Ultrasonic transducer with transmit and receive functions for histotripsy

Abstract

A histotripsy therapeutic system configured for the treatment of tissue is provided. [Solution] Histotripsy treatment systems can include any number of features. Provided herein are systems and methods that provide effective non-invasive and minimally invasive therapeutic, diagnostic, and research procedures. In particular, provided herein are optimized systems and methods that provide targeted, effective 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

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 071,301, filed August 27, 2020, entitled "ULTRASOUND TRANSDUCER WITH TRANSMIT-RECEIVE CAPABILITY FOR HISTOTRIPSY," the entire contents of which are incorporated herein by reference. Government Rights

[0002] This invention was made with government support under CA211217, EB028309, and NS108042 awarded by the National Institutes of Health, and under N00014-17-1-2058 and N00014-18-1-2625 awarded by the Office of Naval Research. The government has certain rights in this invention. Incorporation by Reference

[0003] 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.

[0002]

[0004] This disclosure details novel histotripsy systems configured to generate acoustic cavitation, methods, devices, and procedures for minimally and non-invasive treatment of healthy, diseased, and / or damaged tissue. The histotripsy systems and methods described herein, also referred to as histotripsy, can include transducers, drive electronics, a positioning robot, an imaging system, and integrated treatment planning and control software to provide comprehensive treatment and therapy to a patient's soft tissue. [Background technology]

[0003]

[0005] Many medical conditions require invasive surgical intervention. Invasive procedures often involve incisions, trauma to muscles, nerves, and tissues, bleeding, scarring, trauma to organs, pain, the need for anesthesia during and after the procedure, hospitalization, and risk of infection. To avoid or reduce such problems, non-invasive and minimally invasive procedures are often preferred when possible. Unfortunately, non-invasive and minimally invasive procedures may lack the precision, effectiveness, or safety necessary to treat many types of diseases and conditions. What is needed are enhanced non-invasive and minimally invasive procedures, preferably those that do not require ionizing or thermal energy for therapeutic effect.

[0004]

[0006] Histotripsy, or pulsed ultrasound cavitation therapy, is a technique in which very short, intense bursts of acoustic energy induce controlled cavitation (microbubble formation) within a focal volume. The vigorous expansion and collapse of these microbubbles mechanically homogenizes the cells and tissue structures within the focal volume, a very different end result from the coagulative necrosis characteristic of thermal ablation. To operate within the non-thermal histotripsy regime, acoustic energy must be delivered in the form of low-duty-cycle, high-amplitude acoustic pulses.

[0005]

[0007] Compared to conventional focused ultrasound techniques, Histotripsy has important advantages: 1) the destruction process at the focus is mechanical, not thermal; 2) cavitation appears bright on ultrasound imaging, confirming correct targeting and localization of the treatment; and 3) treated tissue generally, but not always, appears darker (less echogenic) on ultrasound imaging. 1) appears visible, so the operator knows what has been treated, and 2) Histotripsy creates lesions in a controlled and precise manner. It is important to emphasize that unlike thermal ablation techniques such as microwave, radiofrequency, and high intensity focused ultrasound (HIFU), Histotripsy relies on the mechanical action of cavitation for tissue destruction. Summary of the Invention [Means for solving the problem]

[0006]

[0016] Histotripsy generates tissue fractions by dense, energetic bubble clouds generated by short, high-pressure ultrasound pulses. When pulses shorter than two cycles are used, the generation of these energetic bubble clouds depends solely on where the peak negative pressure (P) exceeds a specific threshold for inducing cavitation in the medium (typically 26-30 MPa for soft tissues with high water content).

[0007]

[0017] A transmit / receive driver electronics for a Histotripsy system is provided, comprising: at least one transducer element configured to transmit ultrasonic pulses in a transmit mode and to receive ultrasonic reflections and / or acoustic cavitation emissions in a receive mode; a current sensing resistor configured to measure current in the transmit / receive driver electronics during the receive mode; a bypass circuit electrically coupled to the at least one transducer element and the current sensing resistor, the bypass circuit configured to be switched on during the transmit mode to bypass the current sensing resistor and switched off during the receive mode to allow the current sensing resistor to measure the current; and a gain adjustment circuit electrically coupled to the current sensing resistor and the low-sensitivity resistor, the gain adjustment circuit configured to operate at a high-sensitivity setting where the current sensing resistor is switched on and the low-sensitivity resistor is switched off, and further configured to operate at a low-sensitivity setting where the current sensing resistor and the low-sensitivity resistor are switched on.

[0008]

[0018] In some embodiments, the transmit and receive drive electronics further comprise a drive transformer electrically coupled to the at least one transducer element.

[0019] In some examples, the bypass circuit further comprises a pair of bypass transistors. In other embodiments, the bypass circuit further comprises a pair of bypass diodes.

[0009]

[0020] In some embodiments, the gain adjust circuit further comprises a pair of transistors.In other embodiments, the current sensing resistor has a higher resistance than the low sensitivity resistor.

[0021] In one example, the current sensing resistor has a resistance of about 200 ohms and the low sensitivity resistor has a resistance of about 5 ohms.

[0010]

[0022] Transmit and receive drive electronics for a Histotripsy system are provided, the transmit and receive drive electronics comprising: an ultrasonic transducer array; high-voltage transmit electronics coupled to the ultrasonic transducer array and configured to provide up to several thousand volts to the ultrasonic transducer array to generate one or more Histotripsy pulses; first receive electronics coupled to the ultrasonic transducer array and configured to receive an input voltage signal from the transmitted one or more Histotripsy pulses, the first receive electronics configured to attenuate the input voltage signal by 90-99%; second receive electronics configured to compress all attenuated input voltage signals above 1 V; third receive electronics configured to voltage-shift the attenuated input voltage signal; and an analog-to-digital converter configured to receive the voltage-shifted, attenuated input voltage signal from the third receive electronics for ADC conversion.

[0011]

[0023] In some embodiments, the first electronic device comprises a voltage divider.

[0024] In another embodiment, the voltage divider comprises a capacitive voltage divider.

[0025] In one embodiment, the capacitive voltage divider comprises a first capacitor and a second capacitor in parallel with a first transducer element of the ultrasound transducer array.

[0012]

[0026] In one embodiment, the second receiver electronics comprises a diode resistor voltage divider. In another embodiment, the third receiver electronics is configured to voltage shift the attenuated input voltage signal to a suitable voltage range for the analog-to-digital converter.

[0013]

[0027] In some embodiments, the transmit drive electronics comprises a separate circuitry board configured to be retrofitted to an existing Histotripsy system, including a transmit-only Histotripsy drive system.

[0014]

[0028] In one example, the transmit drive electronics are added in parallel to the transmit-only Histotripsy drive system and are configured to passively receive signals without affecting the transmit-only electronics.

[0015]

[0029] In some embodiments, the transmit / receive driver electronics are further configured to synchronize time clocks for the transmitted one or more Histotripsy pulses, the received input voltage signal, and the ADC conversion to obtain an appropriate time window after each Histotripsy pulse transmission.

[0016]

[0030] In one embodiment, the transmit / receive driver electronics further comprises one or more field programmable gate array (FPGA) boards coupled to the analog-to-digital converter and configured to control the transmit and receive operations of the transmit / receive driver electronics using a single clock. In some examples, the one or more FPGAs include software or firmware configured to reduce the data load of the received signal. In other embodiments, the one or more FPGAs are configured to artificially downsample input data from the analog-to-digital converter. In another embodiment, the one or more FPGAs are configured to oversample and average the received signal to increase the signal-to-noise ratio (SNR).

[0017]

[0031] A method of using a transmit / receive Histotripsy system for cavitation detection is provided, comprising the steps of: transmitting high-voltage Histotripsy therapy pulses to a target tissue using transmit electronics and a Histotripsy therapy transducer array to generate cavitation in the target tissue; receiving low-voltage acoustic cavitation radiation signals from the cavitation using receive electronics and a Histotripsy therapy transducer array; and processing the received acoustic cavitation radiation signals to monitor the progress of the treatment.

[0018]

[0032] In some examples, the method further comprises generating, in real time, a 3D map of the cavitation produced by the transmitted pulses.

[0033] A transmit / receive histotripsy system for aberration correction, comprising: transmitting histotripsy therapy pulses to a target tissue using a histotripsy therapy transducer array having a plurality of transducer elements to generate cavitation in the target tissue; receiving acoustic cavitation radiation signals from the cavitation using the histotripsy therapy transducer array; calculating a travel time from the cavitation to each transducer element of the ultrasound transducer array based on the received acoustic cavitation radiation signals; and adjusting a transmit time delay for at least one transducer element of the plurality of transducer elements based on the calculated travel time so that subsequent histotripsy therapy pulses arrive at the target tissue simultaneously. A method for using the system is provided.

[0019]

[0034] In some embodiments, calculating the travel time includes using information encoded in the acoustic cavitation radiation.

[0035] In one example, the information comprises a start time of acoustic cavitation radiation generated from the cavitation expansion.

[0020]

[0036] In some embodiments, the information comprises a start time of acoustic cavitation radiation generated from cavitation collapse.

[0037] In one embodiment, the information comprises the peak time from cavitation collapse.

[0021]

[0038] A receive driver circuit configured to be retrofitted to one or more transducer elements of an existing transmit-only histotripsy system is provided, comprising: a voltage divider configured to be electrically coupled to a first transducer element, the voltage divider configured to attenuate a voltage signal received by the first transducer element; and a diode resistor divider electrically coupled to the voltage divider, the diode resistor divider configured to provide nonlinear attenuation to compress signals above a predetermined voltage, and further configured to AC couple the received signal to an analog-to-digital converter.

[0022]

[0039] In some embodiments, the voltage divider and diode resistor divider are configured to be disposed on a first circuit configuration board and electrically coupled to high voltage histotripsy drive electronics disposed on a separate second circuit configuration board.

[0023]

[0040] In another embodiment, the receiver driver circuitry and the high voltage histotripsy driver electronics are located on a single circuit board.

[0041] A transmit / receive histotripsy system is provided, comprising: a transducer element; transmit electronics coupled to the transducer element and configured to provide histotripsy pulses to the transducer element; and nonlinear compressor receive electronics coupled to the transducer element, the nonlinear compressor receive electronics configured to compress a first voltage signal with a first attenuation and further configured to compress a second voltage signal with a second attenuation, the first voltage signal being higher than the second voltage signal and the first attenuation being higher than the second attenuation.

[0024]

[0042] Also provided is transmit and receive driver electronics for a histotripsy system, the transmitter and receiver drive electronics comprising: a transducer element; a secondary transformer coil electrically coupled to the transducer element; a primary transformer coil positioned adjacent to the secondary transformer coil, the primary transformer coil configured to generate ultrasonic pulses at the transducer element via the secondary transformer coil; and a third transformer coil positioned adjacent to the secondary transformer coil, the third transformer coil configured to attenuate a voltage signal received by the transducer element by a predetermined amount.

[0025]

[0043] In some embodiments, the third transformer coil is configured to attenuate the received voltage signal by 90-99%. In other embodiments, the third transformer coil is wound with approximately 7-10 times fewer turns than the secondary transformer coil.

[0026]

[0044] In some embodiments, the third transformer coil is configured to saturate during transmission of the ultrasound pulses.

[0045] In another embodiment, the third transformer coil is coupled to a signal transformer having a specially selected core material and size so as to be configured to saturate during transmission of the ultrasound pulse. are combined.

[0027]

[0046] Provided is transmit / receive drive electronics for a Histotripsy system, the transmit / receive drive electronics comprising: an ultrasound transducer array; transmit electronics coupled to the ultrasound transducer array and configured to transmit one or more Histotripsy pulses to generate cavitation in target tissue; receive electronics configured to receive acoustic cavitation radiation from the cavitation; and a transmit / receive switch configured to enable only the transmit electronics during transmission of the one or more Histotripsy pulses, the transmit / receive switch further configured to enable only the receive electronics at a predetermined time after transmission of the one or more Histotripsy pulses to shut off the transmit signal without attenuating the receive signal.

[0028]

[0047] In one embodiment, different linear gains follow the transmit / receive switch to amplify or attenuate selected portions of the received signal based on its amplitude to maximize the receive sensitivity of the receive electronics.

[0029]

[0048] A method of histotripsy therapy is provided, comprising the steps of transmitting histotripsy therapy pulses to a target tissue using a histotripsy therapy transducer array to generate cavitation in the target tissue; receiving acoustic cavitation radiation signals from the cavitation using the histotripsy therapy transducer; detecting and separating selected acoustic cavitation radiation signatures from the tissue signals; calculating cavitation parameters that correlate with tissue damage generated by the histotripsy therapy pulses; determining changes in the cavitation parameters that correlate with treatment progress; and determining changes in the cavitation parameters that correlate with treatment completion.

[0030]

[0049] In one example, the selected acoustic cavitation radiation characteristic comprises the timing of the cavitation bubble expansion signal.

[0050] In another example, the selected acoustic cavitation radiation characteristic comprises the amplitude of a cavitation bubble expansion signal.

[0031]

[0051] In some embodiments, the selected acoustic cavitation radiation characteristic comprises the timing of a cavitation bubble collapse signal.

[0052] In another embodiment, the selected acoustic cavitation radiation characteristic comprises the amplitude of the cavitation bubble collapse signal.

[0032]

[0053] In some embodiments, the selected acoustic cavitation radiation characteristic comprises the timing of a cavitation bubble rebound signal.

[0054] In one embodiment, the selected acoustic cavitation radiation characteristic comprises the amplitude of the cavitation bubble repulsion signal.

[0033]

[0055] In another embodiment, the cavitation parameter comprises a collapse time of the cavitation.

[0056] In some examples, the collapse time comprises the time between the cavitation expansion signal and the collapse signal.

[0034]

[0057] In another embodiment, the cavitation parameter comprises a peak amplitude of the cavitation expansion signal.

[0058] In some embodiments, the cavitation parameter comprises a peak amplitude of the cavitation collapse signal.

[0035]

[0059] In another embodiment, the cavitation parameter comprises an amplitude ratio of the cavitation growth ACE signal.

[0060] In some embodiments, the cavitation parameter comprises an amplitude ratio of the cavitation collapse ACE signal.

[0036]

[0061] In another embodiment, the cavitation parameter comprises a decay rate of the repulsion-related ACE signal amplitude.

[0062] In one example, determining a change in the cavitation parameter that correlates with the progress of the treatment further comprises identifying a gradient of increase in the cavitation parameter.

[0037]

[0063] In another example, determining a change in the cavitation parameter that correlates with completion of the procedure further comprises identifying saturation of the change in the cavitation parameter.

[0038]

[0064] A method for cavitation detection in Histotripsy is provided, comprising the steps of transmitting Histotripsy treatment pulses to a target tissue using a Histotripsy treatment transducer array to generate cavitation in the target tissue; receiving acoustic cavitation radiation signals from the cavitation using the Histotripsy treatment transducer array; detecting and separating selected acoustic cavitation radiation features from the tissue signals; processing and forming a cavitation map based on the selected acoustic cavitation radiation features; and overlaying the cavitation map on an image of the target tissue.

[0039]

[0065] In some examples, the selected acoustic cavitation radiation characteristic comprises a timing of a cavitation bubble expansion signal. In other examples, the selected acoustic cavitation radiation characteristic comprises an amplitude of a cavitation bubble expansion signal. In additional examples, the selected acoustic cavitation radiation characteristic comprises a timing of a cavitation bubble collapse signal. In one embodiment, the selected acoustic cavitation radiation characteristic comprises an amplitude of a cavitation bubble collapse signal. In some embodiments, the selected acoustic cavitation radiation characteristic comprises a timing of a cavitation bubble rebound signal. In another example, the selected acoustic cavitation radiation characteristic comprises an amplitude of a cavitation bubble rebound signal.

[0040]

[0066] A method for performing aberration correction during Histotripsy treatment is provided, comprising the steps of: transmitting Histotripsy treatment pulses to a target tissue using a Histotripsy treatment transducer array to generate cavitation in the target tissue; receiving acoustic cavitation radiation signals from the cavitation using the Histotripsy treatment transducer array; analyzing the acoustic cavitation radiation signals to detect cavitation generated in the target tissue; testing transmit time delay presets to select a series of transmit time delays that maximizes peak signal amplitude in the detected cavitation; and applying the selected series of transmit time delays so that subsequent Histotripsy treatment pulses arrive at the target tissue simultaneously.

[0041] The novel features of the invention are set forth with particularity in the appended claims. 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. [Brief explanation of the drawings]

[0042] [Figure 1A]

[0009] FIG. 1 illustrates an ultrasound imaging and therapy system. [Figure 1B] FIG. 1 illustrates an ultrasound imaging and therapy system. [Figure 2A] FIG. 1 is a schematic diagram illustrating the transmit and receive driver electronics for the Histotripsy system. [Figure 2B] FIG. 1 is a schematic diagram illustrating the transmit and receive driver electronics for the Histotripsy system. [Figure 2C] FIG. 1 is a schematic diagram illustrating the transmit and receive driver electronics for the Histotripsy system. [Figure 2D] FIG. 1 is a schematic diagram illustrating the transmit and receive driver electronics for the Histotripsy system. [Figure 3A]

[0011] FIG. 1 illustrates an embodiment of current sensing electronics for a Histotripsy system. [Figure 3B]FIG. 1 illustrates an embodiment of current sensing electronics for a Histotripsy system. [Figure 3C] FIG. 1 illustrates an embodiment of current sensing electronics for a Histotripsy system. [Figure 4]

[0012] FIG. 1 illustrates a method for providing histotripsy therapy to a patient. [Figure 5]

[0013] FIG. 1 illustrates cavitation mapping through bone, such as the human skull. [Figure 6]

[0014] FIG. 1 illustrates a method of providing histotripsy therapy to a patient. [Figure 7]

[0015] FIG. 1 illustrates data collected via ultrasound signals received from a histotripsy treatment to predict treatment progress and tissue fractionation. [Figure 8] 8A and 8B are diagrams illustrating data collected via ultrasound signals received from a Histotripsy treatment to predict treatment progress and tissue fractionation. [Figure 9] FIG. 10 illustrates data collected via ultrasound signals received from a Histotripsy treatment to predict treatment progress and tissue fractionation. [Figure 10] FIG. 10 illustrates data collected via ultrasound signals received from a Histotripsy treatment to predict treatment progress and tissue fractionation. DETAILED DESCRIPTION OF THE INVENTION

[0043]

[0067] Provided herein are systems and methods that provide effective non-invasive and minimally invasive therapeutic, diagnostic, and research procedures. In particular, provided herein are optimized systems and methods that provide targeted, effective histotripsy in a variety of different regions and under a variety of different conditions without causing undesired tissue damage to intervening / non-target tissues or structures.

[0044]

[0068] Balancing the desired tissue destruction in the target area with avoiding damage to non-target areas presents a technical challenge. This is especially true when a time-efficient procedure is desired. Conditions that provide rapid and effective tissue destruction tend to cause excessive heating in non-target tissue. Excessive heating can be avoided by reducing energy or slowing the delivery of energy, both of which are counter to the goal of rapid and effective destruction of target tissue. A number of techniques are provided herein that individually and collectively enable rapid and effective targeted treatment without undesired damage to non-target areas.

[0045]

[0069] The systems, methods, and devices of the present disclosure provide minimally or non-invasive acoustic cavitation and therapeutic treatment for the treatment of healthy, diseased, and / or injured tissue, including those integrated into extracorporeal, percutaneous, endoscopic, laparoscopic, and / or robotic-enabled medical systems and procedures. Histotripsy can be used to treat tissues that have been previously treated. As described below, a histotripsy system may include various electrical, mechanical, and software subsystems, including a cart, therapy, integrated imaging, robotics, couplings, and software. The system may also include various other components, attachments, and accessories, including, but not limited to, a patient surface, table or bed, computer, cables and connectors, network devices, power supplies, displays, drawers / storage, doors, wheels, illumination and lighting, and various simulation and training tools. All systems, methods, and means for creating / controlling / delivering histotripsy are considered part of this disclosure, including any new related inventions disclosed herein.

[0046]

[0070] In one embodiment, the Histotripsy system is configured as a mobile treatment cart, which further includes a touchscreen display with an integrated control panel with a set of physical controls, a robotic arm, a treatment head located at the distal end of the robot, and a patient interface system and software for operating and controlling the system.

[0047]

[0071] The mobile treatment cart architecture can include internal components housed in a standard rack-mounted frame, including a histotripsy therapy generator, high-voltage power supply, transformers, power distribution, robotic controller, computer, router and modem, and ultrasound imaging engine. The front system interface panel can include input and output locations for connections, including two ultrasound imaging probes (handheld and one coaxially mounted to the therapy transducer), a histotripsy therapy transducer, AC power and circuit breaker switches, network connections, and foot pedals. The rear panel of the cart can include an air intake for directing airflow to exhaust ports located on the side, top, and bottom panels. The side panels of the cart include a holster and a support mechanism for holding the handheld imaging probe. The cart base can consist of a cast base that interfaces with the rack-mounted electronics and provides an interface to the side panels and top cover. The base also includes four recessed casters with a single, full-locking mechanism. The treatment cart's top cover can include a base and interface for the robotic arm and a circumferential handle that follows the contours of the cart body. The cart can include internal mounting features that allow a technician to access the cart components through an access panel.

[0048]

[0072] The touchscreen display and control panel may include user input capabilities, 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 treatment parameters, as well as the robot. The touchscreen support arm is configured to allow for standing and sitting positions, and adjustment of the touchscreen orientation and viewing angle. The support arm may further include a system-level power button and USB and Ethernet connectors.

[0049]

[0073] The robotic arm can be mounted to a mobile treatment cart on a high enough arm base to allow for easy access and placement of the arm in the patient / procedure workspace, from preparation, through procedure, and removal, in various drive modes. The robotic arm can have six degrees of freedom with six rotational joints, an 850 mm reach, and a maximum payload of 5 kg. The arm may be controlled via Histotripsy system software and a 12-inch touchscreen Polyscope with a graphical user interface. The robot is equipped with force sensing and tool flanges with a force (x, y, z) range of 50 N with 3.5 N accuracy and 4.0 N precision, and a torque (x, y, z) range of 10.0 N with 0.2 N m accuracy and 0.3 N m precision. The robot has a posture repeatability of + / - 0.03 mm and a typical TCP speed of 1 m / s (39.4 in / s). In one embodiment, the robot control box has multiple I / O ports, including 16 digital inputs, 16 digital outputs, 2 analog inputs, 2 analog outputs, and 4 quadrature digital inputs, as well as a 24V / 2A I / O power supply. Control box communication is via a 500 Hz control frequency, Modbus It features TCP, PROFINET, Ethernet / IP, and USB 2.0 and 3.0.

[0050]

[0074] The therapy head can include one of a select group of four histotripsy therapy transducers and an ultrasound imaging system / probe, coaxially positioned within the therapy transducer, with an encoding mechanism for rotating the imaging probe to a known location independently of the therapy transducer, and a handle that allows for coarse and fine positioning (e.g., free-drive positioning) of the therapy head, including user input for activating the robot. In some examples, the therapy transducers may vary in size (22 x 17 cm to 28 x 17 cm), focal length from 12 to 18 cm, number of elements ranging from 48 to 64 elements contained within 12 to 16 rings, and all at a frequency of 700 kHz. The therapy head subsystem has an interface to the robotic arm, including a quick-release mechanism that allows removal and / or modification of the therapy head and allows for cleaning, replacement, and / or selection of alternative therapy transducer designs (e.g., with different numbers of elements and geometries), with each therapy transducer electronically keyed for automatic identification in the system software.

[0051]

[0075] The patient coupling system may include a six-degree-of-freedom, six-joint mechanical arm configured with a mounting bracket designed to interface with 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 may be configured to interface with an ultrasound medium container, including a frame system and upper and lower boots. The lower boot is configured to support either a patient-contacting film that fits snugly against the patient or an elastic polymer membrane, either directly contacting the patient within the frame and boot or designed to contain an ultrasound medium (e.g., degassed water or a water mixture) within the membrane / boot structure. In one example, the lower boot has an ultrasound medium container and provides upper and lower windows, approximately 46 cm x 56 cm and 26 cm x 20 cm, respectively, for placement of a therapy transducer located on the patient's abdomen. The upper boot allows the distal end of the robot to connect to the therapy head and / or transducer and may be configured to prevent water leaks / spills. In a preferred embodiment, the upper boot is a sealed system. The frame is also configured to allow bidirectional fluid communication between the ultrasonic medium container and the ultrasonic medium source (e.g., a reservoir or fluidics management system) in a sealed system, including, but not limited to, filling and draining as well as venting for bubble management.

[0052]

[0076] The system software and workflow can be configured to allow a user to control the system via a touchscreen display and physical controls, including but not limited to, ultrasound imaging and treatment parameters. The system's graphical user interface includes a workflow-based flow with general procedural steps consisting of 1) patient enrollment / selection, and 2) planning, imaging the patient (and target location / anatomy) with a freehand imaging probe, robotic-assisted imaging with the transducer head for final coarse and fine targeting, which includes target contouring using target and margin contours that are typically spherical and elliptical in nature, and a bubble cloud calibration step. and executing a test protocol (e.g., test pulses) comprising a calibration initiation threshold and a series of predetermined locations within the volume for assessing other patient / target specific parameters (e.g., treatment depth), which together inform a treatment plan that takes into account the location and acoustic path of the target and any associated blockages (e.g., tissue interfaces, bone, etc.) that may require variation in the level of drive amplitude to initiate and maintain histotripsy. The parameters measured as part of the test protocol, comprising calibration and multi-location test pulses, are configured to provide input / feedback within the system not only to update the bubble cloud location in space (e.g., appropriately calibrated to the target crosshairs) as needed / desired, but also to determine / interpolate the required amplitude between all bubble cloud treatment locations within the treatment volume to ensure thresholds are achieved throughout the volume. Additionally, the parameters, including but not limited to depth and drive voltage, may be used as part of an integrated treatability matrix or lookup table to determine whether additional cooling (e.g., off-time in addition to the time allotted for robotic movements between treatment pattern movements) is necessary to ensure robust cavitation and intervening / accidental thermal effects are managed (e.g., staying below the t43 curve for any known or calculated combination of sequence, pattern and path, and target depth / blockage). As implemented in the system software, the workflow and procedural steps associated with these aspects of planning can be automated, with the robot and control system configured to autonomously or semi-autonomously execute test protocols and localization. Following planning, the next phase of the procedural workflow, 3) the Procedural Phase, begins after the user accepts the treatment plan and initiates the system for treatment. Following this command, the system is configured to execute the treatment protocol and autonomously deliver the treatment until the prescribed volumetric treatment is completed.The treatment status (and bubble cloud position) is displayed in real time adjacent to various treatment parameters, including, but not limited to, total and remaining treatment time, drive voltage, treatment contour (target / margin) and bubble cloud / point position, current position in the treatment pattern (e.g., slice and row), imaging parameters, and other additional contextual data (e.g., optional DICOM data, force-torque data from the robot, etc.). Following the treatment, the user may confirm and verify the treatment using the treatment head probe, followed by a freehand ultrasound probe, as controlled / viewed via the system user interface. If additional target locations are required, the user may plan / treat additional targets or, if no further treatments are planned, dock the robot to the cart's home position.

[0053]

[0077] 1A generally illustrates a histotripsy system 100 according to the present disclosure, including a therapy transducer 102, an imaging system 104, a display and control panel 106, a robotic positioning arm 108, and a cart 110. The system may further include an ultrasound coupling interface and a coupling medium source, not shown.

[0054]

[0078] 1B is a bottom view of the therapy transducer 102 and imaging system 104. As shown, the imaging system can be located at the center of the therapy transducer. However, other embodiments can include an imaging system located at other locations within the therapy transducer or integrated directly into the therapy transducer. In some embodiments, the imaging system is configured to generate real-time imaging at the focal point of the therapy transducer.

[0055]

[0079] The Histotripsy system comprises a treatment subsystem capable of creating, applying, focusing, and delivering acoustic cavitation / Histotripsy via one or more treatment transducers, an integrated imaging subsystem (or connections therefor) that allows real-time visualization of the treatment site and Histotripsy effects during the procedure, and a treatment transducer. The system may include one or more of various subsystems, including a robotic positioning subsystem that mechanically and / or electronically operates and further connects / supports or interacts with a coupling subsystem to enable acoustic coupling between the therapy transducer and the patient; software that communicates, controls, and interfaces with the system and a computer-based control system (and other external systems); various other components, attachments, and accessories, including one or more user interfaces and displays, and associated guided workflows, all of which operate partially or together. The system may further include various fluidics and fluid management components, including, but not limited to, pumps, valves and flow control, temperature and degassing control, irrigation and aspiration capabilities, and fluid provision and storage. The system may also include various power sources and protection devices. cart

[0080] The cart 110 may generally be configured in a variety of ways and form factors based on the specific application and procedure. In some cases, a system may include multiple carts configured in similar or different configurations. In some embodiments, the cart may be configured and arranged for use in a radiology environment, possibly in conjunction with imaging (e.g., CT, cone-beam CT, and / or MRI scans). In other embodiments, the cart may be configured for use in an operating room and sterile environment, or in a robotic-enabled operating room, and may be used alone or as part of a surgical robotic procedure, where the surgical robot performs specific tasks before, during, or after use of the system to perform acoustic cavitation / histotripsy delivery. Thus, depending on the procedural environment based on the aforementioned embodiments, the cart may be arranged to provide sufficient workspace and access to various anatomical locations on the patient (e.g., torso, abdomen, flank, head and neck, etc.), as well as providing workspace for other systems (e.g., anesthesia cart, laparoscopic tower, surgical robot, endoscopic tower, etc.).

[0056]

[0081] The cart may also interface with a patient surface (e.g., a table or bed) to allow for patient presentation and repositioning at many locations, angles, and orientations, including allowing for these changes before, near, and after a procedure. The cart may further comprise the capability to interface and communicate with one or more external imaging systems or image data management and communication systems to support the procedure and / or environment of use, including physical / mechanical interoperability (e.g., compatible within a cone-beam CT workspace for collecting image data before, near, and / or after histotripsy), including but not limited to one or more modalities of ultrasound, CT, fluoroscopy, cone-beam CT, PET, PET / CT, MRI, optical, ultrasound, and image fusion and / or image flow.

[0057]

[0082] In some embodiments, one or more carts may be configured to work together. By way of example, one cart may comprise a bedside mobile cart equipped with one or more robotic arms enabled with therapy transducers, therapy generators / amplifiers, etc., while a companion cart operating in cooperation and remote from the patient may comprise integrated imaging and console / display for controlling the robotic and therapy facets, similar to surgical robotic and master / slave configurations.

[0058]

[0083] In some embodiments, the system may include multiple carts all subordinate to one master cart equipped to perform acoustic cavitation procedures. In some cases, one cart configuration may store certain subsystems in separate locations to reduce clutter in the operating room, while another cart configuration may primarily include bedside subsystems and components (e.g., delivery systems and treatments). That's fine.

[0059]

[0084] Numerous permutations and configurations of cart design can be envisioned, and these examples are in no way intended to limit the scope of this disclosure.

[0060] Histotripsy

[0085] Histotripsy employs short, high-amplitude focused ultrasound pulses to generate a dense, energetic "bubble cloud" capable of fractionating and destroying targeted tissue. When directed at tissue interfaces, including tissue / fluid interfaces, Histotripsy can create controlled tissue erosion, and when targeting bulk tissue, it can achieve distinct tissue fractionation and destruction at the subcellular level. Unlike other forms of ablation, including thermal and radiation-based modalities, Histotripsy does not rely on thermal or ionizing energy to treat tissue. Instead, Histotripsy uses acoustic cavitation generated at the focal point to mechanically affect tissue structure and, in some cases, liquefy, suspend, solubilize, and / or destroy tissue into its subcellular components.

[0061]

[0086] Histotripsy can be applied in various forms, including: 1) Intrinsic Threshold Histotripsy. This involves providing a pulse with at least a single negative / extensional phase sufficient to induce a cluster of intrinsic bubble nuclei in the medium to undergo inertial cavitation. 2) Shock-Scattering Histotripsy. This involves providing a pulse typically 3-20 cycles in duration. The amplitude of the tensile phase of the pulse is sufficient to induce bubble nuclei in the medium to undergo inertial cavitation within the focal zone for the entire duration of the pulse. These nuclei scatter the incident shock wave, inverting the incident wave and constructively interfering with it to exceed the threshold for intrinsic nucleation. 3) Boiling Histotripsy. This involves applying a pulse approximately 1-20 ms in duration. Absorption of the shock pulse rapidly heats the medium, thereby lowering the threshold for intrinsic nucleation. When this intrinsic threshold coincides with the peak negative pressure of the incident wave, a boiling bubble forms at the focal point.

[0062]

[0087] The large pressures generated at the focal point cause a cloud of acoustic cavitation bubbles to form above a certain threshold, which induces localized stresses and strains in the tissue, resulting in mechanical disruption without significant heat deposition. At pressure levels that do not generate cavitation, minimal effects on the tissue at the focal point are observed. This cavitation effect is only observed at pressure levels on the order of 10 to 30 MPa peak negative pressure, significantly greater than the pressure levels that define the threshold for inertial cavitation in water for similar pulse durations.

[0063]

[0088] Histotripsy may be performed using multiple techniques and under different parameters. Histotripsy may be performed completely noninvasively by acoustically coupling a focused ultrasound transducer onto the patient's skin and transmitting acoustic pulses transcutaneously through the overlying (and intervening) tissue to the focal zone (treatment zone and site). Given that the bubble cloud generated by histotripsy can be visible as a highly dynamic echogenic region on, for example, a B-mode ultrasound image, it can be further targeted, planned, directed, and observed under direct visualization with ultrasound imaging, allowing for continuous visualization throughout its use (and related procedures). Similarly, treated and fractionated tissues exhibit dynamic changes (typically decreases) in echogenicity that can be used to assess, plan, observe, and monitor the procedure.

[0064]

[0089] Typically, in histotripsy procedures, an ultrasound pulse with three or more acoustic cycles is applied, and bubble cloud formation is initially triggered, resulting in the formation of a positive shock front (sometimes exceeding 100 MPa, P+) from sparsely distributed bubbles (or a single bubble). It relies on pressure release scattering, which is called the "impact scattering mechanism."

[0065]

[0090] This mechanism relies on one (or a few sparsely distributed) bubbles being triggered by the first negative half-cycle of the pulse at the transducer focal point. Then, a microbubble cloud is formed by backscattering the high-peak positive shock front from these sparsely triggered bubbles. These backscattered high-amplitude rarefaction waves exceed a characteristic threshold and generate a localized dense bubble cloud. Each subsequent acoustic cycle induces further cavitation by backscattering from the bubble cloud's surface, which grows toward the transducer. As a result, an elongated dense bubble cloud growing along the acoustic axis opposite the direction of ultrasound propagation is observed in the shock-scattering mechanism. This shock-scattering process makes bubble cloud generation dependent not only on the peak negative pressure but also on the number of acoustic cycles and the amplitude of the positive shock. Without at least one strong shock front developing through nonlinear propagation, a dense bubble cloud will not be generated if the negative half-cycle peak falls below the characteristic threshold.

[0066]

[0091] If fewer than two ultrasonic pulse cycles are applied, shock scattering can be minimized, and the generation of a dense bubble cloud depends on the negative half-cycle of the applied ultrasonic pulse exceeding the "intrinsic threshold" of the medium. This is called the "intrinsic threshold mechanism."

[0067]

[0092] This threshold can be in the range of 26-30 MPa for soft tissues with high water content, such as those in the human body. In some embodiments, this inherent threshold mechanism may be used to make the spatial extent of the lesion well-defined and more predictable. If the peak negative pressure (P-) is not significantly higher than this threshold, reproducible sub-wavelength lesions as small as half the transducer's -6 dB beamwidth may be produced.

[0068]

[0093] High-frequency Histotripsy pulses result in smaller minimum reproducible lesion sizes, which is beneficial in applications requiring precise lesion generation. However, high-frequency pulses are more susceptible to attenuation and aberrations, making treatment problematic at deeper penetration depths (e.g., deep-body ablation) or through highly aberrated media (e.g., transcranial procedures or procedures in which pulses are transmitted through bone). Histotripsy may also be applied such that a low-frequency "pump" pulse (typically less than two cycles and having a frequency between 100 kHz and 1 MHz) is applied in conjunction with a high-frequency "probe" pulse (typically less than two cycles and having a frequency greater than 2 MHz or in the range of 2 MHz to 10 MHz), where the peak negative pressures of the low- and high-frequency pulses constructively interfere to exceed a specific threshold within the target tissue or medium. Low-frequency pulses are more tolerant of attenuation and aberrations and can raise peak negative pressure P- levels in a region of interest (ROI), while more precise, high-frequency pulses can pinpoint a target location within the ROI and raise peak negative pressure P- above a specific threshold. This approach is sometimes referred to as "dual-frequency," "dual-beam histotripsy," or "parametric histotripsy."

[0069]

[0094] Additional systems, methods, and parameters for delivering optimized Histotripsy using impact scattering, intrinsic thresholds, and various parameters enabling frequency compounding and bubble manipulation are included herein as part of the systems and methods disclosed herein, including additional means for controlling said Histotripsy effects with respect to focal point manipulation and positioning, and simultaneous management of tissue effects (e.g., pre-focal thermal collateral damage) at the treatment site or within intervening tissue. Further, without limitation, various other systems, methods, and parameters for delivering optimized Histotripsy using impact scattering, intrinsic thresholds, and various parameters enabling frequency compounding and bubble manipulation are included herein as part of the systems and methods disclosed herein, including additional means for controlling said Histotripsy effects with respect to focal point manipulation and positioning, and simultaneous management of tissue effects (e.g., pre-focal thermal collateral damage) at the treatment site or within intervening tissue. Various systems and methods are disclosed that may include a number of parameters such as operating frequency, center frequency, pulse repetition frequency, pulses, bursts, number of pulses, cycles, pulse length, pulse amplitude, pulse period, delay, burst repetition frequency, sets of loops, multiple sets of loops, multiple and / or different sets of loops, sets of loops, and various combinations or permutations thereof, and are included as part of this disclosure, including such future envisioned embodiments.

[0070] Technical challenges of histotripsy

[0095] Using ultrasound therapy, such as histotripsy, to treat deep tissue targets (e.g., >8 cm) or through heterogeneous tissue presents two technical challenges: 1) acoustic aberrations and 2) real-time feedback of ultrasound therapy.

[0071]

[0096] Acoustic aberrations are a problem affecting ultrasound therapy and imaging, including histotripsy. Acoustic aberrations can reduce focal pressure and distort the focal spot due to the propagation of ultrasound waves through multiple, heterogeneous tissues. Reduced focal pressure can result in ineffective treatment or reduced treatment efficiency. For example, in histotripsy, the focal pressure at the target tissue site is precisely controlled to generate cavitation there. Reduced focal pressure due to aberrations can prevent cavitation from occurring. Distorted focal spots can also reduce treatment accuracy. Typically, focused ultrasound transducers are shaped as segments of a sphere so that sound waves emitted from all locations from the transducer surface travel the same distance and arrive at the focal spot simultaneously. However, due to variations in the speed of sound between bone and heterogeneous soft tissues, the travel times from different elements of the ultrasound transducer array to the focal spot can vary. As a result, aberrations can cause loss of focal pressure and a shift in the focus, reducing the effectiveness and accuracy of treatment.

[0072]

[0097] Because ultrasound is a non-invasive therapeutic technique, real-time feedback is important for achieving high treatment accuracy and minimizing potential complications. Ultrasound imaging has been used to provide real-time feedback for histotripsy, as the cavitation generated by histotripsy can be visualized as a dynamic bright zone on ultrasound images. Typically, an ultrasound imaging probe is inserted into the central bore of the histotripsy transducer, so that the 2D ultrasound imaging plane includes the histotripsy focus. Ultrasound imaging can then be used to guide targeting, positioning the histotripsy focus at the correct target tissue and monitoring treatment progress. However, using ultrasound imaging as the sole guidance for histotripsy has two major limitations: 1) ultrasound images of the histotripsy focus cannot be obtained if the ultrasound imaging probe is blocked by the patient's bones (e.g., ribs or skull). For example, histotripsy can be used to treat tumor volumes in a patient's liver that are partially behind the ribcage. When the histotripsy transducer is mechanically moved to scan the histotripsy focus and cover the tumor volume, the imaging probe may be blocked by the ribs for a certain duration of treatment, at which point real-time imaging of the treatment is not available. Without feedback during this duration, there is no way to know whether cavitation is still being generated at the tumor target location (i.e., whether treatment is being performed for this duration). 2) The ultrasound imaging probe can only observe tissue and cavitation within the 2D image plane that contains the histotripsy focus. Therefore, the ultrasound imaging probe cannot observe potential undesired cavitation occurring outside the image plane. Undesired cavitation may generate undesired off-target damage.

[0073]

[0098] The problems described above are not only solved by transmitting an ultrasound signal to generate cavitation and provide histotripsy, as described herein, but also by This can be solved using a novel Histotripsy ultrasonic phased array transducer configured to receive ultrasound signals (i.e., a transmit-receive Histotripsy array).

[0074]

[0099] For example, if the ultrasound therapy transducer comprises a phased array, phase correction techniques can be used to correct aberrations and restore reduced focal pressure. This can be achieved by adjusting the phase / time delay in transmission from each transducer element of the phased array to compensate for variations in travel time from each array element to the focal point due to the velocity of sound vibrations. In this way, aberrations can be corrected to increase focal pressure and improve focus.

[0075]

[0100] Ultrasonic phased array transducers capable of delivering histotripsy and receiving acoustic cavitation radiation signals can be further configured to enable cavitation detection, localization, and mapping. Currently, typical histotripsy systems only transmit ultrasound pulses to generate cavitation at a focal point. Transmit-receive histotripsy systems can be used not only to deliver ultrasound pulses to generate cavitation, but also to receive signals such as acoustic cavitation radiation (ACE) signals. Both the rapid expansion and rapid collapse of cavitation bubbles in histotripsy generate shock waves that can be detected by an acoustic receiver. In some embodiments, received reflections of the main treatment pulse (if longer than one to two cycles and not fully converted into shock waves in the cavitation-generating event) or subsequent low-amplitude treatment pulses can be used in various receive applications, as listed below. By processing ACE signals received from a histotripsy transducer array system with hundreds of elements and transmit / receive capabilities, cavitation can be detected, localized, and provide real-time 3D cavitation maps. Using acoustic emission signals from the growth and / or collapse of histotripsy-induced cavitation microbubbles received by the histotripsy array, cavitation can be localized and monitored in 3D and in real time, even in situations where the ultrasound imaging probe is blocked by bone. 3D cavitation mapping can also monitor off-focal cavitation in real time to enhance safety and identify unwanted cavitation.

[0076]

[0101] The transmit and receive drive electronics found in typical phased array systems cannot be directly adapted to Histotripsy phased array transducers due to the extremely high voltages (thousands of volts) required to generate high-voltage Histotripsy pulses. The novel drive electronics described herein are configured to safely block or significantly attenuate transmit signals to the ultrasound transducer array while maintaining high sensitivity and high dynamic range of the received ultrasound signals. This disclosure provides both hardware and software for a phased array Histotripsy transducer array with transmit and receive capabilities. This disclosure further describes methods and signal processing algorithms that can be used with transmit and receive Histotripsy systems for aberration correction and cavitation mapping.

[0077] Transmitter and receiver electric drive system

[0102] The electrical transmit signals to a histotripsy transducer are typically on the order of kilovolts, while the received ultrasound signals are typically in the millivolt to tens of volt range. Accordingly, the transmit and receive electrical drive circuits described herein are designed and configured to block or significantly attenuate high amplitude transmit waveform signals on the order of thousands of volts, while having sufficient sensitivity and dynamic range to receive low amplitude signals on the order of tens of volts.

[0078]

[0103] There are many embodiments of the drive circuitry and methods for achieving the above-described functions / objectives. and implementations are described herein. In some examples, the driver circuitry can be retrofitted or added to an existing transmit-only Histotripsy system to provide transmit and receive functionality. In other embodiments, the driver circuitry is integrated into an entirely new transmit and receive Histotripsy system.

[0079]

[0104] FIG. 2A illustrates one embodiment of a novel receive driver circuitry 200 configured to be retrofitted to an existing transmit-only Histotripsy system to enable transmit and receive functionality. In the illustrated schematic, a nonlinear compressor can attenuate all signals connected to each of the Histotripsy elements, with greater attenuation of high-amplitude signals and less attenuation of low-amplitude signals. For example, capacitive voltage divider 202, as indicated by C1 and C2, can be configured to first attenuate all input / receive voltage signals from transducer element TX1 by approximately 1-10% (or attenuate signals by 90-99%). Next, diode-resistor voltage divider 204, as indicated by D1, D2, and C3, provides nonlinear attenuation to compress all signals above approximately 1 volt, and is configured to couple the alternating current (AC) signal to an analog-to-digital converter (ADC) for ADC conversion. The last component before the ADC is a voltage level shifter 206, represented by R2 and R3, which brings the signal into the appropriate voltage range for the ADC (e.g., typically between + / -0.5V and + / -2V). As explained above, this circuitry is configured to be retrofitted into an existing transmit-only histotripsy drive system. For example, a separate circuitry board can be added and connected to the existing transmit circuitry to add receive functionality. In one embodiment, the receive circuitry is added in parallel with the transmit electronics and passively receives the signal without affecting the transmit electronics.

[0080]

[0105] FIG. 2B illustrates one embodiment of a driver circuitry 200a incorporated into high-voltage histotripsy driver electronics. In the embodiment of FIG. 2B, a bank of capacitors (not shown) in series with the primary coil 20 of a transformer is charged by a high-voltage source. The driver chip U1 then triggers an n-channel MOSFET transistor Q1, which sends a high-voltage AC pulse through the primary coil of the transformer, thereby generating an AC pulse in the secondary coil 22 of the transformer with a voltage proportional to the turns ratio between the coils. The secondary coil can be electrically coupled to each of the transducer elements (transducer element TX1 in this example). In one implementation, a turns ratio of approximately 1:3 was used between the primary and secondary coils. Thus, this receiver driver circuitry can generate single-cycle pulses on the order of approximately 3 kV at the center frequency of the transducer. It should be understood that other turns ratios can be implemented.

[0081]

[0106] Referring to FIG. 2C, another embodiment of the receive drive electronics for a Histotripsy system is illustrated. 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 and used for the receive electronics, thereby providing complete isolation between the driver (e.g., 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 turns than the secondary transformer coil 22, thereby reducing the voltage between the secondary and third coils by a factor of 10. The number of turns in the tertiary or third coil can be adjusted to suit a particular application and need not necessarily be 1 / 10 of the secondary coil. This ratio depends on the amplitude of the receive signal and can be adjusted based on the desired voltage. In one embodiment, the receive winding (third coil 24) from FIG. 2C can be coupled to a second transformer designed for small signals, with a specially selected core material and size, and would be configured to saturate during transmit pulses to protect the analog-to-digital circuitry (ADC) behind it. However, when receiving a signal, the second small signal transformer would not saturate. The antenna may be configured to provide adequate gain and sensitivity for the received signal.

[0082]

[0107] The schematic design of the receiver circuitry for an integrated receiver-enabled histotripsy system is shown in Figure 2D. Compared to the embodiment in Figure 2A, the main difference in the embodiment in Figure 2D is the transformer described in the embodiment in Figure 2C. A VGA circuit is added to the embodiment in Figure 2D, and instead of the level shifter shown in Figure 2A, a "balanced" input with two capacitors C3 and C4 connected in series includes a digitizer.

[0083]

[0108] In another embodiment, the transmit / receive driver circuitry can include a transmit / receive switch. Integrated driver / receiver circuitry, with both transmit and receive circuitry on the same substrate, can use a switch to separate the receive signal from the transmit signal. For example, a conventional TR switch with a diode blocks the high-voltage transmit signal without attenuating the receive signal. Circuits with different linear gains can follow the switch to appropriately amplify or attenuate selected portions of the receive signal based on its amplitude to maximize sensitivity. However, this design wastes a lot of power and is large and expensive.

[0084]

[0109] FIG. 3A illustrates another embodiment of driver-receive circuitry configured to measure current flowing back from transducer TX1 through driver transformer T1 (instead of measuring the voltage generated at the transducer during receive, as discussed above). Compared to conventional imaging transducers, the relatively large surface area of ​​therapy transducer array elements means that the transducer array generates relatively large currents, which increases sensitivity during receive; however, with imaging transducers, it is practical to measure only the voltage induced by the acoustic signal. Typical ultrasound imaging elements are too small to generate usable receive currents. Because the therapy elements described herein have surface areas hundreds to thousands of times larger than conventional imaging elements, the currents are significantly larger and easier to measure (in the milliampere range rather than microamperes). In the illustrated circuitry, the current can be measured by a sense resistor in the electrical path (R1). The driver-receive circuitry is configured to pass excess current from large reflections or during transmit pulses through a series of bypass diodes (D1 and D2). The transmit current can be as large as 40 A. While the drive-receive circuitry receives reflections, such as ultrasonic reflected signals and / or acoustic cavitation emissions, the sense resistor is configured to measure the current induced in the circuitry by those reflections. The voltage developed across the current-sense resistor is coupled to the ADC via a balun (T2) and capacitors C1 and C2. This balanced input configuration is the manufacturer's recommended circuit for the AFE5801 digitizer. Single-ended operation of this or other digitizers would also be possible by directly measuring the voltage across R1 relative to ground.

[0085]

[0110] The driver / receiver circuit configuration of FIG. 3A can be configured to operate in low-gain and high-gain modes. With continued reference to FIG. 3A, this circuit configuration can have two current-sensing resistors R1 and R2 to allow for significant modification of the overall sensitivity of the circuit. As shown, this can be implemented using a pair of transistors Q2 and Q3 configured to switch on and off a small-value resistor R2 (low sensitivity) and a large-value resistor R1 (high sensitivity) in parallel. These transistors are used to very quickly modify the resistance of the circuit, enabling it to use both a low setting for a portion of the received data burst (e.g., a high-amplitude received signal, such as an ultrasound reflection signal from a bone) and a high setting a few microseconds later (e.g., a low-amplitude received signal, such as an acoustic cavitation radiation signal from a cavitation collapse). Unlike variable-gain amplifiers, where the SNR typically worsens with higher gain because the sensor is directly modified, both scales have a very high SNR. In some embodiments, a wider dynamic range can be achieved. For the circuit shown in Figure 3A, the high-gain mode is configured to measure currents up to 5 mA at the ADC coupled to the circuitry via transformer T2, while the low-gain mode is configured to measure currents up to 200 mA at the ADC.

[0086]

[0111] 3B illustrates an alternative embodiment in which low gate threshold MOSFET transistors Q4 and Q5 can be implemented in place of the bypass diodes to pass the large transmit current. Advances in transistors have resulted in smaller, cheaper, and more powerful transistors than the diodes that perform this bypass role. These transistors can have a higher turn-on voltage than a single diode, making it easier to use the full dynamic range of the ADC.

[0087]

[0112] 3C illustrates a third embodiment in which bypass transistors Q4 and Q5 are explicitly controlled as active transmit / receive switches. The transistor gates are connected to a gate drive signal, which can be, for example, + / - 5V, depending on the transistor's drive requirements, turning the transistor fully on (for transmit mode) or fully off (for receive mode). This configuration can reduce RF noise generated during transmit, but at the expense of requiring the passively switched bypass components to be rapidly switched on and off at ultrasonic frequencies. This design trades off a slight increase in complexity.

[0088]

[0113] The analog received signals described above are converted to digital signals and then collected and processed. The signals received from the Histotripsy transducer array may be, for example, reflections from bone or soft tissue, or acoustic emission signals from cavitation. These signals are typically received within a specific time window after the Histotripsy pulse (e.g., tens to hundreds of microseconds after the transmission of the treatment pulse). Therefore, the hardware and software described herein are configured to synchronize the transmit, receive, and ADC conversion and sampling time clocks to obtain the appropriate time window after each Histotripsy pulse that contains the desired received signal. With the synchronization and time window properly set, the desired received signal can be collected and processed.

[0089]

[0114] To achieve proper synchronization and time windows, any of the transmit and receive driver electronics described herein can include embodiments in which a single field-programmable gate array (FPGA) device connected to the ADC can be used to control both the transmit and receive transducer operations as well as the ADC for all or a subset of the channels of a Histotripsy system. By providing the FPGA with a single clock off which the timing of operations performed by individual subsystems is based, synchronization between subsystems can be ensured, especially when multiple FPGAs are used to control various subsets of Histotripsy transducer elements. Setting the appropriate time windows for receiving signals can then be achieved by appropriately assigning the timing of each operation when programming the FPGA. If multiple FPGAs are required, for example, in an array with too many transducer elements to be controlled 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 operations within the appropriate time windows.

[0090]

[0115] Alternatively, any of the transmit and receive driver electronics described herein may include a multi-FPGA system and be configured to operate in a "headless" mode where no centralized "master" FPGA is required to issue / fanout a single shared clock line or to trigger the execution of individual board operations. In this example, each FPGA runs on its own clock and is configured to monitor and update two common "program execution states" and one common "operation running" open-drain hardware IO lines shared by the entire system. The open-drain lines register a signal measured anywhere on the line low when a single FPGA applies a low signal to the line, and register a signal measured anywhere on the line high only if all FPGAs apply a high signal to the line. The two "program execution state" lines are used by the FPGAs to issue system-wide 1) "ready to run" and 2) "execution complete" signals; by default, each FPGA will apply a low signal to each of these lines, and each FPGA will apply a high signal to the "operation running" line. During program execution, when a new executable instruction in the program is reached, each FPGA updates its "ready to run" line, applies a high signal, and enters a wait state, where it monitors both the "ready to run" and "operation running" lines. When all FPGAs reach the "ready to run" state, the signal registered on the "ready to run" line goes high. The first FPGA in the system, detecting a high state on the "ready to run" line, issues a low signal on the "run program" line and registers low everywhere. Upon detecting a low signal on the "run program" line, each FPGA sets the value of its own terminal on the "run program" line low and executes its stored command. When each FPGA finishes executing its respective command, it asserts a high signal on both the "run done" line and the "run program" line. When both the "run done" line and the "run program" line register high, the FPGA resets all shared open-drain line values ​​to default, loads the next instruction in the program, and repeats the process for each instruction until the program is complete.

[0091]

[0116] Because a fully connected series of receiving elements can generate large amounts of data, strategies to reduce the data load are proposed to enable real-time transfer and processing of acquired signals to meet monitoring needs during treatment. These strategies can be applied to any of the transmit / receive driver electronics described herein. Such strategies may include, for example, artificially downsampling the input data from the ADC in firmware running on the FPGA (e.g., by storing only every other data point generated by the ADC or an average of data points generated over multiple acquisition cycles). This effectively reduces the sampling frequency, thereby reducing the data load, but without sacrificing time accuracy, dynamic range, or introducing increased noise in the system. Differential compression schemes may also be applied, in which all data captured after a first time point is stored as the difference between values ​​captured at adjacent time points. For example, for a value of X at time 1 and a value of Y at time 2, instead of directly storing the value of Y, the difference value between Y and X, D=YX, can be stored at time 2, and then during processing, the actual value of Y can be calculated as Y=X+D. Thus, for example, a nominal value of X=64000 and Y=63900, which combined represent four bytes of data, can be stored as X=64000 and D=-100, which combined represent three bytes of data, allowing full recovery of the value of Y. As the length of the data record increases, this compression strategy reduces the data proportionally to the ratio of the size of the variables required to store the difference values ​​compared to the size of the variables required to store the actual values. This typically reduces the data load by 30%-50% in current systems, but can result in significant reductions in systems where the size of individual data elements is large. For applications that do not require real-time processing / compression, further reductions in data size can be achieved by frequency-domain transforms using methods similar to those applied to compressing audio files.

[0092]

[0117] Some of the events that need to be monitored during histotripsy treatment require very high time precision (e.g., signals from individual cavitation events), Others (e.g., signal reflections away from large boundaries such as the skull, ribs, or tissue interfaces) require less precision, and strategies for dynamically changing compression ratios can be implemented to fully utilize the input data for real-time applications. To this end, the firmware and software controlling the data acquisition are configured to allow the sampling frequency and compression strategy used during acquisition to be set for each channel in the array and updated independently in real time, even during individual acquisition events. This not only allows different subapertures of the array to be configured to monitor different characteristics of the treatment at the required sampling frequency and compression settings, but also allows the receiving system to be set to the highest sampling frequency / lowest compression setting across all elements of the array when needed to monitor potentially weak-signal, short-lived events, and then revert to a lower sampling frequency with a higher compression setting outside the window requiring maximum monitoring. This allows full monitoring of these types of short-lived events without the need to interrupt acquisition, reducing the physical size of the actively monitored field and the data load, which could significantly slow down monitoring speed during treatment.

[0093]

[0118] In some situations, the received signal amplitude may be low and noise may be high, resulting in a low signal-to-noise ratio (SNR). One way to reduce noise and improve SNR is to oversample and average the data in firmware (e.g., FPGA firmware) before storing it. This also helps increase the dynamic range and reduce memory requirements. Another technique is to implement a dynamically variable sample rate. For example, an ADC may be configured to always run at 50 MHz, but high time accuracy may be required only during certain parts of the data record. In parts of the signal where such a high frame rate is not required, the samples can be decimated or averaged, significantly reducing storage requirements.

[0094]

[0119] Although the bandwidth of the therapy transducer elements is typically low, high sampling rates can be used for sampling due to good timing accuracy. The received data is very well compressed (at least 10 times, and sometimes more) in the Fourier domain. The FPGA can be configured to perform this compression before storage or transmission in firmware or software. Data compression is key to implementing real-time monitoring, as the system would be overwhelmed by the amount of received data collected.

[0095]

[0120] For applications where real-time monitoring is not essential, or where the treatment speed needs to be kept as fast as possible while simultaneously transferring the complete acquired signal 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 device itself for later transfer to the control computer. This allows for uninterrupted signal acquisition from all delivered pulses without limiting treatment speed. Such a feature is useful for monitoring long-term changes in the acquired signals. For example, while there is inherent variability in the ACE signal features associated with the ablation state of the target tissue, making it difficult to track the tissue state on a pulse-by-pulse basis, characteristic changes in the ACE signal exist over longer treatment timescales (e.g., over 20 applied pulses) that allow for assessment of the tissue's ablation state. Partial signals can be transferred in real time to allow for pulse-by-pulse localization and mapping of cavitation events, while longer recording lengths of signals can be stored and intermittently transferred to the FPGA to assess the ablation state of the treatment target.

[0096]

[0121] In some situations, it is possible to generate focal pressures far greater than twice that nominally required to generate cavitation during treatment, and in such cases, it is possible to generate cavitation using less than half of the Histotripsy transducer array elements. The software controlling the Histotripsy array allows the elements of the array to be easily divided into individually controllable sub-apertures, allowing a single physical Histotripsy transducer array to effectively operate as multiple separate Histotripsy arrays. In this way, multiple locations within the focal volume can be targeted for treatment simultaneously using separate sub-apertures of the array, increasing the treatment speed without having to increase the rate at which pulses are delivered.

[0097] Aberration correction techniques

[0122] Below, examples of novel aberration correction methods and techniques specific to histotripsy treatment are described.

[0098]

[0123] One embodiment of aberration correction enabled by the transmit / receive Histotripsy array utilizes the arrival time of the powerful shock wave emitted by the initial rapid expansion of Histotripsy-induced cavitation bubbles. This can be referred to as the Acoustic Cavitation Emission (ACE) signal. This shock wave structure radiates spherically from the focal cavitation region toward the Histotripsy therapeutic array. Any aberrations in the propagation path can be determined by calculating the travel time from the focal cavitation site to each Histotripsy array element. After processing the arrival time of the ACE signal received by each element, a corrective time delay for each transducer element can be applied to each subsequent transmission, ensuring that the ultrasonic pulse waves generated by each Histotripsy array element arrive at the focal cavitation location simultaneously. This is done by applying changes in the time-of-flight of the ACE signal to the transmit pulse signal to each Histotripsy array element, ensuring that the transmit signals arrive at the cavitation site simultaneously, correcting the aberrations and improving focus.

[0099]

[0124] For ACE-based aberration correction, a specific method and algorithm can be implemented, as illustrated by the flowchart in FIG. 4, including the following operations. In step 402, the method can include transmitting Histotripsy treatment pulses into target tissue using an ultrasound transducer array to generate cavitation in the target tissue. As described above, multiple transducer elements of the array can each transmit a separate Histotripsy pulse into the tissue. Next, in operation 404, the method can include receiving acoustic cavitation emissions (ACE signals) resulting from the Histotripsy-induced cavitation. Reception of the ACE signals can utilize, for example, any of the systems or drive electronics described above. Next, in operation 406, the method can use information encoded in these ACE signals (e.g., start time of emissions generated from cavitation bubble expansion, peak time from cavitation bubble collapse) to calculate travel times from each element of the Histotripsy array to cavitation in the target tissue. Finally, in operation 408, the method can include adjusting the time delay of the driving electrical signals to each array element to compensate for differences in travel time, so that the ultrasound pulses delivered by each element arrive at the focal point / target tissue simultaneously on subsequent transmissions. This method can be used for aberration correction of bone or foreign tissue in the path.

[0100]

[0125] While the methods described above discuss receiving ACE transmissions from rapid cavitation expansions, the same techniques can be used to receive acoustic shock waves / signals from cavitation bubble collapses. The signals from cavitation bubble collapse received by each array element can be used in the same way as cavitation expansion signals to calculate time-of-flight for aberration correction as described above.

[0101]

[0126] The shock wave pressure tends to increase linearly with increasing histotripsy focal pressure. One embodiment of time-of-flight analysis of these shock waves involves using a Hilbert transform to calculate the envelope of these shock waves. A cross-correlation algorithm can then be used to determine the time shifts required to realign these envelope signals. These time shifts are then inverted to correct for time-of-flight variations between histotripsy elements and then applied to subsequent pulses as described above. Other methods of analyzing these signals include detecting the peak pressure of the shock wave or using a window averaging filter and edge detection algorithm to determine the arrival time of the shock wave. Without aberration correction, the focal pressure at subcavitation threshold amplitudes is reduced by 49.7%, and the transducer power required to induce cavitation is tripled. Using the ACE aberration correction method described above, more than 20% of the lost pressure can be recovered, reducing the transducer power required to induce cavitation by approximately 31.5%.

[0102]

[0127] The acoustic cavitation emission (ACE) signal may not always be detectable (e.g., due to attenuation effects from propagation through tissue / bone) and / or may not be distinguishable from background signal components at a level sufficient to perform aberration correction (e.g., the ACE signal may arrive at an array element simultaneously with the reflection / reverberation of the Histotripsy pulse). In such cases, using cavitation events as the basis for aberration correction may be achieved using pulse-echo techniques by dividing the Histotripsy array element into multiple subapertures, one used to generate cavitation events (subaperture A) and the other used to fire interrogation pulses (subaperture B). In this scenario, all elements of subaperture A fire Histotripsy pulses at an amplitude sufficient to generate a cavitation event at the target, e.g., at time = 0. After the generated cavitation event has grown in size, e.g., at time = 100 μs, element subaperture B fires a pulse toward the event. Upon arriving at the cavitation event generated by subaperture A, the pulse from subaperture B is reflected from the cavitation event and scattered towards the array. The array elements of both subapertures can then be used to receive the signals reflected from the cavitation event, and the arrival timing of these signals can be used to calculate the aberration correction delay according to the methods described in

[69] and

[70] . The main advantage of this technique is that the timing of the pulse from subaperture B can be set arbitrarily, which allows the reflected / scattered signal to return to the array elements and be detected in a signal area with minimal background components.

[0103]

[0128] In another embodiment, the aberration correction can be based on scattering signals from soft tissue.

[0129] Focal dithering methods can also be used for aberration correction based on received signals. A challenge in using scattered or reflected signals from soft tissue is that the amplitude from the scattered signal from the target tissue is often small and / or buried in the background signals of scattered signals from other tissues. The scattered signal, where the array focus is at the geometric focus, is detected by all elements of the array (Sc1 n , n is the element number). The array focus can then be dithered to a small distance (e.g., 1 / 2 wavelength or 3 / 2 wavelength) away from the geometric focus, and the scattered signal is also received from all elements of the array (Sc2 n , n is the element number). Both of these signals contain background scattering signals from all the different tissues in the path, but the difference (Sc2 n -Sc1 n ) is due only to the scattered signal from the dither focus in antiphase. Combinations of phase or time delay for all elements are tested to obtain the difference (Sc2 n -Sc1 n ) is determined. The resulting combination can be used for aberration correction. Due to the small difference in the speed of sound between tissues, the variation in time of flight due to disparate soft tissue paths between elements is expected to be small. Therefore, a preset set of delay combinations can be pre-calculated and used for testing. This method allows for aberration correction without generating cavitation, while maintaining a good enough SNR for processing. There is a possibility that this may occur.

[0104]

[0130] For ultrasound therapy, water is often used as a coupling medium to reliably transmit ultrasound waves from a transducer array to a patient's skin. Differences in the speed of sound between water and soft tissue can shift the location of the focal spot significantly (e.g., by several millimeters). Reflected signals from the water-skin interface are received at each array element to determine the time of flight from the surface of each element to the water-skin interface, and the time-of-flight determination can be used to correct for the focal spot shift caused by the coupling medium.

[0105]

[0131] The reflected signal from the bone may have a high amplitude. The methods and algorithms described herein may also include detecting transducer elements blocked by the ribs (via a high amplitude reflected signal) and turning off those transducer elements or reducing the amplitude of the transmitted signal to those transducer elements (amplitude aberration correction) to reduce the possibility of heating the ribs or bones during Histotripsy treatment.

[0106]

[0132] Reflected signals from various tissue surfaces and layers are received by each array element, allowing the tissue layers to be modeled. Based on the speed of sound in each tissue layer using literature values, the time of flight from each element to the array focal point can be calculated for aberration correction. This method only provides coarse aberration correction.

[0107] Cavitation Localization and Mapping

[0133] The ACE signals received by the transmit / receive histotripsy transducer array described above can be used to localize and map cavitations within target tissue. The known location of each histotripsy transducer array element allows for the use of conventional beamforming methods used in ultrasound imaging and passive cavitation mapping. However, because the speed of sound within each element's path may differ, modifications to existing beamforming or passive cavitation mapping algorithms are required to image cavitations behind bone or other aberrators, such as ribs, through the skull, or through deeply concealed tissue, to account for variations in the travel time of different elements to reach the focal point, as discussed herein. The travel time differences can be accounted for using an iterative method that maximizes signal amplitude within the focal cavitation region after beamforming.

[0108]

[0134] For example, a brute force method can be used to iteratively test a range of ultrasound travel time delays for all Histotripsy array elements. The time delay combination that results in the greatest amplitude of the summed ACE signal can be used to localize and map the cavitation. This can be achieved fast enough for real-time imaging. The following example illustrates a 70 Hz frame rate for cavitation localization through a resected human skull with an accuracy of within 1.5 mm based on a transmit-receive Histotripsy system and brute force method. Note that the same method can be used to obtain mapping of the skull surface or ribs in the path, since the strong reflected signal from the bone is received by the Histotripsy array and separated for processing.

[0109]

[0135] Example: Transcranial Cavitation Localization and Mapping. In this example, a brute-force iterative method can be used to localize cavitation through the human skull. The same method can be applied to generate cavitation mapping through the ribs and monitor cavitation behind the ribs. Cavitation localization and mapping is achieved in two steps: 1) signal processing to separate the ACE signal from the skull reflection signal; and 2) generating a cavitation map by projecting the ACE signal acquired by each element of the array into the field and summing their signal amplitudes.

[0110]

[0136] Signal processing to separate the ACE signal from the skull reflection signal can involve three basic steps. First, low-amplitude, sub-cavitation threshold Histotripsy pulses can be delivered to the target tissue, and reflections of the pulses from intervening tissue can be recorded using the transducer array elements. These signals can then be scaled up and subtracted from the ACE-containing signal generated after delivering a high-amplitude Histotripsy pulse to separate the ACE signal from the background. Next, a moving window average can be used to smooth the signal to reduce the spurious effect of noise in the acquired signal on the localization results. The signal magnitude can then be used to calculate the localization algorithm. It can be used as a prerequisite for the program.

[0111]

[0137] Localization and mapping of cavitation events can be achieved through a brute-force iterative method by projecting the acquired ACE signal into the field and generating a volumetric map of the projected signal amplitude at the focal region of the transducer. The volumetric map used in the calculation can be generated in a grid of voxels centered on the expected location of the cavitation event in the field. Based on the known location of the histotripsy transducer element and its distance from each voxel in the volumetric grid, the round-trip flight time of an acoustic pulse propagating between the voxel and the transducer can be calculated under the assumption that the speed of sound is constant everywhere along the voxel and that the known speed of sound is constant. Then, at each respective voxel, the signal amplitudes measured from each transducer at the corresponding time can be summed to determine the total signal amplitude at each voxel. To account for the fact that the speed of sound between the transducer and the voxel is not constant due to the presence of tissue between them, the process of selecting the time point in the acquired ACE signal at which the measured signal amplitude was obtained can be repeated over time by iterating over time for the round-trip time of flight calculated at each voxel element and recalculating the signal amplitude field at each time step. The total signal amplitude at each voxel at the end of the iteration can be considered to be the maximum value calculated at each voxel within the entire iteration window. This process accounts for the combined effect of the speed of sound and thickness of tissue on ultrasound propagation by considering only the final result, which, in this simplified case, produces a uniform modulation of the signal arrival time at the transducer element. This significantly reduces computational complexity and allows the influence of tissue to be taken into account during the localization process using iterative time-shifting operations. The location of the cavitation event can be calculated by finding the centroid of all points within the voxel grid whose amplitude exceeds 90% of the maximum detected value.

[0112]

[0138] Using this method, 3D cavitation localization can be achieved through bones such as ribs or the human skull. ACE feedback localization results are accurate to within 1.5 mm of the actual location (measured by optical imaging) of the center of mass of the generated cavitation event. Considering the physical size of the bubble, it is known that in over 90% of cases, the localization results fall within less than 1 mm of the volume enclosed by the bubble. Using the described method, real-time cavitation localization was achieved during experiments at rates up to 70 Hz, although benchmark tests indicate that higher rates are likely possible with more powerful hardware, as the localization algorithm scales efficiently.

[0113]

[0139] Referring to Figure 5A, the signals received from each element of the transmit / receive histotripsy array are shown, including a reflected signal from the skull at cavitation pressures below the threshold, a skull reflected signal and an ACE signal at cavitation pressures above the threshold, and a processed ACE signal obtained by subtracting the skull reflected signal. Figure 5B illustrates a skull surface map and focal cavitation localization map generated by processing the ACE signal using a brute-force iterative method.

[0114]

[0140] In another embodiment, the methods described for mapping transcranial cavitations are extended for use in applications where the target is located under a highly heterogeneous aberrator (i.e., ribs) or where there is significant variation in path length through tissue en route to the target (e.g., when the transducer must be aligned at an angle to the tissue surface in order to focus on the target). The same signal processing and localization methods described above can be applied with two important additions.

[0115]

[0141] Signal Processing: Additional steps in signal processing may be required to account for the presence of non-uniform aberrators and tilted surfaces. First, each element of the array is fired individually, and the reflection of the pulse from the tissue is recorded by all array elements. Given the known locations of the transducer elements and the speed of sound in the coupling medium, conventional delay-and-sum beamforming can be used to generate a 3D map of the tissue surface and underlying features (i.e., ribs) from the acquired signals.

[0116]

[0142] 2) Cavitation Localization and Mapping: Given the known surface shape of the tissue and / or the location of underlying features such as ribs, non-uniform delays can be applied to the ACE signals acquired during the time-iteration process used to localize cavitation events. In the case of ribs, delays can be assigned to ACE signals known to propagate through ribs, with a fixed offset relative to those that do not, based on their known location, to maximize the signal amplitude projected into the field and thereby localize the cavitation event. Alternatively, for diagonally aligned transducers, given the known surface shape of the tissue, the time delays assigned to each array element can be stepped to account for the different path lengths through tissue that the ACE signal must traverse to reach each element.

[0117]

[0143] In another embodiment, the described methods are extended for use in applications where the target is within a nearly uniform aberration (i.e., the liver) where the speed of sound may not be well known, particularly where changes in path length through the tissue on the way to the target are significant (e.g., where the transducer needs to be aligned at an angle relative to the tissue surface to focus on the target). The same signal processing and localization methods described, as well as the method for mapping tissue surface shape described above, can be applied with the following additions.

[0118]

[0144] Given the known surface geometry of the tissue, the speed of sound in the coupling medium, and the timing of the generated ACE signal, the location of the cavitation event as well as the speed of sound in the nucleation medium itself can be determined by minimizing a system of equations through application of Snell's Law, which accounts for refraction. Given the known locations of the array elements relative to the tissue surface, the time of flight from each element to every point on the tissue surface and the respective trajectories of the pulses relative thereto can be calculated. Upon exiting the tissue, the trajectory of the ACE signal from the cavitation event will change due to the difference in the speed of sound between the tissue and the coupling medium, according to Snell's Law. While the speed of sound in the coupling medium and the distances from the array elements to every point on the tissue surface are known, the point on the tissue surface from which the received portion of the ACE signal acquired by each array element originated is unknown, as are the speed of sound in the tissue and the location of the cavitation event being mapped. The timing of the ACE signal at each array element, t ACE,n is t ACE,n =[D cm,n / C cm,n +D t,n / C t,n ], which depends only on the distance traveled through the coupling medium and tissue and the respective sound velocities, where "D" and "C" correspond to "travel distance" and "medium sound speed", respectively, and the subscripts "cm", "t", and "n" correspond to "coupling medium", "tissue", and "element number", respectively. The values ​​of three of these variables (D cm,n ,D t,n ,C t,n ) is unknown, , D cm,n The value of D t,n and C t,n can be re-expressed purely in terms of their values, and become insignificant due to the application of Snell's law at the boundary of the tissue-coupled medium. ACE,n,exp -t ACE,n The speed of sound in the medium and the location of the generated cavitation can be solved for by minimizing the value returned by ACE,n,exp is C t,n and the value of (D t,nThe timing of the ACE signal is experimentally measured by adjusting the cavitation bubble position in the tissue (expressed as a value of ).

[0119] Real-time treatment monitoring

[0145] As discussed above, Histotripsy generates cavitation to mechanically fractionate target tissue. With increasing dosage or treatment, the treated tissue becomes increasingly soft and eventually liquefies into acellular debris. As a result, over the course of treatment, the generated cavitation bubbles grow larger and take longer to collapse, eventually resulting in cavitation activity mimicking intense cavitation activity in fluids. Signals of cavitation expansion and collapse can be detected via acoustic cavitation emission (ACE) signals received by the transmitting / receiving Histotripsy array and processed to quantitatively monitor treatment progress and determine treatment completion. For example, the time to maximum cavitation bubble growth and bubble collapse time increase during treatment, eventually saturating as the target tissue liquefies and treatment is completed. This increasing trend can be detected by processing the ACE through a specific algorithm, indicating when treatment is progressing, and the saturation trend can be detected by a specific algorithm, allowing treatment completion to be determined, all in real time. An example of such an algorithm involves using peak detection in the acquired waveforms to identify ACE signals associated with bubble growth and collapse and measure the timing between these ACE signals. When signals are buried in a strong background environment, individual waveforms can be processed by autocorrelation to identify the timing between self-similar regions within the waveform (i.e., growing and collapsing ACE signals). Because the background environments of the individual signals are not comparable, ACE signals can be identified by comparing all of the individual autocorrelation results from each array element with each other, e.g., median filtering the autocorrelation results to reveal consistent peaks at times corresponding to the bubble lifetime. Back-projecting the acquired signals into a field imaging the volume as a function of time similarly reveals peaks in the projected signal amplitude within the imaged volume at times corresponding to the growing and collapsing ACE signals.

[0120]

[0146] However, the acoustics of these ACE signals are very complex and can be analyzed in many different ways to obtain the desired criteria for treatment progress monitoring. Therefore, specialized algorithms are required that include the following functions: As shown with reference to the flowchart of FIG. 6, a method for monitoring the progress of a Histotripsy treatment can include detecting and separating selected ACE features (e.g., the timing and amplitude of cavitation bubble expansion, collapse, and / or rebound signals) from tissue signals in step 602, calculating cavitation parameters that correlate with tissue damage generated by Histotripsy (e.g., collapse time, i.e., the time between the expansion and collapse signals, the peak amplitude of the expansion signal, the peak amplitude of the collapse signal, the amplitude ratio between the growth and collapse ACE signals, or the decay rate of the rebound-related ACE signal amplitude) in step 604, determining changes that correlate with normal treatment progress (e.g., the slope of increase of the selected cavitation parameter) in step 606, and determining changes that correlate with completion of the treatment (e.g., saturation of the change in the selected cavitation parameter) in step 608.

[0121]

[0147] An example of the cavitation parameter collapse time is provided. This example shows that the increase and saturation of the cavitation collapse time correlates with the progression and completion of the procedure. The collapse time (t col ) is an indicator of the progression of the tissue fractionation process during histotripsy treatment.

[0122]

[0148] In the experiments, a 500 kHz, 112-element histotripsy array was used to generate single-location lesions in ex vivo bovine liver samples as well as tissue-mimicking agar phantoms of various stiffness levels. Cavitation collapse signals were received and cavitation was imaged using a high-speed camera in the transparent tissue-mimicking phantom. colHigh-speed camera-acquired measurements optically validate the acoustic hydrophone measurements. col An increase in t is observed both with decreasing phantom stiffness and throughout the Histotripsy procedure as the number of applied pulses increases. col The increasing trend of t correlated well with the progression of lesion formation generated in the tissue-mimicking phantom (R = 0.87) (Figure 7). col (left y-axis) and mean lesion intensity (MLI) (right y-axis) versus pulse number out of 100 pulses are shown. MLI, defined as the average pixel intensity across the ROI, was calculated across treatments on a normalized scale from 0 to 1 to indicate treatment progression (0 - no treatment, 1 - treatment completion). col Most of the changes in t and MLI occur simultaneously early in treatment. col The change in σ is larger than the change in MLI in the first few pulses, but both criteria quickly level off and reach a plateau threshold around 40 pulses.

[0123]

[0149] Finally, the response to histotripsy treatment col The increasing trend of t was verified in ex vivo bovine liver. col experienced an overall average increase of approximately 50 μs throughout treatment, reaching this steady-state value around 40 to 50 histotripsy pulses (Figure 8A-8B). In Figure 8A-8B, the decay time t for the first 100 pulses (right, linear scale) and 1000 pulses (left, logarithmic scale) in ex vivo bovine liver (n=4) was col is shown. col Most of the change in is observed within the first 100 pulses of treatment, with little or no change between pulse 100 and pulse 1000.

[0124]

[0150] Acoustic cavitation emission (ACE) signals generated by the cavitation cloud during histotripsy treatment were also investigated as a potential feedback mechanism for tissue integrity during treatment. A 500 kHz, 112-element phased histotripsy array was used to generate approximately 6 x 6 x 7 mm lesions in ex vivo bovine liver tissue by scanning 219 locations with 30 to 1,000 pulses per location. A custom nonlinear voltage compressor was designed and constructed to allow eight elements of the array to transmit histotripsy pulses and receive ACE signals from a central treatment location within the lesion. ACE signals were quantitatively analyzed by measuring changes in peak pressure arrival time during treatment. ACE peak pressure arrival time decreased as the treatment progressed and eventually saturated (Figure 9). Quantified ACE is illustrated using peak pressure arrival time as shown in Figure 9. The trend demonstrated by peak pressure arrival during treatment suggests that the majority of the physical changes affecting this criterion occur within the first 200 pulses. The nonlinear least-squares best fit line is shown in black. The best fit line reached an exponential decay time constant at 80 pulses.

[0125]

[0151] The histology of the treated tissues was analyzed, and correspondingly, cell counts, reticulin-stained type III collagen area, and trichrome-stained type I collagen area all decreased over the course of histotrypsin treatment (Figure 10). Histological analysis of lesions produced by different numbers of pulses was compared with ACE signals using a Pearson correlation coefficient (PCC) at a significance level of 0.05. Histological analysis included viable cell counts, reticulin-stained type III collagen area, and trichrome-stained type I collagen area. The decrease in peak pressure arrival time was found to be statistically significantly correlated with the decrease in reticulin-stained type III collagen area, with a PCC of 0.72 (p=0.043). This indicates the feasibility of using ACE peak pressure arrival time as an indicator for monitoring histotrypsin treatment. Significant improvements in hardware and software can improve the sensitivity of this detection. Referring to Figure 10, histological analysis of 42 histotripsy-treated samples at various doses is shown. Figure 10A illustrates the number of viable cells remaining in the imaged media. This cell population underwent the greatest amount of destruction early in the treatment. Figure 10B illustrates the percent area of ​​intact reticulin-stained collagen, and Figure 10C illustrates the percent area of ​​intact trichrome-stained collagen. Both collagen criteria underwent a slower amount of destruction than the remaining cell population. Nonlinear least-squares best-fit lines are shown in red. All best-fit lines demonstrated statistical significance when compared to normal distributions, as indicated by the p-values ​​in each plot.

[0126]

[0152] The advantages of the transmit / receive Histotripsy phased array described herein can be summarized as follows:

[0153] 1) Aberration Correction - Tx / R Histotripsy can correct aberrations due to variations in the speed of sound in the ultrasound path, improving focus. Because correction must be applied to each array element, correction methods based on the signal received by each element provide the most accurate aberration correction. Advanced Tx / R Histotripsy hardware and software and specialized aberration correction algorithms allow aberration correction to be enabled on the fly, just before or even during a procedure.

[0127]

[0154] 2) Cavitation Localization and Mapping—Because cavitation is the causative factor in histotripsy lesions, real-time 3D cavitation maps can facilitate targeting and treatment monitoring, even when ribs or skull are in the path. 3D cavitation maps can also be used to detect both intended cavitation at the target and potentially unwanted off-target cavitation. Thus, real-time 3D feedback provided by a transmit-receive histotripsy transducer array overcomes the two major limitations of ultrasound imaging feedback previously described.

[0128]

[0155] 3) Treatment Monitoring - Cavitation dynamics correlate with the level of tissue damage produced by histotripsy. Received ACE signals can be processed to monitor treatment progress and determine treatment completion in real time. 3D cavitation mapping can also be co-registered or overlaid onto pre-treatment MRI or CT scans.

[0129]

[0156] 4) Compact System - The transmit / receive Histotripsy array system is compact, similar in size to a transmit-only Histotripsy system, but with many additional features as explained above. The transmit / receive Histotripsy array can be used independently and / or to supplement the ultrasound imaging currently used for Histotripsy feedback.

[0130]

[0157] 5) Automatic Registration - The cavitation map generated by the transducer reception is automatically registered to the treatment site coordinate system. Treatment accuracy then depends only on a single registration between the treatment transducer and the treatment planning imaging.

[0131] How to use

[0158] The transmit / receive ultrasound systems described herein can provide general amplitude aberration correction to enable ultrasound and / or histotripsy therapy making the treatment more effective, and can also provide focal shift correction, as described below.

[0132]

[0159] General amplitude aberration correction

[0160] Methods are provided for providing general amplitude aberration correction during ultrasound treatment. These methods can include transmitting an ultrasound pulse at a single test pulse location (e.g., at the center of a planned treatment volume aligned with the target tissue) and receiving a time delay from the single location. The received delay time can then be used as a representative aberration correction map for the entire planned treatment volume (e.g., all treatment pattern locations within the planned treatment volume). The aberration correction can then be applied to subsequent ultrasound treatment pulses to improve the efficiency of the treatment.

[0133]

[0161] In some examples, multiple distinct test pulse locations (e.g., 7-point test locations) can be used. The method can include receiving a time delay at each test location and modeling the received delays to interpolate an aberration correction map for the entire planned treatment volume.

[0134]

[0162] Alternatively, the method can include real-time testing. For example, the method can include using the received signals for aberration correction at each test pulse and treatment location, and updating the aberration correction in real time during treatment.

[0135]

[0163] In some examples, the test pulse sequence may differ from the treatment pulse (automatic procedure) to provide a smaller cloud or a more thermally favorable sequence to evaluate aberrations / thresholds before moving on to the treatment pulse.

[0136]

[0164] Focal shift correction

[0165] During ultrasound / histotripsy treatment, it is common to see a focal shift, typically along the "Z" axis, primarily due to differences in the speed of sound between water (the coupling medium) and tissue. This is typically corrected in ultrasound systems by visualizing the bubble cloud using an imaging system (e.g., ultrasound imaging). As described herein, the receiving capabilities of the system can be used to map the reflected signal from the water-skin interface, determine the time-of-flight from each element surface to the water-skin interface, and use that time-of-flight determination to correct for the focal shift caused by the coupling medium.

[0137]

[0166] To build and extend this method, other inputs can be used to make the focus shift prediction more accurate. For example, focus shift correction can be based on a single test pulse (e.g., at the center of the planned treatment volume) or multiple test pulses interpolated across the volume.

[0138]

[0167] The received data received by the system can be registered with the imaging data from the imaging system to provide more visual feedback on the cavitation. Additionally, the received and imaging data can be registered to the robotic positioning arm of the treatment system, so that the image / received data is associated with the six degrees of freedom of the positioning arm.

[0139]

[0168] The methods described above can be used to correct focus shifts / aberrations when the imaging system is obscured (such as when the focal zone is behind a bone or another aberrator).

[0140]

[0169] When a feature or element is referred to herein 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. When an element is referred to as being "connected," "attached," or "coupled" to another feature or element, it will be understood that it can be directly connected, attached, or coupled to the other feature or element, or that 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 illustrated with respect to one embodiment, features and elements so described or illustrated may be applicable to other embodiments. Those skilled in the art will also understand that references to structures or features located "adjacent" to another feature may have portions that overlap or underlie the adjacent feature.

[0141]

[0170] The terms used herein are for the purpose of describing particular embodiments only and are 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 unless the context clearly dictates otherwise. As used herein, it will be further understood that the terms "comprises" and / or "comprising" specify the presence of stated features, steps, operations, elements, and / or components, but do not exclude 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 list items and may be abbreviated as " / ."

[0142]

[0171] Spatially relative terms such as "below," "below," "bottom," "above," and "on top" may be used herein to describe the relationship of one element or feature to another element(s) or feature(s), as illustrated in the figures, for ease of description. It should be understood that the spatially relative terms are intended to encompass different orientations of the device during use or operation in addition to the orientation shown in the figures. For example, if the device in the figures were inverted, an element described as "below" or "directly below" the other element or feature would be oriented "above" the other element or feature. Thus, the exemplary term "below" can encompass both an orientation of above and below. The device may be oriented in another direction (rotated 90 degrees or at other orientations), and the spatially relative descriptors used herein would be interpreted accordingly. Similarly, terms such as "upward," "downward," "vertical," "horizontal," and the like are used for descriptive purposes only, unless otherwise indicated.

[0143]

[0172] The terms "first" and "second" may be used herein to describe various features / elements (including steps), but these features / elements should not be limited by these terms unless the context dictates otherwise. These terms may be used to distinguish one feature / element from another. Thus, a first feature / element discussed below could be referred to as a second feature / element, and similarly, a second feature / element discussed below could be referred to as a first feature / element, without departing from the teachings of the present invention.

[0144]

[0173] Throughout this specification and the claims that follow, unless the context requires otherwise, the word "comprises," and variations such as "comprises" and "comprising," mean that various components (e.g., compositions and apparatuses, including devices and methods) can be applied together in methods and articles. For example, the term "comprising" will be understood to mean the inclusion of any recited element or step, but not the exclusion of any other elements or steps.

[0145]

[0174] As used herein and in the claims, including in the examples, In certain cases, unless specifically stated otherwise, all numbers can be read as if preceded by the word "about" or "approximately," even if that term does not explicitly appear. The phrase "about" or "approximately" may be used when describing a size and / or location to indicate that the described value and / or location is within a reasonably expected range of values ​​and / or locations. For example, a numerical 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 value given herein should be understood to include about or approximately that value unless the context dictates otherwise. For example, if a value of "10" is disclosed, "about 10" is also disclosed. Any numerical range recited herein is intended to include all subranges subsumed therein. When a value is disclosed, it is understood that "less than or equal to" that value, "greater than or equal to" that value, and possible ranges between those values ​​are also disclosed, as would be appropriately understood by one of ordinary skill in the art. For example, if a value "X" (e.g., where X is a numeric value) is disclosed, not only "less than or equal to X" but also "greater than or equal to X" is disclosed. It is also understood that throughout this application, data is provided in a number of different formats, and this data represents endpoints and starting points, and ranges for any combination of the data points. For example, if a specific data point "10" and a specific data point "15" are disclosed, it is understood that greater than 10 and 15, greater than or equal to 10 and 15, less than 10 and 15, less than or equal to 10 and 15, and equal to 10 and 15 are also considered to be disclosed between 10 and 15. It is understood that each unit between two specified units is also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0146]

[0175] While various exemplary embodiments have been described above, any number of modifications may be made to the various embodiments without departing from the scope of the invention as set forth in the claims. For example, the order in which the various described method steps are performed is often changed in alternative embodiments, and in other alternative embodiments, one or more method steps may be omitted entirely. Optional features of the various device and system embodiments may be included in some embodiments and not in other embodiments. Accordingly, the foregoing description has been provided primarily for illustrative purposes and should not be construed as limiting the scope of the invention as set forth in the claims.

[0147]

[0176] The examples and illustrations contained herein illustrate, by way of example and not limitation, specific embodiments in which the subject matter may be practiced. As noted above, other embodiments may be utilized and derived therefrom, such that structural and logical substitutions and changes may be made without departing from the scope of the present disclosure. Such embodiments of the inventive subject matter, when in fact more than one, may be referred to herein individually or collectively by the term "invention" merely for convenience, without intending to intentionally limit the scope of this application to any single invention or inventive concept. Thus, while specific embodiments have been illustrated and described herein, any configuration calculated to achieve the same purpose may be substituted for the specific embodiments illustrated. The disclosure is intended to cover any adaptations or variations of the various embodiments. Combinations of the above embodiments, as well as other embodiments not specifically described herein, will become apparent to those skilled in the art upon reviewing the above description.

Claims

1. A transmitter / receiver driver electronics for a Histotripsy system, comprising: at least one transducer element configured to transmit ultrasonic pulses in a transmit mode and to receive ultrasonic reflections and / or acoustic cavitation emissions in a receive mode; a current sensing resistor configured to measure current in the transmit / receive driver electronics during the receive mode; a bypass circuit electrically coupled to the at least one transducer element and the current sensing resistor, the bypass circuit configured to be switched on during the transmit mode to bypass the current sensing resistor and switched off during the receive mode to allow the current sensing resistor to measure the current; a gain adjust circuit electrically coupled to the current sensing resistor and the low-sensitivity resistor, the gain adjust circuit configured to operate at a high-sensitivity setting where the current sensing resistor is switched on and the low-sensitivity resistor is switched off, and further configured to operate at a low-sensitivity setting where the current sensing resistor and the low-sensitivity resistor are switched on.

2. The transceiver driving electronics of claim 1 , further comprising a driving transformer electrically coupled to the at least one transducer element.

3. 2. The transmitter-receiver driver electronic device according to claim 1, wherein the bypass circuit further comprises a pair of bypass transistors.

4. 2. The transmitter / receiver driver electronic device according to claim 1, wherein the bypass circuit further comprises a pair of bypass diodes.

5. 2. The transmitter / receiver driver electronic device according to claim 1, wherein the gain adjustment circuit further comprises a pair of transistors.

6. 2. The transceiver driver electronic device according to claim 1, wherein the current sensing resistor has a higher resistance than the low sensitivity resistor.

7. 2. The transmit / receive driver electronic device of claim 1, wherein the current sensing resistor has a resistance of approximately 200 ohms and the low sensitivity resistor has a resistance of approximately 5 ohms.

8. A transmitter / receiver driver electronics for a Histotripsy system, comprising: an ultrasonic transducer array; high voltage transmit electronics coupled to the ultrasound transducer array and configured to provide up to several thousand volts to the ultrasound transducer array to generate one or more histotripsy pulses; first receive electronics coupled to the ultrasound transducer array and configured to receive an input voltage signal from one or more transmitted histotripsy-pulses, the first receive electronics configured to attenuate the input voltage signal by 90-99%; second receiving electronics configured to compress all attenuated input voltage signals above 1 V; third receiver electronics configured to voltage shift the attenuated input voltage signal; The voltage-shifted attenuated signal is then transferred from the third receiving electronics for ADC conversion. an analog-to-digital converter configured to receive an input voltage signal; A transmission / reception driving electronic device comprising:

9. The transmitter / receiver driver electronics of claim 8 , wherein the first electronics comprises a voltage divider.

10. The transceiver driver electronic device of claim 9 , wherein the voltage divider comprises a capacitive voltage divider.

11. The transmit / receive driver electronics of claim 10 , wherein the capacitive voltage divider comprises a first capacitor and a second capacitor in parallel with a first transducer element of the ultrasonic transducer array.

12. The transmit / receive driver electronics of claim 8 , wherein the second receive electronics comprises a diode resistor voltage divider.

13. The transmit / receive driver electronics of claim 8 , wherein the third receive electronics is configured to voltage shift the attenuated input voltage signal to a suitable voltage range for the analog-to-digital converter.

14. The transmit / receive driver electronics of claim 8 , wherein the transmit driver electronics comprises a separate circuitry board configured to be retrofitted to an existing Histotripsy system, including a transmit-only Histotripsy driver system.

15. The transmit / receive driver electronics of claim 14 , wherein the transmit driver electronics are added in parallel to the transmit-only histotripsy driver system and configured to passively receive signals without affecting the transmit-only electronics.

16. 9. The transmit / receive driver electronics of claim 8, further configured to synchronize time clocks of the transmitted one or more Histotripsy-pulses, the received input voltage signal, and the ADC conversion to obtain an appropriate time window after each Histotripsy-pulse transmission.

17. 9. The transmit / receive driver electronics of claim 8, further comprising one or more field programmable gate array (FPGA) boards coupled to the analog-to-digital converter and configured to control transmit and receive operations of the transmit / receive driver electronics using a single clock.

18. 20. The transceiver driver electronics of claim 17, wherein the one or more FPGAs include software or firmware configured to reduce the data load of received signals.

19. The transmit / receive driver electronics of claim 17 , wherein the one or more FPGAs are configured to artificially downsample input data from the analog-to-digital converter.

20. The transmit / receive driver electronics of claim 17, wherein the one or more FPGAs are configured to oversample and average received signals to increase signal-to-noise ratio (SNR).

21. 1. A method of using a transmit / receive histotripsy system for cavitation detection, comprising: Transmitting high voltage histotripsy therapy pulses to the target tissue using transmitting electronics and a histotripsy therapy transducer array to generate cavitation in the target tissue. and receiving low voltage acoustic cavitation radiation signals from the cavitation using receiving electronics and the histotripsy therapy transducer array; processing the received acoustic cavitation radiation signals to monitor the progress of the treatment; A method comprising:

22. 22. The method of claim 21, further comprising generating a 3D map in real time of the cavitation produced by the transmitted pulses.

23. 1. A method of using a transmit / receive histotripsy system for aberration correction, comprising: transmitting histotripsy therapy pulses to a target tissue using a histotripsy therapy transducer array having a plurality of transducer elements to generate cavitation in the target tissue; receiving acoustic cavitation radiation signals from the cavitation using the histotripsy therapy transducer array; calculating a travel time from the cavitation to each transducer element of an ultrasonic transducer array based on the received acoustic cavitation radiation signal; adjusting a transmit time delay for at least one transducer element of the plurality of transducer elements based on the calculated travel time so that subsequent histotripsy therapy pulses arrive at the target tissue simultaneously; A method comprising:

24. 24. The method of claim 23, wherein calculating the travel time comprises using information encoded in the acoustic cavitation radiation.

25. 25. The method of claim 24, wherein the information comprises a start time of the acoustic cavitation radiation produced from a cavitation expansion.

26. 25. The method of claim 24, wherein the information comprises a start time of the acoustic cavitation radiation produced from cavitation collapse.

27. The method of claim 24 , wherein the information comprises a peak time from cavitation collapse.

28. 1. A receive driver circuit configured to be retrofitted to one or more transducer elements of an existing transmit-only histotripsy system, comprising: a voltage divider configured to be electrically coupled to a first transducer element, the voltage divider configured to attenuate a voltage signal received by the first transducer element; a diode resistor divider electrically coupled to the voltage divider, the diode resistor divider configured to provide nonlinear attenuation to compress signals above a predetermined voltage, and further configured to AC couple the received signal to an analog-to-digital converter.

29. 30. The receiver driver circuit of claim 28, wherein the voltage divider and the diode resistor divider are configured to be disposed on a first circuit configuration board and electrically coupled to high voltage histotripsy drive electronics disposed on a separate second circuit configuration board.

30. 30. The receiver driver circuit of claim 28, wherein the receiver driver circuit and high voltage histotripsy driver electronics are located on a single circuit configuration board.

31. A transmitting and receiving histotripsy system, a transducer element; transmit electronics coupled to the transducer elements and configured to provide histotripsy pulses to the transducer elements; nonlinear compressor receive electronics coupled to the transducer element, the nonlinear compressor receive electronics configured to compress a first voltage signal with a first attenuation and further configured to compress a second voltage signal with a second attenuation, the first voltage signal being higher than the second voltage signal and the first attenuation being higher than the second attenuation; A transmitting and receiving histotripsy system comprising:

32. A transmitter / receiver driver electronics for a Histotripsy system, comprising: a transducer element; a secondary transformer coil electrically coupled to the transducer element; a primary transformer coil disposed adjacent to the secondary transformer coil, the primary transformer coil configured to generate ultrasonic pulses at the transducer element via the secondary transformer coil; a third transformer coil disposed adjacent to the secondary transformer coil, the third transformer coil configured to attenuate a voltage signal received by the transducer element by a predetermined amount; A transmission / reception driving electronic device comprising:

33. 33. The transmitter / receiver driver electronic device according to claim 32, wherein the third transformer coil is configured to attenuate the received voltage signal by 90 to 99%.

34. 34. The transceiver driver electronic device according to claim 33, wherein the third transformer coil is wound with approximately 7 to 10 times fewer turns than the secondary transformer coil.

35. 33. The transmit / receive driver electronics of claim 32, wherein the third transformer coil is configured to saturate during transmission of an ultrasonic pulse.

36. 36. The transmit / receive driver electronics of claim 35, wherein the third transformer coil is coupled to a signal transformer having a specially selected core material and size so as to be configured to saturate during transmission of an ultrasonic pulse.

37. A transmitting and receiving driving electronic device for a Histotripsy system, an ultrasonic transducer array; transmit electronics coupled to the ultrasound transducer array and configured to transmit one or more histotripsy pulses to generate cavitation in the target tissue; receiving electronics configured to receive acoustic cavitation radiation from the cavitation; a transmit / receive switch configured to enable only the transmit electronics during transmission of the one or more Histotripsy-pulses, and further configured to enable only the receive electronics at a predetermined time after transmission of the one or more Histotripsy-pulses to block a transmit signal without attenuating a receive signal; A transmission / reception driving electronic device comprising:

38. 38. The transmit / receive driver electronics of claim 37, wherein different linear gains follow the transmit / receive switch to amplify or attenuate selected portions of the received signal based on its amplitude to maximize the receive sensitivity of the receive electronics.

39. Method for treating histotripsy, comprising: transmitting histotripsy treatment pulses to a target tissue using a histotripsy treatment transducer array to generate cavitation in the target tissue; receiving an acoustic cavitation radiation signal from the cavitation using the histotripsy therapy transducer; Detecting and separating selected acoustic cavitation radiation signatures from tissue signals; calculating a cavitation parameter that correlates with tissue damage produced by the histotripsy treatment pulse; determining changes in said cavitation parameters that correlate with the progress of the treatment; determining a change in said cavitation parameter that correlates with completion of the treatment; A method comprising:

40. 40. The method of claim 39, wherein the selected acoustic cavitation radiation characteristic comprises timing of a cavitation bubble expansion signal.

41. 40. The method of claim 39, wherein the selected acoustic cavitation radiation characteristic comprises an amplitude of a cavitation bubble expansion signal.

42. 40. The method of claim 39, wherein the selected acoustic cavitation radiation characteristic comprises timing of a cavitation bubble collapse signal.

43. 40. The method of claim 39, wherein the selected acoustic cavitation radiation characteristic comprises an amplitude of a cavitation bubble collapse signal.

44. 40. The method of claim 39, wherein the selected acoustic cavitation radiation characteristic comprises timing of a cavitation bubble repulsion signal.

45. 40. The method of claim 39, wherein the selected acoustic cavitation radiation characteristic comprises an amplitude of a cavitation bubble repulsion signal.

46. 40. The method of claim 39, wherein the cavitation parameter comprises a collapse time of the cavitation.

47. 47. The method of claim 46, wherein the collapse time comprises the time between the cavitation expansion signal and the collapse signal.

48. 40. The method of claim 39, wherein the cavitation parameter comprises a peak amplitude of the cavitation expansion signal.

49. 40. The method of claim 39, wherein the cavitation parameter comprises a peak amplitude of the cavitation collapse signal.

50. 40. The method of claim 39, wherein the cavitation parameter comprises an amplitude ratio of a growth ACE signal of the cavitation.

51. 40. The method of claim 39, wherein the cavitation parameter comprises an amplitude ratio of the collapsed ACE signal of the cavitation.

52. 40. The method of claim 39, wherein the cavitation parameter comprises a decay rate of a repulsion-related ACE signal amplitude.

53. 40. The method of claim 39, wherein determining a change in the cavitation parameter that correlates with treatment progress further comprises identifying an increasing gradient in the cavitation parameter.

54. 40. The method of claim 39, wherein determining a change in the cavitation parameter that correlates with completion of treatment further comprises identifying saturation of a change in the cavitation parameter.

55. 1. A method for detecting cavitation in histotripsy, comprising: transmitting histotripsy treatment pulses to a target tissue using a histotripsy treatment transducer array to generate cavitation in the target tissue; receiving acoustic cavitation radiation signals from the cavitation using the histotripsy therapy transducer array; Detecting and separating selected acoustic cavitation radiation signatures from tissue signals; processing and forming a cavitation map based on the selected acoustic cavitation radiation signature; overlaying the cavitation map onto an image of the target tissue; A method comprising:

56. 56. The method of claim 55, wherein the selected acoustic cavitation radiation characteristic comprises timing of a cavitation bubble expansion signal.

57. 56. The method of claim 55, wherein the selected acoustic cavitation radiation characteristic comprises an amplitude of a cavitation bubble expansion signal.

58. 56. The method of claim 55, wherein the selected acoustic cavitation radiation characteristic comprises timing of a cavitation bubble collapse signal.

59. 56. The method of claim 55, wherein the selected acoustic cavitation radiation characteristic comprises an amplitude of a cavitation bubble collapse signal.

60. 56. The method of claim 55, wherein the selected acoustic cavitation radiation characteristic comprises timing of a cavitation bubble repulsion signal.

61. 56. The method of claim 55, wherein the selected acoustic cavitation radiation characteristic comprises an amplitude of a cavitation bubble repulsion signal.

62. 1. A method for performing aberration correction during histotripsy treatment, comprising: transmitting histotripsy treatment pulses to a target tissue using a histotripsy treatment transducer array to generate cavitation in the target tissue; receiving acoustic cavitation radiation signals from the cavitation using the histotripsy therapy transducer array; analyzing the acoustic cavitation radiation signal to detect the cavitation generated in the target tissue; testing presets of transmit time delays to select a set of transmit time delays that maximizes peak signal amplitude in the detected cavitations; applying the selected series of transmit time delays so that subsequent histotripsy therapy pulses arrive at the target tissue simultaneously; A method comprising:

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