Histotripsy System and Method

Abstract

Histotripsy therapy systems configured for the treatment of tissue are provided, which may include any number of features. Provided herein are systems and methods that provide effective, non-invasive and minimally invasive therapy, diagnostic, and research procedures. In particular, provided herein are optimized systems and methods that provide effective targeted histotripsy in a variety of different regions and under a variety of different conditions without causing undesired tissue damage to intervening / non-target tissues or structures.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims priority to U.S. Provisional Patent Application No. 63 / 381,401, filed October 28, 2022, entitled "HISTOTRIPSY SYSTEMS AND METHODS," which is incorporated herein by reference in its entirety. Incorporation by Reference

[0002]

[0002] All publications and patent applications mentioned in this specification are incorporated by reference herein 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 details novel high intensity therapeutic ultrasound (HITU) systems configured to produce acoustic cavitation, methods, devices, and procedures for minimally invasive and non-invasive treatment of healthy, diseased, and / or injured tissue. The acoustic cavitation systems and methods described herein, also referred to as Histotripsy, can include transducers, drive electronics, positioning robotics, imaging systems, and integrated treatment planning and control software for performing comprehensive treatment and therapy of a patient's soft tissue. [Background technology]

[0004] Histotripsy, or pulsed ultrasound cavitation therapy, is a technique in which extremely short, intense bursts of acoustic energy induce controlled cavitation (microbubble formation) within a focal volume. The violent expansion and collapse of these microbubbles mechanically homogenizes the cellular and tissue structures within the focal volume, a net result that is very different from the coagulation necrosis characteristic of thermal ablation. To operate within the non-thermal histotripsy regime, it is necessary to deliver acoustic energy in the form of low-duty-cycle, high-amplitude acoustic pulses.

[0005]

[0005] Compared with conventional focused ultrasound techniques, Histotripsy has the following important advantages: 1) the destruction process at the focal point is mechanical, not thermal; 2) cavitations appear bright on ultrasound imaging, thereby confirming correct targeting and localization of the treatment; 3) the treated tissue generally, but not always, appears darker (more hypoechoic) on ultrasound imaging, thus allowing the operator to see what has been treated; and 4) Histotripsy presents the lesion in a controlled and precise manner. It is important to emphasize that, unlike thermal ablation techniques such as microwave, radiofrequency, high-intensity focused ultrasound (HIFU), cryo, or radiation, Histotripsy relies on the mechanical action of cavitation for tissue destruction and does not rely on heat, cryo, or ionizing energy.

[0006] The novel features of the invention are set forth with particularity in the claims that follow. A better understanding of the features and advantages of the present invention will be obtained 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 in which: [Brief explanation of the drawings]

[0007] [Figure 1A] FIG. 1 is a diagram of an ultrasound imaging and therapy system. [Figure 1B]FIG. 1 is a diagram of an ultrasound imaging and therapy system. [Figure 2]

[0008] FIG. 1 is a diagram of one embodiment of a histotripsy therapy and imaging system with a coupling system. [Figure 3]

[0009] FIG. 1 is a diagram of one example of an ultrasound pulse for generating histotripsy via an impact scattering mechanism. [Figure 4]

[0010] 4A and 4B are illustrations of a packing technique for treating a target tissue volume. [Figure 5]

[0011] FIG. 5A is an illustration of one embodiment for creating a bubble cloud at a single focal location for a given individual treatment location.

[0012] FIG. 5B is an illustration of an example where multiple focal locations for a given individual treatment location are axially spaced to create a bubble cloud.

[0013] FIG. 5C is an illustration of an example where multiple focal locations for a given individual treatment location are laterally spaced to create a bubble cloud. [Figure 6]

[0014] 6A and 6B are diagrams of one technique for laterally electronic beam steering of an ultrasound transducer to form an enhanced excitation volume. [Figure 7]

[0015] 7A and 7B are diagrams of one technique for electronic beam steering of an ultrasound transducer in 3D space to form an enhanced excitation volume. [Figure 8]

[0016] 8A and 8B are diagrams of one technique for electronic beam steering of an ultrasound transducer in 3D space to form an enhanced excitation volume. [Figure 9]

[0017] Figures 9A, 9B, 9C, and 9D are diagrams of beam profiles of multiple axially spaced bubble cloud focal locations. [Figure 10]

[0018] Figures 10A, 10B, and 10C are diagrams of beam profiles of multiple laterally spaced bubble cloud focal locations. [Figure 11]

[0019] Figures 11A and 11B are diagrams of the effect of spacing between adjacent focus locations. [Figure 12]

[0020] Figure 12A is a diagram of a heat map, exposure level, and lesion level for multiple treatment protocols; Figure 12B is a diagram of a heat map, exposure level, and lesion level for multiple treatment protocols; Figure 12C is a diagram of a heat map, exposure level, and lesion level for multiple treatment protocols; Figure 12D is a diagram of a heat map, exposure level, and lesion level for multiple treatment protocols; Figure 12E is a diagram of a heat map, exposure level, and lesion level for multiple treatment protocols; Figure 12F is a diagram of a heat map, exposure level, and lesion level for multiple treatment protocols; Figure 12G is a diagram of a heat map, exposure level, and lesion level for multiple treatment protocols; Figure 12H is a diagram of a heat map, exposure level, and lesion level for multiple treatment protocols; and Figure 12I is a diagram of a heat map, exposure level, and lesion level for multiple treatment protocols. [Figure 13]

[0021] FIG. 1 is a schematic diagram showing the spacing between focal locations for therapy transducers. [Figure 14]

[0022] 1 is a chart showing the effect of spacing on bubble cloud size. Summary of the Invention [Problem to be solved by the invention]

[0008]

[0023] A method is provided for performing histotripsy therapy on a target tissue, the method comprising: receiving a digital treatment plan including a target tissue volume of a subject divided into a plurality of individual treatment locations; mechanically positioning a focal point of an ultrasound therapy transducer at a first focal location at a first individual treatment location within the target tissue volume; delivering a first histotripsy pulse to the first focal location to create a first cavitation bubble cloud at the first focal location; electronically beam steering the focal point of the ultrasound therapy transducer to a second focal location at the first individual treatment location that overlaps with the first focal location; and delivering a second histotripsy pulse to the second focal location to create a second bubble cloud at the second focal location and to at least partially re-excite the first cavitation bubble cloud at the first focal location. [Means for solving the problem]

[0009]

[0024] In some aspects, the histotripsy pulse comprises a positive half-cycle followed by a peak negative half-cycle followed by a trailing positive half-cycle.

[0010]

[0025] In some embodiments, the trailing positive half cycle has a lower amplitude than the leading positive half cycle.

[0011]

[0026] In one embodiment, delivering a second histotripsy pulse to the second focal location further comprises delivering a second histotripsy pulse to the second focal location to create a second bubble cloud at the second focal location during the life cycle of the first bubble cloud.

[0012]

[0027] In other embodiments, delivering a second Histotripsy pulse to the second focal location further includes delivering a second Histotripsy pulse to the second focal location to create a second bubble cloud at the second focal location during the life cycle of residual cavitation nuclei of the first bubble cloud.

[0013]

[0028] In one embodiment, electronic beam steering the focal point further comprises electronic beam steering the focal point axially relative to the ultrasound therapy transducer.

[0014]

[0029] In other aspects, electronic beam steering the focal point further comprises electronic beam steering the focal point in any lateral direction relative to the ultrasound therapy transducer.

[0015]

[0030] In some aspects, electronic beam steering the focal point further comprises electronic beam steering the focal point laterally and axially relative to the ultrasound therapy transducer.

[0016]

[0031] In another aspect, the method includes repeating the electron beam steering and delivering steps for a third focal location that overlaps with the second focal location.

[0017]

[0032] In some embodiments, the method includes repeating the electron beam steering and delivering steps for a third focal location that overlaps with the first focal location.

[0018]

[0033] In one embodiment, after each delivery step, the method includes delivering at least one low amplitude waveform to the target tissue to spatially manipulate residual cavitation nuclei in the target tissue.

[0019]

[0034] In other aspects, the method includes repeating the delivery and electronic beam steering steps for the first and second focal locations until a desired dose is applied to the first discrete treatment location.

[0020]

[0035] In some embodiments, the method includes mechanically positioning a focal point of the ultrasound therapy transducer at a first focal point location at a second discrete treatment location within the target tissue volume after the desired dose is applied to the first discrete treatment location.

[0021]

[0036] In one embodiment, mechanically positioning the focal point further comprises mechanically positioning the focal point with a robotic positioning system.

[0022]

[0037] Optionally, the method includes: a robotic positioning system; an ultrasound therapy transducer array connected to the robotic positioning system; a generator operatively coupled to the ultrasound therapy transducer array, wherein the generator and the ultrasound therapy transducer array are configured to deliver histotripsy pulses to the subject to generate a cavitation bubble cloud in the subject; and at least one processor operatively coupled to the robotic positioning system and the generator, for controlling the robotic positioning system to mechanically position a focal point of the ultrasound therapy transducer array at a first focal location at a first individual treatment location within the treatment plan; and controlling at least one processor operatively coupled to the ultrasound therapy transducer array to mechanically position a focal point of the ultrasound therapy transducer array at a first focal location at a first individual treatment location within the treatment plan to form a first cavitation bubble cloud at the first focal location. and at least one processor configured to control the robotic positioning system and the generator to provide histotripsy therapy to a subject according to a treatment plan including a plurality of discrete treatment locations within a target tissue volume of the subject by controlling the generator to deliver one histotripsy pulse at a first discrete treatment location, controlling the generator to electronically beam steer a focal point of the ultrasound therapy transducer to a second focal location at a first discrete treatment location overlapping the first focal location, and controlling the generator to deliver at least one histotripsy pulse to the second focal location to create a second bubble cloud at the second focal location and to re-excite the first cavitation bubble cloud at the first focal location.

[0023]

[0038] In some aspects, each Histotripsy pulse includes a positive half-cycle followed by a peak negative half-cycle followed by a trailing positive half-cycle.

[0024]

[0039] In one embodiment, the trailing positive half cycle has a lower amplitude than the leading positive half cycle.

[0025]

[0040] In one embodiment, controlling the generator to deliver at least one Histotripsy pulse to the second focal location further includes controlling the generator to deliver at least one Histotripsy pulse to the second focal location to create a second bubble cloud at the second focal location during the life cycle of the first bubble cloud.

[0026]

[0041] In other embodiments, controlling the generator to deliver at least one Histotripsy pulse to the second focal location further includes controlling the generator to deliver at least one Histotripsy pulse to the second focal location to create a second bubble cloud at the second focal location during a life cycle of residual cavitation nuclei of the first bubble cloud.

[0027]

[0042] In some aspects, controlling the generator to electronically beam steer the focal point further comprises controlling the generator to electronically beam steer the focal point in an axial direction relative to the ultrasound therapy transducer array.

[0028]

[0043] In some aspects, controlling the generator to electronically beam steer the focal point further comprises controlling the generator to electronically beam steer the focal point in any lateral direction relative to the ultrasound therapy transducer array.

[0029]

[0044] In some aspects, controlling the generator to electronically beam steer the focal point further comprises controlling the generator to electronically beam steer the focal point in lateral and axial directions relative to the ultrasound therapy transducer array.

[0030]

[0045] In one embodiment, the system is configured to alternately control the generator to electronic beam steering and control the generator to deliver at least one histotripsy pulse for a third focal location that overlaps with the second focal location.

[0031]

[0046] In other aspects, the system is configured to alternate between controlling the generator to electronic beam steering and controlling the generator to deliver at least one histotripsy pulse for a third focal location that overlaps with the first focal location.

[0032]

[0047] In one embodiment, after controlling the generator to deliver at least one histotripsy pulse, the system is configured to control the generator to deliver at least one low amplitude waveform to the target tissue to spatially manipulate residual cavitation nuclei in the target tissue.

[0033]

[0048] In one embodiment, the system is configured to repeatedly control the generator to electronically steer the beam and control the generator to deliver at least one histotripsy pulse for the first and second focal locations until a desired dose is applied to the first individual treatment location.

[0034]

[0049] In another aspect, the system is configured to control the robotic positioning system to mechanically position the focal point of the ultrasound therapy transducer at a first focal point location at a second discrete treatment location within the target tissue volume after the desired dose is applied to the first discrete treatment location.

[0035]

[0050] A method is provided for performing histotripsy therapy on a target tissue volume, the method comprising the steps of dividing a target tissue volume into a plurality of individual treatment locations, determining a treatment plan including a path for providing therapy to each of the individual treatment locations, positioning a focal point of an ultrasound therapy transducer at a first focal location at the first individual treatment location within the target tissue volume, delivering one or more histotripsy pulses to the first focal location to create a first bubble cloud at the first focal location, electronically beam steering the focal point of the ultrasound therapy transducer to a second focal location at the first individual treatment location that overlaps with the first focal location, delivering one or more histotripsy pulses to the second focal location to create a second bubble cloud at the second focal location, and repeating the positioning and delivery steps for each of the plurality of individual treatment locations according to the treatment plan and the path.

[0036]

[0051] In one embodiment, each Histotripsy pulse comprises a positive half-cycle followed by a peak negative half-cycle followed by a trailing positive half-cycle.

[0037]

[0052] In other embodiments, the trailing positive half cycle has a lower amplitude than the leading positive half cycle.

[0038]

[0053] In some embodiments, delivering one or more histotripsy pulses to the second focal location further includes delivering one or more histotripsy pulses to the second focal location to create a second bubble cloud at the second focal location during the life cycle of the first bubble cloud.

[0039]

[0054] In other embodiments, delivering one or more Histotripsy pulses to the second focal location further includes delivering one or more Histotripsy pulses to the second focal location to create a second bubble cloud at the second focal location during the life cycle of residual cavitation nuclei of the first bubble cloud.

[0040]

[0055] In some aspects, electronic beam steering the focal point further comprises electronic beam steering the focal point axially relative to the ultrasound therapy transducer.

[0041]

[0056] In other aspects, electronic beam steering the focal point further comprises electronic beam steering the focal point in any lateral direction relative to the ultrasound therapy transducer.

[0042]

[0057] In one embodiment, electronic beam steering the focal point further comprises electronic beam steering the focal point laterally and axially relative to the ultrasound therapy transducer.

[0043]

[0058] In another aspect, the method includes repeating the electron beam steering and delivering steps for a third focal location that overlaps with the second focal location.

[0044]

[0059] In some embodiments, the method includes repeating the electron beam steering and delivering steps for a third focal location that overlaps with the first focal location.

[0045]

[0060] In another aspect, after each delivery step, the method includes delivering at least one low amplitude waveform to the target tissue to spatially manipulate residual cavitation nuclei in the target tissue.

[0046]

[0061] In some aspects, the method includes repeating the delivery and electronic beam steering steps for the first and second focal locations until a desired dose is applied to the first discrete treatment location.

[0047]

[0062] In another aspect, the method includes mechanically positioning a focal point of the ultrasound therapy transducer at a first focal point location at a second discrete treatment location within the target tissue volume after the desired dose is applied to the first discrete treatment location.

[0048]

[0063] In some embodiments, mechanically positioning the focal point further comprises mechanically positioning the focal point with a robotic positioning system.

[0049]

[0064] A method is provided for performing histotripsy therapy on a target tissue volume, comprising delivering a first histotripsy therapy pulse to a first focal location to create a corresponding bubble cloud within a first focal zone, electronic beam steering a focal spot to a second focal location, and delivering a second histotripsy therapy pulse to the second focal location to create a corresponding bubble cloud within a second focal zone that spatially overlaps the first focal zone, wherein the second histotripsy pulse is timed to re-excite residual cavitation nuclei in the first focal zone to create an enhanced excitation volume comprising the first focal zone and the second focal zone.

[0050]

[0065] In some aspects, the histotripsy pulse comprises a positive half-cycle followed by a peak negative half-cycle followed by a trailing positive half-cycle.

[0051]

[0066] In other embodiments, the trailing positive half cycle has a lower amplitude than the leading positive half cycle.

[0052]

[0067] In some embodiments, delivering a second histotripsy pulse to the second focal location further includes delivering a second histotripsy pulse to the second focal location to create a second bubble cloud at the second focal location during the life cycle of the first bubble cloud.

[0053]

[0068] In another embodiment, delivering a second Histotripsy pulse to the second focal location further includes delivering a second Histotripsy pulse to the second focal location to create a second bubble cloud at the second focal location during the life cycle of residual cavitation nuclei of the first bubble cloud.

[0054]

[0069] In some aspects, electronic beam steering the focal point further comprises electronic beam steering the focal point axially relative to the ultrasound therapy transducer.

[0055]

[0070] In one embodiment, electronic beam steering the focal point further comprises electronic beam steering the focal point in any lateral direction relative to the ultrasound therapy transducer.

[0056]

[0071] In another aspect, electronic beam steering the focal point further comprises electronic beam steering the focal point laterally and axially relative to the ultrasound therapy transducer.

[0057]

[0072] In some embodiments, the method includes repeating the electron beam steering and delivering steps for a third focal location that overlaps with the second focal location.

[0058]

[0073] In another aspect, the method includes repeating the electron beam steering and delivering steps for a third focal location that overlaps with the first focal location.

[0059]

[0074] In one embodiment, after each delivery step, the method includes delivering at least one low amplitude waveform to the target tissue to spatially manipulate residual cavitation nuclei in the target tissue.

[0060]

[0075] In some aspects, the method includes repeating the delivery and electronic beam steering steps for the first and second focal locations until a desired dose is applied to the first discrete treatment location.

[0061]

[0076] In another aspect, the method includes mechanically positioning a focal point of the ultrasound therapy transducer at a first focal point location at a second discrete treatment location within the target tissue volume after the desired dose is applied to the first discrete treatment location.

[0062]

[0077] In some embodiments, mechanically positioning the focal point further comprises mechanically positioning the focal point with a robotic positioning system.

[0063]

[0078] A method for generating an enhanced excitation volume with histotripsy energy is provided, the method comprising: positioning a focal point of an ultrasound therapy transducer at a first focal location at a first discrete treatment location within a target tissue volume, the first focal location being located along a central axis of the ultrasound therapy transducer; delivering a first histotripsy pulse to the first focal location to generate a first cavitation bubble cloud at the first focal location; electronic beam steering the focal point of the ultrasound therapy transducer to a second focal location at the first discrete treatment location at least partially outside the central axis; delivering a second histotripsy pulse to the second focal location to generate a second bubble cloud at the second focal location; electronic beam steering the focal point of the ultrasound therapy transducer to a focal location at least partially inside the central axis; and delivering a third histotripsy pulse to the focal location to generate a third bubble cloud at the focal location.

[0064]

[0079] In some aspects, the natural focus of the ultrasound therapy transducer array is located along the central axis.

[0065]

[0080] In other embodiments, the first focal location comprises a natural focus.

[0066]

[0081] In some embodiments, the second focal location partially overlaps with the central axis.

[0067]

[0082] In other embodiments, the focal location includes a first focal location.

[0068]

[0083] In a further aspect, the focal locations include a third focal location.

[0069]

[0084] In some embodiments, steering the electronic beam to the second focal location includes laterally steering.

[0070]

[0085] In other embodiments, steering the electron beam to the second focal location includes steering laterally and axially.

[0071]

[0086] a robotic positioning system; an ultrasound therapy transducer array connected to the robotic positioning system; a generator operatively coupled to the ultrasound therapy transducer array, wherein the generator and the ultrasound therapy transducer array are configured to deliver histotripsy pulses to the subject to generate a cavitation bubble cloud in the subject; the generator; and at least one processor operatively coupled to the robotic positioning system and the generator, for controlling the robotic positioning system to mechanically position a focal point of the ultrasound therapy transducer array at a first focal point location at a first individual treatment location within the treatment plan, the first focal point location being positioned along a central axis of the ultrasound therapy transducer array; controlling the generator to deliver at least one histotripsy pulse with the ultrasound therapy transducer array to form a first cavitation bubble cloud at the first focal point location; and at least one processor configured to control the robotic positioning system and the generator to provide histotripsy therapy to the subject according to a treatment plan including a plurality of discrete treatment locations within a target tissue volume of the subject by controlling the generator to electronically beam steer a focal point of the ultrasound therapy transducer to a second focal location at least partially outside the first discrete treatment location, controlling the generator to deliver at least one histotripsy pulse to the second focal location to create a second bubble cloud at the second focal location, controlling the generator to electronically beam steer a focal point of the ultrasound therapy transducer to a focal location at least partially inside the central axis, and controlling the generator to deliver at least one histotripsy pulse to the focal location to create a third bubble cloud at the focal location.

[0072]

[0087] In some aspects, the natural focus of the ultrasound therapy transducer array is located along the central axis.

[0073]

[0088] In other embodiments, the first focal location comprises a natural focus.

[0074]

[0089] In some embodiments, the second focal location partially overlaps with the central axis.

[0075]

[0090] In other embodiments, the focal location includes a first focal location.

[0076]

[0091] In some embodiments, the focal location includes a third focal location.

[0077]

[0092] In other aspects, controlling the generator to steer the electron beam to the second focal location includes laterally steering.

[0078]

[0093] In other embodiments, controlling the generator to steer the electron beam to the second focal location includes steering laterally and axially.

[0079]

[0094] The method includes: providing an ultrasound therapy transducer array; a generator operatively coupled to the ultrasound therapy transducer array, wherein the generator and the ultrasound therapy transducer array are configured to deliver histotripsy pulses to the subject to generate a cavitation bubble cloud in the subject; and at least one processor operatively coupled to the generator, for controlling the generator to deliver at least one histotripsy pulse with the ultrasound therapy transducer array to form a first cavitation bubble cloud at a first focal location in a first individual treatment location within the treatment plan; and at least one processor configured to control the generator to provide histotripsy therapy to the subject according to a treatment plan including a plurality of discrete treatment locations within a target tissue volume of the subject by controlling the generator to electronically beam steer a focal point of the ultrasound therapy transducer to a second focal location in a cavitation configuration and to deliver at least one histotripsy pulse to the second focal location to create a second bubble cloud at the second focal location and to re-excite the first cavitation bubble cloud at the first focal location.

[0080]

[0095] The present invention provides a method for treating a cavitation bubble cloud comprising: an ultrasound therapy transducer array; a generator operatively coupled to the ultrasound therapy transducer array, wherein the generator and the ultrasound therapy transducer array are configured to deliver histotripsy pulses to a subject to generate a cavitation bubble cloud in the subject; and at least one processor operatively coupled to the generator, for controlling the generator to deliver at least one histotripsy pulse with the ultrasound therapy transducer array to form a first cavitation bubble cloud at a first focal location at a first individual treatment location within the treatment plan, the first focal location being positioned along a central axis of the ultrasound therapy transducer array; and controlling the ultrasound therapy transducer array to deliver at least one histotripsy pulse to a second focal location at the first individual treatment location that is at least partially outside of the central axis. and at least one processor configured to control the generator to provide histotripsy therapy to the subject according to a treatment plan including a plurality of discrete treatment locations within a target tissue volume of the subject by controlling the generator to electronically beam steer a focal point of the ultrasound therapy transducer to a focal location at a first discrete treatment location at least partially inside the central axis, controlling the generator to deliver at least one histotripsy pulse to the focal location to create a third bubble cloud at the focal location, controlling the generator to electronically beam steer a focal point of the ultrasound therapy transducer to a focal location at a first discrete treatment location at least partially inside the central axis, and controlling the generator to deliver at least one histotripsy pulse to the focal location to create a third bubble cloud at the focal location. DETAILED DESCRIPTION OF THE INVENTION

[0081]

[0096] The disclosed systems, methods, and devices can be used for open, minimally invasive (laparoscopic and percutaneous), robotic (integrated into robotically enabled medical systems), endoscopic, or fully percutaneous extracorporeal non-invasive acoustic cavitation for the treatment of healthy, diseased, and / or injured tissue, including, but not limited to, tissue disruption, cutting, skeletonizing, and ablation. Furthermore, histotripsy can be used to create cytoskeleton formation, enabling subsequent tissue regeneration through the application of stem cells and other supportive means, due to its tissue selectivity. Finally, histotripsy can be used to trigger the release of delivered agents, such as chemotherapy and immunotherapy, by locally triggering the release of these agents through the application of acoustic energy to the target. As described below, acoustic cavitation systems can include various subsystems, including carts, therapy, integrated imaging, robotics, couplings, and software. The system may also include various other components, ancillary equipment and accessories, including but not limited to computers, cables and connectors, networking devices, power supplies, displays, drawers / storage, doors, wheels, and various simulation and training tools. All systems, methods and means for creating / controlling / implementing Histotripsy are considered part of this disclosure, including any new related inventions disclosed herein.

[0082]

[0097] 1A generally illustrates a histotripsy system 100 according to the present disclosure, including a therapy transducer 102, an imaging system 104, a display and control panel 106, a robotic positioning arm 108, and a cart 110. The system may further include an ultrasound coupling interface and a source of coupling media, not shown.

[0083]

[0098] 1B is a bottom view of the therapy transducer 102 and imaging system 104. As shown, the imaging system can be located at the center of the therapy transducer. Yet, other embodiments can include an imaging system located at other locations within the therapy transducer, or perhaps integrated directly into the therapy transducer. In some embodiments, the imaging system is configured to produce real-time imaging at the focal point of the therapy transducer. The system also allows multiple imaging transducers to be placed within the therapy transducer to simultaneously provide multiple views of the target tissue and combine these images into a single 3D image.

[0084]

[0099] The histotripsy system may include one or more of a variety of subsystems, including a therapy subsystem capable of creating, applying, focusing, and delivering acoustic cavitation / histotripsy through one or more therapy transducers; an integrated imaging subsystem (or connection thereto) that allows real-time visualization of the treatment site and histotripsy effects throughout the procedure; a robotics positioning subsystem for mechanically and / or electronically steering the therapy transducer, which may further connect to / support or interact with the coupling subsystem to enable acoustic coupling between the therapy transducer and the patient; and software for communicating with, controlling, and interfacing with the system and computer-based control system (and other external systems), as well as various other components, auxiliary instruments, and accessories, including one or more user interfaces and displays and associated guided workflows, all functioning partially or together. The system may further include various fluidics and fluid management components, including, but not limited to, pumps, valves, and flow control, temperature and degassing control, and irrigation and aspiration capabilities, as well as providing and storing fluids. The system may also include various power sources and protection devices.

[0085]

[0100] As described above, the histotripsy system can include integrated imaging. Yet, in other embodiments, the histotripsy system can be configured to interface with a separate imaging system, such as a C-arm, fluoroscope, cone-beam CT, MRI, etc., to provide real-time imaging during histotripsy therapy. In some embodiments, the histotripsy system can be sized and configured to fit within a C-arm, fluoroscope, cone-beam CT, MRI, etc.

[0086] cart

[0101] The cart 110 may be configured overall in a variety of styles and form factors based on the specific intended use and procedure. In some cases, a system may include multiple carts configured in similar or different arrangements. In some embodiments, the cart may be configured and arranged for use in a radiology environment, and possibly in conjunction with imaging (e.g., CT, cone-beam CT, and / or MRI scans). In other embodiments, the cart may be arranged for use in an operating room and sterile environment for open or laparoscopic surgery and endoscopic applications, or in a robotic-enabled operating room, and may be used alone or as part of a surgical robotic procedure, with the surgical robot performing specific tasks before, during, or after use of the system and the performance of acoustic cavitation / histotripsy. Accordingly, and depending on the procedure environment based on the aforementioned embodiments, the cart may be arranged to provide sufficient workspace and access to various anatomical locations on the patient (e.g., torso, abdomen, flank, head and neck, etc.), as well as to provide workspace for other systems (e.g., anesthesia cart, laparoscopic tower, surgical robot, endoscopic tower, etc.).

[0087]

[0102] The cart may also operate with a patient surface (e.g., a table or bed) to allow the patient to be presented and repositioned in a multitude of positions, angles, and orientations, including allowing changes to such to be made pre-, peri-, and post-operatively. The cart may further be capable of interfacing and communicating with one or more external imaging or image data management and communication systems, including but not limited to one or more modalities of ultrasound, CT, fluoroscopy, cone beam CT, PET, PET / CT, MRI, optical, ultrasound, and image fusion and / or image flow; supporting a procedure and / or use environment, including physical / mechanical interoperability (e.g., compatibility within a cone beam CT workspace for collecting pre-, peri-, and / or post-histotripsy imaging data); and accessing and displaying patient medical data, including but not limited to laboratory and historical medical record data.

[0088]

[0103] In some embodiments, one or more carts may be configured to operate together. By way of example, one cart may comprise a bedside mobile cart equipped with one or more robotic arms associated with therapy transducers, therapy generators / amplifiers, etc., while a companion cart operating with and away from the patient may comprise integrated imaging and console / display for controlling the robot and therapy facets similar to a surgical robot and master / slave configuration.

[0089]

[0104] In some embodiments, the system may include multiple carts, all slave to one master cart, equipped to perform acoustic cavitation procedures. In some arrangements and in some cases, one cart configuration may allow for storage of specific subsystems at a distance that reduces clutter in the operating room, while another cooperating cart may essentially include bedside subsystems and components (e.g., delivery systems and therapies).

[0090]

[0105] Numerous permutations and configurations of cart designs are possible, and these examples are in no way intended to limit the scope of this disclosure.

[0091] Histotripsy

[0106] Histotripsy uses short, high-amplitude focused ultrasound pulses to generate a dense, energetic "bubble cloud" capable of targeted disruption and destruction of tissue. Histotripsy has the ability to create controlled tissue erosion when directed at tissue interfaces, including tissue / fluid interfaces, as well as well-defined tissue disruption and destruction at the subcellular level when targeted at bulk tissue. Unlike other forms of ablation, including thermal and radiation-based modalities, Histotripsy does not rely on heat, cold, or ionizing energy to treat tissue. Instead, Histotripsy uses acoustic cavitation generated at a focal point to mechanically affect tissue structure, potentially liquefying, suspending, dissolving, and / or disrupting tissue into subcellular components.

[0092]

[0107] Histotripsy can be applied in various forms, including: 1) Intrinsic Threshold Histotripsy: A pulse is typically delivered with 1-2 cycles of high-amplitude reverse / extensional pressure that exceeds the intrinsic threshold for generating cavitation in the medium (e.g., approximately 24-28 MPa for aqueous soft tissue). 2) Shock-Scattered Histotripsy: A pulse is typically delivered with 1-20 cycles of pressure within a duration. Scattered shock waves (compression / forward phase) from the initial individual microbubbles generated form counter shock waves that constructively interfere with the incoming reverse / extensional phase to form a high-amplitude reverse / rarefaction phase that exceeds the intrinsic threshold. In this way, a cluster of cavitation microbubbles is generated. The amplitude of the extensional phase of the pulse is sufficient to cause bubble nuclei in the medium to undergo inertial cavitation within the focal zone throughout the duration of the pulse. These nuclei scatter the incident shock wave, inverting it and constructively interfering with it to exceed the threshold for intrinsic nucleation. 3) Boiling Histotripsy: Employs pulses roughly 1-20 ms in duration. Absorption of the shock pulse rapidly heats the medium, thereby reducing the threshold for intrinsic nucleation. When this threshold coincides with the peak negative pressure of the incident wave, a boiling bubble forms at the focus.

[0093]

[0108] The large pressures generated at the focal point generate a cloud of acoustic cavitation bubbles above a certain threshold, causing localized stress and tension within the tissue, as well as mechanical collapse without significant heat accumulation. At pressure levels where cavitation is not generated, minimal effects are observed in the tissue at the focal point. This cavitation effect is only observed at pressure levels significantly greater than those that define the inertial cavitation threshold in water for similar pulse durations, around 10 to 30 MPa peak negative pressure.

[0094]

[0109] Histotripsy can be performed in numerous ways and under different parameters. Histotripsy can be performed entirely or completely non-invasively by acoustically coupling a focused ultrasound transducer to the patient's skin and delivering acoustic pulses through the skin to a focal zone (treatment zone and site) through overlying (and intervening) tissue. Histotripsy application is not limited to percutaneous approaches, but can be applied through any means that allows for transducer contact with tissue, including open, laparoscopic, percutaneous, and robotic surgical procedures. This can be further targeted, planned, directed, and observed under direct visualization via ultrasound imaging, given that the bubble cloud generated by Histotripsy can be visible, for example, as a highly dynamic echogenic region on B-mode ultrasound images, allowing continuous visualization throughout its use (and associated procedures). Similarly, treated and disrupted tissue exhibits dynamic changes (typically reductions) in echogenicity that can be used to assess, plan, observe, and monitor treatment.

[0095]

[0110] Generally, in histotripsy treatment, an ultrasound pulse with one or more acoustic cycles is applied, and bubble cloud generation relies on the pressure-relief scattering of a positive shock front (sometimes exceeding 100 MPa, P) from an initially initiated, slightly dispersed bubble (or single bubble). This is referred to as the "shock scattering mechanism."

[0096]

[0111] Figure 3 illustrates an ultrasonic pulse that can be used for shock scattering histotripsy. As shown, the ultrasonic pulse can include a leading negative half-cycle, a peak positive half-cycle, a peak negative half-cycle, and a trailing positive half-cycle (the pulse progresses from right to left on the page). As shown, the trailing positive half-cycle has a lower amplitude than the peak positive half-cycle. This mechanism relies on one (or a few sparsely dispersed) bubble being initiated in the initial negative half-cycle of the pulse at the transducer's focal point. A cloud of microbubbles is then generated by pressure-relief backscattering of the high-peak positive shock front from these sparsely initiated bubbles. These backscattered high-amplitude rarefaction waves exceed an intrinsic threshold, thus creating a localized, high-density bubble cloud. Each subsequent acoustic cycle then induces further cavitation by backscattering from the surface of the bubble cloud if the amplitude of these cycles is sufficient to grow toward the transducer. As a result, elongated, dense bubble clouds growing along the acoustic axis opposite to the ultrasound propagation direction are observed via the shock scattering mechanism. This shock scattering process makes bubble cloud generation dependent not only on the peak negative pressure but also on the number of acoustic periods and the amplitude of the positive shock. Without at least one strong shock front caused by nonlinear propagation, a dense bubble cloud is not generated when the peak negative half-period is below an intrinsic threshold.

[0097]

[0112] When the amplitude of the positive half-period of each pulse is limited, impact scattering can be minimized, and the generation of a dense bubble cloud depends on the negative half-period of the applied ultrasound pulse exceeding the "intrinsic threshold" of the medium. This is called the "intrinsic threshold mechanism."

[0098]

[0113] This threshold can be in the range of 26-30 MPa for soft tissues with a high water content, such as human tissue. In some embodiments, using this intrinsic threshold mechanism can result in well-defined and more predictable spatial extent of the lesion. With peak negative pressures (P-) not significantly higher than this threshold, subwavelength reproducible lesions as small as half the transducer's -6 dB beamwidth can be generated.

[0099]

[0114] With high-frequency histotripsy pulses, the minimum reproducible lesion size is smaller, which is beneficial for applications requiring precise lesion creation. However, high-frequency pulses are more susceptible to attenuation and aberrations, making treatment at greater penetration depths (e.g., ablation deep within the body) or through highly aberration-prone media (e.g., transcranial procedures, or procedures in which the pulse is transmitted through bone) uncertain. Histotripsy also applies because low-frequency "pump" pulses (typically <2 cycles and having frequencies between 100 kHz and 1 MHz) can be applied together with high-frequency "probe" pulses (typically <2 cycles and having frequencies greater than 2 MHz or ranging between 2 MHz and 10 MHz), and the peak negative pressures of the low and high-frequency pulses can structurally interfere to exceed the intrinsic threshold of the target tissue or media. Low-frequency pulses, which are more tolerant of attenuation and aberrations, can raise peak negative pressure P- levels in a region of interest (ROI), while high-frequency pulses, which offer greater precision, can pinpoint target locations within the ROI and raise peak negative pressure P- above intrinsic thresholds. This approach is sometimes referred to as "dual frequency," "dual beam histotripsy," or "parametric histotripsy."

[0100]

[0115] Additional systems, methods, and parameters for implementing optimized Histotripsy using impact scattering, intrinsic thresholds, and various parameters enabling frequency compounding and bubble manipulation are included herein as part of the systems and methods disclosed herein, including additional means for controlling such Histotripsy effects as related to steering and positioning the focal spot and simultaneously managing tissue effects (e.g., focal thermal collateral damage) at the treatment site or within intervening tissue. Furthermore, various systems and methods are disclosed as being included as part of the present disclosure, including future contemplated embodiments of such, which may include multiple parameters such as, but not limited to, frequency, operating frequency, center frequency, pulse repetition frequency, pulses, bursts, number of pulses, period, pulse length, pulse amplitude, pulse duration, delay, burst repetition frequency, sets of the former, multiple sets of loops, multiple and / or different sets of loops, sets of loops, and various combinations or permutations thereof.

[0101] The residual / debris cavitation nuclei challenge.

[0116] The concept of residual / debris cavitation nuclei is known. This relates to the phenomenon that after a bubble cloud is generated and quickly disintegrates within a medium (e.g., tissue), bubbles may remain slightly dispersed in the medium where the previous histotripsy therapy was applied. In some circumstances, residual cavitation nuclei may affect the histotripsy treatment and create an undesirable local environment that may challenge the ability to effectively administer histotripsy. This includes the ability of residual cavitation nuclei to disseminate cavitation with subsequent therapy pulses, affecting the spatial distribution of subsequent bubble clouds, resulting in cavitation occurring at previously treated locations while other and / or adjacent sites experience reduced bubble cloud exposure or undertreatment (i.e., a cavitation memory effect). In some scenarios and conditions, debris nuclei may preferentially cause bubble cloud formation away from the prescribed focal location, resulting in less uniform treatment and / or treatment distribution throughout a larger planning volume. Additionally, and potentially more problematic in some cases, debris nuclei can cause shielding / attenuation of subsequent pulses if debris nuclei are present along the acoustic propagation path which can attenuate the incident therapy waveform and reduce the energy delivered to the tissue. In some instances, debris nuclei can partially or completely inhibit therapy.

[0102] Bubble cloud enhancement by fast steering between overlapping focal zones

[0117] As discussed above, histotripsy therapy bubble clouds can be generated in several ways, including methods based on impact scattering and intrinsic threshold pulses. These sequences may include various types of pulses, including, but not limited to, therapy, bubble manipulation pulses, etc. In some cases, bubble manipulation pulses may be used to modify the focus and treatment zone in an attempt to move or manipulate residual bubbles / nuclei left from a previous pulse that may detrimentally affect the histotripsy therapy (e.g., act as inhibitors to subsequent histotripsy pulses).

[0103]

[0118] The present disclosure provides electronic beam steering strategies configured to modify a single focal location environment to overcome blockage, attenuation, and cavitation memory effects. The present disclosure further provides additional systems, methods, and techniques for advantageously using adjacent residual cavitation nuclei to create enhanced or expanded cavitation bubble clouds in a highly controlled manner through the use of specially designed computer-controlled hardware / software systems.

[0104]

[0119] Provided herein are novel systems and methods for forming an "enhanced excitation volume" by enhancing, expanding, and / or shaping a defined histotripsy "excitation volume" using a unique approach for re-exciting debris nuclei to create a larger bubble cloud than would be possible without the re-excitation of debris nuclei. For purposes of this disclosure, an "excitation volume" may comprise a volume in which a cavitation bubble cloud generated by a single individual focal location with an ultrasound therapy transducer array is expected to form. An "enhanced excitation volume" may comprise an enhanced or expanded volume in which a cavitation bubble cloud generated by overlapping focal locations is expected to form using electronic beam steering of the ultrasound therapy transducer array between the overlapping focal locations. As described herein, the pulse sequence and electronic beam steering for the enhanced excitation volume can be selected to advantageously utilize residual cavitation nuclei to enhance the formed cavitation volume in a highly controlled manner. Systems and methods that enable this enhanced excitation volume generally include: 1) initiating a bubble cloud at a first focal location (e.g., the natural focus of a therapy transducer array) and creating a corresponding volume called a "focal zone"; 2) electronic beam steering (e.g., phased array beam steering) the focal point to one or more additional focal locations in 2D or 3D space to create the corresponding focal zone; 3) positioning the corresponding focal zone in time and space to at least partially overlap (with the initial / previous focal zone volume) and where the pressure is at a threshold or range of the peak pressure of the previous focal location / zone; 4) re-exciting any remaining debris nuclei (within the overlap volume); and 5) together creating an overall enhanced excitation volume or "larger bubble cloud" as shown at least in Figures 5B and 5C.

[0105]

[0120] The above-described enhanced excitation volumes may be created in an unlimited permutation based on, but not limited to, the selection of spatial and temporal parameters for creating these 3D excitation volumes. Enhanced excitation volumes may include a variety of shapes and sizes, in part, by modifying the position of the steered focal locations in 3D space (and corresponding focal zones), the specific range and spacing of focal zone overlap, the beam profile overlap, the maximum distance from the first focal location to the farthest focal location, the sequencing, the timing and / or phasing of therapy and / or bubble manipulation pulses including any pauses or wait periods, and / or the number of pulses per focal location and the total number of pulses applied to the defined 3D excitation volume to continuously grow and / or fill within the excitation volume.

[0106]

[0121] Furthermore, in some embodiments, the steering direction design may be selected to minimize the need to steer directly distal to a previously targeted focal location, which not only allows for rapid steering and re-excitation of remnant nuclei, but also helps minimize obstruction or blocking effects that are not conducive to re-exciting the desired effect to create a larger excitation volume. As will be explained later, the order of steered locations can be important in minimizing obstruction or blocking effects in the presently disclosed invention.

[0107] Spatial and Temporal Considerations

[0122] The enhanced excitation volume described above can be designed, configured, and optimized based on various spatial and temporal considerations regarding: 1) the spacing of selected focal locations / zones such that the focal zone of a subsequent pulse overlaps with the focal zone of this / previous pulse, and 2) the timing of the subsequent pulse within a time span sufficient to re-excite residual nuclei present in the overlap zone from one or more previous pulses.

[0123] The selection of the spacing parameters can include selecting both the distance between adjacent focal locations and the distance (range) between the extreme focal locations. In some embodiments, there can be multiple focal location positions at uniformly and / or non-uniformly spaced coordinates (x, y, z), which can be selected / defined based on the desired target excitation volume size (e.g., unique spacing values ​​can result in various bubble cloud areas per pulse). The selection of these parameters can also be based on the unique histotripsy sequence, the properties of the acoustic field, and the corresponding bubble cloud size. In some examples, the distance between steered focal locations can be based on the wavelength of the therapy pulse. In particular, the beam profile can be proportional to the wavelength of the ultrasound signal. In some implementations, the longer the wavelength of the ultrasound signal, the larger the beam profile. Similarly, the shorter the wavelength of the ultrasound signal, the smaller the beam profile. Furthermore, the beam profile per axis (x, y, z) is also affected by the unique geometry of the therapy transducer. For example, a transducer with an f-number between 0.5 and 1 can produce a "stretching" pulse that generates a bubble cloud with a z-dimension that is longer than the dimension in x or y. Following this same principle, this may allow the ability to electronically steer to greater distances in the z direction than in x and y.

[0108]

[0124] In terms of additional temporal aspects, the timing of electronic steering (and creation of overlapping focal zones) to adjacent or distant focal locations can use similar or different pulse repetition frequencies (PRFs) and steering periods, which can be selected based on the desired dose to be delivered. In one example, an enhanced excitation volume is created using one representative histotripsy pulse delivered to a first focal location at a selected PRF, and a subsequent pulse is electronically steered and delivered to a subsequent (or second) focal location that overlaps the first focal location, with the steering period (the time from one electronic steering event to the next) being equal to the therapy PRF (the time from one therapy pulse to the next). This can be repeated until the desired total number of therapy pulses is delivered to the enhanced excitation volume. In another example, based on the number and location of the steered focal locations, some steered locations can have the same or different pulses, steering periods or PRFs, and / or other therapy parameters. For example, the electronic steering period can be shorter (faster) than the PRF. The systems described herein may also incorporate logic and / or algorithms to consider and / or adjust for spatial / temporal relationships.

[0109]

[0125] Volumes can be created based on the selection of spacing distances, various shapes, and configurations of the excitation volumes. These can include continuous or discontinuous volumes, and the selection of these parameters can be based on the application (e.g., complete tumor destruction versus total tissue removal, etc.). As a representative example, some excitation volumes may be elliptical in shape, while others may be more bulb-like. Other shapes and geometries of excitation volumes are contemplated and are within the scope of the present disclosure.

[0110]

[0126] In some embodiments, these can be created by using rapid axial beam steering (z-axis) over short distances (<5 mm) between focal locations of overlapping focal zones to help create longer, continuous enhanced excitation volumes, but using approximately the same number of pulses for a single corresponding natural focus bubble cloud. In some embodiments, lateral beam steering (x-y-axis) can be used to overlap focal locations. In other embodiments, a combination of axial and lateral electronic beam steering between focal locations (and overlapping focal locations) can be used to create more spherical enhanced excitation volumes, in part to enable more efficient / easier packing of such volumes into a larger grid pattern of planned treatment volumes. In some examples, the distribution of foci within electronic steering embodiments can be adjusted to best fit the desired treatment pattern and planning geometry, changing the aspect ratio of the inherent elliptical cloud.

[0111] Plan treatment volumes based on patterned / packed "enhanced excitation volumes"

[0127] Multiple enhanced excitation volumes (or larger bubble clouds) can also be arranged and packed into subsequent larger structures containing predefined 3D patterns and shapes that can be used to create a predefined planned treatment volume. For example, if the target tissue to be treated is a tumor, the treatment volume can encompass the tumor (and any desired margins) and be filled with multiple enhanced excitation volumes. The multiple enhanced excitation volumes can have one or more unique shapes or sizes (based on the spatial selection of focal locations and the manner in which pulses are applied to these locations). The therapy-delivering system and control software can also include logic for populating a desired and / or user-selected planned treatment volume with enhanced excitation volumes using packing rules for the placement, position, and number required to fill this desired volume / shape.

[0112]

[0128] Further arrangement and packing of the enhanced excitation volumes can include selecting their axial and radial spacing and degree of overlap. The planned treatment volume can comprise one iteration of the enhanced excitation volume or a packing of two or more variations of the planned treatment volume. For example, larger enhanced excitation volumes may be packed more centrally within the planned treatment volume, while smaller excitation volumes are placed along the periphery of the planned treatment volume. The rules and logic, including focal zone overlap and time and distance spacing, apply to both the above example and other implementations discussed herein. In a similar example, various shapes can be used to similarly pack the planned treatment volume. In this use case, the use of a more eccentric elliptical shape may be more centrally positioned, and the surrounding / adjacent enhanced treatment volumes are more spherical in shape to better enable packing of the periphery of the treatment volume (and plan).

[0113]

[0129] In particular, the described enhanced excitation volumes are generally larger than excitation volumes formed by a single discreet focal zone volume, such as an excitation volume formed at the natural focus of a therapy transducer array. Therefore, fewer enhanced excitation volumes are required to pack a given treatment volume, such as a 3 cm sphere, compared to the number of discreet excitation volumes that would be required to pack the same volume if the enhanced excitation volume technique were not used. In some embodiments, for a given treatment plan, a specified number of pulses is calculated for each excitation volume or enhanced excitation volume comprising the treatment volume to achieve complete treatment of the treatment plan while managing the thermal dose delivered to the patient. The same number of pulses is employed for each discreet focal zone (excitation volume) or enhanced excitation volume. Because fewer enhanced excitation volumes are required to populate the planned treatment volume, using enhanced excitation volumes enables faster treatment times.

[0114]

[0130] 4A-4B show a comparison of packing a treatment volume with multiple excitation volumes versus an enhanced excitation volume. Figures 4A-4B show a cross-sectional view of the treatment volume in the zx plane of the therapy transducer array. In this example, the therapy transducer array is placed at the top of the page and directs treatment along the z-axis toward the bottom of the page.

[0115]

[0131] FIG. 4A shows a treatment volume 401 packed with multiple excitation volumes 404. In this implementation, an excitation volume is each individual cavitation bubble cloud location within the treatment volume, and each excitation volume is formed at the natural focus 405 of the therapy transducer array. To navigate through the treatment volume of FIG. 4A, the Histotripsy system can use mechanical movement of the ultrasound therapy transducer array between excitation volumes (e.g., mechanically moving the transducer array to a location for a given excitation volume), as controlled by a robotic positioning system, and then perform Histotripsy therapy to generate the bubble cloud / excitation volume. This process can then be repeated for the remainder of the treatment volume by mechanically moving the transducer array to the next location for the next excitation volume, and so on.

[0116]

[0132] In contrast, FIG. 4B shows a treatment volume 401 packed with multiple enhanced excitation volumes 407. In this implementation, the enhanced excitation volumes are formed by rapidly electronically beam steering an ultrasound therapy transducer array to multiple overlapping focal locations within the enhanced excitation volume to form an enhanced or larger bubble cloud by re-exciting residual cavitation nuclei within the enhanced excitation volume. As shown in FIG. 4B, the enhanced excitation volume 407 is larger than the excitation volume 403 of FIG. 4A. This allows the treatment volume 401 to be packed with a smaller number of enhanced excitation volumes 407 compared to the number of excitation volumes 404 required to pack the volume of FIG. 4A. To navigate through the treatment volume of FIG. 4B, the histotripsy system can use mechanical movement of the ultrasound therapy transducer array between the enhanced excitation volumes, as controlled by a robotic positioning system (e.g., mechanically moving the transducer array to a given enhanced excitation volume, then electronically beam steering the ultrasound transducer array within the enhanced excitation volume, and performing histotripsy therapy to generate an enhanced bubble cloud / excited volume). This process can then be repeated for the remainder of the treatment volume by mechanically moving the transducer array to the next enhanced excitation volume, electronically beam steering the transducer, performing histotripsy to form subsequent enhanced excitation volumes, etc.

[0117]

[0133] In one specific implementation, the excitation volume formed at the natural focus of the ultrasound therapy transducer array without rapid electronic beam steering can have volume dimensions of approximately 3 mm × 3 mm × 7 mm. In contrast, the enhanced excitation volume formed by rapid electronic beam steering of the ultrasound transducer array can have volume dimensions of approximately 3 mm × 3 mm × 11 mm. For the 3 cm sphere treatment volume size of FIG. 4A, packing the treatment volume including the natural focus excitation volume requires approximately 1049 excitation volumes. However, achieving an enhanced excitation volume with a larger volume size requires only 605 enhanced excitation volumes to pack the same 3 cm treatment volume sphere. Therefore, it can be seen that the enhanced excitation volume of FIG. 4B requires fewer volumes to pack the same size treatment volume, thereby improving treatment efficiency and reducing treatment time.

[0118]

[0134] Additionally, some permutations of the parameters selected for the design of the enhanced excitation volume may preferentially assist in breaking through the physical-mechanical interfaces of adjacent focal zones (e.g., the focal zone between the natural focus and the subsequent beam-steered location) and / or adjacent excitation volumes (additional individual locations of adjacently placed volumes as part of a larger 3D planned treatment volume).

[0119]

[0135] During therapy, the histotripsy therapy transducer and robotic positioning system can then be configured to sequentially and automatically traverse the focal point of the therapy transducer through each of the discrete therapy locations of the planned treatment volume, which traverse can be, for example, a mechanical movement of the histotripsy therapy transducer by physically changing the position / orientation of the histotripsy therapy transducer with the robotic positioning system.

[0120] Enhanced Excitation Volume Implementation

[0136] As described above, for individual excitation volumes, the transducer focal point is positioned at each individual therapy location (e.g., planned focal location), and a cavitation bubble cloud or focal zone is formed at each location at a predetermined time based on the desired therapy dose for each treatment location. FIG. 5A illustrates an example of an excitation volume 504 defined by a Histotripsy bubble cloud or cavitation 502 formed at an individual focal location. The dashed ellipse of the excitation volume 504 is intended to depict the general location of the bubble cloud but not its specific size relative to the acoustic field. In the illustrated example, the therapy transducer is assumed to be on the right side of the page, and Histotripsy pulses are delivered from right to left on the page along the z-axis of the therapy transducer. In this example, the excitation volume 504 can be placed at an individual treatment location of the treatment plan within the target tissue volume (e.g., as depicted in FIG. 4A). As shown, the bubble cloud 502 can include bubbles, bubble clouds, or cavitations outside of the excitation volume 504.

[0121]

[0137] According to one aspect of the present disclosure, as shown in FIG. 5B , the enhanced excitation volume 507 can include multiple focal zones (e.g., 504 a, 504 b, and 504 c), and the therapy transducer can be configured and controlled to rapidly electronically steer between the multiple closely spaced focal zones 504 a, 504 b, and 504 c to create cavitations or bubble clouds that collectively form the enhanced excitation volume 507. In some embodiments, as shown in FIG. 5B , steering is achieved with electronic beam steering of the therapy transducer array. In some examples, axial steering along the z-axis of the transducer array can be used, starting with the first focal zone 504 a, which is furthest from the transducer. Electronic beam steering through the focal zones can be in any direction, including from most proximal to most distal, or can start at a central focal location and traverse distal or proximal to the next focal zone. Nevertheless, transitioning between focal zones from most distal to most proximal (relative to the transducer) can advantageously limit the shielding effect of residual cavitation nuclei for the first axial pass through the focal zone.

[0122]

[0138] 5B, focal zones 504a, 504b, and 504c partially overlap to create an elongated, continuous, enhanced excitation volume 507 spanning focal zones 504a, 504b, and 504c. It is an objective of this disclosure that the lower amplitude region of the Histotripsy beam sufficiently overlaps with the previously targeted focal location to re-excite residual nuclei. Nevertheless, it should be understood that in other embodiments, the focal zones need not overlap. In general, according to the present disclosure, a system can be configured to position an enhanced excitation volume at a first individual treatment location (e.g., by mechanically moving or manipulating a robotic positioning system), deliver a first Histotripsy pulse to the first treatment location including the enhanced excitation volume to create a bubble cloud / cavitation, rapidly electronically beam steer a transducer array focal point to a second focal location including the enhanced excitation volume, deliver a second Histotripsy pulse to the second focal location to create a second bubble cloud / cavitation, and repeat for the same number of desired focal locations / focal zones for a given enhanced excitation volume positioned at the individual treatment locations.

[0123]

[0139] 5B shows three overlapping focal zones (e.g., 504a, 504b, 504c) per enhanced excitation volume 507, any number of focal zones can be created depending on the treatment plan, target tissue volume size, and desired or prescribed therapy dose. For example, two overlapping focal locations per enhanced excitation volume are possible, as are four or more focal locations per enhanced excitation volume, provided there is sufficient beam overlap of the lower amplitude portions of the beams to re-excite residual cavitation nuclei at previously treated focal locations.

[0124]

[0140] The electronic beam steering distance between focal locations / zones can vary, but generally, the distance between focal locations can be optimized based on the size of the bubble cloud generated by the selected pulse. In some examples, the steering distance between focal locations can be based on the wavelength of the ultrasound pulse and whether the steering is axial or lateral. For histotripsy systems using selected pulses to generate the bubble cloud sizes described and depicted in this disclosure, it has been found that the optimal axial spacing between focal locations can range from 1 mm to 5 mm between subsequent focal locations. In one embodiment, a 2.5 mm spacing between focal locations advantageously provides sufficient overlap between bubble clouds at adjacent focal locations, optimally utilizing the lower amplitude portion of the beam to re-excite residual cavitation nuclei at previously treated focal locations, improving the consistency and continuity of the bubble cloud across all focal locations. In embodiments in which focal locations are laterally spaced from one another, the range of movement / steering can be different from the range of movement / steering in axially spaced embodiments. Generally, lateral spacing can be within a 1 mm radius from the transducer focal point. In one embodiment, 0.5 mm spacing between laterally spaced focal locations advantageously provides overlap between bubble clouds at adjacent focal locations, optimally utilizing lower amplitude portions of the beam to re-excite residual cavitation nuclei at previously treated focal locations, improving bubble cloud consistency and continuity across all focal locations.

[0125]

[0141] The Histotripsy pulse delivered to each focal location can comprise an impacted distributed Histotripsy pulse, such as that illustrated in FIG. 3. For example, in FIG. 5B, the Histotripsy system can be configured to position the therapy transducer focal point at a first focal location 504a and deliver the Histotripsy pulse of FIG. 3 to this first focal location. More specifically, the pulse can include a peak positive half-period, followed by a peak negative half-period, followed by a trailing positive half-period. As shown in FIG. 3, the trailing positive half-period can have a smaller amplitude than the peak positive half-period. After the pulse is delivered to the first focal location, the transducer array can be quickly electronically beam-steered to a second focal location, and a pulse can be delivered to the second focal location. This process can be repeated for a third focal location. In some embodiments, the transducer focal point is steered very quickly, and subsequent pulses are delivered to subsequent focal locations such that bubble clouds can be generated at second or subsequent focal locations during the life cycle of the previous bubble cloud. In some examples, the "life cycle" of a bubble cloud is considered to be the time the bubble cloud is formed within a focal location. In other embodiments, the "life cycle" of a bubble cloud can include the presence of residual nuclei at a focal location even after the initial bubble cloud expands and collapses. For example, a first bubble cloud can be generated at a first focal location with a therapy pulse, and the transducer can then be electronically beam steered quickly to a second focal location and deliver a therapy pulse to the second focal location to generate a second bubble cloud during the life cycle of the first bubble cloud (e.g., before the first bubble cloud collapses). The overlapping focal zones combined with rapid electronic beam steering and repetition of this sequence create a larger, enhanced excitation volume.

[0126]

[0142] In one specific embodiment, the therapy pulses can have a repetition rate of approximately 600 Hz, and the timing of the rapid electronic beam steering can be as follows: 1) One repetition of the therapy pulse is delivered to a first focal location (e.g., 504a in FIG. 5B). 2) The next repetition of the therapy pulse is delivered to a second focal location (e.g., 504b in FIG. 5B) via electronic beam steering. In this example, the duration of steering is equal to the duration of the therapy sequence (1 / 600 Hz ~ 1.7 ms). 3) The next repetition of the therapy pulse is delivered to a third focal location (e.g., 504c in FIG. 5B) via electronic beam steering, with the duration of steering equal to the duration of the therapy sequence (1 / 600 Hz ~ 1.7 ms). 4) The next repetition of the therapy pulse is delivered to the first focal location (e.g., 504a in FIG. 5B) via electronic beam steering, with the duration of steering equal to the duration of the therapy sequence (1 / 600 Hz ~ 1.7 ms). Additionally, the above process can be repeated until a targeted dose, which may include a targeted number of pulses, is delivered to a focal location at the treatment location. While the embodiment described above and in FIG. 5B describes rapid steering between three distinct focal locations for each enhanced excitation volume, it should be understood that other embodiments can include any number of rapidly beam-steerable focal locations (e.g., two, four, five, six, or more) and can be variably positioned in 3D space.

[0127]

[0143] Depending on the desired or prescribed dose for a given individual treatment location, a dose of therapy can be delivered to each focal location multiple times. For example, therapy can be provided to a first focal location, then a second focal location, then a third focal location, then moving back to the first focal location and repeating the process. In other embodiments, only a single dose per focal location may be sufficient to achieve the desired dose for this treatment location. In some embodiments, the dose is varied non-uniformly in space and time across a planned treatment volume that includes multiple enhanced excitation volumes. For example, the spread of therapy in each iteration can also be configurable (e.g., n pulses are delivered to a first focal location, then n pulses are delivered to a second focal location, then n pulses are delivered to a third focal location, and then iterating through the focal locations again, where n can be equal to 1, 2, ..., 100, or more, etc.).

[0128]

[0144] 5B, the therapy transducer can be electronically beam steered axially along the z-axis of the therapy transducer between discrete focal locations. For example, a first focal location 504a can be the natural focal point of the therapy transducer, a second focal location 504b can be axially displaced from the first focal location by a predetermined (overlapping) distance toward the transducer, and a third focal location can be axially displaced from the second focal location toward the transducer.

[0129]

[0145] It should be understood that in other embodiments, electronic beam steering can be performed laterally in the x and y directions. One example of lateral electronic beam steering is shown in FIG. 5C , where a first focal zone 504 a is laterally offset in the x and y directions from a second focal zone 504 b to form an enhanced excitation volume 507. As shown in this embodiment, the focal zones partially overlap, but as discussed above, there are advantages to having the focal zones overlap, but this is not necessary. It should also be understood that any of the steering described in FIGS. 5B and 5C can be performed via electronic beam steering.

[0130]

[0146] While FIG. 5B illustrates an embodiment in which multiple focal zones are axially spaced apart in the z direction, and FIG. 5C illustrates an embodiment in which multiple focal zones are laterally spaced apart in the xy direction, it should be understood that in other embodiments, rapid steering can include a combination of movement / steering in both the xy and z directions.

[0131]

[0147] 6A-6B illustrate one embodiment of an electronic beam steering pattern used to generate an enhanced excitation volume. In this example, the focal point of the ultrasound transducer array can be steered laterally (e.g., in the x- and y-axes) from the natural focal point 604a of the transducer array. The specific sequence and timing of the electronic beam steering can be selected and chosen to optimally maintain cavitation and / or to advantageously use or re-excite residual cavitation. In one specific embodiment, histotripsy therapy can be initiated at the natural focal point 604a of the transducer array. The focal point can then be electronically beam steered sequentially through the remaining focal locations of the enhanced excitation volume, moving from the natural focal point 604a to focal locations 604b, 604c, 604d, 604e, 604f, 604g, 604h, and 604i. The individual points marked as focal locations in FIGS. 6A-6B represent the centers of the focal locations. It should be understood that the focal zones corresponding to the bubble clouds or cavitations created when Histotripsy therapy is administered may themselves overlap in the illustrated embodiment.

[0132]

[0148] Although the beam steering pattern in FIG. 6A is generally shown as a wheel or ring around a central natural focal point, it should be understood that the beam steering pattern can be traversed in either a clockwise or counterclockwise direction.

[0133]

[0149] Furthermore, according to some embodiments, the beam steering pattern can revisit or repeat therapy delivery to some or all of the focal locations as the transducer array is beam steered through the locations. Parameters for revisiting or repeating therapy delivery to the focal locations can be predetermined or customized by the user. In one embodiment, a key element of the electronically steered pattern is that there are successive instances of both new cavitation events and re-stimulation of residual nuclei at the steered focal locations within the enhancement volume. In addition to these events at the current focal location, previously sonicated locations are treated by re-excitation of their residual nuclei. This process of periodically revisiting points can greatly aid in sustained cavitation throughout the enhancement excitation volume, particularly along the central axis of the transducer. In practice, it has been determined that periodically revisiting the central axis of the enhancement excitation volume during traversal of the electronic beam steering pattern is beneficial in maintaining cavitation throughout the enhancement excitation volume.

[0134]

[0150] 6B, the natural focal point 604a of the enhanced excitation volume can be re-excited after a predetermined number of focal locations (e.g., every new focal location, every two focal locations, every three focal locations, etc.) Alternatively, the steering logic can require that no more than two, no more than three, no more than four, or no more than five locations be treated, and then return to a focal location along the central axis of the transducer to re-excite this focal location along the central axis of the transducer.

[0135]

[0151] For example, one unique beam steering pattern may require revisiting and re-energizing the natural focus (or the focal location at the center of the beam steering pattern) at least every three focal locations. Referring to FIG. 6A, this beam steering pattern may start at natural focus 604a, steer the electronic beam to focal location 604b, then to focal location 604c, then return to natural focus 604a, and maintain re-energization of this entire steered sector throughout the raster of the pattern. The pattern may then proceed to focal location 604c, move to focal location 604d, and then return to natural focus 604a. From there, the pattern can continue: focal location 604d, focal location 604e, back to natural focus 604a, focal location 604e, focal location 604f, back to natural focus 604a, focal location 604f, focal location 604g, back to natural focus 604a, focal location 604g, focal location 604h, back to natural focus 604a, focal location 604h, and finally back to focal location 604i. In the above pattern, at least a portion of natural focus 604a is re-excited every three focal locations. This ensures that residual nuclei in the central portion of the enhanced excitation volume (e.g., in an axial plane at least partially intersecting the transducer's natural focus) are periodically re-excited (e.g., after a set number of focal locations), further supporting cavitation formation at peripheral / surrounding focal locations. 6A-6B steers between focal locations only laterally from the natural focus (e.g., in the xy plane), it should be understood that the enhanced excitation volume exists in three dimensions. The result of this lateral steering is to increase the lateral dimensions of the enhanced excitation volume, which helps to create a more spherical excitation volume compared to a generally column-shaped excitation volume formed at a single focal location.

[0136]

[0152] 7A-7B illustrate another embodiment of an electronic beam steering pattern that includes beam steering in 3D space (e.g., a combination of steering in the x, y, and z directions). Similar to the pattern illustrated in FIGS. 6A-6B, the pattern in FIGS. 7A-7B can include multiple equilateral triangular electronic beam steering paths. However, these triangles are spread across the axial (z) dimension, resulting in a curved arc from natural focus (0,0,0) to (0,0,-Z), with two intervening points at ¼ and ½ (-Z). A single arc travels from the natural focus of transducer 704a = (0,0,0) to 704b = ((sqrt(2)*R / 2), from -(sqrt(2)*R) / 2,-Z / 4) to 704c = (R,0,-Z / 2), and back to the central axis at 704d = (0,0,-Z). The entire arc can be rotated 45° every fifth pulse when the pattern returns to 704a at the natural focus. In some embodiments, the rotation can be finer (e.g., less than 45°) or coarser (e.g., up to 90°) depending on the implementation. In the example of FIGS. 7A-7B, residual nuclei at the central axis of the enhanced excitation volume (e.g., the axial plane intersecting the natural focus of the transducer) are at least partially re-excited after a set number of focal locations to maintain cavitation at the central axis and support cavitation formation at focal locations lateral to or outside the central axis of the enhanced excitation volume. The pattern iterates through an ordered list of planned focal locations, with 704a and 704d bracketing each series of four points, resulting in 18 unique focal locations for a pattern with 32 planned focal locations. The 32-point rotated pattern can then be repeated until the forbidden dose per target location within a given volume plan is reached.

[0137]

[0153] 8A-8B illustrate yet another embodiment of an electronic beam steering pattern including beam steering in 3D space between overlapping focal locations. In the embodiment of FIGS. 8A-8B, the beam steering pattern comprises a central row 809a of focal locations positioned within multiple vertical or axial peripheral or outer edge rows 809b / c / d / e of focal locations. It should be understood that in FIGS. 8A-8B, the therapy transducers are positioned at the top of the page and direct ultrasound energy toward the bottom of the page. In some examples, the central row can include the natural focal point 804a, or at least partially overlap with the natural focal point of the therapy transducer array, or be positioned along the central axis of the transducer array. Bubble clouds formed at focal locations in the central row 809a can partially overlap with bubble clouds formed at focal locations in the peripheral rows 809b / c / d / e.

[0138]

[0154] In some embodiments, the beam steering pattern of FIGS. 8A-8B can revisit or repeat therapy delivery to some or all of the focal locations in the central row 809a or within the central axis of the transducer array as the transducer array is beam steered through focal locations in rows 809b / c / d / e. Parameters for revisiting or repeating therapy delivery to focal locations in the central row or central axis can be predetermined or customized by a user. In practice, it has been determined that at least partially periodically revisiting focal locations in the central row or central axis of the enhanced excitation volume during traversal of the electronic beam steering pattern can advantageously re-excite residual cavitation at the center of the volume, thus supporting enhanced cavitation at peripheral or surrounding focal locations. Thus, according to one embodiment and as further depicted in FIG. 8B , focal locations in the central row 809a of focal locations of the enhanced excitation volume can be re-excited after a predetermined number of focal locations (e.g., every new focal location, every two focal locations, every three focal locations, etc.). In practice, it has been determined that periodically revisiting at least one focal location in the central row of the enhanced excitation volume during traversal of the electron beam steering pattern is beneficial in maintaining cavitation throughout the enhanced excitation volume.

[0139]

[0155] In one specific embodiment, the steering pattern begins by forming a cavitation at the natural focal point 804a of the central row 809a. Electronic beam steering can then shift the focus of the transducer array to focal location 804b in row 809b (the central focal location in that row), and then return the focus to focal location 804c in row 809a. To complete excitation in both the central row and row 809b, electronic beam steering can continue by exciting focal location 804d in row 809b, then focal location 804e in the central row 809a, and then focal location 804f in row 809b. The steering pattern can then begin cavitation in a new row (e.g., 809c), exciting focal locations in the outer edge or peripheral rows, and then continuing the pattern of exciting focal locations in the central row. It is noted that in this specific implementation, the excitation / steering order within the rows remains consistent. For example, the order of excitation of focal locations within the central row can start at natural focal point 804a, move to the outer edge or peripheral row, return to focal location 804c, move to the outer edge or peripheral portion, and then return to central focal location 804e within the central row. Similarly, patterns within the outer edge or peripheral row can follow a unique sequence, such as starting at a central focal location within a given outer edge or peripheral row (e.g., focal location 804b in row 809b), returning to the central row, steering again to a lower or distal focal location in the outer edge or peripheral row (e.g., focal location 804d in row 809b), returning to the central row, and then moving to the top or proximal focal location in that row (e.g., focal location 804f in row 809b). In some embodiments, steering can be performed from the most distal point to the most proximal point in any series of three focal locations, then returning to the most distal end of the pattern and beginning a new series of three points.

[0140]

[0156] In some embodiments, the specific order of excitation within the rows can be changed from that described above, but the overall concept of alternating between the central and peripheral rows with each subsequent therapy pulse sequence delivery can be maintained. It may also be desirable to re-excite each focal location within the central row once before repeating the process. For example, instead of re-exciting focal location 804a twice and then re-exciting focal location 804c once, focal locations 804a, 804c, and 804e should all be re-excited in some predetermined order.

[0141]

[0157] Generally, it is desirable to alternate between a single peripheral or edge row and the central row until all points in both rows have been excited / re-excited, and then move to a different peripheral / central row pair. Nevertheless, it should be understood that other embodiments may include electronic steering between rows without exciting / re-exciting all focal locations in each peripheral row.

[0142]

[0158] Figure 8B shows the general path between the focal locations of all the rows. The result is a 3D steering pattern that includes electronic steering between the central and peripheral rows, with control logic calling for re-excitation of the focal location of the central row to help maintain cavitation throughout the enhanced excitation volume.

[0143]

[0159] The rapid electronic beam steering concepts described and illustrated herein help to advantageously take into account residual cavitation nuclei to enhance treatment of individual target locations by creating an enhanced excitation volume with overlapping or adjacent focal zones.

[0144]

[0160] In the example of FIG. 5B , where rapid steering is performed toward the transducer in the z-direction for each subsequent focal location, residual cavitation nuclei tend to remain at the previous focal location. For example, in FIG. 5B , after a first pulse is delivered to a first focal location to form focal zone 504a, the bubble cloud quickly expands and collapses, leaving residual cavitation nuclei near the first focal zone. Instead of transmitting another pulse to the first focal location, the system instead quickly steers to a second focal location and delivers another pulse to this location, forming another and overlapping focal zone 504b that is substantially free of interference or adverse effects of the residual cavitation nuclei remaining in first focal zone 504a. Note that this benefit is achieved by steering the transducer focal point toward the therapy transducer in the z-direction, as opposed to steering it away from the therapy transducer. This allows residual cavitation nuclei to remain distal to the current bubble cloud. If the focal spot were instead steered to a new focal location away from the transducer (e.g., distal to the previous bubble cloud), subsequent pulses would have to travel through residual cavitation nuclei, which could cause problems with bubble cloud formation and / or the variability or uniformity of subsequent bubble clouds. While there are no residual cavitation nuclei in the second focal zone 504b, nuclei remaining near the first focal zone 504a could be re-excited by the pulse delivered to the second focal location, effectively expanding the bubble cloud in this focal zone (e.g., the pulse delivered to the second focal location would create cavitation in the first focal zone 504a and the second focal zone 504b). Similarly, the transducer could then be quickly steered to a third focal location, and another pulse delivered to generate cavitation in the third focal zone 504c. During this first step, the third focal zone 504c is relatively free of residual cavitation nuclei, maximizing the efficiency of the pulse delivered to the third focal location.Additionally, residual cavitation nuclei in the first focal zone 504a and the second focal zone 504b may also be re-excited by the pulse delivered to the third focal location, effectively increasing the size of the enhanced excitation volume. During this first step, the third focal zone 504c is free of debris nuclei. When rapid steering to re-excite debris nuclei is desired, the selection of the electronic steering direction minimizes the number of times the system must steer distal to the point where the previous cloud was generated (thus minimizing the effects of occlusions as much as possible, but not eliminating them). As described, the location of the focal location / zone, as well as the direction and path steered to the next and / or adjacent focal location, can be varied based on the desired effect (e.g., whether resumption is more beneficial versus the possibility of acting as an inhibitor), and it is possible to envision how therapy versus bubble manipulations are performed in tandem within each other's context.

[0145]

[0161] The time to return to a given focal location for additional therapy pulses can also be adjusted or controlled to account for residual cavitation nuclei. In one embodiment, the following equation can be used to determine when to steer the beam between focal locations and / or when to return to a previously treated focal location:

[0146]

[0162]

number

[0147]

[0163] As described in the equation, for some embodiments and focal locations, the time to return to a given focal location can be equal to the number of unique focal locations (e.g., three focal locations) divided by the pulse repetition frequency (PRF) of the pulse.

[0148]

[0164] As mentioned above, the therapy pulse of a given pulse sequence delivered to each focal location can be a bombarded scattering pulse that may include a peak positive half-cycle, followed by a peak negative half-cycle, followed by a trailing peak positive half-cycle, which pulse is generally responsible for creating cavitation at each focal location.

[0149]

[0165] In some embodiments, the unique pulse can include one or more low-amplitude pulses following a therapy pulse designed and configured to manipulate, push, interact with, or suppress residual cavitation nuclei. In one embodiment, these additional pulses can include one, two, or more low-amplitude pulses. These low-amplitude pulses can have amplitudes substantially less than those of the therapy pulses. In some embodiments, the low-amplitude pulses are designed and configured to push or flush residual cavitation nuclei from a previously treated focal location. In other embodiments, the low-amplitude pulses are designed and configured to spatially modulate cavitation nuclei within the previously treated focal location. For example, with reference to FIG. 5B , the transducer focal point can be positioned at a first focal location 504a, and a bombarded scattering pulse can be delivered to the first focal location to create a bubble cloud at the first focal location, as previously described. Immediately following the bombarded scattering pulse, the transducer array can deliver one or more low-amplitude pulses to the focal location to spatially modulate the cavitation nuclei within the first focal location. The transducer array can then be quickly steered to a second focal location and treatment can continue as previously described. Briefly, the pulses can be modified to include multiple low amplitude pulses immediately following the therapy pulse or impacted scattering pulse to advantageously spatially modulate or manipulate residual cavitation nuclei in an advantageous manner.

[0150]

[0166] Figure 9A illustrates axial beam profiles for the axially spaced focal locations illustrated in Figures 9B, 9C, and 9D. These focal locations can correspond to focal zones 504a, 504b, and 504c, as well as the focal locations described above with reference to Figure 5B. In this embodiment, the first focal location shown in Figure 9B corresponds to the natural focus of the therapy transducer. Figure 9C illustrates a second focal location steered 2.5 mm in the z-direction from the first focal location toward the transducer. Figure 9D illustrates a third focal location steered 2.5 mm in the z-direction from the second focal location toward the transducer.

[0151]

[0167] Figure 10A illustrates axial beam profiles for the laterally spaced focal locations illustrated in Figures 10B and 10C. These focal locations can correspond to focal zones 504a and 504b described above with reference to Figure 5C. In this embodiment, the first focal location shown in Figure 10B corresponds to a location steered 0.5 mm in the y-direction toward the natural focal point of the therapy transducer. Figure 10C depicts a second focal location steered 0.5 mm in the opposite direction from the natural focal point of the therapy transducer (e.g., -0.5 mm from the natural focal point).

[0152]

[0168] 11A and 11B illustrate how the spacing between focal locations affects the overlap between adjacent focal zones and can determine whether residual cavitation nuclei are re-excited by a subsequent therapy pulse. In the graph of FIG. 11A, the spacing between the three focal locations includes 7 mm axially between each adjacent focal location, resulting in a first focal location at the natural focal point of the transducer, a second focal location axially spaced 7 mm from the first focal location, and a third focal location axially spaced 7 mm from the second focal location. In this example, the spacing results in focal zones with insufficient overlap between adjacent beam profiles, making the overall treatment at this treatment location (i.e., within the enhanced excitation volume) non-uniform. In contrast, the example of FIG. 9A has 2.5 mm spacing between adjacent focal locations, resulting in sufficient overlap between adjacent focal zones to facilitate re-excitation of residual cavitation nuclei and a more uniform cavitation distribution at the treatment location.

[0153]

[0169] 12A, 12B, and 12C illustrate heat maps of histotripsy therapy performed at 1) a single focal location at a treatment location where 1000 pulses were delivered (FIG. 12A), 2) three axially spaced focal locations at a treatment location where a total of 1000 pulses were delivered (FIG. 12B), and 3) a single focal location at a treatment location where 580 pulses were delivered (FIG. 12C). 12D, 12E, and 12F illustrate exposure levels of histotripsy therapy performed at 1) a single focal location at a treatment location where 1000 pulses were delivered (FIG. 12D), 2) three axially spaced focal locations at a treatment location where a total of 1000 pulses were delivered (FIG. 12E), and 3) a single focal location at a treatment location where 580 pulses were delivered (FIG. 12F). Figures 12G, 12H, and 12I illustrate the lesion and exposure levels of histotripsy therapy performed at 1) a single focal location at a treatment location where 1000 pulses were delivered (Figure 12G), 2) three axially spaced focal locations at a treatment location where a total of 1000 pulses were delivered (Figure 12H), and 3) a single focal location at a treatment location where 580 pulses were delivered (Figure 12I). Compared to treatment at a single focal location, treatments involving three axially spaced focal locations (Figures 12B, 12E, 12H) distribute a sufficiently destructive number of exposures over a larger area for the same number of pulses. In one experiment, treatment of a 3 cm sphere of tissue with multiple individual treatment locations, each treated with a single focal location (e.g., the treatment protocol in Figures 12A, 12D, 12G), resulted in 21 minutes and 26 seconds of "therapy on-time."In contrast, treatment of a 3 cm sphere of tissue with multiple individual treatment locations, where each treatment location is treated at three axially spaced focal locations (e.g., treatment protocols in Figures 12B, 12E, and 12H), resulted in "on-time therapy" of only 12 minutes and 21 seconds, a major reduction in on-time therapy.

[0154]

[0170] The embodiments of Figures 12C, 12F, and 12I show what treatment would be like at a single focal location per individual treatment location in a 3 cm sphere of tissue with on-time therapy matching that of the embodiments of Figures 12B, 12E, and 12H (e.g., 12 minutes and 21 seconds of on-time). As can be seen, the thermal map, exposure level, and lesion generation lag lag behind the other two embodiments. This experiment shows how rapid steering of the transducer between multiple focal locations for a given treatment location can improve therapy quality and quickly reduce the amount of on-time (e.g., ultrasound energy application) delivered for a given treatment. Rapid steering between multiple focal locations for a given individual treatment location uses the same number of pulses more efficiently than single focal location treatment by distributing a sufficiently destructive number of exposures over a larger volume.

[0155]

[0171] 13 is a schematic diagram illustrating the spatial relationship between a therapy transducer 1300, a first focal location 1304a, a second focal location 1304b, and a third focal location 1304c. As mentioned above, in some embodiments, the first focal location can comprise the natural focus of the transducer, and the second and third focal locations can be achieved with electronic steering of the transducer array. In this example, a distance dz separates adjacent focal locations.

[0156]

[0172] Figure 14 illustrates the relationship between bubble cloud size (area) and the distance between adjacent focal locations. As shown in Figure 14, in one embodiment, a 2.5 mm spacing between focal locations also produces the largest cloud per pulse, highlighting how previously excited zones can be re-excited by targeted adjacent zones, expanding the cloud with each pulse.

[0157] Therapy Components

[0173] The therapy subsystem can operate with other subsystems to create, optimize, deliver, visualize, monitor, and control acoustic cavitation, also referred to herein and hereinafter as "histotripsy" and its derivatives, including boiling histotripsy and other thermal high frequency ultrasound approaches. It is noted that the disclosed invention may also benefit from other acoustic therapies that do not include cavitation, mechanical, or histotripsy components. The therapy subsystem can include, among other features, an ultrasound therapy transducer and pulse generator system configured to deliver ultrasound pulses to tissue.

[0158]

[0174] To produce and deliver histotripsy and histotripsy derivatives, the therapy subsystem may also include components including, but not limited to, one or more function generators, amplifiers, therapy transducers, and power sources.

[0159]

[0175] Therapy transducers can comprise single or multiple elements configured to be excited with high-amplitude electrical pulses (>1000V, or any other voltage that may cause harm to the body). The amplitude required to drive a therapy transducer for histotripsy varies depending on the transducer design and material used (e.g., solid or polymer / piezoelectric composites, including ceramic or single crystal), and the transducer center frequency, which is directly proportional to the thickness of the piezoelectric material. Thus, transducers operating at high frequencies require lower voltages to generate a given surface pressure than those required by low-frequency therapy transducers. In some embodiments, the transducer elements are formed using piezoelectric polymer composite materials or solid piezoelectric materials. Furthermore, the piezoelectric material can be of polycrystalline / ceramic or single-crystal composition. In some embodiments, the transducer elements can be formed using silicon using MEMs technology, including CMUT and PMUT designs.

[0160]

[0176] In some embodiments, the function generator may include a field programmable gate array (FPGA) or other suitable function generator. The FPGA may be configured with parameters previously disclosed herein, including but not limited to frequency, pulse repetition frequency, burst, number of bursts, where a burst may include a pulse, number of pulses, pulse length, pulse duration, delay, burst repetition frequency or duration, a set of bursts may include a set of parameters, a set of loops may include various sets of parameters with or without a delay or various delays, multiple loop sets of various time delays and independently controlled, and various combinations and permutations of such, throughout, may be repeated, and / or new loop sets may be introduced.

[0161]

[0177] In some embodiments, the generator or amplifier may be a general-purpose single-cycle or multi-cycle pulse generator configured to support drive via Class D or inductive drive and across all envisioned clinical applications and use environments, some of which are further discussed later in this disclosure. In other embodiments, the Class D or inductive current driver may be configured with converter and / or automatic converter drive circuitry to further provide step-up / down components and, in some cases, preferably to enable amplitude step-up. These may also include inherent protection features to further support the system and provide the ability to protect other components of the system (e.g., therapy transducer and / or amplifier circuitry) and / or the user from various threats, including, but not limited to, the use environment, electrical safety threats that could potentially lead to the system and therapy system, and user harm, adverse effects, or problems.

[0162]

[0178] The disclosed generators can enable and support the system's ability to select, vary, and control (through available software tools) various parameters, including but not limited to those previously disclosed, as well as the ability to start / stop therapy, set and read voltage levels, pulse and / or burst repetition frequencies, number of cycles, duty cycles, active channels and delays, etc., modulate pulse amplitude on fast time scales independent of the high voltage source, and / or perform other service, diagnostic, or therapeutic features.

[0163]

[0179] In some embodiments, the therapy subsystem and / or its components, such as amplifiers, may further comprise integrated computer processing capabilities, may be networked, connected, accessed, and / or may be removable / portable, modular, and / or interchangeable between systems, and / or may be driven / commanded from / by other systems, or various combinations. Other systems may include other acoustic cavitation / histotripsy, HIFU, HITU, radiation therapy, radiofrequency, microwave, and cryoablation systems, navigation and localization systems, open surgery, laparoscopic, single incision / single port, endoscopic, and non-invasive surgical robotics, laparoscopic or surgical towers with other energy-based or vision systems, surgical system racks or booms, imaging carts, etc.

[0164]

[0180] In some embodiments, the amplifier or amplifiers may comprise a class-D amplifier and associated drive circuitry, including matching network components. Depending on the electrical impedance of the transducer element and the selection of matching network components (e.g., an LC circuit made from a series inductor L1 and a parallel capacitor C1), the combined impedance can be set aggressively low to produce the high-amplitude electrical waveform required to drive the transducer element. The maximum amplitude of the class-D amplifier depends on the circuit components used, including the drive MOSFET / IGBT transistor, matching network components or inductors, and transformer or autotransformer, and may typically be in the low kV (e.g., 1-3 kV) range.

[0165]

[0181] The therapy transducer elements are excited with an electrical waveform having an amplitude (voltage) sufficient to produce a pressure output sufficient for histotripsy therapy. The excitation field can be defined as the required waveform voltage per thickness of the piezoelectric element. For example, a piezoelectric element operating a transducer at 1 MHz will be half the thickness of an equivalent 500 kHz element, and will therefore require half the voltage to achieve the same electric field and surface pressure.

[0166]

[0182] The therapy subsystem can also include therapy transducers of various designs and working parameters to support use in various treatments (and treatment environments). The system may be configured with one or more therapy transducers that are further interchangeable and can operate with various aspects of the system in similar or different ways (e.g., can interface to a robotic arm using common interfaces and interchange features, or conversely, can be adapted to operate with application-specific imaging probes, where different imaging probes can interface and integrate with therapy transducers in specifically different ways).

[0167]

[0183] Therapy transducers may be constructed from a variety of parameters that may include size, shape (e.g., rectangular or circular, anatomically curved housing, etc.), geometry, focal length, number of elements, size of elements, distribution of elements (e.g., number of rings in an annular pattern transducer, size of rings), frequency, enabling electronic beam steering, etc. Transducers may be constructed from a variety of materials (e.g., piezoelectric, silicon, etc.), form factors and types (e.g., machined elements, chip-based, etc.), and / or by a variety of methods of their fabrication.

[0168]

[0184] Transducers can be designed and optimized for clinical applications (e.g., abdominal tumors, peripheral vascular disease, fat ablation, etc.) and desired outcomes (e.g., acoustic cavitation / histotripsy without thermal injury to intervening tissues), as well as to provide a wide range of working conditions, including relatively shallow, superficial targets (e.g., thyroid or breast nodules) and deeper or more difficult-to-reach targets such as centrally located liver or brain tumors. They can be configured to enable acoustic cavitation / histotripsy under various parameters and sets, as enabled by the system components described above (e.g., function generators and amplifiers, etc.), including, but not limited to, frequency, pulse repetition rate, pulses, number of pulses, pulse length, pulse duration, delay, repetition, synchronization delay, synchronization period, synchronization pulse, synchronization pulse delay, various loop sets, etc., and permutations thereof. Transducers can also be designed to enable activation of drug payloads stored in tissues through various means, including injection, displacement, or delivery in micelles or nanostructures.

[0169] Integrated Imaging

[0185] The disclosed system can include various imaging modalities that allow the user to visualize, monitor, and collect / use feedback of the patient's anatomy, related areas of interest and treatment / treatment site, as well as surrounding and intervening tissues, to assess, plan, and perform treatment and adjust treatment parameters as needed. Imaging modalities can include various ultrasound, X-ray, CT, MRI, PET, fluoroscopic, optical, contrast- or agent-enhanced versions, and / or various combinations thereof. It is further disclosed that various image processing and characterization techniques can also be utilized to provide enhanced visualization and user decision-making. These can be selected or commanded manually by the user or automatically by the system. The system can be configured to enable side-by-side imaging, toggling, overlay, 3D reconstruction, segmentation, registration, multimodal image fusion, image flow, and / or any other method that allows the user to identify, define, and communicate various aspects of using imaging during treatment as displayed in various system user interfaces and displays. Examples may include, by way of non-limiting example, identifying important structures such as vessels, ducts, nerves, ureters, fissures, capsules, tumors, tissue trauma / injury / disease, other organs, connective tissues, and / or one or more important structures in context with each other (e.g., tumor-draining lymphatics or vasculature, or tumors close to organ capsules or other underlying organs) to locate, display, and characterize potential treatment sites within, on, and / or surrounding an area, organ system, organ, or tissue of interest.

[0170]

[0186] The system may be configured to include on-board integrated imaging hardware, software, sensors, probes, and software, and / or may be configured to communicate and interface with external imaging and image processing systems. The aforementioned components may also be integrated into the system's therapy subsystem components, including probes, imaging arrays, or the like, and electrically, mechanically, or electromechanically integrated with the therapy transducer. This may, in part, provide the ability to perform geometrically aligned imaging and therapy, with therapy directly within the field of view and possibly in line with the imaging. In some embodiments, this integration may provide a fixed orientation of the imaging capability (e.g., imaging probe) to the therapy transducer in a contextualized manner. In other embodiments, the imaging solution may have the ability to move or adjust its position, including modifying angle, range (e.g., distance from the therapy transducer or patient), rotation (e.g., imaging plane in the example of an ultrasound probe), and / or other parameters, including dynamically moving / adjusting them while actively imaging. The imaging component or probe may be encoded such that its orientation and position relative to another aspect of the system, such as a therapy transducer and / or a robotic-enabled positioning component, may be determined.

[0171]

[0187] In one embodiment, the system can include an on-board ultrasound further configured to allow the user to visualize, monitor, and receive feedback about the treatment site through the system display and software, including enabling ultrasound imaging and characterization (and its various forms), ultrasound-guided planning, and ultrasound-guided therapy, all in real time. The system can be configured to allow the user to image the patient manually (e.g., by hand or using a robotic-enabled imager), semi-automated, or fully automated means.

[0172]

[0188] In some embodiments, imaging feedback and monitoring can include monitoring changes in backscatter from the bubble cloud, backscatter speckle reduction, backscatter speckle statistics, tissue mechanical properties (i.e., elastography), tissue perfusion (i.e., ultrasound contrast), shear wave propagation, acoustic emission, electrical impedance tomography, and / or various combinations thereof, including those displayed in or integrated with other forms of imaging (e.g., CT or MRI).

[0173]

[0189] In some embodiments, imaging including feedback and monitoring from backscatter from the bubble cloud can be used as a method for quickly determining whether the histotripsy process has been initiated, properly maintained, or possibly extinguished. For example, this method allows drug delivery, tissue erosion, and the like to be continuously monitored in real time. The method can also provide feedback that allows the histotripsy process to be initiated at high intensity and maintained at much lower intensity. For example, backscatter feedback can be monitored by any transducer or ultrasound imager. By measuring the feedback of the therapy transducer, an accessory transducer can be configured to deliver interrogation pulses or passively detect cavitation. Furthermore, the nature of the received feedback can be used to adjust acoustic parameters (and associated system parameters) to optimize drug delivery and / or the tissue erosion process.

[0174]

[0190] In some embodiments, imaging, including feedback and monitoring from backscatter, and speckle reduction may be configured in the system.

[0175]

[0191] In systems with feedback and monitoring via backscatter, as well as by way of background, as tissue is gradually mechanically subdivided—in other words, homogenized, nonviable, or eroded—this process results in changes in the size and distribution of acoustic scatterers. At some point in the process, the scattering particle size and density are reduced to a level where ultrasound is barely scattered, or the amount scattered is significantly reduced. This results in a significant reduction in speckle, which is the coherent constructive and destructive interference pattern of bright and dark spots seen in images when a coherent illumination source, in this case ultrasound, is used. After some treatment time, speckle reduction results in dark areas within the treatment volume. The amount of speckle reduction is related to the amount of tissue subdivision and can therefore be related to the size of the remaining tissue fragments. When this size is reduced to a subcellular level, it is not expected that cells will survive. Thus, treatment can proceed until the desired speckle reduction level is reached. Speckle is easily seen and evaluated on standard ultrasound imaging systems. Specialized transducers and systems, including those disclosed herein, can also be used to evaluate backscatter changes.

[0176]

[0192] Furthermore, in systems with feedback and monitoring via speckle, as well as by means of background, the image persists from frame to frame and remains largely unchanged unless the scattering distribution changes and the imaged object moves. Nevertheless, scattering may change enough to be detected by signal processing and other means long before it is reduced to a size sufficient to cause speckle reduction. This collection of techniques can act as a detector of speckle statistical changes. For example, the size and location of one or more speckles in the image begin to decorrelate before observable speckle reduction occurs. Speckle decorrelation, after appropriate motion compensation, can be a sensitive measure of tissue mechanical inviability and therefore a measure of therapy efficacy. This feedback and monitoring technique can enable early observation of changes resulting from the acoustic cavitation / histotripsy process and can identify tissue changes (e.g., the onset of erosion) before substantial or complete tissue effects occur. In one embodiment, this method can be used to monitor acoustic cavitation / histotripsy processes for enhanced drug delivery when the treatment site / tissue is temporarily rendered non-viable and tissue damage / erosion is not desired. In other embodiments, this can involve speckle decorrelation with scattering shift in an increasingly fluidized therapy volume, for example, when partial or complete tissue erosion is desired.

[0177]

[0193] For systems with feedback and monitoring via elastography, as well as background measures, as the treatment site / tissue is further subdivided (homogenized, rendered nonviable, or eroded) per acoustic cavitation / histotripsy effect, its mechanical properties change from a soft but interconnected solid to a mucus or paste with few long-range interactions. These changes in mechanical properties can be measured by various imaging modalities, including MRI and ultrasound imaging systems. For example, ultrasound pulses can be used to generate forces (i.e., radiation forces) on localized volumes of tissue. Tissue response (displacement, tension, and velocity) can be significantly altered during histotripsy treatment, allowing the state of tissue nonviability to be determined by imaging or other quantitative means.

[0178]

[0194] The system can also provide feedback and monitoring via shear wave propagation changes. As a background measure, tissue repartitioning makes the tissue more fluid and less solid, and fluid systems generally do not propagate shear waves. Therefore, the degree of tissue fluidization provides an opportunity for feedback and monitoring of the histotripsy process. For example, ultrasound and MRI imaging systems can be used to observe shear wave propagation. The disappearance of such waves in the treated volume is used as a measure of tissue destruction or non-viability. In one system embodiment, the system and support subsystems can be used to generate and measure interacting shear waves. For example, two adjacent ultrasound foci can affect tissue by pushing it in a specific manner. If the adjacent foci are in a fluid, the shear waves will not propagate to interact with each other. If the tissue is not fluidized, the interaction must be detected externally, for example, by a difference frequency that is detected only when two shear waves interact nonlinearly, and the disappearance of the waves can be correlated to tissue damage. Therefore, the system may be configured to use this modality to enhance feedback and monitoring of acoustic cavitation / histotripsy procedures.

[0179]

[0195] For systems with feedback and monitoring via acoustic emissions, as well as background measures, when a tissue volume is subdivided, its effect on acoustic cavitation / histotripsy (e.g., here, bubble clouds) is altered. For example, bubbles may grow larger and have different lifetimes, disrupting the varying properties of intact versus fluidized tissue. Bubbles may also move and interact after tissue is subdivided, creating larger bubbles or cooperative interactions between bubbles, all of which can produce changes in acoustic emissions. These emissions can be heard and change during treatment. Analysis of these changes and their correlation with therapy efficacy allows for monitoring of therapy progress and can be configured as a system feature.

[0180]

[0196] In systems with feedback and monitoring via electrical impedance tomography, and as a background measure, an impedance map of the therapy site can be generated based on the spatial electrical characteristics throughout the therapy site. Imaging of the patient's therapy site's conductivity or permittivity can be inferred from skin surface electrical measurements. Conductive electrodes are affixed to the patient's skin, and a small alternating current is applied to some or all of the electrodes. One or more known currents are injected into the surface, and voltage is measured at several points using the electrodes. The process can be repeated for different configurations of applied current. The resolution of the resulting image can be adjusted by varying the number of electrodes employed. Measures of the therapy site's electrical properties within the skin surface can be obtained from the impedance map, and changes and locations of acoustic cavitation / histotripsy (e.g., specifically bubble clouds), as well as histotripsy processes, can be monitored using this as configured in the system and supporting subsystems.

[0181]

[0197] Through the system software and user interface and display, the user may be enabled to further select, annotate, mark, highlight, and / or outline various regions of interest or treatment sites, as well as predefined treatment targets (on the image) that can be used to command and direct the system where to image, test, and / or treat. In some arrangements, the user may perform the procedure using a manual ultrasound probe (e.g., a diagnostic handheld probe). In other arrangements, the system may use a robotic and / or electro-mechanical positioning system to perform the procedure in a system-directed and / or automated manner, or conversely, the system may allow for a combination of manual and automated usage.

[0182]

[0198] The system may further include the capability to perform image registration, including imaging and image dataset registration, to enable navigation and localization of the system to the patient, including the treatment site (e.g., tumor, critical structures, bony anatomy, anatomical structures and their identifying features, etc.). In one embodiment, the system allows a user to image and identify an area of ​​interest, such as the liver, using integrated ultrasound and select and mark a tumor (or a surrogate marker) contained within the liver through / displayed in the system software, the system registering the image data to a coordinate system defined by the system, further enabling the therapy and robotics subsystem of the system to deliver synchronized acoustic cavitation / histotripsy to the marked tumor. The system may be capable of registering various image sets, including those previously disclosed, with each other and providing navigation and localization (e.g., of a therapy transducer to a CT or MRI / ultrasound fusion image with the therapy transducer and robotics subsystem tracking to the image).

[0183]

[0199] The system may also be capable of operating in a variety of interventional endoscopic and surgical environments, including alone and with other systems (surgical / laparoscopic towers, vision systems, endoscopic systems and towers, ultrasound-enabled endoscopic ultrasound (flexible and rigid), percutaneous / endoscopic / laparoscopic and minimally invasive navigation systems (e.g., optical, electromagnetic, shape-sensing, ultrasound-enabled, etc.) that may operate with or include various optical imaging capabilities (e.g., fiber and / or digital). The disclosed system may be configured to operate with these systems, and in some embodiments, operate in conjunction with them, or in other embodiments, all or part of the system may be integrated into the above systems / platforms (e.g., acoustic cavitation / histotripsy-enabled endoscopic systems or laparoscopic surgical robots). In many of these environments, the therapy transducers may be used, for example, at or around the time of use of an optically guided endoscope / bronchoscope, or as another example, a laparoscopic robot (e.g., Intuitive Digital Vinci*Xi system) is viewing / manipulating the tissue / treatment site. Additionally, these embodiments and examples can include cases where the other systems / platforms described above are used to deliver fluid (locally) to enable the creation of artificial acoustic windows that may not exist under normal circumstances (e.g., fluidizing a lung segment or lobe in preparation for acoustic cavitation / histotripsy via non-invasive transthoracic treatment (e.g., with transducers placed externally on / around the patient)). The systems disclosed herein can also have all or part of these subsystem hardware packaged within other system carts / consoles / systems described herein (e.g., acoustic cavitation / histotripsy systems and / or subsystems integrated and operated from the navigation or laparoscopic systems described above).

[0184]

[0200] The system may also be configured through various of the aforementioned and other parameters to spatiotemporally display real-time visualization of the bubble cloud, including resulting tissue effects during / after treatment from tissue / bubble cloud interactions, and the system can dynamically image, visualize, and display the bubble cloud and any changes to the bubble cloud (e.g., decreasing or increasing echogenicity), which may include intensity, shape, size, location, morphology, persistence, etc. These features can enable the user to continuously track and follow the treatment in real time with one integrated procedure and interface / system, and to confirm treatment safety and efficacy during operation (versus other interventional or surgical modalities that require multiple procedures to accomplish the same, or where the treatment effect is not visible in real time (e.g., radiation therapy) or where such (e.g., real-time visualization of localized tissue during thermal ablation) is not achievable, and / or where other procedures further require invasive approaches (e.g., incisions or drilling) and repeated imaging in a scanner (e.g., CT or MRI scans) between treatment steps). The above disclosed systems, subsystems, components, modalities, features, and workflows / methods of use may be implemented without limitation through enabling hardware, software, user interfaces, and environments of use, and any resulting data and means of using said data for analytics, artificial intelligence, or digital health applications and systems, as well as future improvements, enhancements, and inventions in this area, are considered within the scope of this disclosure.

[0185] Robotics

[0201] The system may comprise various robotic subsystems and components, including, but not limited to, one or more robotic arms and controllers that may further operate in conjunction with other subsystems or components of the system for delivering and monitoring acoustic cavitation / histotripsy. As previously discussed herein, the robotic arms and control systems may be integrated into one or more cart configurations.

[0186]

[0202] For example, one system embodiment can include an integrated robotic arm and control system, as well as a cart with therapy, integrated imaging and software, where the robotic arm and other listed subsystems are controlled by the user through a single bedside cart form factor.

[0187]

[0203] In other embodiments, the robotic subsystem may be configured in one or more separate carts that can be driven in a master / slave configuration from a separate master or cart, with the robot-enabled cart located at the bed / patient side and the master remote from the cart.

[0188]

[0204] The disclosed robotic arms may include multiple joints, segments, and degrees of freedom, and may also include a variety of integrated sensor types and encoders implemented for various uses and safety features. Sensing techniques and data may include, by way of example, vision, potentiometer, position / localization, kinematics, force, torque, speed, acceleration, dynamic loading, and / or others. In some cases, sensors may be used by the user to direct robot commands (e.g., gesturing the robot to a preferred setup position or gesturing to dock home). Additional details regarding robotic arms can be found in U.S. Patent Publication No. 2013 / 0255426 to Kassow et al., which is incorporated herein by reference in its entirety.

[0189]

[0205] The robotic arm receives control signals and commands from a robotic control system that may be housed on the cart. The system may be configured to provide a variety of functions, including but not limited to position, tracking, patterns, triggers, and events / actions.

[0190]

[0206] The positions can be configured to include fixed positions, pallet positions, time controlled positions, distance controlled positions, variable time controlled positions, and variable distance controlled positions.

[0191]

[0207] The tracking may be configured to include time-controlled tracking and / or distance-controlled tracking.

[0192]

[0208] The pattern of movement can be configured to include intermediate positions or waypoints and sequences of positions through defined paths in space.

[0193]

[0209] The trigger may be configured to include distance measurement means, time, and / or various sensor means, including but not limited to those disclosed herein, such as visual / imaging-based force, torque, localization, energy / power feedback, and / or others.

[0194]

[0210] Events / actions can be configured to include a variety of examples including proximity-based (approaching / moving away from a target object), activating or deactivating various end effectors (e.g., therapy transducers), starting / stopping / pausing sequences of the above events, triggering or switching between triggering events / actions, initiating patterns of movement and changing / toggle between patterns of movement, and / or time-based and temporal across defined task and time spaces.

[0195]

[0211] In one embodiment, the system includes a three-degree-of-freedom robotic positioning system that allows a user (through the system's software and associated user interface) to microscopically position the therapy transducer through an X, Y, and Z coordinate system, with the overall macroscopic positioning of the transducer (e.g., aligning the transducer over the patient's body) completed manually. In some embodiments, the robot can have six degrees of freedom, including X, Y, Z, as well as pitch, roll, and yaw. In other embodiments, the robotic subsystem can have additional degrees of freedom, allowing the robotic arm support base to be positioned along a linear axis running parallel to the general direction of the patient surface and / or the support base height to be adjusted up or down, allowing the position of the robotic arm to be modified relative to the patient, patient surface, cart, linkage subsystem, additional robots / robotic arms, and / or additional surgical systems, including, but not limited to, a surgical tower, imaging systems, endoscopic / laparoscopic systems, and / or others.

[0196]

[0212] The one or more robotic arms can also include various features to assist in manual or semi-manual manipulation and correction of arm position, which can interface on or between the therapy transducer and the robotic arm's most distal joint. In some embodiments, the features are configured to include a handle to enable one or more manual manipulations and manual controls. The handle may also be configured to include user input and electronic control features of the robotic arm (e.g., activating or deactivating a free-drive mode) to command various drive capabilities or modes to operate the robot to assist in global or fine positioning of the arm. The workflow for initial positioning of the robotic arm and therapy head can be configured to allow the therapy transducer / head to be positioned first in the docking solution, with the therapy transducer interfaced directly with the arm, or a different workflow allows the user to set up the docking solution first and allow the robotic arm to be interfaced with the therapy transducer / docking solution as a later / final setup step.

[0197]

[0213] In some embodiments, the robotic arm may comprise a laparoscopic, single-port, endoscopic, hybrid or combination thereof, and / or other robotic arm, and the robot of the system may be slave to a master controlling the arm and potentially multiple other arms equipped to simultaneously perform other tasks (visualization, imaging, grasping, cutting, ligating, sealing, closing, stapling, dissecting, suturing, marking, etc.), including actuating one or more laparoscopic arms (and instruments) and various histotripsy system components. For example, a laparoscopic robot may be utilized to prepare the surgical site, including manipulating the position of organs to provide more optimal acoustic access and, in some cases, further stabilizing the organs to minimize respiratory movement. In conjunction with and in parallel with this, a second robotic arm may be used to deliver noninvasive acoustic cavitation through the body cavity as observed under real-time imaging from a therapy transducer (e.g., ultrasound) and with simultaneous visualization via a laparoscopic camera. In other related aspects, similar approaches may be utilized that combine endoscopic and non-invasive approaches, as well as further combine endoscopic, laparoscopic and non-invasive approaches.

[0198] software

[0214] The system may include a variety of software applications, features, and components that allow the user to interact with, control, and use the system for numerous clinical applications. The software may communicate and work with one or more of the subsystems, including, but not limited to, therapy, integrated imaging, robotics, and other components, ancillary instruments, and accessories of the system.

[0199]

[0215] Overall, in no inherent order of importance, software is responsible for initializing and setting up the system; servicing the system; communicating and importing / exporting / storing data; modifying / operating / configuring / controlling / commanding various settings and parameters by the user; mitigating safety and use-related risks; treatment planning; support for various transducer configurations; robotic arms and drive systems; function generator and amplifier circuitry / slaves; test and treatment ultrasound sequences; transducer steering and positioning (e.g., electro-mechanical and electronic beam steering); treatment patterns; imaging and support for imaging probes, their manual and electro-mechanical / robotic enabled movement; imaging support for measuring / characterizing various dimensions in or around the treatment site (e.g., depth from one anatomical location to another); Features and support can be provided for pre-treatment assessments and protocols to measure / characterize the nature and condition of the in situ treatment site (e.g., acoustic cavitation / histotripsy thresholds and their variants), targeting and target alignment, calibration, autonomously, under direct observation and viewing with real-time imaging as displayed through the software including various views and viewports for autonomous viewing, marking / annotating, localizing / navigating, registering, guiding, providing and directing through workflows, treatment steps, execution treatment plans and protocols, providing communication tools (video, audio, sharing, etc.), troubleshooting, instructions, warnings, alerts, and / or enabling communication through various networking devices and protocols.It is further envisioned that the software user interface and supporting displays may comprise various buttons, commands, icons, graphics, text, etc. that enable a user to interact with the system in a user-friendly and effective manner, which may be presented in an unlimited number of permutations, layouts, and designs, may comprise two or more displays (e.g., a touchscreen monitor and touchpad), and / or may be networked to one or more external displays or systems (e.g., another robot, navigation system, system tower, console, monitor, touch display, mobile device, tablet, etc.), and may be displayed in a similar or different style or feature set of the system.

[0200]

[0216] Software as part of a typical system including one or more computer processors can support the various aforementioned function generators (e.g., FPGAs), amplifiers, power supplies, and therapy transducers. The software may be configured to allow a user to select, determine, and monitor various parameters and settings of the acoustic cavitation / histotripsy, and can allow the user to stop / start / modify said parameters and settings upon observing / receiving feedback on performance and status.

[0201]

[0217] The software may be configured to allow the user to select from a list or menu of multiple transducers and support automatic detection of the transducer upon connection to the system (and verification of the appropriate sequence and parameter settings based on the selected application). In other embodiments, the software may update targeting and amplifier settings (e.g., channels) based on the specific transducer selection. The software may also provide transducer recommendations based on pre-treatment and planning inputs. Conversely, the software may provide an error message or warning to the user if the therapy transducer, amplifier, and / or function generator selection or parameters are incorrect or result in an error or failure. This may further include reporting details and location of such.

[0202]

[0218] In addition to the above, the software may be configured to allow a user to select treatment sequences and protocols from lists or menus and store the selected and / or previously selected sequences and protocols as associated with a unique clinical use or patient profile. The associated profile may include any associated patient, treatment procedure, clinical and / or engineering data, and may be used to inform, modify and / or guide current or future treatments or procedures / interventions, whether as decision support (e.g., using continuous data sets to build and guide new treatments) or as an active part of the treatment itself.

[0203]

[0219] As part of planning or during treatment, the software (and working with other components of the system) can enable the user to evaluate and test acoustic cavitation / histotripsy thresholds at various locations in a user-selected region of interest or predefined treatment area / volume to determine a minimum cavitation threshold throughout the region or area / volume and ensure that treatment parameters are optimized to achieve, maintain, and dynamically control acoustic cavitation / histotripsy. In one embodiment, the system allows the user to manually evaluate and test threshold parameters at various points. These points can include points at predefined boundaries, interior boundaries, and central locations / positions of the selected region of interest and treatment area / volume, and the resulting threshold measurements can be reported / displayed to the user and utilized to update therapy parameters prior to treatment. In another embodiment, the system can be configured to enable automated threshold measurements and updates, such as those enabled by the robotics subsystem described above, where the user can direct the robot or the robot can be commanded to perform measurements autonomously.

[0204]

[0220] The software may also be configured to work with a computer processor and one or more function generators, amplifiers, and therapy transducers to enable various permutations of delivering and positioning optimized acoustic cavitation / histotripsy in and through a selected area / volume. This may include systems configured in various combinations including, but not limited to, fixed / natural focus placement using purely electromechanical positioning configurations, electronic beam steering (with or without electromechanical positioning), electronic beam steering to a new selected fixed focus with further electromechanical positioning, axial (Z-axis) electronic beam steering with lateral (X and Y) electromechanical positioning, fast axial electronic beam steering with lateral electromechanical positioning, fast beam steering in 3D space, and dynamically varying one or more acoustic cavitation / histotripsy parameters (e.g., dynamically adjusting amplitude across a treatment area / volume) based on the foregoing and the ability to update treatment parameters based on threshold measurements.

[0205] Other Components, Auxiliaries and Accessories

[0221] Systems may include various other components, aids and accessories, including, but not limited to, computers, computer processors, power supplies including high voltage power supplies, controllers, cables, connectors, networking devices, software applications for integration into security, communications, information systems including hospital information systems, cellular communication devices and modems, handheld wired or wireless controllers, goggles or glasses for advanced visualization, augmented or virtual reality applications, cameras, sensors, tablets, smart devices, phones, Internet of Things enabled capabilities, special use "apps" or user training materials and applications (software or paper-based), virtual proctors or trainers and / or other enabling features, devices, systems or applications, and / or methods of using the above.

[0206] System Variations and Methods / Applications

[0222] In addition to performing a wide range of procedures, the system may enable additional benefits to assist the user, such as enhanced planning, imaging, and guidance. In one embodiment, the system may enable the user to create patient-, target-, and application-specific treatment plans, which may be configured to optimize treatment parameters based on feedback to the system during planning, which may further include the ability to run various test protocols to gather specific inputs to the system and the plan.

[0207]

[0223] The feedback may include various energy, power, location, position, texture and / or other parameters.

[0208]

[0224] The system and the above feedback may also be further configured and used to autonomously (and robotically) execute the delivery of optimized treatment plans and protocols, and start / stop / modify treatment at the user's discretion, as visualized under real-time imaging during the procedure, allowing the user to directly observe the localized treatment tissue effects as the treatment progresses. Both testing and treatment protocols may be updated during the treatment at the direction of the user, or in some embodiments based on logic built into the system.

[0209]

[0225] It is also recognized that many of these benefits can further improve other forms of acoustic therapy, including high intensity focused ultrasound (HIFU), including boiling histotripsy (thermal cavitation), and thermal ablation with high intensity therapeutic ultrasound (HITU), and are considered part of this disclosure. The present disclosure also contemplates the application of histotripsy as a means to activate previously delivered active drug payloads that are inactive, either through protection in micelles, nanostructures, or similar protective structures, or through molecular arrangements that allow activation only upon application of acoustic energy.

[0210]

[0226] In another embodiment, a therapy subsystem, comprising in part one or more amplifiers, transducers, and power sources, may be configured to enable a multitude of acoustic cavitation and histotripsy driving capabilities that provide unique benefits based on application, method, and / or patient-specific usage. These benefits may include, but are not limited to, the ability to better optimize and control treatment parameters, which may enable more desirable thermal profiles, delivery of more energy with increased treatment speed and reduced procedure times, electronic beam steering, and / or other features.

[0211]

[0227] The present disclosure also includes novel systems and concepts, such as those relating to systems and subsystems with new and "universal" amplifiers that can enable multiple drive approaches (e.g., single and multi-period pulsing), which in some embodiments may include various novel features to further protect the system and user from electrical safety or other threats (e.g., adverse effects on transducer and / or amplifier circuitry).

[0212]

[0228] In another aspect, the system and therapy subsystem can include a large number of therapy transducers, configured for specific applications and uses, adapted for treatment across a wide range of working parameters (target size, depth, location, etc.), and capable of including a wide range of working specifications (described in more detail below). The transducers can be further adapted, interfaced, and connected to a robotic-enabled system, as well as a coupling subsystem that allows the transducer to be positioned in or with an acoustic coupling device that, in many embodiments, enables simultaneous imaging and histotripsy treatment through an acceptable acoustic window. The therapy transducers can also include an integrated imaging probe or localization sensor capable of displaying and determining the transducer's position within the treatment site, providing a direct view (or representation) of the treatment site, and such that acoustic cavitation / histotripsy tissue effects and bubble clouds may or may not change in appearance and intensity throughout the treatment, and depending on their location within the treatment (e.g., tumor, surrounding healthy tissue, critical structures, fatty tissue, etc.).

[0213]

[0229] The systems, methods, and uses of the systems disclosed herein may be beneficial in overcoming significant unmet needs in the areas of soft tissue ablation, oncology, cancer immunology, advanced image-guided procedures, surgical procedures including, but not limited to, open, laparoscopic, single-incision, transluminal, endoscopic, non-invasive, and various combinations thereof, various interventional spaces for catheter-based procedures in the vascular, cardiovascular pulmonary, and / or neuroscience spaces, cosmetic / aesthetics, metabolic (e.g., type 2 diabetes), plastic and reconstructive, vision and ophthalmology, orthopedics, gynecology, and human health, and other systems, devices, and methods for treating diseased, injured, unwanted, or healthy tissue, organs, or cells.

[0214]

[0230] Systems and methods are also provided for improving treatment patterns within tissue that can reduce treatment time, improve efficacy, and reduce the amount of energy and focused tissue heating delivered to the patient.

[0215] Usage environment

[0231] The disclosed systems, methods of use, and system usage may be performed in numerous environments and settings, with or without various support systems such as anesthesia, including, but not limited to, treatment suites, operating rooms, hybrid rooms, in-patient and out-patient settings, ambulatory settings, imaging centers, radiology, radiation therapy, oncology, surgery, and / or any medical center, as well as physician offices, mobile healthcare centers or systems, automobiles and related vehicles (e.g., vans), air and sea transport vehicles such as aircraft and ships, and / or any structure capable of providing temporary treatment support (e.g., tents). In some cases, the systems and / or subsystems disclosed herein may also be provided as integrated features into other environments, such as direct integration of the Histotripsy therapy subsystem into an MRI scanner or patient surface / bed, with at least the therapy generator and transducer integrated therein; in other cases, the Histotripsy configuration further includes a robotic positioning system that may be further integrated into a scanner or bed-centric design.

[0216] Concatenation

[0232] The system can include various coupling subsystem embodiments enabled and configured to allow acoustic coupling to the patient to provide effective acoustic access for ultrasound visualization and acoustic cavitation / histotripsy (e.g., providing an acoustic window and medium between the transducer and the patient, and its support). These can include different form factors of such, including open and closed device solutions, as well as several arrangements that can be configured to allow dynamic control over the acoustic medium (e.g., temperature, dissolved gas content, level of particulate filtration, sterility, volume, composition, etc.). Such dynamic control components may be integrated directly into the system (within the cart) or may be in temporary / intermittent or continuous communication with the system, but may be separate devices and / or external to the cart.

[0217]

[0233] The coupling subsystem typically comprises at least a coupling medium (e.g., degassed water or aqueous solution), a reservoir / container for holding the coupling medium, and a support structure (including interfaces to other surfaces or devices). In most embodiments, the coupling medium is water, and the water may be conditioned (e.g., chilled, degassed, filtered, etc.) before or during treatment. Various conditioning parameters may be employed based on the configuration of the system and its intended use / application.

[0218]

[0234] The reservoir or media container can be formed and shaped into various sizes and shapes to conform to the patient, allowing the therapy transducer to engage / access and work within the acoustic medium per defined and required working space (such as a minimum volume of media to allow the therapy transducer to be positioned and / or moved through one or more treatment positions or patterns and at various standoffs or depths from the patient), and the reservoir or media container can also mechanically support the load and load distribution through the use of mechanical and / or electromechanical support structures. Representative examples include support frames. The container may be of various shapes, sizes, curvatures, and dimensions and may include various material compositions (single, multiple, composite, etc.) that may vary throughout. In some embodiments, the container can include features such as insertable and removable films, drapes, membranes, blowers, etc. that can be used to conform to the patient and assist in containing / containing the media within the container. The container can further include various sensors (e.g., volume / fill level), drainage (e.g., inlet / outlet), lighting (e.g., LEDs), markings (e.g., fill lines, setup orientation, etc.), text (e.g., labeling), etc.

[0219]

[0235] In one embodiment, the reservoir or media container includes a sealable frame into which a membrane and / or film can be placed to provide a comfortable means of contacting the reservoir (which will later comprise the therapy head / therapy transducer) as an interface to the patient, further providing a barrier to the media (e.g., water) between the patient and the therapy transducer. In other embodiments, the membrane and / or film can include an opening whose patient-contacting edge provides a fluid / mechanical seal with the patient, but in contrast allows direct media communication with the patient (e.g., a direct degassed water interface with the patient). The reservoir or media container superstructure in both of these examples can further provide a proximal portion (e.g., top) of the structure that is open or enclosed (e.g., to prevent spillage or provide additional features).

[0220]

[0236] The disclosed membranes can include various elastomers, viscoelastic polymers, thermoplastics, thermoplastic elastomers, thermoset polymers, silicones, urethanes, rigid / flexible copolymers, block copolymers, random block copolymers, and the like. Materials can be hydrophilic, hydrophobic, surface-modified, coated, extracted, and the like, and can further contain various additives to enhance performance, appearance, or stability. In some embodiments, the thermoplastic elastomer can be styrene-ethylene-butylene-styrene (SEBS) or other similar strong, flexible elastomers. The membrane form factor can be flat or pre-shaped prior to use. In other embodiments, the membrane can be inelastic (i.e., convex) and pressed against the patient's skin to acoustically couple the transducer to the tissue. Systems and methods for controlling the level of contaminants (e.g., particulates, etc.) on the membrane to maintain an appropriate level of ultrasound coupling are also disclosed. Too many particulates or contaminants can cause ultrasound scattering. This can be achieved with a removable film or coating on the membrane's outer surface to protect against contamination.

[0221]

[0237] The materials may be formed into useful thin films through molding, casting, spraying, ultrasonic spraying, extrusion, and / or any other processing method that yields useful embodiments. The materials may be single-use or reposable / reusable. The materials may be non-sterile, aseptically clean, or sterile, and sterilization may include any known method, including but not limited to, ethylene oxide, gamma, e-beam, autoclaving, steam, hydrogen peroxide, plasma, chemicals, etc. The thin films may further comprise an outer molded or overmolded frame to provide mechanical stability to the thin film during handling, including assembly, setup, and disassembly of the coupling subsystem. Representatively, various parameters of the thin film may be optimized for this use, including thickness, thickness profile, density, formulation (e.g., polymer molecular weight and copolymer ratio, additives, plasticizers, etc.), specifically optimized to maximize acoustic transmission properties, including impact on cavitation onset threshold and / or minimizing ultrasound imaging artifacts, including but not limited to thin film reflections.

[0222]

[0238] The open reservoir or media container can include various methods of filling, including using pre-prepared media or water that can be delivered to the container, possibly to predefined specifications (levels of temperature, gas saturation, etc.), or can include additional features integrated into the design that allow for filling and draining (e.g., ports, valves, hoses, tubing, fittings, bags, pumps, etc.). These features may be further configured to interface into or to other devices, including, for example, the fluidics system. In some cases, the fluidics system can be an in-house media preparation system in a hospital or medical environment room, or conversely, a mobile cart-based system that can prepare and transport media from a cart to a media container, etc.

[0223]

[0239] The enclosed iterations of the reservoir or media container can include various features for sealing, in some embodiments, to the proximal / top portion or structure of the reservoir / container, or in other cases, the sealing can include sealing features on the transducer or transducer housing. Additionally, some embodiments can include dynamic capabilities to control the volume of fluid within these designs, minimize the possibility of air bubbles or turbulence in the fluid, and allow for changes in focal distance to the target area without moving the transducer. Thus, integrated features enabling fluid communication and control thereof can be provided (the ability to provide / remove fluid on demand), including the ability to monitor and control various fluid parameters, some of which are disclosed above. To provide this functionality, the overall system, and as part of it, the coupling subsystem, can include a fluid regulation system, which can include various electromechanical devices, systems, power, sensing, computing, pumping, filtering, and control systems, etc. The reservoir can also be configured to receive signals that deform or change shape in a specific and controlled manner to allow the target point to be adjusted without moving the transducer.

[0224]

[0240] The articulated support system can include a variety of mechanical support devices for interfacing the reservoirs / containers and media to the patient and workspace (e.g., bed, floor, etc.). In some embodiments, the support system comprises a mechanical arm with three or more degrees of freedom. The arm can have a proximal interface with one or more locations (and features) of the bed, including but not limited to a frame, rails, customized rails, or inserts, and one or more distal locations of the reservoirs or containers. The arm can also be a feature embodied on one or more carts, which can be configured in a variety of non-limiting permutations, and in some cases, the cart solely serves to support and provide the disclosed support structure.

[0225]

[0241] In some embodiments, the support structure and arm may be realized as a standalone cart or may be a robot-enabled arm integrated into a cart further comprising two or more system subsystems, or the robot-enabled arm may be the arm of another robot, interventional, surgical, or other type, and may further comprise various user input features for actuating / controlling the robot arm (e.g., disposed on / within the coupling medium) and / or coupling solution features (e.g., fill, drain, etc.). In some examples, the support structure robot arm position encoder may be used to coordinate the operation of a second arm (e.g., comprising a therapy transducer / treatment head), such as placing a therapy transducer at a desired / known location and within the coupled support structure.

[0226]

[0242] Overall, significant unmet needs exist today in interventional and surgical medical procedures across various types of procedures, including procedures utilizing minimally invasive devices and approaches to treat disease and / or injury, and unmet needs may be solved with entirely new medical procedures. Today's medical system capabilities are often limited by access, such that a less invasive or non-invasive approach would be preferable, or today's tools lack the ability to deliver the desired / required tissue effect (e.g., working around / through critical structures without significant injury), or the physical setup of the system makes certain treatment approaches less desirable or possible, and combinations of approaches may enable entirely new procedures and approaches not possible today, along with enhanced tissue-affecting therapies.

[0227]

[0243] Additionally, there is a unique need to enable histotripsy delivery, including robotic histotripsy delivery, where one or more histotripsy therapy transducers may be configured to acoustically couple to the patient using a fully sealed approach (e.g., no acoustic medium communication with the patient's skin) and to allow the one or more histotripsy transducers to be moved within the coupling solution without impeding the movement / movement of the robotic arm or interfering / obstructing the coupling interface, which may affect the intended treatment and / or target location.

[0228]

[0244] By way of non-limiting example, disclosed herein are Histotripsy acoustic and patient coupling systems and methods for enabling Histotripsy therapy / treatment in any setting envisioned from an interventional suite, operating room, hybrid suite, imaging center, medical center, office environment, mobile treatment center, and / or other. The following disclosure further describes novel systems used to create, control, maintain, modify / enhance, monitor, and set up / tear down acoustic and patient coupling systems in a variety of approaches, methods, environments, architectures, and workflows. In general, the disclosed novel system can allow a coupling medium, in some instances degassed water, to be interfaced between a histotripsy therapy transducer and a patient, the acoustic medium providing sufficient acoustic coupling to the patient to enable delivery of histotripsy pulses through a user-desired treatment location (and volume), delivery can require physically moving the histotripsy therapy transducer within a defined workspace that includes the coupling medium, and the coupling system is configured to allow said movement of the therapy transducer (and positioning system, e.g., a robot) freely and unhindered by a coupling support system (e.g., a frame or manifold that holds the coupling medium).

[0229] Interconnected Systems and Subsystems / Components

[0245] The disclosed histotripsy acoustic and patient connection systems may generally comprise one or more of the subsystems and components, examples of which are depicted in FIG. 2 , including, but not limited to: 1) a membrane / barrier film to provide an enclosed, sealed, and conformal patient connection and histotripsy system interface; 2) a frame and assembly to hold the membrane and provide sufficient working and headroom for the required range of motion (x, y, and z, pitch, roll, and yaw) of the histotripsy therapy transducer; 3) a sufficient volume of ultrasound medium to provide acoustic connection and interface to the histotripsy therapy transducer and robotic arm; 4) one or more mechanical support arms to allow installation, positioning, and load support of the frame, assembly, and medium; and 5) a fluidics system to prepare, provide, and remove the ultrasound medium from the frame and assembly.

[0230]

[0246] In some embodiments, the connection system may be completely sealed, while in other embodiments and configurations, the connection system may be partially open to provide immediate access (physical and / or visual).

[0231]

[0247] The acoustic and patient connection systems and subsystems may further comprise various features and functions and associated workflows and may be further configured in various ways to enable Histotripsy procedures as described in more detail below.

[0232]

[0248] 2 illustrates one embodiment of a histotripsy therapy and imaging system 200 that includes a coupling assembly 212. As described above, the histotripsy therapy and imaging system can include a therapy transducer 202, an imaging system 204, a robotic positioning arm 208, and a cart 210.

[0233]

[0249] The therapy and / or imaging transducer can be housed in a coupling assembly 212, which can further include a coupling membrane 214 and a membrane constraint 216 configured to prevent the membrane from extending too far from the transducer. The coupling membrane can be filled with an acoustic coupling medium, such as a fluid or gel. The membrane constraint can be, for example, a semi-rigid or rigid material configured to limit the membrane's extension / movement. In some embodiments, no membrane constraint is used, and the membrane's elastic and tensile strength prevents extension. The coupling membrane can be a mineral oil-infused SEBS membrane to prevent direct fluid contact with the patient's skin. In the illustrated embodiment, the coupling assembly 212 is load-bearing in the xy plane but is supported by a mechanical support arm 218, which can allow for manual or automated z-axis adjustment. The mechanical support arm can be affixed to the floor, patient table, or cart 210. The mechanical support is designed and configured to conform and hold the connecting membrane 214 in place against the patient's skin while still allowing movement of the therapy / imaging transducer relative to the patient and further relative to the connecting membrane 214 with the robotic positioning arm 208.

[0234]

[0250] The system can further include a fluidics system 220, which can include a fluid source, a cooling and degassing system, and a programmable control system. The fluidics system is configured for automated control of fluid sequences for external loading of the coupled membrane. More details about the fluidics system 220 are provided below.

[0235] Thin / Barrier Films and Related Architectures

[0251] The thin membranes and barrier films may be constructed from a variety of biocompatible materials capable of providing a conformal connection to the patient's anatomy with minimal or no trapped air bubbles that could interfere with ultrasound imaging and histotripsy therapy, and a sealed barrier layer between the patient's anatomy and the ultrasound medium contained within the working space provided by the frame and assembly.

[0236]

[0252] The membrane and barrier film materials can comprise flexible and elastic biocompatible materials / polymers, such as various thermoplastic and thermoset materials, as well as permanent or bioabsorbable polymers. Additionally, the UMC frame can also comprise the same materials. In some cases, the membrane can be a pre-shaped or flat rigid or semi-rigid polymer.

[0237] ultrasonic medium

[0253] As previously mentioned, the ultrasound medium can comprise any applicable medium capable of providing sufficient and useful acoustic coupling to enable histotripsy treatment and sufficient clinical imaging (e.g., ultrasound). Ultrasound media can include, but are not limited to, various aqueous solutions / media, including mixtures with other cosolvent fluids, that may have favorable or more favorable acoustic qualities, including the ability to match the speed of sound, as part of the present disclosure and systems. Example media include degassed water and / or mixtures / cosolvents of degassed water with various alcohols, such as ethanol.

[0238] Mechanical Support Arm and Arm Architecture

[0254] Various designs and configurations of mechanical support arms (and arm architectures) can be employed to support the acoustic and patient connection system, including providing an efficient and ergonomic workflow for the user. Support arms can be configured with a range of degrees of freedom, including but not limited to, allowing for x, y, z, pitch, roll, and yaw, as well as additional interface features that may allow for additional height adjustment or translation.

[0239]

[0255] The arms can have various numbers and types of joints and segments. Typically, the arms have a minimum of two segments. In some configurations, the arms can have three to five segments.

[0240]

[0256] The arm is also configured to interface proximally with the main support base or base interface (e.g., robot, table, table / bed rail, cart, floor mount, etc.) and distally with the frame / assembly and overall "UMC" or "connected solution." This unique distal interface can further include features to control the position / orientation of the frame / assembly at the frame / assembly interface.

[0241]

[0257] For example, in some embodiments, the arm / frame interface may comprise a ball-joint wrist. In another example, the interface may include the use of a gimbal wrist or a wrist with adjustable pitch and roll control. These interfaces may further employ unique user interfaces and inputs to assist in interacting with the various wrists, which may include (by way of non-limiting example) additional handles or knobs to further enable positioning of the UMC / articulated solution. For example, a gimbal wrist may benefit from allowing the frame / assembly to have three degrees of freedom (independent of the arm degrees of freedom), including pitch, roll, and yaw adjustment.

[0242]

[0258] The support arm, further configured with an arm wrist interfaced with the frame / assembly, can include features such as brakes, including cable- or electronically-actuated brakes, and quick releases that can interact with one or more axes individually or in groups. The support arm can also include an electronic lift system and base support. In some embodiments, these lift systems / base supports are co-located with the robotic arm base, and the robotic arm is equipped with a histotripsy therapy transducer configured to fit / function within the enclosed articulated solution. In other embodiments, the support arm is placed on a separate cart. In some cases, the separate cart can include a fluidics system or a user console. In other embodiments, the separate cart is interfaced to a bed / table, including, but not limited to, rails, sides, and / or a bed / table base. In other examples / embodiments, the separate cart is interfaced to a floor-based structure / foundation capable of managing weight and tipping requirements.

[0243] Fluid Engineering Systems, Control Systems and System Architecture

[0259] As part of the overall fluidics management, the histotripsy system, including the acoustic / patient connection system, may be configured to include an automated fluidics system, primarily responsible for providing a reservoir for the preparation and use of the connection medium. The preparation may include the ability to degas, cool, monitor, regulate, supply / fill, and remove / drain the connection medium to and from the frame / assembly. The fluidics system may include an emergency high-flow system for rapid drainage of the connection medium from the UMC. In some embodiments, the fluidics system may be configured for single-use of the connection medium or alternatively for reuse of the medium. In some embodiments, the fluidics system may achieve positive air pressure or vacuum to perform leak testing of the UMC and membrane prior to filling the connection medium. Vacuum assistance may also be used to remove air from the UMC during the filling process. The fluidics system may further include a filter configured to prevent particulate contamination from reaching the UMC.

[0244]

[0260] The fluidics system may be implemented in the form of a mobile fluidics cart. The cart may include an input tank, a drain tank, a degassing module, a fill pump, a drain pump, an inert gas tank, an air compressor, tubing / connectors / lines, electronic and manual control systems and input devices, a power source, and one or more batteries. The cart may also optionally include a system check container / reservoir (configured to accommodate the required water volume and workspace for the therapy transducers) for assessing histotripsy system performance and related system diagnostics.

[0245]

[0261] It should be understood that any feature described herein with respect to one embodiment may be substituted for or combined with any feature described with respect to another embodiment.

[0246]

[0262] When a feature or element is referred to as being "on" another feature or element, the feature or element can be directly on the other feature or element, or there may be additional intervening features and / or elements. In contrast, when a feature or element is referred to as being "directly on" another feature or element, there are no intervening features or elements present. When a feature or element is referred to as being "connected," "attached," or "coupled" to another feature or element, it will also be understood that the feature or element can be directly connected, attached, or coupled to the other feature or element, or there may be intervening features or elements present. In contrast, when a feature or element is referred to as being "directly connected," "directly attached," or "directly coupled" to another feature or element, there are no intervening features or elements present. Although described or illustrated with respect to one embodiment, the features and elements so described or illustrated may apply to other embodiments. It will also be recognized by those skilled in the art that a reference to a structure or feature being located "adjacent" another feature may have overlapping or underlying portions of the adjacent feature.

[0247]

[0263] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the present invention. For example, as used herein, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly dictates otherwise. It will be further understood that the terms "comprises" and / or "comprising," when used herein, specify the presence of stated features, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, steps, operations, elements, components, and / or groups thereof. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items and may be abbreviated as " / ."

[0248]

[0264] Spatially relative terms such as "under," "below," "lower," "over," "upper," and the like may be used herein for simplicity of description to describe the relationship of one element or feature to another element or feature as illustrated in the figures. It will be understood that the spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if a device in a figure were inverted, an element described as "under" or "beneath" the other element or feature would therefore be oriented "over" the other element or feature. Thus, the exemplary term "under" can encompass both an orientation of over and under. A device may be otherwise oriented (rotated 90 degrees or at other orientations) and spatially relative descriptors used herein will be interpreted accordingly. Similarly, the terms "upwardly," "downwardly," "vertical," "horizontal," and the like are used herein for descriptive purposes only, unless specifically indicated otherwise.

[0249]

[0265] The terms "first" and "second" may be used herein to describe various features / elements (including steps), but these features / elements should not be limited by these terms unless the context dictates otherwise. These terms may be used to distinguish one feature / element from another. Thus, a first feature / element discussed below may be referred to as a second feature / element, and similarly, a second feature / element discussed below may be referred to as a first feature / element without departing from the teachings of the present invention.

[0250]

[0266] Throughout this specification and the claims that follow, unless the context requires otherwise, the word "comprise," and variations such as "comprises" and "comprising," mean that various elements may be employed together in methods and articles (e.g., compositions and apparatuses, including devices and methods). For example, the term "comprising" will be understood to imply the inclusion of any stated elements or steps, but not the exclusion of any other elements or steps.

[0251]

[0267] As used herein in the specification and claims, including as used in the examples, and unless expressly specified otherwise, all numbers may be read as if preceded by the word "about" or "approximately," even if the term does not explicitly appear. The phrase "about" or "approximately," when describing a magnitude and / or location, may be used to indicate that the described value and / or location is within an expected reasonable range of values ​​and / or locations. For example, a numerical value may have a value of + / - 0.1% of the stated value (or range of values), + / - 1% of the stated value (or range of values), + / - 2% of the stated value (or range of values), + / - 5% of the stated value (or range of values), + / - 10% of the stated value (or range of values), etc. Any numerical value given herein should also be understood to include about or approximately this value, unless the context dictates otherwise. For example, if the value "10" is disclosed, "about 10" is also disclosed. Any numerical range recited herein is intended to include all subranges incorporated therein. When a value is disclosed, it is understood that "less than or equal to," "greater than or equal to," and possible ranges between values ​​are also disclosed, as appropriately understood by one of ordinary skill in the art. For example, if a value "X" is disclosed, "less than or equal to X" and "greater than or equal to X" (e.g., when X is a numeric value) are also disclosed. It is also understood that throughout this application, data is provided in several different formats, and that this data represents endpoints and starting points, and ranges for any combination of the data points. For example, if a specific data point "10" and a specific data point "15" are disclosed, it is understood that not only between 10 and 15, but also greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed. It is also understood that each unit between two specified units is disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0252]

[0268] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It is understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention, and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

1. receiving a digital treatment plan including a target tissue volume of a subject divided into a plurality of individual treatment locations; mechanically positioning a focal point of an ultrasound therapy transducer at a first focal location at a first discrete treatment location within the target tissue volume; delivering a first histotripsy pulse to the first focal location to create a first cavitation bubble cloud at the first focal location; electronically beam steering the focal point of the ultrasound therapy transducer to a second focal point location at the first discrete treatment location that overlaps with the first focal point location; delivering a second histotripsy pulse to the second focal location to create a second bubble cloud at the second focal location and to at least partially re-excite the first cavitation bubble cloud at the first focal location; 1. A method for administering histotripsy to a target tissue, comprising:

2. 2. The method of claim 1, wherein the Histotripsy pulse comprises a positive half-cycle followed by a peak negative half-cycle followed by a trailing positive half-cycle.

3. 3. The method of claim 2, wherein the trailing positive half-cycle has a lower amplitude than the leading positive half-cycle.

4. 2. The method of claim 1, wherein delivering the second Histotripsy pulse to the second focal location further comprises delivering the second Histotripsy pulse to the second focal location to create the second bubble cloud at the second focal location during a life cycle of the first bubble cloud.

5. 5. The method of claim 4, wherein delivering the second Histotripsy pulse to the second focal location further comprises delivering the second Histotripsy pulse to the second focal location to create the second bubble cloud at the second focal location during a life cycle of residual cavitation nuclei of the first bubble cloud.

6. 10. The method of claim 1, wherein electronic beam steering the focal point further comprises electronic beam steering the focal point axially relative to the ultrasound therapy transducer.

7. 10. The method of claim 1, wherein electronic beam steering the focal point further comprises electronic beam steering the focal point in any lateral direction relative to the ultrasound therapy transducer.

8. 10. The method of claim 1, wherein electronic beam steering the focal point further comprises electronic beam steering the focal point laterally and axially relative to the ultrasound therapy transducer.

9. 10. The method of claim 1, further comprising repeating the electronic beam steering and delivering steps for a third focal location that overlaps the second focal location.

10. 10. The method of claim 1, further comprising repeating the electronic beam steering and delivering steps for a third focal location that overlaps the first focal location.

11. 10. The method of claim 1, wherein after each delivery step: delivering at least one low amplitude waveform to the target tissue to spatially manipulate residual cavitation nuclei in the target tissue; The method further comprises:

12. 10. The method of claim 1, further comprising repeating the delivery and electronic beam steering steps for the first and second focal locations until a desired dose is applied to the first individual treatment location.

13. 13. The method of claim 12, further comprising mechanically positioning the focal point of the ultrasound therapy transducer at a first focal point location at a second discrete treatment location within the target tissue volume after the desired dose is applied to the first discrete treatment location.

14. 10. The method of claim 1, wherein mechanically positioning the focal point further comprises mechanically positioning the focal point with a robotic positioning system.

15. A robot positioning system; an ultrasound therapy transducer array connected to the robotic positioning system; a generator operatively coupled to the ultrasound therapy transducer array, wherein the generator and the ultrasound therapy transducer array are configured to deliver histotripsy pulses to the subject to generate a cavitation bubble cloud in the subject; at least one processor operatively coupled to the robot positioning system and the generator, controlling the robotic positioning system to mechanically position a focal point of the ultrasound therapy transducer array at a first focal point location at a first individual treatment location within a treatment plan; controlling the generator to deliver at least one histotripsy pulse at the ultrasound therapy transducer array to form a first cavitation bubble cloud at the first focal location; controlling the generator to electronically beam steer the focal point of the ultrasound therapy transducer to a second focal point location at the first discrete treatment location that overlaps with the first focal point location; and controlling the generator to deliver at least one histotripsy pulse to the second focal location to create a second bubble cloud at the second focal location and to re-excite the first cavitation bubble cloud at the first focal location. at least one processor configured to control the robotic positioning system and the generator to provide histotripsy therapy to the subject according to the treatment plan, the treatment plan including a plurality of discrete treatment locations within a target tissue volume of the subject; An ultrasound therapy system comprising:

16. 16. The system of claim 15, wherein each of the Histotripsy pulses includes a positive half-cycle followed by a peak negative half-cycle followed by a trailing positive half-cycle.

17. 17. The system of claim 16, wherein the trailing positive half-cycle has a lower amplitude than the leading positive half-cycle.

18. 16. The system of claim 15, wherein controlling the generator to deliver the at least one Histotripsy pulse to the second focal location further comprises controlling the generator to deliver the at least one Histotripsy pulse to the second focal location to create the second bubble cloud at the second focal location during a life cycle of the first bubble cloud.

19. 20. The system of claim 18, wherein controlling the generator to deliver the at least one Histotripsy pulse to the second focal location further comprises controlling the generator to deliver the at least one Histotripsy pulse to the second focal location to create the second bubble cloud at the second focal location during a life cycle of residual cavitation nuclei of the first bubble cloud.

20. 16. The system of claim 15, wherein controlling the generator to electronically beam steer the focal point further comprises controlling the generator to electronically beam steer the focal point axially relative to the ultrasound therapy transducer array.

21. 16. The system of claim 15, wherein controlling the generator to electronically beam steer the focal point further comprises controlling the generator to electronically beam steer the focal point in any lateral direction relative to the ultrasound therapy transducer array.

22. 16. The system of claim 15, wherein controlling the generator to electronically beam steer the focal spot further comprises controlling the generator to electronically beam steer the focal spot laterally and axially relative to the ultrasound therapy transducer array.

23. 16. The system of claim 15, further comprising: repeating controlling the generator to electronically steer a beam and controlling the generator to deliver at least one Histotripsy pulse for a third focal location that overlaps the second focal location.

24. 16. The system of claim 15, further comprising: repeating controlling the generator to electronically steer a beam and controlling the generator to deliver at least one Histotripsy pulse for a third focal location that overlaps the first focal location.

25. 16. The system of claim 15, after controlling the generator to deliver at least one histotripsy pulse: controlling the generator to deliver at least one low amplitude waveform to the target tissue to spatially manipulate residual cavitation nuclei in the target tissue. The system further includes:

26. 16. The system of claim 15, further comprising repeating controlling the generator to electronic beam steering and controlling the generator to deliver at least one histotripsy pulse for the first and second focal locations until a desired dose is applied to the first individual treatment location.

27. 27. The system of claim 26, further comprising: controlling the robotic positioning system to mechanically position the focal point of the ultrasound therapy transducer at a first focal point location at a second discrete treatment location within the target tissue volume after the desired dose is applied to the first discrete treatment location.

28. 1. A method of administering histotripsy to a target tissue volume, comprising: dividing the target tissue volume into a plurality of discrete treatment locations; determining a treatment plan including a route for delivering therapy to each of the individual treatment locations; positioning a focal point of an ultrasound therapy transducer at a first focal location at a first discrete treatment location within the target tissue volume; delivering one or more histotripsy pulses to the first focal location to create a first bubble cloud at the first focal location; electronically beam steering the focal point of the ultrasound therapy transducer to a second focal point location at the first discrete treatment location that overlaps with the first focal point location; delivering one or more histotripsy pulses to the second focal location to produce a second bubble cloud at the second focal location; repeating the positioning and delivering steps for each of the plurality of individual treatment locations according to the treatment plan and path; A method comprising:

29. 29. The method of claim 28, wherein each Histotripsy pulse includes a positive half-cycle followed by a peak negative half-cycle followed by a trailing positive half-cycle.

30. 30. The method of claim 29, wherein the trailing positive half-cycle has a lower amplitude than the leading positive half-cycle.

31. 30. The method of claim 28, wherein delivering the one or more Histotripsy pulses to the second focal location further comprises delivering the one or more Histotripsy pulses to the second focal location to create the second bubble cloud at the second focal location during a life cycle of the first bubble cloud.

32. 32. The method of claim 31 , wherein delivering the one or more Histotripsy pulses to the second focal location further comprises delivering the one or more Histotripsy pulses to the second focal location to create the second bubble cloud at the second focal location during a life cycle of residual cavitation nuclei of the first bubble cloud.

33. 30. The method of claim 28, wherein electronic beam steering the focal point further comprises electronic beam steering the focal point axially relative to the ultrasound therapy transducer.

34. 30. The method of claim 28, wherein electronic beam steering the focal point further comprises electronic beam steering the focal point in any lateral direction relative to the ultrasound therapy transducer.

35. 30. The method of claim 28, wherein electronic beam steering the focal point further comprises electronic beam steering the focal point laterally and axially relative to the ultrasound therapy transducer.

36. 30. The method of claim 28, further comprising repeating the electronic beam steering and delivering steps for a third focal location that overlaps the second focal location.

37. 30. The method of claim 28, further comprising repeating the electronic beam steering and delivering steps for a third focal location that overlaps the first focal location.

38. 29. The method of claim 28, after each delivery step: delivering at least one low amplitude waveform to the target tissue to spatially manipulate residual cavitation nuclei in the target tissue; The method further comprises:

39. 30. The method of claim 28, further comprising repeating the delivery and electronic beam steering steps for the first and second focal locations until a desired dose is applied to the first individual treatment location.

40. 40. The method of claim 39, further comprising mechanically positioning the focal point of the ultrasound therapy transducer at a first focal point location at a second discrete treatment location within the target tissue volume after the desired dose is applied to the first discrete treatment location.

41. 30. The method of claim 28, wherein mechanically positioning the focal point further comprises mechanically positioning the focal point with a robotic positioning system.

42. 1. A method of administering histotripsy to a target tissue volume, comprising: delivering a first histotripsy therapy pulse to a first focal location to create a corresponding bubble cloud within a first focal zone; electronic beam steering the focal spot to a second focal spot location; delivering a second histotripsy therapy pulse to the second focal location to create a corresponding bubble cloud within a second focal zone spatially overlapping the first focal zone; wherein the second histotripsy pulse is timed to re-excite residual cavitation nuclei in the first focal zone to create an enhanced excitation volume comprising the first focal zone and a second focal zone.

43. 43. The method of claim 42, wherein the Histotripsy pulse comprises a positive half-cycle followed by a peak negative half-cycle followed by a trailing positive half-cycle.

44. 44. The method of claim 43, wherein the trailing positive half-cycle has a lower amplitude than the leading positive half-cycle.

45. 43. The method of claim 42, wherein delivering the second Histotripsy pulse to the second focal location further comprises delivering the second Histotripsy pulse to the second focal location to create the second bubble cloud at the second focal location during a life cycle of the first bubble cloud.

46. 46. ​​The method of claim 45, wherein delivering the second Histotripsy pulse to the second focal location further comprises delivering the second Histotripsy pulse to the second focal location to create the second bubble cloud at the second focal location during a life cycle of residual cavitation nuclei of the first bubble cloud.

47. 43. The method of claim 42, wherein electronic beam steering the focal point further comprises electronic beam steering the focal point axially relative to the ultrasound therapy transducer.

48. 43. The method of claim 42, wherein electronic beam steering of the focal point further comprises electronic beam steering of the focal point in any lateral direction relative to the ultrasound therapy transducer.

49. 43. The method of claim 42, wherein electronic beam steering the focal point further comprises electronic beam steering the focal point laterally and axially relative to the ultrasound therapy transducer.

50. 43. The method of claim 42, further comprising repeating the electronic beam steering and delivering steps for a third focal location that overlaps the second focal location.

51. 43. The method of claim 42, further comprising repeating the electronic beam steering and delivering steps for a third focal location that overlaps the first focal location.

52. 43. The method of claim 42, after each delivery step: delivering at least one low amplitude waveform to the target tissue to spatially manipulate residual cavitation nuclei in the target tissue; The method further comprises:

53. 43. The method of claim 42, further comprising repeating the delivery and electronic beam steering steps for the first and second focal locations until a desired dose is applied to the first individual treatment location.

54. 54. The method of claim 53, further comprising mechanically positioning the focal point of the ultrasound therapy transducer at a first focal point location at a second discrete treatment location within the target tissue volume after the desired dose is applied to the first discrete treatment location.

55. 43. The method of claim 42, wherein mechanically positioning the focal point further comprises mechanically positioning the focal point with a robotic positioning system.

56. 1. A method for producing an enhanced excitation volume at histotripsy energy, comprising: Positioning a focal point of an ultrasound therapy transducer at a first focal location at a first discrete treatment location within a target tissue volume, the first focal location being positioned along a central axis of the ultrasound therapy transducer; delivering a first histotripsy pulse to the first focal location to create a first cavitation bubble cloud at the first focal location; electronically beam steering the focal point of the ultrasound therapy transducer to a second focal point location at the first discrete treatment location at least partially outside the central axis; delivering a second histotripsy pulse to the second focal location to create a second bubble cloud at the second focal location; electronically beam steering the focal point of the ultrasound therapy transducer to a focal location at least partially inside the central axis; delivering a third histotripsy pulse to the focal location to create a third bubble cloud at the focal location; A method comprising:

57. 57. The method of claim 56, wherein a natural focus of the ultrasound therapy transducer array is located along the central axis.

58. 58. The method of claim 57, wherein the first focal location comprises the natural focal point.

59. 57. The method of claim 56, wherein the second focal location partially overlaps with the central axis.

60. 57. The method of claim 56, wherein the focal location comprises the first focal location.

61. 57. The method of claim 56, wherein the focal location comprises a third focal location.

62. 57. The method of claim 56, wherein steering the electron beam to the second focal location comprises laterally steering.

63. 57. The method of claim 56, wherein steering the electron beam to the second focal location comprises steering laterally and axially.

64. A robot positioning system; an ultrasound therapy transducer array connected to the robotic positioning system; a generator operatively coupled to the ultrasound therapy transducer array, wherein the generator and the ultrasound therapy transducer array are configured to deliver histotripsy pulses to the subject to generate a cavitation bubble cloud in the subject; at least one processor operatively coupled to the robot positioning system and the generator, Controlling the robotic positioning system to mechanically position a focal point of the ultrasound therapy transducer array at a first focal point location at a first individual treatment location within a treatment plan, wherein the first focal point location is positioned along a central axis of the ultrasound therapy transducer array; controlling the generator to deliver at least one histotripsy pulse at the ultrasound therapy transducer array to form a first cavitation bubble cloud at the first focal location; controlling the generator to electronically beam steer the focal point of the ultrasound therapy transducer to a second focal point location at the first discrete treatment location at least partially outside the central axis; controlling the generator to deliver at least one histotripsy pulse to the second focal location to produce a second bubble cloud at the second focal location; controlling the generator to electronically beam steer the focal point of the ultrasound therapy transducer to a focal point location at the first discrete treatment location at least partially inside the central axis; and controlling the generator to deliver at least one histotripsy pulse to the focal location to create a third bubble cloud at the focal location. at least one processor configured to control the robotic positioning system and the generator to provide histotripsy therapy to the subject according to the treatment plan, the treatment plan including a plurality of discrete treatment locations within a target tissue volume of the subject; An ultrasound therapy system comprising:

65. 65. The system of claim 64, wherein a natural focus of the ultrasound therapy transducer array is located along the central axis.

66. 66. The system of claim 65, wherein the first focal location comprises the natural focal point.

67. 65. The system of claim 64, wherein the second focal location partially overlaps with the central axis.

68. 65. The system of claim 64, wherein the focal locations include the first focal location.

69. 65. The system of claim 64, wherein the focal location comprises a third focal location.

70. 65. The system of claim 64, wherein controlling the generator to steer the electron beam to the second focal location comprises laterally steering.

71. 65. The system of claim 64, wherein controlling the generator to steer an electron beam to the second focal location comprises lateral and axial steering.

72. an ultrasound therapy transducer array; a generator operatively coupled to the ultrasound therapy transducer array, wherein the generator and the ultrasound therapy transducer array are configured to deliver histotripsy pulses to the subject to generate a cavitation bubble cloud in the subject; at least one processor operatively coupled to the generator, controlling the generator to deliver at least one histotripsy pulse with the ultrasound therapy transducer array to form a first cavitation bubble cloud at a first focal location at a first discrete treatment location within a treatment plan; controlling the generator to electronically beam steer the focal point of the ultrasound therapy transducer to a second focal point location at the first discrete treatment location that overlaps with the first focal point location; and controlling the generator to deliver at least one histotripsy pulse to the second focal location to create a second bubble cloud at the second focal location and to re-excite the first cavitation bubble cloud at the first focal location. at least one processor configured to control the generator to provide histotripsy therapy to the subject according to the treatment plan, the treatment plan including a plurality of discrete treatment locations within a target tissue volume of the subject; An ultrasound therapy system comprising:

73. an ultrasound therapy transducer array; a generator operatively coupled to the ultrasound therapy transducer array, wherein the generator and the ultrasound therapy transducer array are configured to deliver histotripsy pulses to the subject to generate a cavitation bubble cloud in the subject; at least one processor operatively coupled to the generator, controlling the generator to deliver at least one histotripsy pulse with the ultrasound therapy transducer array to form a first cavitation bubble cloud at a first focal location at a first individual treatment location within a treatment plan, wherein the first focal location is positioned along a central axis of the ultrasound therapy transducer array; controlling the generator to electronically beam steer the focal point of the ultrasound therapy transducer to a second focal point location at the first discrete treatment location at least partially outside the central axis; controlling the generator to deliver at least one histotripsy pulse to the second focal location to produce a second bubble cloud at the second focal location; controlling the generator to electronically beam steer the focal point of the ultrasound therapy transducer to a focal point location at the first discrete treatment location at least partially inside the central axis; and controlling the generator to deliver at least one histotripsy pulse to the focal location to create a third bubble cloud at the focal location. at least one processor configured to control the generator to provide histotripsy therapy to the subject according to the treatment plan, the treatment plan including a plurality of discrete treatment locations within a target tissue volume of the subject; An ultrasound therapy system comprising:

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