Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N7/00—Ultrasound therapy
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B06—GENERATING OR TRANSMITTING MECHANICAL VIBRATIONS IN GENERAL
  • B06B—METHODS OR APPARATUS FOR GENERATING OR TRANSMITTING MECHANICAL VIBRATIONS OF INFRASONIC, SONIC, OR ULTRASONIC FREQUENCY, e.g. FOR PERFORMING MECHANICAL WORK IN GENERAL
  • B06B1/00—Methods or apparatus for generating mechanical vibrations of infrasonic, sonic, or ultrasonic frequency
  • B06B1/02—Methods or apparatus for generating mechanical vibrations of infrasonic, sonic, or ultrasonic frequency making use of electrical energy
  • B06B1/0207—Driving circuits
  • B06B1/0215—Driving circuits for generating pulses, e.g. bursts of oscillations, envelopes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B17/00—Surgical instruments, devices or methods
  • A61B17/22—Implements for squeezing-off ulcers or the like on inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; for invasive removal or destruction of calculus using mechanical vibrations; for removing obstructions in blood vessels, not otherwise provided for
  • A61B17/22004—Implements for squeezing-off ulcers or the like on inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; for invasive removal or destruction of calculus using mechanical vibrations; for removing obstructions in blood vessels, not otherwise provided for using mechanical vibrations, e.g. ultrasonic shock waves
  • A61B2017/22005—Effects, e.g. on tissue
  • A61B2017/22007—Cavitation or pseudocavitation, i.e. creation of gas bubbles generating a secondary shock wave when collapsing
  • A61B2017/22008—Cavitation or pseudocavitation, i.e. creation of gas bubbles generating a secondary shock wave when collapsing used or promoted
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B17/00—Surgical instruments, devices or methods
  • A61B17/32—Surgical cutting instruments
  • A61B17/320068—Surgical cutting instruments using mechanical vibrations, e.g. ultrasonic
  • A61B2017/320069—Surgical cutting instruments using mechanical vibrations, e.g. ultrasonic for ablating tissue
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B90/00—Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
  • A61B90/36—Image-producing devices or illumination devices not otherwise provided for
  • A61B90/37—Surgical systems with images on a monitor during operation
  • A61B2090/378—Surgical systems with images on a monitor during operation using ultrasound
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B34/00—Computer-aided surgery; Manipulators or robots specially adapted for use in surgery
  • A61B34/10—Computer-aided planning, simulation or modelling of surgical operations
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B34/00—Computer-aided surgery; Manipulators or robots specially adapted for use in surgery
  • A61B34/30—Surgical robots
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B34/00—Computer-aided surgery; Manipulators or robots specially adapted for use in surgery
  • A61B34/30—Surgical robots
  • A61B34/32—Surgical robots operating autonomously
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B90/00—Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
  • A61B90/50—Supports for surgical instruments, e.g. articulated arms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N7/00—Ultrasound therapy
  • A61N2007/0004—Applications of ultrasound therapy
  • A61N2007/0021—Neural system treatment
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N7/00—Ultrasound therapy
  • A61N2007/0039—Ultrasound therapy using microbubbles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N7/00—Ultrasound therapy
  • A61N2007/0052—Ultrasound therapy using the same transducer for therapy and imaging
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N7/00—Ultrasound therapy
  • A61N2007/0086—Beam steering
  • A61N2007/0095—Beam steering by modifying an excitation signal
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B06—GENERATING OR TRANSMITTING MECHANICAL VIBRATIONS IN GENERAL
  • B06B—METHODS OR APPARATUS FOR GENERATING OR TRANSMITTING MECHANICAL VIBRATIONS OF INFRASONIC, SONIC, OR ULTRASONIC FREQUENCY, e.g. FOR PERFORMING MECHANICAL WORK IN GENERAL
  • B06B2201/00—Indexing scheme associated with B06B1/0207 for details covered by B06B1/0207 but not provided for in any of its subgroups
  • B06B2201/70—Specific application
  • B06B2201/76—Medical, dental

Definitions

• the present disclosure details novel histotripsy systems configured to produce acoustic cavitation, methods, devices and procedures for the minimally and non-invasive treatment of healthy, diseased and/or injured tissue.
• the histotripsy systems and methods described herein, also referred to Histotripsy may include transducers, drive electronics, positioning robotics, imaging systems, and integrated treatment planning and control software to provide comprehensive treatment and therapy for soft tissues in a patient.
• Histotripsy or pulsed ultrasound cavitation therapy, is a technology where extremely short, intense bursts of acoustic energy induce controlled cavitation (microbubble formation) within the focal volume. The vigorous expansion and collapse of these microbubbles mechanically homogenizes cells and tissue structures within the focal volume. This is a very different end result than the coagulative necrosis characteristic of thermal ablation.
• Histotripsy Compared with conventional focused ultrasound technologies, Histotripsy has important advantages: 1) the destructive process at the focus is mechanical, not thermal; 2) cavitation appears bright on ultrasound imaging thereby confirming correct targeting and localization of treatment; 3) treated tissue generally, but not always, appears darker (more hypoechoic) on ultrasound imaging, so that the operator knows what has been treated; and 4) Histotripsy produces lesions in a controlled and precise manner. It is important to emphasize that unlike thermal ablative technologies such as microwave, radiofrequency, and high-intensity focused ultrasound (HIFU), Histotripsy relies on the mechanical action of cavitation for tissue destruction.
• thermal ablative technologies such as microwave, radiofrequency, and high-intensity focused ultrasound (HIFU)
• FIGS. 1A-1B illustrate an ultrasound imaging and therapy system.
• FIGS. 2A-2D illustrate various schematic illustrations of transmit-receive drive electronics for a histotripsy system.
• FIGS. 3A-3C are embodiments of current sense electronics for a histotripsy system.
• FIG. 4 is a method of providing histotripsy therapy to a patient.
• FIG. 5 illustrates cavitation mapping through bone such as a human skull.
• FIG. 6 is a method of providing histotripsy therapy to a patient.
• FIGS. 7-10 illustrate data collected via received ultrasound signals from histotripsy therapy to predict treatment progress and tissue fractionation.
• Histotripsy produces tissue fractionation through dense energetic bubble clouds generated by short, high-pressure, ultrasound pulses. When using pulses shorter than 2 cycles, the generation of these energetic bubble clouds only depends on where the peak negative pressure (P-) exceeds an intrinsic threshold for inducing cavitation in a medium (typically 26 - 30 MPa in soft tissue with high water content).
• P- peak negative pressure
• a transmit-receive driving electronics for a histotripsy system comprising at least one transducer element configured to transmit ultrasound pulses in a transmit mode and receive ultrasound reflections and/or acoustic cavitation emissions in a receive mode, a current sense resistor configured to measure a current in the transmit-receive driving electronics during the receive mode, a bypass circuit electrically coupled to the at least one transducer element and the current sense resistor, wherein the bypass circuit is configured to be switched on during the transmit mode to bypass the current sense resistor and switched off during the receive mode to allow the sense resistor to measure the current; a gain adjustment circuit electrically coupled to the current sense resistor and to a low sensitivity resistor, the gain adjustment circuit being configured to operate in a high sensitivity setting in which the current sense resistor is switched on and the low sensitivity resistor is switched off, and wherein the gain adjustment circuit is further configured to operate in a low sensitivity setting in which the current sense resistor and the low sensitivity resistor are switched on.
• he transmit-receive driving electronics further comprises a drive transformer electrically coupled to the at least one transducer element.
• the bypass circuit further comprises a pair of bypass transistors. In other embodiments, the bypass circuit further comprises a pair of bypass diodes.
• the gain adjustment circuit further comprises a pair of transistors.
• the current sense resistor has a higher resistance than the low sensitivity resistor.
• the current sense resistor has a resistance of approximately 200 ohms and the low sensitivity resistor has a resistance of approximately 5 ohms.
• a transmit-receive driving electronics for a histotripsy system comprising an ultrasound transducer array, high-voltage transmission electronics coupled to the ultrasound transducer array and configured to provide up to thousands of volts to the ultrasound transducer array to produce one or more histotripsy pulses, first receive electronics coupled to the ultrasound transducer array and configured to receive incoming voltage signals from the transmitted one or more histotripsy pulses, the first receive electronics being configured to attenuate the incoming voltage signals by 90-99%, second receive electronics configured to compress any attenuated incoming voltage signals above IV, and third receive electronics configured to voltage shift the attenuated incoming voltage signals, and an analog-to-digital converter configured to receive the voltage- shifted attenuated incoming voltage signals from the third receive electronics for ADC conversion.
• the first electronics comprise a voltage divider.
• the voltage divider comprises a capacitive voltage divider.
• the capacitive voltage divider comprises a first capacitor and a second capacitor in parallel with a first transducer element of the ultrasound transducer array.
• the second receive electronics comprise a diode-resistor voltage divider.
• the third receive electronics are configured to voltage shift the attenuated incoming voltage signals to an appropriate voltage range for the analog-to-digital converter.
• the transmit-driving electronics comprise a separate circuitry board that is configured to be retrofitted to an existing histotripsy system that includes a transmit-only histotripsy driving system.
• the transmit-driving electronics is added in parallel to the transmit- only histotripsy driving system and is configured to passively receive signals without affecting the transmit-only electronics.
• the transmit-receive driving electronics are further configured to synchronize a time clock of the transmitted one or more histotripsy pulses, received incoming voltage signals, and the ADC conversion to obtain an appropriate time window after each histotripsy pulse transmission.
• the transmit-receive driving electronics further comprise one or more Field Programmable Gate Array (FPGA) boards coupled to the analog-to-digital converter and being configured to control transmit and receive operations of the transmit-receive driving electronics with a single clock.
• FPGA Field Programmable Gate Array
• the one or more FPGA includes software or firmware configured to reduce a data load for received signals.
• the one or more FPGA are configured to artificially downsample incoming data from the analog-to-digital converter.
• the one or more FPGA are configured to oversample and average the received signals to increase a signal to noise ratio (SNR).
• SNR signal to noise ratio
• a method of using a transmit-receive histotripsy system for cavitation detection comprising the steps of transmitting high-voltage histotripsy therapy pulses into a target tissue with transmit electronics and a histotripsy therapy transducer array to generate cavitation in the target tissue, receiving low-voltage acoustic cavitation emission signals from the cavitation with receive electronics and the histotripsy therapy transducer array, processing the received acoustic cavitation emission signals to monitor treatment progression.
• the method further comprises generating a 3D map of cavitation produced by the transmitted pulses in real-time.
• a method of using a transmit-receive histotripsy system for aberration correction comprising the steps of transmitting histotripsy therapy pulses into a target tissue with a histotripsy therapy transducer array having a plurality of transducer elements to generate cavitation in the target tissue, receiving acoustic cavitation emission signals from the cavitation with 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 emission signals, and adjusting a transmission time delay for at least one of the plurality of transducer elements based on the calculated travel times such that subsequent histotripsy therapy pulses arrive at the target tissue simultaneously.
• calculating the travel time includes using information encoded in the acoustic cavitation emissions.
• the information comprises a start time of the acoustic cavitation emission generated from cavitation expansion.
• the information comprises a start time of the acoustic cavitation emission generated from cavitation collapse.
• the information comprises a peak time from cavitation collapse.
• a receive-drive circuit configured to be retrofitted onto 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 voltage signals received by the first transducer element, a diode-resistor voltage divider electrically coupled to the voltage divider, the diode-resistor voltage divider being configured to provide nonlinear attenuation to compress signals above a predetermined voltage, and being further configured to AC couple the received signals to an analog to digital converter.
• the voltage divider and the diode-resistor voltage divider are configured to be disposed on a first circuitry board and that is configured to be electrically coupled to high-voltage histotripsy driving electronics disposed on a separate second circuitry board.
• the receive-drive circuit and high-voltage histotripsy driving electronics are disposed on a single circuitry board.
• a transmit-receive histotripsy system comprising a transducer element, transmit electronics coupled to the transducer element and configured to deliver histotripsy pulses to the transducer element, a non-linear compressor receive electronics coupled to the transducer element, wherein the non-linear compressor receive electronics are configured to compress a first voltage signal with a first attenuation, and are further configured to compress a second voltage signal with a second attenuation, wherein the first voltage signal is higher than the second voltage signal and the first attenuation is higher than the second attenuation.
• a transmit-receive driving electronics for a histotripsy system 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 being configured to generate ultrasound pulses in the transducer element via the secondary transformer coil, a third transformer coil positioned adjacent to the secondary transformer coil, the third transformer coil being configured to attenuate voltage signals received by the transducer element by a predetermined amount.
• the third transformer coil is configured to attenuate the received voltage signals by 90-99%. In another embodiment, the third transformer coil is wound with approximately 7-10x fewer windings than the secondary transformer coil.
• the third transformer coil is configured to saturate during transmission of ultrasound pulses.
• the third transformer coil is coupled to a signal transformer with a specifically chosen core material and size such that the signal transformer is configured to saturate during transmission of ultrasound pulses.
• a transmit-receive driving electronics of a histotripsy system comprising an ultrasound transducer array, transmission electronics coupled to the ultrasound transducer array and configured to transmit one or more histotripsy pulses to generate cavitation in a target tissue, receive electronics configured to receive acoustic cavitation emissions from the cavitation, a transmit-receive switch configured to enable only the transmission electronics during transmission of the one or more histotripsy pulses, the transmit-receive switch being further configured to enable only the receive electronics at a predetermined time after the transmission of the one or more histotripsy pulses, to block transmission signals without attenuating received signals.
• a different linear gain follows the transmit-receive switch to amplify or attenuate a selected portion of the received signal based on its amplitude to maximize a receive sensitivity of the receive electronics.
• a method histotripsy therapy comprising the steps of transmitting histotripsy therapy pulses into a target tissue with a histotripsy therapy transducer array to generate cavitation in the target tissue, receiving acoustic cavitation emission signals from the cavitation with the histotripsy therapy transducer, detecting a selected acoustic cavitation emission feature to separate from tissue signals, calculating a cavitation parameter that correlates to tissue damage generated by the histotripsy therapy pulses, determining a change in the cavitation parameter that correlates to treatment progression, determining a change in the cavitation parameter that correlates to treatment completion.
• the selected acoustic cavitation emission feature comprises a timing of cavitation bubble expansion signals.
• the selected acoustic cavitation emission feature comprises an amplitude of cavitation bubble expansion signals.
• the selected acoustic cavitation emission feature comprises a timing of cavitation bubble collapse signals.
• the selected acoustic cavitation emission feature comprises an amplitude of cavitation bubble collapse signals.
• the selected acoustic cavitation emission feature comprises a timing of cavitation bubble rebound signals.
• the selected acoustic cavitation emission feature comprises an amplitude of cavitation bubble rebound signals.
• the cavitation parameter comprises a collapse time of the cavitation.
• the collapse time comprises a time between expansion and collapse signals of the cavitation.
• the cavitation parameter comprises a peak amplitude of an expansion signal of the cavitation.
• the cavitation parameter comprises a peak amplitude of a collapse signal of the cavitation.
• the cavitation parameter comprises amplitude ratios of a growth ACE signal of the cavitation.
• the cavitation parameter comprises amplitude ratios of a collapse ACE signal of the cavitation.
• the cavitation parameter comprises a decay rate of rebound- associated ACE signal amplitudes.
• determining a change in the cavitation parameter that correlates to treatment progression further comprises identifying an increasing slope in the cavitation parameter.
• determining a change in the cavitation parameter that correlates to treatment completion further comprises identifying saturation of the change in the cavitation parameter.
• a method for cavitation detection during histotripsy comprising the steps of transmitting histotripsy therapy pulses into a target tissue with a histotripsy therapy transducer array to generate cavitation in the target tissue, receiving acoustic cavitation emission signals from the cavitation with the histotripsy therapy transducer array, detecting a selected acoustic cavitation emission feature to separate from tissue signals, processing and forming a cavitation map based on the selected acoustic cavitation emission feature, and overlaying the cavitation map onto an image of the target tissue.
• the selected acoustic cavitation emission feature comprises a timing of cavitation bubble expansion signals. In other examples, the selected acoustic cavitation emission feature comprises an amplitude of cavitation bubble expansion signals. In additional examples, the selected acoustic cavitation emission feature comprises a timing of cavitation bubble collapse signals. In one embodiment, the selected acoustic cavitation emission feature comprises an amplitude of cavitation bubble collapse signals. In some embodiments, the selected acoustic cavitation emission feature comprises a timing of cavitation bubble rebound signals. In another example, the selected acoustic cavitation emission feature comprises an amplitude of cavitation bubble rebound signals.
• a method of performing aberration correction during histotripsy therapy comprising the steps of transmitting histotripsy therapy pulses into a target tissue with a histotripsy therapy transducer array to generate cavitation in the target tissue, receiving acoustic cavitation emission signals from the cavitation with the histotripsy therapy transducer array, analyzing the acoustic cavitation emission signals to detect the cavitation generated in the target tissue, testing presets of transmission time delays to select a set of transmission time delays that can maximize a peak signal amplitude in the detected cavitation, and applying the selected set of transmission time delays such that subsequent histotripsy therapy pulses arrive at the target tissue simultaneously.
• kits and methods that provide efficacious non-invasive and minimally invasive therapeutic, diagnostic and research procedures.
• optimized systems and methods that provide targeted, efficacious histotripsy in a variety of different regions and under a variety of different conditions without causing undesired tissue damage to intervening/non-target tissues or structures.
• the system, methods and devices of the disclosure may be used for the minimally or non-invasive acoustic cavitation and treatment of healthy, diseased and/or injured tissue, including in extracorporeal, percutaneous, endoscopic, laparoscopic, and/or as integrated into a robotically-enabled medical system and procedures.
• the histotripsy system may include various electrical, mechanical and software sub-systems, including a Cart, Therapy, Integrated Imaging, Robotics, Coupling and Software.
• the system also may comprise various Other Components, Ancillaries and Accessories, including but not limited to patient surfaces, tables or beds, computers, cables and connectors, networking devices, power supplies, displays, drawers/storage, doors, wheels, illumination and lighting and various simulation and training tools, etc. All systems, methods and means creating/controlling/delivering histotripsy are considered to be a part of this disclosure, including new related inventions disclosed herein.
• the histotripsy system is configured as a mobile therapy cart, which further includes a touchscreen display with an integrated control panel with a set of physical controls, a robotic arm, a therapy head positioned on the distal end of the robot, a patient coupling system and software to operate and control the system.
• the mobile therapy cart architecture can comprise internal components, housed in a standard rack mount frame, including a histotripsy therapy generator, high voltage power supply, transformer, power distribution, robot controller, computer, router and modem, and an ultrasound imaging engine.
• the front system interface panel can comprise input/output locations for connectors, including those specifically for two ultrasound imaging probes (handheld and probe coaxially mounted in the therapy transducer), a histotripsy therapy transducer, AC power and circuit breaker switches, network connections and a foot pedal.
• the rear panel of the cart can comprise air inlet vents to direct airflow to air exhaust vents located in the side, top and bottom panels.
• the side panels of the cart include a holster and support mechanism for holding the handheld imaging probe.
• the base of the cart can be comprised of a cast base interfacing with the rack mounted electronics and providing an interface to the side panels and top cover.
• the base also includes four recessed casters with a single total locking mechanism.
• the top cover of the therapy cart can comprise the robot arm base and interface, and a circumferential handle that follows the contour of the cart body.
• the cart can have inner mounting features that allow technician access to cart components through access panels.
• the touchscreen display and control panel may include user input features including physical controls in the form of six dials, a space mouse and touchpad, an indicator light bar, and an emergency stop, together configured to control imaging and therapy parameters, and the robot.
• the touchscreen support arm is configured to allow standing and seated positions, and adjustment of the touchscreen orientation and viewing angle.
• the support arm further can comprise a system level power button and USB and ethernet connectors.
• the robotic arm can be mounted to the mobile therapy cart on arm base of sufficient height to allow reach and ease of use positioning the arm in various drive modes into the patient/procedure work space from set up, through the procedure, and take down.
• the robotic arm can comprise six degrees of freedom with six rotating joints, a reach of 850 mm and a maximum payload of 5 kg.
• the arm may be controlled through the histotripsy system software as well as a 12 inch touchscreen polyscope with a graphical user interface.
• the robot can comprise force sensing and a tool flange, with force (x, y, z) with a range of 50 N, precision of 3.5 N and accuracy of 4.0 N, and torque (x, y, z) with a range of 10.0 Nm, precision of 0.2 Nm and accuracy of 0.3 Nm.
• the robot has a pose repeatability of +/- 0.03mm and a typical TCP speed of 1 m/s (39.4 in/s).
• the robot control box has multiple I/O ports, including 16 digital in, 16 digital out, 2 analog in, 2 analog out and 4 quadrature digital inputs, and an I/O power supply of 24V/2A.
• the control box communication comprises 500 Hz control frequency, Modbus TCP, PROFINET, ethernet/IP and USB 2.0 and 3.0.
• the therapy head can comprise one of a select group of four histotripsy therapy transducers and an ultrasound imaging system/probe, coaxially located in the therapy transducer, with an encoded mechanism to rotate said imaging probe independent of the therapy transducer to known positions, and a handle to allow gross and fine positioning of the therapy head, including user inputs for activating the robot (e.g. for free drive positioning).
• the therapy transducers may vary in size (22 x 17 cm to 28 x 17 cm), focal lengths from 12 - 18 cm, number of elements, ranging from 48 to 64 elements, comprised within 12-16 rings, and all with a frequency of 700 kHz.
• the therapy head subsystem has an interface to the robotic arm includes a quick release mechanism to allow removing and/or changing the therapy head to allow cleaning, replacement and/or selection of an alternative therapy transducer design (e.g., of different number of elements and geometry), and each therapy transducer is electronically keyed for auto-identification in the system software.
• the patient coupling system can comprise a six degree of freedom, six joint, mechanical arm, configured with a mounting bracket designed to interface to a surgical/interventional table rail.
• the arm may have a maximum reach of approximately 850 mm and an average diameter of 50 mm.
• the distal end of the arm can be configured to interface with an ultrasound medium container, including a frame system and an upper and lower boot.
• the lower boot is configured to support either a patient contacting film, sealed to patient, or an elastic polymer membrane, both designed to contain ultrasound medium (e.g., degassed water or water mixture), either within the frame and boot and in direct contact with the patient, or within the membrane/boot construct.
• ultrasound medium e.g., degassed water or water mixture
• the lower boot provides, in one example, a top and bottom window of approximately 46 cm x 56 cm and 26 cm x 20 cm, respectively, for placing the therapy transducer with the ultrasound medium container and localized on the patient’ s abdomen.
• the upper boot may be configured to allow the distal end of the robot to interface to the therapy head and/or transducer, and to prevent water leakage/spillage.
• the upper boot is a sealed system.
• the frame is also configured, in a sealed system, to allow two-way fluid communication between the ultrasound medium container and an ultrasound medium source (e.g., reservoir or fluidics management system), including, but not limited for filling and draining, as well as air venting for bubble management.
• an ultrasound medium source e.g., reservoir or fluidics management system
• the system software and workflow can be configured to allow users to control the system through touchscreen display and the physical controls, including but not limited to, ultrasound imaging parameters and therapy parameters.
• the graphical user interface of the system comprises a workflow based flow, with the general procedure steps of 1) registering/selecting a patient, 2) planning, comprising imaging the patient (and target location/anatomy) with the freehand imaging probe, and robot assisted imaging with the transducer head for final gross and fine targeting, including contouring the target with a target and margin contour, of which are typically spherical and ellipsoidal in nature, and running a test protocol (e.g., test pulses) including a bubble cloud calibration step, and a series of predetermined locations in the volume to assess cavitation initiation threshold and other patient/target specific parameters (e.g., treatment depth), that together inform a treatment plan accounting for said target’s location and acoustic pathway, and any related blockage (e.g., tissue interfaces, bone, etc.) that may require varied levels of drive
• Said parameters as measured as a part of the test protocol, comprising calibration and multi-location test pulses, are configured in the system to provide input/feedback for updating bubble cloud location in space as needed/desired (e.g., appropriately calibrated to target cross-hairs), as well as determining/interpolating required amplitudes across all bubble cloud treatment locations in the treatment volume to ensure threshold is achieved throughout the volume.
• needed/desired e.g., appropriately calibrated to target cross-hairs
• said parameters may be also used as part of an embedded treatability matrix or look up table to determine if additional cooling is required (e.g., off-time in addition to time allocated to robot motions between treatment pattern movements) to ensure robust cavitation and intervening/collateral thermal effects are managed (e.g., staying below t43 curve for any known or calculated combination of sequence, pattern and pathway, and target depth/blockage).
• additional cooling e.g., off-time in addition to time allocated to robot motions between treatment pattern movements
• the workflow and procedure steps associated with these facets of planning, as implemented in the system software may be automated, wherein the robot and controls system are configured to run through the test protocol and locations autonomously, or semi-autonomously.
• the next phase of the procedure workflow is initiated following the user accepting the treatment plan and initiating the system for treatment.
• the system is configured to deliver treatment autonomously, running the treatment protocol, until the prescribed volumetric treatment is complete.
• the status of the treatment (and location of the bubble cloud) is displayed in real-time, adjacent to various treatment parameters, including, but not limited to, of which may include total treatment time and remaining treatment time, drive voltage, treatment contours (target/margin) and bubble cloud/point locations, current location in treatment pattern (e.g., slice and column), imaging parameters, and other additional contextual data (e.g., optional DICOM data, force torque data from robot, etc.).
• the user may use the therapy head probe, and subsequently, the freehand ultrasound probe to review and verify treatment, as controlled/viewed through the system user interface. If additional target locations are desired, the user may plan/treat additional targets, or dock the robot to a home position on the cart if no further treatments are planned.
• FIG. 1A generally illustrates histotripsy system 100 according to the present disclosure, comprising a therapy transducer 102, an imaging system 104, a display and control panel 106, a robotic positioning arm 108, and a cart 110.
• the system can further include an ultrasound coupling interface and a source of coupling medium, not shown.
• FIG. IB is a bottom view of the therapy transducer 102 and the imaging system 104. As shown, the imaging system can be positioned in the center of the therapy transducer.
• imaging system positioned in other locations within the therapy transducer, or even directly integrated into the therapy transducer.
• the imaging system is configured to produce real-time imaging at a focal point of the therapy transducer.
• the histotripsy system may comprise one or more of various sub-systems, including a Therapy sub-system that can create, apply, focus and deliver acoustic cavitation/histotripsy through one or more therapy transducers, Integrated Imaging sub-system (or connectivity to) allowing real-time visualization of the treatment site and histotripsy effect through-out the procedure, a Robotics positioning sub-system to mechanically and/or electronically steer the therapy transducer, further enabled to connect/support or interact with a Coupling sub-system to allow acoustic coupling between the therapy transducer and the patient, and Software to communicate, control and interface with the system and computer-based control systems (and other external systems) and various Other Components, Ancillaries and Accessories, including one or more user interfaces and displays, and related guided workflows, all working in part or together.
• a Therapy sub-system that can create, apply, focus and deliver acoustic cavitation/histotripsy through one or more therapy transducers
• Integrated Imaging sub-system
• the system may further comprise various fluidics and fluid management components, including but not limited to, pumps, valve and flow controls, temperature and degassing controls, and irrigation and aspiration capabilities, as well as providing and storing fluids. It may also contain various power supplies and protectors.
• the Cart 110 may be generally configured in a variety of ways and form factors based on the specific uses and procedures. In some cases, systems may comprise multiple Carts, configured with similar or different arrangements. In some embodiments, the cart may be configured and arranged to be used in a radiology environment and in some cases in concert with imaging (e.g., CT, cone beam CT and/or MRI scanning). In other embodiments, it may be arranged for use in an operating room and a sterile environment, or in a robotically enabled operating room, and used alone, or as part of a surgical robotics procedure wherein a surgical robot conducts specific tasks before, during or after use of the system and delivery of acoustic cavitation/histotripsy.
• imaging e.g., CT, cone beam CT and/or MRI scanning
• it may be arranged for use in an operating room and a sterile environment, or in a robotically enabled operating room, and used alone, or as part of a surgical robotics procedure wherein a surgical robot conducts specific tasks before, during or
• the cart may be positioned to provide sufficient work-space and access to various anatomical locations on the patient (e.g., torso, abdomen, flank, head and neck, etc.), as well as providing work-space for other systems (e.g., anesthesia cart, laparoscopic tower, surgical robot, endoscope tower, etc.).
• anesthesia cart e.g., laparoscopic tower, surgical robot, endoscope tower, etc.
• the Cart may also work with a patient surface (e.g., table or bed) to allow the patient to be presented and repositioned in a plethora of positions, angles and orientations, including allowing changes to such to be made pre, peri and post-procedurally.
• a patient surface e.g., table or bed
• It may further comprise the ability to interface and communicate with one or more external imaging or image data management and communication systems, not limited to ultrasound, CT, fluoroscopy, cone beam CT, PET, PET/CT, MRI, optical, ultrasound, and image fusion and or image flow, of one or more modalities, to support the procedures and/or environments of use, including physical/mechanical interoperability (e.g., compatible within cone beam CT work-space for collecting imaging data pre-, peri- and/or post-histotripsy).
• one or more external imaging or image data management and communication systems not limited to ultrasound, CT, fluoroscopy, cone beam CT, PET, PET/CT, MRI, optical, ultrasound, and image fusion and or image flow, of one or more modalities, to support the procedures and/or environments of use, including physical/mechanical interoperability (e.g., compatible within cone beam CT work-space for collecting imaging data pre-, peri- and/or post-histotripsy).
• one or more Carts may be configured to work together.
• one Cart may comprise a bedside mobile Cart equipped with one or more Robotic arms enabled with a Therapy transducer, and Therapy generator/amplifier, etc.
• a companion cart working in concert and at a distance of the patient may comprise Integrated Imaging and a console/display for controlling the Robotic and Therapy facets, analogous to a surgical robot and master/slave configurations.
• the system may comprise a plurality of Carts, all slave to one master Cart, equipped to conduct acoustic cavitation procedures.
• one Cart configuration may allow for storage of specific sub-systems at a distance reducing operating room clutter, while another in concert Cart may comprise essentially bedside sub-systems and componentry (e.g., delivery system and therapy).
• Histotripsy comprises short, high amplitude, focused ultrasound pulses to generate a dense, energetic, “bubble cloud”, capable of the targeted fractionation and destruction of tissue. Histotripsy is capable of creating controlled tissue erosion when directed at a tissue interface, including tissue/fluid interfaces, as well as well-demarcated tissue fractionation and destruction, at sub-cellular levels, when it is targeted at bulk tissue. Unlike other forms of ablation, including thermal and radiation-based modalities, histotripsy does not rely on heat or ionizing (high) energy to treat tissue. Instead, histotripsy uses acoustic cavitation generated at the focus to mechanically effect tissue structure, and in some cases liquefy, suspend, solubilize and/or destruct tissue into sub-cellular components.
• Histotripsy can be applied in various forms, including: 1) Intrinsic-Threshold Histotripsy: Delivers pulses with at least a single negative/tensile phase sufficient to cause a cluster of bubble nuclei intrinsic to the medium to undergo inertial cavitation, 2) Shock- Scattering Histotripsy: Delivers typically pulses 3-20 cycles in duration. The amplitude of the tensile phases of the pulses is sufficient to cause bubble nuclei in the medium to undergo inertial cavitation within the focal zone throughout the duration of the pulse.
• Boiling Histotripsy Employs pulses roughly 1-20 ms in duration. Absorption of the shocked pulse rapidly heats the medium, thereby reducing the threshold for intrinsic nuclei. Once this intrinsic threshold coincides with the peak negative pressure of the incident wave, boiling bubbles form at the focus.
• the large pressure generated at the focus causes a cloud of acoustic cavitation bubbles to form above certain thresholds, which creates localized stress and strain in the tissue and mechanical breakdown without significant heat deposition.
• At pressure levels where cavitation is not generated minimal effect is observed on the tissue at the focus. This cavitation effect is observed only at pressure levels significantly greater than those which define the inertial cavitation threshold in water for similar pulse durations, on the order of 10 to 30 MPa peak negative pressure.
• Histotripsy may be performed in multiple ways and under different parameters. It may be performed totally non-invasively by acoustically coupling a focused ultrasound transducer over the skin of a patient and transmitting acoustic pulses transcutaneously through overlying (and intervening) tissue to the focal zone (treatment zone and site). It may be further targeted, planned, directed and observed under direct visualization, via ultrasound imaging, given the bubble clouds generated by histotripsy may be visible as highly dynamic, echogenic regions on, for example, B Mode ultrasound images, allowing continuous visualization through its use (and related procedures). Likewise, the treated and fractionated tissue shows a dynamic change in echogenicity (typically a reduction), which can be used to evaluate, plan, observe and monitor treatment.
• a dynamic change in echogenicity typically a reduction
• This threshold can be in the range of 26 - 30 MPa for soft tissues with high water content, such as tissues in the human body.
• the spatial extent of the lesion may be well-defined and more predictable.
• peak negative pressures (P-) not significantly higher than this threshold, sub-wavelength reproducible lesions as small as half of the -6dB beam width of a transducer may be generated.
• P- peak negative pressures
• high-frequency pulses are more susceptible to attenuation and aberration, rendering problematical treatments at a larger penetration depth (e.g., ablation deep in the body) or through a highly aberrative medium (e.g., transcranial procedures, or procedures in which the pulses are transmitted through bone(s)).
• Histotripsy may further also be applied as a low-frequency “pump” pulse (typically ⁇ 2 cycles and having a frequency between 100 kHz and 1 MHz) can be applied together with a high-frequency “probe” pulse (typically ⁇ 2 cycles and having a frequency greater than 2 MHz, or ranging between 2 MHz and 10 MHz) wherein the peak negative pressures of the low and high-frequency pulses constructively interfere to exceed the intrinsic threshold in the target tissue or medium.
• the low-frequency pulse which is more resistant to attenuation and aberration, can raise the peak negative pressure P- level for a region of interest (ROI), while the high-frequency pulse, which provides more precision, can pinpoint a targeted location within the ROI and raise the peak negative pressure P- above the intrinsic threshold.
• This approach may be referred to as “dual frequency”, “dual beam histotripsy” or “parametric histotripsy.”
• Additional systems, methods and parameters to deliver optimized histotripsy, using shock scattering, intrinsic threshold, and various parameters enabling frequency compounding and bubble manipulation, are herein included as part of the system and methods disclosed herein, including additional means of controlling said histotripsy effect as pertains to steering and positioning the focus, and concurrently managing tissue effects (e.g., prefocal thermal collateral damage) at the treatment site or within intervening tissue.
• tissue effects e.g., prefocal thermal collateral damage
• the various systems and methods which may include a plurality of parameters, such as but not limited to, frequency, operating frequency, center frequency, pulse repetition frequency, pulses, bursts, number of pulses, cycles, length of pulses, amplitude of pulses, pulse period, delays, burst repetition frequency, sets of the former, loops of multiple sets, loops of multiple and/or different sets, sets of loops, and various combinations or permutations of, etc., are included as a part of this disclosure, including future envisioned embodiments of such.
• parameters such as but not limited to, frequency, operating frequency, center frequency, pulse repetition frequency, pulses, bursts, number of pulses, cycles, length of pulses, amplitude of pulses, pulse period, delays, burst repetition frequency, sets of the former, loops of multiple sets, loops of multiple and/or different sets, sets of loops, and various combinations or permutations of, etc.
• ultrasound therapy such as histotripsy to treat a deep tissue target (e.g., >8 cm) or through heterogenous tissue: 1) acoustic aberration and 2) real-time feedback of the ultrasound therapy.
• Acoustic aberration is a problem that impacts ultrasound therapy and imaging, including histotripsy. Acoustic aberration can reduce the focal pressure and distort the focus due to ultrasound propagation through multi-layer heterogenous tissue. Reduction of the focal pressure can cause ineffective treatment or reduced treatment efficiency. For example, in histotripsy, focal pressures at the target tissue site are precisely controlled to generate cavitation at the target tissue site. Reduction of the focal pressures due to aberration can prevent cavitation from occurring. Distortion of the focus can also decrease treatment accuracy.
• a focused ultrasound transducer is shaped as a segment of a spherical surface, such that the sound wave emitted from all locations from the transducer surface go through the same distance to arrive at the focus at the same time.
• Ultrasound imaging has been used to provide real-time feedback for histotripsy, as histotripsy-generated cavitation can be visualized on ultrasound images as a dynamic, bright zone.
• an ultrasound imaging probe is inserted in a central hole of the histotripsy transducer, thus the 2D ultrasound imaging plane contains the histotripsy focus.
• Ultrasound imaging can then be used to guide the targeting to place histotripsy focus to the correct target tissue and to monitor the treatment progression.
• ultrasound imaging there are two main limitations of using ultrasound imaging as the sole guidance for histotripsy.
• the ultrasound imaging probe When the ultrasound imaging probe is blocked by bone of the patient (e.g., ribs or skull), ultrasound images of the histotripsy focus cannot be obtained.
• histotripsy can be used to treat a tumor volume in the liver of a patient, which is partially behind the ribcage.
• the histotripsy transducer When the histotripsy transducer is mechanically moved to scan the histotripsy focus to cover the tumor volume, the imaging probe can be blocked by the ribs for a certain duration of the therapy, at which point no real-time imaging of the therapy is available due to the rib blockage. Without any feedback during this duration, there is no way of knowing if cavitation is still generated at the target locations in the tumor (i.e., if the treatment is implemented over this duration).
• Ultrasound imaging probes can only view the tissue and cavitation within the 2D image plane that contains the histotripsy focus. Thus, ultrasound imaging probes cannot view any potential unwanted cavitation occurring outside the image plane. Unwanted cavitation may generate undesired off-target damage.
• phase correction techniques can be used to correct aberration to recover reduced focal pressure. This can be accomplished by adjusting the phase/time delay at transmission from each transducer element of the phased array to compensate for the travel time variation from each array element to the focus due to the speed of sound variation. In doing so, the aberration can be corrected to increase the focal pressure and improve the focusing.
• An ultrasound phased array transducer that can delivery histotripsy and receive acoustic cavitation emission signals can further be configured to allow detection, localization, and mapping of cavitation.
• a typical histotripsy system only transmits ultrasound pulses to generate cavitation at the focus.
• a transmit-receive histotripsy system can not only be used to deliver ultrasound pulses to generate cavitation, but also can receive signals such as the acoustic cavitation emission (ACE) signals. Both the rapid expansion and rapid collapse of cavitating bubbles during histotripsy produce shockwaves that can be detected by an acoustic receiver.
• ACE acoustic cavitation emission
• received reflections of the main therapy pulse if > 1-2 cycles long and not fully transformed to shockwave in cavitation generation event
• subsequent low amplitude therapy pulses could be used in various receive application listed below.
• cavitation can be detected and localized to provide a real-time, 3D cavitation map.
• the acoustic emission signals from the growth and/or collapse of histotripsy-induced cavitation microbubbles, received by the histotripsy array can be used to localize and monitor the cavitation in 3D and real-time, even in situations where the ultrasound imaging probe is blocked by bone.
• 3D cavitation mapping can also allow real-time monitoring of any off-focus cavitation to increase safety and identify unwanted cavitation.
• Transmit-receive driving electronics found in typical phased array systems cannot be directly adapted for a histotripsy phased array transducer because of the extremely high voltages (thousands of volts) necessary for generating high-pressure histotripsy pulses.
• a novel driving electronics, as described herein, is configured to safely block or significantly attenuate the transmit signal to the ultrasound transducer array while maintaining high sensitivity and high dynamic range for received ultrasound signals.
• This disclosure provides both hardware and software for a phased array histotripsy transducer array with transmit and receive capability. This disclosure further describes the methods and signal processing algorithms that can be used with the transmit-receive histotripsy system for aberration correction and cavitation mapping.
• the electric transmit signal to a histotripsy transducer is typically on the order of Kilovolts, while received ultrasound signals typically range from millivolts to tens of Volts.
• the transmit-receive electric driving circuitry as described herein is designed and configured to block or heavily attenuate the high-amplitude transmit waveform signals on the order of thousands of Volts, while having sufficient sensitivity and dynamic range to receive the low-amplitude signals on the order of tens of Volts.
• the drive circuitry can be retrofitted or added-on to an existing transmit-only histotripsy system to provide transmit-receive capabilities. In other embodiments, the drive circuitry is integrated into an entirely new transmit-receive histotripsy system.
• FIG. 2A is one embodiment of a novel receive drive circuitry 200 configured to be retrofitted onto an existing transmit-only histotripsy system to enable transmit-receive functionality.
• a non-linear compressor can attenuate all the signals connected to each of the histotripsy elements, but with more attenuation for the high- amplitude signals and less attenuation for the low-amplitude signals.
• a capacitive voltage divider 202 as indicated by Cl and C2, can first be configured to attenuate all incoming/received voltage signals from transducer element TX1 to approximately 1-10% (or to attenuate the signals by 90-99%).
• a diode-resistor voltage divider 204 is configured to provide nonlinear attenuation to compress all signals above approximately 1 Volts and alternating current (AC) couple the signal into the analog to digital converter (ADC) for ADC conversion.
• the final component before the ADC is a voltage level shifter 206, as indicated by R2 and R3, that puts the signal in the appropriate voltage range for the ADC (e.g., typically between +/- 0.5V to +/- 2V).
• this circuitry is configured to be retrofitted to an existing transmit-only histotripsy driving system. For example, separate circuitry boards can be added and connected to the existing transmit circuitry to add the receive functions. In one embodiment, the receive circuitry is added in parallel to the transmit electronics and passively receives signals without affecting the transmit electronics.
• FIG. 2B is one embodiment of a drive circuitry 200a that is integrated into high voltage histotripsy driving electronics.
• a bank of capacitors (not shown) in series with the primary coil 20 of the transformer are charged by a high voltage supply.
• a driver chip, Ul then triggers the n-channel MOSFET transistor, QI, which sends a high voltage AC pulse through the transformer primary coil thereby generating an AC pulse in the transformer secondary coil 22 with a voltage proportional to the turn ratio between the coils.
• the secondary coil can be electrically coupled to each of the transducer elements (in this illustration, transducer element TX1). In one implementation, a turn ratio of approximately 1:3 was used between the primary and secondary coils.
• This receive drive circuitry is thereby able to generate single-cycle pulses at the center frequency of the transducer on the order of 3 kV. It should be understood that other turn ratios can be implemented.
• the receive drive electronics can include a secondary transformer coil 22 coupled to the transducer element TX1. Because the driver for this system already includes a transformer at the output of each channel, a third coil 24 can be added to each transformer to be used for the receive electronics, thereby providing total isolation between the driver (e.g., the primary coil 20) and the receiver (e.g., third coil 24). In one implementation, the receive or third coil can be wound with approximately 10-times fewer windings than the secondary transformer coil 22, thereby providing a 10X reduction in voltage between the secondary coil and the third coil.
• the number of windings on the tertiary or third coil can be tuned for the specific application and need not necessarily be 10-times fewer than the secondary. The ratio depends on the receive signal amplitude and can be adjusted based on desired voltages.
• the receive winding (third coil 24) from Fig. 2C can be coupled to a second transformer designed for small signal use with the specifically chosen core material and size such that it would be configured to saturate during the transmit pulses to protect the analog to digital circuitry (ADC) behind it.
• ADC analog to digital circuitry
• FIG. 2D A schematic design of receive circuitry for the integrated receive-capable histotripsy system is shown in FIG. 2D.
• the primary difference in the embodiment shown in FIG. 2D compared to the embodiment above in FIG. 2A is the transformer, which is described in the embodiment of FIG. 2C.
• the VGA circuit is added in the embodiment of FIG. 2D, and the “balanced” input with the two capacitors C3 and C4 in series instead of the level shifter as shown in FIG. 2A comprises a digitizer.
• the transmit-receive drive circuitry can include a transmitreceive switch.
• An integrated drive-receive circuity with both transmit and receive circuitry on the same board can use a switch to separate the receive signal from the transmit signal.
• a traditional TR switch with diodes blocks high-voltage transmit signals without attenuating receive signals.
• a circuit with different linear gain can follow the switch to amplify or attenuate the selected portion of the receive signal properly based on its amplitude to maximize the sensitivity.
• this design would waste a lot of power, be large, and expensive.
• FIG. 3A illustrates another embodiment of drive-receive circuitry that is configured to measure current flowing back from the transducer TX1 through the drive transformer T1 (instead of measuring voltage generated on the transducer during receive as discussed above).
• the relatively large surface area of therapy transducer array elements compared to a traditional imaging transducer means the transducer array generates a relatively large current, which makes high sensitivity during receive possible, whereas with an imaging transducer, it is only practical to measure the voltage induced by acoustic signals. Normal ultrasound imaging elements would be too small to generate a useable receive current.
• Therapy elements as described herein are hundreds to thousands of times larger in surface area than traditional imaging elements, so the currents are substantially larger and easy to measure (in the milliamp range rather than microamp).
• current can be measured by a sense resistor in the electrical path (Rl).
• the drive-receive circuitry is configured to pass excess current from large reflections or during the transmit pulse through a set of bypass diodes (DI and D2). Transmit currents can be as large as 40 A.
• the sense resistor is configured to measure a current induced in the circuitry by those reflections.
• the drive-receive circuitry of FIG. 3A can be configured to operate in a low gain mode and a high gain mode.
• the circuitry can have two current sensing resistors Rl and R2 so that the overall sensitivity of the circuit can be changed by a large amount. As shown, this can be implemented with a pair of transistors Q2 and Q3 that are configured to switch on/off a small value resistor R2 (low sensitivity) in parallel with the larger value resistor Rl (high sensitivity).
• the resistance of the circuit can be changed very rapidly with these transistors to enable the use of both the low setting over part of a received burst of data (e.g., a received signal with a higher amplitude such as ultrasound reflection signals from bones) and the high setting a few microseconds later (e.g., a received signal with a lower amplitude such as acoustic cavitation emission signal from cavitation collapse).
• both scales have very high SNR unlike a variable gain amplifier where the SNR is usually worse for higher gain.
• additional sense resistors can be implemented in the same manner for even wider dynamic range.
• the high gain mode is configured to measure currents up to 5 mA in the ADC which is coupled to the circuitry via transformer T2, while the low gain mode is configured to measure currents up to 200 mA in the ADC.
• FIG. 3B shows an alternate embodiment where instead of bypass diodes, low gate threshold MOSFET transistors Q4 and Q5 can be implemented for passing the large transmit currents.
• FIG. 3C shows a third embodiment where the bypass transistors Q4 and Q5 are explicitly controlled as an active transmit-receive switch.
• the transistor gates are connected to a gate drive signal to force the transistors fully on (for transmit mode) or fully off (for receive mode) which could be +/- 5 V, for example, depending on the transistor drive requirements.
• This configuration may reduce RF noise generated during transmit where instead passively switched bypass components must turn on and off rapidly at the frequency of the ultrasound. This design has a tradeoff of a minor increase in complexity.
• the analog received signals described above can be converted to digital signals and then collected and processed.
• the signal received from the histotripsy transducer array can be, for example, reflections from bones or soft tissue or acoustic emission signals from cavitation. These signals are typically received in a specific time window after the histotripsy pulse (e.g., tens to hundreds of microseconds after transmission of the therapy pulse(s)).
• the hardware and software described herein is configured to synchronize the time clock of transmit, receive, and ADC conversion and sampling to obtain the appropriate time window after each histotripsy pulse that contains the desired received signals. If the synchronization and time window is set properly, then the desired received signals can be collected and processed.
• any of the transmit-receive drive electronics described herein can include an embodiment in which a single field- programmable gated array (FPGA) device connected to the ADC can be used to control both the transmit and receive operations of the transducer, as well as the ADC for some subset of or all channels of a histotripsy system.
• FPGA field- programmable gated array
• a single clock line can be fanned out to all of them for synchronization, and a centralized ‘master’ FPGA can be used to trigger the execution of their operations within the appropriate time window.
• any of the transmit-receive driving electronics described herein can include multi-FPGA systems can be setup to run in a ‘headless’ mode wherein no centralized ‘master’ FPGA is required to issue/fan out a single shared clock line or trigger the execution of individual boards’ operations.
• each FPGA would be set to run off of its own individual clock and to monitor and update two common ‘program-execution-state’, and one common ‘execute-operation’, open-drain hardware IO lines shared by the whole system.
• the open-drain lines operate such that, if any single FPGA applies a low signal to the lines, the signal measured anywhere on the line would register low; if and only if all FPGAs apply a high signal to the lines, the signal measured everywhere on the line would register high.
• the two ‘program- execution- state’ lines would be used to the FPGAs to issue system-wide 1) ‘ready-to-execute’ and 2) ‘done-executing’ signals and by default each FPGA would apply a low signal to each of these lines; each FPGA would apply a high signal to the ‘execute-operation’ line.
• each FPGA While running a program, upon reaching a new executable instruction in the program, each FPGA would update the ‘ready-to-execute’ line to apply a high signal to it, and enter a wait state wherein it would monitor the signals on both the ‘ready-to-execute’ line and the ‘execute-operation’ lines. Once all FPGAs reached the ‘ready-to-execute’ state, the signal registered on the ‘ready-to-execute’ line would become high; the first FPGA in the system to detect a high state on the ‘ready-to- execute’ line would issue a low signal on the ‘execute-program’ line causing it to register low everywhere.
• each FPGA Upon detection of the low signal on the ‘execute-program’ line, each FPGA would set the value on its own terminal of the ‘execute-program’ line to be low and execute its stored commands. Once each FPGA finished running its respective commands, it would apply a high signal to both the ‘done-executing’ and ‘execute-program’ lines. Once both the ‘done-executing’ and ‘execute-program’ lines registered high, the FPGAs would reset all of the shared open-drain line values to their defaults, load the next instruction in the program, and repeat the process for each instruction until the program was completed.
• a fully connected set of receiving elements can generate large amounts of data, so strategies to reduce the data load are proposed to allow acquired signals to be transferred and processed in real-time to meet the monitoring needs during therapy. These strategies can be applied to any of the transmit-receive driving electronics described herein. Such strategies may include, for example, artificially down sampling the incoming data from the ADC in the firmware running on FPGA (e.g., by storing only every other data point generated by the ADC, or the average of the data points generated across multiple acquisition cycles). This effectively reduces the sampling frequency, thus reducing the data load, but doesn’t sacrifice temporal precision or dynamic range or result in an increase in noise in the system.
• this compression strategy results in data reductions proportional to ratio of the size of the variable needed to store the difference value compared to the size of the variable required to store the actual value, which can generally reduce data loads in the current system by 30%-50%, but could result in significantly larger reductions in systems where the individual data elements are larger in size.
• further reductions in data size can be achieved through frequency domain transforms using methods similar to those employed to compress audio files.
• the receive signal amplitude may be low and the noise may be high, resulting in a low signal-to-noise ratio (SNR).
• SNR signal-to-noise ratio
• One method to reduce the noise and increase SNR is to oversample and average in firmware (e.g., FPGA firmware) before storing data. This also helps increase dynamic range and reduces memory requirements.
• Another technique is to implement a dynamic variable sample rate.
• the ADC can be configured to always run at 50 MHz, but high time precision may only be needed over certain portions of the data record. In the portions of the signals where such a high frame rate is not needed, samples can be decimated or averaged to greatly reduce storage requirements.
• the bandwidth of the therapy transducer elements is typically low, but a high sampling rate can be used for sampling for good timing precision.
• Receive data should compress exceptionally well in the Fourier domain (at least a factor of 10, maybe a lot more).
• the FPGAs can be configured to perform this compression before storage or transmit either in firmware or in software. Data compression is the key to implementing real time monitoring, the system will be overwhelmed by the amount of receive data collected.
• the system can be configured to transfer only partial signals and/or store the acquired signals directly on the FPGA devices themselves for transfer to the control computer later. This would allow uninterrupted acquisition of signals from all delivered pulses without limiting treatment speed.
• Such capabilities are useful for monitoring long-term changes in acquired signals. For example, there is inherent variability in the ACE signal features associated with the ablative state of the targeted tissues that make the tissue state difficult to track pulse-to-pulse, but characteristic changes in the ACE signals exist over longer treatment time scales (e.g., >20 applied pulses) that allow the ablative state of the tissue to be assessed.
• the software controlling the histotripsy array allows for the elements of the array to be easily partitioned into independently controllable sub-apertures, effectively allowing a single physical histotripsy transducer array to be operated as multiple separate histotripsy arrays. In this way, multiple locations within the focal volume can be targeted for treatment concurrently using the separate sub-apertures of the array, allowing for increases in treatment speed without necessitating an increase in the rate at which pulses are delivered.
• ABERRATION CORRECTION TECHNIQUES [0122] Below are described examples of aberration correction methods and techniques that are new and specific for histotripsy therapy.
• One embodiment of aberration correction enabled by transmit-receive histotripsy arrays utilizes the arrival time of robust shockwaves emitted by the initial rapid expansion of histotripsy-induced cavitation bubbles. This can be referred to as acoustic cavitation emission (ACE) signals.
• ACE acoustic cavitation emission
• This shockwave construct emanates spherically from the focal cavitation region back toward the histotripsy therapy 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.
• a correction time delay for each element can be applied to subsequent transmissions for each respective transducer element, such that the ultrasound pulse wave generated by each histotripsy array element will arrive at the focal cavitation position at the same time. This is done by applying the variation in time-of-flight for ACE signals to the transmission pulse signal to each histotripsy array element, such that the transmission signals would arrive at the cavitation site at the same time, correcting the aberration and improving focusing.
• the method can include transmitting histotripsy therapy pulses into a target tissue with an ultrasound transducer array to generate cavitation in the target tissue. As described above, a plurality of transducer elements of the array can each transmit separate histotripsy pulses into the tissue.
• the method can include receiving acoustic cavitation emissions (ACE signals) resulting from the histotripsy-induced cavitation.
• ACE signals acoustic cavitation emissions
• the method can use the information encoded in these ACE signals (e.g., start time of the emission generated from cavitation bubble expansion, peak time from cavitation bubble collapse) to calculate the travel time from each element of the histotripsy array to the cavitation in the target tissue.
• the method can include adjusting the time delay of the driving electric signal to each array element to correct for the difference in the travel time, such that the ultrasound pulse delivered by each element are configured to arrive at the focus/target tissue at the same time in subsequent transmissions. This method can be used for aberration correction with bones or heterogeneous tissue in the pathway.
• Shockwave pressure tends to increase linearly with increasing histotripsy focal pressure.
• One embodiment of the time of flight analysis of these shockwaves involves using the Hilbert transform to calculate an envelope of these shockwaves.
• a cross-correlation algorithm can then be used to determine the temporal shift required to realign these envelope signals.
• These temporal shifts are then inverted to correct for variations in time-of-flight across histotripsy elements and are then applied to subsequent pulses as described above.
• Other methods for analyzing these signals include detecting the peak shockwave pressure or using a window-averaging filter and edge detection algorithm to determine the arrival time of shockwaves.
• the focal pressure at a sub-cavitation threshold amplitude is found to drop to 49.7%, and the transducer power required to induce cavitation triples.
• the transducer power required to induce cavitation can be reduced by approximately 31.5%.
• Acoustic cavitation emission (ACE) signals may not always be detectable (e.g., due to attenuation effects from propagating through tissues/bone) and/or differentiable from background signals components (e.g., the ACE signals may arrive at the array elements concurrent with histotripsy pulse reflections / reverberations) at sufficient levels to perform aberration correction.
• using the cavitation events as the basis for aberration correction may be achieved using pulse-echo techniques by partitioning the histotripsy array elements into multiple sub-apertures, one of which would be used to generate the cavitation events (sub-aperture A), the other of which would be used to fire interrogation pulses (subaperture B).
• the elements sub-aperture B would fire pulses directed towards the event.
• the pulses from sub-aperture B Upon reaching the cavitation event generated by sub-aperture A, the pulses from sub-aperture B would be reflected off of the cavitation event and scattered back towards the array.
• the array elements of both subapertures could then be used to receive the signals reflected off of the cavitation event and the arrival timing of these signals could then be used to calculate the aberration correction delays per the methods described in [69] and [70].
• a key benefit of this technique is that the timing of the pulses from sub-aperture B can be set arbitrarily such that the reflected/scattered signals arrive back at the array elements for detection in a region of the signal where background components are minimal.
• aberration correction can be based on scatter signals from soft tissue.
• a focal dithering method can also be used for aberration correction based on receive signals.
• the challenge of using scatter or reflection signals from soft tissue is that the amplitude from the scatter signal from a target tissue is often small and/or buried by the background signals of scatter signals from other tissues.
• the scattered signals with the array focus at the geometric focus are received from all elements of the array (Scl n , n is the element number). Then the array focus can be dithered to a small distance away (e.g., * or 3/2 wavelength) from the geometric focus, and the scattered signals are also received from all elements of the array (Sc2 n , n is the element number).
• Both these signals contain the background scatter signals from all heterogeneous tissue in the pathway should, while the difference (Sc2 n - Scl n ) is only due to the scatter signal from the dithered focus with the opposite phase.
• Combinations of phase or time delays to all elements will be tested to determine a combination of phase or time delays that can maximize the difference (Sc2 n - Scl n ).
• This resulted combination can then be used for aberration correction.
• a pre-set of combinations of delays can be calculated beforehand to use for testing. This method allows aberration correction without generating cavitation and potentially maintaining a good enough SNR for processing.
• water is often used as a coupling medium to ensure ultrasound transmission from the transducer array to the skin of the patient.
• the speed of sound difference between water and soft tissue can result in a substantial location shift of the focus (e.g., a few millimeters).
• Reflection signals from the water-skin interface can be received by each array element to 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.
• Reflection signals from bone can have high amplitudes.
• the methods and algorithms described herein can also include detection of transducer elements blocked by ribs (via high amplitude reflected signals) and turning off these transducer elements, or reducing the amplitude of the transmission signals to these transducer elements (amplitude aberration correction) to reduce the potential of rib or bone heating during histotripsy treatment.
• the reflection signals from various tissue surfaces and layers may be received by each array element to model the tissue layers. Based on the speed of sound of each tissue layer using a literature value, the time-of-flight from each element to the array focus may be calculated for aberration correction. This method would only provide a coarse aberration correction.
• the ACE signals received by the transmit-receive histotripsy transducer array can be used to localize and map the cavitation in the target tissue.
• conventional beamforming methods used in ultrasound imaging and passive cavitation mapping can be used.
• modifications to existing beamforming or passive cavitation mapping algorithms are required and discussed herein to account for the travel time variation for different elements to arrive at the focus. The travel time difference can be accounted for using iterative methods to maximize the signal amplitude within the focal cavitation region after beamforming.
• a brute force method can be used to test a range of ultrasound travel time delays iteratively for all histotripsy array elements.
• the combination of time delays that results in the highest amplitude of the summed-together ACE signals can then be used for cavitation localization and mapping. This can be achieved sufficiently fast for real-time imaging.
• the example below shows a frame rate of 70Hz for cavitation localization through an excised human skull with accuracy within 1.5 mm based on the transmit-receive histotripsy system and the brute force method. It should be noted that the same method can also be used to obtain mapping of the skull surface or ribs that are in the pathway, as the strong reflection signals from the bone can be received by the histotripsy array and separated for processing.
• 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 to monitor cavitation behind the ribs.
• Cavitation localization and mapping are accomplished with the following two steps: 1) signal processing to separate the ACE signals from the skull reflection signals; and 2) generating a cavitation map by projecting the ACE signals acquired by each element of the array back into the field and summing their signal amplitudes.
• Signal processing to separate the ACE signals from skull reflection signals can include three basic steps. First, low amplitude, sub-cavitation threshold histotripsy pulses can be delivered to the target tissue, and the reflections of the pulses off the intervening tissue can be recorded using the transducer array elements. These signals can then be scaled up and subtracted from the ACE-containing signals generated after delivering high-amplitude histotripsy pulses in order to isolate the ACE signals from the background. Next, the signals can then be smoothed using a moving window average to reduce spurious effects of noise in the acquired signals on the localization results. The magnitudes of the signals can then be taken as a precondition for a localization algorithm.
• the signal amplitudes measured from each transducer at the corresponding times at each respective voxel can then be summed together to determine the sum signal amplitude at each voxel.
• the process of selecting the time points within the acquired ACE signals from which the measured signal amplitudes were taken can be repeated by iterating in time about the calculated there-and-back times-of-flight at each voxel element and recalculating the signal amplitude field at each time step.
• the sum signal amplitude at each voxel at the end of the iterative calculations can be taken to be the maximum value calculated at each voxel within the whole iteration window.
• This process accounts for the combined effects of the tissue sound speed and thickness on ultrasound propagation by considering only the end result, which in this simplified case is to produce a uniform modulation of the signal arrival times at the transducer elements. This greatly reduces computational complexity and allows the effects of tissues to be accounted for during the localization process through iterative time shifting operations.
• the locations of the cavitation events can then be calculated by finding the center-of-mass of all points within the voxel grid whose amplitudes were >90% of the maximum detected value.
• 3D cavitation localization can be achieved through bone, such as through ribs or through a human skull.
• the ACE feedback localization results are accurate to within ⁇ 1.5 mm of the actual positions of the generated cavitation events’ centers-of-mass (as measured through optical imaging).
• localization results have been found to fall within ⁇ 1 mm of the volumes encompassed by the bubbles in >90% of cases. Localization of cavitation in real-time at rates of up to 70 Hz has been achieved during experiments using the described methods, but benchmark tests indicate that the localization algorithm scales efficiently and thus higher rates are likely possible with more powerful hardware.
• FIG. 5A signals received from each element of the transmit-receive histotripsy array are shown, including the reflection signal from the skull at a sub-threshold cavitation pressure, the skull reflection signal and the ACE signal at a supra-threshold cavitation pressure, and post-processing ACE signals acquired by subtracting the skull reflection signal.
• FIG. 5B illustrates a skull surface map and the focal cavitation localization/map produced by processing the ACE signal using the brute-force iterative method.
• the method described for mapping transcranial cavitation is extended for use in applications where targets lie below highly non-uniform aberrators (i.e., the ribs) or where path length variations through tissues en route to the target are significant (e.g., when the transducer must be obliquely aligned with respect to the tissue surface in order to focus at the target).
• targets lie below highly non-uniform aberrators (i.e., the ribs) or where path length variations through tissues en route to the target are significant (e.g., when the transducer must be obliquely aligned with respect to the tissue surface in order to focus at the target).
• the same signal processing and localization methods as described above can be applied with two important additions.
• Signal Processing An additional step in the signal processing may be required to account for the presence of non-uniform aberrators and oblique surfaces. First, each element of the array is fired individually, and the reflections of the pulses off of the tissue(s) are recorded by all array elements. Given the known positions of the transducer elements and sound speed of the coupling medium, traditional delay sum beamforming can be used to generate a 3D map of the tissue surface and underlying features (i.e., the ribs) from the acquired signals.
• the time-delays assigned to each element can be set in a graduated way to account for the different path lengths of tissue through which the ACE signals would need to travel in order to reach each array element.
• the methods described are extended for use in applications where targets lie within an approximately uniform aberrator (i.e., the liver) whose sound speed may not be well known, particularly where path length variations through tissues en route to the target are significant (e.g., when the transducer must be obliquely aligned with respect to the tissue surface in order to focus at the target).
• the same signal processing and localization methods as described, as well as method for mapping the tissue surface geometry described above can be applied with the following addition.
• the location of the cavitation events as well as the sound speed of the nucleation medium itself can be determined via minimization of a coupled system of equations through the application of Snell’s law describing refraction.
• the time of flight from each element to every point on the tissue surface, and the respective trajectories of the pulses with respect to it can be calculated.
• the trajectory of the ACE signal from the cavitation event will be altered due to the difference in sound speeds between the tissue and the coupling medium per Snell’s law.
• the sound speed of the coupling medium, and distance from the array elements to every point on the tissue surface are known, but not which point on the tissue surface the received portion of the ACE signal acquired by each array element originated from; the sound speed of the tissue and the location of the cavitation event being mapped are also unknown.
• tACE.n [Dcm,n/Ccm,n+D t ,n/Ct,n] , where the ‘ ’ and ‘C’ correspond to the ‘distance traveled’ and ‘sound speed of the medium’, respectively, and the subscripts ‘cm’, ‘/’, and ‘n’ correspond to ‘coupling medium’, ‘tissue’, and ‘element number’ respectively.
• histotripsy generates cavitation to mechanically fractionate target tissue.
• treated tissue becomes increasingly soft and eventually liquefied into an acellular debris.
• the cavitation bubbles generated grow larger, take a longer time to collapse, and eventually the cavitation activity mimics strong cavitation activity in fluid.
• the cavitation expansion and collapse signals can be detected via the acoustic cavitation emission (ACE) signals received by the transmit-receive histotripsy array, which can then be processed to quantitatively monitor the treatment progression and determine the treatment completion.
• ACE acoustic cavitation emission
• the time to maximum cavitation bubble growth and bubble collapse time increase over the treatment and eventually saturate when the target tissue is liquefied and the treatment is complete.
• This increasing trend can be detected by processing ACE via specific algorithms to indicate when the treatment is progressing, and the saturation trend can be detected by specific algorithms to determine the treatment is completed, all in real-time. Examples of such algorithms might include using peak detection in the acquired waveforms individually to identify the ACE signals associated with the bubble’s growth and collapse, and measuring the timing between them. In cases where signals are embedded within strong background environments, individual waveforms can be processed via autocorrelation to identify the timings between self-similar regions within the waveforms (i.e., the growth and collapse ACE signals).
• the ACE signals could then be identified by comparing all of the individual autocorrelation results from each array element with each other, for example by median filtering them, which would show consistent peaks at the time corresponding to the bubble’s lifespan.
• B ackprojecting the acquired signals into the field to image for the volume as a function of time would similarly show peaks in the projected signal amplitudes within the image-formed volumes at times corresponding the growth and collapse ACE signals.
• a method of histotripsy treatment progression monitoring can include, at step 602, detecting a selected ACE feature (e.g., the timings and amplitudes of the cavitation bubble expansion signals, collapse signals, and/or rebound signals) to separate from tissue signals, at step 604, calculating a cavitation parameter (e.g., collapse time i.e., the time between the expansion signal and collapse signal, peak amplitude of the expansion signal, peak amplitude of the collapse signal, amplitude ratios of the growth and collapse ACE signals, or the decay rates of the rebound-associated ACE signal amplitudes) that correlates to the tissue damage generated by histotripsy, at step 606, determining a change (e.g., increasing slope of the selected cavitation parameter) that correlates to
• cavitation parameter collapse time An example of the cavitation parameter collapse time is provided. This example shows that the increase and saturation of the cavitation collapse time is correlated with the treatment progression and completion.
• the change in the collapse time (tcoi) of the cavitation bubble cloud over the histotripsy treatment is an indicator for progression of the tissue fractionation process during the histotripsy treatment.
• tcoi left y-axis
• MLI mean lesion intensity
• FIG. 7 tcoi (left y-axis) and mean lesion intensity (MLI) (right y-axis) vs. pulse number throughout 100 pulses are shown.
• the MLI defined as the average pixel intensity over the ROI, was calculated for the entire treatment on a normalized scale from 0 to 1 to indicate the treatment progress (0 - no treatment; 1 - treatment completion).
• the majority of changes in tcoi and MLI occur early in treatment and at the same time.
• the change in tcoi is greater than the change in MLI in the first several pulses, but both metrics even out quickly and reach a plateau threshold around 40 pulses.
• the acoustic cavitation emission (ACE) signal generated by the cavitation cloud during histotripsy therapy was 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 6x6x7 mm lesions within ex vivo bovine liver tissue by scanning over 219 locations with 30-1000 pulses-per-location.
• a custom nonlinear voltage compressor was designed and constructed to allow 8 elements of the array to transmit histotripsy pulses and receive ACE signals from the central treatment location within the lesion.
• the ACE signal was quantitatively analyzed by measuring the change in the peak pressure arrival time throughout treatment. The ACE peak pressure arrival time decreased as the treatment progressed and eventually saturated (FIG. 9).
• quantified ACE using the peak pressure arrival time is shown.
• the trend exhibited by the peak pressure arrival throughout treatment suggests that the majority of physical changes that influence this metric occur in the first 200 pulses.
• a nonlinear least squares best-fit line is shown in black. The best-fit line reached an exponential decay time constant at 80 pulses.
• the histology of the treated tissue was analyzed, and correspondingly the cell count, reticulin- stained type III collagen area, and trichrome- stained type I collagen area all decreased over the course of histotripsy treatment (FIG. 10).
• FIG. 10 a histological analysis of 42 histotripsy treated samples at varying dosages is shown.
• FIG. 10A shows a viable cell count remaining in imaged medium. The cell count experienced the greatest amount of destruction early in treatment.
• FIG. 10B shows a percent area with intact reticulin- stained collagen and
• FIG. 10C shows a percent area with intact trichrome- stained collagen. Both collagen metrics experienced slower amounts of destruction than remaining cell count.
• Nonlinear least square best-fit lines are shown in red. All best fit lines exhibited statistical significance when compared to a normal distribution as indicated by the p-values on each plot.
• Aberration correction - Transmit-receive histotripsy can correct aberration due to the speed of sound variation in the ultrasound pathway and improve focusing. As correction needs to be applied to each array element, the correction methods based on the signal received by each element provides the most accurate aberration correction.
• the advanced transmit-receive histotripsy hardware and software along with the specialized aberration correction algorithms can enable aberration correction on-the-fly immediately before or even during the treatment.
• the 3D cavitation map would also allow us to detect both intended cavitation at the target and any potential unwanted off-target cavitation. Therefore, the real-time 3D feedback provided by the transmit-receive histotripsy transducer array can overcome the two main limitations of the ultrasound imaging feedback as described earlier.
• Treatment monitoring - Cavitation dynamics are correlated to the level of tissue damage generated by histotripsy.
• the received ACE signals can be processed to monitor the treatment progress and determine the completion of the treatment in real-time.
• the 3D cavitation mapping can also be co-registered or overlaid onto a pre-treatment MRI or CT scan.
• the transmit-receive histotripsy array system can be compact and of similar size of a transmit-only histotripsy system, but with many added features as described above.
• the transmit-receive histotripsy array can be used independent of and/or supplemental to the ultrasound imaging that is currently used for histotripsy feedback.
• the transmit-receive ultrasound systems described herein can enable ultrasound and/or histotripsy therapy that provides general amplitude aberration correction to make therapy more efficient, and can further provide corrections for focal shift. These methods are described below:
• Methods of providing general amplitude aberration correction during ultrasound therapy are provided. These methods can include transmitting ultrasound pulses into a single test pulse location (e.g., the center of the planned treatment volume aligned with the target tissue), and receiving time delays from the single location. Next, the received time delays can 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). Aberration correction can then be applied to subsequent ultrasound treatment pulses to increase efficiency of the therapy. [0161] In some examples, multiple discrete test pulse locations can be used (e.g., seven-point test locations). The method can include receiving time delays at each test location/position and modeling the received delays to interpolate the aberration correction map for the entire planned treatment volume.
• the method can include real-time testing.
• the method can include using received signals for aberration correction at each test pulse and treatment location and updating the aberration correction in real-time during therapy.
• test pulse sequences can be different than therapy pulses (automated treatment) to afford smaller clouds or more thermally favorable sequences to assess aberration/threshold, before transitioning to therapy pulses.
• the receive capability of the system can be used to map the reflection signals from the water-skin interface to 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.
• focal shift correction can be based on a single test pulse at (e.g., at the center of the planned treatment volume), or based on multiple test-pulses interpolated over the volume.
• the receive data received by the system can be registered with imaging data from an imaging system to provide more visual feedback regarding cavitation. Additionally, the receive and imaging data can be registered with the robotic positioning arm of the therapy system so the image/receive data is in context to the six degrees of freedom of the positioning arm.
• spatially relative terms such as “under”, “below”, “lower”, “over”, “upper” and the like, may be used herein for ease of description to describe one element or feature’s relationship to another element(s) or feature(s) as illustrated in the figures. It will be understood that the spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if a device in the figures is inverted, elements described as “under” or “beneath” other elements or features would then be oriented “over” the other elements or features. Thus, the exemplary term “under” can encompass both an orientation of over and under.
• the device may be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly.
• the terms “upwardly”, “downwardly”, “vertical”, “horizontal” and the like are used herein for the purpose of explanation only unless specifically indicated otherwise.
• first and second may be used herein to describe various features/elements (including steps), these features/elements should not be limited by these terms, unless the context indicates otherwise. These terms may be used to distinguish one feature/element from another feature/element.
• a first feature/element discussed below could be termed a second feature/element
• a second feature/element discussed below could be termed a first feature/element without departing from the teachings of the present invention.
• a numeric value may have a value that is +/- 0.1% of the stated value (or range of values), +/- 1% of the stated value (or range of values), +/- 2% of the stated value (or range of values), +/- 5% of the stated value (or range of values), +/- 10% of the stated value (or range of values), etc.
• Any numerical values given herein should also be understood to include about or approximately that value, unless the context indicates otherwise. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Any numerical range recited herein is intended to include all sub-ranges subsumed therein.

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