Histotripsy focus imaging systems and methods

Abstract

A histotripsy therapy system configured for the treatment of tissue is provided, which may include any number of features. Provided herein are systems and methods that provide efficacious non-invasive and minimally invasive therapeutic, diagnostic and research procedures. In particular, provided herein are optimized systems and methods that provide targeted, efficacious histotripsy in a variety of different regions and under a variety of different conditions without causing undesired tissue damage to intervening / non-target tissues or structures.

Description

HISTOTRIPSY FOCUS IMAGING SYSTEMS AND METHODSPRIORITY CLAIM

[0001] This patent application claims priority to U.S. provisional patent application no. 63 / 679,353, titled “HISTOTRIPSY FOCUS IMAGING SYSTEMS AND METHODS,” and filed on August 5, 2024, which is herein incorporated by reference in its entirety.INCORPORATION BY REFERENCE

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

[0003] This invention was made with government support under CA282200 awarded by the National Institutes of Health. The government has certain rights in the invention.FIELD

[0004] The present disclosure details novel histotripsy systems configured to produce acoustic cavitation, methods, devices and procedures for the minimally and non-invasive treatment of healthy, diseased and / or injured tissue. The histotripsy systems and methods described herein, also referred to Histotripsy, may include transducers, drive electronics, positioning robotics, imaging systems, and integrated treatment planning and control software to provide comprehensive treatment and therapy for soft tissues in a patient.BACKGROUND

[0005] Many medical conditions require invasive surgical interventions. Invasive procedures often involve incisions, trauma to muscles, nerves and tissues, bleeding, scarring, trauma to organs, pain, need for narcotics during and following procedures, hospital stays, and risks of infection. Non-invasive and minimally invasive procedures are often favored, if available, to avoid or reduce such issues. Unfortunately, non-invasive and minimally invasive procedures may lack the precision, efficacy or safety required for treatment of many types of diseases and conditions. Enhanced non-invasive and minimally invasive procedures are needed, preferably not requiring ionizing or thermal energy for therapeutic effect.

[0006] Histotripsy, or pulsed ultrasound cavitation therapy, is a technology where extremely short, intense bursts of acoustic energy induce controlled cavitation (microbubble- 1 -SG Docket No. 10860-535.600formation) within the focal volume. The vigorous expansion and collapse of these microbubbles mechanically homogenizes cells and tissue structures within the focal volume. This is a very different end result than the coagulative necrosis characteristic of thermal ablation. To operate within a non-thermal, Histotripsy realm; it is necessary to deliver acoustic energy in the form of high amplitude acoustic pulses with low duty cycle.

[0007] Compared with conventional focused ultrasound technologies, Histotripsy has important advantages: 1) the destructive process at the focus is mechanical, not thermal; 2) cavitation appears bright on ultrasound imaging thereby confirming correct targeting and localization of treatment; 3) treated tissue generally, but not always, appears darker (more hypoechoic) on ultrasound imaging, so that the operator knows what has been treated; and 4) Histotripsy produces lesions in a controlled and precise manner. It is important to emphasize that unlike thermal ablative technologies such as microwave, radiofrequency, and high- intensity focused ultrasound (HIFU), Histotripsy relies on the mechanical action of cavitation for tissue destruction.

[0008] Ultrasound imaging is used for targeting and monitoring histotripsy ablation. During therapy, cavitation appears as a bright, transient, localized echo indicating where ablation is occurring. In a homogeneous medium with known sound speed and attenuation, the exact location of the histotripsy focus can be predicted based on the system design. Real treatments require the sound field to pass through a water coupling bath and multiple tissue layers which aberrate and refract the acoustic beam shifting the true focal location. The large aperture of the therapeutic transducer compared to an imager greatly exacerbates these effects. The current clinical histotripsy system uses an estimated focal location for ultrasound guided targeting based on calibration treatments in a tissue phantom with the imager physically registered to the therapy transducer. There can still be a residual focal shift of several millimeters, hence the focal location is confirmed / corrected at the start of treatment by ramping the ultrasound pressure until cavitation is generated and visualized on ultrasound imaging. This procedure must be repeated at the center and margins of the target volume. Cavitation-based targeting has two major drawbacks. 1) Cavitation generation, even briefly, will cause damage to tissue at the focus. This is a safety concern if a refracted / aberrated focus targets a location outside the planned treatment volume prior to correction. 2) Some portions of the therapy transducer may be blocked by impenetrable structures (ribs, lung / bowel gas) that could be harmed by excess acoustic exposure.SUMMARY OF THE DISCLOSURE- 2 -SG Docket No. 10860-535.600

[0009] Histotripsy produces tissue fractionation through dense energetic bubble clouds generated by short, high-pressure, ultrasound pulses. When using pulses shorter than 2 cycles, the generation of these energetic bubble clouds only depends on where the peak negative pressure (P-) exceeds an intrinsic threshold for inducing cavitation in a medium (typically 26 - 30 MPa in soft tissue with high water content).

[0010] A histotripsy method is provided, comprising transmitting one or more histotripsy pulses from at least one therapy transducer element of a therapy transducer array into tissue, the one or more histotripsy pulses being below a cavitation threshold such that no cavitation is formed at a focal zone region of the therapy transducer array; receiving echoes of the one or more histotripsy pulses with a plurality of receive transducer elements of an ultrasound imaging array separate from the therapy transducer array; beamforming the echoes to form one or more raw ultrasound images of the focal zone region of the therapy transducer array for each of the plurality of the receive transducer elements; and summing the one or more raw ultrasound images to generate a combined image of the focal zone region.

[0011] In some aspects, the combined image is directly registered with the ultrasound imaging array.

[0012] In one aspect, the one or more histotripsy pulses have a frequency below IMhz.

[0013] In some aspects, only a subset of the transducer elements of the therapy transducer array transmit the one or more histotripsy pulses.

[0014] In some aspects, the method includes synchronizing the therapy transducer array with the ultrasound imaging array.

[0015] In other aspects, the method includes displaying the combined image of the focal zone region.

[0016] In some aspects, the method includes overlaying the combined image of the focal zone region over one or more ultrasound images of the tissue.

[0017] In other aspects, the method includes colorizing the combined image.

[0018] A histotripsy system is provided, comprising: a therapy transducer array configured to transmit histotripsy pulses; an ultrasound imaging array configured to receive echoes from the histotripsy pulses; at least one processor operatively coupled to the therapy transducer array and the ultrasound imaging array, the at least one processor being configured to: control one or more transducer elements of the therapy transducer array to transmit one or more histotripsy pulses into a focal zone region within a target tissue, the one or more histotripsy pulses being below a cavitation threshold such that no cavitation is formed at the focal zone region of the therapy transducer array; synchronize the ultrasound imaging array to receive echoes from the target tissue with one or more receive transducer elements of the - 3 -SG Docket No. 10860-535.600ultrasound imaging array; beamform the echoes to form one or more raw ultrasound images of the focal zone region for each of the plurality of the receive transducer elements; sum the one or more raw ultrasound images to generate a combined image of the focal zone region; and display the combined image on a display.

[0019] In some aspects, the combined image is directly registered with the ultrasound imaging array.

[0020] In other aspects, the one or more histotripsy pulses have a frequency below IMhz.

[0021] In some aspects, the at least one processor controls only a subset of the transducer elements of the therapy transducer array transmit the one or more histotripsy pulses.

[0022] In other aspects, the at least one processor is configured to overlay the combined image of the focal zone region over one or more ultrasound images of the tissue.

[0023] In some aspects, the at least one processor is configured to colorize the focal zone region in the combined image.

[0024] A histotripsy method is provided , comprising: transmitting histotripsy pulses from a therapy transducer array into tissue, the histotripsy pulses being below a cavitation threshold such that no cavitation is formed at a focal zone region of the therapy transducer array; transmitting ultrasound imaging pulses from an imaging transducer array into tissue; receiving first echoes of the histotripsy pulses and the ultrasound imaging pulses with a plurality of receive transducer elements of an ultrasound imaging array separate from the therapy transducer array; beamforming the first echoes to form one or more first ultrasound images of the focal zone region; transmitting histotripsy pulses from a therapy transducer array into tissue, the histotripsy pulses being below the cavitation threshold such that no cavitation is formed at the focal zone region; receiving second echoes of the histotripsy pulses with the plurality of receive transducer elements; beamforming the second echoes to form one or more second ultrasound images of the focal zone region; transmitting ultrasound imaging pulses from the imaging transducer array into tissue; receiving third echoes of the ultrasound imaging pulses with the plurality of receive transducer elements; beamforming the third echoes to form one or more third ultrasound images of the focal zone region; subtracting the second and third ultrasound images from the first ultrasound images to isolate a phase shift component from the first, second, and third echoes; and forming a combined image of the focal zone region with the phase shift component.

[0025] In some aspects, the combined image is directly registered with the ultrasound imaging array.

[0026] In other aspects, the one or more histotripsy pulses have a frequency below IMhz.- 4 -SG Docket No. 10860-535.600

[0027] In some aspects, only a subset of the transducer elements of the therapy transducer array transmit the one or more histotripsy pulses.

[0028] In some aspects, the method includes synchronizing the therapy transducer array with the ultrasound imaging array.

[0029] In other aspects, the method includes displaying the combined image of the focal zone region.

[0030] In one aspect, the method includes overlaying the combined image of the focal zone region over one or more ultrasound images of the tissue.

[0031] In another aspect, the method includes colorizing the combined image.

[0032] A histotripsy system is provided, comprising: a therapy transducer array configured to transmit histotripsy pulses; an ultrasound imaging array configured to transmit ultrasound pulses and receive echoes from the histotripsy pulses and / or ultrasound pulses; at least one processor operatively coupled to the therapy transducer array and the ultrasound imaging array, the at least one processor being configured to: control the therapy transducer array to transmit histotripsy pulses into a focal zone region within a target tissue, the histotripsy pulses being below a cavitation threshold such that no cavitation is formed at the focal zone region of the therapy transducer array; control the ultrasound imaging array to transmit imaging pulses into the target tissue; synchronize the ultrasound imaging array to receive first echoes of the histotripsy pulses and the imaging pulses from the target tissue; beamform the first echoes to form first ultrasound images of the focal zone region; control the therapy transducer array to transmit histotripsy pulses into the focal zone region within the target tissue, the histotripsy pulses being below the cavitation threshold such that no cavitation is formed at the focal zone region; synchronize the ultrasound imaging array to receive second echoes of the histotripsy pulses from the target tissue; beamform the second echoes to form one or more second ultrasound images of the focal zone region; control the ultrasound imaging array to transmit imaging pulses into the target tissue; synchronize the ultrasound imaging array to receive third echoes of the imaging pulses from the target tissue; beamform the third echoes to form one or more third ultrasound images of the focal zone region; subtract the second and third ultrasound images from the first ultrasound images to isolate a phase shift component from the first, second, and third echoes; form a combined image of the focal zone region with the phase shift component; and display the combined image.

[0033] In some aspects, the combined image is directly registered with the ultrasound imaging array.

[0034] In one aspect, the one or more histotripsy pulses have a frequency below IMhz.- 5 -SG Docket No. 10860-535.600

[0035] In other aspects, the at least one processor controls only a subset of the transducer elements of the therapy transducer array transmit the one or more histotripsy pulses.

[0036] In one aspect, the at least one processor is configured to overlay the combined image of the focal zone region over one or more ultrasound images of the tissue.

[0037] In additional aspects, the at least one processor is configured to colorize the focal zone region in the combined image.BRIEF DESCRIPTION OF THE DRAWINGS

[0038] The novel features of the invention are set forth with particularity in the claims that follow. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0039] FIGS. 1 A-1B illustrate an ultrasound imaging and therapy system.

[0040] FIGS. 2A-2C illustrate techniques for imaging a focus of a histotripsy therapy transducer without generating cavitation.

[0041] FIG. 3 is a flowchart describing a method of imaging a focal zone of an ultrasound therapy transducer array.

[0042] FIGS. 4A-4B show a flowchart describing another method of imaging a focal zone of an ultrasound therapy transducer array.DETAILED DESCRIPTION

[0043] Provided herein are systems and methods that provide efficacious non-invasive and minimally invasive therapeutic, diagnostic and research procedures. In particular, provided herein are optimized systems and methods that provide targeted, efficacious histotripsy in a variety of different regions and under a variety of different conditions without causing undesired tissue damage to intervening / non-target tissues or structures.

[0044] Balancing desired tissue destruction in target regions with the avoidance of damage to non-target regions presents a technical challenge. This is particularly the case where time efficient procedures are desired. Conditions that provide fast, efficacious tissue destruction tend to cause undue heating in non-target tissues. Undue heating can be avoided by reducing energy or slower delivery of energy, both of which run contrary to the goals of providing a fast and efficacious destruction of target tissue. Provided herein are a number of technologies that individually and collectively allow for fast, efficacious target treatment without undesired damage to non-target regions.- 6 -SG Docket No. 10860-535.600

[0045] The system, methods and devices of the disclosure may be used for the minimally or non-invasive acoustic cavitation and treatment of healthy, diseased and / or injured tissue, including in extracorporeal, percutaneous, endoscopic, laparoscopic, and / or as integrated into a robotically-enabled medical system and procedures. As will be described below, the histotripsy system may include various electrical, mechanical and software sub-systems, including a Cart, Therapy, Integrated Imaging, Robotics, Coupling and Software. The system also may comprise various Other Components, Ancillaries and Accessories, including but not limited to patient surfaces, tables or beds, computers, cables and connectors, networking devices, power supplies, displays, drawers / storage, doors, wheels, illumination and lighting and various simulation and training tools, etc. All systems, methods and means creating / controlling / delivering histotripsy are considered to be a part of this disclosure, including new related inventions disclosed herein.

[0046] In one embodiment, the histotripsy system is configured as a mobile therapy cart, which further includes a touchscreen display with an integrated control panel with a set of physical controls, a robotic arm, a therapy head positioned on the distal end of the robot, a patient coupling system and software to operate and control the system.

[0047] The mobile therapy cart architecture can comprise internal components, housed in a standard rack mount frame, including a histotripsy therapy generator, high voltage power supply, transformer, power distribution, robot controller, computer, router and modem, and an ultrasound imaging engine. The front system interface panel can comprise input / output locations for connectors, including those specifically for two ultrasound imaging probes (handheld and probe coaxially mounted in the therapy transducer), a histotripsy therapy transducer, AC power and circuit breaker switches, network connections and a foot pedal. The rear panel of the cart can comprise air inlet vents to direct airflow to air exhaust vents located in the side, top and bottom panels. The side panels of the cart include a holster and support mechanism for holding the handheld imaging probe. The base of the cart can be comprised of a cast base interfacing with the rack mounted electronics and providing an interface to the side panels and top cover. The base also includes four recessed casters with a single total locking mechanism. The top cover of the therapy cart can comprise the robot arm base and interface, and a circumferential handle that follows the contour of the cart body. The cart can have inner mounting features that allow technician access to cart components through access panels.

[0048] The touchscreen display and control panel may include user input features including physical controls in the form of six dials, a space mouse and touchpad, an indicator light bar, and an emergency stop, together configured to control imaging and therapy- 7 -SG Docket No. 10860-535.600parameters, and the robot. The touchscreen support arm is configured to allow standing and seated positions, and adjustment of the touchscreen orientation and viewing angle. The support arm further can comprise a system level power button and USB and ethemet connectors.

[0049] The robotic arm can be mounted to the mobile therapy cart on arm base of sufficient height to allow reach and ease of use positioning the arm in various drive modes into the patient / procedure work space from set up, through the procedure, and take down. The robotic arm can comprise six degrees of freedom with six rotating joints, a reach of 850 mm and a maximum payload of 5 kg. The arm may be controlled through the histotripsy system software as well as a 12 inch touchscreen polyscope with a graphical user interface. The robot can comprise force sensing and a tool flange, with force (x, y, z) with a range of 50N, precision of 3.5 N and accuracy of 4.0 N, and torque (x, y, z) with a range of 10.0 Nm, precision of 0.2 Nm and accuracy of 0.3 Nm. The robot has a pose repeatability of + / -O.03mm and a typical TCP speed of 1 m / s (39.4 in / s). In one embodiment, the robot control box has multiple I / O ports, including 16 digital in, 16 digital out, 2 analog in, 2 analog out and 4 quadrature digital inputs, and an I / O power supply of 24V / 2A. The control box communication comprises 500 Hz control frequency, Modbus TCP, PROFINET, ethemet / IP and USB 2.0 and 3.0.

[0050] The therapy head can comprise one of a select group of four histotripsy therapy transducers and an ultrasound imaging system / probe, coaxially located in the therapy transducer, with an encoded mechanism to rotate said imaging probe independent of the therapy transducer to known positions, and a handle to allow gross and fine positioning of the therapy head, including user inputs for activating the robot (e.g. for free drive positioning). In some examples, the therapy transducers may vary in size (22 x 17 cm to 28 x 17 cm), focal lengths from 12 - 18 cm, number of elements, ranging from 48 to 64 elements, comprised within 12-16 rings, and all with a frequency of 700 kHz. The therapy head subsystem has an interface to the robotic arm includes a quick release mechanism to allow removing and / or changing the therapy head to allow cleaning, replacement and / or selection of an alternative therapy transducer design (e.g., of different number of elements and geometry), and each therapy transducer is electronically keyed for auto-identification in the system software.

[0051] The patient coupling system can comprise a six degree of freedom, six joint, mechanical arm, configured with a mounting bracket designed to interface to a surgical / interventional table rail. The arm may have a maximum reach of approximately 850 mm and an average diameter of 50 mm. The distal end of the arm can be configured to interface with an ultrasound medium container, including a frame system and an upper and - 8 -SG Docket No. 10860-535.600lower boot. The lower boot is configured to support either a patient contacting film, sealed to patient, or an elastic polymer membrane, both designed to contain ultrasound medium (e.g., degassed water or water mixture), either within the frame and boot and in direct contact with the patient, or within the membrane / boot construct. The lower boot provides, in one example, a top and bottom window of approximately 46 cm x 56 cm and 26 cm x 20 cm, respectively, for placing the therapy transducer with the ultrasound medium container and localized on the patient’s abdomen. The upper boot may be configured to allow the distal end of the robot to interface to the therapy head and / or transducer, and to prevent water leakage / spillage. In preferred embodiments, the upper boot is a sealed system. The frame is also configured, in a sealed system, to allow two-way fluid communication between the ultrasound medium container and an ultrasound medium source (e.g., reservoir or fluidics management system), including, but not limited for filling and draining, as well as air venting for bubble management.

[0052] The system software and work-flow can be configured to allow users to control the system through touchscreen display and the physical controls, including but not limited to, ultrasound imaging parameters and therapy parameters. The graphical user interface of the system comprises a work-flow based flow, with the general procedure steps of 1) registering / selecting a patient, 2) planning, comprising imaging the patient (and target location / anatomy) with the freehand imaging probe, and robot assisted imaging with the transducer head for final gross and fine targeting, including contouring the target with a target and margin contour, of which are typically spherical and ellipsoidal in nature, and running a test protocol (e.g., test pulses) including a bubble cloud calibration step, and a series of predetermined locations in the volume to assess cavitation initiation threshold and other patient / target specific parameters (e.g., treatment depth), that together inform a treatment plan accounting for said target’s location and acoustic pathway, and any related blockage (e.g., tissue interfaces, bone, etc.) that may require varied levels of drive amplitude to initiate and maintain histotripsy. Said parameters, as measured as a part of the test protocol, comprising calibration and multi -location test pulses, are configured in the system to provide input / feedback for updating bubble cloud location in space as needed / desired (e.g., appropriately calibrated to target cross-hairs), as well as determining / interpolating required amplitudes across all bubble cloud treatment locations in the treatment volume to ensure threshold is achieved throughout the volume. Further, said parameters, including but not limited to depth and drive voltage, may be also used as part of an embedded treatability matrix or look up table to determine if additional cooling is required (e.g., off-time in addition to time allocated to robot motions between treatment pattern movements) to ensure- 9 -SG Docket No. 10860-535.600robust cavitation and intervening / collateral thermal effects are managed (e.g., staying below t43 curve for any known or calculated combination of sequence, pattern and pathway, and target depth / blockage). The work-flow and procedure steps associated with these facets of planning, as implemented in the system software may be automated, wherein the robot and controls system are configured to run through the test protocol and locations autonomously, or semi -autonomously. Following planning, the next phase of the procedure work-flow, 3) the treatment phase, is initiated following the user accepting the treatment plan and initiating the system for treatment. Following this command, the system is configured to deliver treatment autonomously, running the treatment protocol, until the prescribed volumetric treatment is complete. The status of the treatment (and location of the bubble cloud) is displayed in real-time, adjacent to various treatment parameters, including, but not limited to, of which may include total treatment time and remaining treatment time, drive voltage, treatment contours (target / margin) and bubble cloud / point locations, current location in treatment pattern (e.g., slice and column), imaging parameters, and other additional contextual data (e.g., optional DICOM data, force torque data from robot, etc.). Following treatment, the user may use the therapy head probe, and subsequently, the freehand ultrasound probe to review and verify treatment, as controlled / viewed through the system user interface. If additional target locations are desired, the user may plan / treat additional targets, or dock the robot to a home position on the cart if no further treatments are planned.

[0053] FIG. 1 A generally illustrates histotripsy system 100 according to the present disclosure, comprising a therapy transducer 102, an imaging system 104, a display and control panel 106, a robotic positioning arm 108, and a cart 110. The system can further include an ultrasound coupling interface and a source of coupling medium, not shown.

[0054] FIG. IB is a bottom view of the therapy transducer 102 and the imaging system 104. As shown, the imaging system can be positioned in the center of the therapy transducer. However, other embodiments can include the imaging system positioned in other locations within the therapy transducer, or even directly integrated into the therapy transducer. In some embodiments, the imaging system is configured to produce real-time imaging at a focal point of the therapy transducer.

[0055] The histotripsy system may comprise one or more of various sub-systems, including a Therapy sub-system that can create, apply, focus and deliver acoustic cavitation / histotripsy through one or more therapy transducers, Integrated Imaging subsystem (or connectivity to) allowing real-time visualization of the treatment site and histotripsy effect through-out the procedure, a Robotics positioning sub-system to mechanically and / or electronically steer the therapy transducer, further enabled to- 10 -SG Docket No. 10860-535.600connect / support or interact with a Coupling sub-system to allow acoustic coupling between the therapy transducer and the patient, and Software to communicate, control and interface with the system and computer-based control systems (and other external systems) and various Other Components, Ancillaries and Accessories, including one or more user interfaces and displays, and related guided work-flows, all working in part or together. The system may further comprise various fluidics and fluid management components, including but not limited to, pumps, valve and flow controls, temperature and degassing controls, and irrigation and aspiration capabilities, as well as providing and storing fluids. It may also contain various power supplies and protectors.CART

[0056] The Cart 110 may be generally configured in a variety of ways and form factors based on the specific uses and procedures. In some cases, systems may comprise multiple Carts, configured with similar or different arrangements. In some embodiments, the cart may be configured and arranged to be used in a radiology environment and in some cases in concert with imaging (e.g., CT, cone beam CT and / or MRI scanning). In other embodiments, it may be arranged for use in an operating room and a sterile environment, or in a robotically enabled operating room, and used alone, or as part of a surgical robotics procedure wherein a surgical robot conducts specific tasks before, during or after use of the system and delivery of acoustic cavitation / histotripsy. As such and depending on the procedure environment based on the aforementioned embodiments, the cart may be positioned to provide sufficient workspace and access to various anatomical locations on the patient (e.g., torso, abdomen, flank, head and neck, etc.), as well as providing work-space for other systems (e.g., anesthesia cart, laparoscopic tower, surgical robot, endoscope tower, etc.).

[0057] The Cart may also work with a patient surface (e.g., table or bed) to allow the patient to be presented and repositioned in a plethora of positions, angles and orientations, including allowing changes to such to be made pre, peri and post-procedurally. It may further comprise the ability to interface and communicate with one or more external imaging or image data management and communication systems, not limited to ultrasound, CT, fluoroscopy, cone beam CT, PET, PET / CT, MRI, optical, ultrasound, and image fusion and or image flow, of one or more modalities, to support the procedures and / or environments of use, including physical / mechanical interoperability (e.g., compatible within cone beam CT work-space for collecting imaging data pre-, peri- and / or post-histotripsy).

[0058] In some embodiments one or more Carts may be configured to work together. As an example, one Cart may comprise a bedside mobile Cart equipped with one or more Robotic arms enabled with a Therapy transducer, and Therapy generator / amplifier, etc., while- 11 -SG Docket No. 10860-535.600a companion cart working in concert and at a distance of the patient may comprise Integrated Imaging and a console / display for controlling the Robotic and Therapy facets, analogous to a surgical robot and master / slave configurations.

[0059] In some embodiments, the system may comprise a plurality of Carts, all slave to one master Cart, equipped to conduct acoustic cavitation procedures. In some arrangements and cases, one Cart configuration may allow for storage of specific sub-systems at a distance reducing operating room clutter, while another in concert Cart may comprise essentially bedside sub-systems and componentry (e.g., delivery system and therapy).

[0060] One can envision a plethora of permutations and configurations of Cart design, and these examples are in no way limiting the scope of the disclosure.HISTOTRIPSY

[0061] Histotripsy comprises short, high amplitude, focused ultrasound pulses to generate a dense, energetic, “bubble cloud”, capable of the targeted fractionation and destruction of tissue. Histotripsy is capable of creating controlled tissue erosion when directed at a tissue interface, including tissue / fluid interfaces, as well as well-demarcated tissue fractionation and destruction, at sub-cellular levels, when it is targeted at bulk tissue. Unlike other forms of ablation, including thermal and radiation-based modalities, histotripsy does not rely on heat or ionizing (high) energy to treat tissue. Instead, histotripsy uses acoustic cavitation generated at the focus to mechanically effect tissue structure, and in some cases liquefy, suspend, solubilize and / or destruct tissue into sub-cellular components.

[0062] Histotripsy can be applied in various forms, including: 1) Intrinsic-Threshold Histotripsy: Delivers pulses with at least a single negative / tensile phase sufficient to cause a cluster of bubble nuclei intrinsic to the medium to undergo inertial cavitation, 2) Shock- Scattering Histotripsy: Delivers typically pulses 3-20 cycles in duration. The amplitude of the tensile phases of the pulses is sufficient to cause bubble nuclei in the medium to undergo inertial cavitation within the focal zone throughout the duration of the pulse. These nuclei scatter the incident shockwaves, which invert and constructively interfere with the incident wave to exceed the threshold for intrinsic nucleation, and 3) Boiling Histotripsy: Employs pulses roughly 1-20 ms in duration. Absorption of the shocked pulse rapidly heats the medium, thereby reducing the threshold for intrinsic nuclei. Once this intrinsic threshold coincides with the peak negative pressure of the incident wave, boiling bubbles form at the focus.

[0063] The large pressure generated at the focus causes a cloud of acoustic cavitation bubbles to form above certain thresholds, which creates localized stress and strain in the tissue and mechanical breakdown without significant heat deposition. At pressure levels- 12 -SG Docket No. 10860-535.600where cavitation is not generated, minimal effect is observed on the tissue at the focus. This cavitation effect is observed only at pressure levels significantly greater than those which define the inertial cavitation threshold in water for similar pulse durations, on the order of 10 to 30 MPa peak negative pressure.

[0064] Histotripsy may be performed in multiple ways and under different parameters. It may be performed totally non-invasively by acoustically coupling a focused ultrasound transducer over the skin of a patient and transmitting acoustic pulses transcutaneously through overlying (and intervening) tissue to the focal zone (treatment zone and site). It may be further targeted, planned, directed and observed under direct visualization, via ultrasound imaging, given the bubble clouds generated by histotripsy may be visible as highly dynamic, echogenic regions on, for example, B Mode ultrasound images, allowing continuous visualization through its use (and related procedures). Likewise, the treated and fractionated tissue shows a dynamic change in echogenicity (typically a reduction), which can be used to evaluate, plan, observe and monitor treatment.

[0065] Generally, in histotripsy treatments, ultrasound pulses with 3 or more acoustic cycles are applied, and the bubble cloud formation relies on the pressure release scattering of the positive shock fronts (sometimes exceeding 100 MPa, P+) from initially initiated, sparsely distributed bubbles (or a single bubble). This is referred to as the “shock scattering mechanism”.

[0066] This mechanism depends on one (or a few sparsely distributed) bubble(s) initiated with the initial negative half cycle(s) of the pulse at the focus of the transducer. A cloud of microbubbles then forms due to the pressure release backscattering of the high peak positive shock fronts from these sparsely initiated bubbles. These back-scattered high-amplitude rarefactional waves exceed the intrinsic threshold thus producing a localized dense bubble cloud. Each of the following acoustic cycles then induces further cavitation by the backscattering from the bubble cloud surface, which grows towards the transducer. As a result, an elongated dense bubble cloud growing along the acoustic axis opposite the ultrasound propagation direction is observed with the shock scattering mechanism. This shock scattering process makes the bubble cloud generation not only dependent on the peak negative pressure, but also the number of acoustic cycles and the amplitudes of the positive shocks. Without at least one intense shock front developed by nonlinear propagation, no dense bubble clouds are generated when the peak negative half-cycles are below the intrinsic threshold.

[0067] When ultrasound pulses less than 2 cycles are applied, shock scattering can be minimized, and the generation of a dense bubble cloud depends on the negative half cycle(s)- 13 -SG Docket No. 10860-535.600of the applied ultrasound pulses exceeding an “intrinsic threshold” of the medium. This is referred to as the “intrinsic threshold mechanism”.

[0068] This threshold can be in the range of 26 - 30 MPa for soft tissues with high water content, such as tissues in the human body. In some embodiments, using this intrinsic threshold mechanism, the spatial extent of the lesion may be well-defined and more predictable. With peak negative pressures (P-) not significantly higher than this threshold, sub -wavelength reproducible lesions as small as half of the -6dB beam width of a transducer may be generated.

[0069] With high-frequency Histotripsy pulses, the size of the smallest reproducible lesion becomes smaller, which is beneficial in applications that require precise lesion generation. However, high-frequency pulses are more susceptible to attenuation and aberration, rendering problematical treatments at a larger penetration depth (e.g., ablation deep in the body) or through a highly aberrative medium (e.g., transcranial procedures, or procedures in which the pulses are transmitted through bone(s)). Histotripsy may further also be applied as a low-frequency “pump” pulse (typically < 2 cycles and having a frequency between 100 kHz and 1 MHz) can be applied together with a high-frequency “probe” pulse (typically < 2 cycles and having a frequency greater than 2 MHz, or ranging between 2 MHz and 10 MHz) wherein the peak negative pressures of the low and high-frequency pulses constructively interfere to exceed the intrinsic threshold in the target tissue or medium. The low-frequency pulse, which is more resistant to attenuation and aberration, can raise the peak negative pressure P- level for a region of interest (ROI), while the high-frequency pulse, which provides more precision, can pinpoint a targeted location within the ROI and raise the peak negative pressure P- above the intrinsic threshold. This approach may be referred to as “dual frequency”, “dual beam histotripsy” or “parametric histotripsy.”

[0070] Additional systems, methods and parameters to deliver optimized histotripsy, using shock scattering, intrinsic threshold, and various parameters enabling frequency compounding and bubble manipulation, are herein included as part of the system and methods disclosed herein, including additional means of controlling said histotripsy effect as pertains to steering and positioning the focus, and concurrently managing tissue effects (e.g., prefocal thermal collateral damage) at the treatment site or within intervening tissue. Further, it is disclosed that the various systems and methods, which may include a plurality of parameters, such as but not limited to, frequency, operating frequency, center frequency, pulse repetition frequency, pulses, bursts, number of pulses, cycles, length of pulses, amplitude of pulses, pulse period, delays, burst repetition frequency, sets of the former, loops of multiple sets, loops of multiple and / or different sets, sets of loops, and various- 14 -SG Docket No. 10860-535.600combinations or permutations of, etc., are included as a part of this disclosure, including future envisioned embodiments of such.DIRECT VISUALIZATION OF A HISTOTRIPSY FOCUS WITHOUT CAVITATION

[0071] This disclosure provides novel systems and methods for directly imaging a histotripsy transducer array focal zone without cavitation. The imaged focus can be coregistered with the target tissue in situ at a safe amplitude below the cavitation threshold prior to the start of treatment. This can be referred to herein as Histotripsy Focus Imaging (HFI).

[0072] In brief, the histotripsy therapy array transducer elements of the therapy transducer (e.g., therapy transducer 102 in FIG. IB) are excited and synchronized with the ultrasound imager (e.g., ultrasound imaging system 104) via one or more processors of the histotripsy system. The imager can be set to receive-only with transmit power set to zero, such that the imager receives echo data but does not transmit ultrasound pulses. Therefore, the ultrasound signals are transmitted with the therapy transducer 102 and received with the imaging system 104. As described herein, the transmitted pulses can be histotripsy pulses, with a frequency below 1MHz. The transmitted signals from the therapy transducer are configured to not generate cavitation in tissue. In some examples, transducer elements of the therapy transducer are excited individually, so as to not generate cavitation. Generally, some subset of the transducer array is excited, but not every element of the transducer array. For example, transducer elements can be excited individually, or in groups of transducer elements. However, the number of elements excited is limited so as to ensure that cavitation is not generated. By exciting the therapy array elements individually or in small groups, the actual focal amplitude is always kept well below the cavitation threshold while the summed amplitude is in the therapeutic range. Therefore, the transmitted pulses are below a cavitation threshold in the tissue.

[0073] The imager can then use the received echo data to form raw RF images. For example, the processors of the histotripsy system can use the received echo data from the transmitted pulses and beamform the data to form raw RF images. The raw RF images from individual imaging probe element excitations can be summed with the processors to generate one or more images of the focal zone region directly registered with B-mode images of the tissue. Non-linear acoustic propagation from the elements provides a robust tissue echo within the bandwidth of the imager whereas the fundamental therapeutic frequency would generally be too low. For example, histotripsy ultrasound transducer typically uses a frequency below 1MHz (e.g., 750kHz) while ultrasound imaging typically uses much higher frequency (>3MHz), but the higher harmonics frequency of the histotripsy ultrasound pulses (3MHz at 4th harmonics of 750kHz) can be received by the ultrasound imaging probe.- 15 -SG Docket No. 10860-535.600

[0074] The HFI techniques described herein provide a direct visualization of the histotripsy focus that can be overlayed on tissue images, without generating cavitation. 2) HFI takes into account the non-linear propagation and aberration, and is thus more accurate than the stereotactic focus estimation. 3) HFI can be used to quickly and safely identify obstructed therapy array elements as they will produce no coherent echoes within the focal region, such as the elements blocked by ribs, lung, and bowel. These elements can then be deactivated during treatment reducing potential for injury to these overlying obstructions. 4) HFI is formed from a single transmit pulse and data captured over <300ps, effectively “freezing” any tissue motion to a single instant in time. 5) HFI can be used for aberration correction without generating cavitation, by iterating different correction delay time sets to maximize the focal imaging intensity.

[0075] Preliminary Data. An example of HFI when targeting a piece of liver with an in vitro setup is shown in FIGS. 2A-2C. FIG. 2A shows a standard ultrasound tissue image. FIG. 2B shows the same tissue image with a color overlay of the HFI result using the signal processing steps described above on a single 4 MPa amplitude therapy transducer pulse transmitted from the top of the page. A bright zone 212 approximately the expected size of the focal region of the therapy transducer (-1x3 A) is observed along with a characteristic hourglass shape for a focused acoustic field in the pre-focal 214 and post-focal 216 regions. Artifacts from bright, specular reflections in the tissue are not evident with only some excess noise appearing at the bottom of the image.

[0076] The HFI prediction matches well with the subsequent histotripsy cavitation cloud 218 appearing in FIG. 2C indicated by an annotated arrow using a peak negative pressure of 40 MPa at a 30 Hz rate. For this case, the error was 0.1 mm lateral and 2.3 mm pre-focal comparing the centroids of the cavitation cloud and HFI prediction. Experiments using high speed optical imaging have often shown a small (one wavelength) pre-focal bias due to shock-scattering when comparing histotripsy cavitation cloud locations in water to acoustic field measurements. For the histotripsy system used in these studies, this distance is 2 mm closely matching the value observed.

[0077] FIG. 3 is a flowchart 300 describing a method of imaging a therapy transducer focal zone within a target tissue. At step 302 of flowchart 300, the method can include transmitting one or more histotripsy pulses from a therapy transducer array into a target tissue without generating cavitation in the target tissue. The histotripsy pulses can have a frequency below 1MHz, for example. In some aspects, the histotripsy pulses are transmitted from individual transducer elements, or from groups of transducer elements or a subset of the- 16 -SG Docket No. 10860-535.600transducer array. By not transmitting pulses from all transducer elements, the pulses will not have sufficient peak negative pressure to generate cavitation in the tissue.

[0078] At step 304 of flowchart 300, the method can include receiving echoes of the one or more histotripsy pulses with an imaging transducer array. As described above, the imaging transducer array is separate from or discrete from the therapy transducer array. The imaging transducer array can be synchronized with the therapy transducer array, such as with one or more processors or controllers of the histotripsy system.

[0079] At step 306 of flowchart 300, the method can include beamforming the echoes to form raw RF images of the target tissue, including the focal zone region of the therapy transducer array. In some aspects, multiple images can be generated, such as images generated from transmissions from individual elements or groups of elements. The images can be summed together to form higher resolution images of the target tissue including the focal zone region.

[0080] When a histotripsy therapy transducer is used, the HFI technique can suffer from low spatial resolution of the focal region because of the low frequency of histotripsy therapy (typically using a frequency below 1MHz) and patchy heterogeneous visualization due to specular reflections in tissue.

[0081] To improve resolution and imaging quality with the HFI technique, additional steps can be taken to “sensitize” an ultrasound image to the presence of the therapeutic ultrasound field. Acoustic propagation through water and tissue is nonlinear with the speed of sound increasing with pressure. When an imaging pulse overlaps with the positive phase of a synchronized therapy field, the local speed of sound is increased slightly (a nonlinear effect of the medium). Compared to the scenario of no therapy field or an overlap with a negative phase, the positive overlapped imaging pulse accumulates a slight phase shift. The effect is very strongly dependent on the amplitude of the therapy field and thus shows the strongest contrast right at the focal region. Using three acquisitions is the most practical way to extract this phase shift and create a higher resolution, higher quality image of the therapy focus.

[0082] Accordingly, in one aspect, three imaging acquisitions are made during a HFI procedure to obtain an image of a focal zone region. A first image acquisition is made with both the therapy transducer array and the imager transmitting ultrasound pulses into the focal zone region. Echoes are received by the imager and beamformed to form the first image. A second image acquisition is made with only the therapy transducer array transmitting ultrasound pulses into the focal zone region and the imager receiving echoes from those transmissions. The echoes are beamformed to form the second image. A third image acquisition is made with only the imager transmitting and receiving ultrasound echoes (e.g.,- 17 -SG Docket No. 10860-535.600with the therapy transducer array turned off or not transmitting). The echoes are beamformed to form the third image. The technique can then include subtracting the second and third image acquisitions / images from the first image acquisition / image, leaving only the phase shift (nonlinear) component. The subtraction can be performed on either the raw imager channel data or beamformed RF data (prior to demodulation). This method is effective for visualizing the focus even when the background tissue target region is heterogeneous.

[0083] As described above, the combined subtraction image leaves just an image of the focal region. Because this subtracted image is constructed from a regular ultrasound image (from the imager), the subtracted image is automatically registered to the ultrasound images of the target tissue. This subtracted image can be color coded and overlaid on top of ultrasound images of the target tissue region, thereby providing real-time imaging of the therapy transducer focal region within the target tissue.

[0084] FIGS. 4A-4B is a flowchart 400 describing another method of imaging a focal zone of an ultrasound therapy transducer array. At step 402 of flowchart 400, the method can include transmitting one or more histotripsy pulses from a therapy transducer array and one or more imaging pulses from an imaging transducer array into a target tissue without generating cavitation in the target tissue. The histotripsy pulses can have a frequency below 1MHz, for example. The imaging pulses can be, for example, B-mode ultrasound imaging pulses. In some aspects, the histotripsy pulses are transmitted from individual transducer elements, or from groups of transducer elements or a subset of the transducer array. By not transmitting pulses from all transducer elements, the pulses will not have sufficient peak negative pressure to generate cavitation in the tissue.

[0085] At step 404 of flowchart 400, the method can include receiving echoes of the one or more histotripsy pulses and the one or more imaging pulses with an imaging transducer array. As described above, the imaging transducer array is separate from or discrete from the therapy transducer array. The imaging transducer array can be synchronized with the therapy transducer array, such as with one or more processors or controllers of the histotripsy system.

[0086] At step 406 of flowchart 400, the method can include beamforming the echoes to form one or more first images of the target tissue, including the focal zone region of the therapy transducer array. In some aspects, multiple images can be generated, such as images generated from transmissions from individual elements or groups of elements. The first images can be summed together to form higher resolution images of the target tissue including the focal zone region.

[0087] At step 408 of flowchart 400, the method can include transmitting one or more histotripsy pulses from a therapy transducer array into a target tissue without generating- 18 -SG Docket No. 10860-535.600cavitation in the target tissue. The histotripsy pulses can have a frequency below 1MHz, for example. In some aspects, the histotripsy pulses are transmitted from individual transducer elements, or from groups of transducer elements or a subset of the transducer array. By not transmitting pulses from all transducer elements, the pulses will not have sufficient peak negative pressure to generate cavitation in the tissue.

[0088] At step 410 of flowchart 400, the method can include receiving echoes of the one or more histotripsy pulses with an imaging transducer array. As described above, the imaging transducer array is separate from or discrete from the therapy transducer array. The imaging transducer array can be synchronized with the therapy transducer array, such as with one or more processors or controllers of the histotripsy system.

[0089] At step 412 of flowchart 400, the method can include beamforming the echoes to form one or more second images of the target tissue, including the focal zone region of the therapy transducer array. In some aspects, multiple images can be generated, such as images generated from transmissions from individual elements or groups of elements. The second images can be summed together to form higher resolution images of the target tissue including the focal zone region.

[0090] Moving on to step 414 of flowchart 400 in FIG. 4B, the method can include transmitting one or more imaging pulses from an imaging transducer array into a target tissue. The imaging pulses can be, for example, B-mode ultrasound imaging pulses.

[0091] At step 416 of flowchart 400, the method can include receiving echoes of the one or more imaging pulses with an imaging transducer array.

[0092] At step 418 of flowchart 400, the method can include beamforming the echoes to form one or more third images of the target tissue. The third images can be summed together to form higher resolution images of the target tissue.

[0093] At steps 420 and 422 of flowchart 400, the method can include subtracting the second and third images from the first image to isolate a phase shift component from the echo data. This step can be performed, for example, by the one or more processors or controllers of the histotripsy system. The combined subtraction image leaves just an image of the focal region. Because this subtracted image is constructed from a regular ultrasound image (from the imager), the subtracted image is automatically registered to the ultrasound images of the target tissue. This subtracted image can be color coded and overlaid on top of ultrasound images of the target tissue region, thereby providing real-time imaging of the therapy transducer focal region within the target tissue.

[0094] When a feature or element is herein referred to as being “on” another feature or element, it can be directly on the other feature or element or intervening features and / or- 19 -SG Docket No. 10860-535.600elements may also be present. In contrast, when a feature or element is referred to as being “directly on” another feature or element, there are no intervening features or elements present. It will also be understood that, when a feature or element is referred to as being “connected”, “attached” or “coupled” to another feature or element, it can be directly connected, attached or coupled to the other feature or element or intervening features or elements may be present. In contrast, when a feature or element is referred to as being “directly connected”, “directly attached” or “directly coupled” to another feature or element, there are no intervening features or elements present. Although described or shown with respect to one embodiment, the features and elements so described or shown can apply to other embodiments. It will also be appreciated by those of skill in the art that references to a structure or feature that is disposed “adjacent” another feature may have portions that overlap or underlie the adjacent feature.

[0095] Terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. For example, as used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms “comprises” and / or “comprising,” when used in this specification, specify the presence of stated features, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, steps, operations, elements, components, and / or groups thereof. As used herein, the term “and / or” includes any and all combinations of one or more of the associated listed items and may be abbreviated as “ / ”.

[0096] Spatially relative terms, such as “under”, “below”, “lower”, “over”, “upper” and the like, may be used herein for ease of description to describe one element or feature’s relationship to another element(s) or feature(s) as illustrated in the figures. It will be understood that the spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if a device in the figures is inverted, elements described as “under” or “beneath” other elements or features would then be oriented “over” the other elements or features. Thus, the exemplary term “under” can encompass both an orientation of over and under. The device may be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly. Similarly, the terms “upwardly”, “downwardly”, “vertical”, “horizontal” and the like are used herein for the purpose of explanation only unless specifically indicated otherwise.

[0097] Although the terms “first” and “second” may be used herein to describe various features / elements (including steps), these features / elements should not be limited by these- 20 -SG Docket No. 10860-535.600terms, unless the context indicates otherwise. These terms may be used to distinguish one feature / element from another feature / element. Thus, a first feature / element discussed below could be termed a second feature / element, and similarly, a second feature / element discussed below could be termed a first feature / element without departing from the teachings of the present invention.

[0098] Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising” means various components can be co-jointly employed in the methods and articles (e.g., compositions and apparatuses including device and methods). For example, the term “comprising” will be understood to imply the inclusion of any stated elements or steps but not the exclusion of any other elements or steps.

[0099] As used herein in the specification and claims, including as used in the examples and unless otherwise expressly specified, all numbers may be read as if prefaced by the word “about” or “approximately,” even if the term does not expressly appear. The phrase “about” or “approximately” may be used when describing magnitude and / or position to indicate that the value and / or position described is within a reasonable expected range of values and / or positions. For example, a numeric value may have a value that is + / - 0.1% of the stated value (or range of values), + / - 1% of the stated value (or range of values), + / - 2% of the stated value (or range of values), + / - 5% of the stated value (or range of values), + / - 10% of the stated value (or range of values), etc. Any numerical values given herein should also be understood to include about or approximately that value, unless the context indicates otherwise. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Any numerical range recited herein is intended to include all sub-ranges subsumed therein. It is also understood that when a value is disclosed that “less than or equal to” the value, “greater than or equal to the value” and possible ranges between values are also disclosed, as appropriately understood by the skilled artisan. For example, if the value “X” is disclosed the “less than or equal to X” as well as “greater than or equal to X” (e.g., where X is a numerical value) is also disclosed. It is also understood that the throughout the application, data is provided in a number of different formats, and that this data, represents endpoints and starting points, and ranges for any combination of the data points. For example, if a particular data point “10” and a particular data point “15” are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.- 21 -SG Docket No. 10860-535.600

[0100] Although various illustrative embodiments are described above, any of a number of changes may be made to various embodiments without departing from the scope of the invention as described by the claims. For example, the order in which various described method steps are performed may often be changed in alternative embodiments, and in other alternative embodiments one or more method steps may be skipped altogether. Optional features of various device and system embodiments may be included in some embodiments and not in others. Therefore, the foregoing description is provided primarily for exemplary purposes and should not be interpreted to limit the scope of the invention as it is set forth in the claims.

[0101] The examples and illustrations included herein show, by way of illustration and not of limitation, specific embodiments in which the subject matter may be practiced. As mentioned, other embodiments may be utilized and derived there from, such that structural and logical substitutions and changes may be made without departing from the scope of this disclosure. Such embodiments of the inventive subject matter may be referred to herein individually or collectively by the term “invention” merely for convenience and without intending to voluntarily limit the scope of this application to any single invention or inventive concept, if more than one is, in fact, disclosed. Thus, although specific embodiments have been illustrated and described herein, any arrangement calculated to achieve the same purpose may be substituted for the specific embodiments shown. This disclosure is intended to cover any and all adaptations or variations of various embodiments. Combinations of the above embodiments, and other embodiments not specifically described herein, will be apparent to those of skill in the art upon reviewing the above description.- 22 -SG Docket No. 10860-535.600

Claims

CLAIMSWhat is claimed is:

1. A histotripsy method, comprising: transmitting one or more histotripsy pulses from at least one therapy transducer element of a therapy transducer array into tissue, the one or more histotripsy pulses being below a cavitation threshold such that no cavitation is formed at a focal zone region of the therapy transducer array; receiving echoes of the one or more histotripsy pulses with a plurality of receive transducer elements of an ultrasound imaging array separate from the therapy transducer array; beamforming the echoes to form one or more raw ultrasound images of the focal zone region of the therapy transducer array for each of the plurality of the receive transducer elements; and summing the one or more raw ultrasound images to generate a combined image of the focal zone region.

2. The method of claim 1, wherein the combined image is directly registered with the ultrasound imaging array.

3. The method of claim 1, wherein the one or more histotripsy pulses have a frequency below IMhz.

4. The method of claim 1, wherein only a subset of the transducer elements of the therapy transducer array transmit the one or more histotripsy pulses.

5. The method of claim 1, further comprising synchronizing the therapy transducer array with the ultrasound imaging array.

6. The method of claim 1, further comprising displaying the combined image of the focal zone region.

7. The method of claim 1, further comprising overlaying the combined image of the focal zone region over one or more ultrasound images of the tissue.- 23 -SG Docket No. 10860-535.6008. The method of claim 7, further comprising colorizing the combined image.

9. A histotripsy system, comprising: a therapy transducer array configured to transmit histotripsy pulses; an ultrasound imaging array configured to receive echoes from the histotripsy pulses; at least one processor operatively coupled to the therapy transducer array and the ultrasound imaging array, the at least one processor being configured to: control one or more transducer elements of the therapy transducer array to transmit one or more histotripsy pulses into a focal zone region within a target tissue, the one or more histotripsy pulses being below a cavitation threshold such that no cavitation is formed at the focal zone region of the therapy transducer array; synchronize the ultrasound imaging array to receive echoes from the target tissue with one or more receive transducer elements of the ultrasound imaging array; beamform the echoes to form one or more raw ultrasound images of the focal zone region for each of the plurality of the receive transducer elements; sum the one or more raw ultrasound images to generate a combined image of the focal zone region; and display the combined image on a display.

10. The system of claim 9, wherein the combined image is directly registered with the ultrasound imaging array.

11. The system of claim 9, wherein the one or more histotripsy pulses have a frequency below IMhz.

12. The system of claim 9, wherein the at least one processor controls only a subset of the transducer elements of the therapy transducer array transmit the one or more histotripsy pulses.

13. The system of claim 9, wherein the at least one processor is configured to overlay the combined image of the focal zone region over one or more ultrasound images of the tissue.

14. The system of claim 13, wherein the at least one processor is configured to colorize the focal zone region in the combined image.- 24 -SG Docket No. 10860-535.60015. A histotripsy method, comprising: transmitting histotripsy pulses from a therapy transducer array into tissue, the histotripsy pulses being below a cavitation threshold such that no cavitation is formed at a focal zone region of the therapy transducer array; transmitting ultrasound imaging pulses from an imaging transducer array into tissue; receiving first echoes of the histotripsy pulses and the ultrasound imaging pulses with a plurality of receive transducer elements of an ultrasound imaging array separate from the therapy transducer array; beamforming the first echoes to form one or more first ultrasound images of the focal zone region; transmitting histotripsy pulses from a therapy transducer array into tissue, the histotripsy pulses being below the cavitation threshold such that no cavitation is formed at the focal zone region; receiving second echoes of the histotripsy pulses with the plurality of receive transducer elements; beamforming the second echoes to form one or more second ultrasound images of the focal zone region; transmitting ultrasound imaging pulses from the imaging transducer array into tissue; receiving third echoes of the ultrasound imaging pulses with the plurality of receive transducer elements; beamforming the third echoes to form one or more third ultrasound images of the focal zone region; subtracting the second and third ultrasound images from the first ultrasound images to isolate a phase shift component from the first, second, and third echoes; and forming a combined image of the focal zone region with the phase shift component.

16. The method of claim 15, wherein the combined image is directly registered with the ultrasound imaging array.

17. The method of claim 15, wherein the one or more histotripsy pulses have a frequency below IMhz.

18. The method of claim 15, wherein only a subset of the transducer elements of the therapy transducer array transmit the one or more histotripsy pulses.- 25 -SG Docket No. 10860-535.60019. The method of claim 15, further comprising synchronizing the therapy transducer array with the ultrasound imaging array.

20. The method of claim 15, further comprising displaying the combined image of the focal zone region.

21. The method of claim 15, further comprising overlaying the combined image of the focal zone region over one or more ultrasound images of the tissue.

22. The method of claim 21, further comprising colorizing the combined image.

23. A histotripsy system, comprising: a therapy transducer array configured to transmit histotripsy pulses; an ultrasound imaging array configured to transmit ultrasound pulses and receive echoes from the histotripsy pulses and / or ultrasound pulses; at least one processor operatively coupled to the therapy transducer array and the ultrasound imaging array, the at least one processor being configured to: control the therapy transducer array to transmit histotripsy pulses into a focal zone region within a target tissue, the histotripsy pulses being below a cavitation threshold such that no cavitation is formed at the focal zone region of the therapy transducer array; control the ultrasound imaging array to transmit imaging pulses into the target tissue; synchronize the ultrasound imaging array to receive first echoes of the histotripsy pulses and the imaging pulses from the target tissue; beamform the first echoes to form first ultrasound images of the focal zone region; control the therapy transducer array to transmit histotripsy pulses into the focal zone region within the target tissue, the histotripsy pulses being below the cavitation threshold such that no cavitation is formed at the focal zone region; synchronize the ultrasound imaging array to receive second echoes of the histotripsy pulses from the target tissue; beamform the second echoes to form one or more second ultrasound images of the focal zone region; control the ultrasound imaging array to transmit imaging pulses into the target tissue; synchronize the ultrasound imaging array to receive third echoes of the imaging pulses from the target tissue;- 26 -SG Docket No. 10860-535.600beamform the third echoes to form one or more third ultrasound images of the focal zone region; subtract the second and third ultrasound images from the first ultrasound images to isolate a phase shift component from the first, second, and third echoes; form a combined image of the focal zone region with the phase shift component; and display the combined image.

24. The system of claim 23, wherein the combined image is directly registered with the ultrasound imaging array.

25. The system of claim 23, wherein the one or more histotripsy pulses have a frequency below IMhz.

26. The system of claim 23, wherein the at least one processor controls only a subset of the transducer elements of the therapy transducer array transmit the one or more histotripsy pulses.

27. The system of claim 23, wherein the at least one processor is configured to overlay the combined image of the focal zone region over one or more ultrasound images of the tissue.

28. The system of claim 27, wherein the at least one processor is configured to colorize the focal zone region in the combined image.- 27 -SG Docket No. 10860-535.600

Images