Histotripsy excitation sequences optimized for bubble cloud formation using shock scattering

Abstract

To provide a method and device for producing cavitation in tissue.SOLUTION: A shock scattering method of Histotripsy therapy comprises delivering an initiation pressure waveform from an ultrasound therapy transducer into tissue, the initiation pressure waveform being configured to produce at least one bubble in the tissue, delivering a scattering pressure waveform from the ultrasound therapy transducer into the at least one bubble within a life-cycle of the at least one bubble, and producing cavitation nuclei near the at least one bubble with the scattering pressure waveform. The scattering pressure waveform can be delivered during a life-cycle of the at least one bubble. In some embodiments, the scattering pressure waveform is delivered within 5 μs to 1 s of the initiation pressure waveform. A system for performing shock scattering Histotripsy therapy is also discussed.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] Cross - Reference to Related Applications

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 61 / 842,820, filed on July 3, 2013, entitled "Modulated Excitation Sequences for Enhanced Pulsed Ultrasound Cavitational Therapy", under 35 U.S.C. § 119, and the entire disclosure of that application is incorporated herein by reference.

[0002]

[0002] All publications and patent applications mentioned in this specification are hereby incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0003]

[0003] This disclosure generally relates to the treatment of tissue by cavitation produced by ultrasound therapy.

Background Art

[0004]

[0004] Histotripsy or pulsed ultrasound cavitation therapy is a technique in which short, intense bursts of acoustic energy induce controlled cavitation (formation of microbubbles or bubble clouds) within a focal region. The active foaming and collapse of these microbubbles automatically homogenize cells and tissue structures within the focal region. This is a significantly different end - result from the coagulative necrosis characteristics of thermal ablation. In order to operate within a non - thermal histotripsy region, it is necessary to supply acoustic energy in the form of high - pressure amplitude acoustic pulses with a low duty cycle.

[0005] Compared with conventional focused ultrasound technology, histotripsy has the following important advantages: (1) The destruction process at the focus is mechanical rather than thermal. (2) The bubble cloud is clearly represented on the ultrasound image, thereby enabling accurate targeting and location of the treatment. (3) The treated tissue is represented darker (hypoechoic) on the ultrasound image, so that the surgeon can recognize what has been treated. (4) Histotripsy produces a controlled and precise trauma. It is important to emphasize that histotripsy is not a thermal physical therapy, unlike microwave, radiofrequency, or high-intensity focused ultrasound (HIFU).

[0006]

[0006] Initial studies in dogs on histotripsy homogenization of prostate tissue employed therapy transducers arranged to deliver histotripsy transabdominally. In these studies, the prostate was located only a short distance from the surface of the muscle, and there was a relatively wide path for focusing ultrasonic energy through the muscle from the transducer. Thus, the spherical histotripsy therapy transducers employed in these studies had a 14 cm aperture and a 10 cm focal length (F number = 0.71). A histotripsy therapy transducer with a large F number is significantly less efficient than one with a small F number. Such inefficiency is mainly due to the non-linear acoustic propagation that results in the formation of shock waves.

[0007]

[0007] Dedicated therapy transducers and drive electronics have been designed to focus histotripsy therapy through the perineum to the prostate. An example of a therapy transducer 100 configured to deliver histotripsy therapy to the prostate is shown in FIG. 1. The transducer 100 may comprise a plurality of ultrasonic transducer elements 102 disposed within a housing 104. The transducer may be connected to a waveform generator configured to supply a histotripsy waveform from the transducer to the tissue. 。The depth of the prostate from this access route is significantly deeper than that in the above-mentioned dog model. Furthermore, the pelvic skeletal anatomy and the transrectal position of the ultrasound imaging probe significantly reduced the effective transducer aperture. The notch 106 on the lower outer periphery of the housing can be configured to accommodate an ultrasound imaging probe (not shown) having an F-number = 0.85 in the major diameter and an F-number = 0.98 in the notch.

[0008]

[0008] Based on bench experiments and modeling, an initial set of therapy transducer excitation parameters (3 cycles / pulse, 750 Vpp, 500 Hz PRF (pulse repetition frequency)) was selected for testing on dogs with this transducer. This excitation sequence generated a non-linear focal pressure waveform with peak negative and positive pressures of approximately 25 MPa and 100 MPa in water. Since this sequence parameter was not optimized for bubble cloud formation, we define this sequence and its variations as a standard, i.e., non-optimized, sequence.

Summary of the Invention

Problems to be Solved by the Invention

[0009]

[0009] This standard excitation sequence and its variations were used to treat approximately 30 dog subjects to establish feasibility, dosing (cumulative number of pulses), and treatment implementation guidelines. Then, an additional 10 dog subjects were treated in a confirmatory study. These studies yielded significantly effective results, but in 2 of the 10 subjects in the confirmatory experiment, obvious microtrauma (subclinical fibrosis) was observed in the rectus abdominis muscle in front of the focus. Therefore, it was concluded that it is necessary to develop a histotripsy pulse sequence that supplies energy more efficiently to improve the safety profile. As the transducer evolves to penetrate deeper into the tissue through skeletal anatomical obstacles, the need to improve the efficiency of histotripsy seems to become more important.

Means for Solving the Problems

[0010]

[0010] The increased efficiency, which translates into reduced pre-focus heating, is achieved with a relatively large F-number ( This is essential when targeting soft tissue deep below the skin surface through skeletal anatomical obstacles, requiring ultrasound therapy transducers with F-numbers >0.8. Optimized sequences for improved histotripsy homogenization of soft tissue have been developed to reduce the likelihood of pre-focal burns by optimizing sequence efficiency. The improved efficiency of optimized excitation sequences increases the likelihood of initiating the generation of histotripsy bubble clouds within the tissue and reduces the occurrence of dissipating bubble clouds as they translate through the tissue. Additionally, optimized sequences can be designed to selectively ablate fibrous or less dense tissues while protecting critical internal structures with higher fibroelasticity, such as neurovascular structures.

[0011]

[0011] An efficient optimized sequence for a large F-number converter is The system is characterized by an initial pulse designed to generate at least one acoustically generated nucleus (bubble), followed by an impact scattering pulse (hereafter referred to as scattering pulse or scattering pressure waveform) after an optimized delay time that allows the shock wave to impinge on the first bubble to generate a bubble cloud. Subsequent scattering pulses may follow with similarly optimized timing to further maintain the bubble cloud effect. Note that pulse and pressure waveform are used interchangeably in this application.

[0012]

[0012] A method of treating tissue with ultrasonic energy includes: The method includes the steps of: delivering an initial pressure waveform from a pressure transducer into tissue, the initial pressure waveform being configured to generate at least one gas bubble in the tissue; and delivering a scattering pressure waveform to at least one The method includes the steps of: delivering an ultrasound therapy transducer into at least one bubble during the bubble's lifetime; and generating cavitation nuclei in the vicinity of the at least one bubble with a scattering pressure waveform.

[0013]

[0013] In some embodiments, the scattered pressure waveform is supplied from 5 μs to within 200 μs from the initial pressure waveform. within 200 μs.

[0014] In one embodiment, the method further comprises repeating the steps of supplying an initial pressure waveform and supplying a scattered pressure waveform until treatment of the tissue is complete. until treatment of the tissue is complete.

[0014]

[0015] In one embodiment, the pressure amplitude and / or number of cycles of the initial pressure waveform is minimized to reduce heating of the tissue. (cycles)

[0016] In another embodiment, the peak pressure value of the scattered pressure waveform is of an amplitude sufficient to create additional cavitation nuclei in the focal region. in the focal region.

[0015]

[0017] In an alternative embodiment, the pressure amplitude and / or number of cycles of the scattered pressure waveform is minimized to reduce heating of the tissue. to reduce heating of the tissue.

[0018] In some embodiments, the method further comprises, after the step of supplying the scattered pressure waveform, supplying a second scattered pressure waveform towards at least one bubble and cavitation nucleus. towards at least one bubble and cavitation nucleus.

[0016]

[0019] In some embodiments, the second scattered pressure waveform is supplied from 5 μs to within 1 s from the scattered pressure waveform. within 1 s.

[0020] In another embodiment, the method further comprises supplying additional scattered pressure waveforms without supplying additional initial pressure waveforms until at least one bubble and / or cavitation nucleus no longer remains in the tissue. until at least one bubble and / or cavitation nucleus no longer remains in the tissue.

[0017]

[0021] In some embodiments, additional scattered pressure waveforms are provided every 5 μs to 1 s. Supplied.

[0022] In one embodiment, a pulse sequence comprising an initial pressure waveform and a scattered pressure waveform has a sequence PRF in the range of 1 to 5000 Hz. Has.

[0018]

[0023] In other embodiments, the scattered pressure waveform supplies less energy to the intervening tissue than the initial pressure waveform. To the tissue.

[0024] In one embodiment, the initial pressure waveform and the scattered pressure waveform have substantially the same pressure amplitude. In another embodiment, the pressure amplitude of the scattered pressure waveform is smaller than the pressure amplitude of the initial pressure waveform. In an alternative embodiment, the pressure amplitude of the scattered pressure waveform is larger than the pressure amplitude of the initial pressure waveform. Has.

[0019]

[0025] A method of treating tissue with ultrasonic energy, the method comprising the steps of: transmitting an initial pressure waveform from an ultrasonic therapy transducer into the tissue, the initial pressure waveform being configured to generate at least one bubble in the tissue; and transmitting a scattered pressure waveform from the ultrasonic therapy transducer into at least one bubble during the lifetime of the at least one bubble, the scattered pressure waveform being configured to be an impact focus pressure waveform having an impact positive pressure half cycle and an impact negative pressure half cycle in the tissue, the impact positive pressure half cycle colliding with, scattering from, and inverting at least one bubble and being configured to constructively interfere with the impact negative pressure half cycle to form a negative pressure half cycle waveform; and generating cavitation nuclei in the vicinity of the at least one bubble by an impact scattering mechanism between the positive pressure half cycle waveform and the at least one bubble. Steps.

[0020]

[0026] A method of supplying ultrasonic energy to tissue, the method comprising at least one Supplying an initial pulse configured to provide a peak negative pressure of at least 5 MPa to generate bubbles from an ultrasonic therapy transducer; supplying a first scattered pulse into at least one bubble within 5 μs to 200 μs from the initial pulse; and generating a cavitation cloud of nuclei in the vicinity of at least one bubble by an impact scattering mechanism between the first scattered pulse and the at least one bubble.

[0021]

[0027] An ultrasonic therapy transducer and an ultrasonic therapy generator coupled to the ultrasonic therapy transducer wherein the ultrasonic therapy generator is configured to drive the ultrasonic therapy transducer to supply an initial pressure waveform into tissue to generate at least one bubble in the tissue, and the ultrasonic therapy generator is further configured to drive the ultrasonic therapy transducer to supply a first scattered pressure waveform into at least one bubble within 5 μs to 200 μs from the initial pressure waveform to generate cavitation nuclei in the vicinity of at least one bubble, and an ultrasonic therapy system comprising the ultrasonic therapy generator is provided.

[0022]

[0028] In some embodiments, the peak pressure value of the first scattered pulse is at least 1 pressure amplitude sufficient to generate cavitation nuclei in the vicinity of at least one bubble.

[0029] In other embodiments, the ultrasonic therapy generator is further configured to drive the ultrasonic therapy transducer to supply at least one additional scattered pulse to generate cavitation nuclei in the vicinity of at least one bubble after the first scattered pressure waveform.

[0023]

[0030] In one embodiment, the ultrasonic therapy generator starts the initial and scattered pressure waveforms A controller configured to generate a complex waveform for this purpose, a high-voltage power supply coupled to the controller, an amplifier configured to receive and amplify the complex waveform from the controller and the high-voltage power supply, and a matching network configured to match the impedance of the ultrasonic therapy transducer with the amplifier are further provided.

[0024]

[0031] A method of treating tissue with ultrasonic energy, comprising the steps of generating at least one bubble in the tissue by ultrasonic energy, colliding a shock focus pressure waveform with at least one bubble, and forming cavitation nuclei in the vicinity of at least one bubble. A method is provided that includes the steps of generating at least one bubble in the tissue by ultrasonic energy, colliding a shock focus pressure waveform with at least one bubble, and forming cavitation nuclei in the vicinity of at least one bubble.

[0025]

[0032] In one embodiment, the step of colliding is performed during the lifetime of at least one bubble. During the lifetime of at least one bubble.

[0033] In another embodiment, the step of colliding is performed within 5 μs to 200 μs from the step of generating. Within 5 μs to 200 μs from the step of generating.

[0026]

[0034] In an alternative embodiment, the step of forming cavitation nuclei is achieved by a shock scattering mechanism between the shock focus pressure waveform and at least one bubble. By a shock scattering mechanism between the shock focus pressure waveform and at least one bubble.

[0035] The novel features of the present invention are described in detail in the following claims. The features and advantages of the present invention will be better understood by referring to the following detailed description of exemplary embodiments in which the principles of the present invention are utilized and the accompanying drawings. The features and advantages of the present invention will be better understood by referring to the following detailed description of exemplary embodiments in which the principles of the present invention are utilized and the accompanying drawings.

Brief Description of the Drawings

[0027]

Figure 1

[0036] A diagram showing an ultrasonic therapy transducer according to one embodiment.

Figure 2

[0037] Figure 2a is a diagram of the start of bubble cloud generation in water. Figure 2b is a diagram of the start of bubble cloud generation in water. Figure 2c is a diagram of the start of bubble cloud generation in water.

Figure 3

[0038] It is a diagram showing the focal pressure waveform according to an embodiment.

Figure 4

[0039] Figure 4a is a conceptual diagram showing shock scattering. Figure 4b is a conceptual diagram showing shock scattering. Figure 4c is a conceptual diagram showing shock scattering. Figure 4d is a conceptual diagram showing shock scattering. Figure 4e is a conceptual diagram showing shock scattering.

Figure 5a

[0040] It is a diagram showing an embodiment of a pulse sequence including an initial pressure waveform and a scattered pressure waveform for supplying ultrasonic waves to tissue.

Figure 5b

Figure 5c

Figure 6

[0041] It is a diagram of a system configured to supply a suitable sequence for treating tissue by cavitation.

Best Mode for Carrying Out the Invention

[0028] Generation of Cavitation

[0042] Cavitation nuclei providing important background information for the development of suitable embodiments And some principles of bubble cloud formation are disclosed herein. Cavitation nuclei are individual bubbles formed as a result of the supply of low pressure to tissue. A bubble cloud consists of a dense group of cavitation nuclei generated at or near the focal point of the transducer. The formation of cavitation nuclei (bubble clouds) is an essential element for both histotripsy therapies.

[0029]

[0043] Possibility of Formation of Cavitation Nuclei

[0044] Cavitation nuclei can be formed in tissue when the tissue is subjected to a peak negative (peak rarefaction) pressure that is near or exceeds the pressure level required to generate at least one cavitation nucleus (bubble). This level is variable and depends on multiple factors such as the characteristics of the tissue (structure and composition, dissolved gas content, and presence of impurities), the shape of the transducer (focal length and f-number), and the sequencing method (PRF; number of pulses (cycles)). The number of cavitation nuclei formed from a single acoustic pulse is thought to be directly related to the peak negative pressure achieved. When the tissue is subjected to a peak negative (peak rarefaction) pressure that is near or exceeds the pressure level required to generate at least one cavitation nucleus (bubble), cavitation nuclei can be formed within the tissue. This level is variable and depends on multiple factors such as the characteristics of the tissue (structure and composition, dissolved gas content, and presence of impurities), the shape of the transducer (focal length and f-number), and the sequencing method (PRF; number of pulses (cycles)). It should be noted that the number of cavitation nuclei formed from a single acoustic pulse is thought to be directly related to the peak negative pressure achieved.

[0030]

[0045] Changes in cavitation over time

[0046] Cavitation nuclei grow to a maximum size and then collapse. The time-course of cavitation, the process of bubble generation, growth, and then collapse, depends on the medium (i.e., the type of tissue). The time-course of cavitation in a liquid takes longer than in gelatin and soft tissue. Table 1 compares the times for the onset, growth, and collapse of cavitation in water and in gelatin. Figures 2a - 2c are diagrams showing the typical time-course of cavitation. Figure 2a shows the onset of cavitation 208 in a medium such as tissue, water, or gelatin. Figure 2b illustrates the growth of cavitation 208 to its maximum size, where the cavitation bubbles coalesce within the focal region. Figure 2c shows the collapse of cavitation 208, where almost all of the cavitation bubbles have collapsed and disappeared. When the tissue is subjected to a peak negative (peak rarefaction) pressure that is near or exceeds the pressure level required to generate at least one cavitation nucleus (bubble), cavitation nuclei can be formed within the tissue. This level is variable and depends on multiple factors such as the characteristics of the tissue (structure and composition, dissolved gas content, and presence of impurities), the shape of the transducer (focal length and f-number), and the sequencing method (PRF; number of pulses (cycles)). It should be noted that the number of cavitation nuclei formed from a single acoustic pulse is thought to be directly related to the peak negative pressure achieved.

[0031]

Table 1

[0032]

[0047] Shock scattering mechanism for acoustic shock and bubble cloud formation

[0048] When an acoustic waveform travels through a medium, the positive (compression) half-cycle is the negative (rarefaction) half-cycle It moves faster. Due to this effect, the pressure waveform becomes non-linear, causing a sharp transition between the positive half-cycle and the negative half-cycle of the pressure waveform. As the slope of this transition increases, the pressure amplitude of the positive half-cycle increases, and the pressure waveform is said to become more non-linear or "impacted". This can be referred to as an impact focus pressure waveform. The level of non-linearity depends on the pressure amplitude of the pressure waveform and the distance propagated within the medium. Figure 3 illustrates an example of an impact focus pressure waveform with positive and negative half-cycles. It should be understood that the impact focus pressure waveform can include multiple positive and negative half-cycles. and the negative half-cycle. As the slope of this transition increases, the pressure amplitude of the positive half-cycle increases, and the pressure waveform is said to become more non-linear or "impacted". This can be referred to as an impact focus pressure waveform. The level of non-linearity depends on the pressure amplitude of the pressure waveform and the distance propagated within the medium. Figure 3 illustrates an example of an impact focus pressure waveform with positive and negative half-cycles. It should be understood that the impact focus pressure waveform can include multiple positive and negative half-cycles.

[0033]

[0049] According to the present disclosure, cavitation nuclei can be formed within tissue as a result of shock scattering. Shock scattering occurs when the positive pressure half-cycle of an acoustic waveform is reflected or scattered by existing bubbles and then inverted so that the positive pressure half-cycle of the shock is additively combined with the negative pressure half-cycle of the incident acoustic waveform. If the generated combined new negative pressure half-cycle is large enough (i.e., greater than the threshold specific to the tissue or medium of interest, for example, greater than 5 MPa peak negative pressure), additional cavitation nuclei will occur in the vicinity of any existing nuclei. This process is repeated until the pressure of the combined new negative pressure half-cycle becomes insufficient to generate new cavitation nuclei. According to the present disclosure, cavitation nuclei can be formed within tissue as a result of shock scattering. Shock scattering occurs when the positive pressure half-cycle of an acoustic waveform is reflected or scattered by existing bubbles and then inverted so that the positive pressure half-cycle of the shock is additively combined with the negative pressure half-cycle of the incident acoustic waveform. If the generated combined new negative pressure half-cycle is large enough (i.e., greater than the threshold specific to the tissue or medium of interest, for example, greater than 5 MPa peak negative pressure), additional cavitation nuclei will occur in the vicinity of any existing nuclei. This process is repeated until the pressure of the combined new negative pressure half-cycle becomes insufficient to generate new cavitation nuclei.

[0034]

[0050] Figures 4a - 4e are conceptual diagrams showing the shock scattering method of histotripsy therapy. The upper frame illustrates existing bubbles 408 and the positive pressure half-cycle 410 of the shock, and the lower frame illustrates the ultrasonic pulse pressure distribution 412 (the horizontal line 414 indicates zero pressure amplitude). The existing bubbles 408 can be formed by an initial pulse or sequence as described above. Then, according to one embodiment of the shock scattering method, the shock pressure waveform can be sent towards the bubbles 408 during the lifetime of the bubbles.

[0035]

[0051] In Figures 4a - 4e, the incident shock pressure waveform 412 is indicated by arrow 416 As shown, it propagates from left to right towards the existing bubble 408. The incident shock pressure waveform can be supplied towards and into the bubble during the lifetime of the bubble, and the incident shock pressure waveform interferes with the bubble. In FIG. 4a, a single existing bubble 408 already generated in the tissue as described above is illustrated. As shown in FIG. 4b, the size of this bubble increases due to the initial negative pressure half-cycle of the incident shock pressure waveform. In FIG. 4c, the shock positive pressure half-cycle 410 of the incident shock pressure waveform 412 collides with the bubble 408, and the positive pressure half-cycle begins to scatter. The scattered shock positive pressure half-cycle is reversed and constructively interferes with the shock negative pressure half-cycle 413 of the incident shock pressure waveform 412 to produce a transient, large-amplitude negative pressure half-cycle 418 (shown as the circular dashed line 418 in FIGS. 4c-4e) that generates additional cavitation nuclei 420 near or behind the bubble 408. The negative pressure half-cycle 418 propagates from right to left as indicated by the arrow 422. As shown in FIG. 4e, additional cavitation nuclei 420 are generated in the opposite direction of the shock positive pressure waveform 410 until the negative pressure half-cycle 418 becomes smaller than the threshold for cavitation nucleus formation. This process can be repeated by a continuous shock pressure waveform sent towards and into the existing bubble 408 and the additional cavitation nuclei 420.

[0036]

[0052] The cavitation nuclei formed by this shock scattering method tend to grow towards the therapy transducer, and the range depends on the number of high-pressure cycles (number of high-pressure cycles) and the pulse repetition frequency (PRF) of the pulse (waveform). Minimizing the number of cycles (number of cycles) of the shock waveform or reducing the sequence PRF is an effective method for reducing the length of the bubble cloud and the time-averaged intensity and thus the thermal dose.

[0037]

[0037]

[0053] Improved bubble cloud formation using shock scattering

[0054] The key element of the preferred histotripsy excitation sequence described in this disclosure The elements are: (1) a first pulse of a sequence, referred to as an initial pulse or an initial pressure waveform, configured to form at least one bubble in tissue; (2) a second pulse of the sequence, referred to as a scattered pulse or a scattered pressure wave form, configured to generate cavitation nuclei in the vicinity of at least one bubble by shock scattering; and (3) a specific delay time between the initial pulse and the scattered pulse. The initial pulse must be configured to generate at least one bubble in the target tissue. This can be achieved, as described above, by a conventional histotripsy initial pulse or other ultrasonic techniques such as HIFU or boiling histotripsy that can induce bubble formation in tissue by boiling. The scattered pulse must have a peak pressure wave high enough for shock scattering formation of cavitation nuclei. In some embodiments, the delay time between these pulses can range from 5 μs to 200 μs. In another embodiment, the delay time between these pulses can range from 5 μs to 40 ms. In another embodiment, the delay time between these pulses can range from 5 μs to 1 s.

[0038]

[0055] For these pulses, the initial pulse must be configured to generate at least one bubble in the target tissue. This can be achieved, as described above, by a conventional histotripsy initial pulse or other ultrasonic techniques such as HIFU or boiling histotripsy that can induce bubble formation in tissue by boiling. The scattered pulse must have a peak pressure wave high enough for shock scattering formation of cavitation nuclei. In some embodiments, the delay time between these pulses can range from 5 μs to 200 μs. In another embodiment, the delay time between these pulses can range from 5 μs to 40 ms. In another embodiment, the delay time between these pulses can range from 5 μs to 1 s. In another embodiment, the pressure amplitude and / or the number of periods (cycles) used in the initial pulse can be increased or decreased. Increasing the pressure amplitude and / or the number of periods in the initial pulse can increase the likelihood of generating cavitation in the tissue. However, this can also increase the time-averaged intensity and heat dose supplied to the tissue, as well as the extent of the bubble cloud. Decreasing the pressure amplitude and / or the number of periods of the initial pulse decreases the intensity and heat dose of the sequence, but may limit the sequence's ability to generate and / or maintain cavitation.

[0039]

[0056] In another embodiment, the pressure amplitude and / or the number of periods (cycles) used in the initial pulse can be increased or decreased. Increasing the pressure amplitude and / or the number of periods in the initial pulse can increase the likelihood of generating cavitation in the tissue. However, this can also increase the time-averaged intensity and heat dose supplied to the tissue, as well as the extent of the bubble cloud. Decreasing the pressure amplitude and / or the number of periods of the initial pulse decreases the intensity and heat dose of the sequence, but may limit the sequence's ability to generate and / or maintain cavitation. In another embodiment, the pressure amplitude and / or the number of periods (cycles) used in the scattered pulse can be increased or decreased. Increasing the pressure amplitude and / or the number of periods in the scattered pulse can increase the likelihood of generating cavitation in the tissue. However, this can also increase the time-averaged intensity and heat dose supplied to the tissue, as well as the extent of the bubble cloud. Decreasing the pressure amplitude and / or the number of periods of the scattered pulse decreases the intensity and heat dose of the sequence, but may limit the sequence's ability to generate and / or maintain cavitation.

[0040]

[0057] In another embodiment, the pressure amplitude and / or the number of periods (cycles) used in the scattered pulse can be increased or decreased. Increasing the pressure amplitude and / or the number of periods in the scattered pulse can increase the likelihood of generating cavitation in the tissue. However, this can also increase the time-averaged intensity and heat dose supplied to the tissue, as well as the extent of the bubble cloud. Decreasing the pressure amplitude and / or the number of periods of the scattered pulse decreases the intensity and heat dose of the sequence, but may limit the sequence's ability to generate and / or maintain cavitation. The number of pulses can be increased or decreased. Increasing the pressure amplitude and / or the number of cycles in the scattered pulse can increase the likelihood of causing cavitation within the tissue. However, this can also increase the time-averaged intensity delivered to the tissue and the thermal dose delivered to the tissue, as well as the extent of the bubble cloud. Decreasing the pressure amplitude and / or the number of cycles of the scattered pulse decreases the intensity and thermal dose of the sequence, but may limit the ability of the sequence to generate and / or maintain cavitation.

[0041]

[0058] Assuming that the sequence PRF is such that the time-averaged intensity and the resulting thermal dose are kept within safe limits it may be about 5000 Hz. The preferred range depends on the tissue being treated. Higher PRFs are recommended for more dense and fibrous tissues, and lower PRFs are recommended for less dense tissues and for the protection of tissues that are more fibrous and often critical. Selectively treating tissues based on their stiffness by histotripsy can be a promising design and performance consideration for sequence deployment.

[0042]

[0059] In some embodiments, additional scattered pulses having a smaller pressure amplitude and / or number of cycles (compared to the pressure amplitude and / or number of cycles of the initial pulse) can be applied to decrease the intensity and thermal dose of the sequence without decreasing the sequence PRF.

[0043]

[0060] Figures 5a - 5c show cavitation within the tissue during the shock scattering method of histotripsy therapy Three different embodiments of the initial and scattered pulse sequences of histotripsy that can be used to generate and maintain a - sion are shown. In FIG. 5a, an initial pulse 524a with a pressure waveform configured to form at least one bubble within the tissue can be delivered into the tissue. After a specific delay time has elapsed, a scattered pulse 526a can be delivered toward and into at least one bubble formed by the initial pulse 524a within the tissue. In some embodiments, the specific delay time between these pulses can range from 5 μs to 200 μs. In another embodiment, the delay time between these pulses can range from 5 μs to 40 ms. In another embodiment, the delay time between these pulses can range from 5 μs to 1 s. As it moves through the tissue, the scattered pulse 526a becomes an impact focus pressure waveform, and at least one positive pressure half - cycle of the scattered pulse collides with at least one bubble and is scattered by at least one bubble. The positive pressure half - cycle of the scattered pulse is inverted and constructively interferes with the negative pressure half - cycle of the scattered pulse to produce a transient, large - amplitude negative pressure half - cycle that generates additional cavitation nuclei behind at least one bubble generated by the initial pulse. These pairs of initial and scattered pulse sequences (pulse pairs 524b / 526b, 524c / 526c, 524d / 526d, ···, 524n / 526n) as illustrated in FIG. 5a can be repeated to achieve the desired ablation effect in the tissue from the resulting cavitation. In this embodiment, the pressure amplitudes and / or the number of cycles of both the initial and scattered pulses can be the same or substantially the same.

[0044]

[0061] FIG. 5b shows that the pressure amplitudes of the scattered pulses 524a - 524n are of the corresponding initial pulses Another embodiment is illustrated that is similar to the embodiment of FIG. 5a, except that it is smaller than the pressure amplitude. By the principle of the shock, the peak positive wave is amplified compared to the peak negative wave, and thus the pressure amplitude used to generate the scattered pulse can be reduced while still supplying the negative pressure required by the reflected and inverted positive wave. This embodiment is more efficient than the embodiment of FIG. 5a, and the amount of energy administered into the tissue is less. However, in another embodiment, the pressure amplitude of the scattered pulse may be greater than the pressure amplitude of the corresponding initial pulse.

[0045]

[0062] FIG. 5c shows another embodiment that is a variation of the embodiments of FIGS. 5a and 5b. In this embodiment, after the initial pulse 524a, after a specific delay time, the scattered pulse 526a follows. Instead of another pair of initial / scattered pulses following as in FIG. 5a, after the scattered pulse 526a, after a second delay time, another scattered pulse 526b follows. To maintain the effect of the bubble cloud (e.g., pulses 526c, 526d) and achieve the desired ablation effect in the tissue from the resulting cavitation, a plurality of scattered pulses can be supplied into the tissue after an appropriate delay time. The pressure amplitude of the scattered pulse may be smaller than, equal to, or larger than the pressure amplitude of the initial pulse. In some embodiments, the delay time for subsequent scattered pressure waveforms may be different from the delay time used for the first scattered pressure. For example, the first scattered pressure waveform may be supplied within 5 μs to 200 μs from the initial pressure waveform, but subsequent scattered pressure waveforms may be supplied within 5 μs to 200 μs, 5 μs to 40 ms, or 5 μs to 1 s. If cavitation needs to be regenerated in the tissue, the sequence may be restarted with another pair of initial / scattered pulses as illustrated by 524n / 526n in FIG. 5c. Similar to the embodiment of FIG. 5b, this embodiment also uses scattered pulses with a smaller pressure amplitude, but fewer initial pulses are used. As a result of this embodiment, the energy dose administered to the tissue is the lowest among the embodiments of FIGS. 5a - 5c. This method has the potential to significantly reduce the dose (e.g., by up to 50%) compared to conventional histotripsy sequences.

[0046]

[0063] Decrease or disappearance of the amplitude of the initial pulse when the bubble cloud is once established

[0064] The purpose of the initial / scattered pair is to generate cavitation in the tissue by shock scattering Once the bubble cloud has been generated, the initiation pulse may no longer be needed to maintain the bubble cloud effect if the focal point is not shifted. In this case, the system may be designed to first generate the bubble cloud with an initiation / scattering pair, followed by a scattering pulse of smaller pressure amplitude (compared to that of the initiation pulse) until the focal point is shifted. At this point, the process is repeated.

[0047]

[0065] Design of system software and hardware to enable sequence deployment

[0066] The Histotripsy system and generator are based on the ultrasound pulse sequence described herein. The system is configured to generate highly complex waveforms to support a variety of therapeutic sequences. A simplified block diagram of the system 600 is shown in Figure 6. The main components of the system are a computer / controller 602, a USB-to-serial converter 604, a microcontroller 606, an FPGA (field programmable gate array) 608, a high voltage controller and power supply 610, an amplifier 612, and a therapy transducer 614.

[0048]

[0067] All control of the generator is performed by a computer / controller 602 (e.g., a standard PC ) and communicating with the generator via USB serial communication 604.

[0049]

[0068] The system 600 receives multiple sets of different drive parameters and loops them. configured to provide the user with the ability to generate a wide range of custom sequences that can be set differently for each generated pulse for all parameters (PRF, voltage amplitude, number of cycles, number of pulses per set, frequency, transducer element channels enabled, and delay time). The delay time between pulses can be specified by the PRF of the parameter set or by specifying zero as the number of cycles per pulse.

[0050]

[0069] For overall voltage amplitude control, the high voltage level is appropriately changed through the microcontroller 606 and the high voltage controller 610. This method cannot be used for dynamic voltage amplitude changes between two pulses because it takes too long for all the capacitors on the high voltage line to discharge. For dynamic voltage amplitude changes between pulses, PWM (pulse width modulation) is used in the FPGA 608 where the duty cycle of the pulse is modulated to generate the desired pulse voltage and the resulting pressure amplitude.

[0051]

[0070] Histotripsy service tool

[0071] The histotripsy service tool is an application that runs on any PC and is used to control the system. The histotripsy service tool can start / stop therapy, set and read the high voltage level and therapy parameters (PRF, number of cycles, duty ratio, available channels, delay, etc.), and set and read items related to other services and maintenance.

[0052]

[0072] USB - serial converter

[0073] The USB - serial converter 604 converts the USB connection to serial for communicating with the microcontroller 606 .

[0053]

[0074] Microcontroller

[0075] The microcontroller 606 communicates with the computer / controller 602 (histotrip service tool), and performs operations such as setting / reading operation parameters, starting / stopping therapy, etc. The microcontroller 606 can use the internal flash memory to store all parameters. The microcontroller communicates with all drive parameters of the FPGA 608 necessary to generate complex pulses. The microcontroller also communicates with the high-voltage controller and power supply 610 using serial communication to set / read the appropriate level of the drive voltage.

[0054]

[0076] FPGA

[0077] The FPGA 608 receives information from the microcontroller 606 and generates a complex pulse sequence necessary to drive the amplifier 61 2. Since it is essential that the speed of the pulses be measured in 10 ns increments, the FPGA is operable at a 100 MHz clock.

[0055]

[0078] High-voltage controller and power supply

[0079] The high-voltage controller and power supply 610 receive instructions from the microcontroller 606 regarding the level of the DC voltage that needs to be supplied to the amplifier circuit in order to obtain an appropriate voltage amplitude level at the output of the amplifier.

[0056]

[0080] Amplifier

[0081] The amplifier 612 receives the pulses generated by the FPGA and is supplied with high voltage from the high-voltage controller and power supply. The amplifier 612 generates a high-voltage amplitude pulse that is supplied to the therapy transducer 614 through a matching network member that appropriately matches the impedance of the therapy transducer to the impedance of the amplifier. It is necessary to use a number of capacitors capable of storing sufficient energy to meet the peak current requirements during the generation of the high-voltage amplitude pulse.

[0057]

[0082] The data structures and codes described in the "Best Mode for Carrying Out the Invention" section are typically stored in a computer-readable storage medium, which may be any device or medium capable of storing code and / or data for use by a computer system. The computer-readable storage medium may include, but is not limited to, volatile memory, or non-volatile memory, or magnetic and optical storage devices such as disk drives or magnetic tapes or CDs (compact discs) or DVDs (digital versatile discs or digital video discs), or other media capable of storing computer-readable storage media known or later developed.

[0058]

[0083] The methods and processes described in the "Best Mode for Carrying Out the Invention" section can be embodied as code and / or data stored in a computer-readable storage medium as described above. When a computer system reads and executes the code and / or data stored in the computer-readable storage medium, the computer system executes the methods and processes embodied as the data structures and code and stored within the computer-readable storage medium.

[0059]

[0084] Furthermore, the methods and processes described above may be included in hardware modules. For example, the hardware modules may include, but are not limited to, application-specific integrated circuit (ASIC) chips, field-programmable gate arrays (FPGAs), and other programmable logic devices known or later developed. When the hardware module is activated, the hardware module implements the methods and processes included within the hardware module.

[0060]

[0085] The examples and illustrations included in this specification are for illustrative purposes and not for purposes of limitation <, shows a specific embodiment in which the subject matter may be practiced. As described above, other embodiments are available and can be derived such that structural and logical substitutions and changes may be made without departing from the scope of the present disclosure. Such embodiments of the subject matter of the present invention, if more than two are actually disclosed, are herein individually or collectively referred to by the term "invention" without any intention of voluntarily limiting the scope of this application to any single invention or inventive concept for convenience only. Thus, although specific embodiments have been illustrated and described herein, any configuration that is expected to achieve the same purpose may be substituted for the specific embodiments shown. The present disclosure is intended to cover any and all adaptations or variations of various embodiments. Combinations of the above-described embodiments and other embodiments not specifically described herein will become apparent to those skilled in the art upon review of the above description.

Claims

1. 1. A method of treating tissue with ultrasound energy, comprising: delivering an initial pressure waveform from an ultrasound therapy transducer into tissue, the initial pressure waveform configured to generate at least one gas bubble in the tissue; providing a scattering pressure waveform from the ultrasound therapy transducer into the at least one bubble during the lifetime of the at least one bubble; generating cavitation nuclei in the vicinity of the at least one bubble with the scattering pressure waveform; A method for providing the above.

2. 2. The method of claim 1, wherein the scattering pressure waveform is delivered within 5 μs to 200 μs of the initiation pressure waveform.

3. 10. The method of claim 1, further comprising repeating the steps of delivering the initiation pressure waveform and delivering the scattering pressure waveform until treatment of the tissue is complete.

4. 10. The method of claim 1, wherein the pressure amplitude and / or number of cycles of the initial pressure waveform are minimized to reduce heating of tissue.

5. 10. The method of claim 1, wherein the peak-to-peak pressure value of the scattering pressure waveform is of sufficient amplitude to cause additional cavitation nuclei in a focal region.

6. 10. The method of claim 1, wherein the pressure amplitude and / or number of cycles of the scattering pressure waveform are minimized to reduce tissue heating.

7. 10. The method of claim 1, further comprising, after the step of applying the scattering pressure waveform, applying a second scattering pressure waveform toward the at least one bubble and the cavitation nuclei.

8. 8. The method of claim 7, wherein the second scattering pressure waveform is delivered within 5 μs to 1 s of the scattering pressure waveform.

9. 8. The method of claim 7, further comprising the step of applying additional scattering pressure waveforms without applying additional initiation pressure waveforms until the at least one bubble and / or the cavitation nuclei no longer remain within the tissue.

10. 10. The method of claim 9, wherein the additional scattering pressure waveform is delivered every 5 μs to 1 s.

11. 10. The method of claim 1, wherein the pulse sequence comprising the initiation pressure waveform and the scattering pressure waveform has a sequence PRF in the range of 1 to 5000 Hz.

12. The method of claim 1 , wherein the scattering pressure waveform delivers less energy to intervening tissue than the initiation pressure waveform.

13. The method of claim 1 , wherein the initiation pressure waveform and the scattering pressure waveform have substantially similar pressure amplitudes.

14. The method of claim 1 , wherein the pressure amplitude of the scattering pressure waveform is less than the pressure amplitude of the initiation pressure waveform.

15. The method of claim 1 , wherein a pressure amplitude of the scattering pressure waveform is greater than a pressure amplitude of the initiation pressure waveform.

16. 1. A method of treating tissue with ultrasound energy, comprising: delivering an initial pressure waveform from an ultrasound therapy transducer into tissue, the initial pressure waveform configured to generate at least one gas bubble in the tissue; transmitting a scattering pressure waveform from the ultrasound therapy transducer into the at least one bubble during a lifetime of the at least one bubble, the scattering pressure waveform configured to result in a shock focal pressure waveform in the tissue having a shock positive pressure half cycle and a shock negative pressure half cycle, the shock positive pressure half cycle configured to impinge on the at least one bubble, scatter, invert, and constructively interfere with the shock negative pressure half cycle to form a negative pressure half cycle waveform; generating cavitation nuclei in the vicinity of the at least one bubble by an impact scattering mechanism between the positive pressure half-period waveform and the at least one bubble; A method for providing the above.

17. 1. A method of delivering ultrasonic energy to tissue, comprising: providing an initial pulse from an ultrasound therapy transducer configured to provide a peak negative pressure of at least 5 MPa to generate at least one gas bubble within the tissue; delivering a first scattering pulse into the at least one bubble within 5 μs to 200 μs of the initial pulse; generating a cavitation cloud of nuclei in the vicinity of the at least one bubble by an impact scattering mechanism between the first scattering pulse and the at least one bubble; A method for providing the above.

18. an ultrasound therapy transducer; an ultrasound therapy generator coupled to the ultrasound therapy transducer, the ultrasound therapy generator configured to drive the ultrasound therapy transducer to deliver an initial pressure waveform into tissue to generate at least one gas bubble in the tissue, the ultrasound therapy generator further configured to drive the ultrasound therapy transducer to deliver a first scattering pressure waveform into the at least one gas bubble within 5 μs to 200 μs of the initial pressure waveform to generate cavitation nuclei in a vicinity of the at least one gas bubble; An ultrasound therapy system comprising:

19. 20. The system of claim 18, wherein the first scattering pulse has a pressure amplitude sufficient to generate cavitation nuclei in the vicinity of the at least one bubble.

20. 20. The system of claim 18, wherein the ultrasound therapy generator is further configured to drive the ultrasound therapy transducer to provide at least one additional scattering pulse after the first scattering pressure waveform to generate cavitation nuclei in the vicinity of the at least one bubble.

21. 20. The system of claim 18, wherein the ultrasound therapy generator comprises: a controller configured to generate a complex waveform to initiate the initiation and scattering pressure waveforms; a high voltage power supply coupled to the controller; an amplifier configured to receive and amplify the complex waveform from the controller and the high voltage power supply; a matching network configured to match the impedance of the ultrasound therapy transducer to the amplifier; The system further comprises:

22. 1. A method of treating tissue with ultrasound energy, comprising: generating at least one gas bubble in the tissue with ultrasonic energy; impinging an impact focal pressure waveform on the at least one bubble; forming a cavitation nucleus in the vicinity of the at least one bubble; A method for providing the above.

23. 23. The method of claim 22, wherein the impacting step is performed during the life of the at least one bubble.

24. 24. The method of claim 23, wherein the impinging step is performed within 5 μs to 200 μs of the generating step.

25. 23. The method of claim 22, wherein the step of forming cavitation nuclei is accomplished by an impact scattering mechanism between the impact focal pressure waveform and the at least one gas bubble.

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