Histotripsy treatment planning and therapy including techniques for packing and traversing a treatment volume

Abstract

A histotripsy therapy system configured for the treatment of tissue is provided, which may include any number of features. Provided herein are systems and methods that provide efficacious non-invasive and minimally invasive therapeutic, diagnostic and research procedures. Treatment planning systems are also provided for preparing and implementing a digital treatment plan. The treatment planning can include dividing a target tissue volume into a plurality of treatment locations, and controlling the speed, and pattern of movement between these tissue locations.

Description

HISTOTRIPSY TREATMENT PLANNING AND THERAPY INCLUDING TECHNIQUES FOR PACKING AND TRAVERSING A TREATMENT VOLUMEPRIORITY CLAIM

[0001] This patent application claims priority to U.S. provisional patent application no. 63 / 672,878, titled “HISTOTRIPSY TREATMENT PLANNING AND THERAPY INCLUDING TECHNIQUES FOR PACKING AND TRAVERSING A TREATMENT VOLUME,”, and filed on July 18, 2024, which is herein incorporated by reference in its entirety.INCORPORATION BY REFERENCE

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

[0003] The present disclosure details novel high intensity therapeutic ultrasound (HITU) systems configured to produce acoustic cavitation, methods, devices and procedures for the minimally and non-invasive treatment of healthy, diseased and / or injured tissue. The acoustic cavitation systems and methods described herein, also referred to Histotripsy, may include transducers, drive electronics, positioning robotics, imaging systems, and integrated treatment planning and control software to provide comprehensive treatment and therapy for soft tissues in a patient.BACKGROUND

[0004] Histotripsy, or pulsed ultrasound cavitation therapy, is a technology where extremely short, intense bursts of acoustic energy induce controlled cavitation (microbubble formation) within the focal volume. The vigorous expansion and collapse of these microbubbles mechanically homogenizes cells and tissue structures within the focal volume. This is a very different end result than the coagulative necrosis characteristic of thermal ablation. To operate within a non-thermal, Histotripsy realm; it is necessary to deliver acoustic energy in the form of high amplitude acoustic pulses with low duty cycle.

[0005] Compared with conventional focused ultrasound technologies, Histotripsy has important advantages: 1) the destructive process at the focus is mechanical, not thermal; 2)cavitation appears bright on ultrasound imaging thereby confirming correct targeting and localization of treatment; 3) treated tissue generally, but not always, appears darker (more hypoechoic) on ultrasound imaging, so that the operator knows what has been treated; and 4) Histotripsy produces lesions in a controlled and precise manner. It is important to emphasize that unlike thermal ablative technologies such as microwave, radiofrequency, high-intensity focused ultrasound (HIFU) cryo or radiation, Histotripsy relies on the mechanical action of cavitation for tissue destruction and not on heat, cold or ionizing energy.SUMMARY OF THE DISCLOSURE

[0006] A method of preparing a treatment plan for a histotripsy procedure is provided, comprising: identifying, in a processor of a histotripsy system, a tissue volume to be treated; segmenting the tissue volume, in the processor, to generate a 2D lateral slice having an outermost margin contour with an arbitrary shape; dividing, in the processor, the 2D lateral slice into a plurality of concentric contours generally sharing the arbitrary shape; placing, in the processor, a first plurality of treatment locations along each of the plurality of concentric contours according to predetermined first spacing parameters; and for each of the first plurality of treatment locations, placing a second plurality of treatment locations in one or more transverse directions within the margin contour according to predetermined second spacing parameters.

[0007] In some aspects, the tissue volume to be treated comprises a tumor or cyst, or can comprise diseased tissue. The tissue volume to be treated can comprise a liver tumor, thyroid tissue, any tumor tissue, or diseased tissue such as prostate tissue.

[0008] In one aspect, the tissue volume is arbitrarily shaped in three dimensions.

[0009] In some aspects, the 2D lateral slice is segmented in an xy axis of a coordinate system of the histotripsy system. In this example, the second plurality of treatment locations can be placed in lines along a z axis of the coordinate system of the histotripsy system.

[0010] In some aspects, the first spacing parameters are based in part on a bubble cloud size / shape of the histotripsy system. The first spacing parameters can be based on a desired amount of overlap between adjacent bubble clouds. The second spacing parameters can also be based in part on a bubble cloud size / shape of the histotripsy system. In some aspects, the second spacing parameters are different than the first spacing parameters.

[0011] In some aspects, the method includes delivering histotripsy therapy to each of the first and second plurality of treatment locations. In some aspects, delivering histotripsy therapy further comprises controlling a robotic system of the histotripsy system to navigatebetween the first and second plurality of treatment locations with predetermined acceleration, deceleration, and maximum velocity parameters

[0012] In other aspects, the method further comprises: dividing the second plurality of treatment locations into groups, wherein each group comprises a common axial position within the tissue volume; initiating histotripsy therapy in a distal-most group of the tissue volume relative to a transducer array of the histotripsy system; delivering histotripsy therapy to each of the treatment locations within the distal-most group; navigating the histotripsy system to a group that is proximally adjacent to the distal-most group; delivering histotripsy therapy to each of the treatment locations within the proximally adjacent group with the histotripsy therapy system; and repeating the process for all remaining groups in a distal to proximal direction.

[0013] In some aspects, the method includes controlling a robotic system of the histotripsy system to navigate between treatment locations with predetermined acceleration, deceleration, and maximum velocity parameters.

[0014] In other aspects, the method includes determining if treatment is on or off before / during / after navigation between treatment locations.

[0015] The method can further comprise adding periods of cooling at selected treatment locations where therapy is turned off.

[0016] A histotripsy treatment method is also provided, comprising: identifying, in a processor of a histotripsy system, an arbitrarily shaped tissue volume within a subject; establishing, in the processor, a 3D treatment volume to be positioned around the tissue volume that encompasses the tissue volume; packing, in the processor, the 3D treatment volume with a plurality of discrete treatment points, wherein some of the discrete treatment points fall outside of the tissue volume; and controlling, with the processor, a focus of a histotripsy system to mechanically move through the plurality of discrete treatment points such that histotripsy therapy is applied to the discrete treatment points within the tissue volume and not applied to the discrete treatment points that fall outside of the tissue volume.

[0017] Another histotripsy therapy system is provided, comprising: 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, the generator and ultrasound therapy transducer array being configured to deliver histotripsy pulses into a subject to generate cavitation in the subject; at least one processor operatively coupled to the robotic positioning system and the generator, the at least one processor being configured to implement a digital treatment plan by: identifying a tissue volume to be treated; segmentingthe tissue volume to generate a 2D lateral slice having an outermost margin contour with an arbitrary shape; dividing the 2D lateral slice into a plurality of concentric contours generally sharing the arbitrary shape; placing a first plurality of treatment locations along each of the plurality of concentric contours according to predetermined first spacing parameters; and for each of the first plurality of treatment locations, placing a second plurality of treatment locations in one or more transverse directions within the margin contour according to predetermined second spacing parameters.

[0018] In some aspects, the tissue volume to be treated comprises a tumor or cyst, or can comprise diseased tissue. The tissue volume to be treated can comprise a liver tumor, thyroid tissue, any tumor tissue, or diseased tissue such as prostate tissue.

[0019] In one aspect, the tissue volume is arbitrarily shaped in three dimensions.

[0020] In some aspects, the 2D lateral slice is segmented in an xy axis of a coordinate system of the histotripsy system.

[0021] In other aspects, the second plurality of treatment locations are placed in lines along a z axis of the coordinate system of the histotripsy system.

[0022] In some aspects, the first spacing parameters are based in part on a bubble cloud size / shape of the histotripsy system. In some aspects, the first spacing parameters are based on a desired amount of overlap between adjacent bubble clouds.

[0023] In one aspect, the second spacing parameters are based in part on a bubble cloud size / shape of the histotripsy system. In some aspects, the second spacing parameters are different than the first spacing parameters.

[0024] In one aspect, the at least one processor is configured to control the robotic positioning system and the generator to deliver histotripsy therapy to each of the first and second plurality of treatment locations.

[0025] In another aspect, the at least one processor is further configured to control the robotic positioning system to navigate between the first and second plurality of treatment locations with predetermined acceleration, deceleration, and maximum velocity parameters

[0026] In some aspects, the at least one processor is configured to control the robotic positioning system and the generator to: divide the second plurality of treatment locations into groups, wherein each group comprises a common axial position within the tissue volume; initiate histotripsy therapy in a distal-most group of the tissue volume relative to a transducer array of the histotripsy system; deliver histotripsy therapy to each of the treatment locations within the distal-most group; navigate the ultrasound therapy transducer to a group that is proximally adjacent to the distal-most group; deliver histotripsy therapy to each of thetreatment locations within the proximally adjacent group with the histotripsy therapy system; and repeat the process for all remaining groups in a distal to proximal direction.

[0027] In some aspects, the at least one processor is further configured to control the robotic positioning system to navigate between treatment locations with predetermined acceleration, deceleration, and maximum velocity parameters.

[0028] In other aspects, the at least one processor is further configured to determine if treatment is on or off before / during / after navigation between treatment locations.

[0029] In additional aspects, the at least one processor is further configured to add periods of cooling at selected treatment locations where therapy is turned off.

[0030] A method of preparing a treatment plan for a histotripsy procedure is provided, comprising: identifying, in a processor of a histotripsy system, a tissue volume to be treated, the tissue volume having a tissue coordinate space that is not aligned with a treatment coordinate space of the histotripsy system; segmenting the tissue volume, in the processor, to generate a 2D lateral slice in the treatment coordinate space that passes through the treatment volume; dividing, in the processor, the 2D lateral slice into a plurality of concentric contours; placing, in the processor, a first plurality of treatment locations along each of the plurality of concentric contours according to predetermined first spacing parameters; and for each of the first plurality of treatment locations, placing a second plurality of treatment locations in one or more transverse directions within the tissue volume according to predetermined second spacing parameters, the second plurality of treatment locations being asymmetrically distributed on either side of the 2D lateral slice due to the mis-alignment of the tissue coordinate space and the treatment coordinate space.

[0031] In some aspects, the tissue volume to be treated comprises a tumor or cyst, or can comprise diseased tissue. The tissue volume to be treated can comprise a liver tumor, thyroid tissue, any tumor tissue, or diseased tissue such as prostate tissue.

[0032] In one aspect, the tissue volume is arbitrarily shaped in three dimensions.

[0033] In some aspects, the 2D lateral slice is segmented in an xy axis of a coordinate system of the histotripsy system. In this example, the second plurality of treatment locations can be placed in lines along a z axis of the coordinate system of the histotripsy system.

[0034] In some aspects, the first spacing parameters are based in part on a bubble cloud size / shape of the histotripsy system. The first spacing parameters can be based on a desired amount of overlap between adjacent bubble clouds. The second spacing parameters can also be based in part on a bubble cloud size / shape of the histotripsy system. In some aspects, the second spacing parameters are different than the first spacing parameters.

[0035] In some aspects, the method includes delivering histotripsy therapy to each of the first and second plurality of treatment locations. In some aspects, delivering histotripsy therapy further comprises controlling a robotic system of the histotripsy system to navigate between the first and second plurality of treatment locations with predetermined acceleration, deceleration, and maximum velocity parameters

[0036] In other aspects, the method further comprises: dividing the second plurality of treatment locations into groups, wherein each group comprises a common axial position within the tissue volume; initiating histotripsy therapy in a distal-most group of the tissue volume relative to a transducer array of the histotripsy system; delivering histotripsy therapy to each of the treatment locations within the distal-most group; navigating the histotripsy system to a group that is proximally adjacent to the distal-most group; delivering histotripsy therapy to each of the treatment locations within the proximally adjacent group with the histotripsy therapy system; and repeating the process for all remaining groups in a distal to proximal direction.

[0037] In some aspects, the method includes controlling a robotic system of the histotripsy system to navigate between treatment locations with predetermined acceleration, deceleration, and maximum velocity parameters.

[0038] In other aspects, the method includes determining if treatment is on or off before / during / after navigation between treatment locations.

[0039] The method can further comprise adding periods of cooling at selected treatment locations where therapy is turned off.

[0040] A histotripsy therapy system is provided, comprising: a robotic positioning system; an ultrasound therapy transducer array connected to the robotic positioning system, the ultrasound therapy transducer array having a treatment coordinate space with a treatment axis; a generator operatively coupled to the ultrasound therapy transducer array, the generator and ultrasound therapy transducer array being configured to deliver histotripsy pulses into a subject to generate cavitation in the subject; at least one processor operatively coupled to the robotic positioning system and the generator, the at least one processor being configured to implement a digital treatment plan by: identifying a tissue volume to be treated, the tissue volume having a tissue coordinate space that is not aligned with the treatment coordinate space of the ultrasound therapy transducer array; segmenting the tissue volume to generate a 2D lateral slice in the treatment coordinate space that passes through the treatment volume; dividing the 2D lateral slice into a plurality of concentric contours; placing a first plurality of treatment locations along each of the plurality of concentric contours according topredetermined first spacing parameters; and for each of the first plurality of treatment locations, placing a second plurality of treatment locations in one or more transverse directions within the tissue volume according to predetermined second spacing parameters, the second plurality of treatment locations being asymmetrically distributed on either side of the 2D lateral slice due to the mis-alignment of the tissue coordinate space and the treatment coordinate space.

[0041] In some aspects, the tissue volume to be treated comprises a tumor or cyst, or can comprise diseased tissue. The tissue volume to be treated can comprise a liver tumor, thyroid tissue, any tumor tissue, or diseased tissue such as prostate tissue.

[0042] In one aspect, the tissue volume is arbitrarily shaped in three dimensions.

[0043] In some aspects, the 2D lateral slice is segmented in an xy axis of a coordinate system of the histotripsy system.

[0044] In other aspects, the second plurality of treatment locations are placed in lines along a z axis of the coordinate system of the histotripsy system.

[0045] In some aspects, the first spacing parameters are based in part on a bubble cloud size / shape of the histotripsy system. In some aspects, the first spacing parameters are based on a desired amount of overlap between adjacent bubble clouds.

[0046] In one aspect, the second spacing parameters are based in part on a bubble cloud size / shape of the histotripsy system. In some aspects, the second spacing parameters are different than the first spacing parameters.

[0047] In one aspect, the at least one processor is configured to control the robotic positioning system and the generator to deliver histotripsy therapy to each of the first and second plurality of treatment locations.

[0048] In another aspect, the at least one processor is further configured to control the robotic positioning system to navigate between the first and second plurality of treatment locations with predetermined acceleration, deceleration, and maximum velocity parameters

[0049] In some aspects, the at least one processor is configured to control the robotic positioning system and the generator to: divide the second plurality of treatment locations into groups, wherein each group comprises a common axial position within the tissue volume; initiate histotripsy therapy in a distal-most group of the tissue volume relative to a transducer array of the histotripsy system; deliver histotripsy therapy to each of the treatment locations within the distal-most group; navigate the ultrasound therapy transducer to a group that is proximally adjacent to the distal-most group; deliver histotripsy therapy to each of thetreatment locations within the proximally adjacent group with the histotripsy therapy system; and repeat the process for all remaining groups in a distal to proximal direction.

[0050] In some aspects, the at least one processor is further configured to control the robotic positioning system to navigate between treatment locations with predetermined acceleration, deceleration, and maximum velocity parameters.

[0051] In other aspects, the at least one processor is further configured to determine if treatment is on or off before / during / after navigation between treatment locations.

[0052] In additional aspects, the at least one processor is further configured to add periods of cooling at selected treatment locations where therapy is turned off.BRIEF DESCRIPTION OF THE DRAWINGS

[0053] 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 of which:

[0054] FIGS. 1 A-1B illustrate an ultrasound imaging and therapy system.

[0055] FIG. 2 is one embodiment of a histotripsy therapy and imaging system with a coupling system.

[0056] FIG. 3 is one example of an ultrasound pulse for generating histotripsy via a shock scattering mechanism.

[0057] FIGS. 4A-4D illustrate one embodiment of a digital treatment plan that includes packing a target treatment volume with a plurality of treatment volumes.

[0058] FIG. 5 A illustrates a treatment volume that shares the same coordinate system as the ultrasound treatment system.

[0059] FIG. 5B shows a treatment volume that is rotated relative to the ultrasound treatment system and therefore has a different coordinate system.

[0060] FIGS. 6A-6B and 7A-7B illustrate one example of packing an arbitrarily rotated treatment volume with discrete treatment points.

[0061] FIGS. 8A-8B illustrate techniques for preventing over-treatment of a tissue volume when the tissue volume is arbitrarily shaped.

[0062] FIGS. 9A-9B illustrate one technique for packing a 2-Dimensional (2D) arbitrarily shaped treatment volume.

[0063] FIGS. 10A-10F illustrate one technique for packing a 3-Dimensional (3D) arbitrarily shaped treatment volume.

[0064] FIG. 11 A-l 1C are examples of traversing a plurality of treatment volumes in a target treatment volume according to a digital treatment plan.

[0065] FIG. 12 illustrates one embodiment of a timing diagram that includes therapy on / off controls for traversing a digital treatment plan.

[0066] FIGS. 13A-13B illustrate another embodiment of a timing diagram for traversing a digital treatment plan.

[0067] FIGS. 14A-14B show another embodiment of a timing diagram for traversing a digital treatment plan.DETAILED DESCRIPTION

[0068] The system, methods and devices of the disclosure may be used for open surgical, minimally invasive surgical (laparoscopic and percutaneous), robotic surgical (integrated into a robotically-enabled medical system), endoscopic or completely transdermal extracorporeal non-invasive acoustic cavitation for the treatment of healthy, diseased and / or injured tissue including but not limited to tissue destruction, cutting, skeletonizing and ablation. Furthermore, due to tissue selective properties, histotripsy may be used to create a cytoskeleton that allows for subsequent tissue regeneration either de novo or through the application of stem cells and other adjuvants. Finally, histotripsy can be used to cause the release of delivered agents such as chemotherapy and immunotherapy by locally causing the release of these agents by the application of acoustic energy to the targets. As will be described below, the acoustic cavitation system may include various sub-systems, including a Cart, Therapy, Integrated Imaging, Robotics, Coupling and Software. The system also may comprise various Other Components, Ancillaries 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, etc. All systems, methods and means creating / controlling / delivering histotripsy are considered to be a part of this disclosure, including new related inventions disclosed herein.

[0069] FIG. 1 A generally illustrates histotripsy system 100 according to the present disclosure, comprising 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 can further include an ultrasound coupling interface and a source of coupling medium, not shown.

[0070] FIG. IB is a bottom view of the therapy transducer 102 and the imaging system 104. As shown, the imaging system can be positioned in the center of the therapy transducer. However, other embodiments can include the imaging system positioned in other locations within the therapy transducer, or even directly integrated into the therapy transducer. In some embodiments, the imaging system is configured to produce real-time imaging at a focal point of the therapy transducer. The system also allows for multiple imaging transducers to be located within the therapy transducer to provide multiple views of the target tissue simultaneously and to integrate these images into a single 3-D image.

[0071] The histotripsy system may comprise one or more of various sub-systems, including a Therapy sub-system that can create, apply, focus and deliver acoustic cavitation / histotripsy through one or more therapy transducers, Integrated Imaging subsystem (or connectivity to) allowing real-time visualization of the treatment site and histotripsy effect through-out the procedure, a Robotics positioning sub-system to mechanically and / or electronically steer the therapy transducer, further enabled to connect / support or interact with a Coupling sub-system to allow acoustic coupling between the therapy transducer and the patient, and Software to communicate, control and interface with the system and computer-based control systems (and other external systems) and various Other Components, Ancillaries and Accessories, including one or more user interfaces and displays, and related guided work-flows, all working in part or together. The system may further comprise various fluidics and fluid management components, including but not limited to, pumps, valve and flow controls, temperature and degassing controls, and irrigation and aspiration capabilities, as well as providing and storing fluids. It may also contain various power supplies and protectors.

[0072] As described above, the histotripsy system may include integrated imaging. However, in other embodiments, the histotripsy system can be configured to interface with separate imaging systems, such as 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. HISTOTRIPSY

[0073] Histotripsy comprises short, high amplitude, focused ultrasound pulses to generate a dense, energetic, “bubble cloud”, capable of the targeted fractionation and destruction of tissue. Histotripsy is capable of creating controlled tissue erosion when directed at a tissue interface, including tissue / fluid interfaces, as well as well-demarcated tissue fractionation and destruction, at sub-cellular levels, when it is targeted at bulk tissue. Unlike other forms ofablation, including thermal and radiation-based modalities, histotripsy does not rely on heat cold or ionizing (high) energy to treat tissue. Instead, histotripsy uses acoustic cavitation generated at the focus to mechanically effect tissue structure, and in some cases liquefy, suspend, solubilize and / or destruct tissue into sub-cellular components.

[0074] Histotripsy can be applied in various forms, including: 1) Intrinsic-Threshold Histotripsy: Delivers pulses typically with a 1-2 cycles of high amplitude negative / tensile phase pressure exceeding the intrinsic threshold to generate cavitation in the medium (e.g., -24-28 MPa for water-based soft tissue), 2) Shock- Scattering Histotripsy: Delivers typically pulses 1-20 cycles in duration. The shockwave (positive / compressive phase) scattered from an initial individual microbubble generated forms inverted shockwave, which constructively interferes with the incoming negative / tensile phase to form high amplitude negative / rarefactional phase exceeding the intrinsic threshold. In this way, a cluster of cavitation microbubbles is generated. The amplitude of the tensile phases of the pulses 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 shockwaves, which invert and constructively interfere with the incident wave to exceed the threshold for intrinsic nucleation, and 3) Boiling Histotripsy: Employs pulses roughly 1-20 ms in duration. Absorption of the shocked pulse rapidly heats the medium, thereby reducing the threshold for intrinsic nuclei. Once this intrinsic threshold coincides with the peak negative pressure of the incident wave, boiling bubbles form at the focus.

[0075] The large pressure generated at the focus causes a cloud of acoustic cavitation bubbles to form above certain thresholds, which creates localized stress and strain in the tissue and mechanical breakdown without significant heat deposition. At pressure levels where cavitation is not generated, minimal effect is observed on the tissue at the focus. This cavitation effect is observed only at pressure levels significantly greater than those which define the inertial cavitation threshold in water for similar pulse durations, on the order of 10 to 30 MPa peak negative pressure.

[0076] Histotripsy may be performed in multiple ways and under different parameters. It may be performed totally non-invasively by acoustically coupling a focused ultrasound transducer over the skin of a patient and transmitting acoustic pulses transcutaneously through overlying (and intervening) tissue to the focal zone (treatment zone and site). The application of histotripsy is not limited to a transdermal approach but can be applied through any means that allow contact of the transducer with tissue including open surgical laparoscopic surgical, percutaneous and robotically mediated surgical procedures. It may befurther targeted, planned, directed and observed under direct visualization, via ultrasound imaging, given the bubble clouds generated by histotripsy may be visible as highly dynamic, echogenic regions on, for example, B Mode ultrasound images, allowing continuous visualization through its use (and related procedures). Likewise, the treated and fractionated tissue shows a dynamic change in echogenicity (typically a reduction), which can be used to evaluate, plan, observe and monitor treatment.

[0077] Generally, in histotripsy treatments, ultrasound pulses with 1 or more acoustic cycles are applied, and the bubble cloud formation relies on the pressure release scattering of the positive shock fronts (sometimes exceeding 100 MPa, P+) from initially initiated, sparsely distributed bubbles (or a single bubble). This is referred to as the “shock scattering mechanism”.

[0078] FIG. 3 illustrates an ultrasound pulse that can be used for shock scattering histotripsy. As shown the ultrasound pulse can include a leading negative half-cycle, a peak positive half-cycle, a peak negative half-cycle, and a trailing positive half-cycle (with the pulse traveling from right to left on the page). As shown, the trailing peak positive half-cycle has a lower amplitude than the peak positive half-cycle. This mechanism depends on one (or a few sparsely distributed) bubble(s) initiated with the initial negative half cycle(s) of the pulse at the focus of the transducer. A cloud of microbubbles then forms due to the pressure release backscattering of the high peak positive shock fronts from these sparsely initiated bubbles. These back- scattered high-amplitude rarefactional waves exceed the intrinsic threshold thus producing a localized dense bubble cloud. Each of the following acoustic cycles then induces further cavitation by the backscattering from the bubble cloud surface if the amplitude of those cycles is sufficient, which grows towards the transducer. As a result, an elongated dense bubble cloud growing along the acoustic axis opposite the ultrasound propagation direction is observed with the shock scattering mechanism. This shock scattering process makes the bubble cloud generation not only dependent on the peak negative half-cycle pressure, but also the number of acoustic cycles and the amplitudes of the positive shocks. Without at least one intense shock front developed by nonlinear propagation, no dense bubble clouds are generated when the peak negative half-cycles are below the intrinsic threshold.

[0079] When the amplitude(s) of positive half-cycle(s) of each pulse are limited, shock scattering can be minimized, and the generation of a dense bubble cloud depends on the negative half-cycle(s) of the applied ultrasound pulses exceeding an “intrinsic threshold” of the medium. This is referred to as the “intrinsic threshold mechanism”.

[0080] This threshold can be in the range of 26 - 30 MPa for soft tissues with high water content, such as tissues in the human body. In some embodiments, using this intrinsic threshold mechanism, the spatial extent of the lesion may be well-defined and more predictable. With peak negative pressures (P-) not significantly higher than this threshold, sub -wavelength reproducible lesions as small as half of the -6dB beam width of a transducer may be generated.

[0081] With high-frequency Histotripsy pulses, the size of the smallest reproducible lesion becomes smaller, which is beneficial in applications that require precise lesion generation. However, high-frequency pulses are more susceptible to attenuation and aberration, rendering problematical treatments at a larger penetration depth (e.g., ablation deep in the body) or through a highly aberrative medium (e.g., transcranial procedures, or procedures in which the pulses are transmitted through bone(s)). Histotripsy may further also be applied as a low-frequency “pump” pulse (typically < 2 cycles and having a frequency between 100 kHz and 1 MHz) can be applied together with a high-frequency “probe” pulse (typically < 2 cycles and having a frequency greater than 2 MHz, or ranging between 2 MHz and 10 MHz) wherein the peak negative pressures of the low and high-frequency pulses constructively interfere to exceed the intrinsic threshold in the target tissue or medium. The low-frequency pulse, which is more resistant to attenuation and aberration, can raise the peak negative pressure P- level for a region of interest (ROI), while the high-frequency pulse, which provides more precision, can pin-point a targeted location within the ROI and raise the peak negative pressure P- above the intrinsic threshold. This approach may be referred to as “dual frequency”, “dual beam histotripsy” or “parametric histotripsy.”

[0082] Additional systems, methods and parameters to deliver optimized histotripsy, using shock scattering, intrinsic threshold, and various parameters enabling frequency compounding and bubble manipulation, are herein included as part of the system and methods disclosed herein, including additional means of controlling said histotripsy effect as pertains to steering and positioning the focus, and concurrently managing tissue effects (e.g., prefocal thermal collateral damage) at the treatment site or within intervening tissue. Further, it is disclosed that the various systems and methods, which may include a plurality of parameters, such as but not limited to, frequency, operating frequency, center frequency, pulse repetition frequency, pulses, bursts, number of pulses, cycles, length of pulses, amplitude of pulses, pulse period, delays, burst repetition frequency, sets of the former, loops of multiple sets, loops of multiple and / or different sets, sets of loops, and variouscombinations or permutations of, etc., are included as a part of this disclosure, including future envisioned embodiments of such.THERAPY COMPONENTS

[0083] The Therapy sub-system may work with other sub-systems to create, optimize, deliver, visualize, monitor and control acoustic cavitation, also referred to herein and in following as “histotripsy”, and its derivatives of, including boiling histotripsy and other thermal high frequency ultrasound approaches. It is noted that the disclosed inventions may also further benefit other acoustic therapies that do not comprise a cavitation, mechanical or histotripsy component. The therapy sub-system can include, among other features, an ultrasound therapy transducer and a pulse generator system configured to deliver ultrasound pulses into tissue.

[0084] In order to create and deliver histotripsy and derivatives of histotripsy, the therapy sub-system may also comprise components, including but not limited to, one or more function generators, amplifiers, therapy transducers and power supplies.

[0085] The therapy transducer can comprise a single element or multiple elements configured to be excited with high amplitude electric pulses (>1000V or any other voltage that can cause harm to living organisms). The amplitude necessary to drive the therapy transducers for Histotripsy vary depending on the design of the transducer and the materials used (e.g., solid or polymer / piezoelectric composite including ceramic or single crystal) and the transducer center frequency which is directly proportional to the thickness of the piezoelectric material. Transducers therefore operating at a high frequency require lower voltage to produce a given surface pressure than is required by low frequency therapy transducers. In some embodiments, the transducer elements are formed using a piezoelectric-polymer composite material or a solid piezoelectric material. Further, the piezoelectric material can be of polycrystalline / ceramic or single crystalline formulation. In some embodiments the transducer elements can be formed using silicon using MEMs technology, including CMUT and PMUT designs.

[0086] In some embodiments, the function generator may comprise a field programmable gate array (FPGA) or other suitable function generator. The FPGA may be configured with parameters disclosed previously herein, including but not limited to frequency, pulse repetition frequency, bursts, burst numbers, where bursts may comprise pulses, numbers of pulses, length of pulses, pulse period, delays, burst repetition frequency or period, where sets of bursts may comprise a parameter set, where loop sets may comprise various parameter sets, with or without delays, or varied delays, where multiple loop sets may be repeatedand / or new loop sets introduced, of varied time delay and independently controlled, and of various combinations and permutations of such, overall and throughout.

[0087] In some embodiments, the generator or amplifier may be configured to be a universal single-cycle or multi-cycle pulse generator, and to support driving via Class D or inductive driving, as well as across all envisioned clinical applications, use environments, also discussed in part later in this disclosure. In other embodiments, the class D or inductive current driver may be configured to comprise transformer and / or auto-transformer driving circuits to further provide step up / down components, and in some cases, to preferably allow a step up in the amplitude. They may also comprise specific protective features, to further support the system, and provide capability to protect other parts of the system (e.g., therapy transducer and / or amplifier circuit components) and / or the user, from various hazards, including but not limited to, electrical safety hazards, which may potentially lead to use environment, system and therapy system, and user harms, damage or issues.

[0088] Disclosed generators may allow and support the ability of the system to select, vary and control various parameters (through enabled software tools), including, but not limited to those previously disclosed, as well as the ability to start / stop therapy, set and read voltage level, pulse and / or burst repetition frequency, number of cycles, duty ratio, channel enabled and delay, etc., modulate pulse amplitude on a fast time-scale independent of a high voltage supply, and / or other service, diagnostic or treatment features.

[0089] In some embodiments, the Therapy sub-system and / or components of, such as the amplifier, may comprise further integrated computer processing capability and may be networked, connected, accessed, and / or be removable / portable, modular, and / or exchangeable between systems, and / or driven / commanded from / by other systems, or in various combinations. Other systems may include other acoustic cavitation / histotripsy, HIFU, HITU, radiation therapy, radiofrequency, microwave, and cryoablation systems, navigation and localization systems, open surgical, laparoscopic, single incision / single port, endoscopic and non-invasive surgical robots, laparoscopic or surgical towers comprising other energy-based or vision systems, surgical system racks or booms, imaging carts, etc.

[0090] In some embodiments, one or more amplifiers may comprise a Class D amplifier and related drive circuitry including matching network components. Depending on the transducer element electric impedance and choice of the matching network components (e.g., an LC circuit made of an inductor LI in series and the capacitor Cl in parallel), the combined impedance can be aggressively set low in order to have high amplitude electric waveform necessary to drive the transducer element. The maximum amplitude that Class D amplifiersis dependent on the circuit components used, including the driving MOSFET / IGBT transistors, matching network components or inductor, and transformer or autotransformer, and of which may be typically in the low kV (e.g., 1-3 kV) range.

[0091] Therapy transducer element(s) are excited with an electrical waveform with an amplitude (voltage) to produce a pressure output sufficient for Histotripsy therapy. The excitation electric field can be defined as the necessary waveform voltage per thickness of the piezoelectric element. For example, because a piezoelectric element operating at 1 MHz transducer is half the thickness of an equivalent 500 kHz element, it will require half the voltage to achieve the same electric field and surface pressure.

[0092] The Therapy sub-system may also comprise therapy transducers of various designs and working parameters, supporting use in various procedures (and procedure settings). Systems may be configured with one or more therapy transducers, that may be further interchangeable, and work with various aspects of the system in similar or different ways (e.g., may interface to a robotic arm using a common interface and exchange feature, or conversely, may adapt to work differently with application specific imaging probes, where different imaging probes may interface and integrate with a therapy transducer in specifically different ways).

[0093] Therapy transducers may be configured of various parameters that may include size, shape (e.g., rectangular or round; anatomically curved housings, etc.), geometry, focal length, number of elements, size of elements, distribution of elements (e.g., number of rings, size of rings for annular patterned transducers), frequency, enabling electronic beam steering, etc. Transducers may be composed of various materials (e.g., piezoelectric, silicon, etc.), form factors and types (e.g., machined elements, chip-based, etc.) and / or by various methods of fabrication of.

[0094] Transducers may 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 tissue), and affording a breadth of working ranges, including relatively shallow and superficial targets (e.g., thyroid or breast nodules), versus, deeper or harder to reach targets, such as central liver or brain tumors. They may be configured to enable acoustic cavitation / histotripsy under various parameters and sets of, as enabled by the aforementioned system components (e.g., function generator and amplifier, etc.), including but not limited to frequency, pulse repetition rate, pulses, number of pulses, pulse length, pulse period, delays, repetitions, sync delays, sync period, sync pulses, sync pulse delays, various loop sets, others, and permutations of. Thetransducer may also be designed to allow for the activation of a drug payload either deposited in tissue through various means including injection, placement or delivery in micelle or nanostructures.INTEGRATED IMAGING

[0095] The disclosed system may comprise various imaging modalities to allow users to visualize, monitor and collect / use feedback of the patient’s anatomy, related regions of interest and treatment / procedure sites, as well as surrounding and intervening tissues to assess, plan and conduct procedures, and adjust treatment parameters as needed. Imaging modalities may comprise various ultrasound, x-ray, CT, MRI, PET, fluoroscopy, optical, contrast or agent enhanced versions, and / or various combinations of. It is further disclosed that various image processing and characterization technologies may also be utilized to afford enhanced visualization and user decision making. These may be selected or commanded manually by the user or in an automated fashion by the system. The system may be configured to allow side by side, toggling, overlays, 3D reconstruction, segmentation, registration, multi-modal image fusion, image flow, and / or any methodology affording the user to identify, define and inform various aspects of using imaging during the procedure, as displayed in the various system user interfaces and displays. Examples may include locating, displaying and characterizing regions of interest, organ systems, potential treatment sites within, with on and / or surrounding organs or tissues, identifying critical structures such as ducts, vessels, nerves, ureters, fissures, capsules, tumors, tissue trauma / injury / disease, other organs, connective tissues, etc., and / or in context to one another, of one or more (e.g., tumor draining lymphatics or vasculature; or tumor proximity to organ capsule or underlying other organ), as unlimited examples.

[0096] Systems may be configured to include onboard integrated imaging hardware, software, sensors, probes and wetware, and / or may be configured to communicate and interface with external imaging and image processing systems. The aforementioned components may be also integrated into the system’s Therapy sub-system components wherein probes, imaging arrays, or the like, and electrically, mechanically or electromechanically integrated into therapy transducers. This may afford, in part, the ability to have geometrically aligned imaging and therapy, with the therapy directly within the field of view, and in some cases in line, with imaging. In some embodiments, this integration may comprise a fixed orientation of the imaging capability (e.g., imaging probe) in context to the therapy transducer. In other embodiments, the imaging solution may be able to move or adjust its position, including modifying angle, extension (e.g., distance from therapytransducer or patient), rotation (e.g., imaging plane in example of an ultrasound probe) and / or other parameters, including moving / adjusting dynamically while actively imaging. The imaging component or probe may be encoded so its orientation and position relative to another aspect of the system, such as the therapy transducer, and / or robotically-enabled positioning component may be determined.

[0097] In one embodiment, the system may comprise onboard ultrasound, further configured to allow users to visualize, monitor and receive feedback for procedure sites through the system displays and software, including allowing ultrasound imaging and characterization (and various forms of), ultrasound guided planning and ultrasound guided treatment, all in real-time. The system may be configured to allow users to manually, semiautomated or in fully automated means image the patient (e.g., by hand or using a robotically- enabled imager).

[0098] In some embodiments, imaging feedback and monitoring can include monitoring changes in: backscatter from bubble clouds; speckle reduction in backscatter; backscatter speckle statistics; mechanical properties of tissue (i.e., elastography); tissue perfusion (i.e., ultrasound contrast); shear wave propagation; acoustic emissions, electrical impedance tomography, and / or various combinations of, including as displayed or integrated with other forms of imaging (e.g., CT or MRI).

[0099] In some embodiments, imaging including feedback and monitoring from backscatter from bubble clouds, may be used as a method to determine immediately if the histotripsy process has been initiated, is being properly maintained, or even if it has been extinguished. For example, this method enables continuously monitored in real time drug delivery, tissue erosion, and the like. The method also can provide feedback permitting the histotripsy process to be initiated at a higher intensity and maintained at a much lower intensity. For example, backscatter feedback can be monitored by any transducer or ultrasonic imager. By measuring feedback for the therapy transducer, an accessory transducer can send out interrogation pulses or be configured to passively detect cavitation. Moreover, the nature of the feedback received can be used to adjust acoustic parameters (and associated system parameters) to optimize the drug delivery and / or tissue erosion process.

[0100] In some embodiments, imaging including feedback and monitoring from backscatter, and speckle reduction, may be configured in the system.

[0101] For systems comprising feedback and monitoring via backscattering, and as means of background, as tissue is progressively mechanically subdivided, in other words homogenized, disrupted, or eroded tissue, this process results in changes in the size anddistribution of acoustic scatter. At some point in the process, the scattering particle size and density is reduced to levels where little ultrasound is scattered, or the amount scattered is reduced significantly. This results in a significant reduction in speckle, which is the coherent constructive and destructive interference patterns of light and dark spots seen on images when coherent sources of illumination are used; in this case, ultrasound. After some treatment time, the speckle reduction results in a dark area in the therapy volume. Since the amount of speckle reduction is related to the amount of tissue subdivision, it can be related to the size of the remaining tissue fragments. When this size is reduced to sub-cellular levels, no cells are assumed to have survived. So, treatment can proceed until a desired speckle reduction level has been reached. Speckle is easily seen and evaluated on standard ultrasound imaging systems. Specialized transducers and systems, including those disclosed herein, may also be used to evaluate the backscatter changes.

[0102] Further, systems comprising feedback and monitoring via speckle, and as means of background, an image may persist from frame to frame and change very little as long as the scatter distribution does not change and there is no movement of the imaged object. However, long before the scatters are reduced enough in size to cause speckle reduction, they may be changed sufficiently to be detected by signal processing and other means. This family of techniques can operate as detectors of speckle statistics changes. For example, the size and position of one or more speckles in an image will begin to decorrelate before observable speckle reduction occurs. Speckle decorrelation, after appropriate motion compensation, can be a sensitive measure of the mechanical disruption of the tissues, and thus a measure of therapeutic efficacy. This feedback and monitoring technique may permit early observation of changes resulting from the acoustic cavitation / histotripsy process and can identify changes in tissue before substantial or complete tissue effect (e.g., erosion occurs). In one embodiment, this method may be used to monitor the acoustic cavitation / histotripsy process for enhanced drug delivery where treatment sites / tissue is temporally disrupted, and tissue damage / erosion is not desired. In other embodiments, this may comprise speckle decorrelation by movement of scatters in an increasingly fluidized therapy volume. For example, in the case where partial or complete tissue erosion is desired.

[0103] For systems comprising feedback and monitoring via elastography, and as means of background, as treatment sites / tissue are further subdivided per an acoustic cavitation / histotripsy effect (homogenized, disrupted, or eroded), its mechanical properties change from a soft but interconnected solid to a viscous fluid or paste with few long-range interactions. These changes in mechanical properties can be measured by various imagingmodalities including MRI and ultrasound imaging systems. For example, an ultrasound pulse can be used to produce a force (i.e., a radiation force) on a localized volume of tissue. The tissue response (displacements, strains, and velocities) can change significantly during histotripsy treatment allowing the state of tissue disruption to be determined by imaging or other quantitative means.

[0104] Systems may also comprise feedback and monitoring via shear wave propagation changes. As means of background, the subdivision of tissues makes the tissue more fluid and less solid and fluid systems generally do not propagate shear waves. Thus, the extent of tissue fluidization provides opportunities for feedback and monitoring of the histotripsy process. For example, ultrasound and MRI imaging systems can be used to observe the propagation of shear waves. The extinction of such waves in a treated volume is used as a measure of tissue destruction or disruption. In one system embodiment, the system and supporting sub-systems may be used to generate and measure the interacting shear waves. For example, two adjacent ultrasound foci might perturb tissue by pushing it in certain ways. If adjacent foci are in a fluid, no shear waves propagate to interact with each other. If the tissue is not fluidized, the interaction would be detected with external means, for example, by a difference frequency only detected when two shear waves interact nonlinearly, with their disappearance correlated to tissue damage. As such, the system may be configured to use this modality to enhance feedback and monitoring of the acoustic cavitation / histotripsy procedure.

[0105] For systems comprising feedback and monitoring via acoustic emission, and as means of background, as a treatment volume is subdivided, its effect on acoustic cavitation / histotripsy (e.g., the bubble cloud here) is changed. For example, bubbles may grow larger and have a different lifetime and collapse changing characteristics in intact versus fluidized tissue. Bubbles may also move and interact after tissue is subdivided producing larger bubbles or cooperative interaction among bubbles, all of which can result in changes in acoustic emission. These emissions can be heard during treatment and they change during treatment. Analysis of these changes, and their correlation to therapeutic efficacy, enables monitoring of the progress of therapy, and may be configured as a feature of the system.

[0106] For systems comprising feedback and monitoring via electrical impedance tomography, and as means of background, an impedance map of a therapy site can be produced based upon the spatial electrical characteristics throughout the therapy site. Imaging of the conductivity or permittivity of the therapy site of a patient can be inferredfrom taking skin surface electrical measurements. Conducting electrodes are attached to a patient's skin and small alternating currents are applied to some or all of the electrodes. One or more known currents are injected into the surface and the voltage is measured at a number of points using the electrodes. The process can be repeated for different configurations of applied current. The resolution of the resultant image can be adjusted by changing the number of electrodes employed. A measure of the electrical properties of the therapy site within the skin surface can be obtained from the impedance map, and changes in and location of the acoustic cavitation / histotripsy (e.g., bubble cloud, specifically) and histotripsy process can be monitored using this as configured in the system and supporting sub-systems.

[0107] The user may be allowed to further select, annotate, mark, highlight, and / or contour, various regions of interest or treatment sites, and defined treatment targets (on the image(s)), of which may be used to command and direct the system where to image, test and / or treat, through the system software and user interfaces and displays. In some arrangements, the user may use a manual ultrasound probe (e.g., diagnostic hand-held probe) to conduct the procedure. In another arrangement, the system may use a robot and / or electromechanical positioning system to conduct the procedure, as directed and / or automated by the system, or conversely, the system can enable combinations of manual and automated uses.

[0108] The system may further include the ability to conduct image registration, including imaging and image data set registration to allow navigation and localization of the system to the patient, including the treatment site (e.g., tumor, critical structure, bony anatomy, anatomy and identifying features of, etc.). In one embodiment, the system allows the user to image and identify a region of interest, for example the liver, using integrated ultrasound, and to select and mark a tumor (or surrogate marker of) comprised within the liver through / di splayed in the system software, and wherein said system registers the image data to a coordinate system defined by the system, that further allows the system’s Therapy and Robotics sub-systems to deliver synchronized acoustic cavitation / histotripsy to said marked tumor. The system may comprise the ability to register various image sets, including those previously disclosed, to one another, as well as to afford navigation and localization (e.g., of a therapy transducer to a CT or MRI / ultrasound fusion image with the therapy transducer and Robotics sub-system tracking to said image).

[0109] The system may also comprise the ability to work in a variety of interventional, endoscopic and surgical environments, including alone and with other systems (surgical / laparoscopic towers, vision systems, endoscope systems and towers, ultrasoundenabled endoscopic ultrasound (flexible and rigid), percutaneous / endoscopic / laparoscopic and minimally invasive navigation systems (e.g., optical, electromagnetic, shape-sensing, ultrasound-enabled, etc.), of also which may work with, or comprise various optical imaging capabilities (e.g., fiber and or digital). The disclosed system may be configured to work with these systems, in some embodiments working alongside them in concert, or in other embodiments where all or some of the system may be integrated into the above systems / platforms (e.g., acoustic cavitation / histotripsy-enabled endoscope system or laparoscopic surgical robot). In many of these environments, a therapy transducer may be utilized at or around the time of use, for example, of an optically guided endoscope / bronchoscope, or as another example, at the time a laparoscopic robot (e.g., Intuitive Da Vinci* Xi system) is viewing / manipulating a tissue / treatment site. Further, these embodiments and examples may include where said other systems / platforms are used to deliver (locally) fluid to enable the creation of a man-made acoustic window, where on under normal circumstances may not exist (e.g., fluidizing a segment or lobe of the lung in preparation for acoustic cavitation / histotripsy via non-invasive transthoracic treatment (e.g., transducer externally placed on / around patient). Systems disclosed herein may also comprise all or some of their sub-system hardware packaged within the other system cart / console / systems described here (e.g., acoustic cavitation / histotripsy system and / or subsystems integrated and operated from said navigation or laparoscopic system).

[0110] The system may also be configured, through various aforementioned parameters and other parameters, to display real-time visualization of a bubble cloud in a spatial- temporal manner, including the resulting tissue effect peri / post-treatment from tissue / bubble cloud interaction, wherein the system can dynamically image and visualize, and display, the bubble cloud, and any changes to it (e.g., decreasing or increasing echogenicity), which may include intensity, shape, size, location, morphology, persistence, etc. These features may allow users to continuously track and follow the treatment in real-time in one integrated procedure and interface / system, and confirm treatment safety and efficacy on the fly (versus other interventional or surgical modalities, which either require multiple procedures to achieve the same, or where the treatment effect is not visible in real-time (e.g., radiation therapy), or where it is not possible to achieve such (e.g., real-time visualization of local tissue during thermal ablation), and / or where the other procedure further require invasive approaches (e.g., incisions or punctures) and iterative imaging in a scanner between procedure steps (e.g., CT or MRI scanning). The above disclosed systems, sub-systems, components, modalities, features and work-flows / methods of use may be implemented in anunlimited fashion through enabling hardware, software, user interfaces and use environments, and future improvements, enhancements and inventions in this area are considered as included in the scope of this disclosure, as well as any of the resulting data and means of using said data for analytics, artificial intelligence or digital health applications and systems. CART[OHl] The Cart 110 may be generally configured in a variety of ways and form factors based on the specific uses and procedures. In some cases, systems may comprise multiple Carts, configured with similar or different arrangements. In some embodiments, the cart may be configured and arranged to be used in a radiology environment and in some cases in concert with imaging (e.g., CT, cone beam CT and / or MRI scanning). In other embodiments, it may be arranged for use in an operating room and a sterile environment for open surgical or laparoscopic surgical and endoscopic application, or in a robotically enabled operating room, and used alone, or as part of a surgical robotics procedure wherein a surgical robot conducts specific tasks before, during or after use of the system and delivery of acoustic cavitation / histotripsy. As such and depending on the procedure environment based on the aforementioned embodiments, the cart may be positioned to provide sufficient work-space and access to various anatomical locations on the patient (e.g., torso, abdomen, flank, head and neck, etc.), as well as providing work-space for other systems (e.g., anesthesia cart, laparoscopic tower, surgical robot, endoscope tower, etc.).

[0112] The Cart may also work with a patient surface (e.g., table or bed) to allow the patient to be presented and repositioned in a plethora of positions, angles and orientations, including allowing changes to such to be made pre, peri and post-procedurally. It may further comprise the ability to interface and communicate with one or more external imaging or image data management and communication systems, not limited to ultrasound, CT, fluoroscopy, cone beam CT, PET, PET / CT, MRI, optical, ultrasound, and image fusion and or image flow, of one or more modalities, to support the procedures and / or environments of use, including physical / mechanical interoperability (e.g., compatible within cone beam CT work-space for collecting imaging data pre, peri and / or post histotripsy) and to provide access to and display of patient medical data including but not limited to laboratory and historical medical record data.

[0113] In some embodiments one or more Carts may be configured to work together. As an example, one Cart may comprise a bedside mobile Cart equipped with one or more Robotic arms enabled with a Therapy transducer, and Therapy generator / amplifier, etc., while a companion cart working in concert and at a distance of the patient may comprise IntegratedImaging and a consol e / di splay for controlling the Robotic and Therapy facets, analogous to a surgical robot and master / slave configurations.

[0114] In some embodiments, the system may comprise a plurality of Carts, all slave to one master Cart, equipped to conduct acoustic cavitation procedures. In some arrangements and cases, one Cart configuration may allow for storage of specific sub-systems at a distance reducing operating room clutter, while another in concert Cart may comprise essentially bedside sub-systems and componentry (e.g., delivery system and therapy).

[0115] One can envision a plethora of permutations and configurations of Cart design, and these examples are in no way limiting the scope of the disclosure.ROBOTICS

[0116] They system may comprise various Robotic sub-systems and components, including but not limited to, one or more robotic arms and controllers, which may further work with other sub-systems or components of the system to deliver and monitor acoustic cavitation / histotripsy. As previously discussed herein, robotic arms and control systems may be integrated into one or more Cart configurations.

[0117] For example, one system embodiment may comprise a Cart with an integrated robotic arm and control system, and Therapy, Integrated Imaging and Software, where the robotic arm and other listed sub-systems are controlled by the user through the form factor of a single bedside Cart.

[0118] In other embodiments, the Robotic sub-system may be configured in one or more separate Carts, that may be a driven in a master / slave configuration from a separate master or Cart, wherein the robotically-enabled Cart is positioned bed / pati ent-side, and the Master is at a distance from said Cart.

[0119] Disclosed robotic arms may be comprised of a plurality of joints, segments, and degrees of freedom and may also include various integrated sensor types and encoders, implemented for various use and safety features. Sensing technologies and data may comprise, as an example, vision, potentiometers, position / localization, kinematics, force, torque, speed, acceleration, dynamic loading, and / or others. In some cases, sensors may be used for users to direct robot commands (e.g., hand gesture the robot into a preferred set up position, or to dock home). Additional details on robotic arms can be found in US Patent Pub. No. 2013 / 0255426 to Kassow et al., which is disclosed herein by reference in its entirety.

[0120] The robotic arm receives control signals and commands from the robotic control system, which may be housed in a Cart. The system may be configured to provide variousfunctionalities, including but not limited to, position, tracking, patterns, triggering, and events / actions.

[0121] Position may be configured to comprise fixed positions, pallet positions, time- controlled positions, distance-controlled positions, variable-time controlled positions, variable-distance controlled positions.

[0122] Tracking may be configured to comprise time-controlled tracking and / or distance- controlled tracking.

[0123] The patterns of movement may be configured to comprise intermediate positions or waypoints, as well as sequence of positions, through a defined path in space.

[0124] Triggers may be configured to comprise distance measuring means, time, and / or various sensor means including those disclosed herein, and not limited to, visual / imaging- based, force, torque, localization, energy / power feedback and / or others.

[0125] Events / actions may be configured to comprise various examples, including proximity -based (approaching / departing a target object), activation or de-activation of various end-effectors (e.g., therapy transducers), starting / stopping / pausing sequences of said events, triggering or switching between triggers of events / actions, initiating patterns of movement and changing / toggling between patterns of movement, and / or time-based and temporal over the defined work and time-space.

[0126] In one embodiment, the system comprises a three degree of freedom robotic positioning system, enabled to allow the user (through the software of the system and related user interfaces), to micro-position a therapy transducer through X, Y, and Z coordinate system, and where gross macro-positioning of the transducer (e.g., aligning the transducer on the patient’s body) is completed manually. In some embodiments, the robot may comprise 6 degrees of freedom including X, Y, Z, and pitch, roll and yaw. In other embodiments, the Robotic sub-system may comprise further degrees of freedom, that allow the robot arm supporting base to be positioned along a linear axis running parallel to the general direction of the patient surface, and / or the supporting 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, Coupling sub-system, additional robots / robotic arms and / or additional surgical systems, including but not limited to, surgical towers, imaging systems, endoscopic / laparoscopic systems, and / or other.

[0127] One or more robotic arms may also comprise various features to assist in maneuvering and modifying the arm position, manually or semi-manually, and of which said features may interface on or between the therapy transducer and the most distal joint of therobotic arm. In some embodiments, the feature is configured to comprise a handle allowing maneuvering and manual control with one or more hands. The handle may also be configured to include user input and electronic control features of the robotic arm, to command various drive capabilities or modes, to actuate the robot to assist in gross or fine positioning of the arm (e.g., activating or deactivating free drive mode). The work-flow for the initial positioning of the robotic arm and therapy head can be configured to allow either first positioning the therapy transducer / head in the coupling solution, with the therapy transducer directly interfaced to the arm, or in a different work-flow, allowing the user to set up the coupling solution first, and enabling the robot arm to be interfaced to the therapy transducer / coupling solution as a later / terminal set up step.

[0128] In some embodiments, the robotic arm may comprise a robotic arm on a laparoscopic, single port, endoscopic, hybrid or combination of, and / or other robot, wherein said robot of the system may be a slave to a master that controls said arm, as well as potentially a plurality of other arms, equipped to concurrently execute other tasks (vision, imaging, grasping, cutting, ligating, sealing, closing, stapling, ablating, 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 organ position to provide more ideal acoustic access and further stabilizing said organ in some cases to minimize respiratory motion. In conjunction and parallel to this, a second robotic arm may be used to deliver non-invasive acoustic cavitation through a body cavity, as observed under real-time imaging from the therapy transducer (e.g., ultrasound) and with concurrent visualization via a laparoscopic camera. In other related aspects, a similar approach may be utilized with a combination of an endoscopic and non-invasive approach, and further, with a combination of an endoscopic, laparoscopic and non-invasive approach.SOFTWARE

[0129] The system may comprise various software applications, features and components which allow the user to interact, control and use the system for a plethora of 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, Ancillaries and Accessories of the system.

[0130] Overall, in no specific order of importance, the software may provide features and support to initialize and set up the system, service the system, communicate and import / export / store data, modify / manipulate / configure / control / command various settings andparameters by the user, mitigate safety and use-related risks, plan procedures, provide support to various configurations of transducers, robotic arms and drive systems, function generators and amplifier circuits / slaves, test and treatment ultrasound sequences, transducer steering and positioning (electromechanical and electronic beam steering, etc.), treatment patterns, support for imaging and imaging probes, manual and electromechanical / robotically-enabling movement of, imaging support for measuring / characterizing various dimensions within or around procedure and treatment sites (e.g., depth from one anatomical location to another, etc., pre-treatment assessments and protocols for measuring / characterizing in situ treatment site properties and conditions (e.g., acoustic cavitation / histotripsy thresholds and heterogeneity of), targeting and target alignment, calibration, marking / annotating, localizing / navigating, registering, guiding, providing and guiding through work-flows, procedure steps, executing treatment plans and protocols autonomously, autonomously and while under direct observation and viewing with real-time imaging as displayed through the software, including various views and viewports for viewing, communication tools (video, audio, sharing, etc.), troubleshooting, providing directions, warnings, alerts, and / or allowing communication through various networking devices and protocols. It is further envisioned that the software user interfaces and supporting displays may comprise various buttons, commands, icons, graphics, text, etc., that allow the user to interact with the system in a user- friendly and effective manner, and these may be presented in an unlimited number of permutations, layouts and designs, and displayed in similar or different manners or feature sets for systems that may comprise more than one display (e.g., touch screen monitor and touch pad), and / or may network to one or more external displays or systems (e.g., another robot, navigation system, system tower, console, monitor, touch display, mobile device, tablet, etc.).

[0131] The software, as a part of a representative system, including one or more computer processors, may support the various aforementioned function generators (e.g., FPGA), amplifiers, power supplies and therapy transducers. The software may be configured to allow users to select, determine and monitor various parameters and settings for acoustic cavitation / histotripsy, and upon observing / receiving feedback on performance and conditions, may allow the user to stop / start / modify said parameters and settings.

[0132] The software may be configured to allow users to select from a list or menu of multiple transducers and support the auto-detection of said transducers upon connection to the system (and verification of the appropriate sequence and parameter settings based on selected application). In other embodiments, the software may update the targeting andamplifier 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 error messages or warnings to the user if said therapy transducer, amplifier and / or function generator selections or parameters are erroneous, yield a fault or failure. This may further comprise reporting the details and location of such.

[0133] In addition to above, the software may be configured to allow users to select treatment sequences and protocols from a list or menu, and to store selected and / or previous selected sequences and protocols as associated with specific clinical uses or patient profiles. Related profiles may comprise any associated patient, procedure, clinical and / or engineering data, and maybe used to inform, modify and / or guide current or future treatments or procedures / interventions, whether as decision support or an active part of a procedure itself (e.g., using serial data sets to build and guide new treatments).

[0134] As a part of planning or during the treatment, the software (and in working with other components of the system) may allow the user to evaluate and test acoustic cavitation / histotripsy thresholds at various locations in a user-selected region of interest or defined treatment area / volume, to determine the minimum cavitation thresholds throughout said region or area / volume, to ensure treatment parameters are optimized to achieve, maintain and dynamically control acoustic cavitation / histotripsy. In one embodiment, the system allows a user to manually evaluate and test threshold parameters at various points. Said points may include those at defined boundary, interior to the boundary and center locations / positions, of the selected region of interest and treatment area / volume, and where resulting threshold measurements may be reported / displayed to the user, as well as utilized to update therapy parameters before treatment. In another embodiment, the system may be configured to allow automated threshold measurements and updates, as enabled by the aforementioned Robotics sub-system, wherein the user may direct the robot, or the robot may be commanded to execute the measurements autonomously.

[0135] Software may also be configured, by working with computer processors and one or more function generators, amplifiers and therapy transducers, to allow various permutations of delivering and positioning optimized acoustic cavitation / histotripsy in and through a selected area / volume. This may include, but not limited to, systems configured with a fixed / natural focus arrangement using purely electromechanical positioning configuration(s), 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) electromechanicalpositioning, high speed axial electronic beam steering with lateral electromechanical positioning, high speed beam steering in 3D space, various combinations of including with dynamically varying one or more acoustic cavitation / histotripsy parameters based on the aforementioned ability to update treatment parameters based on threshold measurements (e.g., dynamically adjusting amplitude across the treatment area / volume).OTHER COMPONENTS, ANCILLARIES AND ACCESSORIES

[0136] The system may comprise various other components, ancillaries 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 security, communication, integration into 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 enabling capabilities, specialized 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.SYSTEM VARIATIONS AND METHODS / APPLICATIONS

[0137] In addition to performing a breadth of procedures, the system may allow additional benefits, such as enhanced planning, imaging and guidance to assist the user. In one embodiment, the system may allow a user to create a patient, target and application specific treatment plan, wherein the system may be configured to optimize treatment parameters based on feedback to the system during planning, and where planning may further comprise the ability to run various test protocols to gather specific inputs to the system and plan.

[0138] Feedback may include various energy, power, location, position, tissue and / or other parameters.

[0139] The system, and the above feedback, may also be further configured and used to autonomously (and robotically) execute the delivery of the optimized treatment plan and protocol, as visualized under real-time imaging during the procedure, allowing the user to directly observe the local treatment tissue effect, as it progresses through treatment, and start / stop / modify treatment at their discretion. Both test and treatment protocols may be updated over the course of the procedure at the direction of the user, or in some embodiments, based on logic embedded within the system.

[0140] It is also recognized that many of these benefits may further improve other forms of acoustic therapy, including thermal ablation with high intensity focused ultrasound (HIFU), high intensity therapeutic ultrasound (HITU) including boiling histotripsy (thermal cavitation), and are considered as part of this disclosure. The disclosure also considers the application of histotripsy as a means to activate previously delivered in active drug payloads whose activity is inert due to protection in a micelle, nanostructure or similar protective structure or through molecular arrangement that allows activation only when struck with acoustic energy.

[0141] In another aspect, the Therapy sub-system, comprising in part, one or more amplifiers, transducers and power supplies, may be configured to allow multiple acoustic cavitation and histotripsy driving capabilities, affording specific benefits based on application, method and / or patient specific use. These benefits may include, but are not limited to, the ability to better optimize and control treatment parameters, which may allow delivery of more energy, with more desirable thermal profiles, increased treatment speed and reduced procedure times, enable electronic beam steering and / or other features.

[0142] This disclosure also includes novel systems and concepts as related to systems and sub-systems comprising new and “universal” amplifiers, which may allow multiple driving approaches (e.g., single and multi-cycle pulsing). In some embodiments, this may include various novel features to further protect the system and user, in terms of electrical safety or other hazards (e.g., damage to transducer and / or amplifier circuitry).

[0143] In another aspect, the system, and Therapy sub-system, may include a plethora of therapy transducers, where said therapy transducers are configured for specific applications and uses and may accommodate treating over a wide range of working parameters (target size, depth, location, etc.) and may comprise a wide range of working specifications (detailed below). Transducers may further adapt, interface and connect to a robotically-enabled system, as well as the Coupling sub-system, allowing the transducer to be positioned within, or along with, an acoustic coupling device allowing, in many embodiments, concurrent imaging and histotripsy treatments through an acceptable acoustic window. The therapy transducer may also comprise an integrated imaging probe or localization sensors, capable of displaying and determining transducer position within the treatment site and affording a direct field of view (or representation of) the treatment site, and as the acoustic cavitation / histotripsy tissue effect and bubble cloud may or may not change in appearance and intensity, throughout the treatment, and as a function of its location within said treatment (e.g., tumor, healthy tissue surrounding, critical structures, adipose tissue, etc.).

[0144] The systems, methods and use of the system disclosed herein, may be beneficial to overcoming significant unmet needs in the areas of soft tissue ablation, oncology, immunooncology, advanced image guided procedures, surgical procedures including but not limited to open, laparoscopic, single incision, natural orifice, endoscopic, non-invasive, various combination of, various interventional spaces for catheter-based procedures of the vascular, cardiovascular pulmonary and / or neurocranial-related spaces, cosmetics / aesthetics, metabolic (e.g., type 2 diabetes), plastic and reconstructive, ocular and ophthalmology, orthopedic, gynecology and men’s health, and other systems, devices and methods of treating diseased, injured, undesired, or healthy tissues, organs or cells.

[0145] 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 prefocal tissue heating delivered to patients.USE ENVIRONMENTS

[0146] The disclosed system, methods of use, and use of the system, may be conducted in a plethora of environments and settings, with or without various support systems such as anesthesia, including but not limited to, procedure suites, operating rooms, hybrid rooms, in and out-patient settings, ambulatory settings, imaging centers, radiology, radiation therapy, oncology, surgical and / or any medical center, as well as physician offices, mobile healthcare centers or systems, automobiles and related vehicles (e.g., van), aero and marine transportation vehicles such as planes and ships, and / or any structure capable of providing temporary procedure support (e.g., tent). In some cases, systems and / or sub-systems disclosed herein may also be provided as integrated features into other environments, for example, the direct integration of the histotripsy Therapy sub-system into a MRI scanner or patient surface / bed, wherein at a minimum the therapy generator and transducer are integral to such, and in other cases wherein the histotripsy configuration further includes a robotic positioning system, which also may be integral to a scanner or bed centered design.COUPLING

[0147] Systems may comprise a variety of Coupling sub-system embodiments, of which are enabled and configured to allow acoustic coupling to the patient to afford effective acoustic access for ultrasound visualization and acoustic cavitation / histotripsy (e.g., provide acoustic window and medium between the transducer(s) and patient, and support of). These may include different form factors of such, including open and enclosed device solutions, and some arrangements which may 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 directly integrated to the system (within the Cart), or may be in temporary / intermittent or continuous communication with the system, but externally situated in a separate device and / or cart.

[0148] The Coupling sub-system typically comprises, at a minimum, coupling medium (e.g., degassed water or water solutions), a reservoir / container to contain said coupling medium, and a support structure (including interfaces to other surfaces or devices). In most embodiments, the coupling medium is water, and wherein the water may be conditioned before or during the procedure (e.g., chilled, degassed, filtered, etc.). Various conditioning parameters may be employed based on the configuration of the system and its intended use / application.

[0149] The reservoir or medium container may be formed and shaped to various sizes and shapes, and to adapt / conform to the patient, allow the therapy transducer to engage / access and work within the acoustic medium, per defined and required working space (minimum volume of medium to allow the therapy transducer to be positioned and / or move through one or more treatment positions or patterns, and at various standoffs or depths from the patient, etc.), and wherein said reservoir or medium container may also mechanically support the load, and distribution of the load, through the use of a mechanical and / or electromechanical support structure. As a representative example, this may include a support frame. The container may be of various shapes, sizes, curvatures, and dimensions, and may be comprised of a variety of materials compositions (single, multiple, composites, etc.), of which may vary throughout. In some embodiments, it may comprise features such as films, drapes, membranes, bellows, etc. that may be insertable and removable, and / or fabricated within, of which may be used to conform to the patient and assist in confining / containing the medium within the container. It may further contain various sensors (e.g., volume / fill level), drains (e.g., inlet / outlet), lighting (e.g., LEDs), markings (e.g., fill lines, set up orientations, etc.), text (e.g., labeling), etc.

[0150] In one embodiment, the reservoir or medium container contains a sealable frame, of which a membrane and / or film may be positioned within, to afford a conformable means of contacting the reservoir (later comprising the treatment head / therapy transducer) as an interface to the patient, that further provides a barrier to the medium (e.g., water) between the patient and therapy transducer). In other embodiments, the membrane and / or film may comprise an opening, the patient contacting edge of which affords a fluid / mechanical seal to the patient, but in contrast allows medium communication directly with the patient (e.g., direct degassed water interface with patient). The superstructure of the reservoir or mediumcontainer in both these examples may further afford the proximal portion of the structure (e.g., top) to be open or enclosed (e.g., to prevent spillage or afford additional features).

[0151] Disclosed membranes may be comprised of various elastomers, viscoelastic polymers, thermoplastics, thermoplastic elastomers, thermoset polymers, silicones, urethanes, rigid / flexible co-polymers, block co-polymers, random block co-polymers, etc. Materials may be hydrophilic, hydrophobic, surface modified, coated, extracted, etc., and may also contain various additives to enhance performance, appearance or stability. In some embodiments, the thermoplastic elastomer may be styrene-ethylene-butylene-styrene (SEBS), or other like strong and flexible elastomers. The membrane form factor can be flat or preshaped prior to use. In other embodiments, the membrane could be inelastic (i.e., a convex shape) and pressed against the patient’s skin to acoustically couple the transducer to the tissue. Systems and methods are further disclosed to control the level of contaminants (e.g., particulates, etc.) on the membrane to maintain the proper level of ultrasound coupling. Too many particulates or contaminants can cause scattering of the ultrasound waves. This can be achieved with removable films or coatings on the outer surfaces of the membrane to protect against contamination.

[0152] Said materials may be formed into useful membranes through molding, casting, spraying, ultrasonic spraying, extruding, and / or any other processing methodology that produces useful embodiments. They may be single use or reposable / reusable. They may be provided non-sterile, aseptically cleaned or sterile, where sterilization may comprise any known method, including but not limited to ethylene oxide, gamma, e-beam, autoclaving, steam, peroxide, plasma, chemical, etc. Membranes can be further configured with an outer molded or over molded frame to provide mechanical stability to the membrane during handling including assembly, set up and take down of the coupling sub-system. Various parameters of the membrane can be optimized for this method of use, including thickness, thickness profile, density, formulation (e.g., polymer molecular weight and copolymer ratios, additives, plasticizers, etc.), including optimizing specifically to maximize acoustic transmission properties, including minimizing impact to cavitation initiation threshold values, and / or ultrasound imaging artifacts, including but not limited to membrane reflections, as representative examples.

[0153] Open reservoirs or medium containers may comprise various methods of filling, including using pre-prepared medium or water, that may be delivered into the containers, in some cases to a defined specification of water (level of temperature, gas saturation, etc.), or they may comprise additional features integral to the design that allow filling and draining(e.g., ports, valves, hoses, tubing, fittings, bags, pumps, etc.). These features may be further configured into or to interface to other devices, including for example, a fluidics system. In some cases, the fluidics system may be an in-house medium preparation system in a hospital or care setting room, or conversely, a mobile cart-based system which can prepare and transport medium to and from the cart to the medium container, etc.

[0154] Enclosed iterations of the reservoir or medium container may comprise various features for sealing, in some embodiments sealing to a proximal / top portion or structure of a reservoir / container, or in other cases where sealing may comprise embodiments that seal to the transducer, or a feature on the transducer housings. Further, some embodiments may comprise the dynamic ability to control the volume of fluid within these designs, to minimize the potential for air bubbles or turbulence in said fluid and to allow for changes in the focal length to the target area without moving the transducer. As such, integrated features allowing fluid communication, and control of, may be provided (ability to provide / remove fluid on demand), including the ability to monitor and control various fluid parameters, some disclosed above. In order to provide this functionality, the overall system, and as part, the Coupling sub-system, may comprise a fluid conditioning system, which may contain various electromechanical devices, systems, power, sensing, computing, pumping, filtering and control systems, etc. The reservoir may also be configured to receive signals that cause it to deform or change shape in a specific and controlled manner to allow the target point to be adjusted without moving the transducer.

[0155] Coupling support systems may include various mechanical support devices to interface the reservoir / container and medium to the patient, and the workspace (e.g., bed, floor, etc.). In some embodiments, the support system comprises a mechanical arm with 3 or more degrees of freedom. Said arm may have a proximal interface with one or more locations (and features) of the bed, including but not limited to, the frame, rails, customized rails or inserts, as well as one or more distal locations of the reservoir or container. The arm may also be a feature implemented on one or more Carts, wherein Carts may be configured in various unlimited permutations, in some cases where a Cart only comprises the role of supporting and providing the disclosed support structure.

[0156] In some embodiments, the support structure and arm may be a robotically-enabled arm, implemented as a stand-alone Cart, or integrated into a Cart further comprising two or more system sub-systems, or where in the robotically-enabled arm is an arm of another robot, of interventional, surgical or other type, and may further comprise various user input features to actuate / control the robotic arm (e.g., positioning into / within coupling medium) and / orCoupling solution features (e.g., filling, draining, etc.). In some examples, the support structure robotic arm positional encoders may be used to coordinate the manipulation of the second arm (e.g. comprising the therapy transducer / treatment head), such as to position the therapy transducer to a desired / known location and pose within the coupling support structure.

[0157] Overall, significant unmet needs exist in interventional and surgical medical procedures today, including those procedures utilizing minimally invasive devices and approaches to treat disease and / or injury, and across various types of procedures where the unmet needs may be solved with entirely new medical procedures. Today’s medical system capabilities are often limited by access, wherein a less or non-invasive approach would be preferred, or wherein today’s tools aren’t capable to deliver preferred / required tissue effects (e.g., operate around / through critical structures without serious injury), or where the physical set up of the systems makes certain procedure approaches less desirable or not possible, and where a combination of approaches, along with enhanced tissue effecting treatments, may enable entirely new procedures and approaches, not possible today.

[0158] In addition, specific needs exist for enabling histotripsy delivery, including robotic histotripsy delivery, wherein one or more histotripsy therapy transducers may be configured to acoustically couple to a patient, using a completely sealed approach (e.g., no acoustic medium communication with the patient’s skin) and allowing the one or more histotripsy transducers to be moved within the coupling solution without impeding the motion / movement of the robotic arm or interfering / disturbing the coupling interface, which could affect the intended treatment and / or target location.

[0159] Disclosed herein are histotripsy acoustic and patient coupling systems and methods, to enable histotripsy therapy / treatment, as envisioned in any setting, from interventional suite, operating room, hybrid suites, imaging centers, medical centers, office settings, mobile treatment centers, and / or others, as non-limiting examples. The following disclosure further describes novel systems used to create, control, maintain, modify / enhance, monitor and setup / takedown acoustic and patient coupling systems, in a variety of approaches, methods, environments, architectures and work-flows. In general, the disclosed novel systems may allow for a coupling medium, in some examples degassed water, to be interfaced between a histotripsy therapy transducer and a patient, wherein the acoustic medium provides sufficient acoustic coupling to said patient, allowing the delivery of histotripsy pulses through a user desired treatment location (and volume), where the delivery may require physically moving the histotripsy therapy transducer within a defined work-space comprising the coupling medium, and also where the coupling system is configured to allow said movement of the therapy transducer (and positioning system, e.g., robot) freely and unencumbered from by the coupling support system (e.g., a frame or manifold holding the coupling medium).COUPLING SYSTEM AND SUB-SYSTEMS / COMPONENTS

[0160] The disclosed histotripsy acoustic and patient coupling systems, in general, may comprise one or more of the following sub-systems and components, an example of which is depicted in FIG. 2, including but not limited to 1) a membrane / barrier film to provide an enclosed, sealed and conformal patient coupling and histotripsy system interface, 2) a frame and assembly to retain the membrane and provide sufficient work and head space for a histotripsy therapy transducers required range of motion (x, y and z, pitch, roll and yaw), 3) a sufficient volume of ultrasound medium to afford acoustic coupling and interfaces to a histotripsy therapy transducer and robotic arm, 4) one or more mechanical support arms to allow placement, positioning and load support of the frame, assembly and medium and 5) a fluidics system to prepare, provide and remove ultrasound medium(s) from the frame and assembly.

[0161] In some embodiments, the coupling system may be fully sealed, and in other embodiments and configurations, it may be partially open to afford immediate access (physical and / or visual).

[0162] The acoustic and patient coupling systems and sub-systems may further comprise various features and functionality, and associated work-flows, and may also be configured in a variety of ways to enable histotripsy procedures as detailed below.

[0163] FIG. 2 illustrates one embodiment of a histotripsy therapy and imaging system 200, including a coupling assembly 212. A histotripsy therapy and imaging system can include a therapy transducer 202, an imaging system 204 (e.g., such as the co-axial imaging probe 104 of FIG. IB), a robotic positioning arm 208, a treatment cart 209 (e.g., coupled to and controlling the robotic positioning arm), and a fluidics cart 210.

[0164] The therapy and / or imaging transducers 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 expanding too far from the transducer. The coupling membrane can be filled with an acoustic coupling medium such as a fluid or a gel. The membrane constraint can be, for example, a semi-rigid or rigid material configured to restrict expansion / movement of the membrane. In some embodiments, the membrane constraint is not used, and the elasticity and tensile strength of the membrane prevent overexpansion. 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 can optionally be supported by a mechanical support arm 218 which can be load bearing in the x-y plane but allow for manual or automated z-axis adjustment. The mechanical support arm can be attached to the floor, the patient table, or the fluidics cart 210. The mechanical support is designed and configured to conform and hold the coupling membrane 214 in place against the patient’s skin while still allowing movement of the therapy / imaging transducer relative to the patient and also relative to the coupling membrane 214 with the robotic positioning arm 208. In some embodiments, the coupling assembly can be supported by another supporting element or rest directly on the patient.

[0165] The fluidics cart 210 can include a fluid source, a degassing system and optional temperature control system, and a programmable control system. The fluidics cart is configured for external loading of the coupling membrane with manual or automated control of fluidic sequences. The fluidics cart can include a separate user interface or graphical user interface (GUI) 220.MEMBRANES / BARRIER FILMS AND RELATED ARCHITECTURES

[0166] Membranes and barrier films may be composed of various biocompatible materials which allow conformal coupling to patient anatomy with minimal or no entrapped bubbles capable of interfering with ultrasound imaging and histotripsy therapy, and that are capable of providing a sealed barrier layer between said patient anatomy and the ultrasound medium, of which is contained within the work-space provided by the frame and assembly.

[0167] Membrane and barrier film materials may comprise flexible and elastomeric biocompatible materials / polymers, such as various thermoplastic and thermoset materials, as well as permanent or bioresorbable polymers. Additionally, the frame of the coupling assembly can also comprise the same materials. In some examples, the membrane may be rigid or semi-rigid polymers which are pre-shaped or flat.ULTRASOUND MEDIUM

[0168] As previously described, the ultrasound medium may comprise any applicable medium capable of providing sufficient and useful acoustic coupling to allow histotripsy treatments and enable sufficient clinical imaging (e.g., ultrasound). Ultrasound mediums, as a part of this disclosure and system, may comprise, but are not limited to, various aqueous solutions / mediums, including mixtures with other co-soluble fluids, of which may have preferred or more preferred acoustic qualities, including ability to match speed of sound, etc.Example mediums may comprise degassed water and / or mixtures / co-solutions of degassed water and various alcohols, such as ethanol.MECHANICAL SUPPORT ARMS AND ARM ARCHITECTURES

[0169] In order to support the acoustic and patient coupling system, including providing efficient and ergonomic work-flows for users, various designs and configurations of mechanical support arms (and arm architectures) may be employed. Support arms may be configured with a range of degrees of freedom, including but not limited to allowing, x, y, z, pitch, roll and yaw, as well additional interfacing features that may allow additional height adjustment or translation.

[0170] Arms may comprise a varied number and type of joints and segments. Typically, arms may comprise a minimum of 2 segments. In some configurations, arms may comprise 3 to 5 segments.

[0171] Arms are also be configured to interface proximally to a main support base or base interface (e.g., robot, table, table / bed rail, cart, floor mount, etc.) and distally to the frame / assembly and overall “coupling assembly” or “coupling solution”. This specific distal interface may further include features for controlling position / orientation of the frame / assembly, at the frame / assembly interface.

[0172] For example, in some embodiments, the arm / frame interface may comprise a ball joint wrist. In another example, the interface may include use of a gimbal wrist or an adjustable pitch and roll controlled wrist. These interfaces may be further employed with specific user interfaces and inputs, to assist with interacting with the various wrists, of which may include additional handles or knobs (as an unlimited example), to further enable positioning the coupling assembly / coupling solution. For example, a gimbal wrist may benefit from allowing the frame / assembly to have 3 degrees of freedom (independent of the arm degrees of freedom), including pitch, roll and yaw adjustments.

[0173] Support arms, configured with arm wrists, further interfaced with frames / assemblies, may comprise features such as brakes, including cable or electronic actuated brakes, and quick releases, which may interact with one or more axis, individually, or in groupings. They may also include electronic lift systems and base supports. In some embodiments, these lift systems / base supports are co-located with robot arm bases, wherein said robot arm is equipped with the histotripsy therapy transducer configured to fit / work within the enclosed coupling solution. In other embodiments, the support arm is located on a separate cart. In some cases, the separate cart may comprise a fluidics system or user console. In other embodiments, it is interfaced to a bed / table, including but not limited to arail, side surface, and / or bed / table base. In other examples / embodiments, it’s interfaced to a floor-based structure / footing, capable of managing weight and tipping requirements.FLUIDICS SYSTEMS, CONTROL SYSTEMS AND SYSTEM ARCHITECTURES

[0174] As a part of overall fluidics management, histotripsy systems including acoustic / patient coupling systems, may be configured to include an automated fluidics system, which primarily is responsible for providing a reservoir for preparation and use of coupling medium, where preparation may include the ability to degas, temperature adjust, monitor, adjust, dispense / fill, and retrieve / drain coupling medium to / from the frame / assembly. The fluidics system may include an emergency high flow rate system for rapid draining of the coupling medium from the coupling assembly. In some embodiments, the fluidics system can be configured for a single use of the coupling medium, or alternatively, for re-use of the medium. In some embodiments, the fluidics system can implement positive air pressure or vacuum to carry out leak tests of the coupling assembly and membrane prior to filling with a coupling medium. Vacuum assist can also be used for removal of air from the coupling assembly during the filling process. The fluidics system can further include filters configured to prevent particulate contamination from reaching the coupling assembly.

[0175] The fluidics system may implemented in the form of a mobile fluidics cart. The cart may comprise an input tank, drain tank, degassing module, fill pump, drain pump, inert gas tank, air compressor, tubing / connectors / lines, electronic and manual controls systems and input devices, power supplies and one or more batteries. The cart in some cases may also comprise a system check vessel / reservoir for evaluating histotripsy system performance and related system diagnostics (configured to accommodate a required water volume and workspace for a therapy transducer).TREATMENT PLANNING, TREATMENT VOLUME PACKING, AND NAVIGATION / PATHWAY PATTERNS THROUGH TREATMENT VOLUME

[0176] For purposes of this disclosure, the term “target tissue volume”, “tissue volume”, “lesion”, or “tumor” refers to a tissue volume within a patient or subject that is to be treated with ultrasound therapy. The tissue volume can be a 3-dimensional tissue volume with an arbitrary shape. For purposes of this disclosure, an “arbitrary” shape is defined to be a shape that is non-uniform in one or more dimensions. For example, circular, rectangular, elliptical, spherical, ellipsoidal, or cuboid shapes would be considered to be “uniform” shapes. In practice, many tissue volumes such as tumors or volumes of diseased tissue are not precisely uniform, but instead include non-uniform or arbitrary shapes, edges, contours, or perimeters.In some aspects, the tissue volume can be diseased, such as a tumor or other malignant grouping of cells within the subject. The term “target treatment volume” or “treatment volume” refers to a user or system-defined treatment volume. Often, this target treatment volume is contoured to a specific target tissue volume (e.g., a tumor within the liver). As a tissue volume or tumor typically has an arbitrary or non-uniform shape, a treatment volume can include uniform or arbitrary shapes configured to fully encompass or encapsulate a given tissue volume. The term “focal locations” or “treatment locations” can refer to points within the target treatment volume that the bubble cloud is to be generated at to treat a discrete portion of the overall treatment volume. “Bubble cloud size” can refer to the physical dimensions of a single bubble cloud with respect to each of the primary transducer dimensions (lateral “X” and “Y”, and axially "Z”). Bubble cloud “spacing parameters” refer to the spacing parameters and logic used to pack a treatment volume up to the boundary of the target treatment volume. These parameters are also considered when determining the point spacing to achieve the desired overlap (of the bubble cloud) and / or margins. Similarly, “point spacing configuration parameters” (X,Y, and Z, xy, yz, and xz) refer to the desired (maximum) physical separation of adjacent bubble clouds in the target tissue volume such that the desired treatment overlap is achieved. The desired overlap of adjacent bubble clouds can be, for example, 100% overlap all the way to significant physical separation (e.g., no overlap) depending on what is desired for a specific treatment.

[0177] The systems and methods described herein may further employ software, algorithms, or other automated processes for treatment planning which can include identifying or determining a target tissue volume within a subject, generating a treatment volume that encompasses or partially encompasses the target tissue volume, packing or filling the treatment volume with a plurality of discrete treatment locations, and establishing a treatment pathway for systematically navigating the treatment head / therapeutic transducer array of the histotripsy system through the treatment volume to complete a given therapeutic procedure of the target tissue volume.

[0178] Treatment Volume Packing

[0179] Prior to a histotripsy procedure, the system and / or user must first identify the size and / or shape of a target tissue volume / target lesion to be treated. The size and shape of the target tissue volume may depend based on the type of procedure being performed, the specific location of the lesion or target tissue, type of tissue / lesion, and other factors including the depth of the target tissue, the acoustic window to the target tissue, the nature of surrounding tissues, treatment constraints including a maximum treatment time and / ormaximum energy dose to be delivered, and / or patient specific parameters including age, gender, prior treatment history, body composition, etc.

[0180] Systems and methods, including hardware and software are provided herein for providing treatment planning and preparing a digital treatment plan for a histotripsy procedure, that can include identifying a tissue location to be treated, generating a target tissue volume corresponding to the tissue location, and placing a plurality of treatment locations within the target tissue volume. The digital treatment plan can be implemented or executed by a histotripsy therapy system to apply the digital treatment plan to the tissue location of the patient.

[0181] The systems and methods described herein may further employ software, algorithms, or other automated processes for treatment planning which can include identifying or determining a target tissue volume within a subject, packing or filling the target tissue volume with a plurality of discrete treatment locations, and establishing a treatment pathway for systematically navigating the treatment head / therapeutic transducer array of the histotripsy system through the target tissue volume to complete a given therapeutic procedure of the target tissue volume.

[0182] For example, if the tissue location to be treated includes a tumor in the subject(e.g., liver tumor, pancreatic tumor, kidney tumor, thyroid tumor, brain tumor, or other soft tissue tumor) then the system and / or the user can determine the target treatment volume size based on the size of the tumor plus any desired margins to ensure complete treatment. The margin size can be pre-configured in the system or determined by the user, and may vary depending on the tumor type and / or tumor location, surgeon preference, other patient risk factors, etc. Non-tumor diseased tissues can also be treated by the systems and methods herein, including but not limited to prostate tissue (e.g., for treatment of BPH).

[0183] The target treatment volume shape may also be customized or modified depending on the tissue location to be treated. While the examples provided herein generally describe spherical or ellipsoidal target treatment volumes, it should be understood that other target treatment volume shapes are considered. The overall dimensions of the target treatment volume can be changed to ensure that the tissue location to be treated (e.g., a tumor) is fully treated according to a desired or pre-set treatment plan while limiting the amount of energy delivered to or through non-diseased or healthy surrounding tissues. In some aspects, a target treatment volume can be as small as a single bubble cloud (e.g., only a single discrete treatment location), and in other embodiments, the target treatment volume can be filled during treatment planning with a plurality of discrete treatment locations, with the volume oftissue treated at each discrete treatment location determined by the size of the bubble cloud. In some aspects, the size and shape of target treatment volume can be chosen based on pretreatment diagnostics including medical imaging such as CT, MRI, or ultrasound.

[0184] Bubble cloud size is determined by many factors, including the overall pulse sequence used to generate and maintain cavitation bubble clouds (e.g., intrinsic threshold sequences, shock scattering sequences, etc.), frequency, pulse repetition frequency (PRF), driving voltage, tissue type, depth, intervening tissue type, etc. For a given pulse sequence and driving parameters, a bubble cloud generated by the histotripsy systems described herein will generally be the same size or within an acceptable threshold. However, it should be understood that the nature of cavitation or bubble clouds generated by histotripsy are dynamic and therefore bubble cloud locations and size can vary and can further be affected by other factors such as residual cavitation nuclei in a target treatment volume, particularly after therapy has started.For purposes of this disclosure, the term “target tissue volume” refers to the entire physical volume that is intended to be treated. Often, this target tissue volume is contoured to a specific target tissue (e.g., a tumor within the liver). The term “focal locations” or “treatment locations” can refer to points within the target tissue volume that the bubble cloud is to be generated at to treat a discrete portion of the overall treatment volume. “Bubble cloud size” can refer to the physical dimensions of a single bubble cloud with respect to each of the primary transducer dimensions (lateral “X” and “Y”, and axially "Z”). Bubble cloud “spacing parameters” refer to the spacing parameters and logic used to pack a treatment volume up to the boundary of the target tissue volume. These parameters are also considered when determining the point spacing to achieve the desired overlap and / or margins. Similarly, “point spacing configuration parameters” (X,Y, and Z, xy, yz, and xz) refer to the desired (maximum) physical separation of adjacent bubble clouds in the primary transducer dimensions such that the desired treatment overlap is achieved. The desired overlap can be, for example, 100% overlap all the way to significant physical separation (e.g., no overlap) depending on what is desired for a specific treatment.

[0185] FIG. 4A is a cross-sectional (x-y axis) view of an ellipsoidal target treatment volume 422 having diameters in each axis of Dx, Dy, and Dz. During a treatment planning aspect of a histotripsy procedure, the system can use the dimensions of the target treatment volume in combination with bubble cloud size parameters and desired spacing parameters (X point spacing configuration parameter, Y point spacing configuration parameter, Z point spacing configuration parameter) between discrete treatment locations to pack the targettreatment volume with a plurality of discrete treatment locations to ensure complete treatment of the target treatment volume according to the treatment plan. As described above, the percentage of the target treatment volume treated can vary depending on the specific tissue type and disease state to be treated. In some examples, forming cavitation within 90-100% of the target treatment volume may be considered complete treatment, while in other embodiments as little as 10-20% treatment of the target treatment volume is desired. The bubble cloud size for a known transducer / sequence combination can include diameters in each axis of Bx, By, and Bz, and point spacing between treatment locations can be defined by spacing distances apart on each axis of Sx, Sy, and Sz. In some examples, the spacing parameters are defined as the distances between center-points of adjacent focal locations. The desired treatment size as configured by the user can further include a margin M that further increases the overall size of the target treatment volume to ensure complete ablation / liquefication / lysing of the diseased tissue in the target treatment volume.

[0186] In one aspect, the spacing parameters in the x-y axis, Sx and Sy, are the same, and the spacing parameter in the z axis, Sz, is different than Sx and Sy. This can account for ellipsoidal shaped bubble clouds that are longer in the z direction than they are wide in the x- y direction. However, it should be understood that if different sized or shaped bubble clouds are used, then the spacing parameters can be adjusted or changed. For example, with spherically or uniformly shaped bubble clouds, all the spacing parameters may be similar or the same.

[0187] In FIG. 4A, the target treatment volume 422 includes a margin contour 424 that, in the x-y view, is defined by diameters of Dx + M and Dy + M. In one embodiment, FIG. 4A represents a central slice in the x-y view of the target treatment volume (e.g., the largest diameter Dx and Dy in the target treatment volume). As described above, this figure shows an x-y slice of a three-dimensional target treatment volume. In one implementation, a treatment planning algorithm first packs margin contour 424 with concentric contours 426a- 426f, spaced evenly between a central contour 426a of the volume and an outer contour 426f with major / minor axes of Dx / 2+M-Bx and Dy / 2+M-By. As shown in FIG. 4A, depending on the intended bubble cloud size and the overall target treatment volume size and shape, in some implementations the treatment planning algorithm the central contour 426a may be a row or linear contour instead of an ellipsoidal contour. In some embodiments, the number of ellipses may be set such that the radial spacing between them in the x-y dimensions is not greater than the x-y point spacing configuration parameters.

[0188] It should be understood that in FIG. 4A, since the overall target treatment volume is ellipsoidal, then the most efficient way to pack the volume is with concentric ellipses. However, other shaped target treatment volumes can be packed with shapes that better conform to the outer contour of the target treatment volume (e.g., circular pathways for spherical target treatment volumes, etc.). For example, linear segments between parallel edges could be packed into the target treatment volume. Alternatively, the target treatment volume could be packed with arbitrary shapes of using "shrunk" copies of the perimeter shape with progressive "smoothing" of turns to soften the resulting sharp corners that would result.

[0189] In one implementation of the treatment planning algorithm, referring to FIG. 4B, discrete treatment locations 430 are equally spaced with centers along these x-y contours (426a-426f in FIG. 4 A) such that the spacing adjacent treatment locations does not exceed the average of the x-y point spacing configuration parameters. As shown, the outer contour 426f is the outermost pathway packed with discrete treatment locations, and the spacing between the outer contour 426f and the margin contour 424 is chosen such that the bubble cloud size for a given treatment location along the outer contour 426f does not extend beyond or outside of the margin contour. Due to complexities with spacing along the circumference of an ellipse, in some aspects the requirement that treatment location spacing does not exceed the average of the x-y point spacing configuration parameters may not be strictly enforced. Alternatively, a requirement on average speed of the treatment head / therapy transducer through each pathway / ellipse can be made to ensure that the appropriate dose of energy or number of histotripsy pulses is delivered to each of the treatment points along a given pathway.

[0190] Referring to FIGS. 4C-4D, after the discrete locations have been placed along each contour in the x-y plane, the treatment planning algorithm can extend a line 432 in the Z direction through each discrete treatment location from each x-y contour, and additional treatment locations can be added to the treatment plan in the target treatment volume in the Z- direction along each line 432 such that the outermost treatment locations of the target treatment volume (accounting for the bubble cloud size) do not extend outside the margin contour 424. Additional treatment locations can be spaced along each line such that the spacing between them does not exceed the Z point spacing configuration parameter.

[0191] It is important to note that in FIGS. 4A-4D, the target treatment volume is packed to account for an ellipsoidal bubble cloud shape to be produced at each discrete treatment location. In this embodiment, the bubble clouds produced at each treatment location areintended to have an elongated ellipsoidal shape that extends further in the Z dimension (i.e., away from the therapy transducer) than in the X and Y dimensions. However, it should be noted that advancements in transducer array construction, pulse generators, and optimization of pulse sequences can facilitate bubble clouds with more uniform (i.e., spherical) shapes. Therefore, while the illustrated embodiment describes the use of ellipsoidal bubble clouds, similar packing techniques can be implemented with more uniform spherical shapes. It should be understood that when the bubble clouds are more uniform in shape, the treatment planning algorithm may place more discrete treatment locations on each line 432 extending in the Z direction to compensate for reduced Z dimensions of uniform / spherical bubble clouds compared to ellipsoidal shaped bubble clouds.

[0192] Referring to FIG. 4D, it should be understood that with a spherical / ellipsoidal target treatment volume that is filled with a plurality of spherical / ellipsoidal bubble clouds corresponding to each discrete treatment location, that there may be gaps 434 near the margin contour 424 of the target treatment volume that may not receive any therapeutic energy / bubble clouds. This is simply a function of the shape and size of the target treatment volume and the intended bubble cloud size / shape. Generally the desired margins are intended to ensure that the entirety of the diseased tissue is treated with a given treatment plan even with these gaps in coverage.

[0193] In some embodiments illustrated herein, the treatment planning algorithm is configured to pack the target treatment volume with a plurality of treatment locations based on a uniform bubble cloud size throughout the volume. However, other embodiments of the treatment planning algorithm can employ packing techniques that include two or more bubble cloud sizes and or shapes. For example, the target treatment volume can be divided into a plurality of sub-volumes with a different bubble cloud size / shape intended for each subvolume. In some examples, the target treatment volume can be divided into a first subvolume that comprises an outer shell or perimeter of the target treatment volume, with a second sub-volume that comprises an inner volume that is located entirely within the first sub-volume. In this configuration, it could then be desirable to pack the first / outer subvolume with smaller bubble clouds to better conform to the outer margin and reduce or eliminate gaps, while the second / inner sub-volume could be packed with larger bubble clouds for more efficient treatment or fewer treatment locations. Other implementations are contemplated, including packing a sub-volume of the target treatment volume that is closer to the transducer array with a bubble cloud size / shape that is different than the sub-volume that is further or more distal from the transducer array. In other embodiments, pulse sequenceswith different tissue selectivity could be factored into a treatment plan to be used for different parts of a treatment volume. For example, sequences better suited to treat tumor vs. mostly healthy margin could be implemented into the treatment plan for a target treatment volume.

[0194] Packing and Planning for Arbitrarily Rotated Treatment Volumes

[0195] Systems and methods, including hardware and software are provided herein for providing treatment planning and preparing a digital treatment plan for a histotripsy procedure, that can include identifying a tissue location to be treated, generating a target tissue volume corresponding to the tissue location, and placing a plurality of treatment locations within the target tissue volume. The digital treatment plan can be implemented or executed by a histotripsy therapy system to apply the digital treatment plan to the tissue location of the patient.

[0196] The systems and methods described herein may further employ software, algorithms, or other automated processes for treatment planning which can include identifying or determining a target tissue volume within a subject, packing or filling the target tissue volume with a plurality of discrete treatment locations, and establishing a treatment pathway for systematically navigating the treatment head / therapeutic transducer array of the histotripsy system through the target tissue volume to complete a given therapeutic procedure of the target tissue volume.

[0197] The robotic positioning system and ultrasound therapy array described herein reside within a cartesian treatment coordinate space. According to aspects described herein, the target treatment volume can be packed in the same treatment coordinate space, or alternatively, can be packed in a separate arbitrary coordinate space that is different than the treatment coordinate space. In some aspects, a natural “treatment coordinate space” can be defined from the geometry of the ultrasound therapy array. This treatment coordinate space can be arbitrarily positioned and oriented in 3D space by the robotic positioning system. The target treatment volume can be defined as a shape that is aligned to this treatment coordinate space, or alternatively, as a shape with arbitrary alignment.

[0198] FIG. 5A shows a histotripsy transducer array 502 having a treatment coordinate space 503. In this example, coordinate space 503 of the transducer array defines X, Y, and Z coordinates in 3D space and has a z-axis that generally aligns with a treatment axis of the transducer array, with +z being defined as the direction of sound propagation from the transducer array. FIG. 5A also includes an ellipsoidal target treatment volume (TV) having a tissue coordinate space 505. Generally, since histotripsy cavitation bubble clouds generated by a histotripsy transducer array are ellipsoidal or teardrop shaped, ellipsoidal treatmentvolumes provide for the most efficient treatment packing. In the illustrated example, cavitation bubble clouds generated by transducer array 502 will generally be aligned with the target treatment volume (e.g., the elongated / z-dimension of the bubble cloud ellipsoid will generally be aligned with the elongated / z-dimension of the target tissue volume. Therefore, the individual treatment locations (representing bubble clouds) can be packed into the target tissue volume as described above in FIGS. 4A-4C. It should be understood that any of the treatment volumes described herein could be shapes other than ellipsoidal. Coordinate space 505 of the transducer array in this example is the same as or aligns with coordinate space 503 of the target treatment volume (i.e., the X, Y, and Z axes in coordinate space 503 are parallel or aligned with their respective X, Y, and Z axes in coordinate space 505).

[0199] In contrast, FIG. 5B shows a histotripsy transducer array 502 having a treatment coordinate space 503, which still defines X, Y, and Z coordinates in 3D space and has a z- axis that generally aligns with a treatment axis of the transducer array. In FIG. 5B, the target treatment volume (TV) is rotated in 3D space relative to the treatment volume of FIG. 5 A, and therefore has an arbitrary coordinate space 507. Coordinate space 507 in this example does not align with coordinate space 503 (i.e., the X, Y, and / or Z axes in coordinate space 507 are rotated relative to the X, Y, and Z axes in coordinate space 503). In this example, the target tissue volume is still an ellipsoidal volume, but the z axis that defines the elongated dimension of the ellipsoid is rotated relative to the z axis of the ellipsoidal volume in FIG.5 A. Put another way, the arbitrarily rotated treatment volume is not symmetrical in the Z or axial dimension of the treatment coordinate space 503. However, the transducer array will still produce ellipsoidal cavitation bubble clouds that share an elongated axis with the transducer array (e.g., along the treatment axis). In the illustrated example, cavitation bubble clouds generated by transducer array 502 will generally be aligned along their z-axis with treatment axis. Therefore, the individual treatment locations (representing bubble clouds) cannot be packed into the target tissue volume as described above in FIGS. 4A-4C, since such packing would result in the bubble cloud z-axis aligning with coordinate space 505, and the transducer array is not configured to produce bubble clouds with such an orientation.

[0200] The primary difference between the implementations in FIGS. 5A and 5B is that the arbitrarily oriented treatment volume in FIG. 5B is still packed in the treatment coordinate space 503, since the bubble cloud ellipsoids generated by the transducer array are aligned with that space. However, the 2D target contour used for the initial packing of concentric ellipses within the treatment volume, previously described as the intersection of the XY plane and the planned treatment volume, would instead be the projection of the arbitrarily orientedplan onto the XY plane (i.e. the ‘shadow’ of the plan onto the XY plane). While embodiments described herein and below refer to the XY plane, it should be understood that the same technique can be applied in other planes such as the XZ plane and YZ planes.

[0201] FIGS. 6A-6B illustrate the technique of packing an arbitrarily oriented treatment volume. As described above, software or hardware or both may be used to generate the digital treatment plan for treating the arbitrarily oriented treatment volume. For example, a treatment planning software suite, either separate from or integrated into the histotripsy system, may be used for the treatment planning. In FIG. 6A, the treatment planning software of the histotripsy system projects an elliptical shadow of the treatment volume onto an XY plane projection 609 of the treatment volume. The system then packs / divides the XY plane projection with concentric ellipses (as described in FIG. 4 A above). As described above, the contours can be evenly spaced to fill the XY plane projection. However it should be understood that the spacing can be customized or uneven. In some embodiments, the contour spacing is based on the intended bubble cloud size of the treatment, to ensure that adjacent contours (and bubble clouds) have the appropriate level of overlap if desired. Next, the system adds / packs discrete treatment locations or points along each of the concentric ellipses, just like the packing algorithm as illustrated and described above in FIG. 4B. Again, the spacing of discrete treatment locations can be based on the intended bubble cloud size.

[0202] As described above in FIGS. 4C-4D, after the concentric ellipses are packed with discrete treatment locations or points, the treatment planning algorithm extends a line in the Z direction (treatment coordinate space) through each discrete treatment location from each x-y contour, and additional treatment locations can be added to the treatment plan in the target treatment volume in the Z-direction along each line such that the outermost treatment locations of the target treatment volume (accounting for the bubble cloud size) do not extend outside the margin contour. FIG. 6B shows an arbitrarily rotated treatment volume packed with discrete treatment locations according to the techniques described above.

[0203] However, with the arbitrarily rotated treatment volume, these axially (z-axis) extending points or treatment locations are no longer symmetric above and below the elliptical shadow projected onto the XY plane. When these points are then extended into several points in paths parallel to the Z axis, this method needs to differ again, as these new points will no longer be symmetric above and below the XY plane. FIG. 7A shows an implementation in which the treatment planning algorithm extends lines 732a-732h the Z direction (treatment coordinate system) through each discrete treatment location of the XY plane projection 709 to facilitate additional treatment locations in the target treatment volumein the treatment coordinate system Z-direction (i.e., not the treatment volume coordinate system). Put another way, the lines extend through or transverse to the xy plane 609 previously described. As shown, the lines may be projected entirely below the XY plane projection (line 732a), entirely above (line 732h), or asymmetrically distributed above and below the XY plane projection (lines 732b-732g). FIG. 7A also shows some of the bubble clouds 711 packed onto line 732h by the treatment planning algorithm, and FIG. 7B shows a complete treatment volume with all discrete locations packed by the treatment planning algorithm, with bubble clouds 711 shown on the plan corresponding to bubble clouds 711 in FIG. 7A for illustration.

[0204] The resulting treatment segments (elliptical rings) will include more variation in Z-position (treatment coordinate system) for significantly tilted treatment volume plans, and will thus need to be broken up into arc segments with more similar Z position in order to preserve the “Bottom to Top” treatment strategy described above.

[0205] The above can be realized, for example, by “tilting” the planned treatment volume and adjusting the angle of the arbitrary (volume) coordinate space relative to the treatment coordinate space, while maintaining the orientation of the transducer array. In another nonillustrated example, the transducer array can be tilted to align the treatment axis of the transducer array with a central (z) axis of the arbitrary coordinate away. During the planning portion of workflow, the user or control system can unlock the transducer position and tilt the treatment head out of alignment with a central axis of the planned treatment volume. This can be accomplished with the following procedure:

[0206] 1) The user defines a normal, axis-aligned treatment plan in which the coordinate space of the treatment volume aligns with the coordinate space of the transducer array.

[0207] 2) Later, the user ‘unlocks’ that alignment and tilts the transducer into a more optimal approach angle, which changes the coordinate space of the treatment volume relative to the coordinate space of the transducer array.

[0208] 3) With this change, the treatment plan is no longer aligned with the treatment coordinate space and the new methods described above are necessary.

[0209] Treatment Planning and Packing for Complex Tissue Volumes

[0210] The above techniques describe using ellipsoidal treatment volumes in the treatment planning software to encapsulate and treat tissue within the treatment volume including any desired margins. When the desired tissue to be treated is not ellipsoidally shaped, then overtreatment can occur since discrete treatment locations that fall within the ellipsoidal treatment volume ellipse are outside of the desired tissue to be treated. FIG. 8illustrates an ellipsoidal treatment volume surrounding a tumor tissue volume that is not ellipsoidally shaped, resulting in over treatment in the region between the tumor tissue volume and the margins / border of the treatment volume.

[0211] FIGS. 8A-8B show a technique for preventing overtreatment (e.g., treating or providing therapy to the region between the tissue volume and treatment volume) by packing an ellipsoidal treatment volume as described herein, but designating only the discrete treatment locations falling within the target tissue to receive ultrasound / histotripsy therapy, and preventing therapy from being delivered to treatment locations outside of the target tissue (e.g., between the target tissue and the treatment volume margins). For example, while the treatment could proceed by moving through the entire encapsulating ellipsoidal treatment volume, treatment would only be “on” for points inside the true, complex-shaped, 3D tissue volume (tumor). Traversal through points outside the tissue volume, but inside the treatment volume, could proceed as normal (with therapy off) or modified to “skip” any segments of points that are not to be treated by moving quickly to the next point that will be treated before proceeding as normal again. This would reduce the required total treatment time for a given scenario and prevent delivery of ultrasound energy to treatment locations outside of the target tissue volume.

[0212] In another embodiment, referring to FIG. 9A, a treatment volume (TV) can be any 3D space such as a rectangular prism or sphere, and can be filled with a plurality of discrete treatment locations or points 930. The tissue volume to be treated can be defined with image segmentation techniques to identify and define one or more cross-sections 934 of the complex tissue volume from medical imaging (e.g., CT, MRI, ultrasound, etc.) which can then be used to determine which treatment locations within a treatment volume coinciding with the tissue volume are turned “on” and which treatment locations are turned “off’ or disabled / skipped.

[0213] For example, if some segmentation procedure (or similar method) is used to define a complex shaped 3D tissue volume within the treatment volume, one method to define a packing and traversal for treatment of that tissue volume would be to utilize a uniform packing of 3D space in the treatment volume with discrete treatment locations or points, and then use the complex 3D planned tissue volume cross-section 934 as a mask to identify which points 930 corresponding to the tissue volume 934 within the treatment volume TV should be included in the treatment. The points that fall within the tissue volume cross-section 934 can be turned “on” and the points that fall outside of the tissue volume cross-section 934 can be turned “off’.

[0214] In some aspects, the system can automatically determine which treatment points fall within the tissue volume cross-section 934 and which do not, and can automatically turn on / off the appropriate treatment points. In other embodiments, a user can review the treatment volume and cross-section 934 and manually select or adjust the treatment points that are on / off. In some aspects, when the treatment plan including the tissue volume crosssection 934 and the grid of treatment points within treatment volume TV are displayed to a user, the treatment points can be color coded to indicate which points are turned on and which points are turned off (e.g., on points color coded green, off points color coded red, etc.). In other embodiments, the “off’ points can be dimmed, outlined in dashes, or turned off to indicate that they are off.

[0215] The cross-section 934 described above represents a 2D slice of the tissue volume, similar to the ellipsoidal slices described in FIGS. 4A-4B. To fully pack the tissue volume with treatment points or locations, the packing strategy must also pack the tissue volume in 3- dimensions (e.g., in the Z direction if the cross-sectional slice is in the x-y plane). It would be natural to utilize a packing method with “Z” positions chosen from a finite set of discrete values. This would facilitate a natural binning of the resulting points into treatment layers. Many methods to traverse these layers are possible, most likely taking the form of treatment proceeding to a nearby untreated point within the same layer with some preference included to enforce a desired traversal pattern (e.g. spiral treatment, serpentine treatment, etc.)

[0216] The technique described above in FIG. 9A describes packing the treatment volume 3D space uniformly with treatment points or locations (e.g., each point spaced apart by the same distance in all dimensions). The primary downside to utilizing a uniform spacing is that the outermost points around or within the boundary of the tissue volume cross-section 934 are not optimally or ideally matched to the contour. For example, some treatment points, such as those identified in FIG. 9A by dashed ovals 936, fall within or just outside of the cross-section 934 representing the tissue volume.

[0217] In FIG. 9B, the treatment point locations indicated by dashed ovals 938 have been moved inside of the cross-section 934 of the tissue volume, having tweaks applied by the system or user to points along and / or just outside the perimeter to optimize the match between the actual tissue volume and the planned treatment volume.

[0218] In one embodiment, the treatment points that fall within or outside the intended tissue volume during the masking operation can be identified, and then the position of these points can be modified to be right along or within the boundary of the cross-section. This would utilize the simplicity of uniform packing, but recover the ideal contour matching of ourcurrent method at the cost of a small amount of additional treatment (due to increased overlap in the boundary treatment).

[0219] In some embodiments, the user / system will move any boundary treatment points within the planned treatment volume, such that there may be extra or additional treatments of overlap along the periphery / boundary.

[0220] FIGS. 10A-10F illustrate techniques for packing a 3D arbitrary tissue volume with treatment points, similar to the techniques described above for ellipsoidal shapes. As described above, systems and methods described herein may employ software, algorithms, or other automated processes for treatment planning which can include identifying or determining a target tissue volume within a subject, packing or filling the target tissue volume with a plurality of discrete treatment locations, and establishing a treatment pathway for systematically navigating the treatment head / therapeutic transducer array of the histotripsy system through the target tissue volume to complete a given therapeutic procedure of the target tissue volume.

[0221] FIG. 10A illustrates a 3D arbitrarily shaped tissue volume to be treated. As described above, the arbitrarily shaped volume can have an arbitrary or non-uniform shape in one or more dimensions. The tissue volume can be identified by the treatment planning software, for example (e.g., from medical imaging such as CT, CBCT, MRI, etc. or from segmentation techniques previously described). In FIG. 10B, the software can project a shadow projection 1034 of the 3D arbitrary tissue volume in the x-y plane, as previously described. The shadow projection can correspond to the cross-section of the tissue volume in FIGS. 9A-9B that was identified with a segmentation technique or medical imaging.

[0222] Referring to FIG. 10C, instead of filling the x-y projection with concentric ellipses as was done in the embodiment of FIG. 4A, the complex cross-sectional shape is instead packed by the treatment planning software with shrunken / miniaturized versions of the crosssection 1034, referred to herein as arbitrary 2D contours 1040 according to user specified or predetermined “X” and “Y” spacing parameters. The spacing parameters may be based, for example, on an intended bubble cloud size to provide the proper amount of bubble cloud overlap between contours.

[0223] Referring to FIG. 10D, the treatment planning algorithm can then pack / fill treatment points or locations 1030 along each of these arbitrary 2D contours according to the circumferential spacing parameter (which may be, for example, the average of the X and Y spacing parameters).

[0224] In FIG. 10E, the treatment planning software may extend the treatment points or locations 1030 to lines 1042 in the third dimension (Z) of the transducer array coordinate space. It should be understood that not all lines are shown for clarity. While this is described in the XYZ coordinate space above, it should be understood that the liens 1042 extend transverse to, or through, the projection of the contour.

[0225] Finally, in FIG. 10F, discrete treatment points or locations 1044 corresponding to bubble cloud treatment locations are then packed by the treatment planning software along these lines according to the “Z” spacing parameter of the system. As described above, the X, Y, and Z spacing parameters can be predetermined or user-selected, and can be a function of many factors and parameters including bubble cloud size and desired overlap between adjacent treatment points. The spacing parameters can optionally be user-adjusted depending on the specific tissue type or treatment location within the subject.

[0226] The embodiment of FIGS. 10A-10F described an arbitrarily shaped volume, but one that had a volume coordinate space that was generally aligned with the treatment coordinate space of the histotripsy system. However, this disclosure can also apply the teachings of how to pack / navigate a rotated tissue volume relative to the histotripsy coordinate space (e.g., as taught above in FIGS. 5A-7B) to arbitrarily shaped volumes.

[0227] Navigation or Traversal through the Treatment Patern / Pathways

[0228] This section discussed how a packed volume will be navigated with an ultrasound treatment system to sequentially navigate between treatment points or locations to provide full or partial treatment of the treatment volume. While the section below discusses navigation or traversal through relatively uniform (e.g., ellipsoidal) treatment volumes, it should be understood that the techniques can also be applied to the arbitrarily shaped tissue / treatment volumes discussed above in FIGS. 8A-10F.

[0229] Referring now to FIG. 11 A, with the target treatment volume 522 packed with a plurality of discrete treatment locations along the plurality of x-y contours and Z dimension lines, the treatment planning algorithm can then divide the discrete treatment locations into groups of treatment locations, where each group comprises a contiguous sequence of points that are desired to be treated consecutively without treatment stopping between (e.g. a single treatment point, a column of treatment points, a ring of treatment points, etc.). In some embodiments, the groupings are formed from a single Z position or line from each x-y location along a single x-y contour of the treatment plan. For a given x-y contour (e.g., a single contour from FIG. 4A such as 426f), the six groups may be formed, including 536a, 536b, 536c, 536d, 536e, and 536f, from all of the discrete treatment locations / pointsextending along Z lines originating from the x-y points of a single x-y contour. Notice that for this ellipsoidal treatment volume, the number of treatment locations in the Z direction at each of these x-y points can be different, and therefore the treatment planning algorithm does not always provide continuous, smooth rings like would be seen in a spherical treatment volume.

[0230] In FIG. 11 A, various groupings along the Z-axis are shown for a single x-y contour. FIGS. 1 IB-11C, on the other hand, show groupings of treatment locations for a plurality of x-y contours near the distal (e.g., bottom) of the treatment volume. In one implementation, the treatment planning algorithm can organize the groups from lowest (distal-most) to highest (proximal-most) Z position relative to the therapy transducer array. In cases where the complex packing methods result in groupings with significantly varied “Z” positions (like the outlined points in FIG. 7B), these groupings can be subdivided further by the treatment planning software into portions with similar “Z” position (to preserve a more bottom to top traversal). Navigation or traversal through the collection of groups and treatment locations can then be determined by the treatment planning algorithm. In one implementation, navigation through the groups of treatment locations can start with the distal-most group (e.g., group 540a) and proceed proximally (towards the transducer array) to subsequent groups when the treatment locations in a given group are all treated. Traversal within a group can proceed directionally around the contour (e.g., counter-clockwise or clockwise when viewed along the x-y plane. In one implementation, the treatment planning algorithm uses the last treatment location in a given group to determine the first treatment location to be treated in the subsequent group (e.g., the next closest group above or proximal to / towards the transducer array). For example, referring to FIGS. 1 IB-11C, group 540a can be treated first by navigating the transducer array through the group of treatment locations. The treatment planning algorithm can then direct the next treatment location to be treated as the closest treatment location in group 539a, and treatment can resume until all the treatment locations in that group are treated. The treatment pathway can continue through groups 538a, 537a, 536a, and so forth. In general, the guiding principles can be to treat through the treatment locations of a given group before traversing to the next closest grouping proximally in the Z-direction. It is noted that in this specific implementation, group 540a is the distal- most group in the treatment volume, while also being centrally located within the volume. Group 539a is the next most-distal grouping, while being positioned laterally in the x-y plane from group 540a. The result of this treatment pathway is a traversal that starts with the distal- most grouping and navigated both outwardly (in the x-y plane) and proximally (in the z-plane) through the remaining groupings of treatment locations. While other implementations for navigating between treatment groups are considered, the methodology described above provides the minimum z-travel distance between groups which can increase efficiency and reduce treatment times by limiting travel of the transducer without treating the remaining treatment locations.

[0231] Traversal Speed and Acceleration

[0232] In addition to the treatment planning / packing and traversal / navigation of a treatment volume described above, another aspect that the treatment planning algorithm may consider when preparing a treatment plan is the velocity the transducer array is moved through the target treatment volume by the robotic system, acceleration / deceleration values, and when and where therapy is turned on or off as the transducer array is navigating through the volume. All of these parameters can be optimized and pre-determined and / or adjusted during a given treatment to optimize treatment efficiency and outcomes.

[0233] In one implementation, the treatment planning algorithm can be adapted to configure or adjust the following parameters for a given target treatment volume: 1) Target treatment location (the desired location to move the transducer array focus to), 2) Acceleration / deceleration values, 3) Maximum Velocity, 4) Therapy on / off before move (flag to set therapy on / off before move), 5) Therapy on / off after move (flag to set therapy on / off after move), 6) Ton(idle time after move while stationary with therapy on), 7) Tcooi(idle time after move with therapy off, happens after Ton), and 8) Dwell time at each treatment location (e.g., amount of time to remain at treatment location before moving to next treatment location). These parameters can be chosen to determine where the transducer array is to be moved, how fast the robotic positioning system accelerates / decelerates the transducer array between treatment locations, a maximum velocity that the robotics system can move the transducer array, whether or not therapy is on before, after, or during a move, and whether or not cooling periods (e.g., periods of no therapy) are to be implemented within a given treatment plan.

[0234] FIG. 12 is a general motion step diagram that shows one example of how these parameters may be used while navigating a treatment plan with a robotically controlled histotripsy system. At step 602, the system is positioned at a first location (perhaps a treatment location that has just been treated with histotripsy, or alternatively, at a location outside of the treatment volume and preparing to begin treatment) and is preparing to move to a subsequent treatment location. The system can refer to the treatment plan to determine if therapy is to be on or off before / during this move. In between steps 602 and 604, the roboticsystem moves the transducer array towards the target treatment location with an acceleration value “a” which maxes out at maximum velocity “v”. The system then implements a deceleration value “d” to decelerate the transducer array such that the velocity is 0 when the transducer array focus arrives at the target treatment location. In some examples, this deceleration value can be a distinct value. In other embodiments, the deceleration value can comprise a symmetric deceleration (e.g., if the acceleration value is “a” then the deceleration value is “-a”). At step 604, the system refers to the treatment plan to determine if therapy is to be on or off after this move. In this example, therapy is turned on for a time Ton, followed at step 606 by a cooling period Tcooiwhere the transducer array focus is stationary with the therapy turned off. However, it should be understood that this timing diagram could include therapy / cooling in the on or off position for any of the illustrated segments. The process can then repeat at step 608 for the next or subsequent treatment location. In FIG. 6, the transducer array has a dwell time of Ton+ Tcooibetween moves.

[0235] FIGS. 13A-13B is another example of how the parameters described above can be used during a given treatment (or partial treatment as shown). In this example, the system can implement different parameters for different treatment locations or sections of a treatment group. In this example, the partial ring or contour is broken up to end of cooling segments that terminate at treatment locations 540d and 540g. For purposes of this disclosure, a partial ring or contour can comprise a segment that ends at a point different from where it begins. Treatment location 540a represents the starting treatment location for a partial treatment ring or contour and treatment location 540k represents the end of the partial ring.

[0236] Referring to FIG. 13B, therapy can be turned off and the robotics system / transducer array can be moved to treatment location 540a. Next, the robotics system / transducer array can be moved to treatment locations 540b, 540c, and 540d with therapy on before / after / during moves between these treatment locations. Treatment location 540d is the end of a cooling segment within this treatment plan, so a cooling period is added at treatment location 540d where the robotics system / transducer array is not moving and therapy is turned off. Next, therapy can be turned on again and the robotics system / transducer array can be moved through treatment locations 540e, 540f, and 540g with therapy on before / after / during moves between these treatment locations. Once again, a cooling period is added with therapy turned off at treatment location 540g marking the end of a second treatment segment. The process repeats with treatment on during moves through treatment locations 540h, 540i, 540j, and 540k, with a final cooling period added at the end of the partial ring after treating treatment location 540k.

[0237] FIGS. 14A-14B show another example of treating complete contours or pathways within a treatment volume using the parameters and principles described above. In FIG. 8A, two contours 826a and 826b are shown, which can correspond, for example, to contours 540a and 539a of FIG. 5B. In this example, contour 826a has already been treated, and the system is preparing to treat contour 826b, starting with treatment location 842a. In this example, therapy is off for the move through treatment location 842a, and is turned on as the robotics system / transducer array is moved through treatment locations 842b, 842c, 842d, and 842e, with a cooling period added at the end of treatment location 842e. This process is repeated 4 more times, working around the contour, with cooling periods added after treating locations 842j, 842o, 842t, and 842a. With the entire contour treated, the next contour can be treated similar to as described above.

[0238] Other iterations of movement speed / velocity and therapy on / off are considered. For example, in some embodiments, movement between treatment locations may be performed with therapy turned off. Once the transducer focus is positioned at a target treatment location, movement can be paused or stopped and therapy can be turned on. Once the desired dose is delivered, the therapy can be turned off again and movement can be controlled to the next treatment location.

[0239] In another example, movement between treatment locations can be performed at a constant speed, with therapy turned on to deliver a known / precise dose across all treatment points within a target treatment volume.

[0240] The desired dose to be delivered to a target treatment volume for a given treatment plan can be factored into the movement and navigation between treatment locations. For example, to set the movement speed between two points in a ring so as to achieve a desired total dose comprised of:

[0241] some fraction of the treatment dose applied while approaching the point

[0242] some fraction of the treatment dose applied while dwelling at the point

[0243] some fraction of the treatment dose applied while moving away from the point

[0244] One could fix the dwell time and then given the spacing between the points, calculate the acceleration and velocity such that the movement time towards and away from the point total up to the balance of required treatment time given the treatment rate (pulse repetition frequency, PRF). The point spacing we use are small enough that the robot doesn’t have time to reach a reasonable velocity, so moves within treatment rings are accomplished by acceleration only (robot accelerates from start to halfway and then decelerates from halfway point on to finish point)

[0245] Movement Time = (Desired Dose / PRF) - Dwell Tim

[0246] Acceleration = 4 * Spacing / Movement TimeA2

[0247] However, in our case where the spacing along the circumference of our treatment rings is variable, this would result in uneven treatment in different rings. If instead we set motion parameters to achieve a nominal average velocity over the treatment ring, the dose will be equivalent in all rings regardless of packing density of points along the circumference. This is how we set our robot motion parameters.

[0248] Target Speed = Nominal Spacing * PRF / Desired Dose

[0249] Movement Time = Actual Spacing / Target Speed - Dwell Time = (Actual Spacing / Nominal Spacing) * (Desired Dose / PRF) - Dwell Time

[0250] Acceleration = 4 * Actual Spacing / Movement TimeA2

[0251] It should be understood that any feature described herein with respect to one embodiment can be substituted for or combined with any feature described with respect to another embodiment.

[0252] When a feature or element is herein referred to as being “on” another feature or element, it can be directly on the other feature or element or intervening features and / or elements may also be present. 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. It will also be understood that, when a feature or element is referred to as being “connected”, “attached” or “coupled” to another feature or element, it can be directly connected, attached or coupled to the other feature or element or intervening features or elements may be 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 shown with respect to one embodiment, the features and elements so described or shown can apply to other embodiments. It will also be appreciated by those of skill in the art that references to a structure or feature that is disposed “adjacent” another feature may have portions that overlap or underlie the adjacent feature.

[0253] Terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the 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 indicates otherwise. It will be further understood that the terms “comprises” and / or “comprising,” when used in this specification, specify the presence of stated features, steps, operations, elements, and / or components, but do not preclude the presence or additionof 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 “ / ”.

[0254] Spatially relative terms, such as “under”, “below”, “lower”, “over”, “upper” and the like, may be used herein for ease of description to describe one element or feature’s relationship to another element(s) or feature(s) 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 the figures is inverted, elements described as “under” or “beneath” other elements or features would then be oriented “over” the other elements or features. Thus, the exemplary term “undef ’ can encompass both an orientation of over and under. The device may be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly. Similarly, the terms “upwardly”, “downwardly”, “vertical”, “horizontal” and the like are used herein for the purpose of explanation only unless specifically indicated otherwise.

[0255] Although the terms “first” and “second” may be used herein to describe various features / elements (including steps), these features / elements should not be limited by these terms, unless the context indicates otherwise. These terms may be used to distinguish one feature / element from another feature / element. Thus, a first feature / element discussed below could be termed a second feature / element, and similarly, a second feature / element discussed below could be termed a first feature / element without departing from the teachings of the present invention.

[0256] Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising” means various components can be co-jointly employed in the methods and articles (e.g., compositions and apparatuses including device 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.

[0257] As used herein in the specification and claims, including as used in the examples and unless otherwise expressly specified, all numbers may be read as if prefaced by the word “about” or “approximately,” even if the term does not expressly appear. The phrase “about” or “approximately” may be used when describing magnitude and / or position to indicate that the value and / or position described is within a reasonable expected range of values and / or positions. For example, a numeric value may have a value that is + / - 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 values given herein should also be understood to include about or approximately that value, unless the context indicates otherwise. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Any numerical range recited herein is intended to include all sub-ranges subsumed therein. It is also understood that when a value is disclosed that “less than or equal to” the value, “greater than or equal to the value” and possible ranges between values are also disclosed, as appropriately understood by the skilled artisan. For example, if the value “X” is disclosed the “less than or equal to X” as well as “greater than or equal to X” (e.g., where X is a numerical value) is also disclosed. It is also understood that the throughout the application, data is provided in a number of different formats, and that this data, represents endpoints and starting points, and ranges for any combination of the data points. For example, if a particular data point “10” and a particular data point “15” are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0258] While preferred embodiments of the present invention have been shown and described herein, it will be obvious 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 should be 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

CLAIMSWhat is claimed is:

1. A method of preparing a treatment plan for a histotripsy procedure, comprising: identifying, in a processor of a histotripsy system, a tissue volume to be treated; segmenting the tissue volume, in the processor, to generate a 2D lateral slice having an outermost margin contour with an arbitrary shape; dividing, in the processor, the 2D lateral slice into a plurality of concentric contours generally sharing the arbitrary shape; placing, in the processor, a first plurality of treatment locations along each of the plurality of concentric contours according to predetermined first spacing parameters; and for each of the first plurality of treatment locations, placing a second plurality of treatment locations in one or more transverse directions within the margin contour according to predetermined second spacing parameters.

2. The method of claim 1, wherein the tissue volume to be treated comprises a tumor or cyst.

3. The method of claim 1, wherein the tissue volume to be treated comprises diseased tissue.

4. The method of claim 1, wherein the tissue volume to be treated comprises a liver tumor.

5. The method of claim 1, wherein the tissue volume to be treated comprises prostate tissue.

6. The method of claim 1, wherein the tissue volume is arbitrarily shaped in three dimensions.

7. The method of claim 1, wherein the 2D lateral slice is segmented in an xy axis of a coordinate system of the histotripsy system.

8. The method of claim 7, wherein the second plurality of treatment locations are placed in lines along a z axis of the coordinate system of the histotripsy system.

9. The method of claim 1, wherein the first spacing parameters are based in part on a bubble cloud size / shape of the histotripsy system.

10. The method of claim 1, wherein the first spacing parameters are based on a desired amount of overlap between adjacent bubble clouds.

11. The method of claim 1, wherein the second spacing parameters are based in part on a bubble cloud size / shape of the histotripsy system.

12. The method of claim 1, wherein the second spacing parameters are different than the first spacing parameters.

13. The method of claim 1, further comprising delivering histotripsy therapy to each of the first and second plurality of treatment locations.

14. The method of claim 12, wherein delivering histotripsy therapy further comprises controlling a robotic system of the histotripsy system to navigate between the first and second plurality of treatment locations with predetermined acceleration, deceleration, and maximum velocity parameters15. The method of claim 1, further comprising: dividing the second plurality of treatment locations into groups, wherein each group comprises a common axial position within the tissue volume; initiating histotripsy therapy in a distal-most group of the tissue volume relative to a transducer array of the histotripsy system; delivering histotripsy therapy to each of the treatment locations within the distal-most group; navigating the histotripsy system to a group that is proximally adjacent to the distal- most group; delivering histotripsy therapy to each of the treatment locations within the proximally adjacent group with the histotripsy therapy system;repeating the process for all remaining groups in a distal to proximal direction.

16. The method of claim 15, further comprising controlling a robotic system of the histotripsy system to navigate between treatment locations with predetermined acceleration, deceleration, and maximum velocity parameters.

17. The method of claim 15, further comprising determining if treatment is on or off before / during / after navigation between treatment locations.

18. The method of claim 17, further comprising adding periods of cooling at selected treatment locations where therapy is turned off.

19. A histotripsy treatment method, comprising: identifying, in a processor of a histotripsy system, an arbitrarily shaped tissue volume within a subject; establishing, in the processor, a 3D treatment volume to be positioned around the tissue volume that encompasses the tissue volume; packing, in the processor, the 3D treatment volume with a plurality of discrete treatment points, wherein some of the discrete treatment points fall outside of the tissue volume; and controlling, with the processor, a focus of a histotripsy system to mechanically move through the plurality of discrete treatment points such that histotripsy therapy is applied to the discrete treatment points within the tissue volume and not applied to the discrete treatment points that fall outside of the tissue volume.

20. A histotripsy therapy system, comprising: 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, the generator and ultrasound therapy transducer array being configured to deliver histotripsy pulses into a subject to generate cavitation in the subject; at least one processor operatively coupled to the robotic positioning system and thegenerator, the at least one processor being configured to implement a digital treatment plan by: identifying a tissue volume to be treated; segmenting the tissue volume to generate a 2D lateral slice having an outermost margin contour with an arbitrary shape; dividing the 2D lateral slice into a plurality of concentric contours generally sharing the arbitrary shape; placing a first plurality of treatment locations along each of the plurality of concentric contours according to predetermined first spacing parameters; and for each of the first plurality of treatment locations, placing a second plurality of treatment locations in one or more transverse directions within the margin contour according to predetermined second spacing parameters.

21. The system of claim 20, wherein the tissue volume to be treated comprises a tumor or cyst.

22. The system of claim 20, wherein the tissue volume to be treated comprises diseased tissue.

23. The system of claim 20, wherein the tissue volume to be treated comprises a liver tumor.

24. The system of claim 20, wherein the tissue volume to be treated comprises prostate tissue.

25. The system of claim 20, wherein the tissue volume is arbitrarily shaped in three dimensions.

26. The system of claim 20, wherein the 2D lateral slice is segmented in an xy axis of a coordinate system of the histotripsy system.

27. The system of claim 26, wherein the second plurality of treatment locations are placed in lines along a z axis of the coordinate system of the histotripsy system.

28. The system of claim 20, wherein the first spacing parameters are based in part on a bubble cloud size / shape of the histotripsy system.

29. The v of claim 20, wherein the first spacing parameters are based on a desired amount of overlap between adjacent bubble clouds.

30. The system of claim 20, wherein the second spacing parameters are based in part on a bubble cloud size / shape of the histotripsy system.

31. The system of claim 20, wherein the second spacing parameters are different than the first spacing parameters.

32. The system of claim 20, wherein the at least one processor is configured to control the robotic positioning system and the generator to deliver histotripsy therapy to each of the first and second plurality of treatment locations.

33. The system of claim 32, wherein the at least one processor is further configured to control the robotic positioning system to navigate between the first and second plurality of treatment locations with predetermined acceleration, deceleration, and maximum velocity parameters34. The system of claim 20, wherein the at least one processor is configured to control the robotic positioning system and the generator to: divide the second plurality of treatment locations into groups, wherein each group comprises a common axial position within the tissue volume; initiate histotripsy therapy in a distal-most group of the tissue volume relative to a transducer array of the histotripsy system; deliver histotripsy therapy to each of the treatment locations within the distal-most group; navigate the ultrasound therapy transducer to a group that is proximally adjacent to the distal-most group; deliver histotripsy therapy to each of the treatment locations within the proximally adjacent group with the histotripsy therapy system; and repeat the process for all remaining groups in a distal to proximal direction.

35. The system of claim 34, wherein the at least one processor is further configured to control the robotic positioning system to navigate between treatment locations with predetermined acceleration, deceleration, and maximum velocity parameters.

36. The system of claim 35, wherein the at least one processor is further configured to determine if treatment is on or off before / during / after navigation between treatment locations.

37. The system of claim 36, wherein the at least one processor is further configured to add periods of cooling at selected treatment locations where therapy is turned off.

38. A method of preparing a treatment plan for a histotripsy procedure, comprising: identifying, in a processor of a histotripsy system, a tissue volume to be treated, the tissue volume having a tissue coordinate space that is not aligned with a treatment coordinate space of the histotripsy system; segmenting the tissue volume, in the processor, to generate a 2D lateral slice in the treatment coordinate space that passes through the treatment volume; dividing, in the processor, the 2D lateral slice into a plurality of concentric contours; placing, in the processor, a first plurality of treatment locations along each of the plurality of concentric contours according to predetermined first spacing parameters; and for each of the first plurality of treatment locations, placing a second plurality of treatment locations in one or more transverse directions within the tissue volume according to predetermined second spacing parameters, the second plurality of treatment locations being asymmetrically distributed on either side of the 2D lateral slice due to the mis-alignment of the tissue coordinate space and the treatment coordinate space.

39. The method of claim 38, wherein the tissue volume to be treated comprises a tumor or cyst.

40. The method of claim 38, wherein the tissue volume to be treated comprises diseased tissue.

41. The method of claim 38, wherein the tissue volume to be treated comprises a liver tumor.

42. The method of claim 38, wherein the tissue volume to be treated comprises prostate tissue.

43. The method of claim 38, wherein the tissue volume comprises an ellipsoidal shape, wherein a longest dimension of the ellipsoidal shape is rotated relative to a treatment axis of the histotripsy system.

44. The method of claim 38, wherein the 2D lateral slice is segmented in an xy axis of a coordinate system of the histotripsy system.

45. The method of claim 44, wherein the second plurality of treatment locations are placed in lines along a z axis of the coordinate system of the histotripsy system.

46. The method of claim 38, wherein the first spacing parameters are based in part on a bubble cloud size / shape of the histotripsy system.

47. The method of claim 38, wherein the first spacing parameters are based on a desired amount of overlap between adjacent bubble clouds.

48. The method of claim 38, wherein the second spacing parameters are based in part on a bubble cloud size / shape of the histotripsy system.

49. The method of claim 38, wherein the second spacing parameters are different than the first spacing parameters.

50. The method of claim 38, further comprising delivering histotripsy therapy to each of the first and second plurality of treatment locations.

51. The method of claim 50, wherein delivering histotripsy therapy further comprises controlling a robotic system of the histotripsy system to navigate between the first and second plurality of treatment locations with predetermined acceleration, deceleration, and maximum velocity parameters52. The method of claim 38, further comprising:dividing the second plurality of treatment locations into groups, wherein each group comprises a common axial position within the tissue volume; initiating histotripsy therapy in a distal-most group of the tissue volume relative to a transducer array of the histotripsy system; delivering histotripsy therapy to each of the treatment locations within the distal-most group; navigating the histotripsy system to a group that is proximally adjacent to the distal- most group; delivering histotripsy therapy to each of the treatment locations within the proximally adjacent group with the histotripsy therapy system; repeating the process for all remaining groups in a distal to proximal direction.

53. The method of claim 52, further comprising controlling a robotic system of the histotripsy system to navigate between treatment locations with predetermined acceleration, deceleration, and maximum velocity parameters.

54. The method of claim 53, further comprising determining if treatment is on or off before / during / after navigation between treatment locations.

55. The method of claim 54, further comprising adding periods of cooling at selected treatment locations where therapy is turned off.

56. A histotripsy therapy system, comprising: a robotic positioning system; an ultrasound therapy transducer array connected to the robotic positioning system, the ultrasound therapy transducer array having a treatment coordinate space with a treatment axis; a generator operatively coupled to the ultrasound therapy transducer array, the generator and ultrasound therapy transducer array being configured to deliver histotripsy pulses into a subject to generate cavitation in the subject; at least one processor operatively coupled to the robotic positioning system and the generator, the at least one processor being configured to implement a digital treatment plan by:identifying a tissue volume to be treated, the tissue volume having a tissue coordinate space that is not aligned with the treatment coordinate space of the ultrasound therapy transducer array; segmenting the tissue volume to generate a 2D lateral slice in the treatment coordinate space that passes through the treatment volume; dividing the 2D lateral slice into a plurality of concentric contours; placing a first plurality of treatment locations along each of the plurality of concentric contours according to predetermined first spacing parameters; and for each of the first plurality of treatment locations, placing a second plurality of treatment locations in one or more transverse directions within the tissue volume according to predetermined second spacing parameters, the second plurality of treatment locations being asymmetrically distributed on either side of the 2D lateral slice due to the mis-alignment of the tissue coordinate space and the treatment coordinate space.

57. The system of claim 56, wherein the tissue volume to be treated comprises a tumor or cyst.

58. The system of claim 56, wherein the tissue volume to be treated comprises diseased tissue.

59. The system of claim 56, wherein the tissue volume to be treated comprises a liver tumor.

60. The system of claim 56, wherein the tissue volume to be treated comprises prostate tissue.

61. The system of claim 56, wherein the tissue volume is arbitrarily shaped in three dimensions.

62. The system of claim 56, wherein the 2D lateral slice is segmented in an xy axis of a coordinate system of the histotripsy system.

63. The system of claim 62, wherein the second plurality of treatment locations are placed in lines along a z axis of the coordinate system of the histotripsy system.

64. The system of claim 56, wherein the first spacing parameters are based in part on a bubble cloud size / shape of the histotripsy system.

65. The system of claim 56, wherein the first spacing parameters are based on a desired amount of overlap between adjacent bubble clouds.

66. The system of claim 56, wherein the second spacing parameters are based in part on a bubble cloud size / shape of the histotripsy system.

67. The system of claim 56, wherein the second spacing parameters are different than the first spacing parameters.

68. The system of claim 56, wherein the at least one processor is configured to control the robotic positioning system and the generator to deliver histotripsy therapy to each of the first and second plurality of treatment locations.

69. The system of claim 68, wherein the at least one processor is further configured to control the robotic positioning system to navigate between the first and second plurality of treatment locations with predetermined acceleration, deceleration, and maximum velocity parameters70. The system of claim 56, wherein the at least one processor is configured to control the robotic positioning system and the generator to: divide the second plurality of treatment locations into groups, wherein each group comprises a common axial position within the tissue volume; initiate histotripsy therapy in a distal-most group of the tissue volume relative to a transducer array of the histotripsy system; deliver histotripsy therapy to each of the treatment locations within the distal-most group; navigate the ultrasound therapy transducer to a group that is proximally adjacent to the distal-most group; deliver histotripsy therapy to each of the treatment locations within the proximally adjacent group with the histotripsy therapy system; and repeat the process for all remaining groups in a distal to proximal direction.

71. The system of claim 70, wherein the at least one processor is further configured to control the robotic positioning system to navigate between treatment locations with predetermined acceleration, deceleration, and maximum velocity parameters.

72. The system of claim 71, wherein the at least one processor is further configured to determine if treatment is on or off before / during / after navigation between treatment locations.

73. The system of claim 72, wherein the at least one processor is further configured to add periods of cooling at selected treatment locations where therapy is turned off.

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