Optimized Histotripsy Excitation Sequence for Bubble Cloud Formation Using Impact Scattering

Abstract

A method and device for generating cavitation in tissue is provided. In one embodiment, a method of impact scattering histotripsy therapy includes delivering an initiation pressure waveform from an ultrasound therapy transducer into tissue, the initiation pressure waveform configured to generate 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 lifetime of the at least one bubble; and generating cavitation nuclei in the vicinity of the at least one bubble with the scattering pressure waveform. The scattering pressure waveform may be delivered during the lifetime 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. Systems for impact scattering histotripsy therapy are also contemplated.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

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

[0002]

[0002] All publications and patent applications mentioned in this specification are hereby incorporated by reference 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 relates generally to the treatment of tissue with cavitation caused by ultrasound therapy. [Background technology]

[0004] Histotripsy or Pulsed Ultrasound Cavitation Therapy is a technique in which short, intense bursts of acoustic energy induce controlled cavitation (the formation of microbubbles or bubble clouds) within a focal region. The vigorous foaming and collapse of these microbubbles automatically homogenizes the cells and tissue structures within the focal region, an end result that is significantly different from the coagulation necrosis characteristic of thermal ablation. To work within the non-thermal histotripsy region, it is necessary to deliver acoustic energy in the form of low duty cycle, high voltage amplitude acoustic pulses.

[0005]

[0005] Compared to conventional focused ultrasound techniques, Histotripsy has the following important advantages: (1) the destruction process at the focal point is mechanical, not thermal; (2) the bubble cloud appears bright on the ultrasound image, thereby allowing precise targeting and location of the treatment; (3) treated tissue appears darker (hypoechoic) on the ultrasound image, allowing the surgeon to see what has been treated; and (4) Histotripsy produces controlled and precise lesions. It is important to emphasize that unlike microwave, radiofrequency, or high intensity focused ultrasound (HIFU), Histotripsy is not a thermal physical therapy.

[0006] Early studies of histotripsy homogenization of prostate tissue in dogs employed therapeutic transducers positioned to deliver histotripsy transperitoneally. In these studies, the prostate was located only a short distance from the surface of the skin, providing a relatively wide path for focusing ultrasonic energy from the transducer through the skin. Thus, the spherical histotripsy therapeutic transducers employed in these studies had an aperture of 14 cm and a focal length of 10 cm (F-number = 0.71). Histotripsy therapeutic transducers with large F-numbers are significantly less efficient than those with small F-numbers. This inefficiency is primarily due to nonlinear acoustic propagation resulting 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 include multiple ultrasonic transducer elements 102 disposed within a housing 104. The transducer may be connected to a waveform generator configured to deliver a Histotripsy waveform from the transducer to the tissue. The depth of the prostate from this access is significantly greater than in the dog model described above. Furthermore, the skeletal anatomy of the pelvis and the transrectal location of the ultrasound imaging probe significantly reduced the effective transducer aperture. A cutout 106 in the lower periphery of the housing can be configured to accommodate an ultrasound imaging probe (not shown) with F / #=0.85 at the main diameter and F / #=0.98 at the cutout.

[0008] Based on benchtop experiments and modeling, an initial set of therapeutic transducer excitation parameters (3 cycles / pulse, 750 Vpp, 500 Hz PRF (pulse repetition frequency)) was selected for testing this transducer on dogs. This excitation sequence produced a nonlinear focal pressure waveform with peak negative and positive pressures of approximately 25 MPa and 100 MPa in water. Because this sequence parameters were not optimized for bubble cloud formation, we define this sequence and its variants as the standard, or non-optimized, sequence. Summary of the Invention [Problem to be solved by the invention]

[0009]

[0009] This standard excitation sequence and its variations were used to treat approximately 30 canine subjects to establish feasibility, dosing (cumulative number of pulses), and treatment implementation guidelines. An additional 10 canine subjects were then treated in a confirmatory study. Although these studies yielded remarkably efficacious results, the observation of obvious microtrauma (subclinical fibrosis) in the prefocal rectus abdominis muscle in 2 of the 10 subjects in the confirmatory study led to the conclusion that a Histotripsy pulse sequence must be developed to deliver energy more efficiently and improve the safety profile. As transducers evolve to penetrate deeper into tissues through skeletal anatomical obstacles, the need to improve Histotripsy efficiency is likely to become more critical. [Means for solving the problem]

[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] In some embodiments, the scattering pressure waveform is generated within 5 μs to 5 μs from the initial pressure waveform. Delivered within 200μs.

[0014] In one embodiment, the method includes providing an initial pressure waveform and a scattering pressure The method further includes repeating the step of delivering the waveform until treatment of the tissue is complete.

[0014]

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

[0016] In another embodiment, the pressure peak value of the scattering pressure waveform is adjusted to provide additional capacitance to the focal region. The amplitude is sufficient to produce cavitation nuclei.

[0015]

[0017] In an alternative embodiment, the pressure amplitude and / or number of cycles of the scattering pressure waveform are The heating of the fabric is minimized.

[0018] In some embodiments, the method further comprises the steps of: and applying a second scattering pressure waveform toward the at least one bubble and cavitation nucleus.

[0016]

[0019] In some embodiments, the second scattering pressure waveform is 5 μm away from the scattering pressure waveform. It is supplied within 1s from s.

[0020] In another embodiment, the method further comprises the step of: The method further comprises applying additional scattering pressure waveforms without applying additional initiation pressure waveforms until no nuclei remain in the tissue.

[0017]

[0021] In some embodiments, the additional scattering pressure waveform is provided every 5 μs to 1 s. will be provided.

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

[0018]

[0023] In another embodiment, the scattering pressure waveform has less energy than the initiation pressure waveform. to the intervening tissue.

[0024] In one embodiment, the initiation pressure waveform and the scattering pressure waveform have substantially similar pressure In another embodiment, the pressure amplitude of the scattering pressure waveform is less than the pressure amplitude of the initiation pressure waveform. In an alternative embodiment, the pressure amplitude of the scattering pressure waveform is greater than the pressure amplitude of the initiation pressure waveform.

[0019]

[0025] A method of treating tissue with ultrasonic energy, comprising: The method includes the steps of: transmitting an initial pressure waveform from an ultrasound therapy transducer into tissue, the initial pressure waveform being configured to generate at least one 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 being configured to result in an impact focal 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 being configured to impinge on the at least one bubble, scatter, invert, and 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.

[0020]

[0026] A method of delivering ultrasonic energy to tissue, comprising: A method is provided comprising the steps of: delivering an initial pulse from an ultrasound therapy transducer configured to provide a peak negative pressure of at least 5 MPa to generate a bubble; delivering a first scattering pulse into the at least one bubble within 5 μs to 200 μs of the initial pulse; and 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.

[0021]

[0027] An ultrasound therapy transducer and an ultrasound therapy generator coupled to the ultrasound therapy transducer An ultrasound therapy system is provided, comprising: an ultrasound therapy generator configured to drive an 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 the vicinity of the at least one gas bubble.

[0022]

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

[0029] In another embodiment, the ultrasound therapy generator further drives an ultrasound therapy transducer. and configured to operate 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.

[0023]

[0030] In one embodiment, the ultrasound therapy generator initiates the initiation and scattering pressure waveforms. The ultrasound therapy transducer further comprises a controller configured to generate a complex waveform to transmit the ultrasound therapy transducer to a patient, 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 an impedance of the ultrasound therapy transducer to the amplifier.

[0024]

[0031] A method of treating tissue with ultrasonic energy, comprising: Thus, a method is provided comprising the steps of generating at least one gas bubble in tissue, impinging an impact focal pressure waveform on the at least one gas bubble, and forming a cavitation nucleus in the vicinity of the at least one gas bubble.

[0025]

[0032] In one embodiment, the step of impacting comprises impacting a lifetime of at least one bubble. It is carried out in between.

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

[0026]

[0034] In an alternative embodiment, the step of forming cavitation nuclei comprises impact This is achieved by an impact scattering mechanism between the focal pressure waveform and at least one gas bubble.

[0035] The novel features of the invention are set forth with particularity in the appended claims. The apparent features and advantages will be better understood by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which: [Brief description of the drawings]

[0027] [Figure 1]

[0036] FIG. 1 illustrates an ultrasound therapy transducer, according to one embodiment. [Diagram 2]

[0037] Figure 2a is a diagram of the onset of bubble cloud formation in water, Figure 2b is a diagram of the onset of bubble cloud formation in water, and Figure 2c is a diagram of the onset of bubble cloud formation in water. [Diagram 3]

[0038] FIG. 1 illustrates a focal pressure waveform according to one embodiment. [Figure 4]

[0039] Fig. 4a is a conceptual diagram showing impact scattering. Fig. 4b is a conceptual diagram showing impact scattering. Fig. 4c is a conceptual diagram showing impact scattering. Fig. 4d is a conceptual diagram showing impact scattering. Fig. 4e is a conceptual diagram showing impact scattering. [Figure 5a]

[0040] FIG. 1 illustrates an embodiment of a pulse sequence including an initiation pressure waveform and a scattering pressure waveform for delivering ultrasound to tissue. [Figure 5b] FIG. 13 illustrates another embodiment of a pulse sequence including an initiation pressure waveform and a scattering pressure waveform for delivering ultrasound to tissue. [Figure 5c] FIG. 13 illustrates another embodiment of a pulse sequence including an initiation pressure waveform and a scattering pressure waveform for delivering ultrasound to tissue. [Figure 6]

[0041] 1 is a diagram of a system configured to deliver a preferred sequence for treating tissue with cavitation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] Cavitation Generation

[0042] Cavitation nuclei provide important background information for the development of the preferred embodiment and several principles of bubble cloud formation are disclosed herein. Cavitation nuclei are individual bubbles that form as a result of the application of low pressure to tissue. Bubble clouds consist of a dense group of cavitation nuclei that form at or near the focus of the transducer. The formation of cavitation nuclei (bubble clouds) are both key components of Histotripsy Therapy.

[0029]

[0043] Possibility of cavitation nuclei formation

[0044] A cavitation nucleus produces at least one cavitation nucleus (bubble). Cavitation nuclei can form in tissue when the tissue is subjected to peak negative (peak rarefaction) pressures that approach or exceed the pressure levels required to induce cavitation. Note that this level is variable and depends on several factors, such as tissue properties (structure and composition, dissolved gas content, and presence of impurities), transducer geometry (focal length and f-number), and sequencing method (PRF; frequency (number of cycles)). The number of cavitation nuclei formed from one acoustic pulse is believed 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 cavitation time course of the process of initiation, growth, and then collapse is dependent on the medium (i.e., type of tissue). Cavitation time courses for liquids take longer than those in gelatin and soft tissues. Table 1 compares the time of cavitation initiation, growth, and collapse in water and gelatin. Figures 2a-c show typical cavitation time courses. Figure 2a shows the initiation of cavitation 208 in a medium such as tissue, water, or gelatin. Figure 2b shows the growth of cavitation 208 to its maximum size, where the cavitation bubbles cluster together in the focal region. Figure 2c shows the collapse of cavitation 208, where almost all the cavitation bubbles have collapsed and disappeared.

[0031] [Table 1]

[0032]

[0047] Shock scattering mechanisms for acoustic impact and bubble cloud formation

[0048] As an acoustic wave travels through a medium, the positive (compression) half-cycles are replaced by negative (rarefaction) half-cycles. This effect causes the pressure waveform to become nonlinear and the positive half-cycle of the pressure waveform This creates an abrupt transition between the positive and negative half cycles. 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 "shocked". This may be referred to as a shock-focused pressure waveform. The level of non-linearity depends on the pressure amplitude of the pressure waveform and the distance it propagates through the medium. FIG. 3 illustrates an example of a shock-focused pressure waveform with positive and negative half cycles. It should be understood that a shock-focused pressure waveform may include multiple positive and negative half cycles.

[0033]

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

[0034]

[0050] 4a to 4e are conceptual diagrams showing the impact scattering method of histotripsy therapy. The side frame illustrates a pre-existing bubble 408 and an impulse positive pressure half cycle 410, while the bottom frame illustrates an ultrasonic pulse pressure distribution 412 (horizontal line 414 indicates zero pressure amplitude). The pre-existing bubble 408 may be formed by an initial pulse or sequence as described above. Then, according to one embodiment of the impulse scattering method, an impulse pressure waveform may be delivered towards the bubble 408 for the life of the bubble.

[0035]

[0051] In Figures 4a-4e, an 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 may be delivered towards and into the bubble during the bubble's lifespan, where the incident shock pressure waveform interferes with the bubble. In FIG. 4a, a single existing bubble 408 is shown that has already been created in tissue as described above. As shown in FIG. 4b, the initial negative pressure half cycle of the incident shock pressure waveform increases the size of this bubble. 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 reverses and creates a transient, large amplitude negative pressure half cycle 418 (shown as a circular dashed line 418 in FIG. 4c-4e) that constructively interferes with the shock negative pressure half cycle 413 of the incident shock pressure waveform 412 to generate additional cavitation nuclei 420 near or behind the bubble 408. The negative pressure half cycle 418 propagates from right to left as indicated by arrow 422. Additional cavitation nuclei 420 form in the opposite direction of the impulsive positive pressure waveform 410 until the negative pressure half cycle 418 falls below a threshold for the formation of cavitation nuclei, as illustrated in Figure 4e. This process can be repeated with successive impulsive pressure waveforms being delivered towards and into the existing bubble 408 and additional cavitation nuclei 420.

[0036]

[0052] The cavitation nuclei formed by this impact scattering method are then applied to the therapeutic transducer. The range of the pulse (waveform) high pressure period (number of high pressure cycles) and the pulse repetition frequency (PRF) is dependent on the number of periods (number of cycles) of the shock waveform. Minimizing the number of periods (number of cycles) of the shock waveform or reducing the sequence PRF is an effective way to reduce the bubble cloud length and the time-averaged intensity and therefore the thermal dose.

[0037]

[0053] Enhanced bubble cloud formation using impact scattering

[0054] Key elements of the preferred Histotripsy excitation sequence described in this disclosure are The elements include (1) a first pulse in the sequence, referred to as an initiation pulse or initiation pressure waveform, configured to form at least one gas bubble in tissue; and (2) a scattering pulse or scattering pressure wave. a second pulse in the sequence, referred to as a "cavitation pulse shape," configured to generate cavitation nuclei in the vicinity of at least one bubble by impact scattering; and (3) a particular delay time between the initial pulse and the scattering pulse.

[0038]

[0055] The primary parameters for these pulses are at least 1 The initial pulse must be configured to generate one bubble. This can be accomplished by a conventional Histotripsy initial pulse, as described above, or by other ultrasound techniques such as HIFU or boiling Histotripsy, which can induce bubble formation in tissue by boiling. The scattering pulse must have a high enough pressure peak value for the impact scattering formation of cavitation nuclei. In some embodiments, the delay between these pulses can range from 5 μs to 200 μs. In other embodiments, the delay between these pulses can range from 5 μs to 40 ms. In other embodiments, the delay between these pulses can range from 5 μs to 1 s.

[0039]

[0056] In another embodiment, the pressure amplitude and / or frequency used in the initial pulse may be The number of periods (cycles) can be increased or decreased. Increasing the pressure amplitude and / or number of periods in the initial pulse can increase the likelihood of creating cavitation in the tissue. However, this may also increase the time-averaged intensity and heat dose delivered to the tissue, as well as the extent of the bubble cloud. Decreasing the pressure amplitude and / or number of periods of the initial pulse reduces the intensity and heat dose of the sequence, but may limit the ability of the sequence to create and / or sustain cavitation.

[0040]

[0057] In another embodiment, the pressure amplitude and / or frequency used in the scattering pulse may be The number of periods may be increased or decreased. Increasing the pressure amplitude and / or number of periods in the scattering pulse can increase the likelihood of creating cavitation in tissue. However, this may also increase the time-averaged intensity and thermal dose delivered to the tissue, as well as the extent of the bubble cloud. Decreasing the pressure amplitude and / or number of periods of the scattering pulse reduces the intensity and thermal dose of the sequence, but may limit the ability of the sequence to create and / or sustain cavitation.

[0041]

[0058] The sequence PRF is determined so that the time-averaged intensity and the resulting thermal dose are within safe limits. Assuming that the PRF is kept within the range of 5000 Hz, the preferred range depends on the tissue being treated. Higher PRFs are recommended for denser and more fibrous tissues, and lower PRFs are recommended for less dense tissues and for the protection of more fibrous and often critical tissues. Selective treatment of tissues based on their stiffness with Histotripsy may be a promising design and performance consideration for sequence deployment.

[0042]

[0059] In some embodiments, the sequence PRF is reduced without decreasing the sequence PRF. To reduce the intensity and thermal dose of the scattering pulses, additional scattering pulses having smaller pressure amplitudes and / or frequency (compared to the pressure amplitudes and / or frequency of the initial pulse) may be applied.

[0043]

[0060] Figures 5a-5c show the formation of cavities in tissue during the impact scattering method of histotripsy therapy. FIG. 5 shows three different embodiments of Histotripsy initiation and scattering pulse sequences that may be used to generate and maintain tissue localization. In FIG. 5a, an initiation pulse 524a with a pressure waveform configured to form at least one gas bubble in the tissue may be delivered into the tissue. After a specific delay time has elapsed, a scattering pulse 526a may be delivered into the tissue toward and into the at least one gas bubble formed by the initiation pulse 524a. In some embodiments, the specific delay time between these pulses may range from 5 μs to 200 μs. In another embodiment, the delay time between these pulses may range from 5 μs to 200 μs. The initial pulse sequence may range from 100 ms to 40 ms. In another embodiment, the delay time between these pulses may range from 5 μs to 1 s. As it travels through the tissue, the scattering pulse 526a becomes a shock focal pressure waveform, with at least one shock positive pressure half cycle of the scattering pulse colliding with and being scattered by at least one bubble. The shock positive pressure half cycle of the scattering pulse reverses and creates a transient, large amplitude negative pressure half cycle that constructively interferes with the shock negative pressure half cycle of the scattering pulse to create additional cavitation nuclei behind the at least one bubble created by the initial pulse. These pulse sequence pairs of initial and scattering pulses may be repeated to achieve the desired ablation effect in the tissue from the resulting cavitation, as illustrated in FIG. 5a (pulse pairs 524b / 526b, 524c / 526c, 524d / 526d, . . . , 524n / 526n). In this embodiment, the pressure amplitude and / or number of cycles of both the initial and scattering pulses may be the same or approximately the same.

[0044]

[0061] FIG. 5b shows that the pressure amplitude of the scattered pulses 524a-524n is 5 illustrates another embodiment similar to that of FIG. 5a, except that the pressure amplitude is smaller than the pressure amplitude of the corresponding initial pulse. By the principle of impulse, the peak positive wave is amplified compared to the peak negative wave, and therefore the pressure amplitude used to generate the scattering pulse can be reduced while still providing the negative pressure required by the reflected and inverted positive wave. This embodiment is more efficient and delivers a smaller energy dose into the tissue than the embodiment of FIG. 5a. However, in another embodiment, the pressure amplitude of the scattering pulse may be greater than the pressure amplitude of the corresponding initial pulse.

[0045]

[0062] Figure 5c shows another embodiment, which is a variation of the embodiment of figures 5a and 5b. In this embodiment, the initial pulse 524a is followed after a certain delay by a scattering pulse 526a, but instead of being followed by another initial / scattering pulse pair as in FIG. 5a, the scattering pulse 526a is followed by another scattering pulse 526b after a second delay. Multiple scattering pulses may be delivered into the tissue after appropriate delay times to maintain the bubble cloud effect (e.g., pulses 526c, 526d) and achieve the desired ablation effect in the tissue from the resulting cavitation. The pressure amplitude of the scattering pulse may be less than, equal to, or greater than the pressure amplitude of the initial pulse. In some embodiments, the delay time for the subsequent scattering pressure waveform may be different from the delay time used for the first scattering pressure. For example, the first scattering pressure waveform may be delivered within 5 μs to 200 μs of the initial pressure waveform, while the subsequent scattering pressure waveform may be delivered within 5 μs to 200 μs, 5 μs to 40 ms, or 5 μs to 1 s. If cavitation needs to be recreated in the tissue, the sequence may be restarted with another initiation / scattering pulse pair, as illustrated by 524n / 526n in FIG. 5c. Like the embodiment of FIG. 5b, this embodiment also uses scattering pulses of smaller pressure amplitude, but fewer initiation pulses. This embodiment results in the lowest energy dose to the tissue among the embodiments of FIG. 5a-5c. This approach has the potential to significantly reduce the dose (e.g., by as much as 50%) compared to conventional Histotripsy sequences.

[0046]

[0063] The decrease or disappearance of the amplitude of the initial pulse once the bubble cloud is established.

[0064] The purpose of the initiation / scattering pair is to generate cavitation in tissue by impact 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. The NI 8035A is configured to generate a wide range of custom sequences, providing the user with the ability to generate a wide range of custom sequences where all parameters (PRF, voltage amplitude, number of periods, number of pulses per set, frequency, transducer element channels enabled, and delay time) can be set differently for each pulse generated. The delay time between pulses can be specified by the PRF of the parameter set or by specifying zero as the number of periods per pulse.

[0050]

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

[0051]

[0070] Histotripsy Service Tool

[0071] The Histotripsy Service Tool is an application that runs on any PC. The Histotripsy service tool is used to control the system. It allows the user to start / stop therapy, set and read high voltage levels and therapy parameters (PRF, number of cycles, duty ratio, available channels, delays, etc.), and set and read other service and maintenance related items.

[0052]

[0072] USB to Serial Converter

[0073] The USB-to-serial converter 604 communicates with the microcontroller 606. Converts the USB connection to serial for this purpose.

[0053]

[0074] Microcontroller

[0075] The microcontroller 606 is a computer / controller 602 (history trip The microcontroller 606 communicates with the FPGA 608 (Service Tool) to set / read operating parameters, start / stop therapy, etc. The microcontroller 606 can use internal flash memory to store all parameters. The microcontroller communicates with the FPGA 608 all drive parameters required to generate the complex pulses. The microcontroller also communicates with the high voltage controller and power supply 610 using serial communications to set / read the appropriate levels of drive voltage.

[0054]

[0076] FPGA

[0077] The FPGA 608 receives information from the microcontroller 606 and the amplifier 61 Generate the complex pulse sequence required to drive 2. The pulse speed is 10ns. Since it is essential that time-to-time measurements be taken, the FPGA can be clocked at 100MHz.

[0055]

[0078] High voltage controller and power supply

[0079] The high voltage controller and power supply 610 controls the appropriate voltage swing level at the output of the amplifier. The amplifier circuit receives instructions from the microcontroller 606 as to the level of DC voltage that needs to be supplied to the amplifier circuit to obtain

[0056]

[0080] amplifier

[0081] The amplifier 612 receives the pulses generated by the FPGA and outputs and a power supply. The amplifier 612 generates high voltage amplitude pulses that are supplied to the therapy transducer 614 through a matching network that properly matches the impedance of the therapy transducer to the impedance of the amplifier. It is necessary to use multiple capacitors that can store enough energy to meet the peak current demands during the generation of the high voltage amplitude pulses.

[0057]

[0082] The data structures and code described in the Detailed Description of the Invention are Typically stored on 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. Computer readable storage media include, but are not limited to, volatile or non-volatile memory, or magnetic and optical storage devices such as disk drives or magnetic tapes or CDs (compact disks) or DVDs (digital versatile disks or digital video disks), or other media capable of storing any known or later developed computer readable storage medium.

[0058]

[0083] The methods and processes described in the Detailed Description of the Invention section are The methods and processes embodied as data structures and code may be stored in a computer readable storage medium such as those described above. When a computer system reads and executes the code and / or data stored in the computer readable storage medium, the computer system performs the methods and processes embodied as data structures and code stored in the computer readable storage medium.

[0059]

[0084] Furthermore, the methods and processes described above may be included in a hardware module. For example, a hardware module may include, but is not limited to, an application specific integrated circuit (ASIC) chip, a field programmable gate array (FPGA), and other now known or later developed programmable logic devices. When a hardware module is activated, the hardware module performs the methods and processes contained within the hardware module.

[0060]

[0085] The examples and illustrations contained herein are for purposes of illustration and not limitation, showing specific embodiments in which the subject matter may be practiced. As previously mentioned, other embodiments are available and derivable, 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 related to the present invention, if in fact more than one is disclosed, may be referred to herein, individually or collectively, by the term "invention", merely for convenience, without intending to spontaneously limit the scope of the present application to any single invention or inventive concept. Thus, although specific embodiments have been shown and described herein, any configuration that is expected to achieve a similar purpose may be substituted for the specific embodiment shown. The present disclosure is intended to cover any and all adaptations or modifications of the various embodiments. Combinations of the above-mentioned embodiments and other embodiments not specifically described herein will become apparent to those skilled in the art upon reviewing the above description. [Form 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. [Form 2] 2. The method of claim 1, wherein the scattering pressure waveform is delivered within 5 μs to 200 μs of the initial pressure waveform. [Form 3] 2. 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 completed. [Form 4] 2. 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. [Form 5] 2. The method of claim 1, wherein the pressure peak value of the scattering pressure waveform is of sufficient amplitude to cause additional cavitation nuclei in the focal region. [Form 6] 2. The method of claim 1, wherein the pressure amplitude and / or number of cycles of the scattering pressure waveform are minimized to reduce heating of tissue. [Form 7] 2. 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. [Form 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. [Form 9] 8. The method of claim 7, further comprising the step of applying additional scattering pressure waveforms without applying additional initial pressure waveforms until at least one bubble and / or cavitation nuclei no longer remain within the tissue. [Form 10] 10. The method of claim 9, wherein the additional scattering pressure waveform is delivered every 5 μs to 1 s. [Form 11] 2. 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. [Form 12] 2. The method of claim 1, wherein the scattering pressure waveform delivers less energy to intervening tissue than the initiation pressure waveform. [Form 13] 2. The method of claim 1, wherein the initiation pressure waveform and the scattering pressure waveform have substantially similar pressure amplitudes. [Form 14] 2. 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. [Form 15] 2. The method of claim 1, wherein the pressure amplitude of the scattering pressure waveform is greater than the pressure amplitude of the initial pressure waveform. [Form 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. [Form 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. [Form 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: [Form 19] 19. The system of claim 18, wherein the pressure peak value of the first scattering pulse has a pressure amplitude sufficient to generate cavitation nuclei in the vicinity of the at least one bubble. [Form 20] 19. 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. [Form 21] 19. 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: [Form 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. [Form 23] 23. The method of claim 22, wherein the colliding step is performed during the lifetime of the at least one bubble. [Form 24] 24. The method of claim 23, wherein the colliding step is performed within 5 μs to 200 μs of the generating step. [Form 25] 23. The method of claim 22, wherein forming the cavitation nuclei is accomplished by an impact scattering mechanism between the impact focal pressure waveform and the at least one bubble.

Claims

1. 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 after the initial pressure waveform into the at least one gas bubble during a lifetime of the at least one gas bubble to generate cavitation nuclei in the vicinity of the at least one gas bubble, the pressure amplitude of the first scattering pressure waveform being less than the pressure amplitude of the initial pressure waveform; A histotripsy therapy system comprising:

2. 2. The system of claim 1, The system further comprises: a first scattering pressure waveform configured to be a shock focal pressure waveform having a shock positive pressure half cycle and a shock negative pressure half cycle within the tissue, 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, and generate the cavitation nuclei in the vicinity of the at least one bubble by a shock scattering mechanism between the positive pressure half cycle waveform and the at least one bubble.

3. 2. The system of claim 1, The system, 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.

4. 2. The system of claim 1, wherein the ultrasound therapy generator comprises: a controller configured to generate waveforms to initiate the initiation and scattering pressure waveforms; a high voltage power supply coupled to the controller; an amplifier configured to receive the waveform from the controller and a high voltage from the high voltage power supply and to amplify the waveform; a matching network configured to match the impedance of the ultrasound therapy transducer to the amplifier; The system further comprises:

5. 2. The system of claim 1, The system, wherein the first scattering pressure waveform includes a leading positive pressure half cycle, a negative pressure half cycle, and a trailing positive pressure half cycle having an amplitude less than the leading positive pressure half cycle.

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