Histotripsy treatment monitoring through the ribs

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 TREATMENT MONITORING THROUGH THE RIBSPRIORITY CLAIM

[0001] This patent application claims priority to U.S. provisional patent application no. 63 / 660,903, titled “HISTOTRIPSY TREATMENT MONITORING THROUGH THE RIBS,” and filed on June 17, 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 EB032772 and 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 formation) within the focal volume. The vigorous expansion and collapse of these microbubbles mechanically homogenizes cells and tissue structures within the focal volume. This is a very different end result than the coagulative necrosis characteristic of thermal ablation. To operate within a non-thermal, Histotripsy realm; it is necessary to deliver acoustic energy in the form of high amplitude acoustic pulses with low duty cycle.

[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.BRIEF DESCRIPTION OF THE DRAWINGS

[0008] 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:

[0009] FIGS. 1 A-1B illustrate an ultrasound imaging and therapy system.

[0010] FIGS. 2A-2D illustrate various schematic illustrations of transmit-receive drive electronics for a histotripsy system.

[0011] FIGS. 3A-3C are embodiments of current sense electronics for a histotripsy system.

[0012] FIG. 4 is an example of a histotripsy transducer array.

[0013] FIG. 5 shows a pressure amplitude of received ACE signals.

[0014] FIGS. 6A-6D show a process for receiving ACE collapse signals, subtracting from adjacent pulses to remove static tissue reflection signals, and locating coherent peak shocks.

[0015] FIGS. 7A-7B show pressure amplitudes of ACE signals for each transducer element, and blocked vs. unblocked transducer elements.

[0016] FIGS. 8A-8B show focal pressures generated in tissue for arrays with all elements active vs. blocked elements de-activated.

[0017] FIG. 9 is a tissue heating diagram showing all elements vs. blocked elements deactivated.SUMMARY OF THE DISCLOSURE

[0018] 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).

[0019] A method of providing histotripsy therapy, comprising: transmitting histotripsy pulses from an ultrasound transducer array into tissue to generate cavitation in the tissue; receiving, with a plurality of transducer elements of the ultrasound transducer array, acoustic cavitation emission (ACE) signals from the cavitation; identifying an amplitude of the ACE signals received by each transducer element; and determining that one or more transducer elements are blocked if the amplitude of the ACE signals received by the one or more transducer elements are below a threshold.

[0020] In some aspects, the method includes de-activating the one or more transducer elements that are blocked.

[0021] In other aspects, the method includes reducing a transmission amplitude for the one or more transducer elements that are blocked.

[0022] In additional aspects, the method includes determining that one or more transducer elements are blocked further comprises determining that one or more transducer elements are blocked by a bony aberrator.

[0023] In some aspects, the bony aberrator comprises a rib.

[0024] In some aspects, the method includes presenting a graphical representation of the ultrasound transducer array and the one or more transducer elements that are blocked on a display.

[0025] In other aspects, the method includes repositioning the ultrasound transducer array with a robotic positioning system; and repeating the transmitting, receiving, identifying, and determining steps.

[0026] In additional aspects, the method includes presenting a graphical representation of the ultrasound transducer array and the one or more transducer elements that are blocked on a display in real-time as the ultrasound transducer array is repositioned.

[0027] In some aspects, the method includes calculating a time delay from each transducer element to a focus of the ultrasound transducer array; and adjusting transmission of subsequent histotripsy pulses to such that all histotripsy pulses arrive at the focus simultaneously.

[0028] In other aspects, the method includes localizing and mapping the cavitation for treatment monitoring based on the ACE signals.

[0029] A histotripsy system, comprising: an ultrasound transducer array configured to transmit histotripsy pulses into a focal location within tissue to generate cavitation in the tissue and to receive acoustic cavitation emission (ACE) signals from the cavitation; and one or more processors configured to identify an amplitude of the ACE signals received by each transducer element of the ultrasound transducer array, and further configured to determine that one or more transducer elements are blocked if the amplitude of the ACE signals received by the one or more transducer elements are below a threshold.

[0030] In some aspects, the one or more processors are further configured to de-activate the one or more transducer elements that are blocked.

[0031] In other aspects, the one or more processors are further configured to reduce a transmission amplitude for the one or more transducer elements that are blocked.

[0032] In additional aspects, the one or more processors are further configured to determine that one or more transducer elements are blocked by a bony aberrator.

[0033] In some aspects, the bony aberrator comprises a rib.

[0034] In other aspects, the system includes a display configured to present a graphical representation of the ultrasound transducer array and the one or more transducer elements that are blocked.

[0035] In additional aspects, the graphical representation is color coded to indicate the one or more transducer elements that are blocked.

[0036] In some aspects, the system includes a robotic positioning system coupled to the ultrasound transducer array and configured to adjust a position and / or orientation of the ultrasound transducer array.

[0037] In other aspects, the one or more processors are configured to: control the robotic positioning system to reposition the ultrasound transducer array; and repeat identifying amplitudes of the ACE signals received and determining that one or more transducer elements are blocked.

[0038] In additional aspects, the one or more processors are configured to present an updated graphical representation of the ultrasound transducer array and the one or moretransducer elements that are blocked on the display in real-time as the ultrasound transducer array is repositioned.

[0039] In some aspects, the one or more processors are configured to: calculate a time delay from each transducer element of the ultrasound transducer array to a focus of the ultrasound transducer array; and adjust transmission of subsequent histotripsy pulses to such that all histotripsy pulses arrive at the focus simultaneously.

[0040] A method of providing histotripsy therapy, comprising: obtaining pre-treatment images of a target tissue of a patient including one or more bony aberrators; co-registering the pre-treatment images with a coordinate system of a histotripsy ultrasound transducer; positioning the histotripsy ultrasound transducer near the patient such that a focus of the histotripsy ultrasound transducer is located within the target tissue; identifying positions of one or more aberrators in the patient with respect to one or more transducer elements of the histotripsy ultrasound transducer based on the co-registration between the pre-treatment images and the coordinate system of the histotripsy ultrasound transducer; and determining that one or more transducer elements that are blocked by the one or more aberrators.

[0041] In some aspects, the method includes de-activating the one or more transducer elements that are blocked.

[0042] In other aspects, the method includes reducing a transmission amplitude for the one or more transducer elements that are blocked.

[0043] In additional aspects, the method includes determining that one or more transducer elements are blocked further comprises determining that one or more transducer elements are blocked by a bony aberrator.

[0044] In some aspects, the bony aberrator comprises a rib.

[0045] In some aspects, the method includes presenting a graphical representation of the ultrasound transducer array and the one or more transducer elements that are blocked on a display.

[0046] In other aspects, the method includes repositioning the ultrasound transducer array with a robotic positioning system; and repeating the identifying and determining steps.

[0047] In additional aspects, the method includes presenting a graphical representation of the ultrasound transducer array and the one or more transducer elements that are blocked on a display in real-time as the ultrasound transducer array is repositioned.

[0048] In some aspects, the method includes calculating a time delay from each transducer element to a focus of the ultrasound transducer array; and adjusting transmission of subsequent histotripsy pulses to such that all histotripsy pulses arrive at the focus simultaneously.

[0049] A histotripsy system, comprising: a medical imaging device configured to obtain pre-treatment images of a target tissue of a patient including one more aberrators; an ultrasound transducer array configured to transmit histotripsy pulses into a focal location within the target tissue to generate cavitation in the tissue; a robotic positioning system coupled to the ultrasound transducer array and configured to position the ultrasound transducer array; and one or more processors configured to co-register the pre-treatment images with a coordinate system of the ultrasound transducer array or the robotic positioning system, the one or more processors being further configured to position the ultrasound transducer array near the target tissue, identify positions of the one or more aberrators in the patient with respect to one or more transducer elements of the ultrasound transducer array based on the co-regi strati on between the pre-treatment images and the coordinate system of the ultrasound transducer array, and determine that one or more transducer elements are blocked by the one or more aberrators.

[0050] In some aspects, the one or more processors are further configured to de-activate the one or more transducer elements that are blocked.

[0051] In other aspects, the one or more processors are further configured to reduce a transmission amplitude for the one or more transducer elements that are blocked.

[0052] In additional aspects, the one or more processors are further configured to determine that one or more transducer elements are blocked by a bony aberrator.

[0053] In some aspects, the bony aberrator comprises a rib.

[0054] In other aspects, the system includes a display configured to present a graphical representation of the ultrasound transducer array and the one or more transducer elements that are blocked.

[0055] In additional aspects, the graphical representation is color coded to indicate the one or more transducer elements that are blocked.

[0056] In some aspects, the system includes a robotic positioning system coupled to the ultrasound transducer array and configured to adjust a position and / or orientation of the ultrasound transducer array.

[0057] In other aspects, the one or more processors are configured to: control the robotic positioning system to reposition the ultrasound transducer array; and repeat identifying positions of the one or more aberrators with respect to one or more transducer elements and determining that one or more transducer elements are blocked.

[0058] In additional aspects, the one or more processors are configured to present an updated graphical representation of the ultrasound transducer array and the one or moretransducer elements that are blocked on the display in real-time as the ultrasound transducer array is repositioned.

[0059] In some aspects, the one or more processors are configured to: calculate a time delay from each transducer element of the ultrasound transducer array to a focus of the ultrasound transducer array; and adjust transmission of subsequent histotripsy pulses to such that all histotripsy pulses arrive at the focus simultaneously.DETAILED DESCRIPTION

[0060] 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.

[0061] 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.

[0062] 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.

[0063] 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 ofphysical 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.

[0064] 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.

[0065] 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 parameters, 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.

[0066] 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 50 N, 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 + / -0.03mm and a typical TCP speed of 1 m / s (39.4 in / s). In one embodiment, the robot controlbox 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.

[0067] 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.

[0068] 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 lower 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.

[0069] 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 robust 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 intreatment 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.

[0070] 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.

[0071] 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.

[0072] 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 connect / support or interact with a Coupling sub-system to allow acoustic coupling between the therapy transducer and the patient, and Software to communicate, control and interface with the system and computer-based control systems (and other external systems) and various Other Components, Ancillaries and Accessories, including one or more user interfaces and displays, and related guided work-flows, all working in part or together. The system may further comprise various fluidics and fluid management components, 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

[0073] 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 maybe 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.).

[0074] 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).

[0075] In some embodiments one or more Carts may be configured to work together. As an example, one Cart may comprise a bedside mobile Cart equipped with one or more Robotic arms enabled with a Therapy transducer, and Therapy generator / amplifier, etc., while a companion cart working in concert and at a distance of the patient may comprise Integrated Imaging and a console / display for controlling the Robotic and Therapy facets, analogous to a surgical robot and master / slave configurations.

[0076] 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).

[0077] 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

[0078] Histotripsy comprises short, high amplitude, focused ultrasound pulses to generate a dense, energetic, “bubble cloud”, capable of the targeted fractionation and destruction oftissue. 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.

[0079] 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.

[0080] The large pressure generated at the focus causes a cloud of acoustic cavitation bubbles to form above certain thresholds, which creates localized stress and strain in the tissue and mechanical breakdown without significant heat deposition. At pressure levels where cavitation is not generated, minimal effect is observed on the tissue at the focus. This cavitation effect is observed only at pressure levels significantly greater than those which define the inertial cavitation threshold in water for similar pulse durations, on the order of 10 to 30 MPa peak negative pressure.

[0081] 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 fractionatedtissue shows a dynamic change in echogenicity (typically a reduction), which can be used to evaluate, plan, observe and monitor treatment.

[0082] 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”.

[0083] 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.

[0084] 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) of the applied ultrasound pulses exceeding an “intrinsic threshold” of the medium. This is referred to as the “intrinsic threshold mechanism”.

[0085] 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.

[0086] 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., ablationdeep 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.”

[0087] Additional systems, methods and parameters to deliver optimized histotripsy, using shock scattering, intrinsic threshold, and various parameters enabling frequency compounding and bubble manipulation, are herein included as part of the system and methods disclosed herein, including additional means of controlling said histotripsy effect as pertains to steering and positioning the focus, and concurrently managing tissue effects (e.g., prefocal thermal collateral damage) at the treatment site or within intervening tissue. Further, it is disclosed that the various systems and methods, which may include a plurality of parameters, such as but not limited to, frequency, operating frequency, center frequency, pulse repetition frequency, pulses, bursts, number of pulses, cycles, length of pulses, amplitude of pulses, pulse period, delays, burst repetition frequency, sets of the former, loops of multiple sets, loops of multiple and / or different sets, sets of loops, and various combinations or permutations of, etc., are included as a part of this disclosure, including future envisioned embodiments of such.TECHNICAL CHALLENGES WITH HISTOTRIPSY

[0088] There are two technical challenges for using ultrasound therapy such as histotripsy to treat a deep tissue target (e.g., >8 cm) or through heterogenous tissue: 1) acoustic aberration and 2) real-time feedback of the ultrasound therapy.

[0089] Acoustic aberration is a problem that impacts ultrasound therapy and imaging, including histotripsy. Acoustic aberration can reduce the focal pressure and distort the focus due to ultrasound propagation through multi-layer heterogenous tissue. Reduction of the focal pressure can cause ineffective treatment or reduced treatment efficiency. For example, in histotripsy, focal pressures at the target tissue site are precisely controlled to generate cavitation at the target tissue site. Reduction of the focal pressures due to aberration canprevent cavitation from occurring. Distortion of the focus can also decrease treatment accuracy. Typically, a focused ultrasound transducer is shaped as a segment of a spherical surface, such that the sound wave emitted from all locations from the transducer surface go through the same distance to arrive at the focus at the same time. However, due to the variation of speed of sound across bones and heterogeneous soft tissue, the travel time from different elements of an ultrasound transducer array to arrive at the focus may be different. As a result, aberration can result in loss of focal pressure and defocusing, decreasing treatment efficacy and accuracy.

[0090] As ultrasound is a non-invasive therapy technique, real-time feedback is critical to achieve high treatment accuracy and minimizing any potential complications. Ultrasound imaging has been used to provide real-time feedback for histotripsy, as histotripsy-generated cavitation can be visualized on ultrasound images as a dynamic, bright zone. Typically, an ultrasound imaging probe is inserted in a central hole of the histotripsy transducer, thus the 2D ultrasound imaging plane contains the histotripsy focus. Ultrasound imaging can then be used to guide the targeting to place histotripsy focus to the correct target tissue and to monitor the treatment progression. However, there are two main limitations of using ultrasound imaging as the sole guidance for histotripsy. 1) When the ultrasound imaging probe is blocked by bone of the patient (e.g., ribs or skull), ultrasound images of the histotripsy focus cannot be obtained. For example, histotripsy can be used to treat a tumor volume in the liver of a patient, which is partially behind the ribcage. When the histotripsy transducer is mechanically moved to scan the histotripsy focus to cover the tumor volume, the imaging probe can be blocked by the ribs for a certain duration of the therapy, at which point no realtime imaging of the therapy is available due to the rib blockage. Without any feedback during this duration, there is no way of knowing if cavitation is still generated at the target locations in the tumor (i.e., if the treatment is implemented over this duration). 2) Ultrasound imaging probes can only view the tissue and cavitation within the 2D image plane that contains the histotripsy focus. Thus, ultrasound imaging probes cannot view any potential unwanted cavitation occurring outside the image plane. Unwanted cavitation may generate undesired off-target damage.

[0091] The problems described above can be solved with a novel histotripsy ultrasound phased array transducer, as described herein, that is configured to transmit ultrasound signals to generate cavitation and deliver histotripsy as well as is configured to receive ultrasound signals (i.e., a transmit-receive histotripsy array).

[0092] For example, when the ultrasound therapy transducer comprises a phased array, phase correction techniques can be used to correct aberration to recover reduced focalpressure. This can be accomplished by adjusting the phase / time delay at transmission from each transducer element of the phased array to compensate for the travel time variation from each array element to the focus due to the speed of sound variation. In doing so, the aberration can be corrected to increase the focal pressure and improve the focusing.

[0093] An ultrasound phased array transducer that can delivery histotripsy and receive acoustic cavitation emission signals can further be configured to allow detection, localization, and mapping of cavitation. Currently, a typical histotripsy system only transmits ultrasound pulses to generate cavitation at the focus. A transmit-receive histotripsy system can not only be used to deliver ultrasound pulses to generate cavitation, but also can receive signals such as the acoustic cavitation emission (ACE) signals. Both the rapid expansion and rapid collapse of cavitating bubbles during histotripsy produce shockwaves that can be detected by an acoustic receiver. In some embodiments, received reflections of the main therapy pulse (if > 1-2 cycles long and not fully transformed to shockwave in cavitation generation event) or subsequent low amplitude therapy pulses could be used in various receive application listed below. By processing the ACE signals received from a histotripsy transducer array system with hundreds of elements and transmit-receive capability, cavitation can be detected and localized to provide a real-time, 3D cavitation map. The acoustic emission signals from the growth and / or collapse of histotripsy-induced cavitation microbubbles, received by the histotripsy array, can be used to localize and monitor the cavitation in 3D and real-time, even in situations where the ultrasound imaging probe is blocked by bone. 3D cavitation mapping can also allow real-time monitoring of any off-focus cavitation to increase safety and identify unwanted cavitation.

[0094] Transmit-receive driving electronics found in typical phased array systems cannot be directly adapted for a histotripsy phased array transducer because of the extremely high voltages (thousands of volts) necessary for generating high-pressure histotripsy pulses. A novel driving electronics, as described herein, is configured to safely block or significantly attenuate the transmit signal to the ultrasound transducer array while maintaining high sensitivity and high dynamic range for received ultrasound signals. This disclosure provides both hardware and software for a phased array histotripsy transducer array with transmit and receive capability. This disclosure further describes the methods and signal processing algorithms that can be used with the transmit-receive histotripsy system for aberration correction and cavitation mapping.TRANSMIT-RECEIVE ELECTRIC DRIVING SYSTEM

[0095] The electric transmit signal to a histotripsy transducer is typically on the order ofKilovolts, while received ultrasound signals typically range from millivolts to tens of Volts.Thus, the transmit-receive electric driving circuitry as described herein is designed and configured to block or heavily attenuate the high-amplitude transmit waveform signals on the order of thousands of Volts, while having sufficient sensitivity and dynamic range to receive the low-amplitude signals on the order of tens of Volts.

[0096] Many drive circuitry embodiments and implementations to achieve the stated function / purpose above are described herein. In some examples, the drive circuitry can be retrofitted or added-on to an existing transmit-only histotripsy system to provide transmitreceive capabilities. In other embodiments, the drive circuitry is integrated into an entirely new transmit-receive histotripsy system.

[0097] FIG. 2A is one embodiment of a novel receive drive circuitry 200 configured to be retrofitted onto an existing transmit-only histotripsy system to enable transmit-receive functionality. In the illustrated schematic drawing, a non-linear compressor can attenuate all the signals connected to each of the histotripsy elements, but with more attenuation for the high-amplitude signals and less attenuation for the low-amplitude signals. For example, a capacitive voltage divider 202, as indicated by Cl and C2, can first be configured to attenuate all incoming / received voltage signals from transducer element TX1 to approximately 1-10% (or to attenuate the signals by 90-99%). Then a diode-resistor voltage divider 204, as indicated by DI, D2, and C3, is configured to provide nonlinear attenuation to compress all signals above approximately 1 Volts and alternating current (AC) couple the signal into the analog to digital converter (ADC) for ADC conversion. The final component before the ADC is a voltage level shifter 206, as indicated by R2 and R3, that puts the signal in the appropriate voltage range for the ADC (e.g., typically between + / - 0.5V to + / - 2V). As described above, this circuitry is configured to be retrofitted to an existing transmit-only histotripsy driving system. For example, separate circuitry boards can be added and connected to the existing transmit circuitry to add the receive functions. In one embodiment, the receive circuitry is added in parallel to the transmit electronics and passively receives signals without affecting the transmit electronics.

[0098] FIG. 2B is one embodiment of a drive circuitry 200a that is integrated into high voltage histotripsy driving electronics. In the embodiment of FIG. 2B, a bank of capacitors (not shown) in series with the primary coil 20 of the transformer are charged by a high voltage supply. A driver chip, Ul, then triggers the n-channel MOSFET transistor, QI, which sends a high voltage AC pulse through the transformer primary coil thereby generating an AC pulse in the transformer secondary coil 22 with a voltage proportional to the turn ratio between the coils. The secondary coil can be electrically coupled to each of the transducer elements (in this illustration, transducer element TX1). In one implementation, a turn ratio ofapproximately 1 :3 was used between the primary and secondary coils. This receive drive circuitry is thereby able to generate single-cycle pulses at the center frequency of the transducer on the order of 3 kV. It should be understood that other turn ratios can be implemented.

[0099] Referring to FIG. 2C, another embodiment of receive drive electronics for a histotripsy system are shown. As shown, the receive drive electronics can include a secondary transformer coil 22 coupled to the transducer element TX1. Because the driver for this system already includes a transformer at the output of each channel, a third coil 24 can be added to each transformer to be used for the receive electronics, thereby providing total isolation between the driver (e.g., the primary coil 20) and the receiver (e.g., third coil 24). In one implementation, the receive or third coil can be wound with approximately 10-times fewer windings than the secondary transformer coil 22, thereby providing a 10X reduction in voltage between the secondary coil and the third coil. The number of windings on the tertiary or third coil can be tuned for the specific application and need not necessarily be 10-times fewer than the secondary. The ratio depends on the receive signal amplitude and can be adjusted based on desired voltages. In one embodiment, the receive winding (third coil 24) from FIG. 2C can be coupled to a second transformer designed for small signal use with the specifically chosen core material and size such that it would be configured to saturate during the transmit pulses to protect the analog to digital circuitry (ADC) behind it. When receiving signals, however, the second small signal transformer would be configured to not saturate, thereby enabling the appropriate gain and sensitivity for the received signals.

[0100] A schematic design of receive circuitry for the integrated receive-capable histotripsy system is shown in FIG. 2D. The primary difference in the embodiment shown in FIG. 2D compared to the embodiment above in FIG. 2A is the transformer, which is described in the embodiment of FIG. 2C. The VGA circuit is added in the embodiment of FIG. 2D, and the “balanced” input with the two capacitors C3 and C4 in series instead of the level shifter as shown in FIG. 2A comprises a digitizer.

[0101] In another embodiment, the transmit-receive drive circuitry can include a transmit-receive switch. An integrated drive-receive circuity with both transmit and receive circuitry on the same board can use a switch to separate the receive signal from the transmit signal. For example, a traditional TR switch with diodes blocks high-voltage transmit signals without attenuating receive signals. A circuit with different linear gain can follow the switch to amplify or attenuate the selected portion of the receive signal properly based on its amplitude to maximize the sensitivity. However, this design would waste a lot of power, be large, and expensive.

[0102] FIG. 3 A illustrates another embodiment of drive-receive circuitry that is configured to measure current flowing back from the transducer TX1 through the drive transformer T1 (instead of measuring voltage generated on the transducer during receive as discussed above). The relatively large surface area of therapy transducer array elements compared to a traditional imaging transducer means the transducer array generates a relatively large current, which makes high sensitivity during receive possible, whereas with an imaging transducer, it is only practical to measure the voltage induced by acoustic signals. Normal ultrasound imaging elements would be too small to generate a useable receive current. Therapy elements as described herein are hundreds to thousands of times larger in surface area than traditional imaging elements, so the currents are substantially larger and easy to measure (in the milliamp range rather than microamp). In the circuitry illustrated, current can be measured by a sense resistor in the electrical path (Rl). The drive-receive circuitry is configured to pass excess current from large reflections or during the transmit pulse through a set of bypass diodes (DI and D2). Transmit currents can be as large as 40 A. While the drive-receive circuitry is receiving reflections such as ultrasound reflection signals and / or acoustic cavitation emissions, the sense resistor is configured to measure a current induced in the circuitry by those reflections. Voltage generated across the current sensing resistor is coupled to the ADC through a Balun (T2) and Capacitors Cl and C2. This balanced input configuration is the manufacturer’s preferred circuit for the AFE5801 digitizer. Single-ended operation would also be possible for this or other digitizers by directly measuring the voltage on Rl with respect to ground.

[0103] The drive-receive circuitry of FIG. 3 A can be configured to operate in a low gain mode and a high gain mode. Referring still to FIG. 3 A, the circuitry can have two current sensing resistors Rl and R2 so that the overall sensitivity of the circuit can be changed by a large amount. As shown, this can be implemented with a pair of transistors Q2 and Q3 that are configured to switch on / off a small value resistor R2 (low sensitivity) in parallel with the larger value resistor Rl (high sensitivity). The resistance of the circuit can be changed very rapidly with these transistors to enable the use of both the low setting over part of a received burst of data (e.g., a received signal with a higher amplitude such as ultrasound reflection signals from bones) and the high setting a few microseconds later (e.g., a received signal with a lower amplitude such as acoustic cavitation emission signal from cavitation collapse). Because the sensor is directly changed, both scales have very high SNR unlike a variable gain amplifier where the SNR is usually worse for higher gain. In some embodiments, additional sense resistors can be implemented in the same manner for even wider dynamic range. For the circuit shown in FIG. 3 A, the high gain mode is configured to measure currents up to 5mA in the ADC which is coupled to the circuitry via transformer T2, while the low gain mode is configured to measure currents up to 200 mA in the ADC.

[0104] FIG. 3B shows an alternate embodiment where instead of bypass diodes, low gate threshold MOSFET transistors Q4 and Q5 can be implemented for passing the large transmit currents. With the advances in transistors, there are now transistors that are smaller, cheaper, and higher performance than any diode for this bypass role. These transistors can have a higher turn on voltage than a single diode, which allows the use of the full dynamic range of the ADC more easily.

[0105] FIG. 3C shows a third embodiment where the bypass transistors Q4 and Q5 are explicitly controlled as an active transmit-receive switch. The transistor gates are connected to a gate drive signal to force the transistors fully on (for transmit mode) or fully off (for receive mode) which could be + / - 5 V, for example, depending on the transistor drive requirements. This configuration may reduce RF noise generated during transmit where instead passively switched bypass components must turn on and off rapidly at the frequency of the ultrasound. This design has a tradeoff of a minor increase in complexity.

[0106] The analog received signals described above can be converted to digital signals and then collected and processed. The signal received from the histotripsy transducer array can be, for example, reflections from bones or soft tissue or acoustic emission signals from cavitation. These signals are typically received in a specific time window after the histotripsy pulse (e.g., tens to hundreds of microseconds after transmission of the therapy pulse(s)). Thus, the hardware and software described herein is configured to synchronize the time clock of transmit, receive, and ADC conversion and sampling to obtain the appropriate time window after each histotripsy pulse that contains the desired received signals. If the synchronization and time window is set properly, then the desired received signals can be collected and processed.

[0107] To achieve proper synchronization and time windowing, any of the transmitreceive drive electronics described herein can include an embodiment in which a single field- programmable gated array (FPGA) device connected to the ADC can be used to control both the transmit and receive operations of the transducer, as well as the ADC for some subset of or all channels of a histotripsy system. By providing the FPGA with a single clock off of which the timings of the operations to be executed by the separate subsystems are based, synchronization between subsystems can be guaranteed especially when multiple FPGAs are used to control various subsets of histotripsy transducer elements. Setting the appropriate time window to receive the signals can then be achieved through appropriate assignment of the timings of the respective operations when programming of the FPGA. In cases wheremultiple FPGAs are required, for instance in arrays with too many transducer elements to control from a single device, a single clock line can be fanned out to all of them for synchronization, and a centralized ‘master’ FPGA can be used to trigger the execution of their operations within the appropriate time window.

[0108] Alternatively, any of the transmit-receive driving electronics described herein can include multi-FPGA systems can be setup to run in a ‘headless’ mode wherein no centralized ‘master’ FPGA is required to issue / fan out a single shared clock line or trigger the execution of individual boards’ operations. In such a mode, each FPGA would be set to run off of its own individual clock and to monitor and update two common ‘program-execution-state’, and one common ‘execute-operation’, open-drain hardware IO lines shared by the whole system. The open-drain lines operate such that, if any single FPGA applies a low signal to the lines, the signal measured anywhere on the line would register low; if and only if all FPGAs apply a high signal to the lines, the signal measured everywhere on the line would register high.The two ‘program -execution- state’ lines would be used to the FPGAs to issue system-wide 1) ‘ ready -to-execute’ and 2) ‘done-executing’ signals and by default each FPGA would apply a low signal to each of these lines; each FPGA would apply a high signal to the ‘executeoperation’ line. While running a program, upon reaching a new executable instruction in the program, each FPGA would update the ‘ready -to-execute’ line to apply a high signal to it, and enter a wait state wherein it would monitor the signals on both the ‘ready-to-execute’ line and the ‘execute-operation’ lines. Once all FPGAs reached the ‘ready-to-execute’ state, the signal registered on the ‘ready-to-execute’ line would become high; the first FPGA in the system to detect a high state on the ‘ready-to-execute’ line would issue a low signal on the ‘execute-program’ line causing it to register low everywhere. Upon detection of the low signal on the ‘execute-program’ line, each FPGA would set the value on its own terminal of the ‘execute-program’ line to be low and execute its stored commands. Once each FPGA finished running its respective commands, it would apply a high signal to both the ‘done- executing’ and ‘execute-program’ lines. Once both the ‘done-executing’ and ‘executeprogram’ lines registered high, the FPGAs would reset all of the shared open-drain line values to their defaults, load the next instruction in the program, and repeat the process for each instruction until the program was completed.

[0109] A fully connected set of receiving elements can generate large amounts of data, so strategies to reduce the data load are proposed to allow acquired signals to be transferred and processed in real-time to meet the monitoring needs during therapy. These strategies can be applied to any of the transmit-receive driving electronics described herein. Such strategies may include, for example, artificially down sampling the incoming data from the ADC in thefirmware running on FPGA (e.g., by storing only every other data point generated by the ADC, or the average of the data points generated across multiple acquisition cycles). This effectively reduces the sampling frequency, thus reducing the data load, but doesn’t sacrifice temporal precision or dynamic range or result in an increase in noise in the system. Differential compression schemes, wherein all data captured after the first time point is stored as the difference between the values captured at adjacent time points may also be applied. For example, for a value at time 1 of X, and at time 2 of Y, one could store the value of the difference between Y and X, D = Y-X, at time 2 instead of the value of Y directly, and then calculate the actual value of Y during processing as Y = X + D. In this way, nominal values of say X=64000 and Y=63900, which combined represent 4 bytes of data, could be stored as X=64000 and D=-100, which combined represent 3 bytes of data and allow the full recovery of the value of Y. As the length of the data record gets longer, this compression strategy results in data reductions proportional to ratio of the size of the variable needed to store the difference value compared to the size of the variable required to store the actual value, which can generally reduce data loads in the current system by 30%-50%, but could result in significantly larger reductions in systems where the individual data elements are larger in size. In applications not demanding real-time processing / compression, further reductions in data size can be achieved through frequency domain transforms using methods similar to those employed to compress audio files.

[0110] As some of the events that need to be monitored during histotripsy therapies will require very high temporal precision (e.g., the signals from individual cavitation events), while others will require little precision (e.g., the reflections of signals off of large boundaries, e.g., the skull, ribs, tissue interfaces), strategies to dynamically alter the compression ratio can be implemented to fully utilize the incoming data for real-time applications. To that end, the firmware and software that control the data acquisition have been configured such that the sampling frequency and compression strategy used during acquisition can be set on a per-channel basis in the array, and can be independently updated in real-time, even in the middle of an individual acquisition event. This allows for different sub-apertures of the array to be set up to monitor different features of the therapy at the requisite sampling frequency and compression settings, as well as for the receive system to be set to the maximum sampling frequency / minimum compression settings across all elements of the array as needed to monitor short-lived events with potentially weak signals, and then set back to lower sampling frequencies with higher compression settings outside the window requiring maximal monitoring. This allows short-lived events of this type to be fully monitored without necessitating cut-offs in the acquisition to reduce the data load whichcould otherwise potentially result in reducing the physical size of the actively-monitored field or drastic reductions in monitoring speed during therapy.[OHl] In some situations, the receive signal amplitude may be low and the noise may be high, resulting in a low signal -to-noise ratio (SNR). One method to reduce the noise and increase SNR is to oversample and average in firmware (e.g., FPGA firmware) before storing data. This also helps increase dynamic range and reduces memory requirements. Another technique is to implement a dynamic variable sample rate. For example, the ADC can be configured to always run at 50 MHz, but high time precision may only be needed over certain portions of the data record. In the portions of the signals where such a high frame rate is not needed, samples can be decimated or averaged to greatly reduce storage requirements.

[0112] The bandwidth of the therapy transducer elements is typically low, but a high sampling rate can be used for sampling for good timing precision. Receive data should compress exceptionally well in the Fourier domain (at least a factor of 10, maybe a lot more). The FPGAs can be configured to perform this compression before storage or transmit either in firmware or in software. Data compression is the key to implementing real time monitoring, the system will be overwhelmed by the amount of receive data collected.

[0113] In applications where real time monitoring is not essential, or where treatment speed needs to remain higher than possible while simultaneously transferring the full acquired signals to the user’s computer after each pulse, the system can be configured to transfer only partial signals and / or store the acquired signals directly on the FPGA devices themselves for transfer to the control computer later. This would allow uninterrupted acquisition of signals from all delivered pulses without limiting treatment speed. Such capabilities are useful for monitoring long-term changes in acquired signals. For example, there is inherent variability in the ACE signal features associated with the ablative state of the targeted tissues that make the tissue state difficult to track pulse-to-pulse, but characteristic changes in the ACE signals exist over longer treatment time scales (e.g., >20 applied pulses) that allow the ablative state of the tissue to be assessed. One could transfer partial signals in real time to allow localization and mapping of the cavitation events on a per-pulse basis, while storing larger-record length signals on the FPGA to be transferred intermittently to assess the state of the ablation in the therapy target.

[0114] In some situations, it is possible to generate focal pressures far in excess of twice what is nominally required to generate cavitation during therapy and in such cases it may be possible to generate cavitation using fewer than half of the histotripsy transducer array elements. The software controlling the histotripsy array allows for the elements of the array to be easily partitioned into independently controllable sub-apertures, effectively allowing asingle physical histotripsy transducer array to be operated as multiple separate histotripsy arrays. In this way, multiple locations within the focal volume can be targeted for treatment concurrently using the separate sub-apertures of the array, allowing for increases in treatment speed without necessitating an increase in the rate at which pulses are delivered.TREATMENT MONITORING THROUGH THE RIBS

[0115] This disclosure describes new methods for transcostal histotripsy treatments to 1) reduce heating and risk of tissue damage by detecting and turning off the ultrasound array elements blocked by the ribs and 2) to monitor treatment by mapping cavitation through the ribs. These are achieved using the transmit-receive capable histotripsy array as described as follows.

[0116] During transcostal histotripsy treatments, ribs or other bone aberrators strongly attenuate and absorb ultrasound, causing unwanted heating of adjacent tissue. To reduce tissue heating during transcostal histotripsy, this disclosure provides systems and methods that use a receive-capable, histotripsy phased array to transmit histotripsy pulses into tissue to create cavitation within the tissue, and receive acoustic cavitation emission (ACE) signals emitted by the collapse of the histotripsy cavitation cloud. An example of a 260 element receive capable histotripsy phased array is shown in FIG. 4. This can be, for example, the array described above in FIGS. 1 A-1B.

[0117] In one embodiment, the ACE collapse signal received by the transducer array can be identified by first subtracting from an adjacent pulse to remove the static tissue reflection signals and then locating the coherent peak shocks 508, as shown in FIG. 5. This process is described in further detail below in FIGS. 6A-6D. The coherent peak shocks can indicate that cavitation has formed at the focus of the transducer array. If the amplitude of the ACE collapse signal received by a given transducer element of the receive-capable histotripsy phased array is below a threshold, or more specifically, if the peak shocks are below the threshold, the system can determine that the transducer element is blocked by ribs (or another bone aberrator).

[0118] FIGS. 6A-6B show waveforms received by all receivers from two subsequent pulses (a first pulse 602 and a second pulse 604). FIG. 6C is the result of subtracting the waveforms from the first and second pulses, showing a subtracted pulse 606. FIG. 6D shows a measure of waveform coherence called a coherence factor. The ACE collapse signal is detected by finding the peak 608 of this coherence factor value and then set a time window (shown as lines 610) around the time point of the peak.

[0119] In the first step, multiple successive histotripsy pulses are delivered by the transducer array, varying the amplitude between pulses so that the timing of the ACEcollapse signal alternates from pulse to pulse. Then, one or more processors of the system can subtract the waveforms from subsequent histotripsy pulses to reduce background clutter signals (resulting in FIG. 6C). The system / processors can detect the collapse signal by measuring the coherence of the waveforms by computing a coherence factor (FIG. 6D) and detecting a peak 608. The system can present a time window (lines 610) around the peak to isolate the collapse signal from the rest of the signal acquisition.

[0120] FIG. 7A is a diagram showing the ACE collapse signal amplitudes for each transducer element of the array of FIG. 4. In some embodiments, a graphical representation of the transducer array can be presented to a user, such as on a display, with information indicating the ACE collapse signal amplitudes for some or all of the transducer elements of the array. In some examples, the amplitudes can be color coded such that different colors on the graphical representation indicate different (increasing or decreasing) ACE collapse signal amplitudes.

[0121] Blocked elements can then be selectively de-activated during the treatment delivery to reduce the acoustic energy delivered directly through the ribs and thus reduce tissue heating. FIG. 7B shows a graphical representation of the transducer array indicating which transducer elements are blocked and which transducer elements are unblocked. In some embodiments, this graphical representation can be color coded (e.g., a first color such as blue indicating unblocked elements and a second color such as red indicating blocked elements). The graphical representation can be presented to a user, such as on a display of the histotripsy system. Other graphical techniques for indicating blocked vs. unblocked elements are also within the scope of this disclosure.

[0122] De-activation of elements blocked by the ribs and detected with the collapse signal can produce equivalent maximum focal pressure amplitude to transmission with all elements. FIG. 8A shows the focal pressure amplitude with all elements active, and FIG. 8B shows the focal pressure amplitude with blocked transducer elements de-activated. In one example, using ACE collapse detection based de-activation of blocked elements resulted in maximum focal pressures within 0.3 dB of the max focal pressure without element deactivation.

[0123] Meanwhile, the temperature increase in tissue near the ribs during treatment is significantly lower by de-activating the blocked elements using the above method. FIG. 9 shows tissue heating resulting from histotripsy with all elements active (top plot) vs. blocked elements de-activated (bottom plot). This technique helps improve the safety and efficiency of histotripsy treatments through intervening ribs.

[0124] Histotripsy typically is guided by ultrasound imaging using an ultrasound imaging probe inserted in the center of or co-aligned with the histotripsy ultrasound transducer. However, for transcostal treatment, the imaging probe can be blocked by the ribs, such that the target behind the ribs cannot be seen. Using transmit-receive capable histotripsy array, ACE collapse signals can be received and processed to produce a 3D map of cavitation on and off the target, allowing the 3D real-time treatment monitoring when the ultrasound imaging is not usable. The 3D cavitation map can be overlaid onto pre-treatment MR.I / CT scan. In vitro experiments with excised porcine abdominal wall show a cavitation map through the ribcage. This treatment monitoring method can be combined with the deactivating elements, or reducing the amplitude for specified elements above to optimize the histotripsy treatment through the ribs.

[0125] Another method for detecting ribs or other bony aberrators is provided which can use pre-treatment MR / CT scans co-registered with the histotripsy ultrasound transducer location to identify aberrator locations with respect to the ultrasound transducer, or to individual transducer elements of the transducer array. During treatment, when the transducer is moved by the robotic arm with respect to the ribs or aberrator, the locations of any transducer elements can be calculated, and any elements positioned adjacent to the aberrator can be de-activated to minimize the energy delivery and optimize the histotripsy treatment. In some embodiments, the method can use not only the location / position of individual elements to determine if they should be de-activated but can also use the pose / orientation of each individual element to determine if ultrasound energy transmitted by those elements will be blocked by bone or other aberrators.

[0126] 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 elements 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 astructure or feature that is disposed “adjacent” another feature may have portions that overlap or underlie the adjacent feature.

[0127] 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 “ / ”.

[0128] 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.

[0129] 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 terms, 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.

[0130] 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, theterm “comprising” will be understood to imply the inclusion of any stated elements or steps but not the exclusion of any other elements or steps.

[0131] 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.

[0132] 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.

[0133] 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.

Claims

CLAIMSWhat is claimed is:

1. A method of providing histotripsy therapy, comprising: transmitting histotripsy pulses from an ultrasound transducer array into tissue to generate cavitation in the tissue; receiving, with a plurality of transducer elements of the ultrasound transducer array, acoustic cavitation emission (ACE) signals from the cavitation; identifying an amplitude of the ACE signals received by each transducer element; and determining that one or more transducer elements are blocked if the amplitude of the ACE signals received by the one or more transducer elements are below a threshold.

2. The method of claim 1, further comprising de-activating the one or more transducer elements that are blocked.

3. The method of claim 1, further comprising reducing a transmission amplitude for the one or more transducer elements that are blocked.

4. The method of claim 1, wherein determining that one or more transducer elements are blocked further comprises determining that one or more transducer elements are blocked by a bony aberrator.

5. The method of claim 4, wherein the bony aberrator comprises a rib.

6. The method of claim 1, further comprising presenting a graphical representation of the ultrasound transducer array and the one or more transducer elements that are blocked on a display.

7. The method of claim 1, further comprising: repositioning the ultrasound transducer array with a robotic positioning system; and repeating the transmitting, receiving, identifying, and determining steps.

8. The method of claim 7, further comprising presenting a graphical representation of the ultrasound transducer array and the one or more transducer elements that are blocked on a display in real-time as the ultrasound transducer array is repositioned.

9. The method of claim 1, further comprising calculating a time delay from each transducer element to a focus of the ultrasound transducer array; and adjusting transmission of subsequent histotripsy pulses to such that all histotripsy pulses arrive at the focus simultaneously.

10. The method of claim 1, further comprising localizing and mapping the cavitation for treatment monitoring based on the ACE signals.

11. A histotripsy system, comprising: an ultrasound transducer array configured to transmit histotripsy pulses into a focal location within tissue to generate cavitation in the tissue and to receive acoustic cavitation emission (ACE) signals from the cavitation; and one or more processors configured to identify an amplitude of the ACE signals received by each transducer element of the ultrasound transducer array, and further configured to determine that one or more transducer elements are blocked if the amplitude of the ACE signals received by the one or more transducer elements are below a threshold.

12. The system of claim 11, wherein the one or more processors are further configured to de-activate the one or more transducer elements that are blocked.

13. The system of claim 11, wherein the one or more processors are further configured to reduce a transmission amplitude for the one or more transducer elements that are blocked.

14. The system of claim 11, wherein the one or more processors are further configured to determine that one or more transducer elements are blocked by a bony aberrator.

15. The system of claim 14, wherein the bony aberrator comprises a rib.

16. The system of claim 1, further comprising a display configured to present a graphical representation of the ultrasound transducer array and the one or more transducer elements that are blocked.

17. The system of claim 16, wherein the graphical representation is color coded to indicate the one or more transducer elements that are blocked.

18. The system of claim 11, further comprising a robotic positioning system coupled to the ultrasound transducer array and configured to adjust a position and / or orientation of the ultrasound transducer array.

19. The system of claim 18, wherein the one or more processors are configured to: control the robotic positioning system to reposition the ultrasound transducer array; and repeat identifying amplitudes of the ACE signals received and determining that one or more transducer elements are blocked.

20. The system of claim 11, wherein the one or more processors are further configured to localize and map the cavitation for treatment monitoring based on the ACE signals.

21. The system of claim 19, wherein the one or more processors are configured to present an updated graphical representation of the ultrasound transducer array and the one or more transducer elements that are blocked on the display in real-time as the ultrasound transducer array is repositioned.

22. The system of claim 11, wherein the one or more processors are configured to: calculate a time delay from each transducer element of the ultrasound transducer array to a focus of the ultrasound transducer array; and adjust transmission of subsequent histotripsy pulses to such that all histotripsy pulses arrive at the focus simultaneously.

23. A method of providing histotripsy therapy, comprising: obtaining pre-treatment images of a target tissue of a patient including one or more bony aberrators; co-registering the pre-treatment images with a coordinate system of a histotripsy ultrasound transducer; positioning the histotripsy ultrasound transducer near the patient such that a focus of the histotripsy ultrasound transducer is located within the target tissue; identifying positions of one or more aberrators in the patient with respect to one or more transducer elements of the histotripsy ultrasound transducer based on the co-regi strati on between the pre-treatment images and the coordinate system of the histotripsy ultrasound transducer; anddetermining that one or more transducer elements that are blocked by the one or more aberrators.

24. The method of claim 23, further comprising de-activating the one or more transducer elements that are blocked.

25. The method of claim 23, further comprising reducing a transmission amplitude for the one or more transducer elements that are blocked.

26. The method of claim 23, wherein determining that one or more transducer elements are blocked further comprises determining that one or more transducer elements are blocked by a bony aberrator.

27. The method of claim 26, wherein the bony aberrator comprises a rib.

28. The method of claim 1, further comprising presenting a graphical representation of the ultrasound transducer array and the one or more transducer elements that are blocked on a display.

29. The method of claim 23, further comprising: repositioning the ultrasound transducer array with a robotic positioning system; and repeating the identifying and determining steps.

30. The method of claim 29, further comprising presenting a graphical representation of the ultrasound transducer array and the one or more transducer elements that are blocked on a display in real-time as the ultrasound transducer array is repositioned.

31. A histotripsy system, comprising: a medical imaging device configured to obtain pre-treatment images of a target tissue of a patient including one more aberrators; an ultrasound transducer array configured to transmit histotripsy pulses into a focal location within the target tissue to generate cavitation in the tissue; a robotic positioning system coupled to the ultrasound transducer array and configured to position the ultrasound transducer array;one or more processors configured to co-register the pre-treatment images with a coordinate system of the ultrasound transducer array or the robotic positioning system, the one or more processors being further configured to position the ultrasound transducer array near the target tissue, identify positions of the one or more aberrators in the patient with respect to one or more transducer elements of the ultrasound transducer array based on the co-regi strati on between the pre-treatment images and the coordinate system of the ultrasound transducer array, and determine that one or more transducer elements are blocked by the one or more aberrators.

32. The system of claim 31, wherein the one or more processors are further configured to de-activate the one or more transducer elements that are blocked.

33. The system of claim 31, wherein the one or more processors are further configured to reduce a transmission amplitude for the one or more transducer elements that are blocked.

34. The system of claim 31, wherein the one or more aberrators comprises a rib.

35. The system of claim 31, further comprising a display configured to present a graphical representation of the ultrasound transducer array and the one or more transducer elements that are blocked.

36. The system of claim 35, wherein the graphical representation is color coded to indicate the one or more transducer elements that are blocked.

37. The system of claim 31, wherein the one or more processors are configured to: control the robotic positioning system to reposition the ultrasound transducer array; and repeat identifying positions of the one or more aberrators with respect to one or more transducer elements and determining that one or more transducer elements are blocked.

38. The system of claim 37, wherein the one or more processors are configured to present an updated graphical representation of the ultrasound transducer array and the one or more transducer elements that are blocked on the display in real-time as the ultrasound transducer array is repositioned.

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