Fluidics Cart and Degassing System for Histotripsy System and Method

Abstract

Histotripsy therapy systems configured for the treatment of tissue are provided, which may include any number of features. Provided herein are systems and methods for providing effective, non-invasive and minimally invasive therapy, diagnostic, and research procedures. Additional embodiments herein provide fluidics systems configured to provide degassed fluid to the UMC of a histotripsy therapy system and to remove fluid from the UMC after treatment.

Description

[Technical Field]

[0001] Priority claims

[0001] This patent application claims priority to U.S. Provisional Patent Application No. 63 / 386,785, filed December 9, 2022, entitled "FLUIDICS CART AND DEGASSING SYSTEM FOR HISTOTRIPSY SYSTEMS AND METHODS," which is incorporated herein by reference in its entirety.

[0002] Incorporation by Reference

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

[0003]

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

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

[0005]

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

[0006]

[0006] A fluidics system configured to support acoustic coupling of an ultrasonic transducer to a patient, comprising: a storage container, a fluid tank within the storage container, a first tubing set having a first input / output port and a second input / output port, a degassing mechanism fluidly connected to the first tubing set, a first pump operatively connected to the first tubing set, a waste container, a second tubing set having a third input / output port, a second pump operatively connected to the second tubing set, and a processor operatively connected to the first and second pumps, the system comprising: 1) a filling configuration in which the first input / output port is fluidly connected to a fluid source and the second input / output port is fluidly connected to the fluid tank, the first pump being controlled in a first operating direction to move fluid from the fluid source into the first input / output port, through the degassing mechanism, out the second input / output port, and into the fluid tank to remove a first percentage of gas from the fluid; 2) a filling configuration in which the first and second input / output ports are fluidly connected to a fluid source and a fluid tank, the first pump being controlled in a first operating direction to move fluid from the fluid source into the first input / output port, through the degassing mechanism, out the second input / output port, and into the fluid tank to remove a first percentage of gas from the fluid; 2) a fluid transfer configuration, wherein the first input / output port is fluidly coupled to the acoustic coupling container and the second input / output is fluidly coupled to the fluid tank, and the first pump is controlled in the second direction of operation to move fluid from the fluid tank into the second input / output port, through the degassing mechanism, out the first input / output port, and into the acoustic coupling container, to remove a third percentage of gas from the fluid; and 3) a drain configuration, wherein the third input / output port of the second tubing set is fluidly coupled to the acoustic coupling container and the second pump is controlled to move fluid from the coupled container to a waste container.

[0007] In some embodiments, the first, second, and third percentages comprise approximately 20 to 40 percent of the remaining gas in the fluid.

[0008] In another aspect, at least one or more of the first, second, and third percentages comprise approximately 20 to 40 percent of the remaining gas in the fluid.

[0009] In some embodiments, at least one or more of the first, second, and third percentages comprise approximately 60 to 80 percent of the remaining gas in the fluid.

[0010] In some embodiments, the degassing mechanism is selected from the group consisting of a degassing membrane, an ultrasonic degasser, an inert gas degassing, and other forms of degassing.

[0011] In one aspect, the processor is configured to automatically execute the circulation configuration to maintain a preferred gas percentage within the fluid.

[0012] In another aspect, the processor is configured to perform the cyclic configuration at preset time intervals.

[0013] In some aspects, the system is configured to release a preset volume of fluid into the acoustically coupled container in a filling configuration.

[0014] In one embodiment, the preset volume is between 1 and 40 L.

[0015] In another aspect, the system includes one or more sensors operatively coupled to the processor for verifying the release of the preset volume of fluid.

[0016] In some aspects, the system includes a weight sensor operatively coupled to the fluid tank for measuring the volume of fluid in the fluid tank.

[0017] In one aspect, the system includes a fluid level sensor operatively coupled to the fluid tank for determining the volume of fluid in the fluid tank.

[0018]

[0018] In another aspect, the system includes a first flow sensor positioned in or near a first input / output port and a second flow sensor positioned in or near a second input / output port, the first and second flow sensors configured to calculate the volume of fluid in the fluid tank.

[0019]

[0019] A method of filling an ultrasonically coupled container is provided, comprising pumping fluid from a fluid source to a fluid tank in a remote cart through a degassing mechanism to remove a first percentage of gas from the fluid, and pumping fluid from the fluid tank in the remote cart to the ultrasonically coupled container through a degassing mechanism to remove a second percentage of gas from the fluid.

[0020]

[0020] In some embodiments, pumping fluid from a fluid source to a fluid tank further includes fluidly connecting a first input / output port of the first tubing set to the fluid source, fluidly connecting a second input / output port of the first tubing set to the fluid tank, and controlling a first pump to move fluid through the first tubing set and the degassing mechanism.

[0021]

[0021] In some embodiments, pumping the fluid from the fluid tank to the ultrasonically connected container further includes fluidly connecting a first input / output port of the first tubing set to the ultrasonically connected container, fluidly connecting a second input / output port of the first tubing set to the fluid tank, and controlling a first pump to move the fluid through the first tubing set and the degassing mechanism.

[0022] In some embodiments, the method includes recirculating the fluid from the fluid tank through the first tubing set and the degassing mechanism to remove a third percentage of the gas from the fluid.

[0023]

[0023] In one embodiment, recirculating the fluid further includes fluidly connecting the first and second input / output ports of the first tubing set to a fluid tank, and controlling a first pump to move the fluid through the first tubing set and degassing mechanism and back into the fluid tank.

[0024] In some embodiments, the first and second percentages comprise 20 to 40 percent.

[0025] In one aspect, the method includes pumping fluid from an ultrasonically coupled container to a waste container.

[0026]

[0026] In some embodiments, pumping the fluid from the ultrasonically connected container to the waste container further includes fluidly connecting a third input / output port of the second tubing set to the ultrasonically connected container and controlling a second pump to move the fluid through the second tubing set and into the waste container.

[0027]

[0027] A histotripsy system is provided, comprising an ultrasound medium container (UMC) configured to be placed on a patient, a membrane coupled to the UMC and configured to contain an ultrasound coupling medium within the UMC and form an acoustic interface with the patient's skin, a main tank, first and second tubing sets removably coupled to the main tank, a pump configured to pump fluid into the main tank and transfer fluid from the main tank to the UMC, and a fluidics cart including a degassing mechanism in line with the first and second tubing sets to control the percentage of oxygen in the ultrasound coupling medium for optimized acoustic coupling of the histotripsy therapy transducer to the patient.

[0028] In some embodiments, the first and second tubing sets are disposable.

[0029] In another aspect, the first and second tubing sets are removably coupled to a fluidics cart.

[0030]

[0030] In some embodiments, the pump is disposable.

[0031] In one embodiment, the pump is removably coupled to a fluidics cart.

[0032]

[0032] A fluidics system configured to support acoustic coupling of an ultrasonic transducer to a patient, comprising: a storage container, a fluid tank within the storage container, a disposable first tubing set having a first input / output port and a second input / output port, a degassing mechanism fluidly connected to the disposable first tubing set, a first pump operatively connected to the disposable first tubing set, and a processor operatively connected to the first pump, the processor configured to control the fluidics system to operate in a fluid transfer configuration in which the first input / output port is fluidly connected to the acoustic coupling container and the second input / output is fluidly connected to the fluid tank, and the first pump is controlled in a second operating direction to move fluid from the fluid tank into the second input / output port, through the degassing mechanism, out of the first input / output port, and into the acoustic coupling container to remove a preset percentage of gas from the fluid.

[0033]

[0033] A fluidics system configured to support acoustic coupling of an ultrasound transducer to a patient, comprising: a portable cart housing, a fluid tank within the portable cart housing, a first tubing set having a first input / output port and a second input / output port, a degassing mechanism fluidly connected to the first tubing set, a first pump operatively connected to the first tubing set, and a processor operatively connected to the first pump, comprising: 1) a filling configuration in which the first input / output port is fluidly connected to a fluid source and the second input / output is fluidly connected to the fluid tank, the first pump being controlled in a first operating direction to move fluid from the fluid source into the first input / output port, through the degassing mechanism, out the second input / output port, and into the fluid tank to remove a first preset percentage of gas from the fluid; 2) a filling configuration in which the first and a fluidics system comprising: a processor configured to control the fluidics system to operate in: 1) a circulation configuration, in which the second input / output port is fluidly coupled to a fluid tank, and the first pump is automatically controlled in a first operating direction or a second operating direction to circulate fluid from the fluid tank through the first tubing set and the degassing mechanism to remove a second preset percentage of gas from the fluid; and 2) a fluid transfer configuration, in which the first input / output port is fluidly coupled to an acoustically coupled container and the second input / output is fluidly coupled to the fluid tank, and the first pump is controlled in a second operating direction to move fluid from the fluid tank into the second input / output port, through the degassing mechanism, out of the first input / output port, and into the acoustically coupled container to remove a third preset percentage of gas from the fluid.

[0034]

[0034] A fluidics system configured to support acoustic coupling of an ultrasonic transducer to a patient, comprising: a storage container, a fluid tank within the storage container, a sensor operatively connected to the fluid tank, the sensor configured to determine the volume of fluid in the fluid tank, a first tubing set having a first input / output port and a second input / output port, a degassing mechanism fluidly connected to the first tubing set, a first pump operatively connected to the first tubing set, and a processor operatively connected to the first pump and the sensor, the processor configured to control the fluidics system to draw fluid into the first input / output port of the first tubing set and release fluid into the fluid tank having the second input / output port of the first tubing set until the volume of fluid as determined by the sensor is equal to a desired fill volume.

[0035] In some aspects, the sensor comprises a weight sensor.

[0036] In another aspect, the sensor comprises a fluid level sensor.

[0037]

[0037] An ultrasound therapy method comprising: pumping fluid from a fluid source into an acoustically coupled container in contact with a patient through a degassing mechanism to remove at least 50 percent of dissolved oxygen from the fluid; and placing an ultrasound transducer in the fluid in the acoustically coupled container to acoustically couple the ultrasound transducer to the patient with the fluid.

[0038] 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: [Brief explanation of the drawings]

[0039] [Figure 1A]

[0039] FIG. 1 is a diagram of an ultrasound imaging and therapy system. [Figure 1B] FIG. 1 is a diagram of an ultrasound imaging and therapy system. [Figure 2]

[0040] FIG. 1 is a diagram of one embodiment of a histotripsy therapy and imaging system with a coupling system. [Figure 3A]

[0041] FIG. 1 is a diagram of one embodiment of a fluidics system including a fluidics cart. [Figure 3B] FIG. 1 is a diagram of one embodiment of a fluidics system including a fluidics cart. [Figure 3C] FIG. 1 is a diagram of one embodiment of a fluidics system including a fluidics cart. [Figure 3D] FIG. 1 is a diagram of one embodiment of a fluidics system including a fluidics cart. [Figure 3E] FIG. 1 is a diagram of one embodiment of a fluidics system including a fluidics cart. [Figure 3F] FIG. 1 is a diagram of one embodiment of a fluidics system including a fluidics cart. [Figure 3G] FIG. 1 is a diagram of one embodiment of a fluidics system including a fluidics cart. [Figure 3H] FIG. 1 is a diagram of one embodiment of a fluidics system including a fluidics cart. [Figure 3I] FIG. 1 is a diagram of one embodiment of a fluidics system including a fluidics cart. [Figure 3J] FIG. 1 is a diagram of one embodiment of a fluidics system including a fluidics cart. [Figure 4]

[0042] FIG. 10 is a diagram of another embodiment of a fluidics system. [Figure 5A]

[0043] FIG. 1 is a diagram of a disposable kit containing disposable components of a fluidics system. [Figure 5B] FIG. 1 is a diagram of a disposable kit containing disposable components of a fluidics system. [Figure 5C]FIG. 1 is a diagram of a disposable kit containing disposable components of a fluidics system. [Figure 5D] FIG. 1 is a diagram of a disposable kit containing disposable components of a fluidics system. [Figure 5E] FIG. 1 is a diagram of a disposable kit containing disposable components of a fluidics system. DETAILED DESCRIPTION OF THE INVENTION

[0040]

[0044] The disclosed systems, methods, and devices can be used for open, minimally invasive (laparoscopic and percutaneous), robotic (integrated into robotically enabled medical systems), endoscopic, or fully percutaneous extracorporeal non-invasive acoustic cavitation for the treatment of healthy, diseased, and / or injured tissue, including, but not limited to, tissue disruption, cutting, skeletonizing, and ablation. Furthermore, histotripsy can be used to create cytoskeleton formation, enabling subsequent tissue regeneration through the application of stem cells and other supportive means, due to its tissue selectivity. Finally, histotripsy can be used to trigger the release of delivered agents, such as chemotherapy and immunotherapy, by locally triggering the release of these agents through the application of acoustic energy to the target. As described below, acoustic cavitation systems can include various subsystems, including carts, therapy, integrated imaging, robotics, couplings, and software. The system may also include various other components, ancillary equipment and accessories, including but not limited to computers, cables and connectors, networking devices, power supplies, displays, drawers / storage, doors, wheels, and various simulation and training tools. All systems, methods and means for creating / controlling / implementing Histotripsy are considered part of this disclosure, including any new related inventions disclosed herein.

[0041]

[0045] 1A generally illustrates a histotripsy system 100 according to the present disclosure, including a therapy transducer 102, an imaging system 104, a display and control panel 106, a robotic positioning arm 108, and a cart 110. The system may further include an ultrasound coupling interface and a source of coupling media, not shown.

[0042]

[0046] 1B is a bottom view of the therapy transducer 102 and imaging system 104. As shown, the imaging system can be located at the center of the therapy transducer. Yet, other embodiments can include an imaging system located at other locations within the therapy transducer, or perhaps integrated directly into the therapy transducer. In some embodiments, the imaging system is configured to produce real-time imaging at the focal point of the therapy transducer. The system also allows multiple imaging transducers to be placed within the therapy transducer to simultaneously provide multiple views of the target tissue and combine these images into a single 3D image.

[0043]

[0047] The histotripsy system may include one or more of a variety of subsystems, including a therapy subsystem capable of creating, applying, focusing, and delivering acoustic cavitation / histotripsy through one or more therapy transducers; an integrated imaging subsystem (or connection thereto) that allows real-time visualization of the treatment site and histotripsy effects throughout the procedure; a robotics positioning subsystem for mechanically and / or electronically steering the therapy transducer, which may further connect to / support or interact with the coupling subsystem to enable acoustic coupling between the therapy transducer and the patient; and software for communicating with, controlling, and interfacing with the system and computer-based control system (and other external systems), as well as various other components, auxiliary instruments, and accessories, including one or more user interfaces and displays and associated guided workflows, all functioning partially or together. The system may further include various fluidics and fluid management components, including, but not limited to, pumps, valves, and flow control, temperature and degassing control, and irrigation and aspiration capabilities, as well as providing and storing fluids. The system may also include various power sources and protection devices.

[0044]

[0048] As described above, the histotripsy system can include integrated imaging. Yet, in other embodiments, the histotripsy system can be configured to interface with a separate imaging system, such as a C-arm, fluoroscope, cone-beam CT, MRI, etc., to provide real-time imaging during histotripsy therapy. In some embodiments, the histotripsy system can be sized and configured to fit within a C-arm, fluoroscope, cone-beam CT, MRI, etc.

[0045] cart

[0049] The cart 110 may be configured overall in a variety of styles and form factors based on the specific intended use and procedure. In some cases, a system may include multiple carts configured in similar or different arrangements. In some embodiments, the cart may be configured and arranged for use in a radiology environment, and possibly in conjunction with imaging (e.g., CT, cone-beam CT, and / or MRI scans). In other embodiments, the cart may be arranged for use in an operating room and sterile environment for open or laparoscopic surgery and endoscopic applications, or in a robotic-enabled operating room, and may be used alone or as part of a surgical robotic procedure, with the surgical robot performing specific tasks before, during, or after use of the system and the performance of acoustic cavitation / histotripsy. Accordingly, and depending on the procedure environment based on the aforementioned embodiments, the cart may be arranged to provide sufficient workspace and access to various anatomical locations on the patient (e.g., torso, abdomen, flank, head and neck, etc.), as well as to provide workspace for other systems (e.g., anesthesia cart, laparoscopic tower, surgical robot, endoscopic tower, etc.).

[0046]

[0050] The cart may also operate with a patient surface (e.g., a table or bed) to allow the patient to be presented and repositioned in a multitude of positions, angles, and orientations, including allowing changes to such to be made pre-, peri-, and post-operatively. The cart may further be capable of interfacing and communicating with one or more external imaging or image data management and communication systems, including but not limited to one or more modalities of ultrasound, CT, fluoroscopy, cone beam CT, PET, PET / CT, MRI, optical, ultrasound, and image fusion and / or image flow; supporting a procedure and / or use environment, including physical / mechanical interoperability (e.g., compatibility within a cone beam CT workspace for collecting pre-, peri-, and / or post-histotripsy imaging data); and accessing and displaying patient medical data, including but not limited to laboratory and historical medical record data.

[0047]

[0051] In some embodiments, one or more carts may be configured to operate together. By way of example, one cart may comprise a bedside mobile cart equipped with one or more robotic arms associated with therapy transducers, therapy generators / amplifiers, etc., while a companion cart operating with and away from the patient may comprise integrated imaging and console / display for controlling the robot and therapy facets similar to a surgical robot and master / slave configuration.

[0048]

[0052] In some embodiments, the system may include multiple carts, all slave to one master cart, equipped to perform acoustic cavitation procedures. In some arrangements and in some cases, one cart configuration may allow for storage of specific subsystems at a distance that reduces clutter in the operating room, while another cooperating cart may essentially include bedside subsystems and components (e.g., delivery systems and therapies).

[0049]

[0053] Numerous permutations and configurations of cart designs are possible, and these examples are not intended to limit the scope of this disclosure in any way.

[0050] Histotripsy

[0054] Histotripsy uses short, high-amplitude focused ultrasound pulses to generate a dense, energetic "bubble cloud" capable of targeted disruption and destruction of tissue. Histotripsy has the ability to create controlled tissue erosion when directed at tissue interfaces, including tissue / fluid interfaces, as well as well-defined tissue disruption and destruction at the subcellular level when targeted at bulk tissue. Unlike other forms of ablation, including thermal and radiation-based modalities, Histotripsy does not rely on heat, cold, or ionizing energy to treat tissue. Instead, Histotripsy uses acoustic cavitation generated at a focal point to mechanically affect tissue structure, potentially liquefying, suspending, dissolving, and / or disrupting tissue into subcellular components.

[0051]

[0055] Histotripsy can be applied in various forms, including: 1) Intrinsic Threshold Histotripsy: A pulse is delivered with one to two cycles of high-amplitude reverse / extensional pressure that exceeds the intrinsic threshold for generating cavitation in the medium (e.g., approximately 24-28 MPa for aqueous soft tissue). 2) Shock-Scattering Histotripsy: A pulse of three to 20 cycles is typically delivered within a duration. Scattered shock waves (compression / forward phase) from the initial individual microbubbles generate a counter shock wave that constructively interferes with the incoming reverse / extensional phase to form a high-amplitude reverse / extensional phase that exceeds the intrinsic threshold. In this way, a cluster of cavitation microbubbles is generated. The amplitude of the extensional phase of the pulse is sufficient to cause bubble nuclei in the medium to undergo inertial cavitation within the focal zone throughout the duration of the pulse. These nuclei scatter the incident shock wave, reversing it and constructively interfering with it to exceed the threshold for intrinsic nucleation. and 3) boiling histotripsy: employing pulses of approximately 1-20 ms in duration. Absorption of the impinging pulse rapidly heats the medium, thereby reducing the intrinsic nucleus threshold. When this intrinsic threshold coincides with the peak negative pressure of the incident wave, a boiling bubble forms at the focus.

[0052]

[0056] The large pressures generated at the focal point generate a cloud of acoustic cavitation bubbles above a certain threshold, causing localized stress and tension within the tissue, as well as mechanical collapse without significant heat accumulation. At pressure levels where cavitation is not generated, minimal effects are observed in the tissue at the focal point. This cavitation effect is only observed at pressure levels significantly greater than those that define the inertial cavitation threshold in water for similar pulse durations, around 10 to 30 MPa peak negative pressure.

[0053]

[0057] Histotripsy can be performed in numerous ways and under different parameters. Histotripsy can be performed completely noninvasively by acoustically coupling a focused ultrasound transducer to the patient's skin and delivering acoustic pulses through the skin to the focal zone (treatment zone and site) through the overlying (and intervening) tissue. Histotripsy application is not limited to percutaneous approaches, but can be applied through any means that allows transducer contact with tissue, including open, laparoscopic, percutaneous, and robotic surgical procedures. This allows for further targeting, planning, directing, and observation under direct visualization via ultrasound imaging, given that the bubble cloud generated by Histotripsy can be visible, for example, as a highly dynamic echogenic region on B-mode ultrasound images, allowing continuous visualization throughout its use (and associated procedures). Similarly, treated and disrupted tissue exhibits dynamic changes (typically reductions) in echogenicity that can be used to assess, plan, observe, and monitor treatment.

[0054]

[0058] Generally, in histotripsy treatment, an ultrasound pulse with one or more acoustic cycles is applied, and bubble cloud generation relies on the pressure-relief scattering of a positive shock front (sometimes exceeding 100 MPa, P) from an initially initiated, slightly dispersed bubble (or single bubble). This is referred to as the "shock scattering mechanism."

[0055]

[0059] This mechanism relies on a single (or a few sparsely dispersed) bubble being initiated during the initial negative half-cycle of the pulse at the transducer focal point. A microbubble cloud is then generated by the pressure-relief backscattering of a high-peak positive shock front from these sparsely initiated bubbles. These backscattered high-amplitude rarefaction waves exceed the intrinsic threshold, thus creating a localized high-density bubble cloud. Each subsequent acoustic cycle then induces further cavitation by backscattering from the bubble cloud's surface, which grows toward the transducer. As a result, an elongated high-density bubble cloud growing along the acoustic axis opposite to the ultrasound propagation direction is observed in the impact scattering mechanism. This impact scattering process makes bubble cloud generation dependent not only on the peak negative pressure but also on the number of acoustic cycles and the amplitude of the positive shock. Without at least one strong shock front caused by nonlinear propagation, a high-density bubble cloud is not generated when the peak negative half-cycle falls below the intrinsic threshold.

[0056]

[0060] When ultrasound pulses of less than two periods are applied, impact scattering can be minimized, and the generation of a dense bubble cloud depends on the negative half-period of the applied ultrasound pulse exceeding the "intrinsic threshold" of the medium. This is called the "intrinsic threshold mechanism."

[0057]

[0061] This threshold can be in the range of 26-30 MPa for soft tissues with a high water content, such as human tissue. In some embodiments, using this intrinsic threshold mechanism can result in well-defined and more predictable spatial extent of the lesion. With peak negative pressures (P-) not significantly higher than this threshold, subwavelength reproducible lesions as small as half the transducer's -6 dB beamwidth can be generated.

[0058]

[0062] With high-frequency histotripsy pulses, the minimum reproducible lesion size is smaller, which is beneficial for applications requiring precise lesion creation. However, high-frequency pulses are more susceptible to attenuation and aberrations, making treatment at greater penetration depths (e.g., ablation deep within the body) or through highly aberration-prone media (e.g., transcranial procedures, or procedures in which the pulse is transmitted through bone) uncertain. Histotripsy also applies because low-frequency "pump" pulses (typically <2 cycles and having frequencies between 100 kHz and 1 MHz) can be applied together with high-frequency "probe" pulses (typically <2 cycles and having frequencies greater than 2 MHz or ranging between 2 MHz and 10 MHz), and the peak negative pressures of the low and high-frequency pulses can structurally interfere to exceed the intrinsic threshold of the target tissue or media. Low-frequency pulses, which are more tolerant of attenuation and aberrations, can raise peak negative pressure P- levels in a region of interest (ROI), while high-frequency pulses, which offer greater precision, can pinpoint target locations within the ROI and raise peak negative pressure P- above intrinsic thresholds. This approach is sometimes referred to as "dual frequency," "dual beam histotripsy," or "parametric histotripsy."

[0059]

[0063] Additional systems, methods, and parameters for implementing optimized Histotripsy using impact scattering, intrinsic thresholds, and various parameters enabling frequency compounding and bubble manipulation are included herein as part of the systems and methods disclosed herein, including additional means for controlling such Histotripsy effects as related to steering and positioning the focal spot and simultaneously managing tissue effects (e.g., focal thermal collateral damage) at the treatment site or within intervening tissue. Furthermore, various systems and methods are disclosed as being included as part of the present disclosure, including future contemplated embodiments of such, which may include multiple parameters such as, but not limited to, frequency, operating frequency, center frequency, pulse repetition frequency, pulses, bursts, number of pulses, period, pulse length, pulse amplitude, pulse duration, delay, burst repetition frequency, sets of the former, multiple sets of loops, multiple and / or different sets of loops, sets of loops, and various combinations or permutations thereof.

[0060] Therapy Components

[0064] The therapy subsystem can operate with other subsystems to create, optimize, deliver, visualize, monitor, and control acoustic cavitation, also referred to herein and hereinafter as "histotripsy" and its derivatives, including boiling histotripsy and other thermal high frequency ultrasound approaches. It is noted that the disclosed invention may also benefit from other acoustic therapies that do not include cavitation, mechanical, or histotripsy components. The therapy subsystem can include, among other features, an ultrasound therapy transducer and pulse generator system configured to deliver ultrasound pulses to tissue.

[0061]

[0065] To produce and deliver histotripsy and histotripsy derivatives, the therapy subsystem may also include components including, but not limited to, one or more function generators, amplifiers, therapy transducers, and power sources.

[0062]

[0066] Therapy transducers can comprise single or multiple elements configured to be excited with high-amplitude electrical pulses (>1000V, or any other voltage that may cause harm to the body). The amplitude required to drive a therapy transducer for histotripsy varies depending on the transducer design and material used (e.g., solid or polymer / piezoelectric composites, including ceramic or single crystal), and the transducer center frequency, which is directly proportional to the thickness of the piezoelectric material. Thus, transducers operating at high frequencies require lower voltages to generate a given surface pressure than those required by low-frequency therapy transducers. In some embodiments, the transducer elements are formed using piezoelectric polymer composite materials or solid piezoelectric materials. Furthermore, the piezoelectric material can be of polycrystalline / ceramic or single-crystal composition. In some embodiments, the transducer elements can be formed using silicon using MEMs technology, including CMUT and PMUT designs.

[0063]

[0067] In some embodiments, the function generator may include a field programmable gate array (FPGA) or other suitable function generator. The FPGA may be configured with parameters previously disclosed herein, including but not limited to frequency, pulse repetition frequency, burst, number of bursts, where a burst may include a pulse, number of pulses, pulse length, pulse duration, delay, burst repetition frequency or duration, a set of bursts may include a set of parameters, a set of loops may include various sets of parameters with or without a delay or various delays, multiple loop sets of various time delays and independently controlled, and various combinations and permutations of such, throughout, may be repeated, and / or new loop sets may be introduced.

[0064]

[0068] In some embodiments, the generator or amplifier may be a general-purpose single-cycle or multi-cycle pulse generator configured to support drive via Class D or inductive drive and across all envisioned clinical applications and use environments, some of which are further discussed later in this disclosure. In other embodiments, the Class D or inductive current driver may be configured with converter and / or automatic converter drive circuitry to further provide step-up / down components and, in some cases, preferably to enable amplitude step-up. These may also include inherent protection features to further support the system and provide the ability to protect other components of the system (e.g., therapy transducer and / or amplifier circuitry) and / or the user from various threats, including, but not limited to, the use environment, electrical safety threats that could potentially lead to the system and therapy system, and user harm, adverse effects, or problems.

[0065]

[0069] The disclosed generators can enable and support the system's ability to select, vary, and control (through available software tools) various parameters, including but not limited to those previously disclosed, as well as the ability to start / stop therapy, set and read voltage levels, pulse and / or burst repetition frequencies, number of cycles, duty cycles, active channels and delays, etc., modulate pulse amplitude on fast time scales independent of the high voltage source, and / or perform other service, diagnostic, or therapeutic features.

[0066]

[0070] In some embodiments, the therapy subsystem and / or its components, such as amplifiers, may further comprise integrated computer processing capabilities, may be networked, connected, accessed, and / or may be removable / portable, modular, and / or interchangeable between systems, and / or may be driven / commanded from / by other systems, or various combinations. Other systems may include other acoustic cavitation / histotripsy, HIFU, HITU, radiation therapy, radiofrequency, microwave, and cryoablation systems, navigation and localization systems, open surgery, laparoscopic, single incision / single port, endoscopic, and non-invasive surgical robotics, laparoscopic or surgical towers with other energy-based or vision systems, surgical system racks or booms, imaging carts, etc.

[0067]

[0071] In some embodiments, the amplifier or amplifiers may comprise a class-D amplifier and associated drive circuitry, including matching network components. Depending on the electrical impedance of the transducer element and the selection of matching network components (e.g., an LC circuit made from a series inductor L1 and a parallel capacitor C1), the combined impedance can be set aggressively low to produce the high-amplitude electrical waveform required to drive the transducer element. The maximum amplitude of the class-D amplifier depends on the circuit components used, including the drive MOSFET / IGBT transistor, matching network components or inductors, and transformer or autotransformer, and may typically be in the low kV (e.g., 1-3 kV) range.

[0068]

[0072] The therapy transducer elements are excited with an electrical waveform having an amplitude (voltage) sufficient to produce a pressure output sufficient for histotripsy therapy. The excitation field can be defined as the required waveform voltage per thickness of the piezoelectric element. For example, a piezoelectric element operating a transducer at 1 MHz will be half the thickness of an equivalent 500 kHz element, and will therefore require half the voltage to achieve the same electric field and surface pressure.

[0069]

[0073] The therapy subsystem can also include therapy transducers of various designs and working parameters to support use in various treatments (and treatment environments). The system may be configured with one or more therapy transducers that are further interchangeable and can operate with various aspects of the system in similar or different ways (e.g., can interface to a robotic arm using common interfaces and interchange features, or conversely, can be adapted to operate with application-specific imaging probes, where different imaging probes can interface and integrate with therapy transducers in specifically different ways).

[0070]

[0074] Therapy transducers may be constructed from a variety of parameters that may include size, shape (e.g., rectangular or circular, anatomically curved housing, etc.), geometry, focal length, number of elements, size of elements, distribution of elements (e.g., number of rings in an annular pattern transducer, size of rings), frequency, enabling electronic beam steering, etc. Transducers may be constructed from a variety of materials (e.g., piezoelectric, silicon, etc.), form factors and types (e.g., machined elements, chip-based, etc.), and / or by a variety of methods of their fabrication.

[0071]

[0075] Transducers can be designed and optimized for clinical applications (e.g., abdominal tumors, peripheral vascular disease, fat ablation, etc.) and desired outcomes (e.g., acoustic cavitation / histotripsy without thermal injury to intervening tissue), as well as to provide a wide range of working conditions, including relatively shallow, superficial targets (e.g., thyroid or breast nodules) and deeper or more difficult-to-reach targets such as centrally located liver or brain tumors. They can be configured to enable acoustic cavitation / histotripsy under various parameters and sets, as enabled by the system components described above (e.g., function generators and amplifiers, etc.), including, but not limited to, frequency, pulse repetition rate, pulses, number of pulses, pulse length, pulse duration, delay, repetition, synchronization delay, synchronization period, synchronization pulse, synchronization pulse delay, various loop sets, etc., and permutations thereof. Transducers can also be designed to enable activation of drug payloads stored in tissue through various means, including injection, displacement, or delivery in micelles or nanostructures.

[0072] Integrated Imaging

[0076] The disclosed system can include various imaging modalities that allow the user to visualize, monitor, and collect / use feedback of the patient's anatomy, related areas of interest and treatment / treatment site, as well as surrounding and intervening tissues, to assess, plan, and perform treatment and adjust treatment parameters as needed. Imaging modalities can include various ultrasound, X-ray, CT, MRI, PET, fluoroscopic, optical, contrast- or agent-enhanced versions, and / or various combinations thereof. It is further disclosed that various image processing and characterization techniques can also be utilized to provide enhanced visualization and user decision-making. These can be selected or commanded manually by the user or automatically by the system. The system can be configured to enable side-by-side imaging, toggling, overlay, 3D reconstruction, segmentation, registration, multimodal image fusion, image flow, and / or any other method that allows the user to identify, define, and communicate various aspects of using imaging during treatment as displayed in various system user interfaces and displays. Examples may include, by way of non-limiting example, identifying important structures such as vessels, ducts, nerves, ureters, fissures, capsules, tumors, tissue trauma / injury / disease, other organs, connective tissues, and / or one or more important structures in context with each other (e.g., tumor-draining lymphatics or vasculature, or tumors close to organ capsules or other underlying organs) to locate, display, and characterize potential treatment sites within, on, and / or surrounding an area, organ system, organ, or tissue of interest.

[0073]

[0077] The system may be configured to include on-board integrated imaging hardware, software, sensors, probes, and software, and / or may be configured to communicate and interface with external imaging and image processing systems. The aforementioned components may also be integrated into the system's therapy subsystem components, including probes, imaging arrays, or the like, and electrically, mechanically, or electromechanically integrated with the therapy transducer. This may, in part, provide the ability to perform geometrically aligned imaging and therapy, with therapy directly within the field of view and possibly in line with the imaging. In some embodiments, this integration may provide a fixed orientation of the imaging capability (e.g., imaging probe) to the therapy transducer in a contextualized manner. In other embodiments, the imaging solution may have the ability to move or adjust its position, including modifying angle, range (e.g., distance from the therapy transducer or patient), rotation (e.g., imaging plane in the example of an ultrasound probe), and / or other parameters, including dynamically moving / adjusting them while actively imaging. The imaging component or probe may be encoded such that its orientation and position relative to another aspect of the system, such as a therapy transducer and / or a robotic-enabled positioning component, may be determined.

[0074]

[0078] In one embodiment, the system can include an on-board ultrasound further configured to allow the user to visualize, monitor, and receive feedback about the treatment site through the system display and software, including enabling ultrasound imaging and characterization (and its various forms), ultrasound-guided planning, and ultrasound-guided therapy, all in real time. The system can be configured to allow the user to image the patient manually (e.g., by hand or using a robotic-enabled imager), semi-automated, or fully automated means.

[0075]

[0079] In some embodiments, imaging feedback and monitoring can include monitoring changes in backscatter from the bubble cloud, backscatter speckle reduction, backscatter speckle statistics, tissue mechanical properties (i.e., elastography), tissue perfusion (i.e., ultrasound contrast), shear wave propagation, acoustic emission, electrical impedance tomography, and / or various combinations thereof, including those displayed in or integrated with other forms of imaging (e.g., CT or MRI).

[0076]

[0080] In some embodiments, imaging including feedback and monitoring from backscatter from the bubble cloud can be used as a method for quickly determining whether the histotripsy process has been initiated, properly maintained, or possibly extinguished. For example, this method allows drug delivery, tissue erosion, and the like to be continuously monitored in real time. The method can also provide feedback that allows the histotripsy process to be initiated at high intensity and maintained at much lower intensity. For example, backscatter feedback can be monitored by any transducer or ultrasound imager. By measuring the feedback of the therapy transducer, an accessory transducer can be configured to deliver interrogation pulses or passively detect cavitation. Furthermore, the nature of the received feedback can be used to adjust acoustic parameters (and associated system parameters) to optimize drug delivery and / or the tissue erosion process.

[0077]

[0081] In some embodiments, imaging, including feedback and monitoring from backscatter, and speckle reduction may be configured in the system.

[0078]

[0082] In systems with feedback and monitoring via backscatter, as well as by way of background, as tissue is gradually mechanically subdivided—in other words, homogenized, nonviable, or eroded—this process results in changes in the size and distribution of acoustic scatterers. At some point in the process, the scattering particle size and density are reduced to a level where ultrasound is barely scattered, or the amount scattered is significantly reduced. This results in a significant reduction in speckle, which is the coherent constructive and destructive interference pattern of bright and dark spots seen in images when a coherent illumination source, in this case ultrasound, is used. After some treatment time, speckle reduction results in dark areas within the treatment volume. The amount of speckle reduction is related to the amount of tissue subdivision and can therefore be related to the size of the remaining tissue fragments. When this size is reduced to a subcellular level, it is not expected that cells will survive. Thus, treatment can proceed until the desired speckle reduction level is reached. Speckle is easily seen and evaluated on standard ultrasound imaging systems. Specialized transducers and systems, including those disclosed herein, can also be used to evaluate backscatter changes.

[0079]

[0083] Furthermore, in systems with feedback and monitoring via speckle, as well as by means of background, the image persists from frame to frame and remains largely unchanged unless the scattering distribution changes and the imaged object moves. Nevertheless, scattering may change enough to be detected by signal processing and other means long before it is reduced to a size sufficient to cause speckle reduction. This collection of techniques can act as a detector of speckle statistical changes. For example, the size and location of one or more speckles in the image begin to decorrelate before observable speckle reduction occurs. Speckle decorrelation, after appropriate motion compensation, can be a sensitive measure of tissue mechanical inviability and therefore a measure of therapy efficacy. This feedback and monitoring technique can enable early observation of changes resulting from the acoustic cavitation / histotripsy process and can identify tissue changes (e.g., the onset of erosion) before substantial or complete tissue effects occur. In one embodiment, this method can be used to monitor acoustic cavitation / histotripsy processes for enhanced drug delivery when the treatment site / tissue is temporarily rendered non-viable and tissue damage / erosion is not desired. In other embodiments, this can involve speckle decorrelation with scattering shift in an increasingly fluidized therapy volume, for example, when partial or complete tissue erosion is desired.

[0080]

[0084] For systems with feedback and monitoring via elastography, as well as background measures, as the treatment site / tissue is further subdivided (homogenized, rendered nonviable, or eroded) per acoustic cavitation / histotripsy effect, its mechanical properties change from a soft but interconnected solid to a mucus or paste with few long-range interactions. These changes in mechanical properties can be measured by various imaging modalities, including MRI and ultrasound imaging systems. For example, ultrasound pulses can be used to generate forces (i.e., radiation forces) on localized volumes of tissue. Tissue response (displacement, tension, and velocity) can be significantly altered during histotripsy treatment, allowing the state of tissue nonviability to be determined by imaging or other quantitative means.

[0081]

[0085] The system can also provide feedback and monitoring via shear wave propagation changes. As a background measure, tissue repartitioning makes the tissue more fluid and less solid, and fluid systems generally do not propagate shear waves. Therefore, the degree of tissue fluidization provides an opportunity for feedback and monitoring of the histotripsy process. For example, ultrasound and MRI imaging systems can be used to observe shear wave propagation. The disappearance of such waves in the treated volume is used as a measure of tissue destruction or non-viability. In one system embodiment, the system and support subsystems can be used to generate and measure interacting shear waves. For example, two adjacent ultrasound foci can affect tissue by pushing it in a specific manner. If the adjacent foci are in a fluid, the shear waves will not propagate to interact with each other. If the tissue is not fluidized, the interaction must be detected externally, for example, by a difference frequency that is detected only when two shear waves interact nonlinearly, and the disappearance of the waves can be correlated to tissue damage. Therefore, the system may be configured to use this modality to enhance feedback and monitoring of acoustic cavitation / histotripsy procedures.

[0082]

[0086] For systems with feedback and monitoring via acoustic emissions, as well as background measures, when a tissue volume is subdivided, its effect on acoustic cavitation / histotripsy (e.g., here, bubble clouds) is altered. For example, bubbles may grow larger and have different lifetimes, disrupting the varying properties of intact versus fluidized tissue. Bubbles may also move and interact after tissue is subdivided, creating larger bubbles or cooperative interactions between bubbles, all of which can produce changes in acoustic emissions. These emissions can be heard and change during treatment. Analysis of these changes and their correlation with therapy efficacy allows for monitoring of therapy progress and can be configured as a system feature.

[0083]

[0087] In systems with feedback and monitoring via electrical impedance tomography, and as a background measure, an impedance map of the therapy site can be generated based on the spatial electrical characteristics throughout the therapy site. Imaging of the patient's therapy site's conductivity or permittivity can be inferred from skin surface electrical measurements. Conductive electrodes are affixed to the patient's skin, and a small alternating current is applied to some or all of the electrodes. One or more known currents are injected into the surface, and voltage is measured at several points using the electrodes. The process can be repeated for different configurations of applied current. The resolution of the resulting image can be adjusted by varying the number of electrodes employed. Measures of the therapy site's electrical properties within the skin surface can be obtained from the impedance map, and changes and locations of acoustic cavitation / histotripsy (e.g., specifically bubble clouds), as well as histotripsy processes, can be monitored using this as configured in the system and supporting subsystems.

[0084]

[0088] Through the system software and user interface and display, the user may be enabled to further select, annotate, mark, highlight, and / or outline various regions of interest or treatment sites, as well as predefined treatment targets (on the image) that can be used to command and direct the system where to image, test, and / or treat. In some arrangements, the user may perform the procedure using a manual ultrasound probe (e.g., a diagnostic handheld probe). In other arrangements, the system may use a robotic and / or electro-mechanical positioning system to perform the procedure in a system-directed and / or automated manner, or conversely, the system may allow for a combination of manual and automated usage.

[0085]

[0089] The system may further include the capability to perform image registration, including imaging and image dataset registration, to enable navigation and localization of the system to the patient, including the treatment site (e.g., tumor, critical structures, bony anatomy, anatomical structures and their identifying features, etc.). In one embodiment, the system allows a user to image and identify an area of ​​interest, such as the liver, using integrated ultrasound and select and mark a tumor (or a surrogate marker) contained within the liver through / displayed in the system software, the system registering the image data to a coordinate system defined by the system, further enabling the therapy and robotics subsystem of the system to deliver synchronized acoustic cavitation / histotripsy to the marked tumor. The system may be capable of registering various image sets, including those previously disclosed, with each other and providing navigation and localization (e.g., of a therapy transducer to a CT or MRI / ultrasound fusion image with the therapy transducer and robotics subsystem tracking to the image).

[0086]

[0090] The system may also be capable of operating in a variety of interventional endoscopic and surgical environments, including alone and with other systems (surgical / laparoscopic towers, vision systems, endoscopic systems and towers, ultrasound-enabled endoscopic ultrasound (flexible and rigid), percutaneous / endoscopic / laparoscopic and minimally invasive navigation systems (e.g., optical, electromagnetic, shape-sensing, ultrasound-enabled, etc.) that may operate with or include various optical imaging capabilities (e.g., fiber and / or digital). The disclosed system may be configured to operate with these systems, and in some embodiments, operate in conjunction with them, or in other embodiments, all or part of the system may be integrated into the above systems / platforms (e.g., acoustic cavitation / histotripsy-enabled endoscopic systems or laparoscopic surgical robots). In many of these environments, the therapy transducers may be used, for example, at or around the time of use of an optically guided endoscope / bronchoscope, or as another example, a laparoscopic robot (e.g., Intuitive Digital Vinci*Xi system) is viewing / manipulating the tissue / treatment site. Additionally, these embodiments and examples can include cases where the other systems / platforms described above are used to deliver fluid (locally) to enable the creation of artificial acoustic windows that may not exist under normal circumstances (e.g., fluidizing a lung segment or lobe in preparation for acoustic cavitation / histotripsy via non-invasive transthoracic treatment (e.g., with transducers placed externally on / around the patient)). The systems disclosed herein can also have all or part of these subsystem hardware packaged within other system carts / consoles / systems described herein (e.g., acoustic cavitation / histotripsy systems and / or subsystems integrated and operated from the navigation or laparoscopic systems described above).

[0087]

[0091] The system may also be configured through various of the aforementioned and other parameters to spatiotemporally display real-time visualization of the bubble cloud, including resulting tissue effects during / after treatment from tissue / bubble cloud interactions, and the system can dynamically image, visualize, and display the bubble cloud and any changes to the bubble cloud (e.g., decreasing or increasing echogenicity), which may include intensity, shape, size, location, morphology, persistence, etc. These features can enable the user to continuously track and follow the treatment in real time with one integrated procedure and interface / system, and to confirm treatment safety and efficacy during operation (versus other interventional or surgical modalities that require multiple procedures to accomplish the same, or where the treatment effect is not visible in real time (e.g., radiation therapy) or where such (e.g., real-time visualization of localized tissue during thermal ablation) is not achievable, and / or where other procedures further require invasive approaches (e.g., incisions or drilling) and repeated imaging in a scanner (e.g., CT or MRI scans) between treatment steps). The above disclosed systems, subsystems, components, modalities, features, and workflows / methods of use may be implemented without limitation through enabling hardware, software, user interfaces, and environments of use, and any resulting data and means of using said data for analytics, artificial intelligence, or digital health applications and systems, as well as future improvements, enhancements, and inventions in this area, are considered within the scope of this disclosure.

[0088] Robotics

[0092] The system may comprise various robotic subsystems and components, including, but not limited to, one or more robotic arms and controllers that may further operate in conjunction with other subsystems or components of the system for delivering and monitoring acoustic cavitation / histotripsy. As previously discussed herein, the robotic arms and control systems may be integrated into one or more cart configurations.

[0089]

[0093] For example, one system embodiment can include an integrated robotic arm and control system, as well as a cart with therapy, integrated imaging and software, where the robotic arm and other listed subsystems are controlled by the user through a single bedside cart form factor.

[0090]

[0094] In other embodiments, the robotic subsystem may be configured in one or more separate carts that can be driven in a master / slave configuration from a separate master or cart, with the robot-enabled cart located at the bed / patient side and the master remote from the cart.

[0091]

[0095] The disclosed robotic arms may include multiple joints, segments, and degrees of freedom, and may also include a variety of integrated sensor types and encoders implemented for various uses and safety features. Sensing techniques and data may include, by way of example, vision, potentiometer, position / localization, kinematics, force, torque, speed, acceleration, dynamic loading, and / or others. In some cases, sensors may be used by the user to direct robot commands (e.g., gesturing the robot to a preferred setup position or gesturing to dock home). Additional details regarding robotic arms can be found in U.S. Patent Publication No. 2013 / 0255426 to Kassow et al., which is incorporated herein by reference in its entirety.

[0092]

[0096] The robotic arm receives control signals and commands from a robotic control system that may be housed on the cart. The system may be configured to provide a variety of functions, including but not limited to position, tracking, patterns, triggers, and events / actions.

[0093]

[0097] The positions can be configured to include fixed positions, pallet positions, time controlled positions, distance controlled positions, variable time controlled positions, and variable distance controlled positions.

[0094]

[0098] The tracking may be configured to include time-controlled tracking and / or distance-controlled tracking.

[0095]

[0099] The pattern of movement can be configured to include intermediate positions or waypoints and sequences of positions through defined paths in space.

[0096]

[0100] The trigger may be configured to include distance measurement means, time, and / or various sensor means, including but not limited to those disclosed herein, such as visual / imaging-based force, torque, localization, energy / power feedback, and / or others.

[0097]

[0101] Events / actions can be configured to include a variety of examples including proximity-based (approaching / moving away from a target object), activating or deactivating various end effectors (e.g., therapy transducers), starting / stopping / pausing sequences of the above events, triggering or switching between triggering events / actions, initiating patterns of movement and changing / toggle between patterns of movement, and / or time-based and temporal across defined task and time spaces.

[0098]

[0102] In one embodiment, the system includes a three-degree-of-freedom robotic positioning system that allows a user (through the system's software and associated user interface) to microscopically position the therapy transducer through an X, Y, and Z coordinate system, with the overall macroscopic positioning of the transducer (e.g., aligning the transducer over the patient's body) completed manually. In some embodiments, the robot can have six degrees of freedom, including X, Y, Z, as well as pitch, roll, and yaw. In other embodiments, the robotic subsystem can have additional degrees of freedom, allowing the robotic arm support base to be positioned along a linear axis running parallel to the general direction of the patient surface and / or the support base height to be adjusted up or down, allowing the position of the robotic arm to be modified relative to the patient, patient surface, cart, linkage subsystem, additional robots / robotic arms, and / or additional surgical systems, including, but not limited to, a surgical tower, imaging systems, endoscopic / laparoscopic systems, and / or others.

[0099]

[0103] The one or more robotic arms can also include various features to assist in manual or semi-manual manipulation and correction of arm position, which can interface on or between the therapy transducer and the robotic arm's most distal joint. In some embodiments, the features are configured to include a handle to enable one or more manual manipulations and manual controls. The handle may also be configured to include user input and electronic control features of the robotic arm (e.g., activating or deactivating a free-drive mode) to command various drive capabilities or modes to operate the robot to assist in global or fine positioning of the arm. The workflow for initial positioning of the robotic arm and therapy head can be configured to allow the therapy transducer / head to be positioned first in the docking solution, with the therapy transducer interfaced directly with the arm, or a different workflow allows the user to set up the docking solution first and allow the robotic arm to be interfaced with the therapy transducer / docking solution as a later / final setup step.

[0100]

[0104] In some embodiments, the robotic arm may comprise a laparoscopic, single-port, endoscopic, hybrid or combination thereof, and / or other robotic arm, and the robot of the system may be slave to a master controlling the arm and potentially multiple other arms equipped to simultaneously perform other tasks (visualization, imaging, grasping, cutting, ligating, sealing, closing, stapling, dissecting, suturing, marking, etc.), including actuating one or more laparoscopic arms (and instruments) and various histotripsy system components. For example, a laparoscopic robot may be utilized to prepare the surgical site, including manipulating the position of organs to provide more optimal acoustic access and, in some cases, further stabilizing the organs to minimize respiratory movement. In conjunction with and in parallel with this, a second robotic arm may be used to deliver noninvasive acoustic cavitation through the body cavity as observed under real-time imaging from a therapy transducer (e.g., ultrasound) and with simultaneous visualization via a laparoscopic camera. In other related aspects, similar approaches may be utilized that combine endoscopic and non-invasive approaches, as well as further combine endoscopic, laparoscopic and non-invasive approaches.

[0101] software

[0105] The system may include a variety of software applications, features, and components that allow the user to interact with, control, and use the system for numerous clinical applications. The software may communicate and work with one or more of the subsystems, including, but not limited to, therapy, integrated imaging, robotics, and other components, ancillary instruments, and accessories of the system.

[0102]

[0106] Overall, in no inherent order of importance, software is responsible for initializing and setting up the system; servicing the system; communicating and importing / exporting / storing data; modifying / operating / configuring / controlling / commanding various settings and parameters by the user; mitigating safety and use-related risks; treatment planning; support for various transducer configurations; robotic arms and drive systems; function generator and amplifier circuitry / slaves; test and treatment ultrasound sequences; transducer steering and positioning (e.g., electro-mechanical and electronic beam steering); treatment patterns; imaging and support for imaging probes, their manual and electro-mechanical / robotic enabled movement; imaging support for measuring / characterizing various dimensions in or around the treatment site (e.g., depth from one anatomical location to another); Features and support can be provided for pre-treatment assessments and protocols to measure / characterize the nature and condition of the in situ treatment site (e.g., acoustic cavitation / histotripsy thresholds and their variants), targeting and target alignment, calibration, autonomously, under direct observation and viewing with real-time imaging as displayed through the software including various views and viewports for autonomous viewing, marking / annotating, localizing / navigating, registering, guiding, providing and directing through workflows, treatment steps, execution treatment plans and protocols, providing communication tools (video, audio, sharing, etc.), troubleshooting, instructions, warnings, alerts, and / or enabling communication through various networking devices and protocols.It is further envisioned that the software user interface and supporting displays may comprise various buttons, commands, icons, graphics, text, etc. that enable a user to interact with the system in a user-friendly and effective manner, which may be presented in an unlimited number of permutations, layouts, and designs, may comprise two or more displays (e.g., a touchscreen monitor and touchpad), and / or may be networked to one or more external displays or systems (e.g., another robot, navigation system, system tower, console, monitor, touch display, mobile device, tablet, etc.), and may be displayed in a similar or different style or feature set of the system.

[0103]

[0107] Software as part of a typical system including one or more computer processors can support the various aforementioned function generators (e.g., FPGAs), amplifiers, power supplies, and therapy transducers. The software may be configured to allow a user to select, determine, and monitor various parameters and settings of the acoustic cavitation / histotripsy, and can allow the user to stop / start / modify said parameters and settings upon observing / receiving feedback on performance and status.

[0104]

[0108] The software may be configured to allow the user to select from a list or menu of multiple transducers and support automatic detection of the transducer upon connection to the system (and verification of the appropriate sequence and parameter settings based on the selected application). In other embodiments, the software may update targeting and amplifier settings (e.g., channels) based on the specific transducer selection. The software may also provide transducer recommendations based on pre-treatment and planning inputs. Conversely, the software may provide an error message or warning to the user if the therapy transducer, amplifier, and / or function generator selection or parameters are incorrect or result in an error or failure. This may further include reporting details and location of such.

[0105]

[0109] In addition to the above, the software may be configured to allow a user to select treatment sequences and protocols from lists or menus and store the selected and / or previously selected sequences and protocols as associated with a unique clinical use or patient profile. The associated profile may include any associated patient, treatment procedure, clinical and / or engineering data, and may be used to inform, modify and / or guide current or future treatments or procedures / interventions, whether as decision support (e.g., using continuous data sets to build and guide new treatments) or as an active part of the treatment itself.

[0106]

[0110] As part of planning or during treatment, the software (and working with other components of the system) can enable the user to evaluate and test acoustic cavitation / histotripsy thresholds at various locations in a user-selected region of interest or predefined treatment area / volume to determine a minimum cavitation threshold throughout the region or area / volume and ensure that treatment parameters are optimized to achieve, maintain, and dynamically control acoustic cavitation / histotripsy. In one embodiment, the system allows the user to manually evaluate and test threshold parameters at various points. These points can include points at predefined boundaries, interior boundaries, and central locations / positions of the selected region of interest and treatment area / volume, and the resulting threshold measurements can be reported / displayed to the user and utilized to update therapy parameters prior to treatment. In another embodiment, the system can be configured to enable automated threshold measurements and updates, such as those enabled by the robotics subsystem described above, where the user can direct the robot or the robot can be commanded to perform measurements autonomously.

[0107]

[0111] The software may also be configured to work with a computer processor and one or more function generators, amplifiers, and therapy transducers to enable various permutations of delivering and positioning optimized acoustic cavitation / histotripsy in and through a selected area / volume. This may include systems configured in various combinations including, but not limited to, fixed / natural focus placement using purely electromechanical positioning configurations, electronic beam steering (with or without electromechanical positioning), electronic beam steering to a new selected fixed focus with further electromechanical positioning, axial (Z-axis) electronic beam steering with lateral (X and Y) electromechanical positioning, fast axial electronic beam steering with lateral electromechanical positioning, fast beam steering in 3D space, and dynamically varying one or more acoustic cavitation / histotripsy parameters (e.g., dynamically adjusting amplitude across a treatment area / volume) based on the foregoing and the ability to update treatment parameters based on threshold measurements.

[0108] Other Components, Auxiliaries and Accessories

[0112] Systems may include various other components, aids and accessories, including, but not limited to, computers, computer processors, power supplies including high voltage power supplies, controllers, cables, connectors, networking devices, software applications for integration into security, communications, information systems including hospital information systems, cellular communication devices and modems, handheld wired or wireless controllers, goggles or glasses for advanced visualization, augmented or virtual reality applications, cameras, sensors, tablets, smart devices, phones, Internet of Things enabled capabilities, special use "apps" or user training materials and applications (software or paper-based), virtual proctors or trainers and / or other enabling features, devices, systems or applications, and / or methods of using the above.

[0109] System Variations and Methods / Applications

[0113] In addition to performing a wide range of procedures, the system may enable additional benefits to assist the user, such as enhanced planning, imaging, and guidance. In one embodiment, the system may enable the user to create patient-, target-, and application-specific treatment plans, which may be configured to optimize treatment parameters based on feedback to the system during planning, which may further include the ability to run various test protocols to gather specific inputs to the system and the plan.

[0110]

[0114] The feedback may include various energy, power, location, position, texture and / or other parameters.

[0111]

[0115] The system and the above feedback may also be further configured and used to autonomously (and robotically) execute the delivery of optimized treatment plans and protocols, and start / stop / modify treatment at the user's discretion, as visualized under real-time imaging during the procedure, allowing the user to directly observe the localized treatment tissue effects as the treatment progresses. Both testing and treatment protocols may be updated during the treatment at the direction of the user, or in some embodiments based on logic built into the system.

[0112]

[0116] It is also recognized that many of these benefits can further improve other forms of acoustic therapy, including high intensity focused ultrasound (HIFU), including boiling histotripsy (thermal cavitation), and thermal ablation with high intensity therapeutic ultrasound (HITU), and are considered part of this disclosure. The present disclosure also contemplates the application of histotripsy as a means to activate previously delivered active drug payloads that are inactive, either through protection in micelles, nanostructures, or similar protective structures, or through molecular arrangements that allow activation only upon application of acoustic energy.

[0113]

[0117] In another embodiment, a therapy subsystem, comprising in part one or more amplifiers, transducers, and power sources, may be configured to enable a multitude of acoustic cavitation and histotripsy driving capabilities that provide unique benefits based on application, method, and / or patient-specific usage. These benefits may include, but are not limited to, the ability to better optimize and control treatment parameters, which may enable more desirable thermal profiles, delivery of more energy with increased treatment speed and reduced procedure times, electronic beam steering, and / or other features.

[0114]

[0118] The present disclosure also includes novel systems and concepts, such as those relating to systems and subsystems with new and "universal" amplifiers that can enable multiple drive approaches (e.g., single and multi-period pulsing), which in some embodiments may include various novel features to further protect the system and user from electrical safety or other threats (e.g., adverse effects on transducer and / or amplifier circuitry).

[0115]

[0119] In another aspect, the system and therapy subsystem can include a large number of therapy transducers, configured for specific applications and uses, adapted for treatment across a wide range of working parameters (target size, depth, location, etc.), and capable of including a wide range of working specifications (described in more detail below). The transducers can be further adapted, interfaced, and connected to a robotic-enabled system, as well as a coupling subsystem that allows the transducer to be positioned in or with an acoustic coupling device that, in many embodiments, enables simultaneous imaging and histotripsy treatment through an acceptable acoustic window. The therapy transducers can also include an integrated imaging probe or localization sensor capable of displaying and determining the transducer's position within the treatment site, providing a direct view (or representation) of the treatment site, and such that acoustic cavitation / histotripsy tissue effects and bubble clouds may or may not change in appearance and intensity throughout the treatment, and depending on their location within the treatment (e.g., tumor, surrounding healthy tissue, critical structures, fatty tissue, etc.).

[0116]

[0120] The systems, methods, and uses of the systems disclosed herein may be beneficial in overcoming significant unmet needs in the areas of soft tissue ablation, oncology, cancer immunology, advanced image-guided procedures, surgical procedures including, but not limited to, open, laparoscopic, single-incision, transluminal, endoscopic, non-invasive, and various combinations thereof, various interventional spaces for catheter-based procedures in the vascular, cardiovascular pulmonary, and / or neuroscience spaces, cosmetic / aesthetics, metabolic (e.g., type 2 diabetes), plastic and reconstructive, vision and ophthalmology, orthopedics, gynecology, and human health, and other systems, devices, and methods for treating diseased, injured, unwanted, or healthy tissue, organs, or cells.

[0117]

[0121] Systems and methods are also provided for improving treatment patterns within tissue that can reduce treatment time, improve efficacy, and reduce the amount of energy and focused tissue heating delivered to the patient.

[0118] Usage environment

[0122] The disclosed systems, methods of use, and system usage may be performed in numerous environments and settings, with or without various support systems such as anesthesia, including, but not limited to, treatment suites, operating rooms, hybrid rooms, in-patient and out-patient settings, ambulatory settings, imaging centers, radiology, radiation therapy, oncology, surgery, and / or any medical center, as well as physician offices, mobile healthcare centers or systems, automobiles and related vehicles (e.g., vans), air and sea transport vehicles such as aircraft and ships, and / or any structure capable of providing temporary treatment support (e.g., tents). In some cases, the systems and / or subsystems disclosed herein may also be provided as integrated features into other environments, such as direct integration of the Histotripsy therapy subsystem into an MRI scanner or patient surface / bed, with at least the therapy generator and transducer integrated therein; in other cases, the Histotripsy configuration further includes a robotic positioning system that may be further integrated into a scanner or bed-centric design.

[0119] Concatenation

[0123] The system can include various coupling subsystem embodiments enabled and configured to allow acoustic coupling to the patient to provide effective acoustic access for ultrasound visualization and acoustic cavitation / histotripsy (e.g., providing an acoustic window and medium between the transducer and the patient, and its support). These can include different form factors of such, including open and closed device solutions, as well as several arrangements that can be configured to allow dynamic control over the acoustic medium (e.g., temperature, dissolved gas content, level of particulate filtration, sterility, volume, composition, etc.). Such dynamic control components may be integrated directly into the system (within the cart) or may be in temporary / intermittent or continuous communication with the system, but may be separate devices and / or external to the cart.

[0120]

[0124] The coupling subsystem typically comprises at least a coupling medium (e.g., degassed water or aqueous solution), a reservoir / container for holding the coupling medium, and a support structure (including interfaces to other surfaces or devices). In most embodiments, the coupling medium is water, and the water may be conditioned (e.g., chilled, degassed, filtered, etc.) before or during treatment. Various conditioning parameters may be employed based on the configuration of the system and its intended use / application.

[0121]

[0125] The reservoir or media container can be formed and shaped into various sizes and shapes to conform to the patient, allowing the therapy transducer to engage / access and work within the acoustic medium per defined and required working space (such as a minimum volume of media to allow the therapy transducer to be positioned and / or moved through one or more treatment positions or patterns and at various standoffs or depths from the patient), and the reservoir or media container can also mechanically support the load and load distribution through the use of mechanical and / or electromechanical support structures. Representative examples include support frames. The container may be of various shapes, sizes, curvatures, and dimensions and may include various material compositions (single, multiple, composite, etc.) that may vary throughout. In some embodiments, the container can include features such as insertable and removable films, drapes, membranes, blowers, etc. that can be used to conform to the patient and assist in containing / containing the media within the container. The container can further include various sensors (e.g., volume / fill level), drainage (e.g., inlet / outlet), lighting (e.g., LEDs), markings (e.g., fill lines, setup orientation, etc.), text (e.g., labeling), etc.

[0122]

[0126] In one embodiment, the reservoir or media container includes a sealable frame into which a membrane and / or film can be placed to provide a comfortable means of contacting the reservoir (which will later comprise the therapy head / therapy transducer) as an interface to the patient, further providing a barrier to the media (e.g., water) between the patient and the therapy transducer. In other embodiments, the membrane and / or film can include an opening whose patient-contacting edge provides a fluid / mechanical seal with the patient, but in contrast allows direct media communication with the patient (e.g., a direct degassed water interface with the patient). The reservoir or media container superstructure in both of these examples can further provide a proximal portion (e.g., top) of the structure that is open or enclosed (e.g., to prevent spillage or provide additional features).

[0123]

[0127] The disclosed membranes can include various elastomers, viscoelastic polymers, thermoplastics, thermoplastic elastomers, thermoset polymers, silicones, urethanes, rigid / flexible copolymers, block copolymers, random block copolymers, and the like. Materials can be hydrophilic, hydrophobic, surface-modified, coated, extracted, and the like, and can further contain various additives to enhance performance, appearance, or stability. In some embodiments, the thermoplastic elastomer can be styrene-ethylene-butylene-styrene (SEBS) or other similar strong, flexible elastomers. The membrane form factor can be flat or pre-shaped prior to use. In other embodiments, the membrane can be inelastic (i.e., convex) and pressed against the patient's skin to acoustically couple the transducer to the tissue. Systems and methods for controlling the level of contaminants (e.g., particulates, etc.) on the membrane to maintain an appropriate level of ultrasound coupling are also disclosed. Too many particulates or contaminants can cause ultrasound scattering. This can be achieved with a removable film or coating on the membrane's outer surface to protect against contamination.

[0124]

[0128] The materials may be formed into useful thin films through molding, casting, spraying, ultrasonic spraying, extrusion, and / or any other processing method that yields useful embodiments. The materials may be single-use or reposable / reusable. The materials may be non-sterile, aseptically clean, or sterile, and sterilization may include any known method, including but not limited to, ethylene oxide, gamma, e-beam, autoclaving, steam, hydrogen peroxide, plasma, chemicals, etc. The thin films may further comprise an outer molded or overmolded frame to provide mechanical stability to the thin film during handling, including assembly, setup, and disassembly of the coupling subsystem. Representatively, various parameters of the thin film may be optimized for this use, including thickness, thickness profile, density, formulation (e.g., polymer molecular weight and copolymer ratio, additives, plasticizers, etc.), specifically optimized to maximize acoustic transmission properties, including impact on cavitation onset threshold and / or minimizing ultrasound imaging artifacts, including but not limited to thin film reflections.

[0125]

[0129] The open reservoir or media container can include various methods of filling, including using pre-prepared media or water that can be delivered to the container, possibly to predefined specifications (levels of temperature, gas saturation, etc.), or can include additional features integrated into the design that allow for filling and draining (e.g., ports, valves, hoses, tubing, fittings, bags, pumps, etc.). These features may be further configured to interface into or to other devices, including, for example, the fluidics system. In some cases, the fluidics system can be an in-house media preparation system in a hospital or medical environment room, or conversely, a mobile cart-based system that can prepare and transport media from a cart to a media container, etc.

[0126]

[0130] The enclosed iterations of the reservoir or media container can include various features for sealing, in some embodiments, to the proximal / top portion or structure of the reservoir / container, or in other cases, the sealing can include sealing features on the transducer or transducer housing. Additionally, some embodiments can include dynamic capabilities to control the volume of fluid within these designs, minimize the possibility of air bubbles or turbulence in the fluid, and allow for changes in focal distance to the target area without moving the transducer. Thus, integrated features enabling fluid communication and control thereof can be provided (the ability to provide / remove fluid on demand), including the ability to monitor and control various fluid parameters, some of which are disclosed above. To provide this functionality, the overall system, and as part of it, the coupling subsystem, can include a fluid regulation system, which can include various electromechanical devices, systems, power, sensing, computing, pumping, filtering, and control systems, etc. The reservoir can also be configured to receive signals that deform or change shape in a specific and controlled manner to allow the target point to be adjusted without moving the transducer.

[0127]

[0131] The articulated support system can include a variety of mechanical support devices for interfacing the reservoirs / containers and media to the patient and workspace (e.g., bed, floor, etc.). In some embodiments, the support system comprises a mechanical arm with three or more degrees of freedom. The arm can have a proximal interface with one or more locations (and features) of the bed, including but not limited to a frame, rails, customized rails, or inserts, and one or more distal locations of the reservoirs or containers. The arm can also be a feature embodied on one or more carts, which can be configured in a variety of non-limiting permutations, and in some cases, the cart solely serves to support and provide the disclosed support structure.

[0128]

[0132] In some embodiments, the support structure and arm may be realized as a standalone cart or may be a robot-enabled arm integrated into a cart further comprising two or more system subsystems, or the robot-enabled arm may be the arm of another robot, interventional, surgical, or other type, and may further comprise various user input features for actuating / controlling the robot arm (e.g., disposed on / within the coupling medium) and / or coupling solution features (e.g., fill, drain, etc.). In some examples, the support structure robot arm position encoder may be used to coordinate the operation of a second arm (e.g., comprising a therapy transducer / treatment head), such as placing a therapy transducer at a desired / known location and within the coupled support structure.

[0129]

[0133] Overall, significant unmet needs exist today in interventional and surgical medical procedures across various types of procedures, including procedures utilizing minimally invasive devices and approaches to treat disease and / or injury, and unmet needs may be solved with entirely new medical procedures. Today's medical system capabilities are often limited by access, such that a less invasive or non-invasive approach would be preferable, or today's tools lack the ability to deliver the desired / required tissue effect (e.g., working around / through critical structures without significant injury), or the physical setup of the system makes certain treatment approaches less desirable or possible, and combinations of approaches may enable entirely new procedures and approaches not possible today, along with enhanced tissue-affecting therapies.

[0130]

[0134] Additionally, there is a unique need to enable histotripsy delivery, including robotic histotripsy delivery, where one or more histotripsy therapy transducers may be configured to acoustically couple to the patient using a fully sealed approach (e.g., no acoustic medium communication with the patient's skin) and to allow the one or more histotripsy transducers to be moved within the coupling solution without impeding the movement / movement of the robotic arm or interfering / obstructing the coupling interface, which may affect the intended treatment and / or target location.

[0131]

[0135] By way of non-limiting example, disclosed herein are Histotripsy acoustic and patient coupling systems and methods for enabling Histotripsy therapy / treatment in any setting envisioned from an interventional suite, operating room, hybrid suite, imaging center, medical center, office environment, mobile treatment center, and / or other. The following disclosure further describes novel systems used to create, control, maintain, modify / enhance, monitor, and set up / tear down acoustic and patient coupling systems in a variety of approaches, methods, environments, architectures, and workflows. In general, the disclosed novel system can allow a coupling medium, in some instances degassed water, to be interfaced between a histotripsy therapy transducer and a patient, the acoustic medium providing sufficient acoustic coupling to the patient to enable delivery of histotripsy pulses through a user-desired treatment location (and volume), delivery can require physically moving the histotripsy therapy transducer within a defined workspace that includes the coupling medium, and the coupling system is configured to allow said movement of the therapy transducer (and positioning system, e.g., a robot) freely and unhindered by a coupling support system (e.g., a frame or manifold that holds the coupling medium).

[0132] Interconnected Systems and Subsystems / Components

[0136] The disclosed histotripsy acoustic and patient connection systems may generally comprise one or more of the subsystems and components, examples of which are depicted in FIG. 2 , including, but not limited to: 1) a membrane / barrier film to provide an enclosed, sealed, and conformal patient connection and histotripsy system interface; 2) a frame and assembly to hold the membrane and provide sufficient working and headroom for the required range of motion (x, y, and z, pitch, roll, and yaw) of the histotripsy therapy transducer; 3) a sufficient volume of ultrasound medium to provide acoustic connection and interface to the histotripsy therapy transducer and robotic arm; 4) one or more mechanical support arms to allow installation, positioning, and load support of the frame, assembly, and medium; and 5) a fluidics system to prepare, provide, and remove the ultrasound medium from the frame and assembly.

[0133]

[0137] In some embodiments, the connection system may be completely sealed, while in other embodiments and configurations, the connection system may be partially open to provide immediate access (physical and / or visual).

[0134]

[0138] The acoustic and patient connection systems and subsystems may further comprise various features and functions and associated workflows and may be further configured in various ways to enable Histotripsy procedures as described in more detail below.

[0135]

[0139] 2 illustrates one embodiment of a histotripsy therapy and imaging system 200 including a coupling assembly 212. As described above, the histotripsy therapy and imaging system can include a therapy transducer 202, an imaging system 204, a robotic positioning arm 208, and a fluidics cart 210.

[0136]

[0140] The therapy and / or imaging transducer can be housed in a coupling assembly 212, which can further include a coupling membrane 214 and a membrane constraint 216 configured to prevent the membrane from extending too far from the transducer. The coupling membrane can be filled with an acoustic coupling medium, such as a fluid or gel. The membrane constraint can be, for example, a semi-rigid or rigid material configured to limit the membrane's extension / movement. In some embodiments, no membrane constraint is used, and the membrane's elastic and tensile strength prevents extension. The coupling membrane can be a mineral oil-infused SEBS membrane to prevent direct fluid contact with the patient's skin. In the illustrated embodiment, the coupling assembly 212 is load-bearing in the xy plane but is supported by a mechanical support arm 218, which can allow manual or automated z-axis adjustment. The mechanical support arm can be affixed to the floor, patient table, or fluidics cart 210. The mechanical support is designed and configured to conform and hold the connecting membrane 214 in place against the patient's skin while still allowing movement of the therapy / imaging transducer relative to the patient and further relative to the connecting membrane 214 with the robotic positioning arm 208.

[0137]

[0141] The fluidics cart 210 can include additional features, including fluid tanks 220, a cooling and degassing system, and a programmable control system. The fluidics cart is configured for automated control of fluid sequencing and external loading of the coupled membrane. Further details about the fluidics cart 210 are provided below.

[0138] Thin / Barrier Films and Related Architectures

[0142] The thin membranes and barrier films may be constructed from a variety of biocompatible materials capable of providing a conformal connection to the patient's anatomy with minimal or no trapped air bubbles that could interfere with ultrasound imaging and histotripsy therapy, and a sealed barrier layer between the patient's anatomy and the ultrasound medium contained within the working space provided by the frame and assembly.

[0139]

[0143] The membrane and barrier film materials can comprise flexible and elastic biocompatible materials / polymers, such as various thermoplastic and thermoset materials, as well as permanent or bioabsorbable polymers. Additionally, the frame of the ultrasound medium container (UMC) can also comprise the same materials. In some cases, the membrane can be a pre-shaped or flat rigid or semi-rigid polymer.

[0140] ultrasonic medium

[0144] As previously mentioned, the ultrasound medium can comprise any applicable medium capable of providing sufficient and useful acoustic coupling to enable histotripsy treatment and sufficient clinical imaging (e.g., ultrasound). Ultrasound media can include, but are not limited to, various aqueous solutions / media, including mixtures with other cosolvent fluids, that may have favorable or more favorable acoustic qualities, including the ability to match the speed of sound, as part of the present disclosure and systems. Example media include degassed water and / or mixtures / cosolvents of degassed water with various alcohols, such as ethanol.

[0141] Mechanical Support Arm and Arm Architecture

[0145] Various designs and configurations of mechanical support arms (and arm architectures) can be employed to support the acoustic and patient connection system, including providing an efficient and ergonomic workflow for the user. Support arms can be configured with a range of degrees of freedom, including but not limited to, allowing for x, y, z, pitch, roll, and yaw, as well as additional interface features that may allow for additional height adjustment or translation.

[0142]

[0146] The arms can have various numbers and types of joints and segments. Typically, the arms have a minimum of two segments. In some configurations, the arms can have three to five segments.

[0143]

[0147] The arm is also configured to interface proximally with the main support base or base interface (e.g., robot, table, table / bed rail, cart, floor mount, etc.) and distally with the frame / assembly and overall "UMC" or "connected solution." This unique distal interface can further include features to control the position / orientation of the frame / assembly at the frame / assembly interface.

[0144]

[0148] For example, in some embodiments, the arm / frame interface may comprise a ball-joint wrist. In another example, the interface may include the use of a gimbal wrist or a wrist with adjustable pitch and roll control. These interfaces may further employ unique user interfaces and inputs to assist in interacting with the various wrists, which may include (by way of non-limiting example) additional handles or knobs to further enable positioning of the UMC / articulated solution. For example, a gimbal wrist may benefit from allowing the frame / assembly to have three degrees of freedom (independent of the arm degrees of freedom), including pitch, roll, and yaw adjustment.

[0145]

[0149] The support arm, further configured with an arm wrist interfaced with the frame / assembly, can include features such as brakes, including cable- or electronically-actuated brakes, and quick releases that can interact with one or more axes individually or in groups. The support arm can also include an electronic lift system and base support. In some embodiments, these lift systems / base supports are co-located with the robotic arm base, and the robotic arm is equipped with a histotripsy therapy transducer configured to fit / function within the enclosed articulated solution. In other embodiments, the support arm is placed on a separate cart. In some cases, the separate cart can include a fluidics system or a user console. In other embodiments, the separate cart is interfaced to a bed / table, including, but not limited to, rails, sides, and / or a bed / table base. In other examples / embodiments, the separate cart is interfaced to a floor-based structure / foundation capable of managing weight and tipping requirements.

[0146] Fluid Engineering Systems, Control Systems and System Architecture

[0150] As part of the overall fluidics management, the histotripsy system, including the acoustic / patient connection system, may be configured to include an automated fluidics system, which is primarily responsible for providing a reservoir for the preparation and use of connection media. The fluidics system may include the ability to degas, cool, monitor, regulate, supply / fill, and remove / drain connection media to and from the connection frame / assembly.

[0147]

[0151] The fluidics system can include an emergency high-flow system for rapid filling and draining of connection media from the UMC. The fluidics system can be configured to fill the UMC with fluid on demand or at a predetermined fill volume (e.g., automatic filling of the current volume of fluid, such as 1 L, 3 L, 6 L, 9 L, up to about 20 L, etc.). Specifically, about 12 L per procedure can be targeted in some embodiments.

[0148]

[0152] 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 degassing system or mechanism, such as a degassing membrane, that can be configured to degas the fluid as it flows from the fluid source into a fluid tank of the fluidics system. The degassing system can be further configured to degas the fluid as it flows from the fluid tank to the UMC. In some implementations, the fluid is degassed to a first degassing threshold while the fluid tank is filled from the fluid source and optionally held at the first degassing threshold. The fluidics tank can be further degassed (e.g., to a second degassing threshold) by performing a circulation cycle to reduce the amount of remaining dissolved oxygen. The fluidics system can then further degas the fluid again (e.g., to a third, lower degassing threshold) as the fluid is transferred from the fluid tank to the UMC. In some embodiments, the second degassing threshold is lower than the first degassing threshold. In other embodiments, the third degassing threshold is lower than both the second and first degassing thresholds. In some embodiments, each degassing cycle can remove approximately 20-40 percent of the remaining dissolved oxygen. In some embodiments, the first and third degassing cycles remove 20-40 percent of the remaining dissolved oxygen, while the second cycle removes 60-80 percent of the dissolved oxygen during the second cycle. In other embodiments, the second cycle can be run for a longer period than either the first or third cycle.

[0149]

[0153] In some embodiments, the fluidics system can be configured for single use of the coupling medium or alternatively for reuse of the medium. In some embodiments, the fluidics system can provide positive air pressure or vacuum to perform leak testing of the UMC and membrane prior to filling with the coupling medium. Vacuum assistance can also be used to remove air from the UMC during the filling process. The fluidics system can further include a filter configured to prevent particulate contamination from reaching the UMC.

[0150]

[0154] The fluidics system may be implemented in the form of a mobile fluidics cart. The cart may include an input tank, a drain tank, a degassing module, a fill pump, a drain pump, an inert gas tank, an air compressor, tubing / connectors / lines, electronic and manual control systems and input devices, a power source, and one or more batteries. The cart may also optionally include a system check container / reservoir (configured to accommodate the required water volume and workspace for the therapy transducer) for evaluating histotripsy system performance and related system diagnostics. In embodiments, a system check for the therapy head may be performed within the fluid tank of the fluidics cart. Briefly, the system check involves lowering the therapy head into the fluidics tank, initiating a bubble cloud, and marking the desired location (e.g., center point) in the bubble cloud while verifying that the offset, offset limit, and voltage are all within acceptable ranges.

[0151]

[0155] 3A-3F illustrate one embodiment of a fluidics cart 310 of a fluidics system. With reference to FIG. 3A, the fluidics cart 310 can be mobile (e.g., includes wheels) to allow a clinician to prepare and transport the ultrasound medium from a clinical water source (e.g., house tap water or other) and into / around the procedure room. The fluidics cart 310 can also include wheel locks 354 (FIG. 3J) to lock or limit the movement of up to four wheels.

[0152]

[0156] The fluidics cart 310 can include a main fluid tank 320 (here with optional lid 330), which can be centrally located within the fluidics cart, and a drain tank 321 (also with optional lid 332), which can be centrally located or located on the side / interior of the cart and below the main tank as shown. The drain tank can optionally include a pull-out slide for access / removal of the drain tank. In some embodiments, the main tank can have a volume sufficient to store and provide fluid for more than one histotripsy therapy treatment. For example, if the UMC of a histotripsy system requires a 10 L volume for a histotripsy treatment, the main tank 320 can be configured to store 30-40 L or more of fluid (e.g., the equivalent of 3-4 treatments). The drain tank 321 can be of a similar volume to the main tank, or alternatively, the drain tank can be sized sufficiently to hold only the volume of fluid from a single treatment, as drain / waste fluid is typically removed and disposed of after each treatment. Thus, in some embodiments, the drain tank may have a volume ranging from as little as 10-15L.

[0153]

[0157] In some embodiments, the main fluid reservoir may include a mirror or other reflective surface located at the bottom of the reservoir (not shown). This mirror may be used to visualize the Histotripsy therapy head when positioned within the main reservoir. Being able to position and visualize the therapy head within the main reservoir may be useful for performing diagnostic or calibration procedures on the Histotripsy therapy system prior to filling the UMC and positioning the patient for treatment.

[0154]

[0158] In FIG. 3A , the fluidics cart 310 can further include a main compartment 322 and a drain compartment 324 that can house pumps and other system components for the main and drain tanks, respectively. The compartments 322 and 324 can be, for example, doors, hatches, or panels that can be removed or opened to access the internal components. The fluidics cart can further include one or more grooves or notches 345 / 347 extending from one or more of the compartments 322 and / or 324 to the main tank to accommodate tubing sets for filling and draining the main tank, as discussed in more detail below. The fluidics cart 310 can further include a UI / GUI 326 and a handle or rail system 328 for operating the cart. The UI / GUI can include a display and any combination of touchscreen controls via the display and physical controls such as knobs, buttons, levers, or switches, as shown. The rail system 328 is positioned on top of the fluidics cart and extends in a circular or squircle configuration. The rails can extend continuously or discontinuously around the perimeter of the top of the cart from the first side of the UI to the second side of the UI. The fluidics cart also includes four wheels and up to four wheel locks for movement of the cart and for locking the cart in place during installation, filling, cycling, or emptying steps. In particular, two of the wheels, which may be the two front wheels, can include directional locks to assist in movement / mobility of the fluidics cart. In particular, a pedal or brake can be depressed to initiate the directional locking of the two wheels.

[0155]

[0159] 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 on the outside of the cart, and an optional mirror 321 is shown on the bottom of the main tank. The optional mirror 321 can be used during system checks on the treatment head. The tanks can include optional lids 330 and 332. Behind the main compartment are the main pump 334 and main cartridge 335, which are 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 a main tubing set 340 and a degassing mechanism / membrane 338. The degassing mechanism 338 can comprise, for example, a silicone hollow fiber membrane. Degassing mechanism 338 may also include a vacuum (not shown), which may be configured to assist in removing gases from the fluid. When the main cartridge is attached to the cart, main pump 334 automatically comes into communication with main tubing set 340, allowing the main pump to push fluid flow in both directions through the main tubing set. Similarly, behind drain compartment 324 is drain pump 336 and drain cartridge 337, which may include drain pump 336 and drain tubing set 342. Like the main cartridge, drain cartridge 337 snaps or is compression-fit into place behind the drain compartment, placing drain tubing set 342 in communication with drain pump 336, which may create fluid flow in the drain tubing set in either direction. The pump may be, for example, a peristaltic pump configured to mechanically interface with the tubing set to move fluid through the tubing set.Note that in some embodiments, there is no degassing mechanism / membrane within the drain cartridge 337 or behind the drain compartment 324, as all degassing functions may be performed via the degassing mechanism / membrane 338.

[0156]

[0160] The fluidics cart can include several sensors for monitoring parameters of the cart and / or the fluid contained therein. In some embodiments, the fluidics cart can include weight and / or fluid level sensors 323 in both the main and drain tanks. For example, weight or fluid sensors can be incorporated into the tray or platform that supports the main or drain tanks. Alternatively, optical or fluid level sensors can be incorporated into the cart cavity to measure the fluid level in one or both tanks. In particular, a weight sensor can be utilized when initially filling the main tank, communicating with the user when approximately 30 L, 20 L, or a preset volume of fluid has been achieved / placed in the main tank, which in embodiments may be less. The cart can also include a pressure sensor in at least the main tank, but optionally in the drain tank. In some implementations, fluid release into / out of the main and drain tanks can be confirmed or calculated by some combination of weight sensors, fill level sensors, and / or pump speed / operation time. Optionally, a flow sensor can be located in the tubing set to measure or calculate the volume of fluid in the tanks. For example, flow sensors in the main and drain tubing sets can measure flow into and out of the main tank, which can be used to determine the current volume of fluid in the tank. Additionally, conductivity sensors or other sensors can optionally be used in the fluid tanks to measure the percentage or amount of gas in the fluid. Furthermore, temperature sensors can also be employed in the fluidics cart to measure fluid temperature. In embodiments, a thermocouple can be placed in the main tank to measure a temperature that can be displayed to the user via the UI. If desired, a thermocouple or other temperature sensor can be placed in a distal portion of the mounting feature so that the temperature in the UMC can also be monitored.

[0157]

[0161] The main fluid tank may include features to allow disruption or recirculation of the fluid within the tank. In some embodiments, fins, rotors, or fluid / gas / air streams may be implemented to circulate or mix the fluid within the tank.

[0158]

[0162] FIG. 3C is a diagram of another embodiment of a fluidics cart 310 with a main tubing set 340 and a drain tubing set 342. While this embodiment shows the tubing sets as integrated (e.g., permanently attached) to the cart, it should be understood that in other embodiments, the tubing sets are disposable and can be included in a disposable cartridge (such as cartridges 335 and 337 in FIG. 3B ). Main tubing set 340 can be operatively connected to a degassing mechanism / membrane 338 and a main pump 334. Drain tubing set 342 can be operatively connected to a drain pump 336. As shown, main tubing set 340 can include a first input / output port 344 having a free end that can be removably attached to a water source (e.g., tap water), main tank 320, or UMC. This end of first input / output port 344 is considered a free end and can be moved between various components of the histotripsy system (e.g., between the fluidics cart and the UMC). Main tube set 340 also includes second input / output port 346 that can be removably or fixedly attached or coupled to main tank 320 of fluidics cart 310. Here, first input / output port 344 and second input / output port 346 are shown residing in grooves or notches 345 / 347, respectively. In one example, the first input / output port is located on the longer length of main tube set compared to the second input / output port located on the shorter length of main tube set.

[0159]

[0163] Although the main pump 334 and the drain pump 336 are shown as being mounted on a cart in this embodiment, in other embodiments the main and drain pumps can be removably mounted on a (e.g., disposable) cart.

[0160]

[0164] When main pump 334 operates in a first operating direction, i.e., a fill mode of operation, fluid can flow from a fluid source (e.g., a tap water source) into first input / output port 344 and through main tubing set 340, through degassing mechanism 338, and out second input / output port 346 to 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 the fluid passes through main tubing set 340 and degassing mechanism 338, a specified or set percentage of remaining gas (e.g., dissolved oxygen) is removed from the fluid. In one embodiment, degassing mechanism 338 is configured to remove between 20-40% of the remaining gas from the fluid.

[0161]

[0165] When the main pump 334 operates in a second operating direction (e.g., opposite to the first operating direction), i.e., a fluid transfer operating mode, fluid can flow from the main tank 320 into the second input / output port 346 and the main tubing set 340, through the degassing mechanism 338, and out the first input / output port 344. This configuration may be used, for example, when the first input / output port is placed in the UMC 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. Notably, fluid may be moved or transferred from the fluidics cart and into the UMC or any other desired container in preparation for a histotripsy procedure.

[0162]

[0166] The drain tubing set 342 can include an input / output port 348 that includes a free end that can be removably attached to a fluidics cart and other fluid sources, such as a UMC or drain tank 321 .

[0163]

[0167] Additionally, when drain pump 336 operates in a first direction of operation or drain-fill mode of operation, fluid can flow from a fluid source (e.g., a UMC) into input / output port 348 and through drain tubing set 342 and out drain tubing set 340 into drain tank 321. This configuration may be used, for example, when input / output port 348 is placed in a UMC after a histotripsy procedure to drain spent coupling media from the UMC into the drain tank. In this configuration, input / output port 348 functions as an input port.

[0164]

[0168] When the drain pump 336 operates in a second direction of operation (e.g., opposite to the first direction of operation), i.e., a drain emptying mode of operation, fluid can flow from the drain tank 321 through the drain tubing set 342 and out the input / output port 348. This configuration can 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 container). In this configuration, the input / output port 348 functions as an output port. In some examples, the tubing sets can further include mounting features that can be used to attach the input / output port (e.g., free end) of each tubing set to a fluidics cart, a fluid source (e.g., a tap water source), and / or a UMC. For example, mounting features on the first input / output port 344 and the second input / output port of the main tubing set 340 can be used to secure the free end of the main tubing set to the fluidics cart and direct it to the input / output port in the main tank.

[0165]

[0169] 3D-3E illustrate one example of a first input / output port 344 attached to the main tank 320 of a fluidics cart with one or more mounting features 350. FIGS. 3F-3G illustrate another example of a first input / output port 344 attached to a UMC 312. As shown in FIG. 3E, the mounting feature 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 drain tank, and / or the UMC. In some embodiments, the main tank, the drain tank, or the UMC 312 can include corresponding mounting points configured to attach to the mounting features of the input / output port. The interface between the mounting feature and the mounting point can be designed and configured to provide a preferred orientation or angle when the input / output port is attached. For example, referring to FIGS. 3D-3E, the mounting feature can include a first mounting point 351 configured to engage with the main tank to maintain a vertical configuration when the input / output port is mounted to the main tank. This can advantageously position the distal ends of the input / output ports and any fluid ports 349 along the side of the main tank, toward the bottom of the main tank. Alternatively, with reference to Figures 3F-3G, the mounting feature can include a second mounting point 353 configured to interface with the UMC 312 such that the input / output ports maintain an angled orientation that matches the angle of the sidewall of the UMC 312.

[0166]

[0170] As shown in FIGS. 3D-3G , the main tank, drain tank, and / or UMC can include one or more attachment points that receive the main tubing set's attachment features to direct the main tubing set's input / output ports into the main tank or UMC. Note that the attachment features are configured to allow the main tubing set to securely attach to both the fluidics cart and the UMC. Notably, in some embodiments, the input / output ports include shrouds 352 that extend over and cover the ends of the main tubing set. This shroud-type configuration of the input / output ports can direct the fluid flow exiting the main tubing set at a 90-degree bend or angle. This 90-degree angle also facilitates circulation of fluid within the main tank during a circulation cycle. While a 90-degree angle is preferred, other angles and geometries are contemplated that optimize water circulation within the main tank. In some embodiments, the cart itself has corresponding features configured to receive or interface with the main and drain tubing set's attachment features.

[0167]

[0171] The drain tubing set may also be used with attachment features that may be the same or different from the attachment features of the main tubing set. The attachment features will allow the drain tubing set to attach to the UMC.

[0168]

[0172] 3A-3G , operation of the fluidics cart will now be discussed. When the fluidics cart, and in particular the main tank 320, is empty, the first input / output port 344 of the main tubing set 340 can be disconnected from the cart 310 and connected 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 to or connected directly to a faucet or spigot. Alternatively, the first input / output port can be submerged within a volume of fluid (e.g., within a bucket or other container filled with water or any other fluid medium). Then, during a fill mode of operation, the main pump 334 can be controlled (e.g., from a GUI) to operate in a first direction to draw fluid from the inlet / outlet of the main tubing set 340 through the degassing mechanism / membrane 338 and into the main tank via the second input / output port 346. During this filling operation, the degassing mechanism / membrane 338 can be configured to remove a first percentage of gas from the fluid as it enters the main tank.

[0169]

[0173] Once the main fluid tank 320 is full or sufficiently full (e.g., a desired volume of fluid has been charged 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 in the tank can be maintained at a specific temperature and with a specified gas percentage. In some embodiments, the fluidics cart can recirculate the fluid in the main tank during this standby or circulating configuration. During this circulating configuration, the fluidics cart can perform a recirculation cycle in which the pump 334 is operable in a first direction of operation to draw fluid from the main tank into the first input / output port 344, through the degassing mechanism 338, and back into the main tank via the second input / output port 346. Alternatively, the pump 334 is operable in a second direction of operation to draw fluid from the main tank into the second input / output port 346, through the degassing mechanism 338, and back into the main tank via the first input / output port 344. The recirculation cycle can be run on a time-based, volume-based basis, or set to degas until the percentage of dissolved oxygen remaining in the system is sufficiently low. In some embodiments, this can be a closed-loop process where an oxygen or gas sensor in the fluid tank measures the percentage of dissolved oxygen in the tank and can automatically run a recirculation configuration to maintain a desired oxygen percentage in the fluid. In some embodiments, this recirculation or degassing cycle can be run at regular intervals or at a specific time when the fluidics cart system is not running.

[0170]

[0174] For example, during each degassing or recirculation cycle, approximately 20-40 percent, and in some embodiments, approximately 30 percent, of the remaining gas will be removed from the fluid. For example, when the fluid in the main tank has approximately 80 percent gas (e.g., dissolved oxygen), 30 percent of the 80% (80 x 30 = 24) will be removed from the fluid, which is 24% of the gas. Before the next degassing cycle, the fluid will have 56 percent gas. At the completion of the subsequent degassing (described below), 30 percent of the remaining 56 percent of gas will be removed from the fluid.

[0171]

[0175] In another example, during at least the first and optionally the third degassing or recirculation cycles, approximately 20-40 percent of the remaining gas will be removed from the fluid. A second degassing or recirculation cycle can remove approximately 60-80 percent of the remaining gas from the fluid (from the start of the second cycle). This second cycle can be run for a longer period or length of time to remove a higher percentage of the remaining gas.

[0172]

[0176] Prior to a histotripsy procedure, the fluidics cart can be moved or positioned adjacent to the UMC of the histotripsy system. The main tubing set can be removed from the cart and attached to or placed within the UMC. The user can then initiate filling of the UMC from the main reservoir of the fluidics cart in a fluid transfer operating mode. In some implementations, the fill can be initiated via the UI / GUI of the fluidics or therapy cart. The fill can be manual (e.g., the user can determine when the fill should end) or automated and automatically terminated when the desired volume of fluid has been transferred. In one example, the user can provide an input to the fluidics cart to release a dose or predetermined volume of fluid from the cart to the UMC. For example, if the UMC requires 10 L for filling, the fluidics cart can automatically release the requested amount and terminate the fill when the amount is released. This volume or dose can be verified / confirmed with the sensors described above. In some embodiments, a number of different doses or pre-determined volumes can be released via the UI / GUI (e.g., 1 L, 3 L, 6 L, or any other volume). In some embodiments, the user can program or specify the user-selected dose or volume to be released from the cart to the UMC.

[0173]

[0177] Filling of the UMC from the fluidics cart can be performed with the main pump 334 operating in a second direction (e.g., reverse of the first direction during the fill main tank procedure described above). While the fluidics cart is filling the UMC, 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., remove another percentage of gas from the fluid). Optionally, the main hose inlet / outlet can remain at the UMC during the procedure if more fluid is needed within the UMC. In other embodiments, the main tubing set and mounting features will be removed from the UMC after the UMC has been filled to an acceptable volume. The fluidics cart will still primarily remain near or near the treatment site if more fluid is needed to fill the UMC.

[0174]

[0178] After the histotripsy procedure is performed, the fluidics cart 310 can be used to remove the spent fluid from the UMC. To do so, the drain hose 342 inlet / outlet can be removed from the cart and placed inside the UMC. The drain pump 336 can then operate to draw fluid from the UMC into the drain tank 321. Similar to the fill procedure described above, sensors in the cart and / or drain tank 321 can measure or calculate the volume of fluid removed from the UMC. In some embodiments, the fluid removed from the UMC can be compared to the fluid added to the UMC during the fill procedure. Note that the volumes may not match due to spillage or other ways in which fluid is transferred from the UMC unless the UMC is a sealed system. After the UMC is drained, the drain hose can be reattached to the cart.

[0175]

[0179] In a subsequent step, after all histotripsy procedures are completed, any remaining water in the fluidics tanks, including both the main tank and the drain tank, can be emptied. The 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 fluid. Once the tubing is positioned for emptying, in a single step, the user can instruct the UI to drain or empty the fluid cart of all fluid. At the same time, both the drain and main tanks can be emptied, and the drain tubing can optionally be disposed of. Alternatively, the drain tank 321 can be removed for proper disposal of the waste fluid.

[0176]

[0180] Figure 3H is an additional exploded view of the fluidics cart 310 showing additional structural and paneled components, Figure 31 is a front view of the cart, and Figure 3J is a rear perspective view of the cart showing optional wheel locks 354 in the form of foot pedals.

[0177]

[0181] FIG. 4 is an alternative design of a fluidics cart 410 that may include any of the features described above and may be assumed to function similarly with similar names / reference numbers unless otherwise explicitly stated, including a main tank 420, a waste tank 421, first and second input / output ports 444, 446, first and second pumps 434 / 436, and a GUI 426 that may include any combination of physical and / or touchscreen inputs along with a display.

[0178]

[0182] FIG. 5A is a diagram of a disposable kit 555 including a main cartridge 535, a degassing mechanism 538, a main tubing set 540, and first and second input / output ports 544 / 546 mounted within disposable shipping packaging 557. The disposable shipping packaging 557 may include guides, restraints, or other tabbed or notched features to hold the main cartridge and associated components in an organized and untangled / straightened orientation prior to use. While the disposable shipping packaging 557 is shown in an open configuration, it can fold upon itself along fold line 563 for more compact and protective packaging, as described below. FIG. 5B shows the disposable kit without its shipping packaging.

[0179]

[0183] Figure 5C is a diagram of a disposable kit 559 including a drain cartridge 537 having a drain tubing set 542, a third input / output port 548, and a drain tank input / output port 549 mounted within disposable shipping packaging 561. Figure 5D shows the drain cartridge 537, drain tubing set 542, a third input / output port 548, and a drain tank input / output port 549 outside of the disposable shipping packaging.

[0180]

[0184] Figure 5E shows a complete package 567 of disposable kits 555 and 559. In this example, disposable shipping packaging 555 is folded on itself (along fold line 563 in Figure 5A) and disposable shipping packaging 561 is stacked on top of packaging 555 and placed within one or more sterile bags 569. A label 565 can be placed on the complete package 567 to indicate its contents.

[0181]

[0185] The cart can be powered through a standard electrical service / connector and with a battery that can be located within the main cart body or wheeled base to enable portable or off-grid use. The battery can also provide emergency power. The cart can also include a nitrogen tank and / or air compressor (not shown) to allow blowdown of the main / drain tubing to ensure it remains dry / clean (under a nitrogen blanket). In some examples, the cart can include various processors or electronic controllers configured to program / monitor / report water status and parameters. Parameters can include oxygen saturation, temperature, particulate debris, pH, mix ratio, flow rate, fill level, power / battery level, etc., and can be detected in real time by any number of sensors located in and around the system. Parameters can be read out to a UI screen on the fluidics cart and / or displayed / controlled on the therapy system cart display (through a software UI).

[0182]

[0186] The degassing module may include a filter or degassing membrane configured to remove particulates / debris, a degassing contactor, and a vacuum or peristaltic pump for moving the fluid through the system. In some examples, the filter may have a pore size of 0.2 microns. The degassing contactor may have the capability to draw down to 1 part per billion at a flow of approximately 4 liters per minute and remove dissolved O, CO, and N gases. The vacuum pump may include key features such as pure transfer and drainage, high compatibility with steam and condensate, chemical resistance, and gas tightness (very low leakage). In some examples, the vacuum pump is a cable that draws down to 8 Torr. In some embodiments, the degassing system can omit the pump and rely on a water source flow rate (e.g., tap water flow rate) to move the fluid through the system.

[0183]

[0187] The tubing / connectors / lines, plastic and / or metal, are configured to allow fluid and air communication through the system and the overall acoustic / patient connection system. These may also include various components such as valves (e.g., 2-way, 3-way, etc.).

[0184]

[0188] Electronic and manual controls provide system and user-facing control for all system functions, including but not limited to pump and degas controls. The control system can further include a variety of in-line and on-board sensors for sensing temperature, pressure, flow rate, dissolved oxygen concentration, volume, etc.

[0185]

[0189] The fluidics system and cart can also have various electrical connections for power, including utilizing external power, and / or can be equipped with a battery / toroid to enable an untethered, fully mobile configuration. This allows the fluidics cart to be carried to prepare / setup a histotripsy procedure and then carried away once all fluidics-related workflow steps are complete so that the fluidics cart does not require being next to the patient during treatment / therapy.

[0186]

[0190] The fluidics cart architecture and design may also include handles, individual or central locking casters, an upper work surface, an integrated user display device, connectivity (e.g., Ethernet, etc.), and in some embodiments may be designed to allow for further integration of a support arm. It may also be equipped with long / extended tubing to support intra-imaging system fill / drain when use within, for example, a CT or MRI is desired, so that there is no entire media / water volume in close proximity to the scanner, and / or when fill during setup is required to further evaluate pre / post fill image / body differences.

[0187]

[0191] example

[0188]

[0192] In one example, the fluidics cart of the present disclosure can be operated near a fluid or water supply line in a hospital or procedure room. The first inlet / outlet port can be directly or indirectly attached (through the use of a fluid container) to a fluid source. A user can start the first pump to operate in a first direction, and fluid enters the first inlet / outlet port, passes through a degasser, and exits the second inlet / outlet port into the main tank of the fluidics cart. During this fill or prime cycle, approximately 20 to 40 percent of the dissolved oxygen is removed from the fluid. After approximately 30 L has been filled into the main tank, the first pump is stopped and the first inlet / outlet pump is disconnected from the fluid source. The fluidics cart can then be moved adjacent to the histotripsy system during preparation for the histotripsy procedure.

[0189]

[0193] A second, longer degassing cycle is then performed. During this second circulation cycle, the pump is run in the second, reverse direction, with the fluid entering the second inlet / outlet port, passing through the degasser mechanism, and then being returned to the fill tank via the first inlet / outlet port. During the circulation cycle, both the first and second inlet / outlet ports are attached or clipped to the side of the fill tank, so that one or more distal portions of each of the outlets are submerged in the fluid as circulation occurs. This reduces fluid turbulence and the generation of gas or air bubbles during this cycle. The circulation cycle will remove approximately 60-80 percent of the remaining dissolved oxygen from the start of the circulation cycle. Note that the second degassing or circulation cycle can be performed in either direction, as long as at least one of the first or second input / output ports through which the fluid enters is submerged in the main fluid tank.

[0190]

[0194] Next, one of the first or second inlet or outlet ports is attached or clipped to the side of the connection assembly or ultrasound medium container ("UMC"), while the other inlet / outlet port remains in the fill tank. When the third or fill cycle is performed, the pump is turned on and may be in a second direction, resulting in fluid being pumped from the fluid tank and into the connection assembly. As water is pumped through the fluid tank, the fluid passes through the degasser a third time, removing approximately 20-40 percent of the remaining dissolved oxygen in the fluid. Once the desired amount of fluid, which may be approximately 10 L, has been pumped into the connection assembly, the pump may be turned off. The inlet / outlet port is removed from the connection assembly prior to the histotripsy procedure.

[0191]

[0195] Once the histotripsy procedure is complete, the third of the inlet / outlet ports is connected to the connecting assembly, so that the distal segment is submerged in fluid. The second pump is turned on, and fluid is removed from the connecting assembly and placed in a waste tank. The waste tank is emptied at the end of the procedure.

[0192]

[0196] Additional details regarding the present invention, materials, and manufacturing techniques may be employed as within the level of ordinary skill in the art. The same may be true for method-based aspects of the invention in terms of additional acts commonly or logically adopted. It is also contemplated that any optional features of the described inventive variations may be described and claimed independently or in combination with any one or more of the features described herein. Similarly, reference to a singular item includes the possibility that a plural of the same item is present. More particularly, as used in this specification and 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. Accordingly, this statement is intended to serve as a predicate for the use of exclusive terminology such as "solely," "only," and the like, or the use of a "negative" limitation in conjunction with the recitation of claim elements. Unless otherwise defined 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 scope of the present invention should not be limited by the subject specification, but rather only by the plain meaning of the claims as they are adopted.

Claims

1. 1. A fluidics system configured to support acoustic coupling of an ultrasound transducer to a patient, comprising: Storage container, a fluid tank within the container; a first tubing set having a first input / output port and a second input / output port; a degassing mechanism fluidly connected to the first tubing set; a first pump operatively connected to the first tubing set; waste containers, a second tubing set having a third input / output port; a second pump operatively connected to the second tubing set; a processor operatively coupled to the first pump and the second pump, 1) a filling configuration in which the first input / output port is fluidly connected to a fluid source and the second input / output is fluidly connected to the fluid tank, and the first pump is controlled in a first direction of operation to move the fluid from the fluid source into the first input / output port, through the degassing mechanism, out the second input / output port, and into the fluid tank to remove a first percentage of gas from the fluid; 2) a circulation configuration in which the first and second input / output ports are fluidly connected to the fluid reservoir, and the first pump is controlled in the first or second operating direction to circulate the fluid from the fluid reservoir through the first tubing set and degassing mechanism to remove a second percentage of gas from the fluid; 3) a fluid transfer arrangement, the first input / output port being fluidly connected to an acoustically coupled container and the second input / output being fluidly connected to the fluid tank, the first pump being controlled in the second direction of operation to move the fluid from the fluid tank into the second input / output port, through the degassing mechanism, out the first input / output port, and into the acoustically coupled container to remove a third percentage of gas from the fluid; and 4) a drainage configuration, wherein the third input / output port of the second tubing set is fluidly connected to the acoustic coupling container, and the second pump is controlled to move fluid from the coupling container to the waste container. a processor configured to control the fluidics system to operate with A fluid engineering system comprising:

2. 10. The system of claim 1, wherein the first, second, and third percentages comprise approximately 20 to 40 percent of the remaining gas in the fluid.

3. 10. The system of claim 1, wherein at least one or more of the first, second, and third percentages comprises approximately 20 to 40 percent of the remaining gas in the fluid.

4. 10. The system of claim 1, wherein at least one or more of the first, second, and third percentages comprises approximately 60 to 80 percent of the remaining gas in the fluid.

5. 10. The system of claim 1, wherein the degassing mechanism is selected from the group consisting of a degassing membrane, an ultrasonic degasser, an inert gas degasser, and other forms of degassing.

6. 10. The system of claim 1, wherein the processor is configured to automatically perform the circulation configuration to maintain a preferred gas percentage within the fluid.

7. 2. The system of claim 1, wherein the processor is configured to execute the cyclic configuration at preset time intervals.

8. The system of claim 1 , wherein the system is configured to release a preset volume of fluid into the acoustically coupled container in the filled configuration.

9. 9. The system of claim 8, wherein the preset volume is between 1 and 40 liters.

10. 10. The system of claim 8, further comprising one or more sensors operatively coupled to the processor for verifying the release of the preset volume of fluid.

11. 10. The system of claim 1, further comprising a weight sensor operatively connected to the fluid reservoir for measuring a volume of fluid in the fluid reservoir.

12. 10. The system of claim 1, further comprising a fluid level sensor operatively connected to the fluid reservoir for determining a volume of fluid in the fluid reservoir.

13. 10. The system of claim 1, further comprising a first flow sensor disposed in or near the first input / output port and a second flow sensor disposed in or near the second input / output port, the first and second flow sensors configured to calculate a volume of fluid in the fluid tank.

14. 1. A method of filling an ultrasonically coupled container, comprising: pumping fluid from a fluid source through a degassing mechanism to a fluid tank in a remote cart to remove a first percentage of gas from the fluid; pumping the fluid from the fluid reservoir of the remote cart to the ultrasound-coupled container through the degassing mechanism to remove a second percentage of gas from the fluid. A method comprising:

15. 15. The method of claim 14, wherein the step of pumping fluid from the fluid source to the fluid tank comprises: fluidly connecting a first input / output port of a first tubing set to the fluid source; fluidly connecting a second input / output port of the first tubing set to the fluid reservoir; controlling a first pump to move fluid through the first tubing set and the degassing mechanism; The method further comprises:

16. 16. The method of claim 15, wherein the step of pumping fluid from the fluid tank to the ultrasound-coupled container comprises: fluidly connecting the first input / output port of the first tubing set to the ultrasound coupling container; fluidly connecting the second input / output port of the first tubing set to the fluid reservoir; controlling the first pump to move fluid through the first tubing set and the degassing mechanism. The method further comprises:

17. 15. The method of claim 14, further comprising recirculating fluid from the fluid tank through the first tubing set and the degassing mechanism to remove a third percentage of gas from the fluid.

18. 20. The method of claim 17, wherein the step of recirculating the fluid comprises: fluidly connecting the first and second input / output ports of a first tubing set to the fluid reservoir; controlling the first pump to move fluid through the first tubing set, the degassing mechanism, and back into the fluid reservoir; The method further comprises:

19. 15. The method of claim 14, wherein the first and second percentages comprise 20 to 40 percent.

20. 15. The method of claim 14, further comprising the step of pumping fluid from the ultrasonically coupled container to a waste container.

21. 21. The method of claim 20, wherein the step of pumping fluid from the ultrasonically coupled container to the waste container comprises: fluidly connecting a third input / output port of a second tubing set to the ultrasound coupling container; controlling a second pump to move fluid through the second tubing set and into the waste container; The method further comprises:

22. an ultrasound medium container (UMC) configured to be placed on a patient; a membrane coupled to the UMC and configured to contain an ultrasound coupling medium within the UMC and form an acoustic interface with the patient's skin; a fluidics cart including a main tank, first and second tubing sets removably coupled to the main tank, a pump configured to draw fluid into the main tank and transfer fluid from the main tank to the UMC, and a degassing mechanism in line with the first and second tubing sets to control the percentage of oxygen in the ultrasound coupling medium for optimized acoustic coupling of a histotripsy therapy transducer to the patient. A histotripsy system comprising:

23. 23. The system of claim 22, wherein the first and second tubing sets are disposable.

24. 23. The system of claim 22, wherein the first and second tubing sets are removably coupled to the fluidics cart.

25. 23. The system of claim 22, wherein the pump is disposable.

26. 23. The system of claim 22, wherein the pump is removably coupled to the fluidics cart.

27. 1. A fluidics system configured to support acoustic coupling of an ultrasound transducer to a patient, comprising: Storage container, a fluid tank within the container; a disposable first tubing set having a first input / output port and a second input / output port; a degassing mechanism fluidly connected to the disposable first tubing set; a first pump operatively connected to the first disposable tubing set; a processor operatively coupled to the first pump and configured to control the fluidics system to operate in a fluid transfer configuration where the first input / output port is fluidly coupled to an acoustically coupled container and the second input / output is fluidly coupled to the fluid tank, the first pump being controlled in a second direction of operation to move the fluid from the fluid tank into the second input / output port, through the degassing mechanism, out the first input / output port, and into the acoustically coupled container to remove a preset percentage of gas from the fluid. A fluid engineering system comprising:

28. 1. A fluidics system configured to support acoustic coupling of an ultrasound transducer to a patient, comprising: Portable cart storage container, a fluid tank within the portable cart storage container; a first tubing set having a first input / output port and a second input / output port; a degassing mechanism fluidly connected to the first tubing set; a first pump operatively connected to the first tubing set; a processor operatively connected to the first pump, 1) a filling configuration, wherein the first input / output port is fluidly connected to a fluid source and the second input / output is fluidly connected to the fluid tank, and the first pump is controlled in a first direction of operation to move the fluid from the fluid source into the first input / output port, through the degassing mechanism, out the second input / output port, and into the fluid tank to remove a first preset percentage of gas from the fluid; 2) a circulation configuration in which the first and second input / output ports are fluidly connected to the fluid tank, and the first pump is automatically controlled in the first or second operating direction to circulate the fluid from the fluid tank through the first tubing set and degassing mechanism to remove a second preset percentage of gas from the fluid; 3) a fluid transfer arrangement, wherein the first input / output port is fluidly coupled to an acoustically coupled container and the second input / output is fluidly coupled to the fluid tank, and the first pump is controlled in the second direction of operation to move the fluid from the fluid tank into the second input / output port, through the degassing mechanism, out of the first input / output port, and into the acoustically coupled container to remove a third preset percentage of gas from the fluid. a processor configured to control the fluidics system to operate with A fluid engineering system comprising:

29. 1. A fluidics system configured to support acoustic coupling of an ultrasound transducer to a patient, comprising: Storage container, a fluid tank within the container; a sensor operatively connected to the fluid tank, the sensor configured to determine a volume of fluid in the fluid tank; a first tubing set having a first input / output port and a second input / output port; a degassing mechanism fluidly connected to the first tubing set; a first pump operatively connected to the first tubing set; a processor operatively coupled to the first pump and the sensor, the processor configured to control the fluidics system to draw fluid into the first input / output port of the first tubing set and expel the fluid into the fluid reservoir having the second input / output port of the first tubing set until the volume of fluid as determined by the sensor equals a desired fill volume. A fluid engineering system comprising:

30. 30. The fluidics system of claim 29, wherein the sensor comprises a weight sensor.

31. 30. The fluidics system of claim 29, wherein the sensor comprises a fluid level sensor.

32. pumping a fluid from a fluid source into an acoustically coupled container in contact with a patient through a degassing mechanism to remove at least 50 percent of the dissolved oxygen from the fluid; placing the ultrasound transducer in the fluid in the acoustic coupling container to acoustically couple the ultrasound transducer to the patient with the fluid; An ultrasound therapy method comprising:

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