Robotic histotripsy systems with interchangeable probes

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. Methods of biological tissue modification are also provided. The systems and methods disclosed here are uniquely different in that they aim to target, plan and treat target tissue, and selectively destroy and modify cellular architecture, but with specific intent and treatment parameters specialized for retaining specific target physical biological structures within the cell itself.

Description

ROBOTIC HISTOTRIPSY SYSTEMS WITH INTERCHANGEABLE PROBESPRIORITY CLAIM

[0001] This patent application claims priority to U.S. provisional patent application no. 63 / 725,322, titled “ROBOTIC HISTOTRIPSY SYSTEMS WITH INTERCHANGEABLE PROBES,” and filed on November 26, 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- 1 -SG Docket No. 10860-741.600hypoechoic) 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

[0006] A histotripsy method is provided, comprising: marking a tissue surface corresponding to a target tissue with an ultrasound-visible marker; identifying the ultrasound- visible marker with a histotripsy therapy probe; positioning, moving, tracing, or tracking the histotripsy therapy probe along or within the ultrasound visible marker; and delivering histotripsy therapy to the target tissue based on the ultrasound-visible marker.

[0007] In some aspects, the ultrasound-visible marker comprises an ultrasound visible ink.

[0008] In one aspect, a robotic arm is used for positioning, moving, tracking, or tracking the histotripsy therapy probe along or within the ultrasound visible marker.

[0009] In other aspects, the robotic arm automatically performs the positioning, moving, tracing, or tracking step.

[0010] In some aspects, the histotripsy therapy probe is handheld.

[0011] In additional aspects, the tissue surface comprises a skin surface. In some aspects, the target tissue is on the skin surface. In other aspects, the target tissue is below the skin surface. In some aspects, the tissue surface comprises an organ. In one aspect, the tissue surface comprises a tumor. In some aspects, the target tissue comprises thyroid tissue.

[0012] In some aspects, the method further comprises generating a treatment plan based at least in part on the ultrasound-visible marker. In some aspects, the treatment plan includes a target tissue volume populated with individual treatment locations. In some aspects, delivering histotripsy therapy to the target tissue further comprises delivering histotripsy therapy according to the treatment plan.

[0013] A histotripsy system is provided, comprising: a marking device configured to apply a marking to a tissue location to define a treatment volume; an imaging system configured to identify the marking; and a therapy transducer configured to deliver ultrasound pulses to or within the marking to generate cavitation within the treatment volume.

[0014] In some aspects, the marking device, the imaging system, and / or the therapy transducer is hand-held. In some aspects, the marking device, imaging system, and therapy- 2 -SG Docket No. 10860-741.600transducer are integrated into a therapy probe. In one aspect, the therapy probe is coupled to a robotic arm. In some aspects, one or more processors are configured to control the therapy probe and the robotic arm to automatically deliver histotripsy therapy to the treatment volume using the marking.

[0015] In one aspect, the marking is an ultrasound-visible marking. In some aspects, the marking is an ultrasound-visible sticker. In one aspect, the marking contains the treatment volume. In some aspects, the marking at least partially contains the treatment volume. In some aspects, the tissue location comprises a skin surface, and the treatment volume is disposed below the skin surface. In other aspects, the marking can include a treatment start point and end point.BRIEF DESCRIPTION OF THE DRAWINGS

[0016] 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:

[0017] FIGS. 1 A-1B illustrate an ultrasound imaging and therapy system.

[0018] FIG. 2 is one embodiment of a histotripsy therapy and imaging system with a coupling system.

[0019] FIG. 3 is one example of an ultrasound pulse for generating histotripsy via a shock scattering mechanism.

[0020] FIG. 4 is a flowchart describing a histotripsy method.

[0021] FIG. 5 is a schematic showing an overall system architecture for a histotripsy system.DETAILED DESCRIPTION

[0022] 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- 3 -SG Docket No. 10860-741.600application of stem cells and other adjuvants. Histotripsy may also be used to alter the permeability of cell membranes to enhance the penetration of agents into cells. 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.

[0023] FIG. 1 A generally illustrates histotripsy system 100 according to the present disclosure, comprising a swappable or removeable transducer probe 102 which may include integrated therapy transducer elements and one or more imaging transducer elements, 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. In some embodiments, however, the transducer probe can be coupled directly to the skin of the patient, alternatively with an acoustic coupling medium such as a gel. The transducer probe 102 can include an end-firing tip, as shown, in which ultrasound waves are transmitted along a longitudinal axis of the probe, or a side-firing tip (not shown), in which the ultrasound waves are transmitted transverse to the longitudinal axis.

[0024] The system can be configured to work with any number of swappable or removeable transducer probes 102. In some examples, the various probes can have different sizes or focal depths depending on the tissue being targeted. For example, the probes can have transducer array diameters ranging from 5 mm to 50 mm. Some probes may be better suited for generating cavitation in tissue at or near the skin surface, while other probes may be better suited for generating cavitation deeper in tissue or behind bone or other aberrators. While the probe can be a conventional end-firing probe that directs ultrasound signals away from the bottom of the probe, other embodiments can include side-firing designs in which the transducers are located on a side of the probe.

[0025] FIG. IB is a bottom view of the transducer probe 102 which can include one or more therapy transducer elements 103 and one or more imaging transducer elements 104. As shown, the imaging system can be positioned in the center of the therapy transducer. The- 4 -SG Docket No. 10860-741.600therapy transducer can be oriented in a ring around the imaging transducer, and can be one or more individual transducer elements. However, other embodiments can include the imaging system positioned in other locations within the therapy transducer, or even directly integrated into the therapy transducer. Additionally, the therapy transducer need not be arranged in a ring, but can have other configurations as known in the art.

[0026] 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.

[0027] 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.

[0028] 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. CART

[0029] 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- 5 -SG Docket No. 10860-741.600concert 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.).

[0030] 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.

[0031] 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 Integrated Imaging and a console / display for controlling the Robotic and Therapy facets, analogous to a surgical robot and master / slave configurations.

[0032] 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).

[0033] 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.- 6 -SG Docket No. 10860-741.600HISTOTRIPSY

[0034] 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 of ablation, 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.

[0035] 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 interfere 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.

[0036] 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.- 7 -SG Docket No. 10860-741.600

[0037] 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 allows contact of the transducer with tissue including open surgical laparoscopic surgical, percutaneous and robotically mediated surgical procedures. It may be further 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.

[0038] 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”.

[0039] 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 peak positive half cycle (with the pulse traveling from right to left on the page). As shown, the trailing peak positive cycle has a lower amplitude than the peak positive 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 pressure, but also the number of acoustic cycles and the amplitudes of the positive shocks. Without at least one- 8 -SG Docket No. 10860-741.600intense shock front developed by nonlinear propagation, no dense bubble clouds are generated when the peak negative half-cycles are below the intrinsic threshold.

[0040] 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”.

[0041] 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.

[0042] 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.”

[0043] 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,- 9 -SG Docket No. 10860-741.600it 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 various combinations or permutations of, etc., are included as a part of this disclosure, including future envisioned embodiments of such.THERAPY COMPONENTS

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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- 10 -SG Docket No. 10860-741.600parameters 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 repeated and / or new loop sets introduced, of varied time delay and independently controlled, and of various combinations and permutations of such, overall and throughout.

[0048] 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.

[0049] 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.

[0050] 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.- 11 -SG Docket No. 10860-741.600

[0051] 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 amplifiers is 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.

[0052] 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.

[0053] 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).

[0054] 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.

[0055] 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- 12 -SG Docket No. 10860-741.600or 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. The transducer 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

[0056] 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.

[0057] 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- 13 -SG Docket No. 10860-741.600electromechanically 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 therapy transducer 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.

[0058] 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).

[0059] 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).

[0060] 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.- 14 -SG Docket No. 10860-741.600Moreover, 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.

[0061] In some embodiments, imaging including feedback and monitoring from backscatter, and speckle reduction, may be configured in the system.

[0062] 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 and distribution 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.

[0063] 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- 15 -SG Docket No. 10860-741.600may 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.

[0064] 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 imaging modalities 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.

[0065] 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.

[0066] For systems comprising feedback and monitoring via acoustic emission, and as means of background, as a tissue 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- 16 -SG Docket No. 10860-741.600change 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.

[0067] 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 inferred from 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.

[0068] 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.

[0069] 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 / displayed 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- 17 -SG Docket No. 10860-741.600marked 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).

[0070] 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, ultrasound enabled 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).

[0071] 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- 18 -SG Docket No. 10860-741.600other 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 an unlimited 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.ROBOTICS

[0072] 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.

[0073] 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.

[0074] 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 / patient-side, and the Master is at a distance from said Cart.

[0075] 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.- 19 -SG Docket No. 10860-741.600

[0076] 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 various functionalities, including but not limited to, position, tracking, patterns, triggering, and events / actions.

[0077] Position may be configured to comprise fixed positions, pallet positions, time- controlled positions, distance-controlled positions, variable-time controlled positions, variable-distance controlled positions.

[0078] Tracking may be configured to comprise time-controlled tracking and / or distance- controlled tracking.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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 rob ots / rob otic arms and / or additional surgical systems, including but not limited to, surgical towers, imaging systems, endoscopic / laparoscopic systems, and / or other.- 20 -SG Docket No. 10860-741.600

[0083] 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 the robotic 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.

[0084] 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

[0085] 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.- 21 -SG Docket No. 10860-741.600

[0086] 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 and parameters 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.).

[0087] 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.- 22 -SG Docket No. 10860-741.600

[0088] 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 and amplifier settings (e.g., channels) based on the specific transducer selection. The software may also provide transducer recommendations based on pre-treatment and planning inputs. Conversely, the software may provide 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.

[0089] 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).

[0090] 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.

[0091] 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- 23 -SG Docket No. 10860-741.600with 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) electromechanical positioning, 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

[0092] 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

[0093] 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.

[0094] Feedback may include various energy, power, location, position, tissue and / or other parameters.

[0095] 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- 24 -SG Docket No. 10860-741.600start / 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.

[0096] 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.

[0097] 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.

[0098] 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).

[0099] 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- 25 -SG Docket No. 10860-741.600cavitation / 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.).

[0100] 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.

[0101] 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

[0102] 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

[0103] 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- 26 -SG Docket No. 10860-741.600may 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.

[0104] 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.

[0105] 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.

[0106] 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- 27 -SG Docket No. 10860-741.600comprise 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 medium container 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).

[0107] 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.

[0108] 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.- 28 -SG Docket No. 10860-741.600

[0109] 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.

[0110] 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.

[0111] 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.- 29 -SG Docket No. 10860-741.600

[0112] 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 / or Coupling 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.

[0113] 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.

[0114] 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.

[0115] 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- 30 -SG Docket No. 10860-741.600novel 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 workspace 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

[0116] 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.

[0117] 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).

[0118] 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.

[0119] FIG. 2 illustrates one embodiment of a histotripsy therapy and imaging system 200, including a coupling assembly 201. As described above, a histotripsy therapy and imaging system can include a therapy transducer 202, an imaging system, a robotic positioning arm 208, and a fluidics cart 210. The robotic positioning arm may be attached to a therapy cart, such as cart 209.

[0120] The therapy and / or imaging transducers can be disposed within in the coupling assembly 201 which can further include a coupling membrane 214 and a membrane- 31 -SG Docket No. 10860-741.600constraint 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 as compared to the membrane, and 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 over expansion. 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 201 is 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.

[0121] The fluidics cart 210 can include additional features, including a fluid tank 220, a cooling and degassing system, and a programmable control system. The fluidics cart is configured for external loading of the coupling membrane with automated control of fluidic sequences. Further details on the fluidics cart are provided below.MEMBRANES / BARRIER FILMS AND RELATED ARCHITECTURES

[0122] 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.

[0123] 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 UMC 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

[0124] 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- 32 -SG Docket No. 10860-741.600solutions / 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

[0125] 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.

[0126] 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.

[0127] 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 “UMC” or “coupling solution”. This specific distal interface may further include features for controlling position / orientation of the frame / assembly, at the frame / assembly interface.

[0128] 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 UMC / 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.

[0129] 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- 33 -SG Docket No. 10860-741.600separate 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 a rail, 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

[0130] 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, chill, 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 UMC. 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 UMC and membrane prior to filling with a coupling medium. Vacuum assist can also be used for removal of air from the UMC during the filling process. The fluidics system can further include filters configured to prevent particulate contamination from reaching the UMC.

[0131] 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).HISTOTRIPSY TREATMENT PLANNING SOFTWARE TOOLS AND SYSTEMS

[0132] Histotripsy therapy is provided by transmitting ultrasound signals from a plurality of transducer elements towards a common focal location. Pressures generated at this focal location induce cavitation in the target tissue to mechanically fractionate, liquefy, or lyse tissue. However, the efficiency and efficacy of therapy can be affected by a number of patient specific factors, including, for example, obstructions between the transducer array and the target tissue, variations in intervening tissue between the transducer and the focal location including tissue density changes, tissue type variations, and pockets of gas or air. Creating an- 34 -SG Docket No. 10860-741.600optimal acoustic window to a particular target in the body can be quite challenging given a subject’s anatomy and variations in body composition and makeup from subject to subject.

[0133] This disclosure provides treatment planning tools that can be implemented in software on one or more computing systems. In some embodiments, the treatment planning tools are implemented in a console of the histotripsy system. In other embodiments, the treatment planning tools are implemented on a cloud or remote server or computing platform. The cloud or remote computing platform can be in communication with the histotripsy system / console. For example, a physician or medical provider can create and review a treatment plan on a first computing platform (e.g., a personal computer, smartphone, tablet, etc.) and transfer or transmit the treatment plan to the histotripsy system console that will be used for the actual histotripsy procedure to carry out the treatment plan.PRE-OPERATIVE IMAGING, CO-REGISTRATION, AND EVALUATION

[0134] Treatment planning tools are provided herein for Histotripsy therapy that can be used to plan and assist for histotripsy treatments and procedures. The treatment planning tools disclosed herein can import and co-register pre-operative imaging from a variety of imaging modalities (e.g., CT, CBCT, MRI, Ultrasound, X-ray, etc.) Software and hardware within the operating room, or remote to the operating room / treatment location, can provide treatment planning tools can be configured to allow a user to evaluate the pre-operative imaging and identify a tissue target such as a tumor. While the description herein refers to pre-operative imaging, it should be understood that in some embodiments, imaging can be performed during a histotripsy procedure, and any of the steps or techniques described herein can therefore apply to real-time or intra-operative imaging in addition to or instead of preoperative imaging.

[0135] In some embodiments, the treatment planning tool can use imaging of the patient when the patient is lying on the procedure table or positioned on a scanner gantry, in the position that the patient will be in during the procedure. Additionally, any surgical prep equipment, gowns, clothing, and / or acoustic coupling containers that will be necessary for the procedure can be in place on or around the patient to provide the most accurate medical imaging of the patient’s body for the planned procedure. For example, acoustic coupling containers as described herein and used with histotripsy procedures can be large rigid or semi-rigid containers that are placed on top of a patient and filled with an acoustic coupling medium (e.g., water) to allow for acoustic coupling of a therapy transducer array to the patient’s skin. In some examples, these acoustic coupling containers can be filled with 30L or more of fluid, which represents a significant weight that can compress, squish, or deform- 35 -SG Docket No. 10860-741.600the patient’s soft tissue. Therefore, it may be desirable to perform pre-operative imaging with such an acoustic coupling container in place, such that any deformations that will be seen during the procedure will also show up on pre-operative imaging. In some embodiments, however, this may not be practical or possible. Therefore, in some embodiments, treatment planning can be based on pre-operative imaging, and once the patient is on the operating table with the acoustic coupling container filled and in place, additional imaging can be taken to identify the deformations from the acoustic coupling container. The system can then be configured to co-register the pre-operative images (upon which the treatment planning is based) with the images that are deformed by compression of the acoustic coupling container, and make any adjustments to the treatment plan, target tissue volume, and / or pose or angle of the treatment head based on these deformations and the co-regi strati on.TREATMENT PLANNING AND THERAPY USING ULTRASOUND OR X-RAY VISIBLE TARGETS OR ARBITRARY USER-DEFINED TARGETS

[0136] The systems described herein can be used in conjunction with ultrasound or x-ray visible markers, including ultrasound-visible or radiopaque “ink”, tape, stickers, liquid, aerosol spray, or other structures which can be placed or defined on a subject or patient by a user to define a tissue target. Alternatively, the system can use optical tracking systems to allow for the use of any type of markers or ink, including those that are not radio-opaque. Referring to flowchart 400 in FIG. 4, a method of delivering ultrasound therapy to a patient can include, at step 402, applying ultrasound-visible marker(s) to a subject to define a tissue target. In some examples, the user can identify and define a visible target with the ultrasound-visible markers, ink, stickers or tape, by depositing, marking, drawing, adhering, or placing the ultrasound visible marker directly on a tissue or surface of the patient, such as on the skin, or directly on a surgically exposed organ or patient cavity. In some examples, the ultrasound probe itself can directly deposit the ultrasound visible marker on the tissue while it is used to obtain imaging data of a target tissue below the skin. For example, the ultrasound probe may automatically apply the ultrasound-visible marker when imaging is turned on. Alternatively, the probe may include a button or input device that allows the user to turn on or off the marker application. In other examples, the user can use the ultrasound- visible marker identify and define a target which may be at least partially visible beneath a tissue or surface (e.g., skin surface), for example, a vascular structure such as veins or blood vessels.

[0137] At step 404, the method can include optionally generating a treatment plan based at least in part on the ultrasound-visible markers applied at step 402. In some examples, the- 36 -SG Docket No. 10860-741.600ultrasound-visible markers can be used in conjunction with ultrasound imaging data obtained with the imaging transducer of the probe described above to provide treatment planning for nonvisible lesions / target tissues. For example, the system can interrogate the ultrasound data to determine a depth of the target tissue along the ultrasound visible marking / trace. Additionally, the system can provide an extension laterally relative to the ultrasound visible marking / trace. With the ultrasound imaging data, and the ultrasound-visible markers deposited on the skin or directly on the tissue and correlated to the ultrasound imaging data, the system can be used to create treatment plans. In one embodiment, the system can use the ultrasound-visible marker to generate a treatment plan that identifies a target tissue volume, determines a depth of the target tissue volume (optionally using imaging data), identifies a pose / position / orientation of the probe for accessing the target tissue volume based on the ultrasound-visible marker, and populates the target tissue volume with individual bubble cloud locations to treat the target tissue volume. The system can correlate the location of individual bubble cloud locations with a location along the ultrasound-visible marker, to allow for ultrasound therapy delivery to a specific bubble cloud location when the ultrasound probe passes or reaches that specific location on the ultrasound-visible marker.

[0138] At step 406, the method can include moving the ultrasound therapy probe along the ultrasound-visible marker(s) to deliver ultrasound / histotripsy therapy to the tissue target. This therapy can be delivered automatically in some embodiments. The system can use the treatment plan to deliver treatment to the target tissue volume by moving the ultrasound probe over the ultrasound-visible markers and delivering histotripsy pulses to the individual bubble cloud locations within the target tissue volume. For example, the histotripsy system can use the imaging transducer to identify the ultrasound-visible markers / trace, and the ultrasound probe can track or follow the ultrasound visible markers / trace to deliver histotripsy energy, and create cavitation within the target tissue. In some examples, the ultrasound probe can be mounted on a robotic arm, and the robotic arm can be configured to automatically track or follow the ultrasound-visible markers to deliver histotripsy according to the treatment plan. Alternatively, the robot can automatically move to the “center” of the marked region to deliver the planned therapy. In other embodiments, the ultrasound probe can be moved manually over the ultrasound- visible marker(s), such as by a user or physician, but the system can automatically deliver ultrasound therapy to an appropriate bubble cloud location when the probe is in the proper position along the ultrasound-visible marker.

[0139] The systems and techniques described herein provide a universal solution for any “surface” target including a skin surface, surface of a cavity, or organ exposed at surgery.- 37 -SG Docket No. 10860-741.600The ultrasound markers / ink can be used to deliver histotripsy plans automatically to user- identified regions (cosmetic, fat-busting, wrinkles, vascular structures, etc.). The systems and techniques described above can also be used for superficial targets, or targets just below the skin surface (e.g., the thyroid or other shallow organs or anatomies). Additionally, the use of the ultrasound visible markers allows the histotripsy robot to adjust for patient movement automatically. Alternatively, a hand-held histotripsy device can be used to visibly trace or follow a marked lesion for treatment of histotripsy. These techniques can be used for deep targets in addition to shallow targets by creating a surface defined reference to the deep target for movement tracking of the target defined by US imaging or MR fusion.SYSTEM ARCHICTECTURE

[0140] FIG. 5 is a schematic diagram showing a system architecture for a histotripsy system that can include any of the components described herein. The overall device configuration can include, generally, a treatment planning system 502, a guidance system 504, guidance software 506, the histotripsy positioning robot or robotic arm 508, the histotripsy generator / driver 510, and the histotripsy treatment head or probe 512.

[0141] The planning system 502 can be a treatment planning software configured to define a treatment volume, populate the treatment volume with individual treatment or bubble cloud locations, optionally define a pathway through the individual treatment locations, and can include additional details on the treatment including but not limited to tissue volume depth, driving voltages required for each treatment location to generate cavitation, and cooling or other safety protocols. The planning system can be complex (e.g., using advanced software and imaging to identify the target tissue, determine treatment parameters and margins, identify optimal acoustic windows, etc.) or can be relatively simple (e.g., applying histotripsy to a target volume of a predetermined size at a specified depth or location).

[0142] The guidance system 504 for using ultrasound visible tracking / ink can use only ultrasound (US) imaging / tracking of the ultrasound-visible markers, e.g., on the probe itself, or alternatively, the guidance system can further incorporate or use an optical tracking system to track various components of the system and of the target tissue, including the markers patient, treatment head, coupling container, patient table, etc. For optical tracking, the markers need not be ultrasound-visible.

[0143] Software 506 for the guidance system can be used by a physician to manually track or trace the ultrasound visible markers, or alternatively, the system can control the robotic arm to automatically trace and track the markers. In some embodiments, the software 506 can be a completely automated system that implements a treatment plan when the- 38 -SG Docket No. 10860-741.600ultrasound visible markers are in place by controlling the robotic arm to trace along the markers and deliver histotripsy therapy to the target tissue volume according to the treatment plan.

[0144] In some embodiments, a user can insert or provide a marking directly in a user interface of the system. For example, the user can review medical imaging of a target treatment location (e.g., pre-operative imaging) and / or a digital treatment plan for the target tissue. The user can trace or mark directly on a screen with an input device (e.g., a mouse, joystick, trackpad, apple pencil, etc.). The input can be read directly into the digital treatment plan and the robotic system can follow plan laid out by user directly on the screen.

[0145] The robotic system or arm 508 itself can come in different sizes, depending on the target tissue and the specifics of the case. For example, there may be four or more sized robots, including large, medium, small, and extra-small.

[0146] The driver or generator 510 of the system can also be chosen based on the specifics of the therapy and the type of robot / probe in use. For example, certain drivers may be better suited for the smaller probes, and other drivers may be better suited for larger probes, higher power probes, or probes that need to generate larger or deeper lesions.

[0147] The probe 512 itself can come in various sizes, as described above, and can be an end-shooting probe or a side-shooting probe. The transmit (tx) transducers can be various sizes, for example ranging from 5mm to 50 mm, or alternatively from 8 mm to 25 mm or more, and can be donut / ring shaped transducers or other configurations as described above. The imaging transducer used in the probe can also vary depending on the probe. For example, probes intended to treat the surface of the skin, or shallow targets may use lower resolution imagers than larger probes intended to treat deeper target tissues.

[0148] 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.

[0149] 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- 39 -SG Docket No. 10860-741.600“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.

[0150] 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 addition of one or more other features, steps, operations, elements, components, and / or groups thereof. As used herein, the term “and / or” includes any and all combinations of one or more of the associated listed items and may be abbreviated as “ / ”.

[0151] 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 “under” 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.

[0152] 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.- 40 -SG Docket No. 10860-741.600

[0153] 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.

[0154] 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.

[0155] 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- 41 -SG Docket No. 10860-741.600that 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.- 42 -SG Docket No. 10860-741.600

Claims

CLAIMSWhat is claimed is:

1. A histotripsy method, comprising: marking a tissue surface corresponding to a target tissue with an ultrasound-visible marker; identifying the ultrasound-visible marker with a histotripsy therapy probe; positioning, moving, tracing, or tracking the histotripsy therapy probe along or within the ultrasound visible marker; and delivering histotripsy therapy to the target tissue based on the ultrasound-visible marker.

2. The method of claim 1, wherein the ultrasound-visible marker comprises an ultrasound visible ink.

3. The method of claim 1, wherein a robotic arm is used for positioning, moving, tracking, or tracking the histotripsy therapy probe along or within the ultrasound visible marker.

4. The method of claim 3, wherein the robotic arm automatically performs the positioning, moving, tracing, or tracking step.

5. The method of claim 1, wherein the histotripsy therapy probe is handheld.

6. The method of claim 1, wherein the tissue surface comprises a skin surface.

7. The method of claim 6, wherein the target tissue is on the skin surface.

8. The method of claim 6, wherein the target tissue is below the skin surface.

9. The method of claim 1, wherein the tissue surface comprises an organ.

10. The method of claim 1, wherein the tissue surface comprises a tumor.- 43 -SG Docket No. 10860-741.60011. The method of claim 1, wherein the target tissue comprises thyroid tissue.

12. The method of claim 1, further comprising generating a treatment plan based at least in part on the ultrasound-visible marker.

13. The method of claim 12, wherein the treatment plan includes a target tissue volume populated with individual treatment locations.

14. The method of claim 12, wherein delivering histotripsy therapy to the target tissue further comprises delivering histotripsy therapy according to the treatment plan.

15. A histotripsy system, comprising: a marking device configured to apply a marking to a tissue location to define a treatment volume; an imaging system configured to identify the marking; a therapy transducer configured to deliver ultrasound pulses to or within the marking to generate cavitation within the treatment volume.

16. The system of claim 15, wherein the marking device is hand-held.

17. The system of claim 15, wherein the imaging system is hand-held.

18. The system of claim 15, wherein the therapy transducer is hand-held.

19. The system of claim 15, wherein the marking device, imaging system, and therapy transducer are integrated into a therapy probe.

20. The system of claim 19, wherein the therapy probe is coupled to a robotic arm.

21. The system of claim 20, further comprising one or more processors configured to control the therapy probe and the robotic arm to automatically deliver histotripsy therapy to the treatment volume using the marking.

22. The system of claim 15, wherein the marking is an ultrasound-visible marking.- 44 -SG Docket No. 10860-741.60023. The system of claim 15, wherein the marking is an ultrasound-visible sticker.

24. The system of claim 15, wherein the marking contains the treatment volume.

25. The system of claim 15, wherein the marking at least partially contains the treatment volume.

26. The system of claim 15, wherein the tissue location comprises a skin surface, and the treatment volume is disposed below the skin surface.

27. The system of claim 15, wherein the marking can include a treatment start point and end point.- 45 -SG Docket No. 10860-741.600

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