Histotripsy systems and associated methods including user interfaces and workflows for fluidic acoustic coupling

Abstract

A fluidic acoustic coupling system configured for management of fluids in histotripsy therapy is provided, which may include any number of features. Provided herein are systems and methods that provide management and control of fluid delivery and drainage of reservoirs within a fluidics cart of a histotripsy system. Additional embodiments are provided herein.

Description

HISTOTRIPSY SYSTEMS AND ASSOCIATED METHODS INCLUDING USER INTERFACES AND WORKFLOWS FOR FLUIDIC ACOUSTIC COUPLING PRIORITY CLAIM

[0001] This patent application claims priority to U.S. Provisional Patent Application No. 63 / 658,807, titled “HISTOTRIPSY SYSTEMS AND ASSOCIATED METHODS INCLUDING USER INTERFACES AND WORKFLOWS FOR FLUIDIC ACOUSTIC COUPLING,” and filed on June 11, 2024, which is herein incorporated by reference in its entirety. INCORPORATION BY REFERENCE

[0002] This application is related to International Patent Application No. PCT / US2024 / 025730, filed April 22, 2024, and U.S. Provisional Patent Appl. No. 63 / 649,153, filed May 17, 2024, incorporated by reference herein. 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. More specifically, the present disclosure related to fluid management and fluidic acoustic coupling in a histotripsy treatment system. 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 - 1 - SG Docket No.10860-734.600ablation. To operate within a non-thermal, Histotripsy realm; it is necessary to deliver acoustic energy in the form of high amplitude acoustic pulses with low duty cycle.

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

[0006] Transducer design and manufacturing for Histotripsy capable transducers is incredibly difficult to achieve. Currently, Histotripsy transducers are manufactured by shaping their piezoelectric composite and matching layer to the desired radius of curvature for the transducer design. Bulk piezoelectric and matching layer materials are both manufactured flat. The piezoelectric material is cut in two orthogonal directions to form a plurality of diced posts in the material, which are then filled with epoxy resin. This curving process can be very challenging due to the stress that it imparts on the composite structure. The cured or semi-cured epoxy needs to widen to accommodate the curving as the piezoelectric posts / pillars are rigid. Dis-bonding of the epoxy and piezoelectric post / pillar or crack formation can occur leading to physical or electrical failure of the structure.

[0007] Additionally, transducer frequency is dictated by composite thickness, therefore the likelihood of these failures to occur increases with a decrease in transducer frequency for a given transducer radius of curvature. As a result, prior therapy transducers are limited in the driving frequencies they can support, since lower therapy frequencies require thinner Also, there are similar limitations with respect to the percentage of the composite that is occupied by piezoelectric material. This is termed piezoelectric composite volume fraction. With a higher piezoelectric volume fraction there is less epoxy filler to widen during the curving process.

[0008] Histotripsy treatment systems often utilize or may require fluid for fluidic coupling of transducers and therapy pulse. Problematically, this requires management of fluid flow through reservoirs and fluid and drainage sources within a histotripsy system. What is needed is an efficient and controlled way to fill, drain, and move fluids within a histotripsy system and its reservoirs according to desired fluid parameters such as reservoir fill volumes. - 2 - SG Docket No.10860-734.600SUMMARY OF THE DISCLOSURE

[0009] A histotripsy system comprising: a coupling assembly comprising a container and a coupling membrane, the coupling assembling being configured to be filled with an acoustic coupling medium and to receive an ultrasound treatment head for histotripsy therapy; a fluidics cart comprising one or more fluid reservoirs, one or more tubing sets, and one or more pumps configured to move fluid between the at least one reservoir and the coupling assembly via the one or more tubing sets; a display; and a memory, storing thereon instructions that when executed by a processor operably connected to the memory cause the processor to: determine a volume status of the one or more fluid reservoirs and / or the coupling assembly; and present the volume status on the display.

[0010] In some aspects, the volume status comprises a volume of fluid in the one or more fluid reservoirs and a volume of fluid in the coupling assembly.

[0011] In one aspect, the one or more fluid reservoirs comprise a main reservoir and a waste reservoir.

[0012] In other aspects, the volume status comprises a volume of fluid in the main reservoir, a volume of fluid in the waste reservoir, and a volume of fluid in the coupling assembly.

[0013] In some aspects, the system includes one or more sensors operatively coupled to the one or more fluid reservoirs, the one or more sensors being configured to determine the volume status of the one or more fluid reservoirs. In some aspects, the one or more sensors comprise weight sensors or optical sensors. In other aspects, the processor is configured to determine the volume status based on the pump speed and or pump operation time.

[0014] In one aspect, the system includes a user-input device, wherein the processor is configured to receive, via the user interface, an input to move a pre-determined volume of fluid between the one or more fluid reservoirs and the coupling assembly. In some aspects, upon receiving the input, the processor is configured to control the one or more pumps to move the pre-determined volume of fluid between the one or more fluid reservoirs and the coupling assembly. Additionally, the processor can be configured to determine periodically repeat determining the volume status of the one or more fluid reservoirs and / or the coupling assembly and presenting the volume status on the display while the pre-determined volume of fluid is moved between the one or more fluid reservoirs and the coupling assembly. In some aspects, the processor is configured to present an icon on the display indicating a direction of fluid flow between the one or more fluid reservoirs and the coupling assembly.

[0015] In other aspects, the system includes a user-input device, wherein the processor is configured to receive, via the user interface, an input to move a pre-determined volume of - 3 - SG Docket No.10860-734.600fluid between the coupling assembly and the one or more reservoirs. In one aspect, upon receiving the input, the processor is configured to control the one or more pumps to move the pre-determined volume of fluid between the coupling assembly and the one or more reservoirs. In other aspects, the processor is configured to determine periodically repeat determining the volume status of the one or more fluid reservoirs and / or the coupling assembly and presenting the volume status on the display while the pre-determined volume of fluid is moved between the coupling assembly and the one or more reservoirs. in additional aspects, the processor is configured to present an icon on the display indicating a direction of fluid flow between the coupling assembly and the one or more reservoirs.

[0016] A histotripsy system is also provided, comprising: a coupling assembly comprising a container and a coupling membrane, the coupling assembling being configured to be filled with an acoustic coupling medium; a coupling assembly comprising a container and a coupling membrane, the coupling assembling being configured to be filled with an acoustic coupling medium and to receive an ultrasound treatment head for histotripsy therapy; a fluidics cart comprising one or more fluid reservoirs, one or more tubing sets, and one or more pumps configured to move fluid between the at least one reservoir and the coupling assembly via the one or more tubing sets; a display; and a memory, storing thereon instructions that when executed by a processor operably connected to the memory cause the processor to: determine a fluid parameter of fluid disposed in the one or more fluid reservoirs and / or the coupling assembly; and present the fluid parameter on the display.

[0017] In some aspects, the fluid parameter comprises a volume of fluid in the one or more fluid reservoirs and a volume of fluid in the coupling assembly. In other aspects, the fluid parameter comprises a temperature of fluid in the one or more fluid reservoirs and a volume of fluid in the coupling assembly. In additional aspects, the fluid parameter comprises a percentage of gas within the fluid in the one or more fluid reservoirs and a volume of fluid in the coupling assembly.

[0018] In one aspect, the one or more fluid reservoirs comprise a main reservoir and a waste reservoir.

[0019] In other aspects, the fluid parameter comprises a volume of fluid in the main reservoir, a volume of fluid in the waste reservoir, and a volume of fluid in the coupling assembly.

[0020] In some aspects, the system includes one or more sensors operatively coupled to the one or more fluid reservoirs, the one or more sensors being configured to determine the fluid parameter of the one or more fluid reservoirs. In some aspects, the one or more sensors - 4 - SG Docket No.10860-734.600comprise weight sensors or optical sensors. In other aspects, the processor is configured to determine the fluid parameter based on the pump speed and or pump operation time.

[0021] In one aspect, the system includes a user-input device, wherein the processor is configured to receive, via the user interface, an input to move a pre-determined volume of fluid between the one or more fluid reservoirs and the coupling assembly. In some aspects, upon receiving the input, the processor is configured to control the one or more pumps to move the pre-determined volume of fluid between the one or more fluid reservoirs and the coupling assembly. Additionally, the processor can be configured to determine periodically repeat determining the fluid parameter of the one or more fluid reservoirs and / or the coupling assembly and presenting the fluid parameter on the display while the pre-determined volume of fluid is moved between the one or more fluid reservoirs and the coupling assembly. In some aspects, the processor is configured to present an icon on the display indicating a direction of fluid flow between the one or more fluid reservoirs and the coupling assembly.

[0022] In other aspects, the system includes a user-input device, wherein the processor is configured to receive, via the user interface, an input to move a pre-determined volume of fluid between the coupling assembly and the one or more reservoirs. In one aspect, upon receiving the input, the processor is configured to control the one or more pumps to move the pre-determined volume of fluid between the coupling assembly and the one or more reservoirs. In other aspects, the processor is configured to determine periodically repeat determining the fluid parameter of the one or more fluid reservoirs and / or the coupling assembly and presenting the fluid parameter on the display while the pre-determined volume of fluid is moved between the coupling assembly and the one or more reservoirs. in additional aspects, the processor is configured to present an icon on the display indicating a direction of fluid flow between the coupling assembly and the one or more reservoirs.

[0023] A method of managing fluid between an ultrasound fluidics system and an ultrasound coupling assembly is provided, comprising: determining a first fluid parameter of fluid disposed in one or more fluid reservoirs of the ultrasound fluidics system; determining a second fluid parameter of fluid disposed in the ultrasound coupling assembly; and presenting the first and second fluid parameters on a display.

[0024] In some aspects, the first fluid parameter comprises a volume of fluid in the one or more fluid reservoirs, and the second fluid parameter comprises a volume of fluid in the coupling assembly.

[0025] In other aspects, the first fluid parameter comprises a temperature of fluid in the one or more fluid reservoirs, and the second fluid parameter comprises a volume of fluid in the coupling assembly. - 5 - SG Docket No.10860-734.600

[0026] In some aspects, the first fluid parameter comprises a percentage of gas within the fluid in the one or more fluid reservoirs and the second fluid parameter comprises a volume of fluid in the coupling assembly.

[0027] In one aspect, the one or more fluid reservoirs comprise a main reservoir and a waste reservoir.

[0028] In another aspect, the first fluid parameter comprises a volume of fluid in the main reservoir, further comprising a third fluid parameter that comprises a volume of fluid in the waste reservoir.

[0029] In another aspect, the method includes determining the first fluid parameter and the second fluid parameter with one or more sensors operatively coupled to the one or more fluid reservoirs.

[0030] In some aspects, the one or more sensors comprise weight sensors.

[0031] In other aspects, the one or more sensors comprise optical sensors.

[0032] In some aspects, the method comprises determining the first and second fluid parameters based on a pump speed and or pump operation time of one or more pumps of the ultrasound fluidics system.

[0033] In another aspect, the method includes receiving an input to move a pre- determined volume of fluid between the one or more fluid reservoirs and the coupling assembly.

[0034] In some aspects, the method comprises automatically moving the pre-determined volume of fluid between the one or more fluid reservoirs and the coupling assembly.

[0035] In other aspects, the method comprises periodically determining the first and second fluid parameters of the one or more fluid reservoirs and / or the coupling assembly and presenting the first and second fluid parameters on the display while the pre-determined volume of fluid is moved between the one or more fluid reservoirs and the coupling assembly.

[0036] In one aspect, the method comprises presenting an icon on the display indicating a direction of fluid flow between the one or more fluid reservoirs and the coupling assembly.

[0037] In another aspect, the method comprises receiving an input to move a pre- determined volume of fluid between the coupling assembly and the one or more reservoirs.

[0038] In some aspects, the method comprises moving the pre-determined volume of fluid between the coupling assembly and the one or more reservoirs.

[0039] In other aspects, the method comprises periodically determining the first and second fluid parameters of the one or more fluid reservoirs and / or the coupling assembly and - 6 - SG Docket No.10860-734.600presenting the first and second fluid parameters on the display while the pre-determined volume of fluid is moved between the coupling assembly and the one or more reservoirs.

[0040] The method can further comprise presenting an icon on the display indicating a direction of fluid flow between the coupling assembly and the one or more reservoirs.

[0041] An ultrasound coupling system is provided, comprising: a coupling assembly configured to be placed on a subject, the coupling assembly including an expandable membrane configured for contact with the subject’s skin; a fluidics system comprising a main tank, a drain tank, and a tubing set having first and second ports, and a degas system coupled to the tubing set, the fluidics system being configured to move a flow of fluid into the first port of the tubing set and out of the second port of the tubing set; a graphical user interface (GUI) operably connected to the fluidics system; a memory, storing thereon instructions that when executed by a processor operably connected to the memory in response to an input received by the GUI cause the fluidics system to perform one or more of the following processes: 1) filling the main tank of the fluidics system with fluid from a fluid source; 2) degassing the fluid in the main tank with the degas system; 3) filling the coupling assembly with fluid from the main tank; 4) degassing the fluid in the coupling assembly; 5) draining the fluid from the coupling assembly to the drain tank; 6) draining the fluid from the main tank, the drain tank, and / or the coupling assembly to an external location; wherein the instructions when executed by the processor are further configured to provide one or more graphical indications to a user on the GUI that include: a) providing visual or audible instructions on where to place the first and second ports of the tubing set; b) providing one or more volume indicators of a volume of fluid within the main tank, the drain tank, and / or the coupling assembly; c) providing one or more flow rate indicators of a rate of fluid flow through the tubing set; d) providing one or more concentration indicators of a gas concentration within the fluid in the main tank and / or the coupling assembly; and e) providing one or more directional indicators of a direction of fluid flow through the tubing set. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] 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:

[0043] FIG.1 illustrates an ultrasound imaging and therapy system.

[0044] FIG.2 is a bottom view of a therapy transducer and the imaging system of FIG.1. - 7 - SG Docket No.10860-734.600

[0045] FIGS.3A-3G illustrate one embodiment of a fluidics system that includes a fluidics cart.

[0046] FIG.4 is another embodiment of a fluidics system.

[0047] FIG.5 is a system diagram showing a histotripsy therapy system that includes a therapy cart, a fluidics cart, and a coupling system.

[0048] FIG.6 is another view of a coupling system of a histotripsy therapy system.

[0049] FIG.7 is a flow chart outlining method for initialization and set-up of fluidics acoustic coupling in the histotripsy system.

[0050] FIGS.8A-8X depict a series of user-interface images following the steps of the flowchart of FIG.7 in accordance with the disclosure. DETAILED DESCRIPTION

[0051] The system, methods and devices of the disclosure may be used for open surgical, minimally invasive surgical (laparoscopic and percutaneous), robotic surgical (integrated into a robotically-enabled medical system), endoscopic or completely transdermal extracorporeal non-invasive acoustic cavitation for the treatment of healthy, diseased and / or injured tissue including but not limited to tissue destruction, cutting, skeletonizing and ablation. Furthermore, due to tissue selective properties, histotripsy may be used to create a cytoskeleton that allows for subsequent tissue regeneration either de novo or through the application of stem cells and other adjuvants. Finally, histotripsy can be used to cause the release of delivered agents such as chemotherapy and immunotherapy by locally causing the release of these agents by the application of acoustic energy to the targets.

[0052] 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 sub- system (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 for fluid storage, de- - 8 - SG Docket No.10860-734.600oxygenation, filling and emptying of the Coupling sub-system. It may also contain various power supplies and protectors.

[0053] 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 ultrasound, C-arm, fluoroscope, cone beam CT, MRI, etc., to provide real-time imaging during histotripsy therapy. In some embodiments, the histotripsy system can be sized and configured to fit within a C-arm, fluoroscope, cone beam CT, MRI, etc. HISTOTRIPSY

[0054] 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.

[0055] 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. - 9 - SG Docket No.10860-734.600

[0056] 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.

[0057] 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.

[0058] 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”.

[0059] Shock scattering waveforms can include a leading negative half cycle, a peak positive half cycle, a peak negative half cycle, and a trailing peak positive half cycle. The trailing peak positive cycle can have 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 - 10 - SG Docket No.10860-734.600transducer. 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 intense shock front developed by nonlinear propagation, no dense bubble clouds are generated when the peak negative half- cycles are below the intrinsic threshold.

[0060] 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”.

[0061] 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.

[0062] 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.” THERAPY COMPONENTS - 11 - SG Docket No.10860-734.600

[0063] As will be described below, the acoustic cavitation system may include various sub-systems, including a Generator, Therapy transducer array, Therapy Cart, 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 / cloud connectivity, power supplies, displays, drawers / storage, doors, wheels, and various simulation and training tools, etc. All systems, methods and techniques for creating / controlling / delivering histotripsy are considered to be a part of this disclosure, including new related inventions disclosed herein.

[0064] 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. Therapy Cart

[0065] FIG.1 generally illustrates histotripsy system 100 according to the present disclosure, comprising a therapy transducer 102, an imaging system 104, a display and control panel 106, a robotic positioning arm 108, and a cart 110. The system can further include an ultrasound coupling interface and a source of coupling medium, not shown.

[0066] FIG.2 is a bottom view of a therapy transducer 202 and imaging system 204. As shown, the imaging system can be positioned in the center of the therapy transducer. However, other embodiments can include the imaging system positioned in other locations within the therapy transducer, or even directly integrated into the therapy transducer. In some embodiments, the imaging system is configured to produce real-time imaging at a focal point of the therapy transducer. The system also allows for multiple imaging transducers to be located within the therapy transducer to provide multiple views of the target tissue simultaneously and to integrate these images into a single 3-D image. Generator

[0067] 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. The generators, amplifiers, power supplies, and other associated electronics may be disposed or contained within, for example, the cart discussed above. - 12 - SG Docket No.10860-734.600

[0068] In some embodiments, the function generator may comprise a field programmable gate array (FPGA) or other suitable function generator. The FPGA may be configured with parameters disclosed previously herein, including but not limited to frequency, pulse repetition frequency, bursts, burst numbers, where bursts may comprise pulses, numbers of pulses, length of pulses, pulse period, delays, burst repetition frequency or period, where sets of bursts may comprise a parameter set, where loop sets may comprise various parameter sets, with or without delays, or varied delays, where multiple loop sets may be 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.

[0069] 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.

[0070] 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.

[0071] 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. - 13 - SG Docket No.10860-734.600

[0072] 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 L1 in series and the capacitor C1 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. General Therapy Transducer

[0073] The therapy transducer, such as therapy transducer 202, 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 piezo-electric 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.

[0074] 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.

[0075] 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 - 14 - SG Docket No.10860-734.600different imaging probes may interface and integrate with a therapy transducer in specifically different ways).

[0076] Therapy transducers may be configured of various parameters that may include size, shape (e.g., rectangular or round; anatomically curved housings, linear or flat array / housing 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.

[0077] Transducers may be designed and optimized for clinical applications (e.g., abdominal tumors, peripheral vascular disease, fat ablation, etc.) and desired outcomes (e.g., acoustic cavitation / histotripsy without thermal injury to intervening tissue), and affording a breadth of working ranges, including relatively shallow and superficial targets (e.g., thyroid or breast nodules), versus, deeper or harder to reach targets, such as central liver or brain tumors. They may be configured to enable acoustic cavitation / histotripsy under various parameters and sets of, as enabled by the aforementioned system components (e.g., function generator and amplifier, etc.), including but not limited to frequency, pulse repetition rate, pulses, number of pulses, pulse length, pulse period, delays, repetitions, sync delays, sync period, sync pulses, sync pulse delays, various loop sets, others, and permutations of. 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

[0078] 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 - 15 - SG Docket No.10860-734.600displayed 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.

[0079] 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. For example, integrated imaging probe or system 304 described above may comprise an ultrasound imaging probe disposed within a bore of the therapy transducer. The aforementioned components may be also integrated into the system’s Therapy sub-system components wherein probes, imaging arrays, or the like, and electrically, mechanically or electromechanically integrated into therapy transducers. This may afford, in part, the ability to have geometrically aligned imaging and therapy, with the therapy directly within the field of view, and in some cases in line, with imaging. In some embodiments, this integration may comprise a fixed orientation of the imaging capability (e.g., imaging probe) in context to the therapy transducer. In other embodiments, the imaging solution may be able to move or adjust its position, including modifying angle, extension (e.g., distance from 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.

[0080] 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, semi- automated or in fully automated means image the patient (e.g., by hand or using a robotically- enabled imager).

[0081] 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., - 16 - SG Docket No.10860-734.600ultrasound 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).

[0082] In some embodiments, imaging including feedback and monitoring from backscatter from bubble clouds, may be used as a method to determine immediately if the histotripsy process has been initiated, is being properly maintained, or even if it has been extinguished. For example, this method enables continuously monitored in real time drug delivery, tissue erosion, and the like. The method also can provide feedback permitting the histotripsy process to be initiated at a higher intensity and maintained at a much lower intensity. For example, backscatter feedback can be monitored by any transducer or ultrasonic imager. By measuring feedback for the therapy transducer, an accessory transducer can send out interrogation pulses or be configured to passively detect cavitation. Moreover, the nature of the feedback received can be used to adjust acoustic parameters (and associated system parameters) to optimize the drug delivery and / or tissue erosion process.

[0083] In some embodiments, imaging including feedback and monitoring from backscatter, and speckle reduction, may be configured in the system.

[0084] 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.

[0085] 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 - 17 - SG Docket No.10860-734.600may be changed sufficiently to be detected by signal processing and other means. This family of techniques can operate as detectors of speckle statistics changes. For example, the size and position of one or more speckles in an image will begin to decorrelate before observable speckle reduction occurs. Speckle decorrelation, after appropriate motion compensation, can be a sensitive measure of the mechanical disruption of the tissues, and thus a measure of therapeutic efficacy. This feedback and monitoring technique may permit early observation of changes resulting from the acoustic cavitation / histotripsy process and can identify changes in tissue before substantial or complete tissue effect (e.g., erosion occurs). In one embodiment, this method may be used to monitor the acoustic cavitation / histotripsy process for enhanced drug delivery where treatment sites / tissue is temporally disrupted, and tissue damage / erosion is not desired. In other embodiments, this may comprise speckle decorrelation by movement of scatters in an increasingly fluidized therapy volume. For example, in the case where partial or complete tissue erosion is desired.

[0086] 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.

[0087] 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 - 18 - SG Docket No.10860-734.600disappearance 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.

[0088] 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 change during treatment. Analysis of these changes, and their correlation to therapeutic efficacy, enables monitoring of the progress of therapy, and may be configured as a feature of the system.

[0089] 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.

[0090] 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. - 19 - SG Docket No.10860-734.600

[0091] 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 marked tumor. The system may comprise the ability to register various image sets, including those previously disclosed, to one another, as well as to afford navigation and localization (e.g., of a therapy transducer to a CT or MRI / ultrasound fusion image with the therapy transducer and Robotics sub-system tracking to said image).

[0092] 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 sub- systems integrated and operated from said navigation or laparoscopic system). - 20 - SG Docket No.10860-734.600

[0093] The system may also be configured, through various aforementioned parameters and other parameters, to display real-time visualization of a bubble cloud in a spatial- temporal manner, including the resulting tissue effect peri / post-treatment from tissue / bubble cloud interaction, wherein the system can dynamically image and visualize, and display, the bubble cloud, and any changes to it (e.g., decreasing or increasing echogenicity), which may include intensity, shape, size, location, morphology, persistence, etc. These features may allow users to continuously track and follow the treatment in real-time in one integrated procedure and interface / system, and confirm treatment safety and efficacy on the fly (versus other interventional or surgical modalities, which either require multiple procedures to achieve the same, or where the treatment effect is not visible in real-time (e.g., radiation therapy), or where it is not possible to achieve such (e.g., real-time visualization of local tissue during thermal ablation), and / or where the other procedure further require invasive approaches (e.g., incisions or punctures) and iterative imaging in a scanner between procedure steps (e.g., CT or MRI scanning). The above disclosed systems, sub-systems, components, modalities, features and work-flows / methods of use may be implemented in 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. Robotic Arms and Positioning Systems

[0094] The system may comprise various robotic sub-systems and components, including but not limited to, one or more robotic arms, such as robotic positioning arm 308, 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.

[0095] 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.

[0096] 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.

[0097] 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, - 21 - SG Docket No.10860-734.600implemented 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.

[0098] 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.

[0099] Position may be configured to comprise fixed positions, pallet positions, time- controlled positions, distance-controlled positions, variable-time controlled positions, variable-distance controlled positions.

[0100] Tracking may be configured to comprise time-controlled tracking and / or distance- controlled tracking.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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 - 22 - SG Docket No.10860-734.600the position of the robotic arm to be modified relative to the patient, patient surface, cart, coupling sub-system, additional robots / robotic arms and / or additional surgical systems, including but not limited to, surgical towers, imaging systems, endoscopic / laparoscopic systems, and / or other.

[0105] 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.

[0106] 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. OTHER COMPONENTS, ANCILLARIES AND ACCESSORIES

[0107] The system may comprise various other components, ancillaries and accessories, including but not limited to computers, computer processors, power supplies including high - 23 - SG Docket No.10860-734.600voltage 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. USE ENVIRONMENTS

[0108] 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. HISTOTRIPSY SOFTWARE TOOLS AND SYSTEMS

[0109] 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 sub-systems, including but not limited to therapy, integrated imaging, robotics and other components, fluidics cart, ancillaries and accessories of the system.

[0110] 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 - 24 - SG Docket No.10860-734.600for 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.).

[0111] 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.

[0112] 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. - 25 - SG Docket No.10860-734.600

[0113] 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).

[0114] 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.

[0115] Software may also be configured, by working with computer processors and one or more function generators, amplifiers and therapy transducers, to allow various permutations of delivering and positioning optimized acoustic cavitation / histotripsy in and through a selected area / volume. This may include, but not limited to, systems configured with a fixed / natural focus arrangement using purely electromechanical positioning configuration(s), electronic beam steering (with or without electromechanical positioning), electronic beam steering to a new selected fixed focus with further electromechanical positioning, axial (Z axis) electronic beam steering with lateral (X and Y) 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). - 26 - SG Docket No.10860-734.600

[0116] 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 optimal 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.

[0117] 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.

[0118] Pre-operative imaging, co-registration, and evaluation

[0119] 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 and after 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 pre-operative imaging.

[0120] 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 - 27 - SG Docket No.10860-734.600imaging 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 the 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-registration.

[0121] Additional systems, methods and parameters to deliver optimized histotripsy, using shock scattering, intrinsic threshold, and various parameters enabling frequency compounding and bubble manipulation, are herein included as part of the system and methods disclosed herein, including additional means of controlling said histotripsy effect as pertains to steering and positioning the focus, and concurrently managing tissue effects (e.g., prefocal thermal collateral damage) at the treatment site or within intervening tissue. Further, it is disclosed that the various systems and methods, which may include a plurality of parameters, such as but not limited to, frequency, operating frequency, center frequency, pulse repetition frequency, pulses, bursts, number of pulses, cycles, length of pulses, amplitude of pulses, pulse period, delays, burst repetition frequency, sets of the former, loops of multiple sets, loops of multiple and / or different sets, sets of loops, and various combinations or permutations of, etc., are included as a part of this disclosure, including future envisioned embodiments of such. SYSTEM VARIATIONS AND METHODS / APPLICATIONS

[0122] 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 - 28 - SG Docket No.10860-734.600parameters 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.

[0123] Feedback may include various energy, power, location, position, tissue and / or other parameters.

[0124] The system, and the above feedback, may also be further configured and used to autonomously (and robotically) execute the delivery of the optimized treatment plan and protocol, as visualized under real-time imaging during the procedure, allowing the user to directly observe the local treatment tissue effect, as it progresses through treatment, and start / stop / modify treatment at their discretion. Both test and treatment protocols may be updated over the course of the procedure at the direction of the user, or in some embodiments, based on logic embedded within the system.

[0125] 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.

[0126] 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).

[0127] 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 - 29 - SG Docket No.10860-734.600cavitation / 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.).

[0128] 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, immuno- oncology, 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.

[0129] 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.

[0130] Coupling

[0131] Systems may comprise a variety of coupling sub-system embodiments, of which are enabled and configured to allow acoustic coupling to the patient to afford effective acoustic access for ultrasound visualization and acoustic cavitation / histotripsy (e.g., provide acoustic window and medium between the transducer(s) and patient, and support of). These may include different form factors of such, including open and enclosed device solutions, and some arrangements which may be configured to allow dynamic control over the acoustic medium (e.g., temperature, dissolved gas content, level of particulate filtration, sterility, volume, composition, etc.). Such dynamic control components may be directly integrated to the system (within the cart), or may be in temporary / intermittent or continuous communication with the system, but externally situated in a separate device and / or cart.

[0132] 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 such as a frame(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.

[0133] The reservoir or coupling container may be formed and shaped to various sizes and shapes, and to adapt / conform to the patient, allow the therapy transducer to - 30 - SG Docket No.10860-734.600engage / access and work within the acoustic medium, per defined and required working space (e.g., 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.

[0134] 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(described herein). 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.

[0135] 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 - 31 - SG Docket No.10860-734.600electromechanical 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.

[0136] 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.

[0137] Disclosed herein are histotripsy acoustic and patient coupling systems and methods, to enable histotripsy therapy / treatment, as envisioned in any setting, from interventional suite, operating room, hybrid suites, imaging centers, medical centers, office settings, mobile treatment centers, and / or others, as non-limiting examples. The following disclosure further describes novel systems used to create, control, maintain, modify / enhance, monitor and setup / takedown acoustic and patient coupling systems, in a variety of approaches, methods, environments, architectures and work-flows. In general, the disclosed novel systems may allow for a coupling medium, in some examples degassed water, to be interfaced between a histotripsy therapy transducer and a patient, wherein the acoustic medium provides sufficient acoustic coupling to said patient, allowing the delivery of histotripsy pulses through a user desired treatment location (and volume), where the delivery may require physically moving the histotripsy therapy transducer within a defined work- space comprising the coupling medium, and also where the coupling system is configured to allow said movement of the therapy transducer (and positioning system, e.g., robot) freely and unencumbered from by the coupling support system (e.g., a frame or manifold holding the coupling medium). Membranes / Barrier Films and Related Architectures

[0138] As described herein, in one embodiment, the reservoir or medium container contains a 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.

[0139] Disclosed membranes may be comprised of various elastomers, viscoelastic polymers, thermoplastics, thermoplastic elastomers, thermoset polymers, silicones, urethanes, - 32 - SG Docket No.10860-734.600rigid / 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 pre- shaped 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.

[0140] 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.

[0141] 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.

[0142] Membrane and barrier film materials may comprise flexible and elastomeric biocompatible materials / polymers, such as various thermoplastic and thermoset materials, as well as permanent or bioresorbable polymers. Additionally, the frame of the coupling - 33 - SG Docket No.10860-734.600container can also comprise the same materials. In some examples, the membrane may be rigid or semi-rigid polymers which are pre-shaped or flat. Mechanical Support Arms and Architectures

[0143] Coupling support systems may additionally 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.

[0144] 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.

[0145] 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.

[0146] Arms are also be configured to interface proximally to a main support base or base interface (e.g., robot, table, table / bed rail, cart, floor mount, etc.) and distally to the frame / assembly and overall coupling assembly. This specific distal interface may further include features for controlling position / orientation of the frame / assembly, at the frame / assembly interface.

[0147] 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. - 34 - SG Docket No.10860-734.600

[0148] Support arms, configured with arm wrists, further interfaced with frames / assemblies, may comprise features such as brakes, including cable or electronic actuated brakes, and quick releases, which may interact with one or more axis, individually, or in groupings. They may also include electronic lift systems and base supports. In some embodiments, these lift systems / base supports are co-located with robot arm bases, wherein said robot arm is equipped with the histotripsy therapy transducer configured to fit / work within the enclosed coupling solution. In other embodiments, the support arm is located on a separate cart. In some cases, the separate cart may comprise a fluidics system or user console. In other embodiments, it is interfaced to a bed / table, including but not limited to 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.

[0149] 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. Ultrasound Medium

[0150] As previously described, the ultrasound medium may comprise any applicable medium capable of providing sufficient and useful acoustic coupling to allow histotripsy treatments and enable sufficient clinical imaging (e.g., ultrasound). Ultrasound mediums, as a part of this disclosure and system, may comprise, but are not limited to, various aqueous solutions / mediums, including mixtures with other co-soluble fluids, of which may have preferred or more preferred acoustic qualities, including ability to match speed of sound, etc. Example mediums may comprise degassed water and / or mixtures / co-solutions of degassed water and various alcohols, such as ethanol. Fluidics Systems, Control Systems, and Architectures

[0151] 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, - 35 - SG Docket No.10860-734.600dispense / fill, and retrieve / drain coupling medium to / from the frame / assembly. The fluidics system may include an emergency high flow rate system for rapid draining of the coupling medium from the coupling assembly. In some embodiments, the fluidics system can be configured for a single use of the coupling medium, or alternatively, for re-use of the medium. In some embodiments, the fluidics system can implement positive air pressure or vacuum to carry out leak tests of the UMC and membrane prior to filling with a coupling medium. Vacuum assist can also be used for removal of air from the coupling assembly during the filling process. The fluidics system can further include filters configured to prevent particulate contamination from reaching the coupling assembly.

[0152] The fluidics system may implemented in the form of a mobile fluidics cart as discussed above. 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.

[0153] In alternate embodiments, a fluidics system may not be utilized but rather, the coupling medium can be provided in pre-filled containers or through a wall unit where the coupling medium can be dispensed from a water line and filled by hand or other non- automated means into the coupling container. COUPLING AND FLUIDICS SYSTEM AND SUB-SYSTEMS / COMPONENTS

[0154] 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 a degassed coupling medium. The fluidics system may include the ability to degas, chill, monitor, adjust, dispense / fill, and retrieve / drain coupling medium to / from the coupling frame / assembly.

[0155] The fluidics system may include an emergency high flow rate system for rapid filling and draining of the coupling medium from the coupling assembly. The fluidics system may be configured to fill the coupling assembly with fluid on demand, or with predetermined fill amounts (e.g., automatic fill of a present volume of fluid such as 1L, 3L 6L, 9L, etc.).

[0156] In some implementations, the fluidics system is configured to connect to or receive fluid from a fluid source such as tap water. The fluidics system can include a degas system or mechanism such as a degas membrane that can be configured to degas fluid as it flows from the fluid source into the fluid tank of the fluidics system. The degas system can be further configured to degas the fluid as it flows from the fluid tank to the coupling - 36 - SG Docket No.10860-734.600assembly. In some implementations, the fluid is degassed to a first degas threshold while the fluid tank is filled from the fluid source, and held at the first degas threshold. The fluidics system can then further degas the fluid as it is transferred from the fluid tank to the coupling assembly (e.g., to a second degas threshold). In some embodiments, the fluidics system can run a degas cycle while fluid is in the fluid tank, circulating the fluids through a degassing membrane / filter.

[0157] In some embodiments, the fluidics system can be configured for a single use of the coupling medium, or alternatively, for re-use of the medium. In some embodiments, the fluidics system can implement positive air pressure or vacuum to carry out leak tests of the coupling assembly and membrane prior to filling with a coupling medium. Vacuum assist can also be used for removal of air from the coupling assembly during the filling process. The fluidics system can further include filters configured to prevent particulate contamination from reaching the coupling assembly.

[0158] The fluidics system may implemented in the form of a mobile fluidics cart. The fluidics cart may comprise a main 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 fluidics 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 work-space for a therapy transducer).

[0159] The fluidics cart may be powered through standard electrical service / connectors, as well as with a battery to allow for portable or off-grid use. The battery may also provide emergency power. The fluidics cart may also comprise a nitrogen tank and / or air compressor (not shown) for allowing blow down of the main / drain tubing to enable ensuring they are maintained dry / clean (under a nitrogen blanket). In some examples, the fluidics cart may include various processors or electronic controllers configured for programming / monitoring / reporting water status and parameters. Parameters may include oxygen saturation, temperature, particulate debris, pH, mix ratio, flow rate, fill level, power level / battery level, etc., which can be detected in real-time by any number of sensors disposed within and around the system. The parameters may be read out on a UI screen on the fluidics cart, and / or may be displayed / controlled on the therapy system cart display (through software UI).

[0160] The degassing module may contain filters or degassing membranes configured to remove particulate / debris, a de-gas contactor and a vacuum or peristaltic pump to move fluid through the system. In some examples, filters may be 0.2 micron in pore size. The de-gas - 37 - SG Docket No.10860-734.600contactor may be able to pull down to parts per billion, with around 3 gallon per minute flow, and capable of removing dissolved O2, CO2 and N2 gas. Vacuum pumps may include key features such as pure transfer and evacuation, high compatibility with vapors and condensation, chemical resistance, and gas tight (very low leakage). In some examples, vacuum pumps are cable of pulling down to 8 torr. In some embodiments, the degassing system can omit the pump and can rely on the water source flow rate (e.g., tap water flow rate) to move the fluid through the system.

[0161] The tubing / connectors / lines, plastic and / or metallic, are configured to allow fluid and air communication through the system and overall acoustic / patient coupling system. These may also contain various components such as valves (e.g., two way, three way, etc.).

[0162] The electronic and manual controls provide system and user-facing system controls over all the functions of the system, including but not limited to pump and de- gassing controls. The control systems may further comprise various sensors, in-line and onboard, for sensing temperature, pressure, flow rate, dissolved oxygen concentration, volume, etc.

[0163] The fluidics system / cart may also have various electrical connections for power including leveraging external power, and / or may comprise a battery / toroid for enabling a detethered fully mobile configuration. This allows the fluidics cart to be wheeled up to prepare / set up a histotripsy procedure, and then wheel away once all fluidics related work- flow steps are complete, so as to not require the fluidics cart to be patient side during treatment / therapy.

[0164] The fluidics cart architecture and design may also include handles, individual or central locking casters, a top work surface, embedded user display devices, connectivity (e.g., ethernet, etc.), and may be designed to allow further integration of the support arm in some embodiments. It may also be outfitted with long / extended tubing to support intra-imaging system filling / draining, if for example, use within a CT or MRI, is desirable, so as to not have the overall medium / water volume in close proximity to the scanner, and / or filling during set up is required to further assess image / body divergence pre / post filling.

[0165] FIGS.3A-3G illustrate one embodiment of a fluidics cart 310 of a fluidics system. Referring to FIG.3A, the fluidics cart 310 can be mobile (e.g., includes wheels) to allow clinicians to prepare acoustic coupling medium and transport it from a clinical water source (e.g., house tap water or other) and to / around the procedure room. The fluidics cart 310 can also include wheel locks 354 (FIG.3J) for locking or restricting motion of up to four wheels.

[0166] The fluidics cart 310 can include a main fluid tank 320 (here with optional lid 330) which can be positioned centrally within the fluidics cart, and a drain tank 321 (also - 38 - SG Docket No.10860-734.600with optional lid 332) which can also be positioned centrally or on a side of / within the cart and below the main tank as shown. The drain tank can optionally include a drawer slide for drain tank access / removal. In some embodiments, the main tank can have a volume sufficient to store and provide fluid for more than one histotripsy therapy procedure. For example, if an acoustic coupling assembly of a histotripsy system requires an acoustic coupling medium volume of 10L for a histotripsy procedure, then the main tank 320 may be configured to store a volume of 30-40L or more (e.g., 3-4 procedures worth) of fluid. The drain tank 321 can be of similar volume to the main tank, or alternatively, the drain tank can be of a size sufficient to hold only the volume of fluid from a single procedure since the drain / waste fluid is typically removed and disposed of after each procedure. Therefore, in some embodiments, the drain tank may have a volume ranging from only 10-15L.

[0167] In some embodiments, the main fluid tank can include a mirror or other reflective surface positioned at a bottom of the tank (not shown). This mirror can be used for various system set-up procedures and / or to visualize a histotripsy therapy head when positioned within the main tank. The ability to position and visualize the therapy head within the main tank can be useful to perform diagnostic or calibration procedures of the histotripsy therapy system prior to filling an acoustic coupling assembly within a membrane and positioning a patient for a procedure.

[0168] In FIG.3A, the fluidics cart 310 can further include a main compartment 322 and a drain compartment 324 which can house the pump(s) and other system components for the main tank and drain tank, respectively. The compartments 322 and 324 can be, for example, doors, hatches, or panels that can be removed or opened to access the components within. The fluidics cart can further include one or more grooves or cutouts 345 / 347 extending from one or more of compartments 322 and / or 324 to the main tank to accommodate tubing sets for filling and draining the main tank, as will be discussed in more detail below. The fluidics cart 310 can further include a UI / GUI 326, and a handle or rail system 328 for maneuvering the cart. The UI / GUI can include a display and any combination of touch screen controls via the display and physical controls such as knobs, buttons, levers, or switches, as shown. The rail system 328 is positioned on a top portion of the fluidics cart and extends in a circular or squircle configuration. The rail can extend around an upper perimeter of the cart continuously or non-continuously from a first side of the UI to a second side of the UI. The fluidics cart also includes four wheels and up to four wheel locks for movement of the cart and locking the cart in place during placement, filling, circulation or emptying steps. In particular, two of the wheels, which may be the two front wheels, may include a directional - 39 - SG Docket No.10860-734.600lock to assist in movement / mobility of the fluidics cart. In particular, the pedals or brakes may be depressed to initiate a two wheel directional lock.

[0169] FIG.3B is an exploded view of the fluidics cart 310, with the main compartment / panel 332 and optional drain compartment panel (not shown) removed. Here, the main tank 320 and drain tank 321 are shown outside of the cart, with optional mirror 377 shown at the bottom of the main tank. Optional mirror 321 may be used during system check on the treatment head. The tanks can include optional lids 330 and 332. Behind the main compartment is a main pump 334 and main cartridge 335 which is removably attachable to the main pump. The main cartridge can be a disposable element that can be configured to snap, or pressure fit into place within the cart. In some embodiments, the main cartridge 335 can include main tubing set 340 and a degas mechanism / membrane 338. The degas mechanism 338 can comprise a silicone hollow fiber membrane, for example. The degas mechanism 338 may also include a vacuum (not shown), which can be configured to assist in removing gas from the fluid. Attachment of the main cartridge to the cart automatically places the main pump 334 in communication with the main tubing set 340, allowing the main pump to push a flow of fluid through the main tubing set in both directions. Similarly, behind the drain compartment 324 is a drain pump 336 and drain cartridge 337, which can include a drain pump 336 and a drain tubing set 342. As with the main cartridge, the drain cartridge 337 can snap or pressure fit into place behind the drain compartment to place the drain tubing set 342 in communication with the drain pump 336 for creating a flow of fluid in the drain tubing set in either direction. The pumps can be, for example, peristaltic pumps configured to mechanically interface with a tubing set to move fluid within the tubing set. It should be noted that in some embodiments, there is no degas mechanism / membrane in the drain cartridge 337 or behind the drain compartment 324, as all degas functions can be performed via the degas mechanism / membrane 338.

[0170] The fluidics cart can include a number of sensors to monitor parameters of the cart and / or the fluid contained within the cart. In some embodiments, the fluidics cart can include weight and / or fluid level sensors 323 on both the main tank and the drain tank. For example, weight or fluid sensors may be incorporated into a tray or platform that supports the main or drain tanks. Alternatively, optical or fluid level sensors can be incorporated into the cavity of the cart to measure a fluid level in one or both tanks as well as the patient membrane. In particular, a weight sensor can be utilized when initially filling the main tank, communicating with the user when about 30L, 20L which in embodiments may be less, or a pre-set volume of fluid has been achieved / placed in the main tank. The cart can also include pressure sensors, at least in the main tank but optionally in the drain tank. In some implementations, - 40 - SG Docket No.10860-734.600fluid delivery into / out of the main and drain tanks can be confirmed or calculated by some combination of the weight sensors, fill level sensors, and or pump speed / operation time.

[0171] In some aspects, the system can determine the minimum fill level of the ultrasound coupling container based on a digital treatment plan of a planned histotripsy procedure. The treatment plan can include information that includes the size of the target tissue, the location / depth of the target tissue, and a treatment pathway through which the ultrasound treatment head / therapy transducer must be moved within the coupling container to be able to target each focal location within the target tissue. The treatment plan determines the overall physical movement of the treatment head, via the robotic arm, and therefore can be used to determine the minimum fill level (or volume) of acoustic fluid to transfer from the fluidics art into the coupling container.

[0172] In one example, the fluid volume held within an acoustic coupling membrane can be calculated and displayed to the user. Optionally flow sensors can be disposed within the tubing set(s) to measure or calculate the volume of fluid in the tank. For example, flow sensors in the main tubing set and drain tubing set can measure flow in and out of the main tank which can be used to determine the current volume of fluid in the tank. Additionally, conductivity or other sensors may optionally be used within the fluid tank to measure the percentage or amount of gas within the fluid. Further, temperature sensors may also be employed in the fluidics cart for measuring fluid temperature. In embodiments, a thermocouple may be disposed in the main tank for measuring temperature, which may be displayed to the user via the UI. If desired, thermocouples or other temperature sensors can be placed on a distal portion of the attachment features such that temperature can also be monitored in the acoustic coupling assembly. Further, the fluidics cart may also be configured to display elapsed time since last degas to the user via the UI.

[0173] The main fluid tank may include features to allow for disruption or recirculation of the fluid within the tank. In some embodiments, fins, rotors, or fluid / gas / air streams may be implemented to cause the fluid to circulate or mix within the tank.

[0174] FIG.3C is a diagram of another embodiment of the fluidics cart 310 with main tubing set 340 and drain tubing set 342. While this embodiment shows the tubing sets as being integrated into the cart (e.g., permanently affixed), it should be understood that in other embodiments the tubing sets can be disposable and included on disposable cartridges (such as cartridges 335 and 337 of FIG.3B). The main tubing set 340 can be operatively coupled to degas mechanism / membrane 338 and main pump 334. The drain tubing set 342 can be operatively coupled to the drain pump 336. As shown, the main tubing set 340 can include a first input / output port 344 having a free end which can be removably attached to a water - 41 - SG Docket No.10860-734.600source (e.g., tap water), the main tank 320, or the coupling assembly. This end of the first input / output port 344 is considered a free end and may move between various components of the histotripsy system (e.g., between the fluidics cart and the coupling assembly. The main tubing set 340 also includes a second input / output port 346 which can be removably or fixedly attached or coupled to the main tank 320 of the fluidics cart 310. Here, the first input / output port 344 and second input / output port 346 are shown residing in grooves or cutouts 345 / 347, respectively. In one example, the first input / output port is disposed on a longer length of the main tubing set as compared to the second input / output port, which is disposed on a shorter length of the main tubing set.

[0175] While the main pump 334 and drain pump 336 are shown attached to the cart in this embodiment, in other embodiments the main and drain pumps can be removably attached to the cart (e.g., disposable).

[0176] When the main pump 334 operates in a first operating direction or in a fill mode of operation, fluid can flow from a fluid source (e.g., tap water source) into the first input / output port 344 and through the main tubing set 340, flow through the degas mechanism 338, and exit out of second input / output port 346 into the main tank 320. In this configuration, the first input / output port functions as an input port and the second input / output port functions as an output port. As fluid passes through the main tubing set 340 and through the degas mechanism 338, a specified or set percentage of remaining gas (e.g., dissolved Oxygen) is removed from the fluid. In one embodiment, the degas mechanism 338 is configured to remove between 20-40% of remaining gas from the fluid.

[0177] When the main pump 334 operates a second operating direction (e.g., opposite the first operating direction) or a fluid transfer mode of operation, fluid can flow from the main tank 320 into the second input / output port 346 and into the main tubing set 340, flow through the degas mechanism 338, and exit out of first input / output port 344. This configuration may be used, for example, when the first input / output port is attached to the coupling assembly prior to a histotripsy procedure. In this configuration, the first input / output port functions as an output port and the second input / output port functions as an input port. In particular, fluid may be moved or transferred from the fluidics cart and into the coupling assembly or any other desired container in preparation for a histotripsy procedure.

[0178] The drain tubing set 342 can include an input / output port 348 including a free end which can be removably attached to the fluidics cart and other sources of fluid such as the coupling assembly or drain tank 321.

[0179] Additionally, when the drain pump 336 operates a first operating direction or a drain fill mode of operation, fluid can flow from a fluid source (e.g., the acoustic coupling - 42 - SG Docket No.10860-734.600assembly) into the input / output port 348 and through the drain tubing set 342, and exit out of drain tubing set 340 into the drain tank 321. This configuration may be used, for example, when the input / output port 348 is placed in the acoustic coupling assembly after a histotripsy procedure to drain the used coupling medium from the acoustic coupling assembly into the drain tank. In this configuration, the input / output port 348 functions as an input port.

[0180] When the drain pump 336 operates a second operating direction or a drain empty mode of operation (e.g., opposite the first operating direction), fluid can flow from the drain tank 321 through the drain tubing set 342, and exit out of the input / output port 348. This configuration may be used, for example, when the drain tank is full and must be drained (e.g., into a sink / drain / basin or other permanent waste receptacle). In this configuration, the input / output port 348 functions as an output port. In some examples, the tubing sets can further include attachment features which can be used to attach the input / output ports (e.g., the free ends) of each tubing set to the fluidics cart, fluid source (e.g., tap water source), and / or the coupling assembly. For example, attachment features on the first input / output port 344 and second input / output port of the main tubing set 340 can be used to secure the free ends of the main tubing set to the fluidics cart and direct the input / output port(s) within the main tank.

[0181] FIGS.3D-3E illustrate one example of the first input / output port 344 attached to the main tank 320 of the fluidics cart with one or more attachment features 350. FIGS.3F- 3G illustrate another example of the first input / output port 344 attached to a coupling assembly 312. As shown in FIG.3E, the attachment feature(s) 350 can include one or more clips or other mechanical interfaces between the first input / output port 344 and one or more tanks or containers, including the main tank, the drainage tank, and / or the coupling assembly. In some embodiments, the main tank, drain tank, or coupling assembly 312 may include corresponding attachment points where the attachment features of the input / output ports are configured to attach. The interface between the attachment features and the attachment points may be designed and configured to cause the input / output port to assume a preferred orientation or angle when attached. For example, referring to FIGS.3D-3E, the attachment features may include a first attachment point 351 configured to engage with the main tank to cause the input / output port to maintain a vertical configuration when mounted to the main tank. This can advantageously position a distal end and any fluid ports 349 of the input / output port along a side of the main tank and towards the bottom of the main tank. Alternatively, referring to FIGS.3F-3G, the attachment features may include a second attachment point 353 configured to interface with the coupling assembly to cause the - 43 - SG Docket No.10860-734.600input / output port to maintain an angled orientation that matches an angle of the sidewalls of the coupling assembly 312.

[0182] As shown in FIGS.3D-3G, the main tank, drain tank, and / or coupling assembly can include one or more attachment points which receive an attachment feature of the main tubing set to direct the input / output ports of the main tubing set into either the main tank or the coupling assembly. It should be noted that the attachment feature is configured such that the main tubing set can attach to both the fluidics cart and the coupling assembly securely. In particular, in some embodiments the input / output ports include a shroud 352 which extends beyond and covers an end portion of the main tubing set. This shrouded configuration of the input / output ports can direct the fluid flow exiting the main tubing set to a 90 degree bend or angle. This 90 degree angle also facilitates circulation of the fluid within the main tank during a circulation cycle. Although 90 degrees is preferred, other angles and geometries are envisioned such that water circulation within the main tank is optimal. In some embodiments, the cart itself has a corresponding feature configured to receive or interface with the attachment features of the main and drain tubing sets.

[0183] The drain tubing set may also be used with an attachment feature which may be the same or different than the main tubing set attachment feature(s). The attachment feature will enable the drain tubing set to attach to the coupling assembly.

[0184] Referring still to FIGS.3A-3G, operation of the fluidics cart will now be discussed. When the fluidics cart and particularly the main tank 320 is empty, the first input / output port 344 of the main tubing set 340 can be detached from the cart 310 and coupled to a fluid source such as a tap water source. For example, in some embodiments the first input / output port 344 of the main tubing set can be attached or coupled directly to a faucet or spigot. Alternatively, the first input / output port can be submerged in a volume of fluid (e.g., in a bucket or other container filled with water or any other fluid medium). Next, during the fill mode of operation, the main pump 334 can be controlled (e.g., from the GUI) to operate in a first direction to pull fluid from the inlet / outlet of the main tubing set 340 through the degas mechanism / membrane 338 and into the main tank via the second input / output port 346. During this fill operation, the degas mechanism / membrane 338 can be configured to remove a first percentage of gas from the fluid as it is entering the main tank.

[0185] Once the main fluid tank 320 is full or sufficiently full (e.g., a desired volume of fluid has been filled into the main tank), the first input / output port 344 can be reattached to the cart and the fluidics cart can enter a standby or ready configuration in which the fluid within the tank may be maintained at a specific temperature and with a specified gas percentage. In some embodiments, the fluidics cart can recirculate the fluid within the main - 44 - SG Docket No.10860-734.600tank during this standby or circulation configuration. During this circulation configuration, the fluidics cart can run a recirculation cycle in which the pump 334 can operate in the first operating direction to pull fluid from the main tank into the first input / output port 344, through the degas mechanism 338, and back into the main tank via the second input / output port 346. Alternatively, the pump 334 can operate in a second operating direction to pull fluid from the main tank into the second input / output port 346, through the degas mechanism 338, and back into the main tank via the first input / output port 344. The recirculation cycle can be set to run either on a time basis, volume basis or degas until a low enough percentage of dissolved oxygen remains in the system. In some embodiments, this can be a closed loop process in which oxygen or gas sensors in the fluid tank can measure the percentage of dissolved oxygen in the tank and automatically run the circulation configuration to maintain the desired oxygen percentage in the fluid. In some embodiments, this recirculation or degassing cycle may run on regular intervals or for a specific amount of time if the fluidics cart system has been idle.

[0186] For example, during each degassing or recirculation cycle, about 20-40 percent, and in some embodiments, about 30 percent of remaining gas will be removed from the fluid. For example, if a fluid in the main tank has about 80 percent of gas (e.g., dissolved Oxygen), 30 percent of 80% (80*.30=24) which is 24% of the gas will be removed from the fluid. Prior to the next degassing cycle, the fluid will have 56 percent of gas. Upon completion of a subsequent degassing (below described), 30 percent of the remaining 56 percent of gas will be removed from the fluid.

[0187] In another example, during at least a first and optionally third degassing or recirculation cycle, about 20-40 percent of the remaining gas will be removed from the fluid. A second degassing or recirculation cycle may remove about 60-80 percent of the remaining gas (from the start of the second cycle) from the fluid. This second cycle may run for a longer period or length of time to remove a higher percentage of remaining gas.

[0188] Prior to a histotripsy procedure, the fluidics cart can be moved or positioned adjacent to a coupling assembly of the histotripsy system. The main tubing set can be removed from the cart and attached to or placed within the coupling assembly. A user can then initiate filling of the coupling assembly from the main tank of the fluidics cart with the fluid transfer mode of operation. In some implementations, the filling can be initiated via the UI / GUI of the fluidics or therapy cart. The filling can be manual (e.g., the user can determine when to terminate filling) or can be automated and terminated automatically when a desired volume of fluid is transferred. In one example, the user can provide an input to the fluidics cart to deliver a bolus or pre-determined volume of fluid from the cart to the coupling - 45 - SG Docket No.10860-734.600assembly. For example, if the coupling assembly requires 10L for filling, then the fluidics cart can automatically deliver the required amount and terminate filling when the amount is delivered. This volume or bolus can be verified / confirmed with the sensors mentioned above. In some embodiments, multiple different boluses or pre-determined volumes can be delivered via the UI / GUI (e.g., 1L, 3L, 6L, or any other volume). In some embodiments, the user can program or specify a user-selected bolus or volume to be delivered from the cart to the coupling assembly.

[0189] Filling of the coupling assembly from the fluidics cart can be performed with the main pump 334 operating in a second direction (e.g., opposite the first direction during the fill main tank procedure above). While the fluidics cart is filling the coupling assembly, the fluid will flow from the main tank 320 through the degassing mechanism / membrane 338 for another degassing cycle. This additional flow of fluid through the degassing mechanism / membrane 338 allows the system to remove additional gas from the fluid (e.g., removing another percentage of gas from the fluid). coupling assembly during a procedure in the event that more fluid is needed within the coupling assembly. In other embodiments, the main tubing set and attachment feature will be removed from the coupling assembly after the coupling assembly has been filled to an acceptable volume. The fluidics cart, however main remain nearby or near the procedure site in the event more fluid is needed to fill the coupling assembly.

[0190] After a histotripsy procedure is performed, the fluidics cart 310 can be used to remove the used fluid from the coupling assembly. To do so, the inlet / outlet of the drain hose 342 can be removed from the cart and placed in the coupling assembly. Next, the drain pump 336 can operate to pull fluid from the coupling assembly into the drain tank 321. As with the fill procedures described above, sensors in the cart and / or drain tank 321 can measure or calculate the volume of fluid removed from the coupling assembly. In some embodiments, the fluid removed from the coupling assembly can be compared to the fluid added to the coupling assembly during the fill procedure. It should be noted that the volumes may not match up due to spillage or other methods in which fluid has been displaced from the coupling assembly, unless the coupling assembly is a sealed system. After the coupling assembly is drained, the drain hose can be re-attached to the cart.

[0191] In a subsequent step, after all histotripsy procedures have been completed, any remaining water in the fluidics tank, including both the main tank and the drain tank can be emptied. Free ends of both the drain tubing set and the main tubing set can be placed in a sink, waste bucket or otherwise near a drain for disposal of any remaining fluids. Once the tubes are positioned for emptying, in a single step, the user may direct the UI to drain or - 46 - SG Docket No.10860-734.600empty the fluidic cart of all fluids. Simultaneously, both the drain and main tanks can be emptied and optionally drain tubes can be disposed of. Alternatively, the drain tank 321 can be removed for proper disposal of the waste fluid.

[0192] FIG.4 is an alternative design of a fluidics cart 410 which can include any of the features described above and can be assumed to function similarly with similar names / reference numbers unless expressly described differently, including a main tank 420, a drain tank 421, first and second input / output ports 444, 446, first and second pumps 434 / 436, and a GUI 426 that can include any combination of physical and / or touch screen inputs along with a display.

[0193] 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 at least FIG.5, 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.

[0194] 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).

[0195] 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.

[0196] FIG.5 illustrates one embodiment of a histotripsy therapy and imaging system 500, including a coupling assembly 501. As described above, a histotripsy therapy and imaging system can include a therapy transducer 502, an imaging system 504, a robotic positioning arm 508, and a fluidics cart 510. The robotic positioning arm may be attached to a therapy cart, such as cart 509.

[0197] The therapy and / or imaging transducers can be disposed within the coupling assembly 501 which can further include a coupling membrane 514 and a membrane constraint 516 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 - 47 - SG Docket No.10860-734.600a 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 501 is supported by a mechanical support arm 518 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 510. The mechanical support is designed and configured to conform and hold the coupling membrane 514 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 514 with the robotic positioning arm 508.

[0198] The fluidics cart 510 can include additional features, including a fluid tank 520, 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.

[0199] FIG.6 illustrates one embodiment of a constraint device 622 coupled to a coupling assembly 601 having a frame body 624 with a patient laying on a patient portion of the constraint device. Particularly, at least some of the attachment features 626 of the coupling assembly are positioned through some of the openings 628 of the peripheral portion 630 of the constraint device 622 to attach (i.e., hang, suspend, connect) the constraint device to the coupling assembly. The coupling membrane can be expanded as the coupling assembly 601 is filled with an ultrasound coupling medium M for acoustic coupling to an ultrasound transducer array. In this example, the stiffness or flexibility of the membrane constraint relative to the stiffness or flexibility of the coupling membrane prevents overexpansion of the coupling membrane. In particular, the stiffness or flexibility or the membrane constraint is less flexible and has a lower % elongation compared to the coupling membrane.

[0200] The flared, angled, or curved edges of the peripheral portions of the constraint device allow for the constraint device to be attached at various points along the coupling assembly while also maintaining a close fit to the contours of the patient. Depending on the location of the target tissue, the patient may be positioned on his or her back, stomach, or side. The flared peripheral portions provide flexibility in how the constraint is attached to the coupling assembly, enabling a variety patient positions, treatment head locations, and coupling assembly locations. - 48 - SG Docket No.10860-734.600USER INTERFACES AND WORKFLOWS FOR FLUIDIC ACOUSTIC COUPLING

[0201] FIG.7 is a flow chart outlining method 700 for initialization and set-up of fluidics acoustic coupling in the histotripsy system.

[0202] According to certain examples, fluidics acoustic coupling in the histotripsy system is managed via fluidics cart 310 (see FIGS.3A-3C).

[0203] At step 702 following powering on of the histotripsy system 100, the software is initialized, which may optionally require input of log-in credentials to the computing device housed in the cart 310 (FIGS.3A-3C).

[0204] Once initialized, the software conducts a system / connection check at step 704, which may include checking fluidics status of basins and various tanks and hose connections. The results of the system / connection check displayed on the user interface such as 326 (FIG. 3A). As described herein below, the fluid should be understood to be the acoustic coupling medium.

[0205] At step 706, one end of main tubing set 340 (FIG.3C) may be connected to a fluid source (e.g., sink) and the other end positioned / connected at a reservoir such as main tank 320 (FIG.3A).

[0206] Next, fill / other parameters may be set at step 708 such as a desired fill volume and options for auto-fill vs. manual fill, or when to pause / restart a fill. In some examples, at step 708 additional or other parameters such as auto-drain, manual drain, when to pause / restart a drain, degassing, or even toggling between filling / draining / degassing within the system may be set.

[0207] Initiation of filling (of acoustic coupling medium within) the system / main tank 320 (FIG.3A) may occur at step 710, according to the fill / other parameters from step 708.

[0208] The acoustic coupling medium within the system may be degassed at step 712, for example via degas mechanism / membrane 338 described in FIG.3B, which may be a vacuum to remove gas or air bubbles from fluid in main tubing set 340 (FIG.3C).

[0209] At step 714, main tubing set 340 (FIG.3C) may be repositioned to connect to a membrane of the coupling assembly instead of main tank 320 (FIG.3A).

[0210] At step 716, the membrane may be filled with the acoustic coupling medium according to the fill / other parameters from step 708.

[0211] At step 718, one end of drain tubing set 342 (FIG.3C) may be connected to a waste container or drain tank 321 (FIG.3A) for draining the membrane.

[0212] Draining of the membrane may occur at step 720.

[0213] At step 722, drain tubing set 342 (FIG.3C) may be repositioned with one end connected to a sink / drain / basin or other permanent waste receptacle, and the other end - 49 - SG Docket No.10860-734.600positioned / connected at the drain tank 321 (FIG.3A) or main tank 320 (FIG.3A) for draining the system.

[0214] At step 724, the system is drained.

[0215] At step 726, it is determined if the system is fully drained or drained to a desired amount, for example according to other parameters pre-defined at step 708. If yes, then the workflow ends. If not, the system may continue draining step 724. Alternatively, if the system is drained, the main tubing set 340 (FIG.3C) may be repositioned / connected at main tank 320 (FIG.3A) to fill the system again at step 710.

[0216] As noted above, this is a high-level description of the process, and further details are provided below in context with their relevant figures.

[0217] FIGS.8A-8X depict a series of user-interface images following the steps of the flowchart of FIG.7 in accordance with the disclosure.

[0218] As shown in FIG.8A, user interface (UI) 800A depicts a graphical representation 810 of the fluidics acoustic coupling system / cart 310 from FIGS.3A-3C. The graphical representation 810 may be displayed following, for example, software initialization 702, system / connection check 704, connecting main tubing to fluid source 706, and setting fill / other parameters 708 steps from FIG.7. Graphical representation 810 of fluidics cart includes a main tank 820 and drain tank 821 (corresponding to main tank 420 and drain tank 421 from FIG.4). Other parameters are also shown including last system degas status 850, water temperature reading 851 of the fluid in the fluidics cart 310 (FIGS.3A-3C), and the fluidics cart’s battery charge status 852. A help icon 853 is also shown which may be selected to display user instructions and explanations.

[0219] The UI 800A can include one or more user input icons, including for example Fill System icon 802, Degas icon, Fill Membrane icon, Drain Membrane icon, and Drain System icon. In the illustrated example, only Fill System icon 802 is available for interaction by a user. In some examples, icons that are available to be interacted with or selected by a user can be highlighted, illuminated, or presented in a manner that is distinguishable from non- selectable icons, which can be greyed out, dimmed, or hidden. While the icons in this example are shown as part of a graphical user interface, it should be understood that in other embodiments the icons and their functions can be implemented as physical buttons or inputs on the system. In this example, pressing Fill System icon 802 will initiate a procedure that fills the main tank 820 of the fluidics cart.

[0220] FIG.8B shows UI 800B including graphical representation 840 of main tubing set 342 (FIG.3C), after receiving an input from the user to fill the main tank of the fluidics cart. Main tubing set 840 is shown coupling main tank 820 to a fluid source 899. In some - 50 - SG Docket No.10860-734.600examples, fluid source 899 is a sink or any other source of fluid, such as a hose, faucet, hospital water supply, or external tanks or reservoirs of fluid or water. The graphical representation 840 of main tubing set is shown indicating the proper positioning of the main tubing set, including the positioning or coupling of a first input / output port positioned at the fluid source 899 and a second input / output port positioned in the main tank 820.

[0221] Also shown is start fill icon 803 which may be selected to initiate filling of main tank 820. In particular, this step should be initiated after the tubing sets have been connected to the sink or other fluid source 899. In certain examples, start fill icon 803 may be selected or clicked once to be automatically filled to a pre-determined volume, or may not be needed and the entire process of filling and draining the reservoirs of the fluidics cart may be automated, as well as connecting and repositioning hoses such as main tubing set 840 and other tubing sets such as drain tubing set (not shown). In yet other examples, start fill icon 903 may be held to manually fill main tank 820 or other reservoirs of the fluidics cart. Arrows 842A show a direction of fluid flow through main tubing set from fluid source 899 to main tank 820. Also shown is menu icon 804 to return to a menu screen, for example to access settings for fill parameters or various menu features for managing and viewing reservoir volume status in fluidics cart 310 (FIGS.3A-3C).

[0222] FIG.8C shows UI 800C with graphical representation of an animation for active filling 840F of main tank 820 from fluid source 899. In certain examples, filling may be paused and restarted by selecting pause fill icon 806. In some examples, fluid volume in main tank 820 may be updated in real-time. In some embodiments, the pre-determined volume can be displayed alongside the current or real-time volume of the main tank. This can provide an indication to the user as to the progress of filling the main tank.

[0223] FIG.8D shows UI 800D with graphical representation of main tank 820 filled to a pre-determined or desire volume, such as 32.0 L, at which filling of main tank 820 stops or is paused as indicated by icon 840S. In some examples, this pre-determined or desired volume is user-configurable and the desired volume may be based on a specified number of histotripsy procedures. In other embodiments, the volume is determined based on the size of the coupling container. In certain examples such as a manual fill situation, icon 840S or a start / continue fill icon (not shown) may be selected to continue filling main tank 820 or other reservoirs of the fluidics cart beyond a current volume.

[0224] FIG.8E shows UI 800E with graphical representation of main tank 820 filled to a pre-determined or desire volume, such as 32.0 L, at which filling of main tank 820 has ended and is not re-activatable to continue filling, for example in an auto-fill setting, so as to prevent overfilling the coupling container and causing a spilling or flooding issue. With the - 51 - SG Docket No.10860-734.600main tank 820 fully filled to the desired volume, a user can selected the Main Menu icon 804 to return to the main menu.

[0225] FIG.8F shows UI 800F after filling the main tank 820 and returning to the main menu, with graphical representation of a coupling membrane 814 such as membrane 514 (FIG.5), here empty at a volume of 0.0 L, and a degas icon 807 which may be selected to remove gas and air bubbles out of fluid in main tank 820 and / or main tubing set 842 as they enter main tank 820 or are recirculated from main tank 820 through main tubing set 842, as previously described via degas mechanism 338 (FIGS.3B). Also shown is a drain system icon 808 to empty the membrane, the main tank 820, and / or drain tank 821 into drain or sink 899.

[0226] FIG.8G shows UI 800G with graphical representation of a degas mechanism 807M fluidly coupled to main tank 820 and / or main tubing set 840. In this example, the main tubing set 840 is shown with both the first and second input / output ports inserted into the main tank 820, indicating to the user the proper positioning of the main tubing set for a degas procedure. Start Degas icon 807S may be selected to begin degassing. Also shown is estimated or actual degassing time 807T. It should be noted that more than one degassing cycle may be selected to achieve a maximum oxygenation of the fluid.

[0227] FIG.8H shows UI 800H with graphical representation of active degassing of fluid in main tank 820 via main tubing set 840 represented by animation 807D, which can comprise for example spinning or rotating arrows to indicate fluid circulating through the main tubing set. Pause degas icon 807P may be selected by a user at any time during this process to stop degassing. Also shown is estimated or actual degassing time 807T, which in some examples may be updated in real-time. In some examples, the percentage of gas in the main tank can be presented in real-time to the user during this operation.

[0228] FIG.8I shows UI 800I with graphical representation of fluidics acoustic coupling system after degassing and returning to the main menu. Last degas status 850 and water temperature reading 851 have been updated. In this example, the last degas procedure was completed 3 minutes prior. At this stage in the process, the user can select another degas process via Degas icon 807, can choose to fill membrane 814 via Fill Membrane icon 815, or can drain the main tank 820 via Drain System icon 808.

[0229] FIG.8J shows UI 800J after selecting the Fill Membrane icon 815, with graphical representation of coupling membrane 814 ready to be filled with fluid from the main tank 820. A graphical representation of the main tubing set 842 shows coupling between the main tank 820 and membrane 814, which shows a first input / output port in the membrane / coupling container and a second input / output port in the main tank 820. The volume of fluid to be - 52 - SG Docket No.10860-734.600transferred from the main tank 820 to the membrane may be set or selected by the user under fill membrane icon 815F, here set at an exemplary volume of 4.0 L. Icons such as arrows may be interacted with by the user to adjust the volume of fluid. The membrane may be auto- filled 815FA or manually filled 815FM. Automatically filling the membrane 814 will transfer a pre-selected or pre-determined volume indicated by fill membrane icon 815F, while manually filling the membrane will transfer fluid as long as the user interacts with the Manually Fill icon 815FM. As an example shown here, main tank 820 has a volume of 32.0 L and membrane 814 is empty with 0.0 L fluid volume. In some embodiments, the fill volume can be displayed alongside the current or real-time volume of the coupling membrane / coupling assembly. This can provide an indication to the user as to the progress of filling the coupling membrane.

[0230] FIG.8K shows UI 800K with graphical representation of coupling membrane 814 undergoing active filling represented by animation 815AF as main tank 820 is drained. Arrows represent direction of fluid flow 815A through main tubing set 841 from main tank 820 to coupling membrane 814. Volume readings in main tank 820 and membrane 814 may be updated in real-time. Filling of membrane 814 may be paused by selecting pause fill icon 815P.

[0231] FIG.8L shows UI 800L with graphical representation of a coupling membrane 814 filled to a pre-set volume, such as 4.0L, with filling of membrane 814 stopped upon reaching the pre-set volume. The volume of main tank 820 drained to fill membrane 814 has been updated, in this case to 28.0 L. The user icons Auto Fill 815FA, Manually Fill 815FM, and Main Menu 804 are available to the user, to either continue filling the membrane or return to the main menu.

[0232] FIG.8M shows UI 800M with graphical representation of a coupling membrane 814 further filled after being filled to a pre-set volume, such as 4.0L. For example membrane 814 is further manually filled or may be auto-filled to a larger volume, with active filling represented by animation 815AF. The volumes of main tank 820 and membrane 814 have been updated, in this case to 19.4 L and 12.6 L, respectively, to represent the increased fill volume in the membrane and reduced volume in the main tank.

[0233] FIG.8N shows UI 800N with graphical representation of a coupling membrane 814 filled to an additional desired volume, here 12.6 L, by draining main tank 820. Volume of main tank 820 has been updated to 19.4 L. In this example, active filling animation 815AF is no longer shown, indicating that the system is no longer active filling. The user icons Auto Fill 815FA, Manually Fill 815FM, and Main Menu 804 are available to the user, to either continue filling the membrane or return to the main menu. - 53 - SG Docket No.10860-734.600

[0234] FIG.8O shows UI 800O with graphical representation of coupling membrane 814 filled and ready for a procedure, such as a histotripsy procedure. In this example, the membrane is filled to the desired volume and the graphical representation of the main tubing set is removed, indicating to a user to remove the tubing set from the membrane / coupling container for the procedure. Next, a treatment head is lowered into the acoustic coupling assembly, at least a portion of the treatment head is submerged within the acoustic coupling medium. The treatment head may include an indicated submerge marking. If the water volume within the membrane is in contact with or above the indicated marking, the user may select to fill additional fluid from the main tank into the membrane 814. Once an acceptable fluid volume has been determined, the histotripsy procedure can be performed. After the procedure has been completed, the user can choose to drain the membrane / coupling container, for example via selecting drain membrane icon 808. In some embodiments, fluid within the membrane 814 may be drained to drain tank 821 within the fluidics cart. Alternatively, for example, if a patient requires repositioning prior to a second histotripsy procedure, the fluid volume within the membrane may need to be increased or decreased to support partial submersion of the treatment head within the acoustic coupling medium. In one example, the fluid may be partially drained, patient repositioned for a subsequent histotripsy procedure, and the user may select to add back into the coupling membrane 814.

[0235] FIG.8P shows UI 800P with graphical representation of a coupling membrane 814 coupled to drain tank 821 for draining, for example via membrane drain tubing set 843. In this example, the graphical representation of the main tubing set can show first input / output port disposed within drain tank 821 and second input / output port positioned within membrane / coupling container. Draining 808 of membrane 814 may be automated 808AD or manually drained 808MD by selecting the appropriate icon. Drain tank 821 is shown empty with a volume of 0.0 L and membrane 814 holds an exemplary volume of 12.6 L before draining.

[0236] FIG.8Q shows UI 800Q with graphical representation of active draining of coupling membrane 814 by animation 808AD, which is coupled to drain tank 821 for draining, for example via membrane drain tubing set 843. Drain tank 821 is shown empty with a volume of 0.0 L and membrane 814 holds an exemplary volume of 12.6 L as draining begins. Arrows 808A show the flow of draining fluid from membrane 814 to drain tank 821. Draining may be paused and restarted via pause drain icon 808PD, for example in a manual drain setting.

[0237] FIG.8R shows UI 800R with graphical representation of a coupling membrane 814 coupled to drain tank 821 with completed draining of membrane 814 into drain tank 821. - 54 - SG Docket No.10860-734.600Drain tank 821 now holds a volume of 12.6 L of fluid and membrane 814 is empty with 0.0 L volume of fluid. The user can select to continue manual draining via Manually Drain icon 808MD or return to the main menu with Main Menu icon 804.

[0238] FIG.8S shows UI 800S with graphical representation of a snapshot of the fluidics acoustic coupling system / cart after a procedure and after a draining operation from the membrane to the drain tank. The UI 800S shows various menu options such as fill system 802, degas 807, fill membrane 815, drain membrane 808, and drain system 898. Main tank 820 is shown holding 19.4 L of fluid. Membrane 814 is empty at 0.0 L. Drain tank 821 holds 12.6 L of fluid. Also shown is sink / basin or fluid source 899. In this example, since the fluidics cart still includes a volume of fluid (e.g., 19.4L remaining), the fluidics cart is available for another histotripsy procedure, or alternatively, can be fully drained via Drain System icon 898.

[0239] FIG.8T shows UI 800T with graphical representation of a snapshot of the fluidics cart and portions of the acoustic coupling assembly after selecting the Drain System icon, showing various menu options related to draining main tank 820 and drain tank 821 to drain fluidics cart 410 (FIG.4). Various menu options may include system icon 800SS to for example display an overview of the fluidics cart, system check 800SC to check volume status in various components of the system, waste 800W which may give information about drain tank 821, and main menu 800MM which may display or expand the various menu options. Main tank 820 is shown holding 19.4 L of fluid, with drain tank 921 holding 12.6 L of fluid. A graphical representation of main tubing set and drain tubing set are shown for the Drain procedure, including coupling the input / output ports of the main tubing set between the main tank and the sink / basin or drain and the input / output ports of the drain tubing set between the waste tank and the sink / basin or drain, which may drain the fluid of main tank 820 and drain tank 821 via one or more tubing sets.

[0240] FIG.8U shows UI 800U with graphical representation of the fluidics system / cart and the membrane / frame during draining. Main tank 820 is shown holding 19.4 L of fluid. Drain tank 921 holds 12.6 L of fluid. Also shown is sink 899, which is draining the fluid of main tank 820 and drain tank 821 via one or more drain tubing sets 843. The direction of fluid drainage from main tank 820 to sink 899 is indicated by arrow 898MA and active drainage along this path is represented by animation 898ADMT. The direction of fluid drainage from waste tank 821 to sink 899 is indicated by arrow 898WA and active drainage along this path is represented by animation 898ADW. Active drainage 898ADMT and / or 898ADW may be paused and restarted simultaneously or individually via selecting a pause - 55 - SG Docket No.10860-734.600drain icon 898P or animation icon(s) 898ADW / 898ADMT, for example in a manual setting. In some examples, drainage may be automated.

[0241] FIG.8V shows UI 800V with graphical representation of the fluidics system / cart of FIG.8U during a pause in system draining, specifically a pause 898PDMT in draining volume from main tank 820 into sink 899. In such an example, UI 800V may only allow drainage and drainage control of this fluid path, for example via pause drainage icon 898P.

[0242] FIG.8W shows UI 800W with graphical representation of the fluidics system / cart of FIG.8U during active draining, specifically active draining 898ADW from drain tank 821 into sink 899. In such an example, UI 800V may only allow drainage and drainage control of this fluid path, for example via pause drainage icon 898P.

[0243] FIG.8X shows UI 800X with graphical representation of the fluidics system / cart completely drained. As shown here, main tank 820, drain tank 821, and membrane 814 are emptied with 0.0 L of fluid displayed. Drain tubing sets have been removed. The system / cart may be filled again by connecting main tube set 840 to reservoirs of the fluidics cart such as main tank 820 or membrane 814 and navigating the various UIs described.

[0244] As for additional details pertinent to the present invention, materials and manufacturing techniques may be employed as within the level of those with skill in the relevant art. The same may hold true with respect to method-based aspects of the invention in terms of additional acts commonly or logically employed. Also, it is contemplated that any optional feature of the inventive variations described may be set forth and claimed independently, or in combination with any one or more of the features described herein. Likewise, reference to a singular item includes the possibility that there are plural of the same items present. More specifically, as used herein and in the appended claims, the singular forms “a,” “and,” “said,” and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation. Unless defined otherwise herein, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The breadth of the present invention is not to be limited by the subject specification, but rather only by the plain meaning of the claim terms employed. - 56 - SG Docket No.10860-734.600

Claims

CLAIMS What is claimed is:

1. A histotripsy system comprising: a coupling assembly comprising a container and a coupling membrane, the coupling assembling being configured to be filled with an acoustic coupling medium and to receive an ultrasound treatment head for histotripsy therapy; a fluidics cart comprising one or more fluid reservoirs, one or more tubing sets, and one or more pumps configured to move fluid between the at least one reservoir and the coupling assembly via the one or more tubing sets; a display; and a memory, storing thereon instructions that when executed by a processor operably connected to the memory cause the processor to: determine a volume status of the one or more fluid reservoirs and / or the coupling assembly; and present the volume status on the display.

2. The system of claim 1, wherein the volume status comprises a volume of fluid in the one or more fluid reservoirs and a volume of fluid in the coupling assembly.

3. The system of claim 1, wherein the one or more fluid reservoirs comprise a main reservoir and a waste reservoir.

4. The system of claim 3, wherein the volume status comprises a volume of fluid in the main reservoir, a volume of fluid in the waste reservoir, and a volume of fluid in the coupling assembly.

5. The system of claim 1, comprising one or more sensors operatively coupled to the one or more fluid reservoirs, the one or more sensors being configured to determine the volume status of the one or more fluid reservoirs.

6. The system of claim 5, wherein the one or more sensors comprise weight sensors.

7. The system of claim 5, wherein the one or more sensors comprise optical sensors. - 57 - SG Docket No.10860-734.6008. The system of claim 1, wherein the processor is configured to determine the volume status based on the pump speed and or pump operation time.

9. The system of claim 1, further comprising a user-input device, wherein the processor is configured to receive, via the user interface, an input to move a pre-determined volume of fluid between the one or more fluid reservoirs and the coupling assembly.

10. The system of claim 9, wherein, upon receiving the input, the processor is configured to control the one or more pumps to move the pre-determined volume of fluid between the one or more fluid reservoirs and the coupling assembly.

11. The system of claim 10, wherein the processor is configured to determine periodically repeat determining the volume status of the one or more fluid reservoirs and / or the coupling assembly and presenting the volume status on the display while the pre-determined volume of fluid is moved between the one or more fluid reservoirs and the coupling assembly.

12. The system of claim 10, wherein the processor is configured to present an icon on the display indicating a direction of fluid flow between the one or more fluid reservoirs and the coupling assembly.

13. The system of claim 1, further comprising a user-input device, wherein the processor is configured to receive, via the user interface, an input to move a pre-determined volume of fluid between the coupling assembly and the one or more reservoirs.

14. The system of claim 13, wherein, upon receiving the input, the processor is configured to control the one or more pumps to move the pre-determined volume of fluid between the coupling assembly and the one or more reservoirs.

15. The system of claim 14, wherein the processor is configured to determine periodically repeat determining the volume status of the one or more fluid reservoirs and / or the coupling assembly and presenting the volume status on the display while the pre-determined volume of fluid is moved between the coupling assembly and the one or more reservoirs. - 58 - SG Docket No.10860-734.60016. The system of claim 14, wherein the processor is configured to present an icon on the display, indicating a direction of fluid flow between the coupling assembly and the one or more reservoirs.

17. A histotripsy system comprising: a coupling assembly comprising a container and a coupling membrane, the coupling assembling being configured to be filled with an acoustic coupling medium; a coupling assembly comprising a container and a coupling membrane, the coupling assembling being configured to be filled with an acoustic coupling medium and to receive an ultrasound treatment head for histotripsy therapy; a fluidics cart comprising one or more fluid reservoirs, one or more tubing sets, and one or more pumps configured to move fluid between the at least one reservoir and the coupling assembly via the one or more tubing sets; a display; and a memory, storing thereon instructions that when executed by a processor operably connected to the memory cause the processor to: determine a fluid parameter of fluid disposed in the one or more fluid reservoirs and / or the coupling assembly; and present the fluid parameter on the display.

18. The system of claim 17, wherein the fluid parameter comprises a volume of fluid in the one or more fluid reservoirs and a volume of fluid in the coupling assembly.

19. The system of claim 17, wherein the fluid parameter comprises a temperature of fluid in the one or more fluid reservoirs and a volume of fluid in the coupling assembly.

20. The system of claim 17, wherein the fluid parameter comprises a percentage of gas within the fluid in the one or more fluid reservoirs and a volume of fluid in the coupling assembly.

21. The system of claim 17, wherein the one or more fluid reservoirs comprise a main reservoir and a waste reservoir. - 59 - SG Docket No.10860-734.60022. The system of claim 21, wherein the fluid parameter comprises a volume of fluid in the main reservoir, a volume of fluid in the waste reservoir, and a volume of fluid in the coupling assembly.

23. The system of claim 17, comprising one or more sensors operatively coupled to the one or more fluid reservoirs, the one or more sensors being configured to determine the fluid parameter of the one or more fluid reservoirs.

24. The system of claim 23, wherein the one or more sensors comprise weight sensors.

25. The system of claim 23, wherein the one or more sensors comprise optical sensors.

26. The system of claim 17, wherein the processor is configured to determine the fluid parameter based on the pump speed and or pump operation time.

27. The system of claim 17, further comprising a user-input device, wherein the processor is configured to receive, via the user interface, an input to move a pre-determined volume of fluid between the one or more fluid reservoirs and the coupling assembly.

28. The system of claim 27, wherein, upon receiving the input, the processor is configured to control the one or more pumps to move the pre-determined volume of fluid between the one or more fluid reservoirs and the coupling assembly.

29. The system of claim 28, wherein the processor is configured to determine periodically repeat determining the fluid parameter of the one or more fluid reservoirs and / or the coupling assembly and presenting the fluid parameter on the display while the pre-determined volume of fluid is moved between the one or more fluid reservoirs and the coupling assembly.

30. The system of claim 28, wherein the processor is configured to present an icon on the display indicating a direction of fluid flow between the one or more fluid reservoirs and the coupling assembly.

31. The system of claim 17, further comprising a user-input device, wherein the processor is configured to receive, via the user interface, an input to move a pre-determined volume of fluid between the coupling assembly and the one or more reservoirs. - 60 - SG Docket No.10860-734.60032. The system of claim 31, wherein, upon receiving the input, the processor is configured to control the one or more pumps to move the pre-determined volume of fluid between the coupling assembly and the one or more reservoirs.

33. The system of claim 32, wherein the processor is configured to determine periodically repeat determining the fluid parameter of the one or more fluid reservoirs and / or the coupling assembly and presenting the fluid parameter on the display while the pre-determined volume of fluid is moved between the coupling assembly and the one or more reservoirs.

34. The system of claim 32, wherein the processor is configured to present an icon on the display indicating a direction of fluid flow between the coupling assembly and the one or more reservoirs.

35. A method of managing fluid between an ultrasound fluidics system and an ultrasound coupling assembly, comprising: determining a first fluid parameter of fluid disposed in one or more fluid reservoirs of the ultrasound fluidics system; determining a second fluid parameter of fluid disposed in the ultrasound coupling assembly; and presenting the first and second fluid parameters on a display.

36. The method of claim 35, wherein the first fluid parameter comprises a volume of fluid in the one or more fluid reservoirs and the second fluid parameter comprises a volume of fluid in the coupling assembly.

37. The method of claim 35, wherein the first fluid parameter comprises a temperature of fluid in the one or more fluid reservoirs and the second fluid parameter comprises a volume of fluid in the coupling assembly.

38. The method of claim 35, wherein the first fluid parameter comprises a percentage of gas within the fluid in the one or more fluid reservoirs and the second fluid parameter comprises a volume of fluid in the coupling assembly.

39. The method of claim 35, wherein the one or more fluid reservoirs comprise a main reservoir and a waste reservoir. - 61 - SG Docket No.10860-734.60040. The method of claim 39, wherein the first fluid parameter comprises a volume of fluid in the main reservoir, further comprising a third fluid parameter that comprises a volume of fluid in the waste reservoir.

41. The method of claim 35, further comprising determining the first fluid parameter and the second fluid parameter with one or more sensors operatively coupled to the one or more fluid reservoirs.

42. The method of claim 41, wherein the one or more sensors comprise weight sensors.

43. The method of claim 41, wherein the one or more sensors comprise optical sensors.

44. The method of claim 35, further comprising determining the first and second fluid parameters based on a pump speed and or pump operation time of one or more pumps of the ultrasound fluidics system.

45. The method of claim 35, further comprising receiving an input to move a pre- determined volume of fluid between the one or more fluid reservoirs and the coupling assembly.

46. The method of claim 45, further comprising automatically moving the pre-determined volume of fluid between the one or more fluid reservoirs and the coupling assembly.

47. The method of claim 46, further comprising periodically determining the first and second fluid parameters of the one or more fluid reservoirs and / or the coupling assembly and presenting the first and second fluid parameters on the display while the pre-determined volume of fluid is moved between the one or more fluid reservoirs and the coupling assembly.

48. The method of claim 46, further comprising presenting an icon on the display indicating a direction of fluid flow between the one or more fluid reservoirs and the coupling assembly.

49. The method of claim 35, further comprising receiving an input to move a pre- determined volume of fluid between the coupling assembly and the one or more reservoirs. - 62 - SG Docket No.10860-734.60050. The method of claim 49, further comprising moving the pre-determined volume of fluid between the coupling assembly and the one or more reservoirs.

51. The method of claim 50, further comprising periodically determining the first and second fluid parameters of the one or more fluid reservoirs and / or the coupling assembly and presenting the first and second fluid parameters on the display while the pre-determined volume of fluid is moved between the coupling assembly and the one or more reservoirs.

52. The method of claim 50, further comprising presenting an icon on the display indicating a direction of fluid flow between the coupling assembly and the one or more reservoirs.

53. An ultrasound coupling system, comprising: a coupling assembly configured to be placed on a subject, the coupling assembly including an expandable membrane configured for contact with the subject’s skin; a fluidics system comprising a main tank, a drain tank, and a tubing set having first and second ports, and a degas system coupled to the tubing set, the fluidics system being configured to move a flow of fluid into the first port of the tubing set and out of the second port of the tubing set; a graphical user interface (GUI) operably connected to the fluidics system; a memory, storing thereon instructions that when executed by a processor operably connected to the memory in response to an input received by the GUI cause the fluidics system to perform one or more of the following processes: 1) filling the main tank of the fluidics system with fluid from a fluid source; 2) degassing the fluid in the main tank with the degas system; 3) filling the coupling assembly with fluid from the main tank; 4) degassing the fluid in the coupling assembly; 5) draining the fluid from the coupling assembly to the drain tank; 6) draining the fluid from the main tank, the drain tank, and / or the coupling assembly to an external location; wherein the instructions when executed by the processor are further configured to provide one or more graphical indications to a user on the GUI that include: a) providing visual or audible instructions on where to place the first and second ports of the tubing set; - 63 - SG Docket No.10860-734.600b) providing one or more volume indicators of a volume of fluid within the main tank, the drain tank, and / or the coupling assembly; c) providing one or more flow rate indicators of a rate of fluid flow through the tubing set; d) providing one or more concentration indicators of a gas concentration within the fluid in the main tank and / or the coupling assembly; and e) providing one or more directional indicators of a direction of fluid flow through the tubing set. - 64 - SG Docket No.10860-734.600

Images