Histotripsy system and method

Abstract

A histotripsy therapy system configured for tissue treatment, which may include any number of features, is provided. Systems and methods providing effective, non-invasive and minimally invasive therapies, diagnostics, and research procedures are provided herein. The systems provided herein may include a flat histotripsy array that provides dry coupling to a patient without a water bath. A dual-material acoustic lens is provided to facilitate the histotripsy array or probe having a flat coupling surface. A histotripsy transducer array is also provided in which a conductive material is embedded in a matching layer of the transducer array to provide high-voltage coupling to the transmission surface of the array.

Description

[Technical Field]

[0001] Claim of priority

[0001] This patent application claims priority to U.S. Provisional Patent Application No. 63 / 496,181, filed on 14 April 2023, entitled "HISTOTRIPSY SYSTEMS AND METHODS," which is incorporated herein by reference in whole.

[0002] Embedding by reference

[0002] All publications and patent applications referenced herein are incorporated herein by reference to the same extent as each individual publication or patent application is specifically and individually indicated to be incorporated by reference.

[0003] Description of research funded by the federal government.

[0003] This invention was made with government support under grant number R01-CA211217, granted by the National Institutes of Health, USA. The government has specific rights to this invention.

[0004]

[0004] 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 known as histotripsy, may 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]

[0005]

[0005] Histotripsy or pulsed ultrasonic cavitation therapy is a technique in which extremely short, powerful bursts of acoustic energy induce controlled cavitation (microbubble formation) within a focal volume. The violent expansion and collapse of these microbubbles mechanically homogenize the cellular and tissue structures within the focal volume. This is a very different end result from the coagulation necrosis characteristics of thermal delamination. To operate within the non-thermal histotripsy region, it is necessary to deliver the acoustic energy in the form of high-amplitude acoustic pulses with a low duty cycle.

[0006]

[0006] Compared to conventional focused ultrasound techniques, histotripsy has several key advantages: 1) the destructive process at the focus is mechanical and not thermal; 2) cavitation appears bright on ultrasound imaging, thereby confirming correct targeting and localization of treatment; 3) the treated tissue appears darker (less echogenic) on ultrasound imaging, not always but generally, so that the operator can see what has been treated; and 4) histotripsy presents lesions in a controlled and precise manner. It is important to emphasize that, unlike thermal dissection techniques such as microwave, radio frequency, 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, cold, or ionizing energy.

[0007]

[0007] A typical histotripsi transducer consists of a number of piezoelectric elements arranged in a spherical geometric shape, enabling high focus gain. To further aid in generating high focus gain, most transducers feature an f# of less than 1. Transducers can be constructed from many flat individual elements or from a large piezoelectric ceramic machined into a number of elements. Both strategies have been used successfully many times, however the latter still requires specialized mechanical equipment, which increases the practical difficulty of such methods for many scientific laboratories building their own equipment. Most commonly, histotripsi transducers are designed for operating frequencies in the range of 500 kHz to 1.5 MHz, but transducers have been built for specific applications at frequencies as low as 250 kHz and as high as 6.8 MHz. The elements are coupled to an acoustic matching layer or lens and electrically isolated to allow for safe operation at high drive voltages.

[0008]

[0008] The simplest form of a histotripsi transducer is a single-focus transducer. Most commonly, this type of transducer is designed using a number of flat piezoelectric elements coupled to an acoustic lens. Often, the acoustic lens is 3D printed and can be integrated into the transducer base for the greatest degree of simplicity. The transducer is designed so that all lenses are confocal, allowing for a very high focal gain at the transducer's geometric focus, even when using a relatively small number of elements. This design property makes it easy and inexpensive to manufacture, as it reduces the required amount of drive channels, and also simplifies the associated drive electronics.

[0009]

[0009] As an alternative to single-focus transducers, phased arrays featuring a flat acoustic matching layer (as opposed to an acoustic lens) are constructed from many elements. The elements are typically arranged in a spherical geometric shape, and as a result, constructive interference at the focus of the transducer allows for high focal gain and the focal pressure necessary to perform histotripsy. Histotripsy phased arrays can feature hundreds of elements and are therefore considerably more complex and expensive to construct compared to single-focus transducers. Furthermore, phased array electrically driven systems allow individual elements to be driven with an arbitrary phase relative to other elements in the array, enabling advanced therapeutic techniques such as EFS.

[0010]

[0010] Histotripsy is the least invasive treatment option and is therefore usually applied percutaneously, but there are areas of the body where acoustic access is very limited, complicating percutaneous treatment. These areas (such as the pelvis and thoracic cavity) can benefit from endocavity, endoscopic, or laparoscopic form factor transducers, which should avoid the limitations of the acoustic window by being inserted into a natural orifice or a small laparoscopic port. This should enable histotripsy treatment of these areas while maintaining a minimally invasive approach. Potential uses of endocavity or laparoscopic histotripsy include, among others, the treatment of prostate cancer, BPH, uterine fibroids, endometriosis, pelvic abscesses, and pancreatic cancer. All of these uses can be treated via insertion into a natural orifice (rectum, vagina, or stomach), which makes non-invasive treatment possible.

[0011]

[0011] Previous work focused on the development of endoscopic histotripsi transducers, with a focus on high-frequency devices for precision dissection. Specifically, these devices were designed for the treatment of brain tumors via a cranial trepanation hole, enabling highly precise targeting and dissection. The focal gain is proportional to the square of the operating frequency, and therefore, increasing the frequency beyond 5 MHz allows for reduction to a range of 5 × 5 mm. Increasing the frequency also reduces the size of the focal zone, making these devices ideally suited for the precision dissection they were designed for, although these devices would not be suitable for large-volume dissection applications due to the long treatment time that would be required. Furthermore, these devices feature a short working distance, which would eliminate the possibility of treating many indications via insertion into a natural orifice.

[0012]

[0012] Percutaneous histotripsy therapy is preferred because it offers the least invasive approach when the acoustic window is in the appropriate area of ​​the body. In particular, percutaneous histotripsy has been developed and is under clinical investigation for the treatment of liver cancer. Furthermore, significant preclinical work has been carried out to develop percutaneous histotripsy for the treatment of DVT, STS, renal cancer, brain tumors, and ICH, among others. Histotripsy is ideally suited for mass non-invasive treatment because it does not suffer from the diffusion (thermal or chemical) effects of other minimally invasive peeling modalities such as radio frequency peeling (RFA), microwave peeling, or percutaneous ethanol injection.

[0013]

[0013] Previously developed modular transdermal histotripsy devices typically feature piezoelectric elements housed in 3D-printed containers. These designs often feature low aperture utilization (50-60% at most), which can reduce peak pressure output and limit the range of locations within the body where histotripsy can be performed. Furthermore, previous studies have shown that therapeutic parameters such as pulse repetition frequency (PRF) can have a dramatic effect on dissection efficiency. As PRF increases, there is a greater chance of re-exciting previous cavitation nuclei, generating new cavitation clouds that closely correspond to the previously generated clouds, thus reducing the actual new damage achieved by each pulse. While efficient pulse-by-pulse dissection can be achieved by simply reducing PRF, this slows down the overall treatment rate.

[0014]

[0014] Phased arrays offer several advantages over conventional monofocal histotripsi transducers. One such advantage is the ability to perform EFS, which can be used to enhance dissection efficiency and increase the treatment rate. Rapid and efficient dissection per pulse is possible by specifically designing the EFS steering sequence to lower local PRF while maintaining high global PRF. While the dissection rate increased dramatically in these studies, the results were partly dependent on low-frequency (250 kHz) hemispherical arrays, which are suitable for handling many indications. In addition to the rapid dissection EFS technique, phased arrays enable other advanced therapeutic capabilities, such as the ability to perform aberration correction (AC) and treatment monitoring techniques. [Overview of the project] [Problems that the invention aims to solve]

[0015]

[0015] A flat transducer array comprising one or more transducer elements, a dual-material acoustic lens coupled to the flat transducer array, having a flat coupling surface, comprising a first material having a first speed of sound in the dual-material acoustic lens and a second material having a second speed of sound in the dual-material acoustic lens, and configured to provide an equal flight time between the flat transducer array and the focus of the ultrasonic device for any radiation distance across the flat transducer array, an ultrasonic device comprising a dual-material acoustic lens.

Means for Solving the Problem

[0016]

[0016] In some embodiments, the dual-material acoustic lens has a constant overall thickness.

[0017] In other embodiments, the first speed of sound in the first material is higher than the second speed of sound in the second material.

[0017]

[0018] In one embodiment, the first speed of sound is greater than 1500 m / s.

[0019] In other embodiments, the second speed of sound is less than 1500 m / s.

[0020] In one embodiment, the first material has a concave shape.

[0018]

[0021] In other embodiments, the first material has an oval shape.

[0022] In one embodiment, the first material comprises 3D printed plastic.

[0023] In other embodiments, the second material comprises a silicon-filled material.

[0019]

[0024] In one embodiment, the dual-material acoustic lens comprises a Fresnel lens.

[0025] In other embodiments, the first material is shaped to include a plurality of steps.

[0026] In some embodiments, each of the steps has a thickness that is an integer multiple of the wavelength of the flat transducer array.

[0020]

[0027] In another embodiment, the dual-material acoustic lens has a thickness of less than 15 mm.

[0028] In some embodiments, the dual-material acoustic lens has a thickness of less than 13 mm.

[0029] In one embodiment, the dual-material acoustic lens has a thickness of less than 5 mm.

[0021]

[0030] In another embodiment, the dual-material acoustic lens has a thickness of less than 4 mm.

[0031] In one embodiment, the dual-material acoustic lens and flat transducer array are positioned on or inside the probe housing container.

[0022]

[0032] In other embodiments, the dual-material acoustic lens provides dry coupling of the flat transducer array to the subject.

[0033] In one embodiment, the device is configured to deliver histotripsi pulses to the subject's tissue to generate cavitation at a focal point.

[0023]

[0034] In one embodiment, the device further includes an ultrasonic imaging transducer array integrated into a central location of a dual-material acoustic lens and / or flat transducer array.

[0024]

[0035] The ultrasonic device also includes a housing container, a flat transducer array comprising one or more transducer elements arranged in the housing container, electrical cable wiring at least partially arranged in the housing container and configured to provide electrical connections to the back of each of the one or more transducer elements, and a matching layer connected to the transmission surface of the flat transducer array, the matching layer having a conductive material embedded in it, the conductive material configured to provide electrical connections to each of the one or more transducer elements on the transmission surface.

[0025]

[0036] In some embodiments, the conductive material comprises a conductive mesh.

[0037] In one embodiment, the conductive material comprises a conductive grid.

[0038] In another embodiment, the conductive material comprises a copper mesh.

[0026]

[0039] In some embodiments, the matching layer is directly coupled to the transmission surface of the flat transducer array.

[0040] In another embodiment, the flat transducer array is directly coupled to a matching layer before being diced into multiple transducer elements.

[0027]

[0041] In one embodiment, the matching layer comprises a dual-material acoustic lens coupled to a flat transducer array, having a flat coupling surface, and comprising a first material having a first velocity of sound in the dual-material acoustic lens and a second material having a second velocity of sound in the dual-material acoustic lens, and configured to provide equal time of flight between the flat transducer array and the focal point of an ultrasonic device for any radiation distance across the entire flat transducer array.

[0028]

[0042] In some embodiments, the dual-material acoustic lens has a certain overall thickness.

[0043] In other embodiments, the first velocity of sound in the first material is higher than the second velocity of sound in the second material.

[0029]

[0044] In one embodiment, the first speed of sound is greater than 1500 m / s.

[0045] In other embodiments, the second speed of sound is less than 1500 m / s.

[0046] In one embodiment, the first material has a concave shape.

[0030]

[0047] In other embodiments, the first material has an oval shape.

[0048] In one embodiment, the first material comprises 3D printed plastic.

[0049] In other embodiments, the second material comprises a silicon-filled material.

[0031]

[0050] In one embodiment, the dual-material acoustic lens comprises a Fresnel lens.

[0051] In other embodiments, the first material is shaped to include multiple steps.

[0052] In some embodiments, each of the steps has a thickness that is an integer multiple of the wavelength of the flat transducer array.

[0032]

[0053] In another embodiment, the dual-material acoustic lens has a thickness of less than 15 mm.

[0054] In some embodiments, the dual-material acoustic lens has a thickness of less than 13 mm.

[0055] In one embodiment, the dual-material acoustic lens has a thickness of less than 5 mm.

[0033]

[0056] In another embodiment, the dual-material acoustic lens has a thickness of less than 4 mm.

[0057] In one embodiment, the dual-material acoustic lens and flat transducer array are positioned on or inside the probe housing container.

[0034]

[0058] In other embodiments, the dual-material acoustic lens provides dry coupling of the flat transducer array to the subject.

[0059] In one embodiment, the device is configured to deliver histotripsi pulses to the subject's tissue to generate cavitation at a focal point.

[0035]

[0060] In one embodiment, the device further includes an ultrasonic imaging transducer array integrated into a central location of a dual-material acoustic lens and / or flat transducer array.

[0036]

[0061] In some embodiments, the conductive material is embedded in the first material.

[0062] In one embodiment, the device further includes a printed circuit board configured to receive a spring-pin electrical connector for each of one or more transducer elements, the spring-pin electrical connector providing an electrical connection between electrical cable wiring and the back of each of the one or more transducer elements.

[0037]

[0063] In another embodiment, the device comprises an intracavitary histotripsy probe or a laparoscopic histotripsy probe.

[0064] A flat histotripsy therapy array is provided, comprising multiple histotripsy transducer elements arranged on a plane and configured to enable acoustic coupling with a patient without the need for water coupling.

[0038]

[0065] The novel features of the present invention are described in detail in the claims that follow. A better understanding of the features and advantages of the present invention will be obtained from the following detailed description and reference to the accompanying drawings, which illustrate exemplary embodiments in which the principles of the present invention are utilized. [Brief explanation of the drawing]

[0039] [Figure 1A]

[0066] This is a diagram of an ultrasound imaging and therapy system. [Figure 1B] This is a diagram of an ultrasound imaging and therapy system. [Figure 2]

[0067] This is a graphic representation of the parameters for determining the flat front profile of a flat profile lens. [Figure 3]

[0068] Figure 3A shows the lens profile of an oval flat-front double-material lens. Figure 3B shows the lens profile of a flat-front Fresnel double-material lens. [Figure 4]

[0069] Figure 4A is a diagram of a laparoscopic transducer. Figure 4B is a diagram of a laparoscopic transducer. [Figure 5]

[0070] Figure 5A is a diagram of the flat intraluminal array design. Figure 5B is a diagram of the flat intraluminal array design. [Figure 6]

[0071] This is a diagram of a soft tissue sarcoma (STS) transducer array. [Modes for carrying out the invention]

[0040]

[0072] The systems, methods, and devices of this disclosure may be used for non-invasive acoustic cavitation for the treatment of healthy, diseased, and / or damaged tissue, including but not limited to tissue destruction, cutting, skeletonizing, and detachment. Furthermore, due to tissue selectivity, histotripsy may be used to create a cytoskeleton that enables subsequent tissue regeneration, either newly or through the application of stem cells and other auxiliary means. Finally, histotripsy may be used to induce the release of delivered agents, such as chemotherapy and immunotherapy, by locally inducing the release of these agents by applying acoustic energy to a target. As described below, acoustic cavitation systems may include various subsystems, including carts, therapy, integrated imaging, robotics, coupling, and software. The system may also comprise various other components, auxiliary devices, 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 producing / controlling / implementing histotripsy, including new and related inventions disclosed herein, are considered part of this disclosure.

[0041]

[0073] Histotripsy therapy is typically induced by ultrasound imaging. Histotripsy can also be induced by MRI. This disclosure describes novel systems (hardware and software) and methods for simultaneous ultrasound and MRI guidance and monitoring for histotripsy therapy. This disclosure describes systems and methods for accurately predicting the trajectory of histotripsy cavitation using low-temperature focused ultrasound (FUS) heating or magnetic resonance (MR) thermometry combined with MR acoustic radiation force imaging (MR-ARFI). Furthermore, histotripsy-generating detachment (e.g., brain detachment) can be visualized using diffusion-weighted MRI (dMRI).

[0042]

[0074] This disclosure also provides techniques for enhancing MR image quality by integrating an ultrasound-transmitting RF receiving coil into a histotripsy system. Furthermore, it provides drive electronics that enable a single-amplifier setup to both transmit histotripsy acoustic pulses and receive subsequent acoustic cavitation emission (ACE) signals. This disclosure provides ACE-based quantitative cavitation monitoring to enable real-time therapeutic ultrasound monitoring at a practical high frame rate (≧50 Hz) for histotripsy implementation and cavitation mapping at target and off-target locations, including on the surface of bone (e.g., skull). Cavitation mapping can be complemented by periodic updates from dMRI to assess tissue damage during histotripsy with both high spatial and temporal resolution.

[0043]

[0075] This disclosure also provides a color-encoded cavitation / damage map based on ACE signals that can be recorded together and superimposed on MR images to form integrated US and MR guidance.

[0044]

[0076] This disclosure also describes a transcranial MR and ultrasound-guided histotripsy (tcMR-USgHt) system. This tcMR-USgHt system can be configured to produce jointly recorded MRI and US therapeutic guidance and monitoring with high spatial and temporal resolution, as well as at all intracranial locations.

[0045]

[0077] Figure 1A illustrates the histotripsy system 100 according to this disclosure as a whole, comprising a therapeutic 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 ultrasonic coupling interface and a source of coupling medium, which are not shown.

[0046]

[0078] Figure 1B is a bottom view of a therapeutic head 101 including a therapeutic transducer 102 and an imaging system 104. As shown, the imaging system can be positioned at the center of the therapeutic transducer. Nevertheless, other embodiments may include an imaging system positioned at other locations within the therapeutic transducer, or possibly directly integrated with the therapeutic transducer. In some embodiments, the imaging system is configured to produce real-time imaging at the focus of the therapeutic transducer. The system also allows multiple imaging transducers to be placed within the therapeutic transducer to provide multiple views of the target tissue simultaneously and integrate these images into a single 3D image.

[0047]

[0079] The histotripsy system may comprise one or more of various subsystems, including a therapeutic subsystem capable of generating, applying, focusing, and performing acoustic cavitation / histtripsy through one or more therapeutic transducers; an integrated imaging subsystem (or connection thereto) enabling real-time visualization of the treatment site and histotripsy effect throughout the procedure; a robotics positioning subsystem for mechanically and / or electronically steering the therapeutic transducers, which may further be capable of connecting to / supporting or interacting with a coupling subsystem to enable acoustic linkage between the therapeutic transducers and the patient; a system and computer-based control system (and other external systems); and software for communicating with, controlling, and interfaceing with various other components, assistive devices and accessories, including one or more user interfaces and displays and associated induction workflows, all of which function partially or together. The system may further comprise various fluid engineering and fluid management components, including pumps, valves and flow control, temperature and degassing control, and without limitation, water injection and suction capabilities, as well as supplying and storing fluids. The system may also comprise various power supplies and protective devices.

[0048]

[0080] As described above, the histotripsy system may include integrated imaging. However, in other embodiments, the histotripsy system may be configured to interface with a separate imaging system such as a C-arm, fluoroscope, cone-beam CT, or MRI to provide real-time imaging during histotripsy therapy. In some embodiments, the histotripsy system may be made to be sized to fit inside a C-arm, fluoroscope, cone-beam CT, or MRI, and may be configured to fit inside such a system.

[0049] cart

[0081] The cart 110 can be configured as a whole in various schemes and form factors based on specific intended use and procedures. In some cases, the system may comprise a number of carts configured in similar or different arrangements. In some embodiments, the carts may be configured and arranged for use in a radiological environment, and optionally in conjunction with imaging (e.g., CT, cone-beam CT and / or MRI scans). In other embodiments, the carts may be arranged for use in operating rooms and sterile environments for invasive or laparoscopic and endoscopic applications, or in robot-enabled operating rooms, and may be used alone or as part of a surgical robot procedure in which the surgical robot performs specific tasks before, during, or after the use of the system and the implementation of acoustic cavitation / histotomy. Accordingly, and depending on the procedure environment based on the embodiments described above, the carts may be positioned to provide ample workspace and access to various anatomical locations of the patient (e.g., torso, abdomen, flanks, head and neck, etc.), as well as to provide workspace for other systems (e.g., anesthesia carts, laparoscopic towers, surgical robots, endoscopic towers, etc.).

[0050]

[0082] The cart may also work with the patient's surface (e.g., a table or bed) to allow the patient to be presented and repositioned in a great many positions, angles, and orientations, including allowing changes to be made pre-operative, perioperative, and post-operative. The cart may further have the ability to interface and communicate with one or more external imaging or image data management and communication systems, not limited to ultrasound, CT, fluoroscopy, cone-beam CT, PET, PET / CT, MRI, optics, ultrasound, and image fusion and / or image flow of one or more modalities, and to support a procedure and / or usage environment, including physical / mechanical interoperability (e.g., compatibility within a cone-beam CT workspace for collecting pre-histotripsy, pre- and post-histotripsy, and / or post-histotripsy imaging data), and to provide access to and display of patient medical data, including but not limited to laboratory and historical medical record data.

[0051]

[0083] In some embodiments, one or more carts may be configured to operate together. For example, one cart may comprise a bedside mobile cart equipped with one or more robotic arms corresponding to a therapy transducer and a therapy generator / amplifier, while companion carts operating with and away from the patient may comprise integrated imaging and console / display for controlling robots and therapy facets similar to surgical robots and master / slave configurations.

[0052]

[0084] In some embodiments, the system may comprise multiple carts, all slaves to one master cart, each equipped to perform acoustic cavitation procedures. In some arrangements and in some cases, one cart configuration may allow for the storage of specific subsystems at a distance that reduces the disruption of the operating room, while another cooperating cart may essentially house bedside subsystems and components (e.g., implementation systems and therapies).

[0053]

[0085] A great many sorting and configurations of cart designs can be envisioned, and these examples do not limit the scope of this disclosure. histotripsy

[0086] Histotripsy employs short, high-amplitude, focused ultrasonic pulses to generate a dense, active “bubble cloud” capable of targeted tissue division and destruction. Histotripsy has the ability to produce controlled tissue erosion when directed at tissue interfaces, including tissue / fluid interfaces, as well as well-bounded tissue division and destruction at subcellular levels when histotripsy targets large amounts of tissue. Unlike other forms of dissection, including thermal and radiation-based modalities, histotripsy does not rely on heat, cold, or ionizing (high) energy to treat tissue. Instead, histotripsy uses acoustic cavitation generated at the focus to mechanically influence tissue structure, potentially causing the tissue to liquefy, float, dissolve, and / or break down into subcellular components.

[0054]

[0087] Histotripsy can be applied in various forms, including: 1) Intrinsic threshold histotripsy: A pulse is delivered with a high amplitude inverse / extension phase pressure of 1-2 periods that exceeds the intrinsic threshold for cavitation in the medium (e.g., approximately 24-28 MPa for aqueous soft tissue). 2) Shock scattering histotripsy: A pulse of 3-20 periods is typically delivered within the duration. The shock waves (positive / compression phase) scattered from the initial individual microbubbles generated form inverse shock waves that structurally interfere with the incoming inverse / extension phase, forming a high amplitude inverse / dilute phase that exceeds the intrinsic threshold. In this way, a cluster of cavitating microbubbles is generated. The amplitude of the extension 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 invert the incident wave and scatter the incident shock wave that structurally interferes with the incident wave, exceeding the threshold for intrinsic nucleation. 3) Boiling histotripsy: A pulse of approximately 1–20 ms is employed during the duration. The absorption of the impacted pulse rapidly heats the medium, thereby lowering the threshold of the intrinsic nucleus. When this intrinsic threshold coincides with the peak negative pressure of the incident wave, boiling bubbles are generated at the focus.

[0055]

[0088] The high pressure generated at the focus creates a cloud of acoustic cavitation bubbles exceeding 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 focus. This cavitation effect is only observed at pressure levels significantly higher than those defining the inertial cavitation threshold in water for similar pulse durations, with peak negative pressures of approximately 10 to 30 MPa.

[0056]

[0089] Histotripsy can be performed in numerous ways and under different parameters. Histotripsy can be performed entirely non-invasively 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 tissues above (and intervening) it. While the application of histotripsy is not limited to percutaneous approaches, it can be applied through any means that allows contact of the transducer with tissue, including percutaneous and robotically bridging surgical procedures between open surgery and laparoscopic surgery. Assuming that the bubble cloud generated by histotripsy can be visible as a highly dynamic echo region on B-mode ultrasound images, for example, enabling continuous visualization through its use (and associated procedures), it can be further targeted, planned, directed and observed under direct visualization via ultrasound imaging. Similarly, treated and dissected tissues exhibit dynamic changes (typically reductions) in echoes that can be used to evaluate, plan, observe and monitor the treatment.

[0057]

[0090] Generally, in histotripsy therapy, an ultrasonic pulse with one or more acoustic periods is applied, and bubble cloud formation depends on the pressure-release scattering (sometimes exceeding 100 MPa, P+) of the positive shock wavefront from the initially initiated, slightly dispersed bubbles (or a single bubble). This is called the "shock scattering mechanism."

[0058]

[0091] This mechanism relies on one (or several slightly dispersed) bubbles initiated in the initial negative half-period of the pulse at the transducer's focus. Then, a cloud of microbubbles is generated by the pressure-releasing backscattering of the high-peak positive shock wavefront from these slightly initiated bubbles. These backscattered high-amplitude tenuous waves exceed the intrinsic threshold, thus creating a localized, high-density bubble cloud. Each subsequent acoustic period then induces further cavitation through backscattering from the surface of the bubble cloud, which grows toward the transducer. As a result, a stretched, high-density bubble cloud, growing along the acoustic axis opposite to the direction of ultrasonic propagation, is observed in the shock scattering mechanism. This shock scattering process makes bubble cloud generation dependent not only on the peak negative pressure but also on the number of acoustic periods and the amplitude of the positive shock. Without at least one strong shock wavefront induced by nonlinear propagation, a high-density bubble cloud would not be generated when the negative half-period of the peak falls below the intrinsic threshold.

[0059]

[0092] When ultrasonic pulses of less than two cycles are applied, shock scattering can be minimized, and the formation of high-density bubble clouds depends on the negative half-cycle of the applied ultrasonic pulse that exceeds the "intrinsic threshold" of the medium. This is called the "intrinsic threshold mechanism."

[0060]

[0093] This threshold can be in the range of 26-30 MPa for soft tissues with high water content, such as human tissue. In some embodiments, using this intrinsic threshold mechanism can make the spatial extent of lesions well-defined and more predictable. At peak negative pressures (P-) not significantly higher than this threshold, subwavelength reproducible lesions can be generated that are only about half the size of the transducer's -6 dB beamwidth.

[0061]

[0094] Using high-frequency histotripsi pulses results in smaller minimum reproducible lesion sizes, which is beneficial for applications requiring precise lesion generation. However, high-frequency pulses are more susceptible to attenuation and aberrations, making treatment at greater penetration depths (e.g., deep tissue dissection) or through highly aberration-prone media (e.g., transcranial procedures or procedures where pulses are transmitted through bone) uncertain. Furthermore, histotripsi can be applied in conjunction with low-frequency "pump" pulses (typically <2 periods and having frequencies between 100 kHz and 1 MHz) and high-frequency "probe" pulses (typically <2 periods and having frequencies greater than 2 MHz or extending between 2 MHz and 10 MHz), and the peak negative pressures of the low and high-frequency pulses structurally interfere to exceed the intrinsic threshold of the target tissue or medium. Low-frequency pulses, which are tolerant of attenuation and aberrations, can raise the peak negative pressure (P-) level in a region of interest (ROI), while high-frequency pulses, which offer higher precision, can precisely pinpoint target locations within the ROI and raise the peak negative pressure (P-) above the intrinsic threshold. This approach is sometimes called "dual-frequency," "dual-beam histotripsy," or "parametric histotripsy."

[0062]

[0095] Additional systems, methods, and parameters for performing optimized histotripsy using various parameters enabling impact scattering, intrinsic thresholds, and frequency compounding and bubble manipulation are included herein as part of the systems and methods disclosed herein, including additional means for controlling the histotripsy effect such as those relating to steering and positioning the focus and simultaneously managing tissue effects (e.g., constant-focus thermal incidental injury) at or within the treatment site. Furthermore, various systems and methods that may include multiple parameters such as, but not limited to, frequency, operating frequency, center frequency, pulse repetition frequency, pulse, burst, number of pulses, period, pulse length, pulse amplitude, pulse duration, delay, burst repetition frequency, set of the former, loops of many sets, loops of many and / or different sets, sets of loops, and various combinations or arrangements thereof are included herein as part of the disclosure, including future conceivable embodiments thereof.

[0063] Therapeutic components

[0096] The therapeutic subsystem can operate in conjunction with other subsystems to produce, optimize, deliver, visualize, monitor, and control acoustic cavitation, also referred herein and hereafter as “histtripsy” and its derivatives, including boiling histotripsy and other high-frequency ultrasonic approaches to heat. It is noted that the inventions of the disclosure may also further benefit from other acoustic therapies that do not involve cavitation, mechanical, or histotripsy components. Among other features, the therapeutic subsystem may include an ultrasonic therapeutic transducer and pulse generator system configured to deliver ultrasonic pulses to tissue.

[0064]

[0097] To produce and deliver histotripsy and histotripsy derivatives, the therapeutic subsystem may also include components including, but not limited to, one or more function generators, amplifiers, therapeutic transducers, and power supplies.

[0065]

[0098] Therapeutic transducers can comprise a single or multiple elements configured to be excited by high-amplitude electrical pulses (>1000V, or any other voltage that may be harmful to the body). The amplitude required to drive the therapeutic transducer for histotripsy varies depending on the transducer design, the material used (e.g., solid or polymer / piezoelectric composites including ceramic or single crystals), and the transducer center frequency, which is directly proportional to the thickness of the piezoelectric material. Thus, a transducer operating at high frequencies requires a lower voltage to produce a given surface pressure than a low-frequency therapeutic transducer. 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 components. In some embodiments, the transducer elements can be formed using silicon using MEM techniques, including CMUT and PMUT designs.

[0066]

[0099] In some embodiments, the function generator may include a field-programmable gate array (FPGA) or other suitable function generator. The FPGA may consist of parameters previously disclosed herein, including but not limited to frequency, pulse repetition frequency, burst, and number of bursts, where a burst may include pulses, number of pulses, pulse length, pulse duration, delay, burst repetition frequency, or duration; a set of bursts may include a parameter set; a loop set may include various parameter sets with or without delays, and various time delays, and independently controlled, and a number of loop sets of various combinations and sorts of such as, and throughout, may be repeated and / or new loop sets may be introduced.

[0067]

[0100] In some embodiments, the generator or amplifier may be a general-purpose single-period or multi-period pulse generator and may be configured to support driving via Class D or inductive drive and across all conceivable clinical applications and operating environments, which will be discussed in part later in this disclosure. In other embodiments, the Class D or inductive current driver may be configured to further provide step-up / down components and, optionally, preferably, enable amplitude step-up, a transducer and / or automatic transducer drive circuit. These may also have inherent protective features to further support the system and provide the ability to protect other components of the system (e.g., therapeutic transducers and / or amplifier circuit components) and / or the user from a variety of threats, including but not limited to electrical safety threats that may potentially lead to the operating environment, the system and the therapeutic system, and harm, adverse effects or problems to the user.

[0068]

[0101] The disclosed generator may enable and support the ability of the system to select, vary, and control a variety of parameters (through an effective software tool), 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 cycle, effective channels and delays, modulate pulse amplitude on a fast time scale independent of the high voltage source, and / or perform other services, diagnostic or therapeutic features.

[0069]

[0102] In some embodiments, the therapeutic subsystem and / or its components, such as amplifiers, may have further integrated computer processing capabilities and may be networked, connected, accessible, and / or removable / portable, modular, and / or interchangeable between systems, and / or driven / commanded by / by other systems, or in various combinations. Other systems may include other acoustic cavitation / histtripsy, HIFU, HITU, radiotherapy, radio frequency, microwave, and cryoablation systems, navigation and positioning systems, invasive surgery, laparoscopy, single-incision / single-port, endoscopic and non-invasive surgical robots, laparoscopy or surgical towers with other energy-based or vision systems, surgical system racks or booms, imaging carts, and the like.

[0070]

[0103] In some embodiments, one or more amplifiers may comprise a Class D amplifier and associated drive circuit equipment including a matching network component. Depending on the electrical impedance of the transducer element and the selection of the matching network component (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 have 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, the matching network component or inductor, and the transducer or autotransformer, and may typically be in the low kV range (e.g., 1–3kV).

[0071]

[0104] Therapeutic transducer elements are excited with an electrical waveform having an amplitude (voltage) sufficient to produce a pressure output for histotripsy therapy. The excitation field can be defined as the required waveform voltage per unit thickness of the piezoelectric element. For example, a piezoelectric element operating at 1 MHz is half the thickness of an equivalent 500 kHz element, so it will require half the voltage to achieve the same electric field and surface pressure.

[0072]

[0105] The therapy subsystem may also include therapy transducers of various designs and working parameters to support use in various procedures (and procedures in various settings). The system may consist of one or more therapy transducers, one or more of which may be further interchangeable and can operate with various aspects of the system in similar or different ways (for example, they may interface with a robotic arm using common interfaces and interchangeable features, or conversely, be adapted to operate with application-specific imaging probes, each of which may interface with and integrate with therapy transducers in a specifically different way).

[0073]

[0106] Therapeutic transducers can consist of various parameters, including size, shape (e.g., rectangular or circular, anatomically curved housing, etc.), geometric shape, focal length, number of elements, size of elements, distribution of elements (e.g., number of rings and ring size in annular pattern transducers), frequency, and electron beam steering that enables them. Transducers can be made from various materials (e.g., piezoelectric, silicon, etc.), form factors and types (e.g., machined elements, chip-based, etc.), and / or by various methods of their manufacture.

[0074]

[0107] Transducers can be designed and optimized for clinical applications (e.g., abdominal tumors, peripheral vascular diseases, fat removal, etc.) and desired outcomes (e.g., acoustic cavitation / histotolypse without burns to interstitial tissues), as well as to provide a broad range of applications including relatively shallow and superficial targets (e.g., thyroid or mammary nodules) and deeper or more difficult-to-reach targets such as central liver or brain tumors. They can be configured to enable acoustic cavitation / histotolypse under various parameters and sets, such as those enabled by the aforementioned system components (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 duration, synchronization pulse, synchronization pulse delay, various loop sets, and others, and their sortings. Transducers can also be designed to enable activation of drug payloads accumulated in tissues through various means, including injection, replacement, or delivery in micelles or nanostructures.

[0075] Histotripsytransducer design

[0108] This paper provides systems and methods for performing miniature intracavitary and laparoscopic histotripsi transducers for volume dissection. These systems and methods enable histotripsi therapy in areas of the body where acoustic access is limited. It also provides novel dual-material flat-front acoustic lens designs and methods. The provided designs and methods can be used to construct flat-front histotripsi transducers exhibiting improved focusing capability compared to traditional lens construction techniques. These devices demonstrate the feasibility of low-frequency gel-coupled histotripsi transducers. Improvements necessary for the clinical transition of such devices are provided, including laparoscopic-sized transducers, integration of real-time ultrasound imaging, and intracavitary phased array deployment.

[0076]

[0109] Furthermore, we provide percutaneous phased array designs for large-volume dissection. In some examples, a modular incision-minimizing approach to therapeutic ultrasound phased array construction is applied to phased array systems designed for treating the human abdominal region. Some embodiments of the resulting phased arrays feature an opening utilization rate of up to 92% (previous modular construction techniques: 50-60%) and can be configured to generate peak negative focal pressures exceeding 100 MPa. We also provide a novel semi-cylindrical phased array design for the treatment of soft tissue sarcomas. The novel geometric shape enables several promising rapid dissection techniques, including multifocal therapy and focal expansion techniques, where the predicted focal volume is greater than the typical focal volume.

[0077]

[0110] This disclosure provides intracavitary or laparoscopic histotripsitransducers that focus on minimizing the opening size while maintaining the transducer specifications necessary to enable clinically relevant dissection rates and transducer performance (such as working distance). Specifically, the systems and methods provided herein are configured to reduce the operating frequency (≤1.5 MHz) while maintaining an opening size (<4 cm opening) suitable for transrectal or transvaginal movement.

[0078] Transcutaneous histotripsy phased array focus

[0111] This disclosure provides fabrication techniques to enable modular, high-opening utilization methods. These methods can be used in designing and fabricating high-power phased arrays for rapid dissection techniques, as well as other advanced histotripsy therapeutic capabilities such as AC and passive acoustic mapping (PAM). Phased arrays specific to the treatment of liver cancer and STS are also provided. Since the anatomical structures surrounding these indications are substantially different, the instrument design is optimized to enable efficient treatment of these locations. Furthermore, the effects of therapeutic parameters such as EFS point spacing, focal pressure, and EFS sequence on dissection rate are explored using the currently produced instruments. This leads to a deeper understanding of the effects of these parameters and enables rapid, large-volume treatment. Through this optimization, dissection rates in the range of >2 cubic centimeters per minute are achievable.

[0079]

[0112] This disclosure provides an intracavitary histotripsy transducer with the ability to perform volume dissection at low frequencies (≒1 MHz) and at a reasonable rate for clinical practice. Clinical treatment rates may range from 1 ml per 10 minutes of treatment, but higher dissection rates are required for larger volume targets. The transducer disclosed herein offers the capability for a range of applications such as dissection of the prostate or chronic pelvic abscesses. The use of an intracavitary histotripsy transducer for the treatment of these applications can avoid limited acoustic windows (due to pelvic bone and other obstructions in the intestines or tissues). To perform intracavitary histotripsy, the transducer is configured to produce a negative focal pressure with a peak of 30 MPa or more. Furthermore, it provides a working distance of 10 to 40 mm. In some embodiments, the transducer may have a size similar to existing transrectal HIFU transducers (with an opening of approximately 35 mm). In some implementations, transducers can be built inexpensively using a relatively simple and reproducible method (requiring only a few hours of construction time and no highly specialized skills) (material cost per transducer is approximately $200). This should allow transducers to be treated as semi-disposable (requiring only moderate durability) and easily replaced if they break.

[0080]

[0113] This disclosure provides a design, fabrication, and characterization process for an intraluminal histotripsy transducer. First, piezoelectric materials, matching layer materials, and drivers can be modeled and selected to determine the combination of materials and drivers best suited to achieving high focal pressure. These results guided the design of the intraluminal transducer.

[0081]

[0114] This disclosure provides a compact histotripsy transducer, but includes additional features that can be included for clinical use. Most notably, an ultrasound imaging guidance system can be integrated into the design to enable real-time targeting and treatment by clinicians or researchers. In some embodiments, this can be a transducer that fits around an existing transrectal or transvaginal imaging probe, or a custom-made low-profile imaging transducer integrated directly into a transducer stand. For example, an imager with an aperture size of approximately 8 × 20 mm can be incorporated into the transducer described above, while still allowing the transducer to generate negative pressure with a peak of 30 MPa. Therapeutic transducers can be recorded together with the imaging transducer to provide pre-treatment targeting and visual feedback throughout the treatment process.

[0082]

[0115] Furthermore, for in vivo use, a coupling mechanism must be implemented to ensure maximum sound transmission from the transducer to the treatment zone. This may include a fluid-filled bag or balloon covering the surface of the transducer. In the case of prostate treatment, this bag or balloon should provide a surface that conforms to the rectal wall and be configured to allow transrectal sound transmission to the prostate.

[0083] Flat front dual-material acoustic lens for histotripsy transducer

[0116] Performing histotripsy therapy with large concave ultrasound transducer arrays currently requires the use of cumbersome water bath coupling systems. These systems involve a large water bolus placed on the patient, with the histotripsy transducers positioned within the bolus, allowing sound to be transmitted through the water bath to the body. While this coupling system has been widely and successfully used, its cumbersome nature and potential challenges during treatment, especially when patient repositioning is necessary, make it clinically impede to accepting histotripsy as a therapeutic modality. This disclosure provides an ultrasound transducer for histotripsy having a flat or slightly convex front, thereby designed to allow direct acoustic coupling to the patient's skin using a standard ultrasound gel, similar to methods using ultrasound imaging probes.

[0084]

[0117] Water bath coupling is a standard coupling method for histotripsy, depending on the size and geometry of the transducers used. To generate the high-amplitude focal pressure required for histotripsy, transducers are typically large and utilize a concave spherical shell geometry to generate high focal gain. In most cases, multiple piezoelectric elements are arranged on top of this spherical shell geometry. Sometimes, each element is coupled to an acoustic lens to further increase focal gain, while other transducers are designed as a phased array capable of performing electronic focus steering and phase aberration correction. Typically, concave lenses fabricated from high-velocity sound (>1500 m / s) materials are used for histotripsy. If a material with a lower velocity of sound than the target medium is used, it is possible to fabricate a convex acoustic lens. This approach is not generally used for histotripsy transducers because most materials with a velocity of sound lower than that of biological tissues (≒1500 m / s) are attenuating, reducing their usefulness for high-amplitude applications.

[0085]

[0118] As an alternative to the concave geometric structures previously described, flat, electronically steering phased arrays have been developed for HIFU therapy. Histotripsy is entirely a non-thermal modality, while HIFU uses long acoustic exposures of intermediate amplitude to induce tissue necrosis via heating, in contrast to histotripsy. Therefore, the transducer engineering requirements differ considerably between transducers designed for HIFU and histotripsy. Nevertheless, current material performance limits for histotripsy are such that the essential focal pressure should be unattainable for such arrays. Due to these limitations, this disclosure provides a lens-based alternative for creating a flat-front histotripsy transducer capable of generating the focal pressure necessary to produce cavitation within tissue.

[0086]

[0119] Traditional acoustic lenses are made from a single material with a sound velocity higher or lower than that of the target medium. When designing lens materials with a high sound velocity, a concave oval shape is used, following Fermat's principle for the minimum time at which the time of flight (tof) between the focal point and all points on the transducer surface is equal. When using low sound velocity lens materials, a convex shape is formed for the same effect. Alternatives to traditional single-material oval lenses include Fresnel zone plates (FZPs) and phase-continuous Fresnel lenses. An FZP is a binary mask that works by effectively blocking a portion of the aperture that would reach the intended focal location out of phase with the rest of the transducer, thus eliminating the occurrence of any canceling interference at the focal location. This can result in a considerable increase in pressure amplitude, but this is inefficient as approximately half of the aperture is blocked from contributing to the pressure field. Phase-continuous Fresnel lenses are designed by removing the thickness of a standard acoustic lens in a stepped shape, where the thickness at each step is an integer multiple of the wavelength, allowing sound from any point on the sound source to reach an in-phase focal point. This approach solves the efficiency problems of FZP, but it does not enable the flat front design that is currently being achieved.

[0087]

[0120] This disclosure provides a flat-front acoustic lens using two materials, one with a high velocity of sound (>1500 m / s) and the other with a lower velocity of sound (<1500 m / s). The high-velocity material can be used to construct a concave lens structure, and the concave lens structure is therefore filled with the lower-velocity material, allowing the lens to have a flat-front profile. The surface profile between the two lenses is specifically designed to take into account the velocity of sound for each material and the velocity of sound in the target medium, as these parameters affect the time of flight (tof) of a single streak of sound from any point on the transducer to the intended focal location. Furthermore, the angle of refraction at each boundary will affect the tof and is taken into consideration on a design-by-design basis.

[0088]

[0121] This disclosure describes the design, fabrication, and characterization of three transducers. The first is a transducer based on a standard single-material concave oval lens. The second is a transducer based on the previously described flat-front design, using high-sonic-velocity lens material and low-sonic-velocity filling material. The third transducer is a flat-front design modified to use the concept of a phase-continuous Fresnel lens, which allows the phase-continuous Fresnel lens to receive more attention than the other designs.

[0089] Lens design algorithm

[0122] Traditional single-material acoustic lenses are well-known, and their curvature follows a simple calculation. However, this explanation of curvature does not correctly describe the lens profile of the desired flat-front double-material lens. This is due to the use of an additional "filling" or low-sound-velocity material to create a flat connecting surface. Including this additional layer means that a boundary is added between the sound source and the focal point, and refraction is added through this layer, affecting the acoustic path length and the time of facies (Tof) between the source and the focal point. This effect can be mitigated by using a filling material whose speed of sound is equal to the speed of sound in the medium the sound is focusing on, but this limits the range of suitable materials that can be used as filling materials. This necessitates an alternative approach to determining the lens profile. To compute this profile, a simple ray-tracing approach can be used, which determines the lens profile such that the Tof between the sound source and the focal point is equal for any radiation distance across the entire transducer range. The following algorithm determines the boundary profile between the two lens materials, assuming that the front of the lens is flat. Furthermore, this algorithm allows the use of Fresnel-based "phase wrapping" to reduce the overall thickness of the lens.

[0090]

[0123] Figure 2 provides a graphical representation of the flat front profile determination parameters for a flat profile lens 200 having a first material 202 and a second material 204. As described above, the first material 202 can have a high sound velocity (>1500 m / s) and a concave shape, while the second material 202, with a lower sound velocity (<1500 m / s), is used as a filler material.

[0091]

[0124] First, calculate the overall thickness of the lens. Referring to FIG. 2, this calculation can be performed by solving for the thickness such that the tof from the center of the lens (Equation 1) to the focus is equal to the tof from the edge of the lens (Equation 2) to the focus. Equation 2 is obtained by recognizing that there is no filling material at the edge of the transducer and the phase correction factor when designing the Fresnel lens. y , , , , , , is the minimum thickness of the high - sound - speed material 202, c p is the speed of sound in the high - sound - speed material, y smax is the maximum thickness of the low - sound - speed material, c s is the speed of sound in the low - sound - speed material, y w is the distance from the water - low - sound - speed material boundary to the desired focus position, c w is the speed of sound in water, r max is the maximum radius of the transducer, n seg is the number of desired Fresnel segments on the lens, and P is the period during which sound is transmitted through the lens.

[0092]

Number

[0093]

[0125] After solving for the thickness of the low - sound - speed material in the lens, a similar ray - tracing approach can be used to determine the profile between the low - sound - speed material and the high - sound - speed material. To perform these calculations, the lens is restricted to have a constant overall thickness across all possible radii, but the thicknesses of the first and second materials can be varied. The center position of the lens is initially set to have the minimum high - sound - speed material thickness (y pmin ) and the maximum low - sound - speed material thickness (y smax ). Then, a numerical approach is used to calculate the lens profile. For the i - th emission point, the calculation is as follows.

[0094]

Number

[0095]

number

[0096]

[0126] Here, Δr is the step size between adjacent radiating points used for profile calculation, and ypr i-1 This is the profile determined in the previous step (Δr is closer to the center of the lens). A graphical representation of the parameters is shown in Figure 2. The profile of a double-material flat-front lens can be determined by solving for a profile in which tof is equal to the tof at the center and edge. If a Fresnel lens is desired, several additional steps must be taken. First, when checking the equivalence between equations 1, 2, and 6, if a profile in which all equations are equal cannot be found, a new "wrap" must be started. Two points must be initialized at the beginning of each new wrap by using approximations to calculate θ1 and θ2. The two points are initialized as follows, where ypr i This is the first point in the new rap, ypr i+1 This is the second point in new rap.

[0097] ypr i =y smax +y pmin -(c p -c s )*P (11) ypr i+1 =yPr i +ypri-1-ypr i-2 (12)

[0127] This initial setup comes very close to providing an ideal time of failure (Tof), but there is an error related to refraction through the low-velocity layer (due to the adjusted thickness). This error allows for simple error loop correction to ensure that the Tof error remains small (10 ns).

[0098]

[0128] This initial setup comes very close to providing an ideal time of failure (Tof), but there is an error associated with refraction through the silicone layer (due to the adjusted thickness). Because of this error, a simple error loop correction was performed to ensure the Tof error remained small (10 ns). After determining the profile, the splines were fitted to the profile for use in simulation and CAD software.

[0099]

[0129] The resulting lens profiles for concave / oval flat-front double-material and flat-front Fresnel double-material lenses can be seen in Figures 3A to 3C. Figure 3A shows a lens 300a with a concave shape made from a high-sonic-velocity material 302 (e.g., >1500 m / s). On the other hand, Figure 3B shows a flat-front double-material lens 300b comprising a first high-sonic-velocity (e.g., >1500 m / s) material 302 and a second low-sonic-velocity (e.g., <1500 m / s) material 304. Lens 300b is considerably thinner than lens 300a and further provides a flat transmission surface 306. As shown, lens 300b is also flat at the interface between the high-sonic-velocity material 302 and the transducer array 301 of one or more transducer elements, allowing the flat transducer array and flat emission surface to be directly connected to the target.

[0100]

[0130] Figure 3C shows an embodiment of a flat-front Fresnel double-material lens 300c comprising a first material 302 for high sound velocity (e.g., >1500 m / s) and a second material 304 for low sound velocity (e.g., <1500 m / s). Lens 300b is thinner than both lenses 300a and 300b and further provides a flat transmission surface 306. A Fresnel step 308 is formed in the first material. Furthermore, lens 300c may include a concave portion 310 at the center of the lens, with the Fresnel step 308 positioned around the periphery of the concave portion.

[0101]

[0131] To provide a flat-front-row profile histotripsy transducer probe or array configured to generate intratissue pressure capable of generating histotripsycavitation, while allowing direct linkage (or using a standard acoustically coupled gel or medium) of the transducer array or probe to the skin or target tissue of a subject, one or more of the lenses described above can be attached to or acoustically coupled to one or more transducer elements 301 or an array of transducer elements 301. The transducer elements 301, lenses 300a / b / c, and any additional electrical connections or components described herein can be incorporated into or arranged within a transducer array or probe housing, as shown in Figure 1B or any other embodiment herein (e.g., the probes in Figures 4A-4B or 5A-5B).

[0102]

[0132] In some embodiments described herein, any embodiment including a dual-material acoustic lens may further include one or more ultrasonic imaging elements incorporated into the transducer and / or lens, such as a centrally located ultrasonic imaging transducer or array (as shown in Figure 5A, for example).

[0103]

[0133] The use of a second low-sonic-velocity material significantly reduces the thickness of the composite lens provided above compared to the oval lens in Figure 3A. In one particular embodiment, the oval lens has a thickness of 23 mm, while the composite lens in Figure 3B is reduced to 12.8 mm or less. By using a phase-lapping technique on the Fresnel lens in Figure 3C, the thickness can be further reduced to 3.7 mm or less. The flat-front dual-material lens and the oval single-material transducer have the ability to generate cavitation with histotripsy pulses when paired with an ultrasonic transducer element and electrically coupled to a histotripsy pulse generator and amplifier, as discussed herein.

[0104]

[0134] The primary advantage of the flat-front lens described herein is its ability to be dry-coupled to the target medium. Typically, focused ultrasound transducers require the use of cumbersome water bath coupling mechanisms to acoustically couple sound from the transducer to the target tissue. The need for a water bath arises from the spherical or oval geometric structure of the focused ultrasound transducer or lens. By developing a flat-front acoustic lens, a tightly focused sound field can be created without the use of concave lenses or spherical focused transducers. This significantly reduces the difficulty of using these transducers and allows for easier operation, particularly in some therapeutic environments such as endoscopic histotripsy.

[0105]

[0135] For some therapeutic ultrasound techniques, such as histotripsy, short pulses (only a few acoustic periods) are desirable. In these cases, a phased array approach is beneficial when developing transducers larger than those presented in this study. As the aperture size increases, the lens thickness increases (for a given working distance). Since lens materials are attenuating, it is desirable to maintain a thin lens. For larger transducers, maintaining a thin lens necessitates the use of a Fresnel-based design. The resulting lens will have many phase laps, requiring the use of longer tone burst drive pulses than would be desirable unless a phased array approach is used. By using a Fresnel-assisted phased array, single-period pulse operation can be used with phase matching each element to account for the number of Fresnel phase laps of the lens and with any desired phase matching for EFS.

[0106]

[0136] An additional benefit of this approach is the reduction in lens thickness. The overall thickness of the transducer is dramatically reduced, especially in Fresnel-based designs. For some therapeutic ultrasound applications, such as endoscopic or laparoscopic procedures, a lower profile transducer can be an advantage, as it allows for easier navigation of the transducer to the target area.

[0107]

[0137] In some embodiments, the high-sonic material can be a 3D-printed plastic container, and the low-sonic material can be a silicone-filled material. The design in this embodiment requires the construction of only a single piezoelectric element, a silicone-filled material, and a simple 3D-printed container. For this reason, this embodiment may be of interest to various fields that require a focused ultrasonic transducer that should benefit from dry coupling. For example, a similar transducer could be used to perform resonant acoustic flow measurement, facilitating the need for coupling while maintaining simple transducer construction and drive electronics. Another example would be the use of a dry-coupled transducer for sonothrombolysis as an alternative extracorporeal transducer for microbubble and nanodroplet-mediated sonothrombolysis.

[0108] Laparoscopic single-focus transducer with imaging

[0138] For practical clinical use, intracavitary and laparoscopic therapy transducers can include an integrated guidance system to provide clinicians with real-time feedback on where the therapy is being applied. The simplest approach to guidance is the integration of a b-mode ultrasound imaging probe into the therapy probe or array. The main limitation for intracavitary and laparoscopic histotripsi probes is size, so imaging probes can have a very low profile so as not to occupy a large amount of available opening space. Many commercially available imaging probes have a suitable (small) effective opening size but also typically feature a large housing designed for ergonomics rather than low profile. For this reason, integrated imaging probes can be custom designed and fabricated for integration with intracavitary histotripsi transducers.

[0109]

[0139] In one embodiment, the design specifications include a desired working distance in the range of 10 to 15 mm, and the maximum width of the transducer does not exceed 20 mm.

[0140] The fabrication of the transducer can be very similar to that of the transducer described above. Figures 4A and 4B show one example of a laparoscopic histotripsitransducer probe 400 including a concave housing 402, the concave housing 402 which incorporates a lens 404 into the housing and provides electrical insulation to the ultrasonic transducer element 401. A backing clamp piece 403 is positioned on the back side of the transducer element 401. An integrated imaging probe 405 is shown extending through the central portion of the housing 402 toward the propagation surface of the probe.

[0110]

[0141] In some embodiments, the transducer housing and backing clamp piece can be 3D printed from Velcroa material (c ≈ 2500 m, ρ ≈ 1200 kg), and the piezoelectric element can be waterjet cut from a stock piece of DL-53 piezo composite. The backing clamp piece can be threaded through a micro coaxial cable and soldered to the piezoelectric element. Other suitable materials can be used. The element can then be epoxy bonded to the housing using epoxy. Clamp pressure is applied through the backing clamp piece to allow the transducer to be secured (cured).

[0111] Flat intraluminal array

[0142] While many studies have been successfully conducted using monofocal histotripsi transducers, phased array transducers offer significant advantages in several respects, including the ability to perform EFS and PAM or passive cavitation imaging (PCI). Depending on the specific indication, the ability to perform one or more of these techniques may be important for clinical use. For example, in the case of particularly large-volume targets such as pelvic abscesses, which can reach volumes greater than 300 milliliters, EFS should allow for the dissection of large volumes with fewer mechanical scans and may therefore be necessary for practical clinical use. For other applications requiring precise therapeutic doses, the ability to receive acoustic cavitation emission (ACE) signals may become significantly important in the future. Therefore, it is necessary to evaluate the feasibility of developing intracavitary phased arrays. This disclosure presents designs, simulations, and initial tests for fabricating such transducers.

[0112]

[0143] Specifically, it offers a novel 2D phased array design. This design enables high steerability and allows for very large dissection relative to the transducer opening size. The opening size is such that the transducer should be suitable for transrectal or transvaginal use and applicable to a wide range of indications. Furthermore, the 2D design offers significant fabrication benefits, allowing the transducer to remain relatively easy and inexpensive to manufacture.

[0113] Flat array histotripsy probe and method of fabrication

[0144] A major challenge lies in the traditional, geometrically focused rapid prototyping techniques for histotripsi transducers. These challenges are particularly evident in the fundamental size range (<3 mm) required for intracavitary histotripsi phased arrays. Therefore, new fabrication techniques are needed. These techniques will not only continue intracavitary and endoscopic transducer technology, but will also advance histotripsi transducer technology as a whole, as they can be applied to larger aperture transducers where reduced element size is desirable.

[0114]

[0145] A significant benefit of constructing 2D transducers is the substantial reduction in manufacturing overhead. Because the array is arranged in two dimensions, machining operations are greatly simplified, and a traditional dicing saw can be used for all operations. This assumes the elements are arranged in a standard grid and that the shape is rectangular. In short, a piezo composite with the same aperture size as a complete array can be coupled to the desired matching layer in a single piece. The piezo composite is then diced into numerous individual elements, leaving the matching layer intact, resulting in elements in a 2D grid. While machining operations are simplified, other challenges arise related to creating reliable high-voltage-compatible electrical contacts for each element. The electrical contacts will need to avoid arc discharge between adjacent elements when driving adjacent elements with phase shifts.

[0115]

[0146] Figures 5A and 5B illustrate one embodiment of a flat array histotripsy transducer array or probe 500. Referring to Figure 5A, the probe 500 may include a transducer array 501 comprising multiple transducer elements, and an optional imaging array 502 comprising one or more imaging transducers positioned within the transducer array 501. As shown in Figure 5A, the imaging array is positioned in the center of the probe. In one implementation, the therapeutic transducer presented herein features a 15.5 × 7 mm central hole for inserting the imaging probe into the probe 500. The imaging probe may feature a center frequency of 15 MHz, which is not high enough to invalidate imaging depths shorter than the desired focal length of the therapeutic transducer, but is such that it provides high image quality for shallow targets.

[0116]

[0147] Figure 5B shows a cross-sectional view of the probe 500 including an array of transducer elements 501. The printed circuit board (PCB) 504 includes spring-pin electrical connectors 505a / b for each of the transducer elements in the array 501. Microcoaxial cable wiring (not shown) can be electrically connected to the spring-pin electrical connector 504a to provide electrical connections to the back of the transducer elements via the spring-pin electrical connector 504b. Soldering the electrical connections to the back of each element is feasible but burdensome. The spring-contact pins through the holes described above have a maximum diameter of 1.1 mm and can have an operating force of 15 to 60 grams. A significant advantage of the spring-contact pins is that they can be designed so that the transducer heads can be detached from the probe, while the cable bundles can be reused with other transducers.

[0117]

[0148] The potential for arc discharge between adjacent elements can also be addressed. Individual elements can be electrically isolated by epoxy bonding, but this would negate the removable advantage of spring pins, as the pins would be permanently coupled to the transducer. Alternatively, high-strength dielectric grease can be used to electrically isolate element 501 from spring pin 505b. In some embodiments, the dielectric grease can withstand up to 4000V pp This reduces the potential for arc discharge, including when the elements are driven with different phases at the drive voltage.

[0118]

[0149] This disclosure provides a strategy other than traditional soldering to create a reliable high-voltage electrical connection to the front of a transducer array element. Direct soldering to the front of the element is not feasible because the piezo composite is bonded to a matching layer before dicing. A conductive mesh epoxy composite matching layer 506 can be used to provide an electrical connection to this face of the element. The matching layer 506 may comprise a grid or mesh pattern of a conductive material, such as copper, arranged to provide an electrical connection to the front surface of each transducer element in a transducer array 501, for example. The conductive material can be embedded in the epoxy or other suitable material matching layer to 1) provide an electrical connection to the front surface of each transducer element, and 2) provide proper acoustic matching between the transducer element and the target tissue or connecting material, enabling the transmission of ultrasonic / histopetal pulses through the conductive material. This matching layer effectively enables reliable driving of the element up to high voltage while also providing effective acoustic matching to the connecting fluid or patient skin / tissue.

[0119]

[0150] While the probes in Figures 5A and 5B are shown with a matching layer and conductive mesh embodiment on or near the flat transmission surface of the probe, it should be understood that in other embodiments, the probe design in Figures 5A and 5B may also include the dual-material flat front lens in Figures 3B and 3C. In additional embodiments, the conductive mesh in Figures 5A and 5B can be incorporated into the dual-material lens in Figures 3B and 3C. For example, the conductive material can be incorporated into the first (oval / concave) material of the dual-material acoustic lens, and the second material can be used to create a planar matching layer.

[0120]

[0151] In histotripsy therapy, a larger focal volume allows for lower frequencies (to a certain extent) and faster treatment rates. Furthermore, lower frequencies are associated with lower attenuation and aberrations. For these reasons, a 1MHz center frequency and 1.3mm size element can be chosen as a starting point for further optimization.

[0121]

[0152] The manufacturing method described above enables the rapid production of probes, which can be completed in just a few hours of effective manufacturing time. The resulting probes can contain a total of 36 or more elements, depending on the desired size of the probe.

[0122]

[0153] One area of ​​interest is the difference in transducer performance trends between 2D flat arrays and spherical focus arrays. For example, in the case of a typical spherical focus array, such as the design presented above, the higher focus gain results in an increase in free-field focus pressure with increasing frequency. This is not true for 2D arrays, as increasing frequency also increases the directionality of each element, meaning the array has a lower ability to be electronically steered to the focus. This effect is also evident in the effective working distance of 2D arrays, and higher frequency arrays are expected to generate even higher pressures from the transducer surface.

[0123]

[0154] The two transducer arrays or probes presented herein require different coupling mechanisms. The laparoscopic transducer uses elements arranged in a spherical geometric shape, as most histotripsi transducers do. This transducer, therefore, requires the practical use of a water balloon or water bath coupling mechanism in a laparoscopic setting. The main advantage of the 2D array is that its geometric structure allows for "dry" coupling using standard ultrasound gel. This negates the need for a water bath or balloon coupling system and should also be advantageous for extracorporeal targets.

[0124]

[0155] Another use for flat array technology is for larger in vitro histotripsy. For example, larger 2D arrays can be configured to treat large volumes in the abdomen, such as in the treatment of liver cancer. Such arrays retain the benefits of steering flexibility associated with flat designs and also have the ability to be bonded to the body with ultrasound gel rather than using a large water bath bonding system.

[0125]

[0156] Alternatively, flat transducer modules can be built as part of a larger spherical focus phased array system. This allows for considerably easier fabrication of arrays with many elements and significantly improved array steerability compared to designs featuring fewer, larger elements. Increasing the number of elements may become of interest as the applications of transmit-receive compatible histotripsia arrays develop further, as more elements can enable higher performance such as more precise aberration correction or cavitation positioning.

[0126] Soft tissue sarcoma array

[0157] Soft tissue sarcoma (STS) is a malignant tumor that often grows in the mesenchymal cells of the arm or leg. According to statistics from the American Cancer Society, approximately 13,000 new cases of STS are diagnosed each year. STS can grow to very large sizes, often exceeding 10 cm in maximum dimensions. Furthermore, STS can enclose nerves and vital canals. Surgical excision is the most important treatment, but it is often difficult to remove because important structures are encased in the STS.

[0127]

[0158] While it is possible to shrink STS tumors with radiation therapy before excision, tumors can be very large, so the required radiation dose may exceed the appropriate range for the specific location of the tumor. Furthermore, STS has a high risk of recurrence, and radiation can only be used once on a particular site. Alternative thermal dissection strategies such as radiofrequency, cryotherapy, and microwave dissection carry the risk of damaging important structures near the tumor, and therefore are not feasible alternative dissection strategies as nerves and tubes are often encapsulated. HIFU has been used to treat STS in humans and dogs, but it carries similar risks to other thermal dissection strategies.

[0128]

[0159] As an alternative to the minimally invasive dissection modalities mentioned earlier, histotripsy has potential for use in the dissection of STSs and offers several significant benefits. Firstly, histotripsy is non-invasive because it delivers therapeutic ultrasound pulses from outside the body. Secondly, histotripsy has shown effectiveness in treating large tissue volumes, which is one of the limitations of thermal dissection modalities. Furthermore, histotripsy has shown to perform tissue selective dissection, meaning that nerves and tubes within STSs can be kept from being severely damaged. Finally, histotripsy has shown to lead to local tumor regression and reduced metastasis and has been shown to be safe for treating the human liver.

[0129]

[0160] Several advancements are needed to adapt histotripsy for the treatment of STS. Firstly, since STS tumors can grow to very large sizes, histotripsy systems and treatment strategies need to be developed to enable rapid treatment of STS tumors. Secondly, since STS tumors can grow very close to the skin surface, treatment strategies need to be developed to minimize skin damage to patients during treatment. Finally, while standard b-mode ultrasound can be used for initial targeting of tumors, 3D monitoring techniques need to be developed to enable treatment monitoring during rapid dissection of STS tumors.

[0130]

[0161] In some embodiments, the transducer design is optimized for the treatment of STS based on patient data about the size and location of the STS tumor.

[0162] Most previously designed histotripsiphased arrays (such as those presented above) feature elements arranged on a spherical shell. In typical arrays (such as roughly square or round elements), the array would have a comparable lateral steering range (i.e., X and Y directions) suitable for a nearly spherical tumor or other mass. In the case of STS, tumors tend to be considerably longer in one dimension. Optimal transducer design will take this into account, enabling therapeutic strategies specifically designed for the size and shape of the tumor being targeted.

[0131]

[0163] Since STS tumors are roughly cylindrical in shape, a semi-cylindrical transducer aperture shape can be used in some embodiments. This aperture shape allows for testing three distinct dissection strategies: 1) traditional EFS, 2) multifocal EFS similar to the aforementioned technique but with multiple spatially separated simultaneous foci, and 3) large-focal dissection, where the array is specifically phase-aligned to create long, very narrow foci that reflect the shape of the tumor. Furthermore, because the semi-cylindrical geometric structure is curved in only one direction, it offers fabrication advantages over spherical-focus transducers.

[0132]

[0164] Compared to spherical focus arrays such as the liver array presented above, the semi-cylindrical geometric structure of the STS array offers significant fabrication advantages. Because the array is curved only in one dimension, flat multi-element modules can be used, enabling fabrication methods similar to those used to fabricate flat 2D phased arrays such as the intraluminal phased array proposed above.

[0133]

[0165] Figure 6 shows one embodiment of the STS histotripsia array 600. The array can be fabricated using 3D printing technology, with three components per module. The first is a matching layer with interlocking features on the back, allowing it to easily interlock with a second piece, which is the module housing. The housing provides the mechanical structure of the module and protection for the module's sides. The final piece is the module lid, incorporating elastomer material using multi-material 3D printing technology to function as tension relief for each cable.

[0134]

[0166] To fabricate the module, the piezoelectric strip 601 can first be coupled to the copper composite strip 602 and a 3D printed plastic matching layer stack (placed in front of the piezoelectric strip). In the case of an array in one embodiment, the piezoelectric strip may have dimensions of 200 × 7.4 mm and may have a 3 × 3 mm section at one corner that is polished or cut to allow electrical access to the copper composite matching layer.

[0135]

[0167] Next, the PZT can be diced into multiple individual elements using a 0.25 mm dicing blade (which creates a 0.25 mm gap between elements). The module housing can then be coupled to a matching layer stack, and the micro coaxial cable can be passed through its respective strain relief and directly soldered to each element in the electrical connection 604. The module can then be backfilled with epoxy, and the strain relief lid can be coupled to the back of the housing to complete the module.

[0136]

[0168] After fabricating the necessary modules for the array, the modules can be mounted on a base. The base can be printed using a large-format 3D printer, or it can be slightly redesigned for machining from aluminum or another material. The base allows each module to be inserted into a slot, which holds each module in a position including the row offset discussed earlier. Screws can be used at each end of any module to secure it to the base.

[0137]

[0169] A strikingly novel aspect of the STS transducer design presented herein is the use of non-standard geometric shapes. Previously, histotripsi transducers were constructed around spherical shell geometric structures due to the focus gain achievable when using arrays of spherical shell geometric structures. Advances in materials have made it possible to achieve cavitation-inducing pressure using non-spherical geometric phased arrays, even with a relatively conservative surface pressure calibration of 2 MPa. Specifically, this offers significant advantages in the treatment of STS. First, the geometric structure of the transducer reflects the geometric structure of the tumor, so the treatment steering range is aligned with the tumor. This allows for the use of EFS over the entire tumor volume as needed. This makes treatment strategies more arbitrary and can help in the development of strategies designed to minimize off-target cavitation, such as rapid dissection strategies or cavitation on the skin surface.

[0138]

[0170] It is important to note that the proposed design utilizes a composite (DL-53) piezoelectric material. The use of composite materials will affect performance in several ways, in contrast to monolithic piezoelectric materials such as PZ36. First, the use of composite materials will increase the pressure output. This performance improvement will enhance the likelihood of success in some aggressive treatment strategies, such as large-focus strategies. Furthermore, since the individual elements are only 7.4 mm wide, the use of composite materials will help ensure uniform surface excitation.

[0139]

[0171] The use of composite piezoelectrics also typically imposes lower PRF limits on transducers. This is important because the primary purpose of these transducers is to rapidly dissipate large tumors, and the use of composite piezoelectrics can limit the treatment rate. The ability to subaperture the array and treat multiple distinct areas of the tumor helps overcome this limitation, as it is still possible to minimize the PRF of individual subapertures or elements of the array while maintaining a high global therapeutic PRF.

[0140]

[0172] Another significant advantage of the cylindrical design is its ease of construction. Because the array is curved in only one dimension, alternative strategies can be used. This fabrication method can significantly reduce the manufacturing burden (time, financial costs, etc.) of the array compared to other histotripsier array fabrication techniques, while retaining the benefits of a modular structure.

[0141]

[0173] Three main treatment strategies were proposed for the treatment of STS. First, traditional EFS has been shown to have potential as a high-rate dissection method. Partly due to the cylindrical geometric structure of the array, multifocal EFS, an extension of traditional EFS, was proposed for this specific indication. This geometric structure means that when using traditional EFS, a small number of array elements bear the majority of the focal pressure. This means that the array can be efficiently sub-apertured to enable multifocal treatment. A spherical focal array with sufficient overhead space, as described above, can be used for multifocal treatment, but the driving voltage of the array should need to increase approximately linearly with the number of sub-apertures used. This is because each element in a spherical focal array provides approximately equal amounts of focal pressure. In contrast, a cylindrical array should require only a small increase in driving voltage to account for the sub-apertures used for multifocal treatment.

[0142]

[0174] We propose a novel large-focus therapeutic method that generates a long, rod-shaped focal region exceeding the cavitation threshold. This focal region is much larger than the conventional EFS focal region and can be much larger than the treatment area with a single pulse. This large focus cannot be electronically steered over a large area, and therefore the transducer must mechanically scan the entire volume to perform the treatment. It is important to note that the length of this large focus can be adjusted by igniting fewer elements at the periphery of the array, allowing the large-focus technique to be used in tumors that are not as long as the array. For practical and rapid clinical treatment of STS, it is likely that a combination of these therapeutic strategies can be used for the greatest benefit. For example, the large-focus technique can be used to treat the central region of the tumor very rapidly, while the multifocal EFS technique, which should allow for higher treatment precision, can be used to treat near the periphery of the tumor.

[0143]

[0175] While there is no doubt that rapid dissection techniques are crucial for treating large STSs, it is also important to implement techniques to minimize skin damage. Since STSs can be very close to the skin, surface cavitation can be a concern, especially when treating near the periphery of the tumor volume. One approach to minimizing surface cavitation may include eliminating elements that are not essential for generating cavitation and minimizing other driving voltages to reduce the pressure generated at the skin surface. Furthermore, it is necessary to ensure that the coupling fluid used in the water bath is highly degassed.

[0144]

[0176] The novel semi-cylindrical array design also offers the potential to conduct a variety of experiments to support a better fundamental understanding of the histotripsy mechanism. Spherical focal arrays can typically only generate histotripsy focal clouds with a maximum dimension of approximately a few wavelengths. The large-focus therapeutic strategy allows for the design of new experiments to investigate the cavitation behavior as the bubble cloud grows larger. Generally, histotripsy bubble clouds expand as a high-density cloud of many bubbles and collapse violently at a single point. Previous studies have suggested that the collapse is primarily responsible for tissue damage. The striking size of the large focus makes the collapse behavior of such bubble clouds of particular interest. If such a cloud collapses at a single point, the most severely damaged area of ​​tissue may be limited to the region surrounding the specific point of collapse. Rather, if the cloud collapses at multiple points, the damage may be more uniformly distributed across the entire volume of the cloud. Experimentally, to answer this question about the effectiveness of this treatment method for damage, it would be necessary to use high-speed photography to determine the collapse process in the free field of large clouds (i.e., single or multiple collapse points). After examining the free-field collapse process, stepwise detachment of the red blood cell (RBC) phantom should allow for the determination of the extent and uniformity of the damage. Furthermore, bubble clouds formed using this treatment method differ from clouds formed using the more typical histotripsy transducer geometry in that the long axis of the cloud is not aligned with the acoustic axis of the transducer. This is unlikely to affect the histotripsy damage mechanism itself, but it may affect other cavitation cloud properties such as bubble cloud density or the tendency toward pre-focus shift.

[0145] Electronic steering

[0177] When using mechanical scanning on a treatment volume in histotripsy, a single location is typically repeatedly exposed to cavitation before it traverses the volume. When forming a histotripsy bubble cloud, many cavitation bubbles rapidly expand and collapse. While the collapse time is typically around several hundred microseconds, residual bubbles persist much longer after collapse, typically in the range of 100–200 ms or more. When using PRFs greater than ≈ 5 Hz (corresponding to the time for residual bubbles to dissolve), these residual bubbles can act to re-excite cavitation, resulting in the formation of nearly identical bubble clouds after the initial treatment pulse, with individual bubbles within the cloud occurring at locations closely corresponding to individual bubbles in the previous cloud. This can reduce the damage efficiency per pulse. This is known as the cavitation memory effect. Numerous studies have been published investigating the cavitation memory effect in histotripsy and strategies to mitigate it. Both passive and active strategies have been employed to mitigate this effect. Passive mitigation of the memory effect consists of reducing the PRF and thus increasing the pulse repetition period so that residual bubbles can be passively dissolved before subsequent therapeutic pulses are applied. The use of this passive approach is problematic during high-volume treatments because it increases treatment time to levels unacceptable for clinical use. As an alternative, active bubble coalescence strategies have been proposed and implemented, consisting of applying multiple subthreshold acoustic pulses between therapeutic pulses. While this strategy has shown effectiveness in attenuating the memory effect, the additional coalescence pulse manipulation may increase heating of the overlying tissue, potentially imposing a substantial limit on the treatment rate.

[0146]

[0178] To avoid the additional pulse manipulation associated with active bubble coalescence strategies, alternatives have been proposed. By using phased array transducers, the focal location can be electronically steered to arbitrary points throughout the treatment volume. By designing the steering location sequence to avoid previously treated locations, the entire volume can be treated with high global PRF while maintaining low local PRF for each individual location or region. Furthermore, when using EFS, low-gain regions of the pressure field can play a role in promoting bubble coalescence of residual bubbles. Previously, these techniques have been used with high success rates when performed with low-frequency (250 kHz) hemispherical histotripsi transducers.

[0147]

[0179] It should be noted that the majority of studies demonstrating the cavitation memory effect and developing mitigation strategies (both active and passive) have relied heavily on the use of permeable agarose-based phantoms to facilitate the use of high-speed photography for visualizing individual cavitation clouds. This approach assumes that cavitation processes (expansion, disintegration, dissolution, re-excitation, etc.) are identical in agarose and biological tissues. Unfortunately, the level of correlation between these processes in agarose and tissues is unclear. Furthermore, histotripsy instruments have advanced considerably since much of these studies were conducted, and current generation systems are often higher power and bandwidth than earlier systems. These differences may play a significant role in the damage efficiency of different histotripsy therapeutic strategies.

[0148]

[0180] The objective of this disclosure is to further explore therapeutic parameter space and EFS sequencing, and to elaborate on previous histotripsy EFS studies by implementing these techniques with current-generation, higher-frequency (750 kHz) non-hemispherical transducers designed to target the human abdominal region. First, the combined effects of focal pressure, dose (pulses per cubic centimeter), and PRF are examined for given transducer power output and treatment time in in vitro bovine liver tissue. Next, the effects of EFS point spacing are explored. Several EFS sequencing strategies are proposed, implemented, and tested using optimized therapeutic parameters.

[0149]

[0181] Previous studies have shown that histotripsy bubble clouds generated with higher peak negative pressures are larger overall and feature larger individual bubbles and higher bubble density. This has shown higher damage efficiency in the erythrocyte phantom per pulse. The question remains whether higher pressure results in higher damage efficiency in tissue when using the same acoustic output and energy. To explore this, the following experiment was conducted in ex vivo bovine liver tissue. The array was programmed to dissect a 2 cm diameter spherical volume using a range of EFS and focal pressure (28–80 MPa). The volume was constructed from 5,918 points densely packed in a hexagonal pattern with 1 mm spacing. The drive voltage for each EFS location was calculated to account for the steering potential of the array, resulting in a uniform pressure being applied to each EFS location. The EFS location coordinates were identical for all dissections. The dose was set based on previous experience to achieve partial dissection. Along with the focal pressure, the dose and PRF were varied between dissections to maintain a constant input power.

[0150]

[0182] Previous studies on histotripsy EFS techniques for rapid dissection have typically relied on low-frequency (250 kHz) transducers and relatively coarse EFS grid spacing (2.5+ mm). The decision to use coarse spacing was made in part by system limitations on the amount of focal locations the system could accommodate, made possible by the large cavitation cloud generated by the relatively low frequency. To completely dissect tissue using this EFS strategy, the array must ignite many times (>100) per EFS location. With advances in systems, it is now feasible to define large-volume EFS grids with much finer spacing (<1 mm) and many more foci. We hypothesized that by reducing the spacing of EFS points, and therefore increasing the EFS point density, more allogeneic lesions could be dissected at lower doses. To test this hypothesis, we performed a series of dissections at three spacings (0.5, 1, and 2 mm). For reference, the focal volume at -6 dB of the transducer is 1.6 × 1.1 × 4.5 mm. The number of repetitions per location was varied to account for differences in point density, ensuring that the same dose was applied at each interval. EFS locations were randomly arranged, and a single pulse was fired at each point, then returned for subsequent repetitions. All delamination was performed with a 1000 Hz PRF and a focal pressure of 40 MPa. The same structured EFS location sequence used for pressure-optimized delamination was used for interval-optimized delamination.

[0151]

[0183] To evaluate the performance of different EFS sequences, dissection was performed using four separate sequences at three dose levels (combinations of 12 different dose sequences) (applying acoustic pulses for every 1cc treatment volume). The first sequence was a simple raster scan included to determine how the cavitation memory effect affects dissection efficiency compared to a sequencing strategy designed to attenuate the cavitation memory effect. The second sequence was a structured sequence designed to attenuate local PRF within a small region of the dissection volume. The third sequence (anti-shielding) was designed to minimize acoustic energy shielding at the intended focus. Acoustic shielding from debris bubbles can occur when residual bubbles from previous pulses remain in the acoustic path from the transducer to the current intended focus location. Pre-focus bubbles of debris can block sound from reaching the subsequent intended location, reducing the likelihood of a robust cavitation cloud forming at the intended focus (especially when using high PRF with limited time for dissolution before subsequent pulses). The final sequence (boundary) was designed to take advantage of the reduced cavitation threshold at the tissue boundary. By completely dissecting the tissue on the side of the dissected volume closest to the transducer, and then proceeding through the volume, the boundary was maintained at the intended dissection location. All volumes dissected for dose-sequenced dissection were spherical volumes with a diameter of 2 cm, consisting of 5,918 dots densely packed into hexagons with a dot spacing of 1 mm. Dissection was performed at a normalized focal pressure of 56.6 MPa and a PRF of 500 Hz. The tissue was prepared identically to that used in previous in vitro dissections.

[0152] Raster EFS Sequence

[0184] The points were aligned using a standard raster pattern, starting at the point furthest from the transducer (distal) and moving towards the transducer (proximal). Alignment from distal to proximal was done to minimize the possibility of pre-focus residue bubbles blocking sound from the intended focal location. The transducer was ignited N times per point before moving to the next (adjacent) point throughout the sequence. One repetition was performed throughout the sequence. Note that this sequence is the only one designed to repeatedly expose a single location to multiple therapeutic pulses before moving to the next EFS location, similar to mechanically scanning the transducer along a defined path.

[0153] Structured EFS sequencing

[0185] This sequence is similar to the sequence proposed above to reduce the cavitation memory effect, but with slight modifications. The points are divided into subgrids, ensuring a minimum lateral spacing of 5 mm between all pairs of points within each subgrid. Within each subgrid, the points are arranged distal to proximal along the acoustic axis in a random sequence of points at the same axial distance from the transducer. Each point was ignited simultaneously before moving to the next point in the subgrid. Once each subgrid was completed, the process was completed with the next subgrid until every subgrid was treated (one pulse applied to each individual location). This entire process was repeated N times to complete the treatment.

[0154] Anti-shielding EFS sequence

[0186] Using the size and shape of the transducer aperture, the points were divided into layered groups that helped to align the points in a way that ensured no acoustic shielding occurred. This consisted of a first group, which was a spherical shell-shaped layer at the most distal boundary of the intended volume, and subsequent layers that gradually became flatter as they approached the proximal boundary of the volume. Starting with the first (most distal) layer, the points were randomly aligned, and a single therapeutic pulse was applied to each point in the layer. N repetitions were completed for each layer, after which the next layer was initiated. This reduced the probability of forming any pre-focus bubbles and thus reduced the possibility of shielding effects reducing therapeutic efficacy.

[0155] Interface EFS sequence

[0187] The interface sequence was identical to the anti-shielding sequence, but performed in reverse (proximal to distal). We hypothesize that completely delaminating the proximal locations within the volume first allows for the formation of an interface between the liquefied and undelaminated tissues, which can facilitate the formation of a cavitation cloud at the liquefied tissue interface and efficient tissue delamination.

[0156]

[0188] One area of ​​concern when attempting large-volume rapid dissection with histotripsy is the potential for off-target injury due to thermal deposition. As focal pressure and PRF increase in an attempt to increase the dissection rate, more energy is deposited in the tissue above, increasing the potential for off-target, unintended injury. Further research will be needed to establish the thermal safety of the pulsed manipulation scheme presented here. While the study presented in this document does not explicitly explore the potential for such injury, the methodology was designed so that the results from optimization should be sustained for adjustment to PRF. Since focal pressure optimization keeps the acoustic output constant for all focal pressures, the approximate thermal deposition should be similar for each set of parameters tested. Note that the duty cycle range used in this study is low (0.05% to 0.4%) and is expected to mitigate thermal effects. If it is necessary to reduce the acoustic output to ensure patient safety with the pulsed manipulation scheme described, two options exist. One option should be to reduce the PRF so that the acoustic input is lowered to a safe level. Alternatively, intermittent cooling pauses in treatment can be implemented to allow the tissue to cool before continuing the treatment.

[0157]

[0189] A particular observation of interest was the delamination efficiency, which depended on the focal pressure. Even with a reduced number of repetitions relative to the treatment volume, substantially more damage was caused at a focal pressure of 56.6 MPa compared to lower focal pressures. This is likely due to several different factors. Previously, we have shown that histotripsy bubble clouds formed at higher peak negative pressures exhibit increased bubble volume and density. Histotripsy bubble clouds are also typically larger when occurring at higher pressures, as a larger focal region will exceed the intrinsic threshold. We believe that the increased bubble volume, density, and cloud size significantly increase the damage inflicted by each pulse as the focal pressure is increased over the 40–56 MPa range. The effect appears to reach saturation before 80 MPa, at which point overall damage decreases, likely due to the reduced number of repetitions applied at higher pressures.

[0158]

[0190] Since relatively high focal pressures demonstrated the highest damage efficiency, there are concerns about transitioning the presented dissection techniques to in vivo scenarios with limited acoustic windows. Specifically, in the case of liver treatment, some areas may require treatment across the ribs, which can limit the focal pressure amplitude even with effective aberration correction algorithms. To optimize the pulse manipulation strategy for the fastest dissection in these cases, it may be necessary to employ adaptive dissection strategies using higher repetitions (lower focal pressure) treatment in blocked areas, and faster treatment at higher pressures in areas of the liver where acoustic access is better. Such strategies would likely need to be developed in combination with advanced targeting techniques, such as X-ray C-arm guided targeting techniques, which can be used to predict which target areas should contain a partially blocked acoustic window. Alternatively, impact scattering histotripsy can be used in blocked areas to lower the cavitation onset threshold while maintaining high-density bubble cloud formation.

[0159]

[0191] No significant effect of EFS spacing on damage efficiency was detected over the focal spacing range of 0.5–2 mm. This is likely due to the transducer's focal volume, which measures 1.6 × 1.1 × 4.5 mm. Although the lateral dimension of the FWHM is less than 2 mm, substantial overlap from adjacent focal locations in the axial direction is likely to make this range of spacing acceptable for achieving homogeneous damage. It should be noted that the acceptable focal spacing range will be greatly influenced by the transducer used (aperture, frequency, etc.). For transducers characterized by higher operating frequencies or lower f#, the acceptable range of focal spacing is likely to be lower than for transducers with lower frequencies or higher f#.

[0160]

[0192] Using the experimental setup and treatment parameters employed in this experiment, >95% of cells within the treatment volume were homogenized within approximately 11,000 pulses / cc of treatment for both layered EFS sequences, resulting in a treatment rate of 2.65 cc / min. For this experiment, complete treatment (>95% of cells) was chosen as the targeted treatment endpoint, but it remains unclear which level of treatment is optimal for many indications. Partial treatment of tumors in histotripsy is currently an active area of ​​research. Studies have shown the potential of partial treatment to stimulate immune responses, resulting in local and unirradiated responses to the treatment. Therefore, effective clinical treatment rates may be influenced by further research into the optimal treatment endpoint.

[0161]

[0193] The results of this study indicated that a focal pressure of 56 MPa was the most effective among those tested, but further optimization of different EFS sequences may allow for similarly rapid delamination at different parameters. For example, a raster-based strategy may enable effective treatment at lower focal pressures and higher PRFs, as residual bubbles should take advantage of the lowered cavitation threshold by remaining at the intended focal location. Furthermore, this strategy should benefit from the shock scattering mechanism, which utilizes the positive pressure of high peaks reflected from the existing bubble cloud to maintain a robust cavitation cloud.

[0162]

[0194] An intriguing finding in the dose-sequence delamination comparison was the relative lack of difference in dose between the different sequences. Previous studies have shown a high reliance on local PRF and the number of pulses required to completely homogenize the tissue. The raster (high local PRF) and structured (low local PRF) sequences require approximately the same dose to completely treat the tissue in this experiment, which seems to contradict previous results. First, the electrically driven system in this experiment is of much higher bandwidth compared to previous studies. The driver used in the current study outputs a clean 1-period sine wave, while the driver used previously outputs a 10-period tone burst driving pulse. This can greatly influence the memory effect observed, as it results in a negative pressure of the maximum amplitude peak at approximately the 10th negative acoustic peak, meaning that lower (subthreshold) pulses repeatedly excite residual nuclei just before the cavitation-inducing pulse. The current system reaches its maximum negative peak at the first negative portion of the acoustic pulse. This can cause new cavitation clouds to be less correlated with previous clouds. Furthermore, the negative focal pressure of the peak used can also impact the degree to which the memory effect is observed. The intrinsic threshold for cavitation in liver tissue has been measured to be in the range of 17–20 MPa for PRF in the 100–1000 Hz range. While previous studies used focal pressures just above the threshold (21 MPa), this study used a pressure nearly three times the threshold (56 MPa). Increasing the focal pressure to this level can, in some cases, almost completely mitigate the memory effect, leading to higher damage efficiency per pulse.

[0163]

[0195] In addition to large-focus therapeutic strategies, multifocal therapeutic strategies using STS arrays are also envisioned. The cylindrical shape of the array presents a unique opportunity to employ efficient sub-aperture without substantially increasing the input acoustic energy (and associated heating and tension on the transducer) required for treatment.

[0164]

[0196] Because STS is generally very close to the skin surface, precautions should be taken to minimize the possibility of surface cavitation causing significant skin damage. One potential way to minimize surface cavitation is to reduce the focal pressure when treating a portion of the treatment volume close to the skin surface. This will likely require a higher dose (pulses / cc) to achieve complete dissection. Furthermore, this will reduce the dissection rate, but as a result, should mitigate surface cavitation and skin damage. Alternatively, one could explore coupling fluids other than degassed water. By using a coupling fluid with a higher intrinsic cavitation threshold, surface cavitation can be reduced, allowing for the determination that higher focal pressures (and associated dissection rates) are safe in areas close to the skin surface.

[0165]

[0197] When multiple treatment strategies (major focus, multifocal, traditional EFS) are successful, it may be beneficial to devise a combined strategy to leverage the strengths of each. For example, a major focus strategy can first be used to very rapidly dissect the central region of the tumor. Then, multifocal therapy can be used to more precisely target the tumor margins or regions outside the targetable major focus zone. To apply this realistically in a vivo environment, algorithms should be written to rapidly segment the tumor region for each treatment strategy.

[0166] Integrated imaging

[0198] The disclosed system may include various imaging techniques that enable the user to visualize, monitor, and collect / use feedback on the patient's anatomical structure, areas of interest and treatment / procedure sites, and surrounding and intervening tissues in order to evaluate, plan, and perform procedures, and to adjust treatment parameters as necessary. The imaging techniques may include various ultrasound, X-ray, CT, MRI, PET, fluoroscopy, optical, contrast or agent-enhanced versions, and / or various combinations thereof. It is further disclosed that various image processing and characterization techniques may also be utilized to provide enhanced visualization and user decision-making. These may be selected or commanded manually by the user or automatically by the system. The system may be configured to enable the user to identify, define, and be informed of various modes of using imaging during a procedure, such as side-by-side, toggling, overlay, 3D reconstruction, segmentation, registration, multimodal image fusion, image flow, and / or displayed on various system user interfaces and displays. Examples, without limitation, may include identifying one or more significant structures (e.g., tumor drainage lymphatic vessels or vascular structures, or tumors near organ encapsulation or underlying organs) in the context of each other, such as blood vessels, tubes, nerves, ureters, fissures, encapsulations, tumors, tissue trauma / injury / disease, other organs, connective tissues, and / or identifying potential therapeutic sites within, on, and / or surrounding areas, organ systems, organs or tissues of interest.

[0167]

[0199] The system may be configured to include onboard integrated imaging hardware, software, sensors, probes, and wetware, and / or to communicate and interface with external imaging and image processing systems. Furthermore, the aforementioned components may be integrated into a therapeutic subsystem component of the system, including probes, imaging arrays, or similar, and may be electrically, mechanically, or electromechanically integrated into a therapeutic transducer. This can partially provide the ability to perform geometrically aligned imaging and therapy, where the therapy is directly in the field of view and, in some cases, aligned with the imaging. In some embodiments, this integration can constitute a fixed orientation of context-adapted imaging capability (e.g., imaging probe) to the therapeutic transducer. In other embodiments, the imaging solution may have the ability to move or adjust its position, including modifying other parameters such as angle, range (e.g., distance from the therapeutic transducer or patient), rotation (e.g., imaging plane in the case of an ultrasound probe), and / or dynamically moving / adjusting while actively imaging. The imaging component or probe may be encoded in such a way that its orientation and position relative to another aspect of the system, such as a therapeutic transducer and / or a robot-compatible positioning component, can be determined.

[0168]

[0200] In one embodiment, the system may further include an onboard ultrasound system configured to allow the user to visualize, monitor, and receive feedback about the treatment site through a system display and software, including enabling ultrasound imaging and characterization (and various forms thereof), ultrasound-guided planning, and ultrasound-guided treatment, all in real time. The system may be configured to allow the user to image the patient manually (e.g., by hand or using a robot-enabled imager), semi-automated, or fully automated means.

[0169]

[0201] In some embodiments, imaging feedback and monitoring may include monitoring changes in various combinations thereof, including backscattering from bubble clouds, backscatter speckle reduction, backscatter speckle statistics, mechanical properties of tissue (i.e., elastography), tissue perfusion (i.e., ultrasound contrast), shear wave propagation, acoustic emission, electrical impedance tomography, and / or other forms of imaging (e.g., CT or MRI) that are displayed or integrated with these.

[0170]

[0202] In some embodiments, imaging including feedback and monitoring from backscatter from bubble clouds can be used as a method to immediately determine whether a histotripsy process has been initiated, properly maintained, or possibly extinguished. For example, this method allows for the continuous monitoring of drug delivery, tissue erosion, and similar processes in real time. The method can also provide feedback that allows the histotripsy process to be initiated at a high intensity and maintained at a much lower intensity. For example, backscatter feedback can be monitored by any transducer or ultrasound imager. By measuring feedback from a therapeutic transducer, an accessory transducer can be configured to emit interrogation pulses or passively detect cavitation. Furthermore, the nature of the feedback received can be used to adjust acoustic parameters (and associated system parameters) to optimize drug delivery and / or tissue erosion processes.

[0171]

[0203] In some embodiments, imaging, including feedback and monitoring from backscatter, and speckle reduction may be configured in the system.

[0204] In systems with feedback and monitoring via backscattering, and as a background means, when the tissue is gradually mechanically subdivided, in other words, homogenized, rendered unviable, or corroded, this process results in changes in the size and distribution of acoustic scattering. At some point in the process, the size and density of scattered particles are reduced to a level where ultrasound is hardly scattered, or the amount scattered is significantly reduced. This results in a significant reduction of speckle, which is a coherent constructive and destructive interference pattern of bright and dark areas seen in an image when a coherent illumination source, in this case ultrasound, is used. After some treatment time, the speckle reduction results in dark areas within the treatment volume. The amount of speckle reduction is related to the amount of tissue subdivision and therefore may be related to the size of the remaining tissue fragments. When this size is reduced to a level smaller than cells, it is not assumed that cells are surviving. Thus, treatment can proceed until the desired level of speckle reduction is achieved. Speckle is readily visible and evaluated on standard ultrasound imaging systems. Specialized transducers and systems, including those disclosed herein, may also be used to evaluate backscattering changes.

[0172]

[0205] Furthermore, in systems with speckle-mediated feedback and monitoring, as well as as a background means, the image persists and changes little from frame to frame, provided that the scattering distribution does not change and there is no movement of the object being imaged. Nevertheless, the scattering can change enough to be detected by signal processing and other means well before it is reduced to a size sufficient to cause speckle reduction. This group of techniques can act as detectors of speckle statistical changes. For example, the size and location of one or more specks in an image begin to decorrelate before observable speckle reduction occurs. Speckle decorrelation, after appropriate motion compensation, can be a highly sensitive measure of the mechanical unviability of tissue and therefore a measure of the efficacy of therapy. This feedback and monitoring technique can enable early observation of changes resulting from acoustic cavitation / histotopsis processes and can identify tissue changes (e.g., the occurrence of erosion) before substantial or complete tissue effects. In one embodiment, this method may be used to monitor acoustic cavitation / histtripsy processes for enhanced drug delivery when the treatment site / tissue is to be temporarily rendered unsustainable and tissue damage / erosion is undesirable. In other embodiments, this may include speckle decorrelation by the movement of scattering in an increasingly fluidized therapeutic volume, for example, when partial or complete tissue erosion is desired.

[0173]

[0206] In systems with feedback and monitoring via elastography, and as a background measure, when the treatment site / tissue is further subdivided (homogenized, rendered unsustainable, or corroded) for each acoustic cavitation / histotomy effect, its mechanical properties change from a soft but interconnected solid to a mucus or paste with little long-range interaction. These changes in mechanical properties can be measured by various imaging techniques, including MRI and ultrasound imaging systems. For example, ultrasound pulses can be used to generate forces (i.e., radiant forces) on localized volumes of tissue. Tissue responses (displacement, tension, and velocity) can be significantly altered during histotripsy treatment, allowing the state of tissue unsustainability to be determined by imaging or other quantitative means.

[0174]

[0207] The system can also incorporate feedback and monitoring via changes in shear wave propagation. As a background measure, tissue repartitioning makes the tissue more fluid and less solid, and fluid systems generally do not propagate shear waves. Thus, 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 volume being treated can be used as a measure of tissue destruction or inviolability. 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 may affect tissue by pushing the tissue in a particular 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 should be detected by external means, for example, by the difference frequency which is detected only when two shear waves interact nonlinearly, and the disappearance of the wave correlates with tissue damage. Therefore, the system can be configured to use this modality to enhance feedback and monitoring of acoustic cavitation / histopexy procedures.

[0175]

[0208] In systems with feedback and monitoring via acoustic emission, as well as as a background means, when tissue volume is subdivided, its effect on acoustic cavitation / histtripsy (e.g., bubble cloud here) changes. For example, bubbles may grow larger, have different lifetimes, and disrupt the changing properties of intact and fluidized tissue. Bubbles may also migrate and interact after tissue subdivision, creating larger bubbles or synergistic interactions between bubbles, all of which can produce changes in acoustic emission. These emissions can be heard during treatment and change during treatment. Analysis of these changes, and their correlation with the efficacy of the therapy, can enable monitoring of the progress of the therapy and may be configured as a feature of the system.

[0176]

[0209] In systems with feedback and monitoring via electrical impedance tomography, and as a background means, it is possible to generate an impedance map of the therapy site based on the spatial electrical properties throughout the therapy site. Imaging of the conductivity or dielectric constant of the patient's therapy site can be inferred from performing surface electrometry. Conductive electrodes are attached 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 the voltage is measured at several points using the electrodes. The process can be repeated for different configurations of the applied current. The resolution of the resulting image can be adjusted by changing the number of electrodes employed. A measure of the electrical properties of the therapy site within the skin surface can be obtained from the impedance map, and changes in acoustic cavitation / histtripsy (e.g., specifically bubble clouds) and their location, as well as the histotripsy process, can be monitored using this as configured in the system and support subsystems.

[0177]

[0210] Through the system software, user interface, and display, users may be able to further select, annotate, mark, highlight, and / or outline various areas of interest or treatment sites, as well as predefined treatment targets (on images) that can be used to instruct and direct the system to image, test, and / or treat the areas to be treated. In some configurations, users may perform procedures using manual ultrasound probes (e.g., diagnostic handheld probes). In other configurations, the system may perform procedures as directed and / or automated by the system using robotic and / or electromechanical positioning systems, or conversely, the system may allow a combination of manual and automated use.

[0178]

[0211] The system may further include the ability to perform image registration, including the registration of imaging and image datasets to enable the system's navigation and localization to a patient, including treatment sites (e.g., tumors, serious structures, anatomical structures of bone, anatomical structures and their distinguishing features). In one embodiment, the system enables a user to image and identify an area of ​​interest, such as the liver, using integrated ultrasound, and to select and mark a tumor (or its surrogate marker) contained within the liver through / displayed in the system software, the system registers the image data in a coordinate system defined by the system, and the system's therapy and robotics subsystems further enable the delivery of synchronized acoustic cavitation / histotopsy to the marked tumor. The system may have the ability to register various image sets, including those previously disclosed, with respect to each other and to provide navigation and localization (e.g., therapy transducers to the images and therapy transducers to CT or MRI / ultrasound fusion images with robotics subsystem tracking).

[0179]

[0212] The system may also be capable of operating in a variety of interventional endoscopic and surgical environments, including independently, and in conjunction with or equipped with various optical imaging capabilities (e.g., fiber and / or digital) and 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.)). The disclosed system may be configured to operate with these systems, and in some embodiments, it may operate together with them, or in other embodiments, all or part of the system may be integrated into the above systems / platforms (e.g., acoustic cavitation / histtripsy-enabled endoscopic systems or laparoscopic surgical robots). In many of these environments, the therapeutic transducer may operate, for example, during or around the time of use of optically guided endoscopes / bronchoscopes, or, as another example, with laparoscopic robots (e.g., Intuitive Da The Vinci*Xi system may be used when browsing / manipulating a tissue / treatment site. Furthermore, these embodiments and examples may include cases where the other systems / platforms described above are used to deliver fluid (locally) to enable the creation of an artificial acoustic window that would not normally exist (e.g., fluidizing a segment or lobe of the lung in preparation for acoustic cavitation / histotolipssis via non-invasive transthoracic treatment (e.g., with the transducer placed externally on / around the patient)). The systems disclosed herein may also comprise all or part of these subsystem hardware packaged within the other system carts / consoles / systems described herein (e.g., acoustic cavitation / histotolipssis systems and / or subsystems integrated and operated from the navigation or laparoscopic systems described above).

[0180]

[0213] The system may also be configured through various aforementioned parameters and other parameters to spatiotemporally display real-time visualization of the bubble cloud, including tissue effects resulting from the treatment phase / post-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 track and follow the treatment in real time and continuously within a single integrated procedure and interface / system, and to verify the safety and efficacy of the treatment in operation (for other interventions or surgical modalities that require numerous steps to achieve the same thing, or when the treatment effect is not visible in real time (e.g., radiotherapy), or when such as (e.g., real-time visualization of local tissue during thermal dissection) is not achievable, and / or when other procedures further require invasive approaches (e.g., incisions or holes) and repeated imaging in a scanner between procedure steps (e.g., CT or MRI scans)). The systems, subsystems, components, modalities, features, and usage workflows / methods of the above disclosure may be implemented without limitation through hardware, software, user interfaces, and usage environments, and any resulting data, as well as any means of using such data for analytics, artificial intelligence, or digital health applications and systems, as well as any future improvements, enhancements, and inventions in this area, are also considered to be within the scope of this disclosure.

[0181] Robotics

[0214] The system may comprise a variety of robotic subsystems and components, including, but not limited to, one or more robotic arms and controllers, which may further operate in conjunction with other subsystems or components of the system for delivering and monitoring acoustic cavitation / histtripsy. As previously discussed herein, the robotic arms and control systems may be integrated into one or more cart configurations.

[0182]

[0215] For example, one system embodiment may 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 mentioned subsystems are controlled by the user through a single bedside cart form factor.

[0183]

[0216] In other embodiments, the robot subsystem may consist of one or more separate carts that can be driven in a master / slave configuration from a separate master cart, the robot-enabled cart being located on the bed / patient side and the master being located away from the cart.

[0184]

[0217] The disclosed robotic arm may include multiple joints, segments, and degrees of freedom, and may also include various integrated sensor types and encoders implemented for various uses and safety features. Sensing techniques and data may include, for example, vision, potentiometers, position / localization, kinematics, force, torque, speed, acceleration, dynamic loading, and / or others. In some cases, sensors may be used for a user to direct robot commands (e.g., to gesture to the robot to a preferred setup position or to dock at home). Further details regarding the robotic arm can be found in U.S. Patent Publication No. 2013 / 0255426 to Kassow et al., which is disclosed herein by reference in whole.

[0185]

[0218] The robotic arm receives control signals and commands from a robotic control system that may be housed in a cart. The system may be configured to provide a variety of functions, including but not limited to position, tracking, pattern, triggering, and event / action.

[0186]

[0219] The positions may be configured to include fixed positions, pallet positions, time-controlled positions, distance-controlled positions, variable time-controlled positions, and variable distance-controlled positions.

[0220] Tracking may be configured to include time-controlled tracking and / or distance-controlled tracking.

[0187]

[0221] The movement pattern may be configured to include intermediate positions or points, and a sequence of positions along a predefined path in space.

[0222] The trigger may be configured to include a variety of sensory means, including distance measuring means, time, and / or those disclosed herein, but not limited to visual / imaging-based force, torque, localization, energy / power feedback, and / or others.

[0188]

[0223] Events / actions may be configured to include a variety of examples, such as proximity-based events (approaching / moving away from a target object), activation or deactivation of various end-effectors (e.g., therapeutic transducers), starting / stopping / pausing sequences of the above events, triggering or switching between triggers of events / actions, starting and changing / toggle between movement patterns, and / or time-based and transient events spanning defined tasks and spatiotemporal space.

[0189]

[0224] In one embodiment, the system includes a three-degree-of-freedom robot positioning system that allows the user to microscopically position the therapeutic transducer through the X, Y, and Z coordinate systems (through the system's software and associated user interface), and the overall macroscopic positioning of the transducer (e.g., aligning the transducer over the patient's body) is completed manually. In some embodiments, the robot may have six degrees of freedom, including X, Y, Z, as well as pitch, roll, and yaw. In other embodiments, the robot subsystem may have further degrees of freedom, allowing the robot arm support base to be positioned along a linear axis running parallel to the overall direction of the patient surface, and / or the support base height to be adjusted up and down, and allowing the position of the robot arm to be corrected relative to the patient, patient surface, cart, linking subsystem, additional robot / robot arm, and / or additional surgical systems, including but not limited to surgical towers, imaging systems, endoscopic / laparoscopic systems, and / or others.

[0190]

[0225] One or more robotic arms may also be equipped with various features to assist in manually or semi-manually manipulating and correcting the arm position, and these features may interface on or between the therapeutic transducer and the most distal joint of the robotic arm. In some embodiments, the features are configured to include a handle that enables manipulation and manual control by one or more hands. 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) for commanding various drive capabilities or modes to actuate the robot to assist in the overall or fine positioning of the arm. The workflow for the initial positioning of the robotic arm and therapeutic head can be configured to allow the therapeutic transducer / head to be positioned first in the coupling solution, with the therapeutic transducer interfaced directly with the arm, or, in a different workflow, to allow the user to set up the coupling solution first, with the robotic arm interfaced with the therapeutic transducer / coupling solution as a later / final setup step.

[0191]

[0226] In some embodiments, one or more robot arms or other features of the robot subsystem may include sensors or other features configured to measure, determine, or predict forces acting on the robot arm and / or a therapy transducer array coupled to the robot arm. These sensors may include force sensors or force transducers, not limited to load cells, pneumatic load cells, capacitive load cells, strain gauge load cells, hydraulic load cells, etc. In some implementations, the force sensors may be located on or within the robot arm, on or within the transducer array or therapy probe, on or within the coupling linkage between the transducer array and the robot arm, or at any other location within the system including the robot subsystem, and one or more force sensors should be adapted and configured to measure forces applied to the robot arm or transducer array. Furthermore, these force sensors may be electronically or motion-coupled to any of the control systems described herein, including an electronic controller, robot positioning system, navigation system, or any other CPU, processor, or controller configured to control the operation of the transducer array, robot subsystem, or any other subsystem during therapy.

[0192]

[0227] In some embodiments, the robotic arm may comprise a robotic arm on a laparoscope, single-port, endoscope, a hybrid or combination thereof, and / or other robot, and the robot in the system may also be a slave to a master controlling the arm and potentially multiple other arms, equipped to simultaneously perform other tasks (such as visualizing, imaging, grasping, cutting, tying, sealing, closing, stapling, dissecting, suturing, marking, etc.) including operating one or more laparoscopic arms (and instruments) and various histotripsy system components. For example, the laparoscopic robot may be used to prepare the surgical site, including manipulating the position of the organ to provide more ideal acoustic access and, optionally, further stabilizing the organ to minimize respiratory movement. In conjunction with and in parallel with this, a second robotic arm may be used to deliver non-invasive acoustic cavitation through body cavities, such as observed under real-time imaging from a therapeutic transducer (e.g., ultrasound) and by simultaneously occurring visualization via a laparoscopic camera. In other related embodiments, similar approaches combining endoscopy and non-invasive approaches, as well as further combining endoscopy, laparoscopy, and non-invasive approaches, may be used.

[0193] software

[0228] The system may feature a variety of software applications, features, and components that enable users to interact with, control, and use the system for a wide range of clinical applications. The software may communicate with and work with one or more subsystems, including but not limited to therapeutic, integrated imaging, robotics, and other components, as well as assistive devices and accessories for the system.

[0194]

[0229] Overall, in no particular order of importance, the 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 usage-related risks, planning procedures, supporting various transducer configurations, robotic arm and drive systems, function generator and amplifier circuits / slaves, test and therapeutic ultrasound sequences, transducer steering and positioning (electromechanical and electron beam steering, etc.), treatment patterns, imaging and imaging probe support, their manual and electromechanical / robot-responsive movement, imaging support for measuring / characterizing various dimensions within or around the procedure and treatment site (e.g., depth from one anatomical location to another), in It can provide features and support for performing pre-procedure assessments and protocols to measure / characterize the nature and state of situ treatment sites (e.g., acoustic cavitation / histotolypse threshold and its heterogeneity), target setting and target alignment, calibration, marking / annotating, localizing / navigating, registering, guiding, providing and guiding, providing communication tools (video, audio, sharing, etc.), troubleshooting, instructions, warnings, alerts, and / or enabling communication through various networking devices and protocols, under direct observation and viewing with real-time imaging such as displayed through software that includes various views and viewports for autonomous, autonomous but browsing.The software user interface and support display may include a variety of buttons, commands, icons, graphics, text, etc., that enable the user to interact with the system in a user-friendly and effective manner, and these may be presented in an unlimited number of arrangements, layouts, and designs, and may include two or more displays (e.g., a touchscreen monitor and a 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 set of features of the system.

[0195]

[0230] The software, as part of a typical system including one or more computer processors, can support various aforementioned function generators (e.g., FPGAs), amplifiers, power supplies, and therapeutic transducers. The software may be configured to allow the user to select, determine, and monitor various parameters and settings of acoustic cavitation / histtripsy, and to allow the user to stop / start / modify the above parameters and settings upon observing / receiving feedback on performance and status.

[0196]

[0231] The software may be configured to allow the user to select from a list or menu of numerous transducers and to support automatic detection of the transducers upon connection to the system (and verification of appropriate sequence and parameter settings based on the selected application). In other embodiments, the software may update target 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 the user with error messages or warnings if the selection or parameters of the therapeutic transducers, amplifiers, and / or function generators are incorrect or result in errors or failures. This may further include reporting details and locations of such errors.

[0197]

[0232] In addition to the above, the software may be configured to allow users to select treatment sequences and protocols from a list or menu and store selected and / or previously selected sequences and protocols so as to be associated with specific clinical use or patient profiles. Associated profiles may include any associated patient, procedure, clinical and / or engineering data, which may be used to inform, modify and / or guide current or future treatments or procedures / interventions, whether as decision support (e.g., using sequential datasets to build and guide new treatments) or as an active part of the procedure itself.

[0198]

[0233] As part of the plan or during treatment, the software (and working with other components of the system) can enable the user to evaluate and test acoustic cavitation / histtripsy thresholds at various locations within a user-selected region of interest or a predefined treatment area / volume to determine a minimum cavitation threshold throughout the region or area / volume, ensuring that treatment parameters are optimized to achieve, maintain, and dynamically control acoustic cavitation / histtripsy. In one embodiment, the system allows the user to manually evaluate and test threshold parameters at various points. These points may include points at the predefined boundaries of the selected region of interest and treatment area / volume, within the boundaries, and at central locations / positions, and the resulting threshold measurements may be reported / displayed to the user and used to update treatment parameters before treatment. In another embodiment, the system may be configured to enable automated threshold measurement and updating, such as enabled by the robotics subsystem described above, where the user can instruct a robot or the robot may be commanded to perform measurements autonomously.

[0199]

[0234] The software may also be configured to enable various sortings of delivering and positioning optimized acoustic cavitation / histtripsy in and through a selected area / volume by working with a computer processor, as well as one or more function generators, amplifiers, and therapeutic transducers. This may include, but is not limited to, systems comprising various combinations including fixed / natural focus placement using pure electromechanical positioning configurations, electron beam steering (with or without electromechanical positioning), electron beam steering to a new selected fixed focus with further electromechanical positioning, axial (Z-axis) electron beam steering with lateral (X and Y) electromechanical positioning, high-speed axial electron beam steering with lateral electromechanical positioning, high-speed beam steering in 3D space, and dynamically varying one or more acoustic cavitation / histtripsy parameters based on the aforementioned ability to update therapeutic parameters based on threshold measurements (e.g., dynamically adjusting amplitude across a therapeutic area / volume).

[0200] Other components, auxiliary devices, and accessories

[0235] The system may comprise a variety of other components, auxiliary equipment and accessories, including but not limited to computers, computer processors, power supplies including high-voltage power supplies, controllers, cables, connectors, networking devices, security, communications, software applications for integration into information systems including hospital information systems, cellular communication devices and modems, handheld wired or wireless controllers, goggles or glasses for advanced visualization, augmented or virtual reality applications, cameras, sensors, tablets, smart devices, telephones, Internet of Things capabilities, special use "apps" or user training materials and applications (software or paper-based), virtual proctors or trainees and / or other enabling features, devices, systems or applications, and / or methods of using the foregoing.

[0201] System variations and methods / applications

[0236] In addition to performing a wide range of procedures, the system can enable users to benefit from additional advantages such as enhanced planning, imaging, and guidance. In one embodiment, the system can enable users to create patient, target, and specific-use treatment plans, and the system may be configured to optimize treatment parameters based on feedback to the system during planning, and planning may further include the ability to perform various test protocols to gather unique inputs to the system and the plan.

[0202]

[0237] The feedback can include various parameters such as energy, power, location, position, organization, and / or other parameters.

[0238] The system and the feedback described above may also be further configured and used to autonomously (and robotically) deliver optimized treatment plans and protocols, such as those visualized under real-time imaging during the procedure, allowing the user to directly observe the local therapeutic tissue effects as the treatment progresses, and to start / stop / modify the treatment at the user's discretion. Both test and treatment protocols may be updated during the procedure at the user's direction, or based on logic built into the system in some embodiments.

[0203]

[0239] Many of these benefits can further improve other forms of acoustic therapy, including thermal dissection by high-intensity focused ultrasound (HIFU) and high-intensity therapeutic ultrasound (HITU), including boiling histotripsy (thermal cavitation), and are also recognized as part of this disclosure. This disclosure also considers the application of histotripsy as a means of activating previously delivered active drug payloads that are inactive, either by protection in micelles, nanostructures or similar protective structures, or through molecular arrangements that enable activation only when acoustic energy is applied.

[0204]

[0240] In another embodiment, a therapeutic subsystem comprising one or more amplifiers, transducers, and power supplies may be configured to enable numerous acoustic cavitation and histotripsy driving capabilities, resulting in unique benefits based on application, method, and / or patient-specific use. These benefits may include, but are not limited to, the ability to better optimize and control therapeutic parameters that enable electron beam steering and / or other features, along with the delivery of more energy, along with a more desirable thermal profile, increased treatment speed, and reduced treatment time.

[0205]

[0241] This disclosure also includes novel systems and concepts such as systems and subsystems comprising a new and "general-purpose" amplifier capable of enabling a number of drive approaches (e.g., single and multi-period pulse generation). In some embodiments, this may include a variety of novel features to further protect the system and user in terms of electrical safety or other threats (e.g., adverse effects on transducers and / or amplifier circuit equipment).

[0206]

[0242] In another embodiment, the system and therapy subsystem may include a very large number of therapy transducers, which may be configured for specific applications and uses, adaptable to therapies across a wide range of working parameters (such as target size, depth, and location), and may include a wide range of working specifications (detailed below). The transducers may be further adapted, interfaced, and connected to robot-enabled systems, as well as to coupling subsystems that allow the transducer to be positioned in or with an acoustic coupling device that enables simultaneous imaging and histotripsy therapy through an acceptable acoustic window in many embodiments. The therapy transducer may also be equipped with an integrated imaging probe or localization sensor that has the ability to display and determine the transducer position within the therapy site and provide a direct view (or representation) of the therapy site, as well as such that the appearance and intensity of acoustic cavitation / histotopsis tissue effects and bubble clouds may or may not change throughout the therapy, and depending on its location within the therapy (e.g., tumor, around healthy tissue, severe structure, fatty tissue, etc.).

[0207]

[0243] The systems, methods, and uses of the systems disclosed herein may be beneficial in overcoming important yet unaddressed needs in the areas of surgical procedures including, but not limited to, soft tissue dissection, oncology, cancer immunology, advanced image-guided procedures, laparotomy, laparoscopy, single incision, transluminal, endoscopic, non-invasive, and various combinations thereof; various intervention spaces for catheter-based procedures in vascular, cardiovascular, pulmonary, and / or neuroscience-related spaces; cosmetic / aesthetics, metabolism (e.g., type 2 diabetes), plastic surgery and reconstruction, vision and ophthalmology, orthopedics, gynecology, and human health conditions, as well as other systems, devices, and methods for treating diseased, injured, undesirable, or healthy tissues, organs, or cells.

[0208]

[0244] Systems and methods are also provided for improving the treatment pattern within tissue, which can reduce treatment time, improve efficacy, and reduce the amount of energy and constant-focus tissue heating delivered to the patient.

[0209] Usage environment

[0245] The disclosed systems, methods of use, and methods of using the systems can be performed in a great many environments and settings, with or without various support systems such as anesthesia, including but not limited to physician's offices, mobile healthcare centers or systems, automobiles and related vehicles (e.g., vans), aircraft and ships and other aerospace and maritime transport vehicles, and / or any structure capable of providing temporary procedural support (e.g., tents). In some cases, the systems and / or subsystems disclosed herein may also be provided as features integrated into other environments, such as direct integration of the histotripsy therapy subsystem into an MRI scanner or patient surface / bed, where at least the therapy generator and transducer are integrated into such a system, and in other cases, the histotripsy configuration further includes a robotic positioning system which may be further integrated into a scanner or bed-centered design.

[0210] Link

[0246] The system may comprise 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 / histopepsis (e.g., providing an acoustic window and medium between the transducer and the patient, and supporting it). These may include different form factors of such as open and closed device solutions, as well as several arrangements that may be configured to allow dynamic control over the acoustic medium (e.g., temperature, oil-soluble gas contents, particulate filtration level, sterility, volume, components, etc.). Such dynamic control components may be directly integrated into the system (in the cart) or may be located in separate devices and / or outside the cart, but in transient / intermittent or continuous communication with the system.

[0211]

[0247] 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 interface to other surfaces or devices). In most embodiments, the coupling medium is water, which may be conditioned before or during treatment (e.g., cooled, degassed, filtered, etc.). Various conditioning parameters may be employed depending on the system configuration and its intended use / application.

[0212]

[0248] Reservoirs or media containers can be formed and shaped in various sizes and shapes to fit / conform to a patient, allowing therapy transducers to engage / access and work within the acoustic media for each defined and required working space (such as the minimum volume of media to allow therapy transducers to be positioned and / or move through one or more therapy positions or patterns and at various standoffs or depths from the patient), and the reservoir or media container may also mechanically support the load and load distribution through the use of mechanical and / or electromechanical support structures. Typical examples include support frames. Containers may also be of various shapes, sizes, curvatures, and dimensions and may include various material components (single, multiple, composite, etc.) which may vary throughout. In some embodiments, the container may have insertable and removable features such as films, drapes, thin films, blowers, etc., which can be used to conform to the patient and assist in confining / filling the medium within the container. The container can also accommodate various sensors (e.g., volume / fill level), drainage (e.g., inlet / outlet), lighting (e.g., LED), markings (e.g., filling line, setup orientation, etc.), text (e.g., labeling), and more.

[0213]

[0249] In one embodiment, the reservoir or medium container includes a sealable frame in which a thin film and / or film may be placed to provide a comfortable means of contact with the reservoir (later comprising a treatment head / therapy transducer) as an interface to the patient, further providing a barrier to the medium (e.g., water) between the patient and the therapy transducer. In other embodiments, the thin film and / or film may have an opening, the edge in which the patient contacts, which provides a fluid / mechanical seal to the patient, but in contrast, directly allows for medium communication with the patient (e.g., a direct degassed water interface with the patient). The superstructure of the reservoir or medium container in both of these examples may further provide a proximal portion (e.g., top) of the structure that will be open or enclosed (e.g., to prevent spillage or to give additional features).

[0214]

[0250] The thin films of disclosure may include various elastic materials, viscoelastic polymers, thermoplastics, thermoplastic elastic materials, thermosetting polymers, silicones, urethanes, rigid / flexible copolymers, block copolymers, random block copolymers, etc. The materials may be hydrophilic, hydrophobic, surface-modified, coated, extracted, etc., and may further contain various additives to enhance performance, appearance, or stability. In some embodiments, the thermoplastic elastic material may be styrene-ethylene-butylene-styrene (SEBS) or other similar strong, flexible elastic materials. The thin film form factor can be flat or pre-formed before use. In other embodiments, the thin film can be inelastic (i.e., convex) and can be pressed against the patient's skin to acoustically couple a transducer to tissue. Systems and methods for controlling the level of contaminants (e.g., particulate matter) on the thin film to maintain an appropriate level of ultrasonic coupling are further disclosed. Too much particulate matter or contaminants may cause ultrasonic scattering. This can be achieved with a removable film or coating on the outer surface of the thin film to protect from contamination.

[0215]

[0251] The above materials may be formed into useful thin films through molding, casting, spraying, ultrasonic spraying, extrusion, and / or any other processing method that produces useful embodiments. The above materials may be single-use or reposable / reusable. The above materials may be non-sterile, antiseptically clean, or sterile, and sterilization may include any known method, including but not limited to ethylene oxide, gamma, e-beam, autoclavation, steam, hydrogen peroxide, plasma, chemicals, etc. The thin film may be further configured with an externally molded or overmolded frame to provide mechanical stability to the thin film during handling, including assembly, setup, and disassembly of linked subsystems. Various parameters of the thin film, including thickness, thickness profile, density, and manufacturing method (e.g., polymer molecular weight and copolymer ratio, additives, plasticizers, etc.), can be optimized for this use, including optimizing in particular to maximize acoustic transmission properties, including minimizing ultrasonic imaging artifacts, including but not limited to impact on the cavitation onset threshold and / or thin film reflections, as a typical example.

[0216]

[0252] An open reservoir or media container may include various methods of filling, including using a pre-prepared media or water that can be delivered to the container to a predefined specification (such as temperature and gas saturation levels), or it may include additional features integrated into the design that enable filling and draining (e.g., ports, valves, hoses, tubes, fittings, bags, pumps, etc.). These features may be further configured to interface with, or into, other devices, such as a fluid engineering system. In some cases, the fluid engineering system may be an in-hospital media preparation system in a hospital or medical environment room, or conversely, a mobile cart-based system capable of preparing and transporting media from a cart to a media container.

[0217]

[0253] Enclosed iterations of a reservoir or media container may include various features for sealing, in some embodiments sealing to the proximal / top part or structure of the reservoir / container, or in other cases, the sealing may include embodiments sealing features on the transducer or transducer housing. Furthermore, some embodiments may 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 changes in the focal length to a target area without moving the transducer. Thus, integrated features and controls enabling fluid communication may be provided, some of which include the ability to monitor and control the various fluid parameters disclosed above (the ability to supply / remove fluid on demand). To provide this functionality, the entire system, and as a part thereof, the linked subsystem may include a fluid conditioning system which may include various electromechanical devices, systems, power, sensing, computing, pumping, filtering, and control systems. The reservoir may also be configured to receive signals that deform or change its shape in a specific and controlled manner to allow the target point to be adjusted without moving the transducer.

[0218]

[0254] The linked support system may include various mechanical support devices for interface the reservoir / container and medium 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 may have a proximal interface to one or more locations (and features) of the bed, including but not limited to frames, rails, customized rails or inserts, as well as one or more distal locations of the reservoir or container. The arm may also be a feature realized on one or more carts, the carts may consist of various unrestricted arrangements, and in some cases the carts may have only the role of supporting and providing the disclosed support structure.

[0219]

[0255] In some embodiments, the support structure and arm may be implemented as a standalone cart or as 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 of an interventional, surgical, or other type, further comprising various user input features and / or coupling solution features (e.g., filling, draining, etc.) for operating / controlling the robot arm (e.g., located in / within a coupling medium). 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 by positioning the therapy transducer at a desired / known location and placing it within the coupling support structure.

[0220]

[0256] Overall, significant unaddressed needs exist today within interventional and surgical medical procedures across a variety of procedures, including those that utilize minimally invasive devices and approaches to treat disease and / or injury, where unaddressed needs may be resolved entirely by novel medical procedures. The capabilities of today's medical systems are often limited by access, making less invasive or non-invasive approaches preferable, or the tools of today lack the ability to deliver preferred / requested tissue effects (e.g., working around / through severe structures without serious injury), or the physical setup of the system makes certain procedural approaches less desirable or impossible, and combinations of approaches, along with treatments affecting enhanced tissue, can enable entirely novel procedures and approaches that are not possible today.

[0221]

[0257] In addition, there is a unique need to enable histotripsy delivery, including robotic histotripsy delivery, and one or more histotripsy therapy transducers may be configured to acoustically couple to a patient using a completely sealed approach (e.g., no acoustic media communication with the patient's skin), and to allow one or more histotripsy transducers to be moved within the coupling solution without interfering with the movement / route of the robotic arm or interfering with / disrupting the coupling interface, which could affect the intended treatment and / or target location.

[0222]

[0258] As a non-limiting example, histotripsy acoustic and patient-connected systems and methods for enabling histotripsy therapy / treatment in any setting, such as intervention suites, operating rooms, hybrid suites, imaging centers, medical centers, office environments, mobile treatment centers, and / or others, are disclosed herein. The following disclosures further describe novel systems used to create, control, maintain, modify / enhance, monitor, and set up / deconstruct acoustic and patient-connected systems in a variety of approaches, methods, environments, architectures, and workflows. Generally, the novel systems of the disclosure can enable a coupling medium, in some cases degassed water, to interface 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 therapeutic location (and volume), the delivery may require the physical movement of the histotripsy therapy transducer within a defined workspace including the coupling medium, and the coupling system is configured to allow the above movement of the therapy transducer (and the positioning of the system, e.g., a robot) to be free and unhindered by a coupling support system (e.g., a frame or manifold holding the coupling medium).

[0223] Connecting systems and subsystems / components

[0259] The disclosed histotripsy acoustic and patient coupling system may generally comprise one or more subsystems and components, including but not limited to: 1) a thin film / barrier film for providing an enclosed, sealed, and equiangular patient coupling and histotripsy system interface; 2) a frame and assembly for holding the thin film and providing sufficient working and overhead space for the required range of motion (x, y, and z, pitch, roll, and yaw) of the histotripsy therapy transducer; 3) an ultrasonic medium of sufficient volume to provide acoustic coupling and interface to the histotripsy therapy transducer and robotic arm; 4) one or more mechanical support arms for enabling installation, positioning, and load support of the frame, assembly, and medium; and 5) a fluid engineering system for preparing, supplying, and removing the ultrasonic medium from the frame and assembly.

[0224]

[0260] In some embodiments, the coupling system may be completely sealed, while in other embodiments and configurations, the coupling system may be partially open to provide immediate access (physical and / or visual).

[0225]

[0261] Acoustic and patient coupling systems and subsystems may further feature a variety of characteristics and functions, as well as associated workflows, and may be further configured in various ways to enable histotripsy procedures as detailed below.

[0226]

[0262] Therapeutic and / or imaging transducers can be housed in a coupling assembly, which may further include a coupling film and a film constraint configured to prevent the film from expanding too far from the transducer. The coupling film can be filled with an acoustic coupling medium such as a fluid or gel. The film constraint can be a semi-rigid or rigid material configured, for example, to limit the expansion / movement of the film. In some embodiments, the film constraint is not used, and the stretch and tensile strength of the film prevents expansion. The coupling film can be a mineral oil-injected SEBS film to prevent direct fluid contact with the patient's skin. In exemplary embodiments, the coupling assembly is supported by a mechanical support arm that is load-bearing in the xy plane but capable of allowing manual or automated z-axis adjustment. The mechanical support arm can be attached to the floor, patient table, or cart. The mechanical support is designed and configured to align and hold the coupling film in appropriate position relative to the patient's skin, while still allowing movement of the therapy / imaging transducer relative to the patient and further relative to the coupling film by a robotic positioning arm.

[0227]

[0263] The system may further include a fluid engineering system which may include a fluid source, a cooling and degassing system, and a programmable control system. The fluid engineering system is configured for the external loading of the linked thin film with automated control of the fluid sequence. Further details about the fluid engineering system are provided below.

[0228] Thin films / barrier films and related architectures

[0264] Thin films and barrier films may consist of a variety of biocompatible materials capable of enabling conformal linkage to the patient's anatomical structures with minimal or no trapped bubbles that could interfere with ultrasound imaging and histotripsy therapy, and providing a sealed barrier layer between the aforementioned patient's anatomical structures and the ultrasound medium, contained within the working space provided by the frame and assembly.

[0229]

[0265] Thin film and barrier film materials can comprise flexible and elastic biocompatible materials / polymers, such as various thermoplastics and thermosetting materials, as well as permanent or bioabsorbable polymers. Additionally, UMC frames can also comprise the same materials. In some examples, the thin film may be a pre-formed or flat rigid or semi-rigid polymer.

[0230] ultrasonic medium

[0266] As described above, the ultrasonic medium may comprise any applicable medium capable of providing sufficient and useful acoustic coupling to enable histotripsy therapy and adequate clinical imaging (e.g., ultrasound). The ultrasonic medium may include, but is not limited to, a variety of aqueous solutions / mediums, including mixtures with other soluble fluids that may have preferred or more preferred acoustic qualities, including the ability to match the speed of sound, as part of this disclosure and system. Examples of media may include defasted water, and / or mixtures / cosolutions of defasted water with various alcohols such as ethanol.

[0231] Mechanical support arms and arm architectures

[0267] Various designs and configurations of mechanical support arms (and arm architectures) may be employed to support acoustic and patient linkage systems, including providing users with an efficient and ergonomic workflow. Support arms may be configured with a range of degrees of freedom that include, but are not limited to, x, y, z, pitch, roll, and yaw, as well as additional interface features that may allow for additional height adjustment or translation.

[0232]

[0268] Arms can have a variety of joints and segments of different numbers and types. Typically, an arm can have at least two segments. In some configurations, an arm can have three to five segments.

[0233]

[0269] The arm is also configured to interface proximal to the main support base or base interface (e.g., robot, table, table / bed rail, cart, floor mount, etc.) and distally to the frame / assembly and the overall "UMC" or "connection solution". This specific distal interface may further include features for controlling the position / orientation of the frame / assembly within the frame / assembly interface.

[0234]

[0270] For example, in some embodiments, the arm / frame interface may include a ball-jointed 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 interaction with various wrists, which may include additional handles or knobs (as an unrestricted example) to further allow for the placement of UMC / coupling solutions. For example, a gimbal wrist can benefit from allowing the frame / assembly to have three degrees of freedom (independent of arm degrees of freedom), including pitch, roll, and yaw adjustments.

[0235]

[0271] The support arm, comprising a frame / assembly and an arm wrist further interfaced with it, may feature brakes, including cable-operated or electronically actuated brakes, and quick-release mechanisms that can interact with one or more axes individually or in groups. The support arm may also include an electronic lift system and base support. In some embodiments, these lift systems / base supports are located in the same place as the robot arm base, and the robot arm is equipped with a histotripsy therapy transducer configured to fit / function within an enclosed coupling solution. In other embodiments, the support arm is placed on a separate cart. In some cases, the separate cart may include a fluid mechanics 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 base structure / foundation capable of managing weight and tipping requirements.

[0236] Fluid dynamics systems, control systems, and system architectures

[0272] As part of the overall fluid engineering management, the histotripsy system, including the acoustic / patient coupling system, may be configured to include an automated fluid engineering system, which is primarily responsible for providing a reservoir for the preparation and use of the coupling medium, and preparation may include the ability to degas, cool, monitor, regulate, supply / fill, and remove / drain the coupling medium from the frame / assembly. The fluid engineering system may include an emergency high-flow system for rapid drainage of the coupling medium from the UMC. In some embodiments, the fluid engineering system may be configured for single use of the coupling medium or for reuse of the medium as an alternative. In some embodiments, the fluid engineering system may achieve positive pressure or vacuum to perform leak tests of the UMC and thin film before filling with the coupling medium. Vacuum assistance may also be used for the removal of air from the UMC during the filling process. The fluid engineering system may further include filters configured to prevent particulate contamination from reaching the UMC.

[0237]

[0273] The fluid engineering system may be implemented in the form of a mobile fluid engineering cart. The cart may include an input tank, a drain tank, a degassing module, a filling pump, a drain pump, an inert gas tank, an air compressor, tubing / connectors / lines, electronic and manual control systems and input devices, a power supply and one or more batteries. The cart may also optionally include a system check container / reservoir for evaluating histotripsy system performance and relational system diagnostics (configured to accommodate the required water volume and working space for therapeutic transducers).

[0238]

[0274] Regarding additional details relating to the present invention, materials and manufacturing techniques may be adopted as being within the level of those skilled in the art. The same may apply to method-based embodiments of the present invention in terms of additional actions adopted generally or logically. Furthermore, it may be assumed that any optional feature of any variant of the described invention can be described and claimed independently or in combination with any one or more of the features described herein. Similarly, references to singular items include the possibility that plural forms of the same item exist. More specifically, as used herein and in the appended claims, the singular “a,” “and,” “the said,” and “the said” include plural referents unless the context otherwise explicitly indicates. It should be further noted that the claims may be drafted to exclude any optional element. Thus, this statement is intended to function as an antecedent for the use of exclusive technical terms such as “solely,” “only,” and similar, or for the use of “negative” limitation, with respect to the enumeration of claim elements. Unless otherwise defined herein, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art in which the invention pertains. The scope of the invention should not be limited by the specification of the subject matter, but rather by the plain meaning of the claims adopted.

Claims

1. A flat transducer array comprising one or more transducer elements, A dual-material acoustic lens connected to the flat transducer array, having a flat connecting surface, comprising a first material having a first velocity of sound in the dual-material acoustic lens and a second material having a second velocity of sound in the dual-material acoustic lens, and configured to provide equal time of flight between the flat transducer array and the focal point of an ultrasonic device for any radiation distance across the entire flat transducer array. An ultrasonic device equipped with [specific features / features].

2. The ultrasonic device according to claim 1, wherein the double-material acoustic lens has a constant overall thickness.

3. The ultrasonic device according to claim 1, wherein the first velocity of sound in the first material is higher than the second velocity of sound in the second material.

4. The ultrasonic device according to claim 1, wherein the first speed of sound is greater than 1500 m / s.

5. The ultrasonic device according to claim 1, wherein the second speed of sound is less than 1500 m / s.

6. The ultrasonic device according to claim 1, wherein the first material has a concave shape.

7. The ultrasonic device according to claim 1, wherein the first material has an oval shape.

8. The ultrasonic device according to claim 1, wherein the first material comprises 3D printed plastic.

9. The ultrasonic device according to claim 8, wherein the second material comprises a silicon-filled material.

10. The ultrasonic device according to claim 1, wherein the dual-material acoustic lens comprises a Fresnel lens.

11. The ultrasonic device according to claim 10, wherein the first material is shaped to include a plurality of steps.

12. The ultrasonic device according to claim 11, wherein each of the plurality of steps has a thickness that is an integer multiple of the wavelength of the flat transducer array.

13. The ultrasonic device according to claim 1, wherein the double-material acoustic lens has a thickness of less than 15 mm.

14. The ultrasonic device according to claim 1, wherein the double-material acoustic lens has a thickness of less than 13 mm.

15. The ultrasonic device according to claim 1, wherein the double-material acoustic lens has a thickness of less than 5 mm.

16. The ultrasonic device according to claim 1, wherein the double-material acoustic lens has a thickness of less than 4 mm.

17. The ultrasonic device according to claim 1, wherein the dual-material acoustic lens and the flat transducer array are arranged on or inside the probe housing container.

18. The ultrasonic device according to claim 1, wherein the dual-material acoustic lens provides dry connection of the flat transducer array to the subject.

19. The ultrasound device according to claim 18, wherein the device is configured to deliver histotripsi pulses to the subject's tissue to generate cavitation at the focal point.

20. The ultrasonic device according to claim 1, further comprising the dual-material acoustic lens and / or an ultrasonic imaging transducer array integrated at the central location of the flat transducer array.

21. Storage containers and A flat transducer array comprising one or more transducer elements arranged in the aforementioned storage container, An electrical cable wiring is provided, at least partially, within the storage container and configured to provide electrical connections to the back of each of the one or more transducer elements. A matching layer connected to the transmission surface of the flat transducer array, the matching layer having a conductive material embedded therein, wherein the conductive material is configured to provide electrical connections to each of the one or more transducer elements on the transmission surface, and An ultrasonic device equipped with [specific features / features].

22. The ultrasonic device according to claim 21, wherein the conductive material comprises a conductive mesh.

23. The ultrasonic device according to claim 21, wherein the conductive material comprises a conductive grid.

24. The ultrasonic device according to claim 21, wherein the conductive material comprises a copper mesh.

25. The ultrasonic device according to claim 21, wherein the matching layer is directly coupled to the transmission surface of the flat transducer array.

26. The ultrasonic device according to claim 25, wherein the flat transducer array is directly coupled to the matching layer before being diced into a plurality of transducer elements.

27. The ultrasonic device according to claim 21, wherein the matching layer is a dual-material acoustic lens connected to the flat transducer array, having a flat connecting surface, and comprising a first material having a first velocity of sound in the dual-material acoustic lens and a second material having a second velocity of sound in the dual-material acoustic lens, and configured to provide equal time of flight between the flat transducer array and the focal point of the ultrasonic device for any radiation distance over the entire flat transducer array.

28. The ultrasonic device according to claim 21, wherein the double-material acoustic lens has a constant overall thickness.

29. The ultrasonic device according to claim 21, wherein the first velocity of sound in the first material is higher than the second velocity of sound in the second material.

30. The ultrasonic device according to claim 21, wherein the first speed of sound is greater than 1500 m / s.

31. The ultrasonic device according to claim 21, wherein the second speed of sound is less than 1500 m / s.

32. The ultrasonic device according to claim 21, wherein the first material has a concave shape.

33. The ultrasonic device according to claim 21, wherein the first material has an oval shape.

34. The ultrasonic device according to claim 21, wherein the first material comprises 3D printed plastic.

35. The ultrasonic device according to claim 34, wherein the second material comprises a silicon-filled material.

36. The ultrasonic device according to claim 21, wherein the dual-material acoustic lens comprises a Fresnel lens.

37. The ultrasonic device according to claim 36, wherein the first material is shaped to include a plurality of steps.

38. The ultrasonic device according to claim 37, wherein each of the plurality of steps has a thickness that is an integer multiple of the wavelength of the flat transducer array.

39. The ultrasonic device according to claim 21, wherein the double-material acoustic lens has a thickness of less than 15 mm.

40. The ultrasonic device according to claim 21, wherein the double-material acoustic lens has a thickness of less than 13 mm.

41. The ultrasonic device according to claim 21, wherein the double-material acoustic lens has a thickness of less than 5 mm.

42. The ultrasonic device according to claim 21, wherein the double-material acoustic lens has a thickness of less than 4 mm.

43. The ultrasonic device according to claim 21, wherein the dual-material acoustic lens and the flat transducer array are arranged on or inside the probe housing container.

44. The ultrasonic device according to claim 21, wherein the dual-material acoustic lens provides dry connection of the flat transducer array to the subject.

45. The ultrasound device according to claim 44, wherein the device is configured to deliver histotripsi pulses to the subject's tissue to generate cavitation at the focal point.

46. The ultrasonic device according to claim 21, further comprising the dual-material acoustic lens and / or an ultrasonic imaging transducer array integrated into the central location of the flat transducer array.

47. The ultrasonic device according to claim 27, wherein the conductive material is embedded in the first material.

48. The ultrasonic device according to claim 21, further comprising a printed circuit board configured to receive a spring pin electrical connector for each of the one or more transducer elements, wherein the spring pin electrical connector provides an electrical connection between the electrical cable wiring and the back surface of each of the one or more transducer elements.

49. The ultrasound device according to claim 1 or 21, wherein the device comprises an intracavitary histotripsi probe or a laparoscopic histotripsi probe.

50. Multiple histotripsitransducer elements arranged on a plane and configured to enable acoustic coupling with the patient without the need for water coupling. A flat histotripsy therapy array equipped with this technology.

Images