WO2018018725A1

WO2018018725A1 - Two-stage hundred-microsecond pulse focused ultrasound tissue destruction method

Info

Publication number: WO2018018725A1
Application number: PCT/CN2016/099266
Authority: WO
Inventors: 陆明珠; 王睿; 关宇波; 李玉娇; 黄伟骏; 马风超; 张灵璐; 万明习
Original assignee: 西安交通大学
Priority date: 2016-07-25
Filing date: 2016-09-19
Publication date: 2018-02-01
Also published as: CN106267593A

Abstract

A two-stage hundred-microsecond pulse focused ultrasound tissue destruction method, comprising: 1) positioning a target tissue of a sample (9) by using a monitoring guidance system, and adjusting a position of the target tissue to a focal point of an HIFU transducer (5); 2) a first stage destruction: forming loose local tissue structures by means of a shock wave excited by a hundred-microsecond pulse focused ultrasound, as well as boiling air bubbles and inertial cavitation generated thereby; 3) a second stage destruction: further mechanically crushing and homogenizing the tissues in a damaged area by means of a pulse focused ultrasound having a hundred-microsecond length, so as to achieve tissue destruction. The method takes full advantage of the following features: a pulse having a relatively high duty cycle exhibits both thermal and mechanical effects, while a pulse having a low duty cycle exhibits good mechanical effects. By controlling a high-intensity ultrasound sequence in which two stages are generated consecutively, a single pulse of which lasts one hundred microseconds, and which has a pulse having a relatively high duty cycle and a low duty ratio to act on a target tissue, highly efficient tissue destruction may be achieved.

Description

Two-stage one hundred microsecond pulse focused ultrasound tissue destruction method

Technical field

The invention belongs to the field of ultrasonic technology and relates to a two-stage one hundred microsecond pulse-focusing ultrasonic tissue destruction method.

Background technique

Histotripsy is a non-invasive and controllable method of tissue ablation that controlled the destruction and homogenization of soft tissue by pulsed ultrasound focused from outside the body to the target without damaging adjacent tissue. Infant heart disease, treatment of prostate lesions, tumor ablation, treatment of thrombosis, etc. have applications. Tissue damage technology belongs to High Intensity Focused Ultrasound (HIFU), which mainly utilizes the mechanical effects of high-intensity focused pulsed ultrasound on tissues and cells, and has become an international research hotspot.

In high-intensity focused ultrasound, thermal and acoustic cavitation dominate. The thermal mechanism and the tissue damage mechanism mainly utilize the thermal effects and cavitation mechanical effects of HIFU, respectively. The study of thermal mechanisms started earlier and more mature, and has been applied in the treatment of substantive tissues, but the method of tissue damage also has its own advantages: (a) the method of tissue damage is not affected by the thermal pool effect (heat-sink) The effects of the treatment can be used to treat the tissue surrounding the blood vessels, and the application range is wider; (b) the damage of the tissue damage method is the result of cavitation mechanical action, which can prevent thermal diffusion and affect healthy tissue; (c) the tissue damage method Cavitation clouds, boiling bubbles, etc. are more convenient for the monitoring of ultrasound equipment, which can be used to judge the process and location of the treatment; (d) tissue damage method to crush the target tissue, no thermal coagulation damage during treatment, can form tissue Absorbable liquid, more suitable for clinical application; (e) tissue damage method for large lesions can be continuously treated around the tumor tissue, cutting the tumor tissue from healthy tissue, greatly improving the treatment efficiency.

In order to make better use of mechanical effects, there are generally two methods of generating cavitation cloud tissue damage using ultra-high intensity pulsed ultrasound and generating boiling bubbles using pulses of several milliseconds. Accurate and controllable and efficient damage is the main goal of the development of organizational damage technology.

The cavitation clouds required for cavitation cloud tissue damage occur only in focal regions where the negative sound pressure exceeds the threshold. Shock wave scattering and intrinsic threshold excitation are the two main ways of cavitation cloud tissue damage: the shock wave scattering mechanism is that the shock wave reflects from a single or multiple microbubbles to form a high amplitude negative sound pressure, which forms more under the action of this negative sound pressure. The microbubbles are aggregated to image a cloud-like microbubble group; the intrinsic threshold excitation is achieved by increasing the individual peak negative sound pressure so that the short pulse energy exceeds the inherent cavitation threshold. Cain, of the University of Michigan, USA, US Patent No. 6,309,355 B1, entitled "Method and assembly for performing ultrasound surgery using cavitation", disclosed earlier in 2001 a method of treatment for tissue destruction using cavitation, which A pulse sequence with a time less than 50 μs uses ultrasonic-induced cavitation effects to cause damage in the target region. Cain, in U.S. Patent No. 8,057,408 B2, entitled "Pulsed cavitational ultrasound therapy", further divides the treatment process into sub-processes such as initial, maintenance, treatment, and feedback. This method of dividing the treatment process into multiple sub-processes utilizes different sound pressure amplitudes, and the ultrasonic waves of the duty cycle and pulse repetition frequency produce different biological effects in the tissue, which overcomes the early cavitation cloud organization. The problem of poor controllability of the damage method is more regular and more suitable for clinical application. Cain, in the U.S. Patent No. 20,130,090,579, issued to the entire disclosure of the entire disclosure of the disclosure of the entire disclosure of the disclosure of the disclosure of which is incorporated herein by reference. Dissipate the ground and eliminate the “cavitation memory”, making the damaged area easier to homogenize. Patent No. WO 2,015,027, 164 A1 to the name of "Histotripsy using very short ultrasound pulses" by Cain proposes to increase the peak negative sound pressure beyond the inherent cavitation threshold and to use short pulses of less than 2 cycles for tissue micro-damage ( Microtripsy) method. The method makes the damage less than one wavelength, so that the damage is more precise and controllable, and the peak negative sound pressure required by the method in the tissue reaches 15-30 MPa, which causes the sound tissue around the target tissue to have a large sound pressure. Put some pressure on clinical applications.

The boiling bubble structure damage mainly utilizes the rapid heating boiling caused by a pulse of several milliseconds and the atomization phenomenon generated by the interface between the tissue and the boiling bubble. When a certain intensity of sound pressure is applied for a certain period of time, the tissue temperature in the focal zone rises above 100 ° C, and boiling bubbles are generated. The name of the invention patent is Michael S. Canney of the University of Washington in the United States. U.S. Patent No. 8,876,740 B2 to "Methods and systems for non-invasive treatment of tissue using high intensity focused ultrasound therapy" discloses the use of pulsed ultrasonic waves having a length of several milliseconds and a positive sound pressure peak of 10 to 100 MPa to generate boiling bubbles in the target tissue. Method and device. Vera KHOKHLOVA, et al., in the patent application "Boiling histotrips methods and systems for uniform volumetric ablation of an object by high-intensity focused ultrasound waves with shocks", WO 2,015,148,966 A1, discloses the use of sequentially guided ultrasound at the target. A method and apparatus for tissue damage using boiling bubbles at different points in the tissue.

At present, cavitation cloud tissue damage and boiling bubble tissue damage are the two main directions of tissue damage technology, and they all adopt pulsed ultrasonic emission mode. Cavitation cloud tissue damage method pulse ultrasonic duration is only about 10μs, peak negative sound pressure is 15 ~ 25MPa, peak positive sound pressure needs to be greater than 80MPa, transducer operating frequency is 0.75 ~ 1MHz; and boiling bubble tissue damage method The pulse duration is several milliseconds, the peak negative sound pressure is 10-15 MPa, the peak positive sound pressure needs to be greater than 40 MPa, and the transducer operating frequency is 1-3 MHz.

The existing methods of tissue damage still need to be improved as follows: 1. The required peak sound pressure is large. As a non-invasive treatment technique, too high peak sound pressure will cause a large sound pressure in the surrounding tissue. Put some pressure on clinical safety. 2. Cavitation cloud tissue damage method The pulse duration is only about 10μs, and the duty cycle is less than 1%, which makes the ultrasonic excitation time shorter, the required damage formation time is longer, and the treatment efficiency is lower. 3. Boiling bubble structure damage technology Because the sound radiation force is not used, the damage often occurs in the head.

Summary of the invention

The object of the present invention is to provide a two-stage one hundred microsecond pulse-focusing ultrasonic tissue damage method, which can improve the safety, efficiency and effectiveness by a two-stage tissue damage method with a length of one hundred microseconds.

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

A two-stage, one-hundred microsecond pulse-focused ultrasound tissue destruction method includes the following steps:

1) Positioning the sample target tissue using a monitoring and guiding system, and adjusting the position of the target tissue to HIFU transduction accordingly Focus of the device (5);

2) Performing the first stage of damage: using a hundred microsecond length pulse to focus the ultrasonically excited shock wave and its resulting boiling bubble and inertial cavitation to form a loose local tissue structure, achieving primary homogenization of the tissue, and generating a cavitation nucleus ;

3) Perform the second stage of damage: further mechanical pulverization and homogenization of the tissue in the damaged area by using a hundred microsecond length pulse focused ultrasound to achieve tissue damage.

Further, the monitoring and guiding system in step 1) is a digital ultrasound imaging device.

Further, a damaged edge is used for the determined target tissue, a tissue cutting scheme, or a direct damage scheme.

Further, step 1) specifically includes the following steps: image guiding through a B-ultrasound probe located at the center of the HIFU transducer (5), by aligning the radial position of the target tissue to the center of the HIFU transducer; The position of the target tissue is adjusted and the image is guided with a digital ultrasound imaging device such that the target tissue is at the focus of the HIFU transducer.

Further, the duty cycle DC range of the pulse focused ultrasound in step 2) is: 3% < DC < 10%; the length of one hundred microseconds refers to a single pulse duration greater than 200 μs, and less than 950 μs; the operation of the pulse focused ultrasound The frequency range is from 1MHz to 5MHz.

Further, in step 3), the duty ratio of the pulsed focused ultrasound is ≤1%, and the length of one hundred microseconds refers to a single pulse duration of more than 200 μs and less than 950 μs; the pulse focused ultrasound has an operating frequency range of 1 MHz to 5 MHz.

Further, the absolute value of the negative sound pressure used in the two-stage damage is less than 12 MPa, and the positive sound pressure is generated to generate the shock wave, and the positive sound pressure generates the shock wave.

Further, in the first stage of damage, the pulsed focused ultrasound consists of 10 sets of pulses, each group consisting of 100 pulse lengths of 100 microseconds, pulse repetition frequency PRF=100 Hz, and 30 ms between the two pulse trains. Stop time; in the second stage of damage, the pulsed focused ultrasound is also composed of 10 sets of pulses, each group consisting of 10 pulses of 100 microseconds, the repetition frequency PRF=100Hz pulse train and the pulse length of 100 microseconds, repetition frequency PRF= The 200 Hz pulse train consists of a 30 ms stop time between the two bursts of each set of pulses, with a 500 ms stop time between the two sets of pulses.

Further, the sample is a phantom or an ex vivo tissue.

Further, the HIFU transducer is a spherical crown single-element circular array transducer, and its working center frequency ranges from 1 MHz to 5 MHz.

Further, the HIFU transducer is provided with a hole in the middle to facilitate the placement of monitoring and guiding equipment such as a B-ultrasound probe.

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

In order to overcome the deficiencies in the prior art tissue damage method, the present invention proposes a two-stage one hundred microsecond pulse-focusing ultrasonic tissue destruction method; the present invention fully utilizes a relatively high duty cycle pulse to take both thermal and mechanical effects into account, and low duty It has the characteristics of good mechanical effect than pulse. Efficient damage to the tissue is achieved by controlling the relatively high duty cycle of a single pulse with a single pulse duration of one hundred microseconds and a low-intensity pulsed high-intensity ultrasound sequence acting on the target tissue.

Further, the present invention adopts a two-stage destruction strategy combining a relatively high duty cycle and a low duty cycle: firstly, a relatively high duty cycle pulse sequence is used to form a loose structure, and a preliminary homogenization of the tissue is realized; A low duty cycle pulse sequence completely homogenizes the tissue. This two-stage method can significantly reduce the peak sound pressure required for tissue damage methods, reduce the impact on surrounding tissue outside the focus, and improve the safety of treatment.

Further, the first stage of the present invention employs a relatively high duty cycle pulse sequence with a single pulse duration of one hundred microseconds, so that the effective action time is higher than the conventional tissue damage method; meanwhile, the relatively high duty cycle The pulse sequence takes into account the heat accumulation and mechanical effects, and produces a boiling bubble. The shock wave at the focus interacts with the boiling bubble to accelerate the destruction of the structure of the focal region. In addition, the focal region is operated under a relatively high duty cycle pulse sequence. A large number of cavitation nucleuses are generated, which accelerates the cavitation effect of the second stage low duty cycle pulse sequence. Based on the above three points, the present invention can improve the treatment efficiency of tissue damage.

DRAWINGS

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

1 is a block diagram of an implementation system of the present invention; in FIG. 1, 1 is a synchronous signal control system, and 2 is an arbitrary waveform generator. 3 is the RF signal power amplifier, 4 is the impedance matching network, 5 is the single-array ring array HIFU transducer, 6 is the digital ultrasound imaging system, 7 is the high speed camera, 8 is the plexiglass container, 9 is the sample, 10 is the constant temperature The device, 11 is deaerated water.

2 is a schematic diagram of a spherical crown ring array HIFU transducer and a sound field distribution simulation diagram of the present invention; FIG. 2: (a) is a schematic diagram of a spherical crown ring array transducer, and (b) is a sound field. Distribution diagram.

Figure 3 is a schematic diagram of a typical pulse sequence in the method of the present invention.

Figure 4 is a sound pressure waveform measured at a focus of a typical excitation waveform employed in the method of the present invention.

Figure 5 is a main flow diagram of the method of the present invention for cutting large tissue boundaries.

Figure 6 is a schematic illustration of the method of the present invention for cutting large tissue boundaries.

Figure 7 is a typical result of monitoring by high-speed imaging in the implementation of the method of the present invention in bovine serum albumin acrylamide imitation; in Figure 7, (a) to (e) are the first phase of relatively high duty cycle pulses. A typical result plot, (f) ~ (j) is a typical result plot for the second stage low duty cycle pulse.

Figure 8 is a graph showing the histological results of the method of the present invention in isolated pig liver; Figure 8: (a) is the damage boundary after the end of treatment, and (b) is the image of the damage boundary in (a) image. Magnification, (c) is the damage boundary after the end of the relatively high duty cycle treatment in the first stage, and (d) is the amplification of the image around the damage boundary in the (c) image.

Figure 9 is a view of the method of the present invention when a cutting boundary is used when the target tissue is large; in Figure 9: (a) is the axial shape of the damage in the phantom; (b) is the transverse shape of the damage in the phantom; (c), (d) are (a), (b) the form after removal of the transparent phantom.

detailed description

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

Based on the research and application status of tissue damage technology, the present invention proposes a two-stage one hundred microsecond pulse-focusing ultrasonic tissue damage method to safely and efficiently perform tissue damage. The biological effects in biological tissues vary significantly with the duty cycle of the ultrasound. In a complete action process, the longer the duration of the ultrasonic action, ie the higher the duty cycle, the more the heat accumulation effect Large, the thermal effect is more obvious; and correspondingly, the shorter the duration of the ultrasonic action, that is, the lower the duty cycle, the main effect is the mechanical effect; the control duty ratio within a certain range can take into account the heat accumulation and mechanical effects.

HIFU mainly acts in the field of ultrasound therapy, but the present invention does not directly relate to the treatment of human diseased tissue, but uses the phantom as a medium to determine its control method, such as pig liver, kidney and other medium with high incidence of isolated tissues and organs. The research object explores the effect of two-stage one hundred microsecond pulse-focusing ultrasound tissue destruction method on improving treatment efficiency and improving safety.

As shown in FIG. 1, the implementation system of the two-stage hundred microsecond pulse-focusing ultrasonic tissue destruction method in the present invention comprises: an ultrasonic excitation system, a monitoring and guiding system, a synchronization signal control system 1 and a reaction container.

The ultrasonic excitation system is mainly composed of an arbitrary waveform generator 2, an RF power amplifier 3, an impedance matching network 4 and a HIFU transducer 5 which are sequentially connected; the monitoring and guiding system is mainly composed of a digital ultrasonic imaging device 6 (B-mode) and a high speed. The camera 7 is composed; the synchronizing signal control system is composed of a multi-channel arbitrary waveform generator 2, and the main function is a synchronous ultrasonic excitation system and a monitoring and guiding system; the reaction container is a rectangular plexiglass container 8 as a reaction place, and contains a constant temperature. Deaerated water 11 and sample 9 of device 10. The synchronizing signal control system 1 generates a synchronizing signal to operate the ultrasonic excitation system and the monitoring and guiding system in synchronization. The ultrasonic excitation system first emits a relatively high duty cycle (>3%, and <10%) pulse sequence to loosen the local tissue structure. And a cavitation nucleus is generated; then the ultrasonic excitation system emits a lower duty cycle (≤1%) pulse sequence to further mechanically pulverize and homogenize the tissue of the damaged region. In the two-stage destruction process, the monitoring and guidance system performs real-time monitoring, including cavitation effects, boiling bubbles and eventually formed damage. The synchronous operation of the ultrasonic excitation system and the monitoring and guiding system is realized by a synchronous signal control system, and the specific implementation thereof is that a multi-channel arbitrary waveform generator generates multiple synchronous signals, one of which is used to control the ultrasonic excitation system, and at the same time Another signal of the synchronous signal control system controls the high-speed camera to acquire images synchronously to monitor the damage during the entire process. In addition, the ultrasound imaging device can also be used to monitor in real time throughout the process, providing B-mode images at any time in the target tissue region.

In order to reduce the peak sound pressure and improve the efficiency of tissue damage, the two-stage hundred microsecond pulse-focusing ultrasonic tissue destruction method of the present invention comprises the following steps:

1) Positioning the sample target tissue using a monitoring guidance system (such as a digital ultrasound imaging device) and adjusting the position of the target tissue to the focus of the HIFU transducer 5 accordingly; wherein, using a monitoring guidance system (such as a digital ultrasound imaging device) Determine the target tissue to be determined, and select the appropriate scheme: the method of cutting the tissue for the larger tissue, the scheme of cutting the tissue, and the scheme of directly destroying the smaller tissue;

2) Perform the first stage of damage: using a hundred microsecond length pulse to focus the ultrasonically excited shock wave and its resulting boiling bubble and inertial cavitation to form a loose local tissue structure, to achieve a preliminary homogenization of the tissue, and generate a large number of cavitation nuclear;

3) Perform the second stage of damage: further mechanical pulverization and homogenization of the damaged area by using a hundred microsecond length pulse focused ultrasound to achieve high-efficiency tissue damage.

Step 1) specifically includes the steps of: image guiding through a B-ultrasound probe located at the center of the HIFU transducer 5, by aligning the radial position of the target tissue to the center of the HIFU transducer; by adjusting the position of the target tissue Image guidance using a digital ultrasound imaging device with the target tissue at the focus of the HIFU transducer.

In step 1), the B-ultrasound image of the desired damaged target tissue is collected. When the target tissue is large (such as a large tumor tissue), the cutting method is adopted, that is, the HIFU transducer is moved multiple times to focus on the tissue. Boundary, multiple tissue damage, and finally the purpose of cutting the target tissue from the surrounding healthy tissue; when the target tissue is small, the direct damage method is adopted, even if the HIFU transducer is focused on the target tissue, One or more tissue damages, directly destroying the target tissue.

Step 2) includes the steps of: the arbitrary waveform generator emits a relatively high duty cycle pulse sequence of a single pulse duration of one hundred microseconds, and after driving the HIFU transducer through the impedance matching network after the RF power amplifier, in the monitoring and guiding system The first stage of destruction of the target tissue is monitored. The relatively high duty cycle (Duty Cycle, DC) DC range is 3% < DC <10%, a hundred microsecond length, refers to a single pulse duration of 200μs <DC <950μs, pulse focused ultrasound, its operating frequency range It is 1MHz to 5MHz. The first stage of the damage first utilizes a relatively high duty cycle (> 3%, and <10%) pulsed ultrasound while utilizing heat accumulation and mechanical effects to reduce the mechanical strength of the target tissue and achieve partial homogenization. The pulsed focused ultrasound in the first stage produces boiling bubbles and shock waves, etc., forming a loose local structure, and inertia. Various mechanical actions, such as cavitation and shock waves, further homogenize the interior of the damage and form a large number of cavitation nuclei. The boiling bubbles in the first stage are achieved in the form of heat accumulation, and there is an upper limit on the duty ratio for the heat accumulation in the focal area without forming a large amount of heat diffusion to be avoided for the surrounding tissue. The sub-verification was set to 10% in the present invention.

Step 3) includes the following steps: the arbitrary waveform generator emits a single pulse duration of a low duty cycle pulse duration of one hundred microseconds, and after passing through the RF power amplifier, drives the HIFU transducer through the impedance matching network under the monitoring of the monitoring and guiding system. The second stage of destruction of the target tissue. The low duty cycle DC range is DC ≤ 1%, a hundred microsecond length, which refers to a single pulse duration of 200 μs < DC < 950 μs, pulse focused ultrasound, and its operating frequency range is 1 MHz ~ 5 MHz. The second stage of the present invention utilizes a lower duty cycle (≤ 1%) pulsed ultrasound sequence that further comminutes and homogenizes the tissue in the focal zone. Benefiting from the damage of the first stage, the local organizational structure becomes more loose, and the number of cavitation nuclei in the damaged area has also increased, making the cavitation effect more likely to occur. The absolute value of the negative sound pressure required for the two-stage tissue damage method can be reduced to less than 12 MPa.

As shown in FIG. 2(a), the spherical crown ring array HIFU transducer 5 in the system of the present invention is a hole-in-the-hole, concave spherical ultrasonic transducer having a radius of curvature R _s and an inner diameter of R _{1 .} outer diameter R _2. Figure 2(b) is a typical spherical crown ring array HIFU transducer used in the implementation system (curvature radius R _s = 100mm, inner diameter R ₁ = 12.5mm, outer diameter R ₂ = 47.5mm) Schematic diagram of the axial sound field simulation.

Further, the basis of the square matrix calculation of the spherical crown ring array HIFU transducer in Fig. 2(b) is as follows:

According to the Reyleigh-Sommerfeld integral, the calculation formula of the spherical crown transducer sound field is:

k=ω/c (2)

Where j is the imaginary unit, ρ is the medium density, c is the speed of sound in the medium, k is the wave number, s is the area of the signal source, u is the vibration velocity of the medium perpendicular to the surface of the sound source, and r is the surface of the observation point away from the element The distance of dS, α is the sound attenuation coefficient. The axial sound pressure can be accurately calculated according to the formula (1) to obtain an analytical solution:

Figure 3 is a schematic diagram of a typical pulse sequence in a two-stage tissue destruction method employed in the present invention. The first stage pulse sequence has a duty cycle of 4.9%, consisting of 10 sets of pulses, pulse length PD=500μs, pulse repetition frequency PRF=100Hz, 30ms stop time between the two sets of pulses; the second stage of the pulse sequence The space ratio is 1%, and is also composed of 10 sets of pulses, each group consisting of 10 pulse lengths PD=500μs, a repetition frequency PRF=100Hz pulse train and a pulse length PD=200μs, and a repetition frequency PRF=200Hz pulse train. There is a 30ms stop time between the two bursts of each set of pulses, and there is a 500ms stop time between the two sets of bursts.

As shown in Fig. 4, a typical sound pressure waveform measured at a focus when the ultrasonic excitation system operates in the two-stage tissue destruction method employed in the present invention. The specific test conditions are as follows: the center frequency of the transducer is 1.06MHz, PRF=100Hz, 500 pulses are emitted, the peak negative sound pressure is 8MPa, the peak positive sound pressure is 35MPa, and a significant shock wave is generated. The peak sound pressure required for cavitation cloud tissue damage and boiling bubble tissue damage methods is significantly reduced, ensuring the safety of normal tissue outside the focus and improving treatment safety.

As shown in FIG. 5, the two-stage tissue destruction method of the present invention performs tissue cutting by using the following process: the S1 digital ultrasound device performs image guidance, and the HIFU transducer is adjusted to focus on the area where tissue damage is required; S2 performs the first The relatively high duty cycle treatment results in loose local tissue structure and cavitation nucleus with image monitoring; S3 performs a second phase of low duty cycle treatment, further mechanical comminution and homogenization of the damaged area, and Accompanied by real-time image monitoring; S4 determines whether the cutting has been completed, and if it is completed, ends the treatment, if not, proceeds to step S5; S5 searches for a new cutting point along the boundary, and repeats steps S1, S2, S3, and S4.

As shown in Fig. 6, the schematic diagram of the tissue cutting of the two-stage tissue destruction method of the present invention is further visualized.

Example 1:

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

2) Fix the spherical crown ring array HIFU transducer and the B-ultrasound probe as shown in Fig. 1, inject an appropriate amount of deaerated water into the reaction vessel, and turn on the thermostat. The ultrasound imaging device is turned on to adjust the point of the phantom that needs to be damaged to the focus of the transducer according to the image guidance.

3) Write the signal to be generated by the arbitrary waveform generator according to Figure 5. When excited, the signal is a sine wave with a frequency of f = 1.06 MHz. The signal is divided into two phases: the first phase is a relatively high duty cycle pulse sequence with a duty ratio of 4.9%, which consists of 10 sets of pulses, the duration of a single pulse is PD = 500 μs, and the pulse repetition frequency is PRF = 100 Hz; The second stage is a low duty cycle pulse sequence with a duty cycle of 1%. It is also composed of 10 sets of pulses, each group consisting of 10 pulse lengths PD=500μs, repetition frequency PRF=100Hz pulse train and pulse length PD =200μs, the repetition frequency PRF=200Hz pulse train composition, the 500μs length pulse has a stop time of 30ms after the action, and there is a 500ms stop time between the two groups of pulses. . The sound power was set to 240 W throughout the treatment.

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

Analysis results:

Bovine serum albumin polyacrylamide imitation is transparent and is similar to tissue characteristics and is often used for mechanism analysis. The formation process of the damage can be clearly observed by high-speed imaging. As shown in Fig. 7, the high-speed image of the damage pattern changes with the treatment time in the phantom, and (a) to (e) are typical results of the first stage, (f ) ~ (j) is the typical result graph of the second stage. As shown in Fig. 7(a), visible damage occurred in 1.8 seconds, as shown in Fig. 7(c), and 2 mm diameter appeared in 6.671s. The boiling bubble, as shown in Figure 7 (d), shows increased fluidity of the damage. As shown in Figure 7(h), the damage appears in multiple divisions. This may be that the ultrasonic waves are reflected multiple times in the axial direction and are formed at multiple points. Further, this is another example of the high therapeutic efficiency of the present invention. As shown in Fig. 7(j), the damage finally appears as a column, and the size is about 8 mm × 2 mm (axial × lateral), and the damage is relatively regular. As a result of high-speed imaging, it can be found that the two-stage one hundred microsecond pulse tissue destruction method used in the present invention can achieve tissue damage with a lower sound pressure.

Example 2:

1) Preparation of an acrylamide analog liquid. Fresh pork kidney tissue was selected, cut into a size of 5 mm × 3 mm × 30 mm, and fixed in a body fluid, and solidified at normal temperature.

2) Fix the spherical crown ring array HIFU transducer and the B-ultrasound probe as shown in Fig. 1, inject an appropriate amount of deaerated water into the reaction vessel, and turn on the thermostat. Turn on the ultrasound imaging device and adjust the center position of the pig kidney to the focus of the transducer according to the image guide.

3) Write the signal to be generated by the arbitrary waveform generator according to Figure 5. The signal is divided into two phases: the pulse sequence of the first phase consists of 10 sets of pulses, each consisting of 100 pulse trains with a pulse length of PD=400μs and a pulse repetition frequency of PRF=100Hz. There is a pulse between the two bursts. 30ms stop time; the second phase of the pulse is also composed of 10 groups of pulses, each group consists of 10 pulse length PD=400μs, repetition frequency PRF=100Hz pulse train and pulse length PD=200μs, repetition frequency PRF=200Hz The pulse train consists of a stop time of 30ms after the pulse of 400μs length is applied, and there is a stop time of 500ms between the two sets of pulses. The sound power was set to 240 W throughout the treatment.

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

5) After the end of the treatment process, the injury is observed through the B-ultrasound device, and then the pig kidney is taken out, and then cut off again. A detailed analysis of the damage. H&E staining was performed on the damaged pig kidney, and the histological results were observed using a high power microscope.

Analysis results:

Morphological observation of the dissected pig kidneys revealed that the two-stage high-efficiency tissue destruction method was used to treat the internal damage of the kidney, and the damage morphology was relatively uniform, and no obvious thermal coagulation damage occurred around the injury. Figure 8 shows the histological results of pig kidney after H&E staining. As shown in Fig. 8(a), the damage boundary after the end of treatment, the left side is the normal tissue, and the right side is the tissue after the injury. The two have clear boundaries and the inside of the damage is completely uniform; as shown in Figure 8(b) It is the enlarged damage boundary that can further find that the cell structure in the normal area is relatively complete, and the damaged area after treatment is completely homogenized; as shown in Fig. 8(c), the damage boundary after the first stage treatment can be found. The lesion area is partially homogenized, but some of the cell debris remains. As shown in Figure 8(d), it is an enlarged view of the damage boundary area after the first stage of treatment, and it can be found that the damage area only appears preliminary. Homogenization, complete homogenization is not achieved. Therefore, the solution proposed by the present invention can damage the tissue with a lower sound pressure, ensure the safety brought by the surrounding tissue outside the focus, improve the safety of the treatment, and improve the treatment efficiency and the like.

Example 3:

1) Preparation of acrylamide-like body fluid, the density of the phantom was 1.06, the sound velocity in the finished phantom was 1477±5 m/s, and the sound attenuation coefficient was 0.42±0.01 dB/cm. Select fresh pig liver tissue, larger pieces, and fix it in the body fluid, and coagulate at room temperature

2) Fix the spherical crown ring array HIFU transducer and the B-ultrasound probe as shown in Fig. 1, inject an appropriate amount of deaerated water into the reaction vessel, and turn on the thermostat. The ultrasound imaging device is turned on, and a point on the boundary of the pig liver that needs to be cut is adjusted according to the image guide to the focus of the transducer.

3) Repeat step 3 in Example 2)

4) Repeat step 4 in Example 2)

5) As shown in Figure 5, repeat the step 4 every 10 mm along the position of the tissue boundary to be cut. Cutting completed

6) Repeat step 5 in embodiment 2)

Analytical results: As shown in Fig. 9, the results of the large tissue cutting treatment of the new method of tissue damage proposed by the present invention, the morphological observation of the cut pig liver can reveal the appearance of white milky substance inside the treatment area. The damaged area has been completely cut. Therefore, the solution proposed by the present invention can cut the boundary of a large target tissue to achieve high-efficiency treatment.

Claims

A two-stage hundred microsecond pulse-focusing ultrasonic tissue destruction method, characterized in that the method comprises the following steps:

1) using a monitoring and guiding system to position the target tissue of the sample and adjust the position of the target tissue to the focus of the HIFU transducer (5) accordingly;

2) Performing the first stage of damage: using a hundred microsecond length pulse to focus the ultrasonically excited shock wave and its resulting boiling bubble and inertial cavitation to form a loose local tissue structure, achieving primary homogenization of the tissue, and generating a cavitation nucleus ;

3) Perform the second stage of damage: further mechanical pulverization and homogenization of the tissue in the damaged area by using a hundred microsecond length pulse focused ultrasound to achieve tissue damage.
The two-stage hundred microsecond pulse focused ultrasound tissue destruction method according to claim 1, wherein the monitoring and guiding system in step 1) comprises a digital ultrasound imaging device and a high speed camera.
The two-stage hundred microsecond pulse-focusing ultrasonic tissue destruction method according to claim 1, characterized in that a damaged edge is used for the determined target tissue, a tissue cutting scheme is adopted, or a direct damage scheme is adopted.
The two-stage hundred microsecond pulse-focusing ultrasonic tissue destruction method according to claim 1, wherein the step 1) specifically comprises the following steps: performing image guidance through a B-ultrasound probe located at the center of the HIFU transducer (5). The radial position of the target tissue is adjusted to align with the center of the HIFU transducer; by adjusting the position of the target tissue, image guidance is performed with a digital ultrasound imaging device such that the target tissue is at the focus of the HIFU transducer.
The two-stage hundred microsecond pulse-focusing ultrasonic tissue destruction method according to claim 1, wherein the duty cycle DC range of the pulse-focused ultrasonic wave in step 2) is: 3% < DC < 10%; a hundred microsecond length , refers to a single pulse duration greater than 200μs, and less than 950μs; pulse focused ultrasound operating frequency range of 1MHz ~ 5MHz.
The two-stage hundred microsecond pulse-focusing ultrasonic tissue destruction method according to claim 1, wherein the duty ratio of the pulse-focusing ultrasonic wave in step 3) is ≤1%, and the length of one hundred microseconds refers to a single pulse duration. More than 200μs, but less than 950μs; pulsed ultrasound has an operating frequency range of 1MHz to 5MHz.
The two-stage hundred microsecond pulse-focusing ultrasonic tissue destruction method according to claim 1, wherein the absolute value of the negative sound pressure used in the two-stage damage is less than 12 MPa, and the positive sound pressure generates a shock wave.
The two-stage hundred microsecond pulse-focusing ultrasonic tissue destruction method according to claim 1, wherein in the first stage of the damage, the pulse focused ultrasound is composed of 10 sets of pulses, each group consisting of 100 pulses and a length of one hundred microseconds. The pulse repetition frequency PRF=100Hz pulse train consists of 30ms stop time between the two sets of pulses; in the second stage damage, the pulse focus ultrasonic wave is also composed of 10 sets of pulses, each group consisting of 10 pulses with a length of 100 microseconds. The pulse train with repetition frequency PRF=100Hz and the pulse length of 100 microseconds, the repetition frequency PRF=200Hz pulse train, 30ms stop time between two pulse trains of each group of pulses, 500ms stop between the two groups of pulses time.
The two-stage hundred microsecond pulse-focusing ultrasonic tissue destruction method according to claim 1, wherein the sample is a phantom or an ex vivo tissue.