue destruction tasks. Here, "array" means several elements, distinguishing it from the "impedance network" used with hundreds of elements. The double-frequency 4-sector split array has 4 impedance matching circuits and 3 2-channel arbitrary waveform transmitters (2 2-channel arbitrary waveform transmitters control 4 power amplifiers, and the other arbitrary waveform transmitter synchronizes the 2 2-channel arbitrary waveform transmitters).

[0200] Implementation steps for the focus mode of the split array system: Step 1: Based on the required split array and focus mode (single focus, 2 focus, 4 focus), use the double-frequency split array sound field formulas (8) and (9) or nonlinear KZK to obtain the sound field distribution, ensure the shock wave, and obtain experimental control parameters such as power, phase difference, and composite pulse parameters.

[0201] Step 2: Use Figure 17 The split array system uses 3D position control to move the prepared sample so that the focal point is located at a certain depth within the sample. At the same time, the ultrasound is used for positioning. The system emits a short pulse that is slightly lower than the treatment pulse to position the focal point for cavitation (the highlighted area is the focal point).

[0202] Step 3: Set the arbitrary waveform generator (group) of the split array using the composite pulse parameters from Step 1, and set the power amplifier (group) of the split array using the power parameters from Step 1, to induce tissue damage. Monitor in real-time using ultrasound. If multiple points (several) are irradiated, set the 3D position control movement path and the focal distance between the two (several) focal points to induce tissue damage.

[0203] Step 4: After treatment, the experimental sample is dissected, H&E stained, or subjected to relevant tests, and preserved by ultrasound or high-speed imaging.

[0204] Example 1 Transparent BSA gel phantoms (bovine serum albumin (BSA) polyacrylamide gel phantoms) have properties similar to tissues; used... Figure 17The system was implemented and experiments were conducted according to the above steps. High-speed imaging was used to observe the bubble formation process in tissue destruction caused by a dual-frequency harmonic 2-element ring array composite pulse, revealing the mechanism of each stage of pulse action. Experimental results are shown below. Figure 18 , Figure 18 High-speed imaging of a transparent BSA gel phantom subjected to 1.1 / 3.3MHz (dual 3rd harmonic) 2-element ring array composite pulse tissue destruction was selected. The first three stages of the millisecond-long pulse tissue destruction process were shown to reveal the boiling bubble activity mechanism. The first stage (only the 3rd harmonic (3.3MHz) was active, the fundamental frequency (1.1 MHz) was not active): (a i Before the first pulse causes boiling, the narrow white area is the shock wave region (very narrow), and the center is the focal point. ii The first pulse boiling bubble appears in the coke zone and is relatively small in size. (a) iii In the first stage, the final pulse of boiling causes an increase in bubble size, appearing in the foreground of the coke zone. In the second stage, both frequencies operate: (b) i The first pulse initiates boiling at the focal point, increasing the cavitation region; note that due to the 0.3 s off-time in the first stage, bubbles in the fore-coke region dissipate, so boiling occurs at the focal point; the addition of the fundamental frequency further increases the cavitation region; (b) ii The second pulse of the second stage: The size of the boiling bubbles increases, pushing them towards the area behind the focal point. (b) iii The second stage, the last pulse: increases the size of the boiling bubbles in the coke zone. The third stage involves both frequencies operating: (c) i The first pulse initiates boiling at the focal point. ii The last pulse of the third stage: boiling bubbles are pushed towards the back zone of the focal point, (c iii After treatment, the lesion contour matches the fundamental frequency focal region.

[0205] This embodiment verifies that the first stage of the composite pulse operates at only 3rd harmonic frequency, with boiling bubbles appearing at the precise focal location without cavitation obstruction; this stage initiates the most powerful tissue disruption at the precise location; boiling bubbles dominate and rapidly increase in size; in (a i Before the first pulse causes boiling, the narrow white area is the shock wave region, which appears very narrow (as opposed to nonlinear calculations). Figure 15(c) Matching the positive pressure region). In the second stage, dual-frequency operation occurs. Due to the dissipation of bubbles in the fore-field region during the 0.3 s off-time added at the end of the first stage, boiling occurs at the focal point in the second stage. Higher duty cycle and efficient operation increase the cavitation region, with large bubbles moving within the focal region. In the third stage, dual-frequency operation is maintained, with an off-time added between pulses, reducing the duty cycle to 1%, allowing bubbles to flow within the focal region. The final tissue damage profile shows an elongated ellipsoid, without a "tadpole-like" shape or damage shifting towards the transducer end. This three-stage efficient tissue damage mechanism reveals and supports a similar mechanism for single-focal phased array transducers with hundreds of elements.

[0206] Example 2 Example of a single-focus tissue destruction method using a dual-frequency-triple-amplitude 2-element ring array composite pulse: Figure 17 The system was implemented using a dual-triple-frequency, two-element ring-array composite pulse tissue ablation single-focus technique and the above-described steps. For a 5 mm diameter 4T1 tumor on one side of a mouse, a single-focus technique was first applied, followed by 3 × 3 = 9 single-focus techniques. The pathways for these 9 focuses are shown below. Figure 19 (c) Figure 19 The following diagram illustrates tissue destruction caused by dual 3-fold frequency harmonic 2-element ring array composite pulses: (a) shows a single-focus elongated ellipsoidal lesion, with arrows indicating the single-focus size; (b) shows a single-focus elongated ellipsoidal lesion; (c) shows a 9-point (times) treatment pathway in a mouse tumor, with a distance of d1 / 2 between the two points (half-coverage); and (d) shows a large-size lesion formed by 9-point (times) treatment in a mouse tumor.

[0207] Figure 19 (b) is a single-focus injury, which is an ellipsoidal lesion within the dashed line obtained by dissecting the target area after treatment and flushing away the liquefied homogenate. The radial dimension is d1. Figure 19 (d) is used Figure 19 (c) represents 9 focal paths, with 3×3=9 (times) single focal points forming large-size damage. The damage within the dashed line is obtained by dissecting the target area after treatment and flushing away the liquefied homogenate, with a width of 2 (d1).

[0208] Example 3 Histological H&E-stained sections of single-focus mouse tumor lesions from 1.1 / 3.3MHz (dual 3rd harmonic) 2-element ring array composite pulse tissue destruction. The experiment was the same as the single-focus lesion in Example 2. Figure 20 The images show H&E-stained sections of mouse tumor single-focus lesions caused by 1.1 / 3.3 MHz (double 3rd harmonic) 2-element ring array composite pulse tissue destruction. (a) shows the lesion outline (dashed line division) on the section, and (b) shows the lesion boundary after magnification (dashed line division).

[0209] Tissue sections stained with H&E after tissue damage: After staining, cell nuclei and other components are stained blue-purple, while cytoplasm and proteins are stained pink. Figure 20 (a) The area inside the dashed line is the damaged area, and the area outside the dashed line is the undamaged tumor tissue area. The dashed line is the boundary between the damaged and undamaged areas. Enlarging the edge of the damaged area as shown... Figure 20 As shown in (b), the boundaries between damaged and undamaged tissues are clear and sharp. The damaged area is completely homogenized (without any cellular structure), while the undamaged area maintains a normal and intact cellular structure.

[0210] Example 4 4-element fan-shaped split array ( Figure 11 (c) Under certain phase difference control, a 4-focal pattern can be generated on the focal plane; this embodiment demonstrates the experimental results of 4-focal mouse tumor damage caused by dual 2-harmonic 4-element fan-shaped split array composite pulse tissue destruction. Figure 17 The system was implemented using a dual-frequency 4-element fan-shaped split array 11, and a dual-frequency 4-element fan-shaped split array with 4 focal points for composite pulse tissue destruction of mouse tumors, and experiments were conducted according to the above steps.

[0211] Figure 21 Composite pulse tissue destruction using a dual-frequency, four-element, fan-shaped split array: (a) shows a large lesion formed by the four focal planes, d2>= 2d1; (b) shows a photograph demonstrating that the four focal planes formed a large lesion in a mouse tumor during treatment, with the radial dimension of the lesion approximately three times that of a single-focal lesion. After treatment, the target area was dissected and the liquefied homogenate was flushed away to obtain... Figure 21 (b) represents 4-focal damage, with a radial dimension three times that of single-focal damage.

[0212] Example 5 This embodiment verifies that a large-scale lesion can be formed by using a 4-focal-point treatment path to create a single (large-point) lesion, followed by a 2-layer, 4-large-point treatment pathway. Using... Figure 17 The system was implemented by using a composite pulse of a dual 2-fold frequency 4-element fan-shaped split array to destroy 4 focal points and 4 (large point) secondary paths of tissue, and the experiment was carried out according to the above steps to destroy isolated porcine kidney tissue.

[0213] Figure 22 Demonstrates tissue destruction using a dual-frequency 4-element fan-shaped split array composite pulse: (a) shows a radially enlarged lesion formed by a 4-focal-plane focal plane; (b) shows a large point lesion with an enlarged radial size formed by a 4-focal-plane focal plane treatment in an isolated porcine kidney; (c) shows an even larger lesion formed by a 2-layer, 4-point treatment path for a 4-focal-plane large point lesion, with a 2 / 3 radial or axial distance between adjacent large points, and 1 / 3 lesion coverage (larger than the 1 / 2 coverage distance of a single focal plane, requiring fewer treatments for large tumors, making it more efficient); (d) shows an even larger lesion formed by a 2-layer, 4-point treatment path for a 4-focal-plane large point lesion in an isolated porcine kidney.

[0214] The distance between two consecutive focal points in a single-focal scan is d1 / 2 (d1 is the diameter of the single-focal lesion, i.e., half coverage, see...). Figure 19 (c) and (d)). The lesion diameter formed by 4 focal scans is d2 (d2>= 2d1), and the distance between two consecutive focal spots in a 4-focal scan is 2(d2) / 3 (2(d2) / 3 distance means one-third coverage). Figure 22 A larger inter-scan point spacing further reduces the number of times the tumor needs to be irradiated, thereby improving treatment efficiency.

[0215] Example 6 This embodiment verifies: real-time ultrasound monitoring of a rabbit kidney tissue destruction experiment using dual-triple-frequency 2-element ring array composite pulses, mainly demonstrating the bubble dissipation results after the fourth-stage pulse: Figure 23 (a) The ultrasound during treatment shows a bright focal area, indicating boiling bubbles and cavitation clouds in the focal area (arrows point to the bright area). (b) The liquefied damage area immediately after treatment (1-2s) shows a low echo (arrows point to the dashed ellipsoid area). The low echo indicates that the bubbles have dissipated and the target area has been liquefied.

[0216] The above six embodiments also support the effects of on-axis single-focus and axisymmetric four-focus double-frequency phased array transducers.

[0217] In summary, this application discloses a novel double-frequency phased array transducer structure with hundreds of elements capable of simultaneous multi-focal 3D large-area electronic scanning; it also discloses a genetic algorithm method for obtaining multi-focal control in double-frequency phased array transducers, thereby generating 3D multi-focals: that is, axisymmetric multi-focals (1, 2, 4, and 6 focal points); and off-axis multi-focals (off-axis 1, 2, 4, and 6 focal points), meaning the multi-focals can be located in the region surrounding the geometric focal point, which means 3D single-focal and multi-focal electronic scanning is possible. A dual-frequency split array can also generate geometrically focal plane axisymmetric multi-focals. Simultaneous multi-focals can significantly increase the treatment damage volume of a single irradiation, improving treatment efficiency.

[0218] The enhanced nonlinear mechanism composite pulse disclosed in this application has four stages that synchronously control the timing of the fundamental frequency array and the harmonic frequency array elements of the dual-frequency system. The first three stages are highly efficient millisecond-long pulses for tissue destruction. In particular, the first stage only allows the harmonic frequency (high duty cycle 2-7%) with shock waves to operate, while the fundamental frequency does not operate, reducing the possible beam obstruction by cavitation bubbles in the front focal region of the dual-frequency system and initiating the most powerful tissue fragmentation at a precise location. The second to fourth stages all operate with dual frequencies. These three stages efficiently produce "long ellipsoidal" (or "spherical") (4-focal) damage. The damage size of these harmonic frequencies is larger than that of single harmonic frequency damage. More notably, the fourth stage is (5-80) The μs pulse primarily aims to rapidly dissipate cavitation clouds, enabling immediate ultrasound monitoring of ablation results. The double-frequency sound pressure level (BFPS) is essentially a shock wave; the boiling time of the shock wave is estimated according to weak shock wave theory to ensure that boiling occurs with each millisecond-long pulse. The fundamental frequency (FPS) does not require a shock wave. Therefore, double-frequency multi-element phased array transducers and split-array multifocal composite pulse tissue ablation significantly improve treatment efficiency in both spatial and temporal dimensions.

[0219] It should be understood that the above description is for illustrative purposes and not for limitation. Many embodiments and applications beyond the provided examples will be apparent to those skilled in the art upon reading the above description. Therefore, the scope of this teaching should not be determined by reference to the above description, but rather by reference to the foregoing claims and the full scope of their equivalents. For purposes of completeness, all articles and references, including patent applications and publications, are incorporated herein by reference. The omission of any aspect of the subject matter disclosed herein in the foregoing claims is not intended as a waiver of that subject matter, nor should it be construed as an indication that the applicant has not considered that subject matter as part of the disclosed inventive subject matter.

Claims

1. A double-frequency phased array composite pulse tissue destruction system, characterized in that, include: Double-frequency phased array transducer, drive control module, focus control module and real-time monitoring module. The double-frequency phased array transducer is a double-frequency phased array transducer with hundreds of array elements or a double-frequency split array transducer; the double-frequency phased array transducer includes a fundamental frequency array element group and a frequency-doubled array element group, the drive control module is used to output drive signals of corresponding frequencies to the two array elements, the focus control module is used to adjust the focus position and number, and the real-time monitoring module is used to track the effect. The double-frequency phased array composite pulse tissue destruction system adopts a four-stage composite pulse timing coordinated control of the working state of the fundamental frequency array element and the frequency doubling array element, combined with a multi-focus control strategy. Among them, the first three stages of the four-stage composite pulse timing sequence are millisecond-long pulses to achieve mechanical ablation, and the fourth stage is microsecond-long short pulses to dissipate cavitation clouds and enable immediate B-ultrasound image monitoring of the ablation effect. The sound pressure output by the frequency doubling array element in each stage is a shock wave and ensures that boiling bubbles are generated in each pulse in the first three stages. The output of the fundamental frequency array element does not require a shock wave. The four-stage composite pulse timing includes: Phase 1: The fundamental frequency does not operate during the off-time; only the harmonic frequency operates. The pulse duration PD = 1–20 ms and the pulse repetition frequency PRF = 1–20 Hz are repeated 5–30 times, followed by an off-time of 0.1–0.5 s, with a duty cycle of 2–7%. Phase 2: Dual-frequency operation, pulse duration PD = 1–20 ms and pulse repetition frequency PRF = 1–20 Hz, pulse repetition S2 = 20–60 times, duty cycle 2–7%; Phase 3: Dual-frequency operation, with concentrated millisecond-long pulse trains of duration PD = 1–20 ms and pulse repetition frequency PRF = 1–20 Hz, repeated 3–10 times, followed by an off time of 1–4 s. These two segments constitute a pulse group repeated N = 2–15 times, with an average duty cycle of 1%. The fourth stage of the double-frequency phased array transducer with hundreds of elements consists of fundamental and frequency-harmonic microsecond long pulses, with specific parameters as follows: pulse duration PD = 5–80 μs, pulse repetition frequency PRF = 100–1000 Hz, pulse repetition S4 = 100–1000 times, and duty cycle ~1%. The fourth stage of the double-frequency split array transducer: simultaneous operation of both frequencies, pulse duration PD = 5–40 μs, pulse repetition frequency PRF = 100–1000 Hz, pulse repetition S4 = 100–1000 times, duty cycle ~1%; The multi-focus control strategy of the double-frequency phased array transducer with hundreds of elements uses a genetic optimization algorithm adapted to the double-frequency characteristics to inversely solve the driving vector corresponding to the multi-focus position, which is used to generate a 3D single-focus or multi-focus mode for 3D single-focus or multi-focus electronic scanning; the multi-focus control strategy of the double-frequency split array generates a single-focus or multi-focus mode by controlling several phase difference modes of adjacent array elements.

2. The double-frequency phased array composite pulse tissue destruction system according to claim 1, characterized in that: The double-frequency phased array transducer is a double-frequency phased array transducer with hundreds of elements or a double-frequency split array transducer with no more than 12 elements; the double-frequency split array transducer uses phase difference control to control forward synthesis of fixed multifocals.

3. The double-frequency phased array composite pulse tissue destruction system according to claim 1, characterized in that: The double-frequency phased array transducer with hundreds of elements has 128, 256, 512, or 1024 elements; the elements are spherical rectangular elements with a projected square shape, arranged in a compact 2D array, and the elements are not aligned; when the elements are distributed in 2D, the focal point can be electronically scanned in 3D space; the dual-frequency of the double-frequency phased array transducer with hundreds of elements is 0.4 to 10 MHz; the dual frequency includes a fundamental frequency f1 and a harmonic frequency f2; f2 = nf1, n = 2 to 10; the double-frequency phased array transducer with hundreds of elements is divided into two annular regions, with the fundamental frequency elements distributed in the outer annular region and the harmonic frequency elements distributed in the inner annular region.

4. The double-frequency phased array composite pulse tissue destruction system according to claim 1, characterized in that: In the double-frequency phased array transducer with hundreds of elements, the element size of the fundamental frequency array element group is larger than the element size of the frequency-doubled array element group.

5. The double-frequency phased array composite pulse tissue destruction system according to claim 1, characterized in that: In the aforementioned double-frequency phased array transducer with hundreds of elements, when the double frequency is double 2, the element size of the base frequency array element group is 1.5 to 2 times the element size of the frequency-doubled array element group; when the double frequency is double 3, the element size of the base frequency array element group is 2 to 3 times the element size of the frequency-doubled array element group.

6. The double-frequency phased array composite pulse tissue destruction system according to claim 1, characterized in that: In the double-frequency phased array transducer with hundreds of elements, the number of elements in the base frequency array element group is less than the number of elements in the double frequency array element group.

7. The double-frequency phased array composite pulse tissue destruction system according to claim 1, characterized in that: The double-frequency phased array composite pulse tissue destruction system also includes a driver for a phased array transducer with hundreds of channels. The driver for the hundreds of phased array transducers transmits element drive signals to the double-frequency phased array transducers through two sets of impedance matching networks for the hundreds of elements. The phased array transducers are divided into two groups: a fundamental frequency group and a frequency-harmonic group. The impedance matching networks are also divided into two groups: a fundamental frequency group and a frequency-harmonic group. The phased array transducer driver includes an arbitrary waveform generator module that controls a composite pulse sequence of two frequencies, using the fundamental frequency pulse sequence waveform and the frequency-harmonic pulse sequence waveform to control the timing of each channel of the fundamental and frequency harmonics, respectively. The phase and amplitude control of the hundreds of channels in the phased array transducer driver receives the multi-focal drive signal corresponding to each element from the double-frequency genetic algorithm. The phase and amplitude; hundreds of phased array transducers correspond to hundreds of phased array transducer channel amplifiers, each element corresponds to the power control of one channel, the power and phase of each channel in the phased array transducer driver are independently controlled, and the pulse timing of each frequency element is a composite pulse frequency pulse waveform timing.

8. The double-frequency phased array composite pulse tissue destruction system according to claim 7, characterized in that: In the control of the double-frequency phased array transducer with hundreds of elements, a genetic optimization algorithm adapted to the double-frequency characteristics is used to realize 3D single-focus and multi-focus. The multi-focus includes axisymmetric multi-focus and off-axis multi-focus. The double-frequency genetic optimization algorithm can realize the distribution of 3D multi-focus on the focal plane, and the distance between adjacent focal points on the focal plane is one fundamental frequency wavelength.

9. The double-frequency phased array composite pulse tissue destruction system according to claim 7, characterized in that: When the double-frequency genetic algorithm in the control of the double-frequency phased array transducer with hundreds of elements reversely solves the driving vector, it can independently control the operation of the frequency-doubling array elements. The multi-focus negative pressure output by the frequency-doubling array elements all exceed 10 MPa of shock waves. The boiling time is calculated by the weak shock theory formula, and the millisecond-long pulse length PD value of the first three stages is designed based on the boiling time.

10. The double-frequency phased array composite pulse tissue destruction system according to claim 1, characterized in that: During electronic scanning, the large-point damage formed by the multi-focus mode of the phased array transducer with hundreds of elements has a spacing of 2 / 3 of the radial or axial dimension of the large-point damage between two adjacent large-point damages, achieving a scanning effect of 1 / 3 coverage.

11. The double-frequency phased array composite pulse tissue destruction system according to claim 1, characterized in that: The double-frequency phased array transducer with hundreds of elements has a through hole at its center. The ultrasound probe of the real-time monitoring module is coaxially installed in the through hole, and the ultrasound probe rotates 180 degrees in both directions to guide and track the focal point destruction process in 3D space using images.

12. The double-frequency phased array composite pulse tissue destruction system according to claim 1, characterized in that: The split array transducer uses the phase difference between adjacent array elements to synthesize a fixed and axisymmetric single-focus, two-focus, four-focus, or six-focus mode. The double harmonic frequency range is 0.4 to 10 MHz, and the harmonic is 2 to 10 times the fundamental frequency. The f-number is less than 1.

13. The double-frequency phased array composite pulse tissue destruction system according to claim 1, characterized in that: The split array transducer is a spherical 2-element ring array, a 4- or 6-element rectangular split array, or a 4- or 6-element fan-shaped split array. The maximum number of focal points of the split array transducer is equal to the number of array elements.

14. The double-frequency phased array composite pulse tissue destruction system according to claim 1, characterized in that: When the large-point damage formed by the multi-focal mode of the split array transducer is mechanically scanned, the spacing between two adjacent large-point damages is 2 / 3 of the radial or axial dimension of the large-point damage, achieving a 1 / 3 coverage scanning effect. When the split array transducer is a 2-element ring array, the phase difference between the two frequencies is set to 135 degrees of the fundamental frequency in the dual 2nd harmonic mode and 60 degrees in the dual 3rd harmonic mode, resulting in confocal enhanced acoustic pressure cavitation. The nonlinear acoustic pressure is quantitatively calculated using the nonlinear KZK equation to ensure the characteristics of the harmonic impulse wave.

15. The double-frequency phased array composite pulse tissue destruction system according to claim 1, characterized in that: The double-frequency split array has no more than 12 elements; the focus of the double-frequency split array is the phase difference control of the split array for multi-focus positive synthesis; the composite ultrasonic pulse waveform of the two frequencies is controlled by the number of channels of an arbitrary waveform generator with the same number of elements as the split array.

16. The double-frequency phased array composite pulse tissue destruction system according to claim 1, characterized in that: The split array transducer is a spherical 2-element ring array, a 4- or 6-element rectangular split array, a 4- or 6-element fan-shaped split array, or a fan-shaped spiral split array. The maximum number of focal points of the split array transducer is equal to the number of array elements, and the adjacent spacing of the multiple focal points on the focal plane is one fundamental frequency wavelength.

17. The double-frequency phased array composite pulse tissue destruction system according to claim 1, characterized in that: The phase difference control of the split array transducer adopts a forward synthesis algorithm. By adjusting the phase difference combination of adjacent array elements, the switching between single focus, 2 focus, 4 focus or 6 focus can be realized, and the sound pressure of the multi-focus all meet the mechanical ablation requirements.

18. The double-frequency phased array composite pulse tissue destruction system according to claim 1, characterized in that: The split array transducer has a through hole at its center, and the B-mode ultrasound probe of the real-time monitoring module is coaxially installed in the through hole to monitor the cavitation cloud dissipation state and liquefaction damage area in real time. The B-mode ultrasound probe, together with the 3D position control module, tracks the focal point damage process.

19. The double-frequency phased array composite pulse tissue destruction system according to any one of claims 1 to 10, characterized in that, include: The double-frequency phased array transducer with hundreds of elements adopts a four-stage composite pulse timing coordinated control of the working state of the fundamental frequency array element and the frequency-doubled array element, combined with the multi-focus control strategy of the phased array transducer with hundreds of elements. The multi-focus control strategy for the double-frequency phased array transducer with hundreds of elements includes: Design the position of the focal plane multifocal points Monofocal, 2-focal, 4-focal, 6-focal, off-axis monofocal, off-axis multifocal; Using a double-frequency genetic algorithm to solve multifocal problems in reverse. corresponding drive signals ; A precise calculation program for a phased array transducer containing a dual-frequency spherical rectangular array element was used, along with the obtained... The 3D sound field focusing characteristics were obtained through simulation to verify whether they met the requirements. Only the double-frequency single-frequency drive was used, and the double-frequency sound pressure level had to exceed 10 MPa. The boiling time was calculated using the weak impact theory formula, and the millisecond-long pulse length PD value was designed based on the boiling time to ensure that boiling bubbles occurred with each pulse. use A driver for a phased array transducer with hundreds of channels was installed, and composite pulse parameters were loaded into the driver for multifocal tissue destruction.

20. The double-frequency phased array composite pulse tissue destruction system according to any one of claims 1, 12 to 18, characterized in that, The double-frequency split array transducer adopts a four-stage composite pulse timing coordinated control of the fundamental frequency array element and the frequency multiplier array element, combined with a split array multi-focus control strategy. The multi-focus control strategy for the split array includes: Based on the required split array and focal mode, the sound field distribution is obtained using the double-frequency split array sound field formula or nonlinear KZK, ensuring the frequency-doubled shock wave and obtaining experimental control parameters; The prepared sample is moved using 3D position control so that the focal point is located at a certain depth within the sample, while ultrasound positioning is used to emit short pulses to cavitation the focal point. Use the composite pulse parameters to set the arbitrary waveform generator of the split array, and use the power settings of step 1 to set the power amplifier of the split array to emit tissue damage; monitor in real time with ultrasound; if multi-point irradiation is used, set the 3D position control movement path and the 2-focal distance to emit tissue damage.

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