Ultrasound coupling membranes for use with ultrasound coupling systems for histotripsy

Abstract

A histotripsy therapy system configured for the treatment of tissue is provided, which may include any number of features. Provided herein are systems and methods that provide efficacious non-invasive and minimally invasive therapeutic, diagnostic and research procedures. Additional embodiments herein provide coupling systems for histotripsy including various ultrasound coupling membranes configured to interface with any ultrasound medium container and / or ultrasound medium associated with a histotripsy procedure.

Description

ULTRASOUND COUPLING MEMBRANES FOR USE WITH ULTRASOUND COUPLING SYSTEMS FOR HISTOTRIPSYPRIORITY CLAIM

[0001] This patent application claims priority to U.S. provisional patent application no. 63 / 724,102, titled “ULTRASOUND COUPLING MEMBRANES FOR USE WITH ULTRASOUND COUPLING SYSTEMS FOR HISTOTRIPSY,” and filed on November 22, 2024, which is herein incorporated by reference in its entirety.INCORPORATION BY REFERENCE

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

[0003] The present disclosure details novel high intensity therapeutic ultrasound (HITU) systems configured to produce acoustic cavitation, methods, devices and procedures for the minimally and non-invasive treatment of healthy, diseased and / or injured tissue. The acoustic cavitation systems and methods described herein, also referred to as Histotripsy, may include transducers, drive electronics, positioning robotics, imaging systems, ultrasound coupling systems, and integrated treatment planning and control software to provide comprehensive treatment and therapy for soft tissues in a patient. The ultrasound coupling systems include a coupling membrane designed specifically for use with any histotripsy or acoustic cavitation system therapy 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 ablation. To operate within a non-thermal, Histotripsy realm; it is necessary to deliver acoustic energy in the form of high amplitude acoustic pulses with low duty cycle.

[0005] Compared with conventional focused ultrasound technologies, Histotripsy has important advantages: 1) the destructive process at the focus is mechanical, not thermal; 2)- 1 -SG Docket No. 10860-742.600cavitation 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] Histotripsy, as well as other acoustic cavitation systems, further rely on an ultrasound coupling system to provide an acoustic pathway to deliver ultrasound energy from a transducer to a patient.

[0007] FIG. 1 is schematic representation of a coupling system 30 of an acoustic cavitation system positioned on a patient 32 and including a comparative coupling membrane 34. The comparative coupling membrane 34 includes and displays mechanical and / or physical characteristics (e.g., tensile strength, elongation, stress-to-strain ratios, etc.) which greatly hinder and / or prevent the comparative coupling membrane 34 from making sufficient direct contact with a patient 32. Thus, a reliable acoustic coupling between the patient 32 and a transducer 31 is difficult to form and / or maintain for a sufficient amount of time to deliver uninterrupted therapy.

[0008] As depicted in FIG. 1, the comparative coupling membrane 34 displays mechanical and / or physical characteristics which either remain generally constant and / or are too low to provide any proper resistance to the expansion of the membrane by a combination of the coupling medium, the transducer, and gravity applied thereto. As a result, no useful amount of coupling medium 36 can be added to the coupling system 30 without the membrane 34 running-away from the patient and / or creating over-bulging 34a of the membrane 34. The running-away and / or over-bulging 34a of the membrane 34 can: create air gaps 37 between the patient 32 and the membrane 34 due to the membrane’s inability to accommodate the natural exterior curvature of the patient 32; and / or prevent the transducer 31 from being sufficiently submerged in the medium 36 and failing to form an acoustic coupling between the transducer 31 and the patient 32. In some instances, the comparative membranes 34 are in need of a restraint (not shown in FIG. 1) which is connected to the coupling system 30, often the ultrasound medium carrier 33, and wraps around the patient 32 to prevent the comparative membrane 34 form running-away from the patient 32 and / or overbulging 34a so an acoustic coupling can be formed.- 2 -SG Docket No. 10860-742.600

[0009] It would be beneficial to provide an acoustic cavitation system, such as a histotripsy system, with an ultrasound coupling system, and particularly an ultrasound coupling membrane, which is: acoustically transparent; visually transparent; adaptable to various sized patient; usable with various suitable coupling medium carriers; and / or usable with various suitable coupling medium. It would further be beneficial to provide an ultrasound coupling membrane which includes and / or displays mechanical and / or tensile properties which allow the coupling membrane to expand in a controlled manner which maintains contact with a patient without running-away and / or over-bulging.SUMMARY

[0010] The present disclosure describes an ultrasound therapy system such as for histotripsy (and / or any other acoustic cavitation therapy system) including a coupling system, and particularly a coupling membrane, which is acoustically transparent, visually transparent, adaptable to any size patient, usable with any suitable coupling medium carrier, and / or usable with any suitable coupling medium. The coupling system includes at least an ultrasound medium (i.e., coupling medium and / or acoustic medium), an ultrasound medium carrier or reservoir (i.e., coupling medium carrier and / or acoustic medium carrier), and a coupling membrane.

[0011] The present disclosure describes an ultrasound coupling membrane designed for use with any suitable acoustic cavitation therapeutic system, including histotripsy. The present disclosure describes an ultrasound coupling membrane designed for use with any suitable ultrasound medium and / or ultrasound medium carrier.

[0012] In some embodiments, the ultrasound coupling membrane includes and / or displays one or more of the following increasing mechanical and / or tensile properties: a tensile strength at 100% elongation of about 0.01 - 0.05 MPa; a tensile strength at 300% elongation of about 0.03 - 0.1 MPa; a tensile strength at 500% elongation of about 0.04 - 0.15 MPa; or a tensile strength at 1000% elongation of about 0.05 - 0.6 MPa. In embodiments where the ultrasound coupling membrane includes and / or displays two or more of the above tensile strength per percentage elongation properties, the tensile strength at 100% elongation< tensile strength at 300% elongation< tensile strength at 500% elongation< tensile strength at 1000% elongation.

[0013] In some embodiments, the ultrasound coupling membrane includes and / or displays one or more of the following increasing mechanical and / or tensile properties: a first stress-to-strain ratio ranging from about 0.015-0.025 MPa / 100% strain up to 600% strain; a second stress-to-strain ratio ranging from about 0.03-0.05 MPa / 100% strain- 3 -SG Docket No. 10860-742.600from 601-800% strain; or a third stress-to-strain ratio ranging from about 0.055-0.85 MPa / 100% strain from 801-1000% strain. In some embodiments, the ultrasound coupling membrane includes and / or displays all three of the above stress-to-strain ratios.

[0014] In some embodiments, the ultrasound coupling membrane includes and / or displays a combination of the above tensile strength per percentage elongation properties and the above stress-to-strain ratios. As a non-limiting example, the ultrasound coupling membrane may include and / or display: one or more of a tensile strength at 100% elongation of about 0.01 - 0.05 MPa, a tensile strength at 300% elongation of about 0.03 - 0.1 MPa, or a tensile strength at 500% elongation of about 0.04 - 0.15 MPa; and one or more of a second stress-to-strain ratio ranging from about 0.03-0.05 MPa / 100% strain from 601-800% strain or a third stress-to-strain ratio ranging from about 0.055-0.85 MPa / 100% strain from 801- 1000% strain. Other various combinations are also envisioned.

[0015] In some embodiments, the ultrasound coupling membrane includes and / or is made from an oil-infused polymeric material, such as an oil-infused styrene-ethylene-butylene- styrene (SEBS) polymeric material.

[0016] The present disclosure further describes an ultrasound coupling system for use with an ultrasound therapeutic system, such as histotripsy. The ultrasound coupling system includes an ultrasound medium; an ultrasound medium carrier defining a cavity therethrough; and an ultrasound coupling membrane extending across the cavity at or near a patient-facing side of the ultrasound medium carrier sealing the patient-facing side of the ultrasound medium carrier for the ultrasound medium to be received and / or maintained in the cavity. The ultrasound coupling membrane configured to transition from an original planar and / or non-expanded configuration to a non-planar and / or expanded configuration.

[0017] In some embodiments, the coupling system includes an ultrasound coupling membrane which includes and / or displays one or more of the following increasing mechanical and / or tensile properties: a tensile strength at 100% elongation of about 0.01 - 0.05 MPa; a tensile strength at 300% elongation of about 0.03 - 0.1 MPa; the membrane further displays a tensile strength at 500% elongation of about 0.04 - 0.15 MPa; or a tensile strength at 1000% elongation of about 0.05 - 0.6 MPa. In embodiments where the ultrasound coupling membrane includes and / or displays two or more of the above tensile strength per percentage elongation properties, the tensile strength at 100% elongation< tensile strength at 300% elongation< tensile strength at 500% elongation< tensile strength at 1000% elongation.

[0018] In some embodiments, the coupling system includes an ultrasound coupling membrane which includes and / or displays one or more of the following increasing mechanical and / or tensile properties: a first stress-to-strain ratio ranging from about 0.015-- 4 -SG Docket No. 10860-742.6000.025 MPa / 100% strain up to 600% strain; a second stress-to-strain ratio ranging from about 0.03-0.05 MPa / 100% strain from 601-800% strain; or a third stress-to-strain ratio ranging from about 0.055-0.85 MPa / 100% strain from 801-1000% strain. In some embodiments, the ultrasound coupling membrane includes and / or displays all three of the above stress-to-strain ratios.

[0019] In some embodiments, the coupling system includes an ultrasound coupling membrane which includes and / or displays a combination of the above tensile strength per percentage elongation properties and the above stress-to-strain ratios.

[0020] The present disclosure further describes an ultrasound therapeutic system, such as histotripsy, having one or more ultrasound transducers and an ultrasound coupling system as provided herein. The ultrasound therapy transducer configured to provide ultrasound therapy and / or ultrasound imaging when acoustically coupled to a patient via the coupling system positioned therebetween. The ultrasound therapy transducer is designed to be at least partially submerged within an ultrasound coupling medium maintained in an ultrasound medium carrier including an ultrasound coupling membrane to form an acoustic coupling. At least the ultrasound medium and the ultrasound membrane being acoustically transparent, visually transparent, and / or free of any air bubbles and contaminants. The ultrasound coupling membrane configured to transition from an original planar and / or non-expanded configuration to a non-planar and / or expanded configuration.

[0021] In some embodiments, the ultrasound therapeutic system includes a coupling system with an ultrasound coupling membrane which includes and / or displays one or more of the following increasing mechanical and / or tensile properties: a tensile strength at 100% elongation of about 0.01 - 0.05 MPa; a tensile strength at 300% elongation of about 0.03 - 0.1 MPa; the membrane further displays a tensile strength at 500% elongation of about 0.04 - 0.15 MPa; or a tensile strength at 1000% elongation of about 0.05 - 0.6 MPa. In embodiments where the ultrasound coupling membrane includes and / or displays two or more of the above tensile strength per percentage elongation properties, the tensile strength at 100% elongation< tensile strength at 300% elongation< tensile strength at 500% elongation< tensile strength at 1000% elongation.

[0022] In some embodiments, the ultrasound therapeutic system includes a coupling system with an ultrasound coupling membrane which includes and / or displays one or more of the following increasing mechanical and / or tensile properties: a first stress-to-strain ratio ranging from about 0.015-0.025 MPa / 100% strain up to 600% strain; a second stress-to-strain ratio ranging from about 0.03-0.05 MPa / 100% strain from 601-800% strain; or a third stress- to-strain ratio ranging from about 0.055-0.85 MPa / 100% strain from 801-1000% strain. In - 5 -SG Docket No. 10860-742.600some embodiments, the ultrasound coupling membrane includes and / or displays all three of the above stress-to-strain ratios.

[0023] In some embodiments, the ultrasound therapeutic system includes a coupling system with an ultrasound coupling membrane which includes and / or displays a combination of the above tensile strength per percentage elongation properties and the above stress-to- strain ratios.

[0024] Methods of forming an acoustic coupling between an ultrasound transducer of an ultrasound therapeutic system, such as histotripsy, and a patient prior to ultrasound treatment and / or imaging are also provided. The methods generally provide: positioning an ultrasound coupling system as provided herein over a patient including a coupling membrane in a planar and / or non-expanded configuration; and adding one or more amounts of an ultrasound coupling medium to the ultrasound coupling system to transform the coupling membrane from the planar and / or non-expanded configuration to one or more subsequent non-planar and / or expanded configurations, wherein the coupling membrane makes direct contact with an exterior of the patient and expands across the natural curvature of the exterior of the patient while maintain direct contact thereto and without over-bulging and / or running away from the patient, particularly when the expansion and / or elongation of the membrane is less than 1000%.BRIEF DESCRIPTION OF THE DRAWINGS

[0025] 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:

[0026] FIG. l is a schematic illustration of a comparative ultrasound coupling system including a comparative ultrasound coupling membrane.

[0027] FIG. 2A is a perspective view of a histotripsy system in accordance with the disclosure.

[0028] FIG. 2B depicts a therapy transducer and imaging transducer in accordance with the disclosure.

[0029] FIG. 3 depicts a histotripsy system deployed to treat a patient in accordance with the disclosure.- 6 -SG Docket No. 10860-742.600

[0030] FIG. 4 is a plot of a pressure wave during application of a histotripsy ultrasound pulse in accordance with the disclosure.

[0031] FIG. 5 is an expanded perspective view of at least one ultrasound medium coupling system in accordance with the disclosure.

[0032] FIGS. 6A-6D are a schematic representation of a method of forming an acoustic coupling in accordance with the disclosure.

[0033] FIGS. 7 and 8 are graphs depicting the stress-to-strain characteristics of at least some of the coupling membranes provided herein.DETAILED DESCRIPTION

[0034] The present disclosure is directed to acoustic cavitation systems, such as histotripsy systems, and the various systems, subsystems, methods, and devices associated therewith. More particularly the present disclosure is directed to acoustic coupling systems suitable for use in acoustic cavitation systems, such as histotripsy systems, and the various systems, subsystems, methods, and devices associated therewith. The acoustic coupling systems described herein are designed to be used within any acoustic cavitation or histotripsy system.

[0035] Acoustic cavitation systems (interchangeably referred to herein as histotripsy or ultrasound therapy systems) and the associated systems, subsystems, methods and devices of the present 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.

[0036] The histotripsy system may include various sub-systems, including a Cart, Therapy, Integrated Imaging, Robotics, Coupling, and Software. The histotripsy system also may comprise various Other Components, Ancillaries, and Accessories, including but not limited to computers, cables and connectors, networking devices, power supplies, displays, drawers / storage, doors, wheels, and various simulation and training tools, etc. All systems, methods, devices, systems (or subsystems), and means creating / controlling / delivering - 7 -SG Docket No. 10860-742.600histotripsy are considered to be a part of this disclosure, including new related inventions disclosed herein.THE SYSTEM

[0037] FIG. 2A depicts a histotripsy system 100 in accordance with the disclosure. The histotripsy system 100 includes 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 (FIG. 3).

[0038] FIG. 2B is a bottom view of the therapy transducer 102 and the imaging system 104. As shown, the imaging system 104 can be positioned in the center of the therapy transducer 102. However, other embodiments can include the imaging system 104 positioned in other locations within the therapy transducer 102, or even directly integrated into the therapy transducer 102. In some embodiments, the imaging system is configured to produce real-time imaging at a focal point of the therapy transducer 102. The system also allows for multiple imaging transducers 104 to be located within the therapy transducer 102 to provide multiple views of the target tissue simultaneously and to integrate these images into a single 3-D image.

[0039] The histotripsy system 100 may comprise, and the cart 110 may enclose, 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 102, an integrated imaging sub-system (or connectivity thereto) allowing real-time visualization and display of the treatment site and histotripsy effect through-out the procedure (e.g., via, a robotics positioning sub-system to mechanically and / or electronically steer the therapy transducer) and further enabled to connect / support or interact with a coupling sub-system to allow acoustic coupling between the therapy transducer 102 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 histotripsy system 100 may further comprise various fluidics and fluid management components, including but not limited to, pumps, valve and flow controls, temperature and degassing controls, and irrigation and aspiration capabilities, as well as providing and storing fluids. It may also contain various power supplies and protectors.

[0040] As described in greater detail below, the cart 110 may be configured and arranged to be used in a radiology environment and in some cases in concert with imaging (e.g., computed tomography (CT), cone beam CT and / or magnetic resonance imaging (MRI) scanning). In other embodiments, the cart 110 may be arranged for use in an operating room - 8 -SG Docket No. 10860-742.600and a sterile environment for open surgical or laparoscopic surgical and endoscopic application, or in a robotically enabled operating room, and used alone, or as part of a surgical robotics procedure wherein a surgical robot conducts specific tasks before, during or after use of the system and delivery of acoustic cavitation / histotripsy. As such, depending on the procedure environment based on the aforementioned embodiments, the cart may be positioned to provide sufficient work-space and access to various anatomical locations on the patient (e.g., torso, abdomen, flank, head and neck, etc.), as well as providing work-space for other systems (e.g., anesthesia cart, laparoscopic tower, surgical robot, endoscope tower, etc.).

[0041] The cart 110 may also work with a patient surface (e.g., table or bed) to allow the patient to be presented and repositioned in a variety of positions, angles and orientations, including allowing changes to such to be made pre, peri and post-procedurally. The cart 110, and subsystems thereof, may further comprise the ability to interface and communicate with one or more external imaging or image data management and communication systems, not limited to ultrasound, CT, fluoroscopy, cone beam CT, positron emission tomography (PET), PET / CT, MRI, optical, ultrasound, and image fusion and or image flow, of one or more modalities, to support the procedures and / or environments of use, including physical / mechanical interoperability (e.g., compatible within cone beam CT work-space for collecting imaging data pre, peri, intra and / or post histotripsy) and to provide access to and display of patient medical data including but not limited to laboratory and historical medical record data.

[0042] In some embodiments one or more carts may be configured to work together. As an example, one cart may comprise a bedside mobile cart equipped with one or more robotic arms enabled with a therapy transducer, and therapy generator / amplifier, etc., while a companion cart working in concert and at a distance of the patient may comprise integrated imaging and a console / display for controlling the robotic and therapy facets, analogous to a surgical robot and master / slave configurations.

[0043] FIG. 3 illustrates one embodiment of a histotripsy therapy and imaging system 200, including an ultrasound coupling system or assembly 212. As described above, a histotripsy therapy and imaging system can include a therapy transducer 202, an imaging system 204, a robotic positioning arm 208, and a cart 210.

[0044] The therapy and / or imaging transducers 202, 204 are placed in the ultrasound coupling system 212 which can include an ultrasound medium carrier 206, an ultrasound coupling membrane 214, and an ultrasound medium 222. The coupling membrane 214 including and / or displaying mechanical properties which substantially hinder and / or prevent - 9 -SG Docket No. 10860-742.600the coupling membrane 214 from over-bulging and / or running-away from the patient (and / or the transducer(s) 202, 204) when the coupling system 212 includes and / or is filled with coupling medium 222, such as a fluid or a gel. An ultrasound membrane constraint 216 configured to further aid in preventing the membrane 214 from over-bulging and / or running- away from the patient (and / or the transducer(s) 202, 204) may also optionally be used.

[0045] In the illustrated embodiment, the coupling system 212 is supported by a mechanical support arm 218 which can be load bearing in the x-y plane but allow for manual or automated z-axis adjustment. The mechanical support arm 218 can be attached to the floor, the patient table, or the cart 210. The coupling system 212 is designed and configured to conform and hold the coupling membrane 214 in place against the patient’s skin while still allowing movement of the therapy / imaging transducer 202, 204 relative to the patient and the coupling membrane 214 with the robotic positioning arm 208.

[0046] The system can further include a fluidics system 220 that can include a fluid and / or ultrasound medium 222, a cooling and degassing system, and a programmable control system. The fluidics system is configured for external loading of the coupling system 212 with automated control of fluidic sequences so that the coupling membrane 214 can conform around the patient.HISTOTRIPSY

[0047] Histotripsy is achieved by generating 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 affect tissue structure, and in some cases liquefy, suspend, solubilize and / or destruct tissue into sub-cellular components.

[0048] Histotripsy can be applied in various forms, including: 1) intrinsic-threshold histotripsy which 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 which 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- 10 -SG Docket No. 10860-742.600of 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 which 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.

[0049] 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.

[0050] 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.

[0051] 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.”

[0052] FIG. 4 illustrates an ultrasound pulse that can be used for shock scattering histotripsy. As shown the ultrasound pulse can include a leading negative half cycle, a peak- 11 -SG Docket No. 10860-742.600positive half cycle, a peak negative half cycle, and a trailing peak positive half cycle (with the pulse traveling from right to left on the page). As shown, the trailing peak positive cycle has a lower amplitude than the peak positive cycle. This mechanism depends on one (or a few sparsely distributed) bubble(s) initiated with the initial negative half cycle(s) of the pulse at the focus of the transducer. A cloud of microbubbles then forms due to the pressure release backscattering of the high peak positive shock fronts from these sparsely initiated bubbles. These back-scattered high-amplitude rarefactional waves exceed the intrinsic threshold thus producing a localized dense bubble cloud. Each of the following acoustic cycles then induces further cavitation by the backscattering from the bubble cloud surface if the amplitude of those cycles is sufficient, which grows towards the transducer. As a result, an elongated dense bubble cloud growing along the acoustic axis opposite the ultrasound propagation direction is observed with the shock scattering mechanism. This shock scattering process makes the bubble cloud generation not only dependent on the peak negative pressure, but also the number of acoustic cycles and the amplitudes of the positive shocks. Without at least one intense shock front developed by nonlinear propagation, no dense bubble clouds are generated when the peak negative half-cycles are below the intrinsic threshold.

[0053] 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.”

[0054] 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.

[0055] 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- 12 -SG Docket No. 10860-742.600and 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.”

[0056] 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.COUPLING SYSTEM

[0057] The present disclosure further describes an ultrasound coupling system for use with an ultrasound and / or acoustic cavitation therapy system, such as a histotripsy system, which utilizes an acoustic coupling to deliver ultrasound energy between an ultrasound transducer and a patient. The coupling systems described herein include at least an ultrasound coupling medium, an ultrasound medium carrier, and an ultrasound coupling membrane which includes and / or displays one or more of the various mechanical and / or tensile properties provided herein.

[0058] FIG. 5 depicts an example of an ultrasound coupling system 312 suitable for use with an ultrasound and / or acoustic cavitation therapy system, such as a histotripsy system. The coupling system 312 includes an ultrasound medium carrier (UMC or reservoir) 313 and an ultrasound coupling membrane 314. The medium carrier 313 has a one-piece or multipiece frame body 315 defining a cavity 318 therethrough. The coupling membrane 314 covers and / or spans the cavity 318 to seal the medium carrier 313 at or near the patient-facing side 313a of the medium carrier 313. An optional locking member 317 may be included to- 13 -SG Docket No. 10860-742.600secure and / or seal the coupling membrane 314 to the medium carrier 313. The cavity 318 of the combined carrier 313 and membrane 314 is configured to be filled (i.e., receive and / or maintain) with a coupling medium therein (not shown in FIG. 5). The coupling membrane 314 is visually transparent and acoustically transparent. The coupling membrane 314 is free of any tears and contaminants, such as particulate matter, air bubbles, streaks, etc.

[0059] As provided in more detail hereinbelow, to form an acoustic coupling between the transducer and the patient, the transducer is aimed at the patient and submerged in an ultrasound coupling medium maintained with an ultrasound medium carrier which is sealed on a patient-side of the carrier by an ultrasound coupling membrane. The coupling membrane is designed to contact the patient directly, generally without air bubbles therebetween, as the coupling membrane expands and / or elongates.

[0060] The coupling membranes described herein include and / or display tensile properties (e.g., tensile strength at a given elongation percent, stress-to-strain ratios, etc.) which increase during the various stages of the filling process of the coupling system, as described in more detail hereinbelow. The coupling membranes described herein may include and / or display mechanical and / or tensile properties which increase as the membrane is expanded and / or elongated by the addition of the coupling medium into the medium carrier.

[0061] In some embodiments, a first mechanical and / or tensile property of the ultrasound coupling membrane, which increases with expansion of the membrane, is presented as a tensile strength at a given elongation percent. The coupling membranes provided herein include and / or display a tensile strength which increases as the elongation percentage of the coupling membrane increases. For example, the coupling membranes provided herein display a different tensile strength at 100%, 300%, 500%, and 1000% elongation wherein the tensile strength at 100% elongation< tensile strength at 300% elongation< tensile strength at 500% elongation< tensile strength at 1000% elongation.

[0062] The coupling membranes provided herein may include and / or display a tensile strength at 100% elongation of about 0.01 - 0.05 MPa (megapascals). In some embodiments, the tensile strength at 100% elongation is from about 0.02 - 0.03 MPa. In some embodiments, the tensile strength at 100% elongation is from about 0.024 - 0.027 MPa. In some embodiments, the tensile strength at 100% elongation is 0.0259±0.0010 MPa.

[0063] The coupling membranes provided herein may further include and / or display a tensile strength at 300% elongation which is greater than the tensile strength at 100% elongation. The tensile strength at 300% elongation is from about 0.03 - 0.1 MPa. In some embodiments, the tensile strength at 300% elongation is from about 0.05 - 0.07 MPa. In- 14 -SG Docket No. 10860-742.600some embodiments, the tensile strength at 300% elongation is from about 0.055 - 0.065 MPa. In some embodiments, the tensile strength at 300% elongation is 0.053±0.0035 MPa.

[0064] The coupling membranes provided herein may further include and / or display a tensile strength at 500% elongation which is greater than the tensile strength at 100% elongation and 300% elongation. The tensile strength at 500% elongation is from about 0.04- 0.15 MPa. In some embodiments, the tensile strength at 500% elongation is from about 0.075 - 0.12 MPa. In some embodiments, the tensile strength at 500% elongation is from about 0.08 - 0.10 MPa. In some embodiments, the tensile strength at 500% elongation is 0.091±0.010 MPa.

[0065] The coupling membranes provided herein may further include and / or display a tensile strength at 1000% elongation which is greater than the tensile strength at 100% elongation, 300% elongation, and 500% elongation. The tensile strength at 1000% elongation is from about 0.05 - 0.6MPa. In some embodiments, the tensile strength at 1000% elongation is from about 0.1- 0.5 MPa. In some embodiments, the tensile strength at 1000% elongation is from about 0.15 - 0.45 MPa. In some embodiments, the tensile strength at 1000% elongation is 0.3±0.12 MPa.

[0066] Any combination of the various tensile strength per elongation percentage characteristics are envisioned. For example, in some embodiments, the coupling membranes provided herein include and / or display two or more of the following: tensile strength at 100% elongation is from about 0.02 - 0.03 MPa; a tensile strength at 300% elongation is from about 0.05 - 0.07 MPa; tensile strength at 500% elongation is from about 0.075 - 0.12 MPa; tensile strength at 1000% elongation is from about 0.1- 0.5 MPa.

[0067] In some embodiments, the coupling membranes provided herein include and / or display two or more of the following: tensile strength at 100% elongation is from about 0.024- 0.027 MPa; a tensile strength at 300% elongation is from about 0.055 - 0.065 MPa; tensile strength at 500% elongation is from about 0.08 - 0.10 MPa; tensile strength at 1000% elongation is from about 0.15 - 0.45 MPa.

[0068] In some embodiments, the coupling membranes provided herein include and / or display two or more of the following: tensile strength at 100% elongation is 0.0259±0.0010 MPa; a tensile strength at 300% elongation is 0.053±0.0035 MPa; tensile strength at 500% elongation is 0.091±0.010 MPa; tensile strength at 1000% elongation is from 0.3±0.12 MPa.

[0069] In some embodiments, a second mechanical and / or tensile property of the ultrasound coupling membrane, which increases with expansion of the membrane, is presented as a stress-to-strain ratio. The coupling membranes provided herein include and / or display a stress-to-strain ratio which increases as the elongation percentage of the coupling- 15 -SG Docket No. 10860-742.600membrane increases. For example, the coupling membranes provided herein may display a different stress-to-strain ratio at 600%, 800%, and 1000% elongation wherein the stress-to- strain ratio up to about 600% elongation< the stress-to-strain ratio at about 800% elongation< the stress-to-strain ratio at about 1000% elongation.

[0070] The coupling membranes provided herein may include and / or display a first stress-to-strain ratio ranging from 0.015-0.025 MPa / 100% strain up to 600% strain. In some embodiments, the first stress-to-strain ratio is about 0.02 MPa / 100% strain up to 600% strain.

[0071] The coupling membranes provided herein may further include and / or display a second stress-to-strain ratio ranging from 0.03-0.05 MPa / 100% strain from 601-800% strain. The second stress-to-strain ratio being greater than the first stress-to-strain ratio. In some embodiments, the second stress-to-strain ratio is about 0.04 MPa / 100% strain from 601-800% strain.

[0072] The coupling membranes provided herein may further include and / or displays a third stress-to-strain ratio ranging from 0.055-0.85 MPa / 100% strain from 801-1000% strain. The third stress-to-strain ratio being greater than the first and / or second stress-to-strain ratios. In some embodiments, the third stress-to-strain ratio is about 0.06 - 0.08 MPa / 100% strain from 801-1000% strain.

[0073] Any combination of the various stress-to-strain characteristics are envisioned. For example, in some embodiments, the coupling membranes provided herein include and / or display two or more of the following: a first stress-to-strain ratio is about 0.02 MPa / 100% strain up to 600% strain; a second stress-to-strain ratio is about 0.04 MPa / 100% strain from 601-800%; or a third stress-to-strain ratio is about 0.06 - 0.08 MPa / 100% strain from 801- 1000% strain.

[0074] The coupling membranes provided herein may further include and / or display some additional mechanical properties. For example, the coupling membranes may include and / or display an elongation at break of greater than 1500%. In some embodiments, the elongation at break is from about 1525%-2500%, In some embodiments, the elongation at break is from about 1600-2300%. In some embodiments, the elongation at break is from about 1700-2200%.

[0075] In some embodiments, the coupling membranes includes and / or display a strain at offset yield of about 1-15%. In some embodiments, the strain at offset yield is from about 2- 10%. In some embodiments, the strain at offset yield is 9.18±5.16%.

[0076] In some embodiments, the coupling membranes includes and / or display a hardness (Shore 00) from about 5 to 50. In some embodiments, a hardness (Shore 00) from about 10 to 25.- 16 -SG Docket No. 10860-742.600

[0077] The coupling membrane may be made from an expandable biocompatible polymeric material which includes and / or displays the tensile properties provided herein. Some non-limiting examples of suitable biocompatible polymeric materials include thermoplastic styrenic elastomers such as styrene-butadiene-styrene (SBS) copolymers or styrene-ethylene-butylene-styrene (SEBS) copolymers. In some embodiments, the coupling membrane is formed from a SEBS copolymer.

[0078] In some embodiments, the biocompatible polymeric material is an oil-infused polymeric material. Oil-infused polymers are materials that have absorbed an oil, often in excess. Oil-infused polymers are designed to provide a thin layer of the oil along the surface of the polymer and / or a reservoir of oil within the polymer which can be leached. The addition of the oil may improve the coupling membranes’ ability to directly contact the patient while expanding, as well as aid in preventing air bubbles between the membrane and the patient during expansion.

[0079] In some embodiments, the coupling membrane is formed from an oil-infused thermoplastic styrenic elastomer. In some embodiments, the coupling membrane is formed from an oil-infused SEBS copolymer.

[0080] The coupling membranes and / or medium carriers may be formed using any suitable method within the purview of those skilled in the art, including but not limited to, extrusion, molding, solvent casting, pressing, spinning, and combinations thereof. In some embodiments, the coupling membranes and / or the carriers are formed via an injection molding process.

[0081] The coupling systems described herein may utilize any suitable ultrasound 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. In some embodiments, the coupling medium is water (of any type, sterile, pathogen free, distilled, spring, etc.).

[0082] The coupling system may further include some known optional items (not shown), such as a mechanical arm designed to support and / or maintain the coupling system in a fixed position relative to the patient, the therapeutic system, and / or the transducer, as well as a cover for the medium carrier, and / or a rotatable trigger mechanism for inverting the coupling system if needed.- 17 -SG Docket No. 10860-742.600

[0083] FIGS. 6A-6D are schematic representations of a method of forming an acoustic coupling between a transducer 402 (and / or histotripsy system) and a patient 404 using a coupling system 412 as provided herein. The patient 402 is schematically represented lying in a prone position on table 406, however the patient may be positioned in any suitable sitting, standing, or laying manner relative to the system, with or without a table.

[0084] FIGS. 6A-6D also provide a schematic representation of a method of filling the ultrasound medium carrier 413 including a coupling membrane 414 as provided herein. The term “filling” is directed to the addition of a sufficient amount of coupling medium 416 to form an acoustic coupling between the transducer 402 (and / or histotripsy system) and the patient 404. Although the medium carrier 413 may be completely filled with the coupling medium 416, in most instances, a sufficient amount of coupling medium 416 needed to form an acoustic coupling will not completely fill the carrier 413.

[0085] FIG. 6 A depicts a coupling system 412 prior to the addition of a coupling medium to the coupling medium carrier 413 and / or prior to the formation of an acoustic coupling between the transducer 402 and the patient 404. The ultrasound coupling system 412, including the ultrasound medium carrier 413 and the ultrasound coupling membrane 414, is positioned over the patient 404. The coupling membrane 414 extends across a cavity 418 of the carrier 413 at or near a patient-facing side 413a of the carrier 414 to seal the patientfacing side 413a of the carrier 413 so that an ultrasound coupling medium 416 can added to the carrier 413. The coupling membrane 414 is initially in a generally planar and / or nonexpanded configuration prior to the addition of the coupling medium 416 (i.e., prior to filling).

[0086] The transducer 402 is shown positioned near or within the coupling medium carrier 413 in each of FIGS. 6A-6D, however the transducer 402 may be combined with the coupling system 412 at any time during the filling process (e.g., before filling, during filling, and / or after filling).

[0087] FIG. 6B depicts the coupling system 412 during an initial phase of a filling process. During the initial phase of filling, a first amount of coupling medium 416 is added into the coupling medium carrier 413. The first amount of medium 416 is sufficient to transform the coupling membrane 414 from a generally planar and / or non-expanded configuration (FIG. 6A) into a first non-planar and / or expanded configuration as shown in FIG. 6B.

[0088] In the first non-planar and / or expanded configuration (FIG. 6B), a first part 414a of the membrane 414 comes into direct contact with an exterior 404e of the patient 404 and begins to follow a section of the natural curvature of the exterior 404e of the patient 404. As - 18 -SG Docket No. 10860-742.600further depicted, during the initial phase of filling, the transducer 402 may not yet submerged in the medium and no acoustic coupling has yet been formed.

[0089] In the first non-planar and / or expanded configuration, the membrane 414 includes and / or displays at least one first mechanical and / or tensile property. The first property may be selected from a tensile strength at 100% elongation of about 0.01 - 0.05 MPa, a tensile strength at 300% elongation of about 0.03 - 0.1 MPa, a tensile strength at 500% elongation of about 0.04 - 0.15 MPa, or a first stress-to-strain ratio ranging from 0.015-0.025 MPa / 100% strain up to 600% strain.

[0090] FIG. 6C depicts the coupling system 412 during a second phase of the filling process. During the second phase of filling, a second amount of coupling medium 416 is added into the coupling medium carrier 413. The second amount of medium 416 is sufficient to transform the membrane 414 from a first non-planar and / or expanded configuration (FIG. 6B) to a second non-planar and / or expanded configuration (FIG. 6C). The second amount of medium 416 is also sufficient to allow the transducer 402 to be submerged in the coupling medium 416. The weight of the added second amount of medium 416 causes a second part 414b of the membrane 414 to further expand outwardly across the exterior 404e of the patient 404.

[0091] In the second non-planar and / or expanded configuration, the membrane 414 includes and / or displays at least one second mechanical and / or tensile property. The second property may be selected from a tensile strength at 300% elongation of about 0.03 - 0.1 MPa, a tensile strength at 500% elongation of about 0.04 - 0.15 MPa, a tensile strength at 1000% elongation of about 0.05 - 0.6 MPa, a second stress-to-strain ratio ranging from 0.03-0.05 MPa / 100% strain from 601-800% strain, or a third stress-to-strain ratio ranging from 0.055- 0.85 MPa / 100% strain from 801-1000% strain. The second property being higher than the first property of the membrane.

[0092] FIG. 6D depicts the coupling system 412 during an optional third phase of the filling process. During the third phase of filling, an increased third amount of coupling medium 416 is added into the coupling medium carrier 413. The third amount of medium 416 is sufficient to transform the membrane 414 from the second non-planar and / or expanded configuration (FIG. 6C) to a third non-planar and / or expanded configuration (FIG. 6D). The second amount of medium 416 is also sufficient to allow the transducer 402 to be submerged and remain submerged within the medium 416 while pivoted to change the angle of the transducer 402 relative to the patient 404. The added weight of the third amount of coupling medium 416 causes a third part 414c of the membrane 414 to further expand outwardly across the exterior 404e of the patient 404.- 19 -SG Docket No. 10860-742.600

[0093] In the third non-planar and / or expanded configuration, the membrane 414 includes and / or displays at least one third mechanical and / or tensile property. The third property may be selected from a tensile strength at 500% elongation of about 0.04 - 0.15 MPa, a tensile strength at 1000% elongation of about 0.05 - 0.6 MPa, or a third stress-to-strain ratio ranging from 0.055-0.85 MPa / 100% strain from 801-1000% strain. The third property being higher than the first and second properties of the membrane.

[0094] Because the transducer may remain at least partially submerged in the medium, an acoustic coupling may be formed and / or maintained between the transducer and the patient during the third phase of filling and / or during pivoting of the transducer.

[0095] Unlike in FIGS. 6A-6C where the therapeutic face 403 of the transducer 402 is generally perpendicular to the patient 404, in FIG. 6D the transducer 402 is depicted in a pivoted (e.g., tilted and / or angled) configuration. In the pivoted configuration, the face 403 of the transducer 402 is tilted and / or angled towards the target or body part of the patient 404. In some instances, the transducer 402 is pivoted to remain aimed at the target or body part of the patient 404, while also attempting to avoid and / or minimize exposing ultrasound energy to another part of the body, such as an organ or bone, positioned therebetween. Because the face 403 of the transducer 402 is tilted, more medium may be needed to ensure the pivoted face 403 of the transducer 402 is and / or remains submerged.

[0096] As shown in FIGS. 6B-6D, throughout the medium filling process, the membranes described herein continue to expand across and / or in contact with the patient. Because the tensile properties of the membranes described herein increase as the membrane expands, the membrane in the expanded configurations shown in FIGS. 6B-6D may not over-bulge and / or run-away from the patient during the filling process. Although the membranes described herein may not need a separate restraint member to prevent the membrane from over-bulging and / or running-away from the patient, the membranes described herein may still be used with a separate restraint.

[0097] In some embodiments, the coupling membranes described herein are configured to prevent over-bulging and / or run-away up to 800% elongation of a membrane having and / or displaying an elongation at break of at least about 1500% and up to about 3000% .

[0098] In some embodiments, the coupling membranes described herein are configured to prevent over-bulging and / or run-away up to 1000% elongation of a membrane having and / or displaying an elongation at break of at least about 1500% and up to about 3000% .

[0099] 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- 20 -SG Docket No. 10860-742.600in 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. As used in herein, the term “about” means plus or minus ten percent of a given number or range. 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.Examples

[0100] Two sets of five (5) ultrasound coupling membranes were formed via injection molding from an oil-infused SEBS polymeric material. Each of the membranes were visually examined to be transparent and free of any contaminants. The tensile properties of each set of five (5) coupling membranes were tested according to ISO 37:2017 using an Instron 5564 electromechanical UTM and further according to the following conditions and parameters of Table 1 below.Table 1- 21 -SG Docket No. 10860-742.600

[0101] The mechanical and / or tensile properties of the first set of five samples tested are provided in Table 2 below. FIG. 7 depicts the engineering stress-strain curve of the first set of five samples tested.Table 2

[0102] The mechanical and / or tensile properties of the second set of five samples tested are provided in Table 3 below. FIG. 8 depicts the engineering stress-strain curve of the first set of five samples tested.Table 3- 22 -SG Docket No. 10860-742.600

Claims

CLAIMSWhat is claimed is:

1. An ultrasound coupling membrane for use with a histotripsy system, the ultrasound coupling membrane comprising: an oil-infused polymeric material, wherein the ultrasound coupling membrane displays: a tensile strength at 100% elongation of about 0.01 - 0.05 MPa; and a tensile strength at 300% elongation of about 0.03 - 0.1 MPa, the tensile strength at 300% elongation being greater than the tensile strength at 100% elongation.

2. The ultrasound coupling membrane of claim 1, wherein the oil-infused polymeric material is SEBS.

3. The ultrasound coupling membrane of claim 1, wherein the tensile strength at 100% elongation is about 0.024 - 0.027 MPa.

4. The ultrasound coupling membrane of claim 1, wherein the tensile strength at 300% elongation of about 0.055 - 0.065.

5. The ultrasound coupling membrane of claim 1, wherein the membrane further displays a tensile strength at 500% elongation of about 0.04 - 0.15 MPa, the tensile strength at 500% elongation being greater than the tensile strength at 100% elongation and / or the tensile strength at 300% elongation.

6. The ultrasound coupling membrane of claim 5, wherein the tensile strength at 500% elongation is about 0.08 - 0.10 MPa.

7. The ultrasound coupling membrane of claim 1, wherein the membrane further displays a tensile strength at 1000% elongation of about 0.05 - 0.6 MPa, the tensile strength at 1000% elongation being greater than the tensile strength at 100% elongation, the tensile strength at 300% elongation, and / or the tensile strength at 500% elongation.- 23 -SG Docket No. 10860-742.6008. The ultrasound coupling membrane of claim 7, wherein the tensile strength at 1000% elongation is about 0.15 - 0.45 MPa.

9. The ultrasound coupling membrane of claim 1, wherein the coupling membrane further displays one or more of the following: a modulus E from about 0.04 - 0.05 MPa; an offset yield stress from about 0.001 - 0.01 MPa; or a strain at offset yield from about 1-15%.

10. The ultrasound coupling membrane of claim 1, wherein the coupling membrane further displays a first stress-to-strain ratio ranging from 0.015-0.025 MPa / 100% strain up to 600% strain.

11. The ultrasound coupling membrane of claim 10, wherein the coupling membrane further displays a second stress-to-strain ratio ranging from 0.03-0.05 MPa / 100% strain from 601-800% strain.

12. The ultrasound coupling membrane of claim 11, wherein the coupling membrane further displays a third stress-to-strain ratio ranging from 0.055-0.85 MPa / 100% strain from 801-1000% strain.

13. The ultrasound coupling membrane of claim 1, wherein the coupling membrane is acoustically transparent and / or visually transparent.

14. An ultrasound coupling membrane for use with a histotripsy system, the ultrasound coupling membrane comprising: an oil-infused polymeric material, wherein the ultrasound coupling membrane displays: a first stress-to-strain ratio ranging from 0.015-0.025 MPa / 100% strain up to 600% strain; a second stress-to-strain ratio ranging from 0.03-0.05 MPa / 100% strain from 601- 800% strain; and a third stress-to-strain ratio ranging from 0.055-0.85 MPa / 100% strain from 801- 1000% strain.- 24 -SG Docket No. 10860-742.60015. An ultrasound coupling system for use with a histotripsy system, the ultrasound coupling system comprising: an ultrasound medium; an ultrasound medium carrier defining a cavity therethrough; and an ultrasound coupling membrane in a non-expanded configuration extending across the cavity at or near a patient-facing side of the ultrasound medium carrier, the ultrasound coupling membrane sealing the patient-facing side of the ultrasound medium carrier for the ultrasound medium to be received and / or maintained in the cavity, wherein the ultrasound coupling membrane displays: a tensile strength at 100% elongation of about 0.01 - 0.05 MPa; and a tensile strength at 300% elongation of about 0.03 - 0.1 MPa, the tensile strength at 300% elongation being greater than the tensile strength at 100% elongation.

16. The ultrasound coupling system of claim 15, wherein the ultrasound coupling membrane comprises an oil-infused SEBS.

17. The ultrasound coupling system of claim 15, wherein: the tensile strength at 100% elongation is about 0.024 - 0.027 MPa and the tensile strength at 300% elongation of about 0.055 - 0.065.

18. The ultrasound coupling system of claim 15, wherein the ultrasound coupling membrane further displays a tensile strength at 500% elongation of about 0.04 - 0.15 MPa, the tensile strength at 500% elongation being greater than the tensile strength at 100% elongation and the tensile strength at 300% elongation.

19. The ultrasound coupling system of claim 18, wherein the membrane further displays a tensile strength at 1000% elongation of about 0.05 - 0.6 MPa, the tensile strength at 1000% elongation being greater than the tensile strength at 100% elongation, the tensile strength at 300% elongation, and the tensile strength at 500% elongation.

20. The ultrasound coupling system of claim 15, wherein the coupling membrane further includes one or more of: a first stress-to-strain ratio ranging from 0.015-0.025 MPa / 100% strain up to 600% strain;- 25 -SG Docket No. 10860-742.600a second stress-to-strain ratio ranging from 0.03-0.05 MPa / 100% strain from 601- 800% strain; or a third stress-to-strain ratio ranging from 0.055-0.85 MPa / 100% strain from 801- 1000% strain.

21. A histotripsy system comprising: an ultrasound coupling system including: an ultrasound medium carrier defining a cavity therethrough, and an ultrasound coupling membrane in a non-expanded configuration extending across the cavity at or near a patient-facing side of the ultrasound medium carrier, the ultrasound coupling membrane sealing the patient-facing side of the ultrasound medium carrier for the ultrasound medium to be received and / or maintained in the cavity, wherein the ultrasound coupling membrane displays a tensile strength at 100% elongation of about 0.01 - 0.05 MPa and a tensile strength at 300% elongation of about 0.03 - 0.1 MPa, the tensile strength at 300% elongation being greater than the tensile strength at 100% elongation; and an ultrasound therapy transducer configured to provide ultrasound therapy when at least partially submerged within the ultrasound coupling medium maintained in the ultrasound medium carrier and acoustically coupled to a patient.

22. The histotripsy system of claim 21, wherein the ultrasound coupling membrane comprises an oil-infused SEBS.

23. The histotripsy system of claim 21, wherein: the tensile strength at 100% elongation is about 0.024 - 0.027 MPa and the tensile strength at 300% elongation of about 0.055 - 0.065.

24. The histotripsy system of claim 21, wherein the ultrasound coupling membrane further displays a tensile strength at 500% elongation of about 0.04 - 0.15 MPa, the tensile strength at 500% elongation being greater than the tensile strength at 100% elongation and the tensile strength at 300% elongation.

25. The histotripsy system of claim 24, wherein the membrane further displays a tensile strength at 1000% elongation of about 0.05 - 0.6 MPa, the tensile strength at 1000% elongation being greater than the tensile strength at 100% elongation, the tensile strength at 300% elongation, and the tensile strength at 500% elongation.- 26 -SG Docket No. 10860-742.60026. The histotripsy system of claim 21, wherein the coupling membrane further includes one or more of: a first stress-to-strain ratio ranging from 0.015-0.025 MPa / 100% strain up to 600% strain; a second stress-to-strain ratio ranging from 0.03-0.05 MPa / 100% strain from 601- 800% strain; or a third stress-to-strain ratio ranging from 0.055-0.85 MPa / 100% strain from 801- 1000% strain.

27. A method of acoustically coupling a transducer of a histotripsy treatment system to a patient prior to treatment, comprising: positioning an ultrasound coupling system over a patient, the ultrasound coupling system including an ultrasound medium carrier defining a cavity therethrough, and an ultrasound coupling membrane in a planar configuration extending across the cavity at or near a patient-facing side of the ultrasound medium carrier, the ultrasound coupling membrane sealing the patient-facing side of the ultrasound medium carrier for an ultrasound coupling medium to be added to the ultrasound medium carrier, adding a first amount of the ultrasound coupling medium to the ultrasound medium carrier, the first amount sufficient to transform the ultrasound coupling membrane from the planar configuration to a first non-planar configuration without submerging the transducer in the ultrasound coupling medium, the ultrasound coupling membrane in the first non-planar configuration displaying a first tensile property; adding a second amount of the ultrasound coupling medium to the ultrasound medium carrier, the second amount sufficient to transform the ultrasound coupling membrane from the first non-planar configuration to a second non-planar configuration, the transducer submerged the ultrasound coupling medium, the ultrasound coupling membrane in the second non-planar configuration displaying a second tensile property, wherein the first tensile property and the second tensile property is selected from: a tensile strength at 100% elongation of about 0.01 - 0.05 MPa; a tensile strength at 300% elongation of about 0.03 - 0.1 MPa, a tensile strength at 500% elongation of about 0.04 - 0.15 MPa, or a tensile strength at 1000% elongation of about 0.05 - 0.6 MPa, and the second tensile property is higher than the first tensile property.

28. The method of claim 27, wherein:- 27 -SG Docket No. 10860-742.600the first tensile property is selected from the tensile strength at 100% elongation of about 0.01 - 0.05 MPa or the tensile strength at 300% elongation of about 0.03 - 0.1 MPa; and the second tensile property is selected from the tensile strength at 500% elongation of about 0.04 - 0.15 MPa or the tensile strength at 1000% elongation of about 0.05 - 0.6 MPa.

29. The method of claim 27, further comprising adding a third amount of the ultrasound coupling medium to the ultrasound medium carrier, the third amount sufficient to transform the ultrasound coupling membrane from the second non-planar configuration to a third non-planar configuration, the transducer remaining submerged in the ultrasound coupling medium, the ultrasound coupling membrane in the third non-planar configuration displaying a third tensile property, wherein the third tensile property is selected from the tensile strength at 500% elongation of about 0.04 - 0.15 MPa or the tensile strength at 1000% elongation of about 0.05 - 0.6 MPa.

30. An ultrasound coupling membrane for use with a histotripsy system, the ultrasound coupling membrane comprising: an oil-infused polymeric material, wherein the ultrasound coupling membrane displays one or more of the following tensile properties: a first stress-to-strain ratio ranging from 0.015-0.025 MPa / 100% strain up to 600% strain; a second stress-to-strain ratio ranging from 0.03-0.05 MPa / 100% strain from 601- 800% strain; or a third stress-to-strain ratio ranging from 0.055-0.85 MPa / 100% strain from 801- 1000% strain.

31. The ultrasound coupling membrane of claim 30, wherein the oil-infused polymeric material is SEBS.

32. The ultrasound coupling membrane of claim 30, wherein the ultrasound coupling membrane displays all three of the tensile properties.

33. The ultrasound coupling membrane of claim 30, wherein the coupling membrane further displays an elongation at break greater than about 1500%.- 28 -SG Docket No. 10860-742.60034. An ultrasound coupling system for use with a histotripsy system, the ultrasound coupling system comprising: an ultrasound medium; an ultrasound medium carrier defining a cavity therethrough; and an ultrasound coupling membrane in a non-expanded configuration extending across the cavity at or near a patient-facing side of the ultrasound medium carrier, the ultrasound coupling membrane sealing the patient-facing side of the ultrasound medium carrier for the ultrasound medium to be received and / or maintained in the cavity, wherein the ultrasound coupling membrane displays one or more of the following tensile properties: a first stress-to-strain ratio ranging from 0.015-0.025 MPa / 100% strain up to 600% strain; a second stress-to-strain ratio ranging from 0.03-0.05 MPa / 100% strain from 601- 800% strain; or a third stress-to-strain ratio ranging from 0.055-0.85 MPa / 100% strain from 801- 1000% strain.

35. The ultrasound coupling system of claim 34, wherein the ultrasound coupling membrane comprises an oil-infused SEBS polymeric material.

36. The ultrasound coupling system of claim 34, wherein the ultrasound coupling membrane displays all three of the tensile properties.

37. The ultrasound coupling system of claim 34, wherein the ultrasound coupling membrane further displays an elongation at break greater than about 1500%.

38. A histotripsy system comprising: an ultrasound coupling system including: an ultrasound medium carrier defining a cavity therethrough, and an ultrasound coupling membrane in a non-expanded configuration extending across the cavity at or near a patient-facing side of the ultrasound medium carrier, the ultrasound coupling membrane sealing the patient-facing side of the ultrasound medium carrier for the ultrasound medium to be received and / or maintained in the cavity, wherein the ultrasound coupling membrane displays one or more of the following tensile properties: a first stress-to-strain ratio ranging from 0.015-0.025 MPa / 100% strain up to 600% strain;- 29 -SG Docket No. 10860-742.600a second stress-to-strain ratio ranging from 0.03-0.05 MPa / 100% strain from 601-800% strain; and a third stress-to-strain ratio ranging from 0.055-0.85 MPa / 100% strain from 801-1000% strain, and an ultrasound therapy transducer configured to provide ultrasound therapy when at least partially submerged within the ultrasound coupling medium maintained in the ultrasound medium carrier and acoustically coupled to a patient.

39. The histotripsy system of claim 38, wherein the ultrasound coupling membrane comprises an oil-infused SEBS polymeric material.

40. The histotripsy system of claim 38, wherein the ultrasound coupling membrane displays all three of the tensile properties.

41. The histotripsy system of claim 38, wherein the ultrasound coupling membrane further displays an elongation at break greater than about 1500%.

42. A method of acoustically coupling a transducer of a histotripsy treatment system to a patient prior to treatment, comprising: positioning an ultrasound coupling system over a patient, the ultrasound coupling system including an ultrasound medium carrier defining a cavity therethrough, and an ultrasound coupling membrane in a planar configuration extending across the cavity at or near a patient-facing side of the ultrasound medium carrier, the ultrasound coupling membrane sealing the patient-facing side of the ultrasound medium carrier for an ultrasound coupling medium to be added to the ultrasound medium carrier, adding a first amount of the ultrasound coupling medium to the ultrasound medium carrier, the first amount sufficient to transform the ultrasound coupling membrane from the planar configuration to a first non-planar configuration without submerging the transducer in the ultrasound coupling medium, the ultrasound coupling membrane in the first non-planar configuration displaying a first stress-to-strain ratio ranging from 0.015-0.025 MPa / 100% strain up to 600% strain; adding a second amount of the ultrasound coupling medium to the ultrasound medium carrier, the second amount sufficient to transform the ultrasound coupling membrane from the first non-planar configuration to a second non-planar configuration, the transducer submerged the ultrasound coupling medium, the ultrasound coupling membrane in the second- 30 -SG Docket No. 10860-742.600non-planar configuration displaying one or more of a second stress-to-strain ratio ranging from 0.03-0.05 MPa / 100% strain from 601-800% strain, or a third stress-to-strain ratio ranging from 0.055-0.85 MPa / 100% strain from 801-1000% strain a second tensile property.

43. The method of claim 42, wherein the ultrasound coupling membrane comprises an oil-infused SEBS polymeric material.

44. The method of claim 42, wherein the ultrasound coupling membrane further displays an elongation at break greater than about 1500%.- 31 -SG Docket No. 10860-742.600

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