Tissue destruction system and method

Abstract

The present invention provides a tissue destruction system, which includes: one or more ultrasonic transducers, which are configured to generate acoustic cavitation in tissue located at a target location; and one or more computer processors, which are configured to control the power and positioning of the ultrasonic transducers, wherein the one or more processors are configured to implement a treatment mode in the one or more ultrasonic transducers, wherein the one or more ultrasonic transducers generate bubble clouds at multiple different locations in the target tissue within multiple time periods, wherein at least two of the locations treated in consecutive time periods are located in adjacent columns of the target tissue.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 62 / 772,473, filed on November 28, 2018, entitled “HISTOTRIPSY SYSTEMS AND METHODS,” the entire contents of which are incorporated herein by reference.

[0003] Incorporated by Reference

[0004] All publications and patent applications mentioned in this specification are herein incorporated by reference as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. Technical Field

[0005] The present disclosure describes in detail novel tissue destruction systems configured to generate acoustic cavitation, methods, devices, and procedures for minimally invasive and non-invasive treatment of healthy, diseased, and / or injured tissue. The tissue destruction systems and methods described herein, also known as Histotripsy, may include a transducer, drive electronics, positioning robots, imaging systems, and integrated treatment planning and control software to provide integrated treatment and therapy for soft tissue of a patient. Background Art

[0006] Many medical conditions require invasive surgical intervention. Invasive surgery often involves incisions, trauma to muscles, nerves and tissues, bleeding, scarring, trauma to organs, pain, the need for anesthetics during and after surgery, hospitalization, and the risk of infection. In order to avoid or reduce such problems, non-invasive and minimally invasive procedures are often preferred when feasible. Unfortunately, non-invasive and minimally invasive procedures may lack the precision, effectiveness or safety required to treat a variety of diseases and conditions. There is a need to provide improved non-invasive and minimally invasive procedures, preferably without the need for ionization or thermal energy to achieve a therapeutic effect.

[0007] Tissue destruction, or pulsed ultrasound cavitation therapy, is a technique in which extremely short, high-intensity bursts of acoustic energy induce controlled cavitation (microbubble formation) within the lesion mass. The dramatic expansion and rupture of these microbubbles mechanically homogenizes the cells and tissue structures within the lesion mass. This end result is very different from the coagulative necrosis characteristic of thermal ablation. In order to operate within the non-thermal, tissue destruction field, it is necessary to deliver acoustic energy in the form of high-amplitude acoustic pulses with a low duty cycle.

[0008] Compared to conventional focused ultrasound techniques, tissue ablation has important advantages: 1) the destruction process at the focal point is mechanical, not thermal; 2) cavitation appears bright on ultrasound imaging, which confirms the correct target and location of treatment; 3) treated tissue usually (but not always) appears darker (less echogenic) on ultrasound imaging, so the operator knows what has been treated; and 4) tissue ablation produces damage in a controlled and precise manner. It is important to emphasize that, unlike thermal ablation techniques such as microwaves, radiofrequency, and high-intensity focused ultrasound (HIFU), tissue ablation relies on the mechanical action of cavitation to destroy tissue.

[0009] BRIEF DESCRIPTION OF THE DRAWINGS

[0010] The novel features of the invention are particularly set forth in the claims that follow. A better understanding of the features and advantages of the invention will be obtained by reference to the following detailed description, which sets forth illustrative embodiments in which the principles of the invention are utilized, and the accompanying drawings, in which:

[0011] Figure 1A-1B An ultrasound imaging and therapy system is shown.

[0012] Figure 2 A schematic diagram of an inductive drive circuit configured to excite an ultrasonic transducer for tissue destruction is provided.

[0013] Figure 3 The schematic diagram of the autotransforming inductor driving circuit including the inductor Lx with a center tap is shown, which solves the problem of Figure 2 The disadvantages of the inductor drive circuit shown.

[0014] Figure 4 A schematic diagram of an autotransformer inductor drive with another active or passive electronic component is shown.

[0015] Figure 5 A schematic diagram of an autotransformer inductor driver with a protection circuit is shown.

[0016] Figure 6 Another schematic diagram of an autotransformer inductor driver with a protection circuit is shown.

[0017] Figure 7A-7B One example of a treatment mode for ablating a target tissue mass is shown.

[0018] Figure 8-9 An example of a columnar bubble cloud is shown.

[0019] Fig.10 An example of a linear treatment pattern is shown.

[0020] Figures 11A-11E An example of a radiation therapy pattern is shown.

[0021] Fig.12 is a schematic diagram of one example using seven test pulse positions within a spherical treatment volume.

[0022] Figures 13A-13B The temperature profiles resulting from six different tissue destruction pulse protocols are shown.

[0023] Figures 14A-14B The temperature profiles resulting from three different tissue destruction pulse protocols are shown.

[0024] Figures 15A-15B Shown are thermal curves resulting from five treatment protocols used to investigate the implementation of a cooling step during volumetric treatment.

[0025] Figures 16A-16B The thermal effect of a high PRF sequence with a cool-down period is shown.

[0026] Figures 17A-17E An example of a graphical user interface for the system is shown. Summary of the invention

[0027] Tissue destruction produces tissue disruption through a dense cloud of high-energy bubbles generated by short high-pressure ultrasound pulses. When pulses shorter than 2 cycles are used, the generation of these high-energy bubble clouds depends only on the peak negative pressure (P-) exceeding the inherent threshold for initiating cavitation in the medium (usually 26-30 MPa in soft tissues with high water content).

[0028] The present invention provides a method for treating tissue, the method comprising the following steps: using at least one ultrasonic transducer to transmit an ultrasonic pulse to a first test position, determining a first cavitation threshold at the first test position, using at least one ultrasonic transducer to transmit an ultrasonic pulse to a second test position, determining a second cavitation threshold at the second test position, adjusting a first drive voltage and / or a pulse repetition frequency of at least one ultrasonic transducer based on the first cavitation threshold, using at least one ultrasonic transducer to transmit an ultrasonic pulse to the first test position at the first adjusted drive voltage and / or pulse repetition frequency to generate cavitation at the first test position, adjusting the second drive voltage and / or pulse repetition frequency of at least one ultrasonic transducer based on the second cavitation threshold, and using at least one ultrasonic transducer to transmit an ultrasonic pulse to the second test position at the second adjusted drive voltage and / or pulse repetition frequency to generate cavitation at the second test position.

[0029] In some embodiments, the method further comprises repeating these steps at three or more test locations in the tissue.

[0030] In other embodiments, the method further comprises repeating the steps at six or more test locations in the tissue.The six or more test locations may be positioned in cubic coordinates around the center of the target location.

[0031] In some embodiments, the method further comprises repeating the steps at seven or more test locations in the tissue.The six target locations may be positioned and spaced apart in a cubic coordinate around the central test location.

[0032] In some embodiments, the method further includes determining a cavitation threshold for a third test position between the first test position and the second test position by extrapolating the cavitation threshold based on the cavitation thresholds for the first test position and the second test position.

[0033] In some other embodiments, the method further includes interpolating the required drive amplitudes for the first test position, the second test position, and the third test position to ensure that each cavitation threshold can be reached. The first test position and the second test position may be located near an outer boundary of the tissue.

[0034] In some embodiments, the tissue comprises a tumor volume. In other embodiments, the tissue comprises a tumor volume and a margin surrounding the tumor volume.

[0035] In some embodiments, the first test location and the second test location are two or more tumors.

[0036] In some embodiments, the method further includes locating a first test location and a second test location on the tissue in a graphical user interface.

[0037] In some embodiments, these steps are performed automatically without user intervention.

[0038] In some embodiments, the method further includes taking depth measurements at the first test location and the second test location.

[0039] In other embodiments, the method further includes determining a maximum energy that can be applied to the first test location without causing undesirable damage to the first test location or surrounding intervening tissue.

[0040] In some embodiments, the method further includes determining an energy threshold that can be applied to the first location without causing undesirable damage to the first test location or surrounding intervening tissue.

[0041] In an alternative embodiment, the method further comprises positioning at least one ultrasound transducer 3 cm or more from the tissue.

[0042] In some embodiments, the method further comprises positioning at least one ultrasound transducer 5 cm or more from the tissue.

[0043] In other embodiments, the method further comprises positioning at least one ultrasound transducer 10 cm or more from the tissue.

[0044] In some embodiments, one or more bone structures are located between at least one ultrasound transducer and the tissue.

[0045] In some examples, the ultrasound pulses include tissue ablation pulses.

[0046] The present invention provides a method for generating acoustic cavitation to treat tissue using a pulse repetition frequency (PRF) of 400 Hz or higher, the method comprising the following steps: using at least one ultrasonic transducer to transmit an ultrasonic pulse to a first test position, determining a first cavitation threshold at the first test position, using at least one ultrasonic transducer to transmit an ultrasonic pulse to a second test position, determining a second cavitation threshold at the second test position, adjusting a first drive voltage and / or a pulse repetition frequency of at least one ultrasonic transducer based on the first cavitation threshold, using at least one ultrasonic transducer to transmit an ultrasonic pulse to the first test position at a first adjusted drive voltage to generate cavitation at the first test position, adjusting a second drive voltage and / or a pulse repetition frequency of at least one ultrasonic transducer based on the second cavitation threshold, and using at least one ultrasonic transducer to transmit an ultrasonic pulse to the second test position at a second adjusted drive voltage to generate cavitation at the second test position.

[0047] In some examples, the pulse repetition frequency is between 400 Hz and 900 Hz, between 600 Hz and 900 Hz, between 500 Hz and 700 Hz, or the pulse repetition frequency is 600 Hz.

[0048] In some embodiments, the method further comprises implementing a testing protocol that determines a treatment power threshold at two or more test locations in the tissue.

[0049] In some embodiments, the method further comprises implementing a treatment plan based on the power of the test plan to one or more treatment locations within the tissue selected.

[0050] In other embodiments, the method further includes utilizing the robot to emit ultrasonic pulses.

[0051] In some embodiments, the method further comprises destroying cells in the target tissue with the emitted pulses. In other embodiments, the method further comprises destroying cells in the target tissue without damaging critical tissue structures. The critical tissue structures may be selected from blood vessels, bile ducts, collecting systems, organ capsules, and visceral structures.

[0052] The present invention provides a method for treating tissue using ultrasonic energy, the method comprising the following steps: using one or more ultrasonic transducers to transmit ultrasonic pulses into target tissue to generate acoustic cavitation in the target tissue; adjusting the power and positioning of one or more ultrasonic transducers within multiple time periods to generate bubble clouds at multiple different locations in the target tissue, thereby treating at least two locations in a discontinuous area of ​​the target tissue within a continuous time period.

[0053] In some embodiments, the method further comprises forming a plurality of treatment lines across the target tissue. In some examples, the plurality of treatment lines comprises a first line spanning from a first side of the target tissue to a second side of the target tissue. In other examples, the plurality of treatment lines further advances along a second line from the first side of the target tissue to the second side of the target tissue.

[0054] In some embodiments, multiple treatment lines are further advanced along the third and subsequent lines, each line spanning from a first side of the target tissue to a second side of the target tissue.

[0055] In some embodiments, the first side includes a top region of the target tissue closest to the one or more ultrasound transducers and the second side includes a bottom region of the target tissue farthest from the one or more ultrasound transducers.

[0056] In some embodiments, the method further comprises determining a treatment power threshold at two or more test locations in the target tissue.

[0057] In some embodiments, the method further comprises adjusting a power level of one or more ultrasound transducers based on the therapeutic power threshold.

[0058] In other embodiments, the method further includes performing depth measurements at two or more test locations.

[0059] In some embodiments, the method further comprises positioning the one or more ultrasound transducers using a robotic arm having three or more degrees of freedom.

[0060] In further embodiments, the method further comprises positioning one or more ultrasound transducers with a robotic arm, wherein the three or more degrees of freedom are six degrees of freedom.

[0061] In some embodiments, the method further comprises displaying real-time visualization of the bubble cloud in the first position and subsequent positions of the treatment pattern during the treatment.

[0062] In other embodiments, the method further comprises displaying the status of the treatment and the positioning of the bubble cloud in the planned treatment pattern, wherein the status comprises information derived from the position, positioning, percentage of treatment completed, percentage of treatment remaining, and time. In some embodiments, such display may comprise displaying a combination of real-time visualization and CT and / or MRI images.

[0063] The present invention provides a system comprising one or more ultrasonic transducers configured to generate acoustic cavitation in tissue at a target location, and one or more computer processors configured to control the power and positioning of the ultrasonic transducers, wherein the one or more processors are configured to implement a treatment mode in the one or more ultrasonic transducers, the treatment mode generating bubble clouds at multiple different locations in the target tissue over multiple time periods, wherein at least two locations treated in consecutive time periods are located in adjacent columns in the target tissue.

[0064] In some embodiments, the treatment pattern includes multiple treatment trains across the target location.

[0065] In other embodiments, the treatment pattern progresses along the first column of positions to the starting position of the second column of positions.

[0066] In some examples, the treatment pattern further progresses along a second column from the first column position within the target position to a third column starting position within the target position.

[0067] In other embodiments, the treatment pattern further advances along third and subsequent columns of target locations.

[0068] In some embodiments, the treatment pattern comprises a radial spiral pattern.The radial spiral pattern can be formed from an inner position to an outer position.

[0069] In some embodiments, one or more processors are further configured to execute a test protocol that determines a treatment power threshold at two or more test locations in the target location. Information obtained from the test protocol can be used to select a power to be applied in the treatment mode. The test protocol can further include a depth measurement.

[0070] In some examples, the system is configured to dynamically control treatment parameters at multiple treatment locations in the target tissue. In other embodiments, the system is further configured to include a robotic arm having three or more degrees of freedom to control the position of the one or more ultrasonic transducers. In addition, the system can be further configured to include a robotic arm, wherein the three or more degrees of freedom are six degrees of freedom to control the positioning of the one or more ultrasonic transducers.

[0071] The system may also be configured to display a real-time visualization of the bubble cloud at the first and subsequent locations in the treatment mode during treatment, the real-time visualization being displayed to the user in one or more system user interfaces.

[0072] In some embodiments, the system is configured to display the status of the treatment and the position of the bubble cloud in the planned treatment pattern, wherein the status includes information derived from a list including location, position, percentage of treatment completed, percentage of treatment remaining, and time.

[0073] The present invention provides a system comprising one or more ultrasonic transducers configured to generate acoustic cavitation in tissue at a target location, and one or more computer processors configured to control the power and positioning of the ultrasonic transducers, wherein the one or more processors are configured to adjust energy transmission from the one or more ultrasonic transducers based on treatment-specific parameters in the target location based on tissue changes and / or obstacles located between the transducers and the target location.

[0074] Energy modulation may include the timing of energy delivery, or the amplitude of energy delivery, or the selection of a cooling time period.

[0075] In some examples, the timing of energy delivery includes applying energy for a first time period at a first location in the target tissue and applying energy for a second, different time period at a second location in the target tissue. Alternatively, the timing of energy delivery includes applying energy of a first amplitude at a first location in the target tissue and applying energy of a second, different amplitude at a second location in the target tissue. In some examples, the timing of energy delivery includes applying energy for a third or more time periods at corresponding third or more locations in the target tissue.

[0076] In one embodiment, the amplitude of energy delivery includes applying energy of third or more amplitudes at corresponding third or more locations in the target tissue.

[0077] In some examples, the system includes one or more user interfaces for receiving user-provided input of the treatment-specific parameters.

[0078] In one embodiment, treatment specific parameters are extracted from a lookup table containing energy delivery information indexed against target tissue depth. The target tissue depth can be determined based on the distance of the center of the target tissue from the body wall between the target tissue and the one or more ultrasonic transducers. In some embodiments, the lookup table is specific to the one or more ultrasonic transducers. In other embodiments, the lookup table is specific to the target tissue type.

[0079] The present invention also provides a method for treating a target tissue using ultrasound energy, wherein the target tissue includes a first tissue portion and a second tissue portion, the method comprising the step of transmitting ultrasound pulses to the target tissue to form cavitation in the first tissue portion but not in the second tissue portion.

[0080] The present invention also provides an autotransformer inductor driver constructed to excite an ultrasonic transducer, the autotransformer inductor driver comprising an IGBT transistor, an oscillation circuit constructed to temporarily store energy in a magnetic field when the IGBT transistor is excited by a single pulse, wherein the oscillation circuit comprises an inductor having a tap, the tap being positioned along the length of the inductor to increase the voltage generated across the inductor.

[0081] A method for treating a target tissue mass using an ultrasound system, the method comprising determining a depth of the target tissue mass, determining a total treatment time, positioning a focus of the ultrasound system on the target tissue mass, selecting a drive voltage, automatically determining in the ultrasound system a first percentage of the total treatment time during which ultrasound pulses are delivered to the target tissue volume and a second percentage of the total treatment time during which no ultrasound pulses are delivered to the target tissue volume for the selected drive voltage, and initiating a pulse sequence in the ultrasound system, the ultrasound system being configured to deliver ultrasound pulses to the target tissue within the first percentage of the total treatment time.

[0082] In some examples, determining the first percentage and the second percentage further includes using a lookup table based on the drive voltage and the depth.

[0083] In one embodiment, the driving voltage and the depth of the target tissue volume are used to determine the first percentage and the second percentage.

[0084] In some embodiments, a lookup table provides a cooling factor for determining a ratio between the first percentage and the second percentage.

[0085] In some examples, the first percentage includes 50%, the second percentage includes 50%, the first percentage includes 33%, the second percentage includes 67%, the first percentage includes 25%, the second percentage includes 75%, the first percentage includes 20%, the second percentage includes 80%, the first percentage includes 16%, and the second percentage includes 84%.

[0086] In one embodiment, delivering ultrasound pulses to the target tissue within a first percentage of the total treatment time can prevent undesired damage to surrounding tissue. DETAILED DESCRIPTION

[0087] The present invention provides systems and methods for providing effective non-invasive and minimally invasive treatment, diagnosis and research procedures. In particular, the present invention provides optimized systems and methods that provide targeted, effective tissue destruction in a variety of different areas and under a variety of different conditions without causing undesirable tissue damage to intervening / non-targeted tissues or structures.

[0088] Striking a balance between producing destruction of desired tissue in a target area while avoiding damage to non-target areas is a technical challenge. This is particularly true in situations where time-efficient surgery is required. Conditions that provide rapid, effective tissue destruction often result in overheating of non-target tissue. Overheating can be avoided by reducing the energy or slowing the energy delivery, both of which defeat the goal of providing rapid, effective destruction of target tissue. The present invention provides a variety of techniques that, individually or collectively, allow for rapid, effective targeted treatment without causing undesirable damage to non-target areas.

[0089] The systems, methods and devices disclosed herein can be used for minimally invasive or non-invasive acoustic cavitation and treatment of healthy, diseased and / or injured tissues, including in vitro, percutaneous, endoscopic, laparoscopic and / or for integration into automated medical systems and procedures. As described below, tissue destruction may include various electrical, mechanical and software subsystems, including carts, treatments, integrated imaging, robots, connectors and software. The system may also include various other components, auxiliary equipment and accessories, including but not limited to patient surfaces, tables or beds, computers, cables and connectors, network equipment, power supplies, displays, drawers / storage equipment, doors, wheels, lighting and lights, and various simulation and training tools, etc. All systems, methods and means for generating / controlling / delivering tissue destruction are considered part of the present disclosure, including new related inventions disclosed herein.

[0090] In one embodiment, the tissue destruction system is constructed as a mobile treatment cart, which further includes a touch screen display with an integrated control panel (the integrated control panel has a set of physical controls), a robotic arm, a treatment head located at the distal end of the robot, a patient connection system, and software for operating and controlling the system.

[0091] The architecture of the mobile treatment cart may include internal components that are mounted in a standard rack mounting frame, including a tissue blasting generator, a high voltage power supply, a transformer, a power distribution device, a robotic controller, a computer, a router and a modem, and an ultrasound imaging engine. The front system interface panel may include input / output locations for connectors, in particular, including input / output locations for two ultrasound imaging probes (a handheld probe and a probe coaxially mounted in a treatment transducer), a tissue blasting transducer, an AC power supply and a circuit breaker switch, a network connector, and a foot pedal. The rear panel of the cart may include an air inlet to direct airflow to exhaust ports located at the side panels, the top panel, and the bottom panel. The side panels of the cart include a sleeve and a support mechanism for holding a handheld imaging probe. The base of the cart may be composed of a cast base that is connected to the electrical equipment mounted to the rack and provides an interface with the side panels and the top cover. The base also includes four recessed casters with a single integral locking mechanism. The top cover of the treatment cart may include a robotic arm base and interface, as well as a circumferential handle that follows the contour of the cart body. The cart may have internal mounting features to allow a technician to access the cart components through an entry panel.

[0092] The touch screen display and control panel may include user input features including six physical controls in the form of dials, a space mouse and touch pad, an indicator light bar, and an emergency stop, which together are configured to control imaging and treatment parameters, as well as the robot. The touch screen support arm is configured to allow standing and seated positions, and to allow adjustment of the orientation and viewing angle of the touch screen. The support arm may also include a system-level power button, and USB and Ethernet connectors.

[0093] The robot arm can be mounted to an arm base with sufficient height on a mobile treatment cart, allowing the robot arm to be accessible and easy to use to position to the patient / surgical workspace with various drive modes during setup, surgery, and removal. The robot arm can include six degrees of freedom with six rotational joints, a reachable range of 850mm, and a maximum payload of 5kg. The arm can be controlled by a 12-inch touch screen transilluminator (polyscope) with a graphical user interface through the tissue destruction system software. The robot may include a force sensor and a tool flange, wherein the range of force (x, y, z) is 50N, its precision is 3.5N, and the accuracy is 4.0N, and the range of torque (x, y, z) is 10.0Nm, its precision is 0.2Nm, and the accuracy is 0.3Nm. The repeatability of the robot is + / -0.03mm, and its TCP speed is usually 1m / s (39.4 inches / second). In one embodiment, the robot control box has multiple input / output ports, including 16 digital inputs, 16 digital outputs, 2 analog inputs, 2 analog outputs, and 4 quadrature digital inputs, and 24V / 2A input / output power. The control box communication includes a control frequency of 500Hz, TCP protocol, Industrial Ethernet communication protocol (PROFINET), Ethernet / IP, and USB 2.0, 3.0.

[0094] The treatment head may include one of a selected set of four tissue destruction transducers and an ultrasound imaging system / probe coaxially positioned within the treatment transducer, the ultrasound imaging system / probe having an encoding mechanism to rotate the imaging probe to a known position independently of the treatment transducer, and a handle that allows for coarse and fine positioning of the treatment head, the handle including a user input for activating the robot (e.g., for free drive positioning). In some examples, the treatment transducer may vary in size (22×17 cm to 28×17 cm), focal length 12-18 cm, number of elements 48-64 elements, included within 12-16 rings, and all at 700 kHz. The treatment head subsystem has an interface to the robotic arm that includes a quick release mechanism to allow removal and / or replacement of the treatment head, thereby allowing cleaning, replacement, and / or selection of alternative treatment transducer designs (e.g., different number of elements and different geometries), and each treatment transducer is electronically keyed for automatic recognition by the system software.

[0095] The patient connection system may include a six-degree-of-freedom, six-jointed robotic arm configured with a mounting bracket designed to interface with a track on a surgical / interventional table. The arm may have a maximum reach of approximately 850 mm and an average diameter of 50 mm. The distal end of the arm may be configured to interface with an ultrasound medium container, which includes a frame system and an upper sheath and a lower sheath. The lower sheath is configured to support a patient contact membrane sealed to the patient, or an elastic polymer membrane, both of which are designed to accommodate ultrasound media (e.g., degassed water or a water-based mixture), both of which either accommodate ultrasound media in direct contact with the patient in the frame and sheath, or accommodate ultrasound media in a membrane / sheath structure. In one example, the lower sheath provides a top window and a bottom window of approximately 46 cm×56 cm and 26 cm×20 cm, respectively, for placing a treatment transducer and an ultrasound medium container and positioning it on the patient's abdomen. The upper sheath may be configured to allow the distal end of the robot to interface with the treatment head and / or transducer and prevent water leakage / overflow. In a preferred embodiment, the upper sheath is a sealed system. The frame is also configured to allow bidirectional fluid communication between the ultrasound medium container and the ultrasound medium source (e.g., a reservoir or fluid management system) in a sealed system, including but not limited to venting for filling and draining, and for bubble management.

[0096] The system software and workflow can be configured to allow the user to control the system, including but not limited to ultrasound imaging parameters and treatment parameters, through the touch screen display and physical controls. The graphical user interface of the system includes a workflow based on the following general procedural steps: 1) registration / selection of a patient, 2) planning, including imaging of the patient (and target location / anatomy) using a freehand imaging probe, and robotic-assisted imaging using a transducer head to achieve final coarse and fine targeting, which includes delineating the target using target and edge contours, which are generally spherical and ellipsoidal in nature, and running test protocols (e.g., test pulses), including a bubble cloud calibration step and a series of predetermined locations in the block for evaluating cavitation initiation thresholds and other patient / target specific parameters (e.g., treatment depth), which together give a treatment plan that describes the target location and acoustic path, as well as any associated obstructions (e.g., tissue interfaces, bone, etc.), which may require different levels of drive amplitudes to initiate and maintain tissue destruction. The parameters measured as part of the test protocol include calibration and multi-position test pulses, which are configured in the system to provide input / feedback for updating the bubble cloud position in space as needed / desired (e.g., appropriately calibrated to the target crosshairs), and determining / interpolating the amplitude required at all bubble cloud treatment locations in the treatment block to ensure that thresholds are achieved throughout the block. In addition, the parameters, including but not limited to depth and drive voltage, can also be used as part of an embedded treatability matrix or lookup table to determine whether additional cooling is required (e.g., off time in addition to the time allocated to the robot movement between treatment mode movements) to ensure that robust cavitation and intermediate / additive thermal effects are managed (e.g., staying below the t43 curve for any known or calculated sequence, mode and path, and target depth / block combination). As implemented in the system software, the workflow and surgical steps associated with these aspects of the plan can be automated, with the robot and control system configured to run the test protocol and positions autonomously or semi-autonomously. After planning, the next stage of the surgical workflow, (3) the treatment phase, begins after the user accepts the treatment plan and activates the treatment system. Based on the instructions, the system is configured to autonomously provide treatment, running the treatment plan until the prescribed amount of treatment is completed. The treatment status (and bubble cloud position) is displayed in real time adjacent to various treatment parameters, including but not limited to, total treatment time and remaining treatment time, drive voltage, treatment contour (target / margin) and bubble cloud / spot position, current position in treatment mode (e.g., slice and column), imaging parameters, and other additional contextual data (e.g., optional DICOM data, force torque data from the robot, etc.).After treatment, the user can use the treatment head probe and then the freehand ultrasound probe to check and verify the treatment, which can be controlled / viewed through the system user interface. If additional target locations are needed, the user can plan / treat additional targets, or dock the robot in its original position on the cart if no further treatments are planned.

[0097] Figure 1A A tissue ablation system 100 in accordance with the present disclosure is generally shown including a therapy transducer 102, an imaging system 104, a display and control panel 106, a robotic positioning arm 108, and a cart 110. The system may also include an ultrasound coupling interface and a coupling medium source (not shown).

[0098] Figure 1B 1 is a bottom view of the therapeutic transducer 102 and the imaging system 104. As shown, the imaging system can be located in the center of the therapeutic transducer. However, other embodiments may include an imaging system located elsewhere within the therapeutic transducer, or even integrated directly into the therapeutic transducer. In some embodiments, the imaging system is configured to produce real-time imaging at the focal point of the therapeutic transducer.

[0099] The tissue destruction system may include one or more different subsystems, including a treatment subsystem that can generate, apply, focus and deliver acoustic cavitation / tissue destruction through one or more treatment transducers, an integrated imaging subsystem (or connectivity) that allows real-time visualization of the treatment location and tissue destruction effects throughout the process, and a robotic positioning subsystem that mechanically and / or electronically manipulates the treatment transducer, and is also capable of connecting / supporting or interacting with the coupling subsystem to allow acoustic connection between the treatment transducer and the patient, as well as software that communicates, controls and interacts with the system and a computer-based control system (and other external systems) and various other components, auxiliary equipment and accessories (including one or more user interfaces and displays), and related workflow guidance, all of which subsystems work in part or together. The system may also include various fluidics and fluid management components, including but not limited to pumps, valves and flow controls, temperature and degassing controls, flushing and aspiration capabilities, and providing and storing fluids. It may also include various power supplies and protectors.

[0100] Cart

[0101] The cart 110 can be configured in a variety of ways and shapes based on specific uses and surgeries. In some cases, the system may include multiple carts that are configured in similar or different settings. In some embodiments, the cart can be constructed and configured for use in a radiation environment and in some cases in conjunction with imaging (e.g., CT, cone beam CT and / or MRI scanning). In other embodiments, it can be arranged for use in an operating room and a sterile environment, or in a robot-enabled operating room, and used alone, or as part of a surgical robotic surgery, where the surgical robot performs specific tasks before, during, or after the use of the system and delivery of acoustic cavitation / tissue destruction. Similarly, depending on the surgical environment based on the aforementioned embodiments, the cart can be positioned to provide sufficient working space and access to various anatomical locations of the patient (e.g., torso, abdomen, side, head and neck, etc.), as well as providing working space for other systems (e.g., anesthesia carts, laparoscopic towers, surgical robots, endoscope towers, etc.).

[0102] The cart may also be used in conjunction with a patient surface (e.g., a table or bed) to allow the patient to be presented and repositioned in a variety of positions, angles, and orientations, including allowing this to be changed before, during, and after surgery. It may also include the ability to interface and communicate with one or more external imaging or image data management and communication systems of one or more modalities, including but not limited to ultrasound, CT, fluoroscopy, cone beam CT, PET, PET / CT, MRI, optical, ultrasound, and image fusion and / or image streaming to support the procedure and / or use environment, including physical / mechanical interoperability (e.g., compatible within the workspace of a cone beam CT for collecting imaging data before, during, and / or after tissue destruction).

[0103] In some embodiments, one or more carts may be configured to work together. For example, a cart may include a bedside mobile cart equipped with one or more robotic arms that enable therapy transducers and therapy generators / amplifiers, etc., while a companion cart working in conjunction with it and at a distance from the patient may include integrated imaging and consoles / displays for controlling aspects of the robot and therapy, similar to a surgical robot and a master / slave configuration.

[0104] In some embodiments, the system may include multiple carts, all of which are subordinate to a master cart and are equipped to perform acoustic cavitation procedures. In some settings and situations, the cart configuration may allow for storage of specific subsystems at a distance that reduces clutter in the operating room, while another cooperative cart may essentially include bedside subsystems and components (e.g., delivery systems and treatment systems).

[0105] One can envision many arrangements and configurations of cart designs, and these examples in no way limit the scope of the present disclosure.

[0106] Tissue destruction

[0107] Tissue destruction includes short, high-amplitude focused ultrasound pulses to produce dense, high-energy "bubble clouds" that can target and destroy tissue. When acting directly on tissue interfaces (including tissue / liquid interfaces), tissue destruction can produce controlled tissue erosion, and when targeting large pieces of tissue, tissue destruction can produce well-defined tissue separation and destruction at the subcellular level. Unlike other forms of ablation (including heat- and radiation-based modes), tissue destruction does not rely on heat or ionization (high) energy to treat tissue. Instead, tissue destruction uses acoustic cavitation generated at the lesion to mechanically affect tissue structure, and in some cases liquefies, suspends, dissolves and / or destroys tissue to make it a subcellular component.

[0108] Tissue destruction can be applied in a variety of forms, including: 1) Intrinsic Threshold Tissue Destruction: delivering pulses with at least a single negative / stretch phase sufficient to cause a cluster of bubble nuclei intrinsic to the medium to undergo inertial cavitation, 2) Shock Scattering Tissue Destruction: delivering pulses with a duration of typically 3-20 cycles. The amplitude of the stretch phase of the pulse is sufficient to cause bubble nuclei in the medium to undergo inertial cavitation within the focal region for the entire duration of the pulse. These bubble nuclei scatter the incident shock wave, which reverses and constructively interferes with the incident wave to exceed the threshold for intrinsic nucleation, and 3) Boiling Tissue Destruction: using pulses with a duration of approximately 1-20 ms. Absorption of the shock pulse rapidly heats the medium, thereby lowering the threshold for intrinsic bubble nuclei. Once this intrinsic threshold coincides with the peak negative pressure of the incident wave, boiling bubbles form at the focal point.

[0109] The higher pressure generated at the focus leads to the formation of an acoustic cavitation bubble cloud above a certain threshold, which produces local stress and strain and mechanical damage in the tissue without significant heat deposition. At pressure levels where cavitation does not occur, minimal cavitation can be observed in the tissue at the focus. This cavitation effect can only be observed at pressure levels significantly above the inertial cavitation threshold in water that defines similar pulse durations, with a peak negative pressure of about 10 to 30 MPa.

[0110] Tissue destruction can be performed in a variety of ways and with a variety of different parameters. It can be achieved completely non-invasively by acoustically coupling a focused ultrasound transducer to the patient's skin and transmitting acoustic pulses to the focal zone (treatment area and site) through overlying (and intervening) tissue. Since the bubble cloud produced by tissue destruction can be seen as a highly dynamic echogenic area on, for example, a B-ultrasound image, further targeting, planning, guidance, and observation can be achieved under direct visualization by ultrasound imaging to allow continuous visualization through the use of ultrasound imaging (and related procedures). Likewise, the treated and separated tissue shows dynamic changes (usually decreases) in echogenicity, which can be used to assess, plan, observe, and monitor treatment.

[0111] Typically, an ultrasound pulse with one or more acoustic cycles is applied in tissue destruction, and the formation of the bubble cloud relies on the scattering of the pressure release of the positive shock wave front (sometimes exceeding 100 MPa, P+) from the initially initiated sparsely distributed bubbles (or a single bubble). This is called the "shock scattering mechanism".

[0112] The mechanism relies on one (or a few sparsely distributed) bubbles being initiated by the initial negative half-cycle of the pulse at the transducer focus. A cloud of microbubbles then forms due to pressure release backscattering from the high-peak positive shock wave fronts of these sparsely initiated bubbles. These backscattered high-amplitude rarefaction waves exceed the intrinsic threshold, resulting in a localized dense bubble cloud. Each subsequent acoustic cycle induces further cavitation by backscattering from the bubble cloud surface, towards the transducer. Thus, an elongated dense bubble cloud growing along the acoustic axis opposite to the ultrasonic propagation direction can be observed using the shock scattering mechanism. This shock wave scattering process makes the bubble cloud generation dependent not only on the peak negative pressure, but also on the number of acoustic cycles and the amplitude of the positive shock wave. Without at least one strong shock wave front formed by nonlinear propagation, a dense bubble cloud will not be generated when the negative half-cycle peak is below the intrinsic threshold.

[0113] When an ultrasonic pulse of less than 2 cycles is applied, the impact scattering can be minimized, and the generation of a dense bubble cloud depends on the negative half-cycle of the applied ultrasonic pulse exceeding the "intrinsic threshold" of the medium. This is called the "intrinsic threshold mechanism."

[0114] For soft tissues with high water content, such as human tissue, this threshold can be in the range of 26-30 MPa. In some embodiments, using this inherent threshold mechanism, the spatial extent of the lesion can be better defined and more predictable. If the peak negative pressure (P–) is not significantly above this threshold, sub-wavelength reproducible lesions as small as half the transducer's –6 dB beamwidth can be produced.

[0115] With high-frequency tissue ablation pulses, the size of the minimum reproducible lesion is reduced, which is beneficial in applications where lesions need to be produced precisely. However, high-frequency pulses are more susceptible to attenuation and aberrations, making them problematic in treatments with greater penetration depths (e.g., ablation deep within the body) or through highly aberrated media (e.g., transcranial surgery, or surgery where pulses are delivered through bone). Tissue ablation can also be further used as a low-frequency "pump" pulse (typically less than 2 cycles and with a frequency between 100kHz and 1MHz) is used in conjunction with a high-frequency "probe" pulse (typically less than 2 cycles and with a frequency greater than 2MHz, or with a frequency between 2MHz and 10MHz), where the peak negative pressures of the low-frequency pulse and the high-frequency pulse constructively interfere to exceed an intrinsic threshold in the target tissue or medium. The low-frequency pulse is more resistant to attenuation and aberrations, which can increase the peak negative pressure level in the region of interest (ROI), while the high-frequency pulse provides greater precision, which can lock onto the target location within the ROI and increase the peak negative pressure above the intrinsic threshold. This approach may be referred to as "dual frequency," "dual-beam tissue ablation," or "parametric tissue ablation."

[0116] Additional systems, methods, and parameters are included in the present invention as part of the systems and methods disclosed herein, which use impact scattering, inherent thresholds, and various parameters that allow frequency compounding and bubble manipulation to deliver optimized tissue destruction, including additional means for controlling the tissue destruction, such as with respect to steering and positioning the focus, and simultaneously managing tissue effects (e.g., local thermal collateral damage) at the treatment site or in the intermediate tissue. In addition, various systems and methods, which include multiple parameters, such as, but not limited to, frequency, operating frequency, center frequency, pulse repetition frequency, pulses, pulse trains, number of pulses, period, pulse length, pulse amplitude, pulse period, delay, pulse train repetition frequency, combinations of the foregoing parameters, multiple groups of cycles, multiple and / or different groups of cycles, combinations of cycles, and various combinations or permutations of cycles, etc., are included in the present invention and disclosed as part of the present invention, including such embodiments contemplated in the future.

[0117] Treatment components

[0118] The treatment subsystem can work with other subsystems to generate, optimize, deliver, visualize, monitor and control acoustic cavitation, also referred to herein and hereinafter as "tissue destruction", and its derivatives, including boiling tissue destruction and other thermal high frequency ultrasound methods. It should be noted that the disclosed invention can also be further beneficial to other acoustic therapies that do not include cavitation, mechanical or tissue destruction components. Among other features, the treatment subsystem can include an ultrasonic treatment transducer and a pulse generator system configured to deliver ultrasonic pulses into tissue.

[0119] To generate and deliver tissue destruction and its derivatives, the treatment subsystem may also include components including, but not limited to, one or more function generators, amplifiers, treatment transducers, and power supplies.

[0120] The therapeutic transducer may include a single element or multiple elements that are constructed to be excited with high amplitude electrical pulses (>1000V or any other voltage that may cause harm to a living organism). The amplitude required for a therapeutic transducer for driving tissue destruction varies according to the following parameters: the design of the transducer and the materials used (e.g., solid or polymer / piezoelectric composites, including ceramics or single crystals) and the transducer center frequency, which is proportional to the thickness of the piezoelectric material. Therefore, a transducer operating at a high frequency requires a lower voltage to generate a given surface pressure compared to a low-frequency therapeutic transducer. In some embodiments, the transducer element is formed using a piezoelectric polymer composite or a solid piezoelectric material. In addition, the piezoelectric material can be a polycrystalline / ceramic or single crystal formulation. In some embodiments, the transducer element can be formed using silicon using MEMs technology, including CMUT and PMUT designs.

[0121] In some embodiments, the function generator may include a field programmable gate array (FPGA) or other suitable function generator. The FPGA may be configured with the parameters disclosed above in the present invention with variable time delays and independently controlled throughout the text, as well as various combinations and permutations of these parameters, including but not limited to frequency, pulse repetition frequency, pulse train, number of pulse trains, wherein the pulse train may include pulses, number of pulses, pulse length, pulse period, delay, pulse train repetition frequency or period, wherein the pulse train set may include parameters, wherein the cycle set may include various parameter sets with or without delay or with variable delay, wherein multiple cycle sets may be repeated and / or new cycle sets may be introduced.

[0122] In some embodiments, the generator or amplifier can be constructed as a general-purpose single-cycle or multi-cycle pulse generator and is constructed to support driving through a Class D drive or an inductive drive, as well as to cover all envisioned clinical applications and use environments, which are also discussed in the following sections of this disclosure. In other embodiments, the Class D or inductive current driver can be constructed to include a transformer and / or autotransformer drive circuit to further provide a step-up / step-down component and, in some cases, to preferably allow an increase in amplitude. They may also include specific protection features to further support the system and provide the ability to protect other parts of the system (e.g., therapeutic transducers and / or amplifier circuit components) and / or users from various hazards, including but not limited to electrical safety hazards, which may potentially cause harm, damage or problems to the use environment, the system and the treatment system, and the user.

[0123] The generator disclosed in the present invention can allow and support the system's ability to select, change and control various parameters (including but not limited to those previously disclosed) (through enabled software tools), as well as the ability to start / stop treatment, set and read voltage levels, pulse and / or burst repetition frequency, number of cycles, duty cycle, channel enable and delay, etc., modulate pulse amplitude on a fast time scale independent of the high voltage power supply, and / or other service, diagnostic or treatment features.

[0124] In some embodiments, the treatment subsystem and / or components such as amplifiers may further include integrated computer processing capabilities and may be networked, connected, accessed and / or may be mobile / portable, modular and / or exchangeable between systems, and / or driven / commanded from / by other systems, or in various combinations. Other systems may include other acoustic cavitation / tissue destruction, HIFU, HITU, radiation therapy, radiofrequency, microwave, and cryoablation systems, navigation and positioning systems, laparoscopes, single incision / single port, endoscopic and non-invasive surgical robots, laparoscopes or surgical towers including other energy-based systems or vision systems, surgical system stands or booms, imaging carts, etc.

[0125] In some embodiments, one or more amplifiers may include a Class D amplifier and associated drive circuitry including matching network components. Depending on the electrical impedance of the transducer element and the selection of the matching network components (e.g., an LC circuit consisting of a series inductor L1 and a parallel capacitor C1), the combined impedance may be set aggressively low in order to have the high amplitude electrical waveform required to drive the transducer element. The maximum amplitude of the Class D amplifier depends on the circuit components used, including the drive MOSFET / IGBT transistors, the matching network components or inductors, and the transformer or autotransformer, which may typically be in the low kilovolt (e.g., 1-3 kilovolt) range.

[0126] The therapeutic transducer element is excited by an electrical waveform having an amplitude (voltage) to produce a pressure output sufficient for tissue destruction therapy. The excitation electric field can be defined as the waveform voltage required per thickness of the piezoelectric element. For example, since a piezoelectric element operating at a 1 MHz transducer is half the thickness of an equivalent 500 kHz element, it requires half the voltage to achieve the same electric field and surface pressure.

[0127] In order to adequately drive a therapeutic transducer for tissue destruction, in other embodiments, it may be necessary for the amplifier to generate voltages that exceed the operating limits of conventional amplifier circuit components. For example, Figure 2 A schematic diagram of an inductive drive circuit configured to excite an ultrasonic transducer for tissue destruction is provided. Figure 2With the inductive drive circuit shown, the therapeutic transducer element can be driven to a positive peak of about 3 kV or a peak-to-peak of about 4.5 kV. For example, these voltages may be sufficient for a therapeutic transducer operating at 1 MHz, but may not be sufficient for a 500 kHz transducer. The maximum drive voltage in this inductive driver example is limited by the maximum operating voltage of the IGBT transistor Q1 and its switching time. The best performing IGBT transistors currently available for inductive drive circuits are rated for a maximum of 3 kV. It should be understood that this drive voltage can be increased as transistors advance.

[0128] The inductive driver circuit described above also provides many advantages for high frequency transducers, including the ability to produce smaller / more precise bubble clouds (i.e., microtissue ablation) and reduced thermal effects in tissue, etc.

[0129] Figure 2 The inductive drive circuit shown is designed and constructed to use the transducer element as a capacitor in parallel with the L1 inductor to create an oscillating circuit. When a single pulse excites the IGBT transistor, current flows through the inductor L1, which temporarily stores energy in a magnetic field. Once the drive pulse disappears, the magnetic field is converted back into an ultra-high amplitude electrical pulse, and the process is repeated continuously at the resonant frequency of the LC circuit (L1 and Y1 in the illustrated example). The time required to charge the inductor (i.e., the charging time) can vary and will proportionally affect the output amplitude. As mentioned above, this high electrical pulse is limited to a positive peak of 3kV.

[0130] Although Figure 2 The inductor drive circuit shown provides higher voltages than conventional Class D amplifiers, but has its own limitations, including 1) it can only be driven with one pulse at a time. Increasing the interval between pulses can achieve multiple cycles to allow the inductor to charge for the next cycle; 2) if the transducer element is accidentally disconnected, the resonant circuit will begin to oscillate at a higher frequency and produce an amplitude that may exceed 3kV positive peak, which may damage the IGBT transistor and cause catastrophic failure of the system; 3) if the transducer element is shorted, the current will bypass the inductor and short directly to ground through the IGBT transistor Q1, which may cause the high voltage supply to drop or the IGBT transistor to fail due to excessive current; and 4) the inductor drive circuit is currently limited to approximately 3kV positive peak or approximately 4.5kV positive and negative peak.

[0131] Figure 3 The schematic diagram of the autotransformer inductor driving circuit including the inductor Lx with a center tap is shown, which solves the problem of Figure 2Disadvantages of the inductor drive circuit shown. In this embodiment, the drive signal is generated in the generator G1 and reaches the optically isolated IGBT driver U1 through the resistor R1. As a result, a drive square wave pulse with an amplitude of 15V is generated at U1 pins 6 and 7 and applied to the gate of the IGBT transistor Q1. When the signal at the gate is high (e.g., 15V), the transistor Q1 is turned on and the current from the "+HV" terminal flows through the first part (L1) of the Lx inductor, the diode D1, and flows through the transistor Q1 (from the collector to the emitter) to GND. Capacitor C3 is a bypass capacitor that supports the instantaneous current consumption of the circuit. C3 has a rated voltage exceeding the maximum "+HV" voltage and the capacitance required to support the instantaneous current consumption. The current flowing through a part (L1) of the inductor Lx generates a magnetic field and charges the inductor Lx. Once the driving signal becomes low level, the IGBT transistor Q1 is turned off, and the magnetic field (energy) generated in the first part L1 of the inductor Lx is stored in the entire inductor Lx and converted into electrical energy across the entire inductor Lx (Lx=L1+L2).

[0132] By changing the power supply voltage "+HV" within the range of 0-1000VDC and changing the charging time or width of the driving pulse within the range of 0-10us, the peak voltage at the center tap of the inductor Lx (where L1 is connected to L2) can reach a positive peak voltage of 3000V, as shown in the previous Figure 2 As described in the inductor drive circuit shown in FIG. , this positive peak voltage is limited by transistor Q1. Figure 3 The inductor Lx shown is not just a regular inductor, but an inductor with a center tap, which makes it an autotransformer. The voltage across the inductor Lx can be customized based on the turns ratio between one portion (L1) and the other portion (L2) of the inductor Lx. For example: if the center tap of the inductor Lx is in the middle of the inductor, then the ratio between L1 and Lx will be 1 to 2 (1:2). This means that if the maximum voltage generated by L1 can be effectively doubled using the autotransformer inductor described here, and in this case, a positive peak voltage of up to 6000V is generated on Lx, which is applied to the therapy transducer Y1. For therapy transducers with lower operating frequencies, higher voltages may be required to obtain the desired acoustic output. In this case, a different design of Lx with a customized ratio L1:Lx is required. Using this approach (more aggressive turns ratio L1:Lx), the voltage generated across Lx can be very high, and only isolation limiting can safely handle the generated high voltage pulses.

[0133] As mentioned above, Figure 3The autotransformer Lx shown is combined with capacitor C1 and therapeutic transducer Y1 to produce a resonant circuit constructed to act as a pulse generator capable of generating ultra-high voltage AC pulses for driving the therapeutic transducer, which produces the maximum acoustic output required for tissue destruction treatment.

[0134] Figure 3 The total value of the inductor Lx shown can be determined based on the electrical impedance of the transducer element and the operating frequency. In some examples, the value of the inductor Lx can be determined based on the optimal desired acoustic output (desired pulse frequency, peak positive and peak negative pressure of each voltage, etc.). For tissue destruction, the applied total value of the inductor Lx can be in the range of 1-1000uH.

[0135] As mentioned above, the center frequency of the therapy transducer is proportional to the thickness of the piezoelectric material that the therapy transducer is made of. Therefore, the thickness of the piezoelectric will determine the maximum safe operating voltage required to output the maximum sound pressure. In addition, the maximum operating voltage will determine the required inductor (autotransformer) turns ratio (L1:Lx). In other words, it will determine where a center tap needs to be placed in the inductor wire winding, and when this tap is placed, the inductor becomes an autotransformer.

[0136] Capacitor C1 is Figure 3 A very important part of the circuit shown. Capacitor C1 is connected in parallel with a portion of the autotransformer L1 to form a resonant circuit that oscillates at the same frequency as the autotransformer Lx connected in parallel with the therapy transducer Y1. The rated voltage of capacitor C1 should be at least 10% higher than the maximum drive voltage. The capacitance value of capacitor C1 is determined using the following formula to calculate the resonant frequency:

[0137]

[0138] However, small changes in the capacitance value can fine-tune the resonant frequency of the entire circuit. It is recommended that the final value of the capacitor be determined by the desired acoustic output (peak positive pressure, peak negative pressure, frequency, etc...). For example, for tissue necrosis treatment, the value of capacitor C1 can be in the range of 100pF-100nF.

[0139] Figure 3 The capacitor C1 shown can be replaced by another active or passive electronic component, such as a resistor, a diode, an inductor, etc., as well as a combination of multiple different components. For example, if the capacitor C1 is Figure 4The manner shown is replaced by a combination of components such as capacitor Cx, diode Dx and resistor Rx, then a more asymmetric waveform with a larger negative peak or a larger positive peak can be obtained according to the direction of diode Dx. The degree of asymmetry is determined by the value of resistor Rx, and the frequency is determined by the value of capacitor Cx. Switching transistor Q4 can be an IGBT transistor or any other high power switching device, such as MOSFET, bipolar transistor, or other device.

[0140] Figure 3 The illustrated autotransformer inductive drive circuit provides the ability to generate ultra-high amplitudes without the limitations of the above-mentioned Class D and inductive drive generators. As described above, in the event of a single fault condition where the therapeutic transducer is disconnected, the autotransformer inductive drive circuit does not generate an ultra-high voltage peak that can damage the IGBT transistor Q1, and therefore catastrophic failure of the system does not occur. In this case, the IGBT transistor Q1 continues to operate in a normal state because the resonant circuit composed of capacitor C1 and inductor L1 (the main part of the autotransformer Lx) still operates normally, just as if the therapeutic transducer Y1 is connected.

[0141] In the event of a single fault condition where the treatment transducer is shorted, there is no high current or short circuit of the high voltage supply "+HV" that can damage the IGBT transistor Q1, so there is no catastrophic failure of the system as would occur using a conventional inductor driven generator. The IGBT transistor Q1 continues to operate in a normal state because the resonant circuit composed of capacitor C1 and inductor L1 (the main part of the autotransformer Lx) still operates normally, just as if the treatment transducer Y1 is connected.

[0142] Alternatively, for additional safety of maintenance personnel and general users, Figure 3 The autotransformer inductive driver circuit shown can be powered by a negative voltage supply. In this case, the +HV terminal as shown in the figure above can be connected to the ground (GND) and the ground terminal can be connected to the negative voltage supply (-HV). Figure 5 As shown. Note that the 15V supply refers to the -HV terminal. This can be easily achieved using an isolated DC / DC converter where the negative secondary terminal is connected to the –HV terminal. The isolated DC / DC converter must be rated for the -HV supply level.

[0143] The main safety benefit of a negative voltage supply is that one electrode of the transducer (usually a shielded BNC or another connector) is always connected to ground (GND), so it is safe for operators or maintenance personnel to touch, connect, or disconnect the transducer when the amplifier is powered. If the circuit were normally powered by a positive supply voltage, one electrode of the transducer would be connected to the high voltage supply and would therefore be unsafe to operate.

[0144] It is also possible to add capacitor C1 in parallel to Figure 6 The inductor L1 and ultrasonic transducer Y1 shown are used to Figure 5 The protection circuit shown. The value of capacitor C1 can be calculated as small as possible to make the oscillation circuit oscillate within a safe frequency and voltage angle range to prevent the generation of a voltage exceeding the operating voltage of transistor Q1 in the event of an ultrasonic transducer disconnection or an open circuit fault.

[0145] The combined capacitance of capacitor C1 and transducer Y1 is used to calculate the operating frequency of the resonant circuit (ie, capacitor C1, inductor L1, and ultrasonic transducer Y1). Alternatively, varying the capacitor C1 value can be used to fine-tune the operating frequency of the entire circuit.

[0146] In the event of a short-circuit fault in the transducer, a fast-acting fuse is connected in series with the power supply +HV. The value of the fast-acting fuse F1 is calculated to be 10% or more higher than the current consumption of the entire circuit at maximum amplitude and duty cycle. In the event of a fault, DC current will begin to flow through the short-circuited sensor Y1 and transistor Q1. At this point, the fast-acting fuse F1 will open due to the excessive current, protecting transistor Q1 and the entire system from catastrophic failure.

[0147] The therapy subsystem may also include therapy transducers with various designs and operating parameters to support use in a variety of procedures (and surgical settings). The system may be configured with one or more therapy transducers that are further interchangeable and work with various aspects of the system in similar or different ways (e.g., may interface with a robotic arm using a common interface and exchange features, or conversely may be adapted to work with different imaging probes for specific applications, where the different imaging probes may interface and integrate with the therapy transducers in specific different ways).

[0148] Therapeutic transducers can be configured by various parameters, which can include size, shape (e.g., rectangular or circular; anatomically curved housing, etc.), geometry, focal length, number of elements, element size, element distribution (e.g., number of rings, ring size for a ring transducer), frequency, beam steering, etc. Transducers can be composed of various materials (e.g., piezoelectric, silicon, etc.), form factors and types (e.g., machined elements, chip-based, etc.), and / or made by various manufacturing methods.

[0149] Transducers can be designed and optimized for clinical applications (e.g., abdominal tumors, peripheral vascular disease, fat ablation, etc.) and desired outcomes (e.g., acoustic cavitation / tissue destruction without thermal damage to interstitial tissue), as well as the breadth of operating range provided, which includes relatively shallow and superficial targets (e.g., thyroid or breast nodules) as opposed to deeper or more difficult to reach targets (e.g., interstitial liver or brain tumors). They can be configured to achieve acoustic cavitation / tissue destruction at various parameters and parameter sets (e.g., enabled by the above-mentioned system components (e.g., function generators and amplifiers, etc.), including but not limited to frequency, pulse repetition rate, pulses, number of pulses, pulse length, pulse period, delay, repetition, synchronization delay, synchronization period, synchronization pulses, synchronization pulse delays, various cycle sets, others, and their permutations).

[0150] Integrated imaging

[0151] The system disclosed in the present invention may include various imaging modes to allow the user to visualize, monitor and collect / use feedback from the patient's anatomical structures, relevant areas of interest and treatment / surgical sites, and surrounding and intermediate tissues to evaluate, plan and implement surgery, and adjust treatment parameters as needed. Imaging modes may include various ultrasound, X-ray, CT, MRI, PET, fluoroscopy, optical, contrast or contrast agent enhanced versions, and / or various combinations of the above. The present invention also discloses that various image processing and characterization techniques can also be used to provide enhanced visualization and user decision-making. These can be manually selected or instructed by the user, or selected or instructed by the system in an automatic manner. The system can be configured to allow side-by-side, switching, overlay, 3D reconstruction, segmentation, registration, multimodal image fusion, image streaming and / or provide the user with any method of identifying, defining and giving various aspects of the use of imaging during surgery, as displayed in various system user interfaces and displays. As non-limiting examples, examples may include locating, displaying and characterizing areas of interest, organ systems, potential treatment sites located in, on and / or around organs or tissues, identifying key structures such as ducts, vessels, nerves, ureters, fissures, capsules, tumors, tissue trauma / injury / disease, other organs, connective tissue, etc., and / or one or more of the context (e.g., tumor draining lymphatics or vasculature; or a tumor close to an organ capsule or located beneath other organs).

[0152] The system can be configured to include onboard integrated imaging hardware, software, sensors, probes, and human nervous systems, and / or can be configured to communicate and interface with external imaging and image processing systems. The aforementioned components can also be integrated into the treatment subsystem components of the system, wherein the probe, imaging array, etc., and are electrically, mechanically, or electromechanically integrated into the treatment transducer. This can partially provide the ability to align imaging and treatment geometries, wherein the treatment is directly located within the field of view and in some cases is consistent with the imaging. In some embodiments, this integration can include a fixed orientation of the imaging capability (e.g., an imaging probe) in the treatment transducer environment. In other embodiments, the imaging solution may be able to move or adjust its position, including modifying angles, extensions (e.g., distance from the treatment transducer or patient), rotations (e.g., imaging planes in ultrasound probe examples), and / or other parameters, including dynamically moving / adjusting while actively imaging. The imaging component or probe can be encoded so that its direction and position relative to another aspect of the system (e.g., a treatment transducer and / or an automated positioning component) can be determined.

[0153] In one embodiment, the system may include onboard ultrasound, which is further configured to allow the user to visualize, monitor, and receive feedback on the surgical site via the system display and software, including allowing ultrasound imaging and characterization (and various modalities), ultrasound-guided planning, and ultrasound-guided treatment, all in real-time. The system may be configured to allow the user to image the patient in a manual, semi-automatic, or fully automated manner (e.g., manually or using an automated imager).

[0154] In some embodiments, imaging feedback and monitoring may include monitoring changes in: backscatter from the bubble cloud; reduction of speckle in backscatter; backscatter speckle statistics; mechanical properties of tissue (i.e., elasticity imaging); tissue perfusion (i.e., ultrasound contrast imaging); shear wave propagation; acoustic emission, electrical impedance tomography, and / or various combinations of the above, including co-display or integration with other forms of imaging (e.g., CT or MRI).

[0155] In some embodiments, feedback and monitoring imaging including backscattering from the bubble cloud can be used as a method to immediately determine whether the tissue destruction process has been initiated, whether it has been properly maintained, or even whether it has been eliminated. For example, the method can continuously monitor drug delivery, tissue erosion, etc. in real time. The method can also provide feedback that allows the tissue destruction procedure to be initiated at a higher intensity and to maintain the process at a much lower intensity. For example, backscatter feedback can be monitored by any transducer or ultrasonic imager. By measuring the feedback of the treatment transducer, the auxiliary transducer can send an inquiry pulse or be configured to passively detect cavitation. In addition, the nature of the feedback received can be used to adjust acoustic parameters (and related system parameters) to optimize the process of drug delivery and / or tissue erosion.

[0156] In some embodiments, imaging including feedback and monitoring from backscatter as well as speckle reduction may be configured in the system.

[0157] For systems that include feedback and monitoring through backscatter as a background method, as the tissue is gradually mechanically subdivided, in other words, the tissue is homogenized, fragmented or eroded, the size and distribution of the acoustic scattering that results in the procedure changes. At some point in the procedure, the size and density of the scattering particles are reduced to a level where there is almost no ultrasonic scattering, or a significant reduction in scattering. This results in a significant reduction in speckle, which is the coherent constructive and destructive interference pattern of bright and dark spots seen on an image when a coherent illumination source is used; in this case, ultrasound. After a period of treatment time, the reduction in speckle results in dark areas in the treatment volume. Since the amount of speckle reduction is related to the amount of tissue subdivision, the amount of speckle reduction can be related to the size of the remaining tissue fragments. When this size is reduced to the subcellular level, it is believed that no cells survive. Therefore, treatment can continue until the desired level of speckle reduction is achieved. Speckle is easily seen and evaluated on a standard ultrasound imaging system. Special transducers and systems, including those disclosed herein, can also be used to evaluate backscatter changes.

[0158] In addition, the system includes feedback and monitoring of speckle and will serve as a background method, so that the image can persist from frame to frame and change very little as long as the scattering distribution does not change and the imaged object does not move. However, long before the size of the scatterers is reduced enough to cause speckle reduction, they can be sufficiently changed to be detected by signal processing and other means. This series of techniques can be used as a detector of changes in speckle statistics. For example, the size and position of one or more speckles in the image will begin to decorrelate before the observed speckle reduction occurs. Speckle decorrelation after appropriate motion compensation can be a sensitive measure of mechanical disruption of tissue and therefore a measure of treatment effectiveness. This feedback and monitoring technique can allow early observation of changes caused by the acoustic cavitation / tissue destruction process and can identify changes in tissue before substantial or complete tissue effects (e.g., erosion) occur. In one embodiment, the method can be used to monitor the acoustic cavitation / tissue destruction process to enhance drug delivery, where the treatment site / tissue is temporarily disrupted and tissue damage / erosion is undesirable. In other embodiments, this can include speckle decorrelation through the movement of scatterers in the gradually fluidized treatment volume. For example, where partial or complete tissue erosion is desired.

[0159] For systems that include feedback and monitoring by elastography, as a background method, as the treatment site / tissue is further subdivided by the acoustic cavitation / tissue destruction effect (homogenization, destruction or erosion), its mechanical properties change from a soft but interconnected solid to a viscous fluid or paste with little long-range interaction. These changes in mechanical properties can be measured by various imaging methods, including MRI and ultrasound imaging systems. For example, ultrasound pulses can be used to generate forces (i.e., radiation forces) on localized volumes of tissue. Tissue responses (displacement, strain, and velocity) will change significantly during tissue destruction, allowing the state of tissue destruction to be determined by imaging or other quantitative means.

[0160] The system may also include feedback and monitoring of changes in shear wave propagation. Using this system as a background method, the subdivision of tissue makes the tissue more fluid and less solid, and fluid systems generally do not propagate shear waves. Therefore, the degree of tissue fluidization provides an opportunity for feedback and monitoring of the tissue destruction process. For example, ultrasound and MRI imaging systems can be used to observe the propagation of shear waves. The disappearance of such waves in the treatment volume is used as a measure of tissue damage or fragmentation. In one system embodiment, the system and supporting subsystems can be used to generate and measure interacting shear waves. For example, two adjacent ultrasound focuses may interfere with the tissue by pushing the tissue in some way. If the adjacent focuses are in the fluid, there is no shear wave propagation to interact. If the tissue is not fluidized, the interaction can be detected by external means, for example, by difference frequencies that can only be detected when two shear waves interact nonlinearly, and their disappearance is associated with tissue damage. Therefore, the system can be configured to use this modality to enhance feedback and monitoring of the acoustic cavitation / tissue destruction process.

[0161] For systems that include feedback and monitoring via acoustic emissions, as a background approach, as the tissue volume is subdivided, its effect on acoustic cavitation / tissue destruction (e.g., the bubble cloud here) changes. For example, bubbles in intact tissue may be larger and have different lifespan and fragmentation variation characteristics compared to fluidized tissue. After the tissue is subdivided, the bubbles may also move and interact with each other, resulting in larger bubbles or synergies between bubbles, all of which result in changes in acoustic emissions. These emissions can be heard during treatment and can change during treatment. Analysis of these changes and their correlation with treatment effectiveness can monitor the progress of treatment and can be configured as a feature of the system.

[0162] For systems including feedback and monitoring by electrical impedance tomography, as a background method, an impedance map of the treatment site can be generated based on the spatial electrical properties of the entire treatment site. Imaging of the conductivity or dielectric constant of the patient's treatment site can be inferred by electrical measurements on the skin surface. Conductive electrodes are attached to the patient's skin, and a small alternating current is applied to some or all of the electrodes. One or more known currents are injected into the surface, and the voltage is measured at multiple points using the electrodes. The process can be repeated for different configurations of the applied current. The resolution of the resulting image can be adjusted by changing the number of electrodes used. Measurements of the electrical properties of the treatment site within the skin surface can be obtained from the impedance map, and the measurements configured in the system and supporting subsystems can be used to monitor changes and positions in the acoustic cavitation / tissue destruction (e.g., specifically, bubble clouds) and tissue destruction processes.

[0163] The user may be allowed to further select, annotate, mark, highlight and / or outline various areas of interest or treatment sites, and defined treatment targets (on the image), which may be used to instruct and direct the system via the system software and user interface and display where to image, test and / or treat. In some settings, the user may use a manual ultrasound probe (e.g., a diagnostic handheld probe) to perform the procedure. In other settings, the system may use a robotic and / or electromechanical positioning system to perform the procedure, or conversely, the system may implement a combination of manual and automated use, as directed and / or automatically by the system.

[0164] The system may also include the ability to perform image registration, including imaging and image data set registration, to allow the system to navigate and position to the patient, including the treatment site (e.g., tumor, critical structures, bony anatomy, anatomical and identifying features, etc.). In one embodiment, the system allows a user to image and identify an area of ​​interest (e.g., liver) using integrated ultrasound, and select and mark a tumor (or surrogate marker) contained within the liver via system software / displayed in the system software, and wherein the system records the image data into a coordinate system defined by the system, which further allows the system's treatment subsystem and robotic subsystem to deliver synchronized acoustic cavitation / tissue destruction to the marked tumor. The system may include the ability to register various image sets (including previously disclosed image sets) to each other, as well as the ability to provide navigation and positioning (e.g., registration of a treatment transducer to a CT or MRI / ultrasound fusion image, and tracking of the treatment transducer and robotic subsystem to the image).

[0165] The system may also include the ability to work in a variety of interventional, endoscopic, and surgical environments, including the ability to work alone and with other systems (surgical / laparoscopic towers, vision systems, endoscopic systems and endoscopic towers, ultrasound endoscopes, ultrasonic (flexible and rigid), percutaneous / endoscopic / laparoscopic, and minimally invasive navigation systems (e.g., optical, electromagnetic, shape sensing, ultrasonic, etc.), which may also work with or include various optical imaging capabilities (e.g., fiber optic and / or digital). The systems disclosed herein may be configured to work with these systems, in some embodiments, in conjunction with these systems, or in other embodiments, all or some of the systems may be integrated into the above systems / platforms (e.g., an endoscopic system or laparoscopic surgical robot capable of using acoustic cavitation / tissue destruction). In many of these environments, the therapeutic transducer may be used during or before or after the use of, for example, an optically guided endoscope / bronchoscope, or as another example, when a laparoscopic robot (e.g., Intuitive The DaVinci*Xi system) uses a therapeutic transducer while the tissue / treatment site is being viewed / manipulated. In addition, these embodiments and examples may include situations where the other systems / platforms described are used to deliver (locally) fluid to create an artificial acoustic window that may not exist under normal circumstances (e.g., fluidizing a segment or lobe of a lung in preparation for acoustic cavitation / tissue destruction via minimally invasive transthoracic treatment (e.g., transducers placed externally on / around the patient)). The systems disclosed in the present invention may also include all or some of the subsystem hardware encapsulated in the other system carts / consoles / systems described herein (e.g., acoustic cavitation / tissue destruction and / or subsystems integrated and operated from the navigation system or laparoscopic system).

[0166] The system can also be configured, via the various aforementioned parameters and other parameters, to display real-time visualization of the bubble cloud in a spatiotemporal manner, including tissue effects resulting from pre / post-treatment tissue / bubble cloud interactions, wherein the system can dynamically image and visualize and display the bubble cloud and any changes thereto (e.g., decreased or increased echogenicity), which may include intensity, shape, size, location, morphology, persistence, etc. These features allow users to continuously track and follow treatments in real time and instantly confirm treatment safety and effectiveness in an integrated program and interface / system (compared to other interventional or surgical modes that require multiple procedures to achieve the same effect, or are unable to display treatment effects in real time (e.g., radiation therapy), or are unable to achieve such effects (e.g., real-time visualization of local tissue during thermal ablation), and / or other procedures that also require invasive methods (e.g., incisions or punctures) and iterative imaging in a scanner between surgical steps (e.g., CT or MRI scans). The systems, subsystems, components, modes, features, and workflows / methods of use disclosed above can be implemented in a non-limiting manner by enabling hardware, software, user interfaces, and usage environments, and future improvements, enhancements, and inventions in this field, as well as any resulting data and methods of using the data for analysis, artificial intelligence, or digital health applications and systems, are considered to be included within the scope of the present disclosure.

[0167] robot

[0168] The system may include various robotic subsystems and components, including but not limited to one or more robotic arms and controllers, which may further work with other subsystems or components of the system to deliver and monitor acoustic cavitation / tissue destruction. As previously described, the robotic arms and control systems may be integrated into one or more cart configurations.

[0169] For example, one system embodiment may include a cart with an integrated robotic arm and control system, as well as a therapy subsystem, an integrated imaging subsystem, and software, where the robotic arm and other listed subsystems are controlled by a user through a single bedside cart form factor.

[0170] In other embodiments, the robotic subsystems may be configured in one or more separate carts that may be driven in a master / slave configuration relative to a separate master or cart, where the robotized cart is positioned to the bed / patient side and the master is located a distance from the cart.

[0171] The disclosed robotic arm can be composed of multiple joints, segments, and degrees of freedom, and can also include various integrated sensor types and encoders for various uses and safety features. For example, sensing technology and data can include vision, potentiometers, fixed point / positioning, kinematics, force, torque, speed, acceleration, dynamic load, and / or other. In some cases, sensors can be used to allow users to guide robot commands (e.g., using gestures to move the robot to a preferred setting position, or stop at a target position). For more details about the robotic arm, please refer to U.S. Patent Publication No. 2013 / 0255426 to Kassow et al., the entire contents of which are incorporated herein by reference.

[0172] The robotic arm receives control signals and instructions from a robotic control system, which may be mounted in a cart. The system may be configured to provide a variety of functions including, but not limited to, positioning, tracking, modes, triggers, and events / actions.

[0173] Positioning can be configured to include fixed positioning, tray positioning, time-controlled positioning, distance-controlled positioning, time-variable controlled positioning, and distance-variable controlled positioning.

[0174] Tracking may be configured to include time controlled tracking and / or distance controlled tracking.

[0175] Movement patterns may be configured to include intermediate locations or waypoints, as well as sequences of locations through a defined path in space.

[0176] Triggers may be configured to include distance measurement devices, time, and / or various sensor devices including, but not limited to, vision / imaging based, force, torque, positioning, energy / power feedback, and / or others.

[0177] Events / actions can be configured to include various examples, including proximity-based (approaching / leaving a target object), activation or deactivation of various end effectors (e.g., therapeutic transducers), starting / stopping / pausing a sequence of events, triggers that trigger events / actions or switch events / actions, initiating motion modes and changing / switching motion modes, and / or time-based and temporary in a defined work and time space.

[0178] In one embodiment, the system includes a three-degree-of-freedom robotic positioning system that allows a user (via the system's software and associated user interface) to micro-position the therapeutic transducer via an X, Y, and Z coordinate system, and wherein macro-positioning of the transducer (e.g., aligning the transducer with the patient's body) is accomplished manually. In some embodiments, the robot may include six degrees of freedom, including X, Y, Z, as well as pitch, roll, and yaw. In other embodiments, the robotic subsystem may include more degrees of freedom that allow the robotic arm support base to be positioned along a linear axis extending in a general direction parallel to the patient's surface, and / or the support base height to be adjusted up and down to allow the position of the robotic arm to be modified relative to the patient, the patient's surface, the cart, the coupling subsystem, additional robots / robotic arms, and / or additional surgical systems (including but not limited to surgical towers, imaging systems, endoscopic / laparoscopic systems, and / or others).

[0179] One or more robotic arms may also include various features to assist in manually or semi-manually manipulating and modifying the position of the arm, and wherein the features may be connected above or between the treatment transducer and the distal-most joint of the robotic arm. In some embodiments, the feature is configured to include a handle that allows manipulation and manual control with one or more hands. The handle may also be configured to include user input and electronic control features of the robotic arm to instruct various drive capabilities or modes to drive the robot to assist in the rough or fine positioning of the arm (e.g., activating or deactivating a free drive mode). The workflow for initially positioning the robotic arm and the treatment head may be configured to allow the treatment transducer / head to be first positioned in the connection solution and the treatment transducer to be directly connected to the robotic arm, or in a different workflow, allow the user to first set up the connection solution and enable the robotic arm to be connected to the treatment transducer / connection solution as a subsequent / final setup step.

[0180] In some embodiments, the robotic arm may include a robotic arm located on a laparoscope, a monoport, an endoscope, a combination or combination of the above, and / or other robots, wherein the robot in the system may be a slave robot of a master robot that controls the arm and potentially multiple other arms (equipped to perform other tasks (vision, imaging, grasping, cutting, ligation, sealing, closure, suturing, ablation, suturing, marking, etc.) simultaneously, including actuating one or more laparoscopic arms (and instruments) and various tissue destruction system components). For example, a laparoscopic robot can be used to prepare the surgical site, including manipulating the position of the organ to provide a more ideal acoustic pathway, and in some cases further stabilizing the organ to minimize respiratory motion. In conjunction with this and simultaneously, a second robotic arm can be used to deliver non-invasive acoustic cavitation through the body cavity, as observed under real-time imaging from a therapeutic transducer (e.g., ultrasound), and simultaneously visualized by a laparoscopic camera. In other related aspects, similar methods can be used in combination with endoscopic and non-invasive methods, and further used in combination with endoscopic, laparoscopic and non-invasive methods.

[0181] Join

[0182] The system can include various coupling subsystem embodiments that are used and configured to allow acoustic coupling to the patient to provide effective acoustic cavitation / tissue destruction (e.g., provide an acoustic medium between the transducer and the patient and support the acoustic medium). They can include different form factors, including open and closed schemes, and some settings that can be configured to allow dynamic control of the acoustic medium (e.g., temperature, dissolved gas content, particle filtration level, sterility, etc.). Such dynamic control components can be directly integrated into the system (located within the cart) or can communicate with the system but be located externally.

[0183] The coupling subsystem typically includes at least a coupling medium, a reservoir / container containing the coupling medium, and a support structure. In most embodiments, the coupling medium is water, and the water may be conditioned (e.g., cooled, degassed, filtered, etc.) before or during surgery. Various conditioning parameters may be employed depending on the system configuration and its intended use / application.

[0184] The reservoir or media container can be formed and shaped to accommodate / conform to the shape of the patient, allowing the therapeutic transducer to engage and operate in the acoustic medium in each defined and required working space (minimum media volume that allows the therapeutic transducer to be positioned and / or moved through one or more treatment positions or modes, and at different distances or depths from the patient, etc.), and wherein the container or media container can also mechanically support the load and the distribution of the load by using mechanical and / or electromechanical support structures. The container can have a variety of shapes, sizes, curvatures and scales, and can be composed of various materials (single material, multi-material, composite materials, etc.), which can vary across the container. In some embodiments, the container can include features such as membranes, curtains, films, bellows, etc., which can be inserted and removed, and / or manufactured therein. The container can also contain various sensors, drains, lighting (e.g., LEDs), markings, text, etc.

[0185] In one embodiment, the reservoir or media container comprises a sealable frame, wherein the membrane and / or film may be located within the frame to provide a consistent way of contacting the reservoir (and later the therapeutic transducer) as an interface with the patient, which further provides a barrier to the medium (e.g., water) between the patient and the transducer. In other embodiments, the membrane and / or film may include an opening, the edge of which provides a mechanical seal to the patient, but otherwise allows media communication with the patient (e.g., direct water interface with the patient). In both examples, the upper structure of the reservoir or media container may also allow the proximal portion (e.g., top) of the structure to be open or closed (e.g., to prevent spillage or to provide additional features).

[0186] The film disclosed in the present invention can be composed of various elastomers, viscoelastic polymers, thermoplastics, thermoplastic elastomers, thermosetting polymers, silicone resins, polyurethanes, rigid / flexible copolymers, block copolymers, random block copolymers, etc. The material can be hydrophilic, hydrophobic, surface modified, coated, extracted, etc. And various additives can also be included to enhance performance, appearance or stability. In certain embodiments, the thermoplastic elastomer can be styrene-ethylene-butylene-styrene (SEBS), or other similar strong and flexible elastomers.

[0187] The material can be formed into a useful film by molding, casting, spraying, ultrasonic spraying and / or any other processing method that provides a useful embodiment. They can be disposable or recyclable / reusable. They can be non-sterile, sterile clean or sterile, wherein sterilization can include any known method, including but not limited to ethylene oxide, gamma rays, electron beams, high pressure sterilization, steam, peroxides, plasma, chemicals, etc. The membrane can be further configured with an external molded frame to provide mechanical stability during the assembly of the coupling subsystem. For this method of use, various parameters of the membrane can be optimized, including thickness, thickness distribution, density, formulation (such as polymer molecular weight and copolymer ratio), including special optimization to maximize acoustic properties, including minimizing the impact on cavitation initiation threshold, and / or ultrasonic imaging artifacts (including but not limited to membrane reflections).

[0188] Open containers or media containers may include a variety of filling methods, including the use of pre-prepared media or water that can be delivered to the container, in some cases to specified water specifications (temperature level and gas saturation, etc.), or they may include additional features that are integral to the design to allow filling and draining (e.g., ports, valves, hoses, pipes, fittings, bags, pumps, etc.).

[0189] The closed loop of the container or medium container can include various features for sealing, in some embodiments, sealing to the proximal / top end portion or structure of the reservoir / container, or in other cases, the sealing can include embodiments of features sealed to the transducer or transducer housing. In addition, some embodiments can include the dynamic ability to control the volume of the fluid in these designs to minimize the possibility of bubbles or turbulence in the fluid. In this way, integrated features that allow fluid communication and control (the ability to provide / remove fluid as needed) can be provided, including the ability to monitor and control various fluid parameters, some of which are disclosed above. In order to provide this functionality, the entire system and the connection subsystem as a part thereof can include a fluid regulation system, which can include various electromechanical devices, systems, power supplies, sensors, calculations and control systems, etc.

[0190] The coupling support system may include various mechanical support devices to connect the reservoir / container and media to the patient and the workspace (e.g., bed). In some embodiments, the support system includes a mechanical arm with 3 or more degrees of freedom. The arm may be connected to one or more locations (and features) of the bed, including but not limited to the frame, rails, custom rails or plug-ins, and one or more locations of the reservoir or container. The arm may be a feature implemented on one or more carts, wherein the carts may be configured into various non-limiting transformations, in some cases, the carts only include the role of supporting and providing the disclosed support structure.

[0191] In some embodiments, the support structure and arm can be an automated arm that is implemented as a stand-alone cart, or integrated into a cart that also includes two or more system subsystems, or the automated arm is the arm of another interventional, surgical, or other type of robot, and can further include various user input features to actuate / control the robotic arm (e.g., positioning in the coupling medium) and / or coupling solution features (e.g., filling, draining, etc.).

[0192] software

[0193] The system may include various software applications, features and components that allow the user to interact, control and use the system for a variety of clinical applications. The software may communicate and work with one or more subsystems, including but not limited to the system's treatment subsystem, integrated imaging subsystem, robotic subsystem and other components, ancillary devices and accessories.

[0194] In general, and in no particular order of importance, the software may provide features and support: initialization and setup of the system, servicing of the system, communication and import / export / storage of data, modification / operation / configuration / control / command of various settings and parameters by the user, and mitigation of safety and use-related risks, planning of surgery, support for transducers in various configurations, robotic arms and drive systems, function generators and amplifier circuits / accessories, test and therapeutic ultrasound sequences, transducer steering and positioning (electromechanical and electronic beam steering, etc.), and treatment modes, support for imaging and imaging probes, manual and electromechanical / automated motion, and imaging support for: measurement / characterization of surgery and Various dimensions within or around the treatment site (e.g., depth from one anatomical location to another, etc.), pre-treatment assessment and planning for measuring / characterizing the characteristics and conditions of the in situ treatment site (e.g., acoustic cavitation / tissue destruction thresholds and heterogeneity), targeting and target alignment, calibration, marking / annotation, positioning / navigation, registration, guidance, providing and guiding in the workflow, surgical steps, direct observation and viewing through real-time imaging displayed by the software while autonomously executing treatment plans and protocols, including various views and viewports for viewing, communication tools (video, audio, sharing, etc.), troubleshooting, providing directions, warnings, alarms and / or allowing communication through various network devices and protocols. It is further contemplated that the software user interface and supporting display may include various buttons, commands, icons, graphics, text, and the like that allow a user to interact with the system in a user-friendly and efficient manner, and that these may be presented in a non-limiting number of arrangements, layouts, and designs, and displayed in similar or different manners or feature sets for use with systems that may include more than one display (e.g., a touch screen monitor and touchpad), and / or may be connected to one or more external displays or systems (e.g., another robot, a navigation system, a system tower, a console, a monitor, a touch screen display, a mobile device, a tablet computer, etc.).

[0195] As part of a representative system including one or more computer processors, software can support various aforementioned functional generators (e.g., field programmable gate arrays), amplifiers, power supplies, and therapeutic transducers. The software can be configured to allow the user to select, determine, and monitor various parameters and settings for acoustic cavitation / tissue destruction, and upon observing / receiving feedback on performance and status, can allow the user to stop / start / modify the parameters and settings.

[0196] The software can be configured to allow the user to select from a list or menu of multiple transducers and support automatic detection of the transducer when connected to the system (as well as verification of appropriate sequence and parameter settings based on the selected application). In other embodiments, the software can update the target and amplifier settings (e.g., channels) based on the specific transducer selected. The software can also provide transducer recommendations based on pre-treatment and input plans. Conversely, if the selection or parameters of the treatment transducer, amplifier and / or function generator are incorrect, resulting in a malfunction or failure, the software can provide error messages or warnings to the user. This can further include reporting the details and location of these error messages or warnings.

[0197] In addition to the above, the software can be configured to allow the user to select treatment sequences and protocols from a list or menu, and to store the selected and / or previously selected sequences and protocols as associated with a particular clinical use or patient profile. The relevant features may include any relevant patient, surgical, clinical and / or engineering data, and may be used to inform, modify and / or guide current or future treatments or surgeries / interventions, either as decision support or as an active part of the procedure itself (e.g., using a series data set to establish and guide a new treatment).

[0198] As part of planning or during treatment, the software (and working with other components of the system) can allow the user to evaluate and test acoustic cavitation / tissue destruction thresholds at different locations in a user-selected area of ​​interest or defined treatment area / volume to determine the minimum cavitation threshold throughout the area or area / volume, thereby ensuring that treatment parameters are optimized to achieve, maintain and dynamically control acoustic cavitation / tissue destruction. In one embodiment, the system allows the user to manually evaluate and test threshold parameters at different points. The points may include those located at the defined boundaries, interior of the boundaries, and center positions / locations of the selected area of ​​interest and treatment area / volume, and the resulting threshold measurements may be reported / displayed to the user and used to update treatment parameters prior to treatment. In another embodiment, the system may be configured to allow automatic threshold measurement and updating, as implemented by the aforementioned robotic subsystem, where the user can direct the robot, or the robot can be instructed to perform measurements autonomously.

[0199] The software may also be configured to work with the computer processor and one or more function generators, amplifiers and treatment transducers to allow for various variations of delivery and localization of optimized acoustic cavitation / tissue destruction within and through a selected region / volume. This may include, but is not limited to, systems configured with fixed / natural focus settings using a purely electromechanical positioning configuration, beam steering (with or without electromechanical positioning), beam steering to a newly selected fixed focus with further electromechanical positioning, axial (Z-axis) beam steering with lateral (X and Y) electromechanical positioning, high-speed axial beam steering with lateral electromechanical positioning, high-speed beam steering in 3D space, various combinations including the ability to dynamically update one or more acoustic cavitation / tissue destruction parameters (e.g., dynamically adjust amplitude throughout the treatment region / volume) based on the above-described ability to update treatment parameters based on threshold measurements.

[0200] Other components, auxiliary equipment and accessories

[0201] The system may include various other components, ancillary equipment and accessories including, but not limited to, computers, computer processors, power supplies including high voltage power supplies, controllers, cables, connectors, networking equipment, software applications for security, communications equipment, integration into information systems, including hospital information systems, cellular communications equipment and modems, handheld wired or wireless controllers, goggles or glasses for advanced visualization, augmented or virtual reality applications, cameras, sensors, tablets, smart devices, phones, Internet of Things capabilities, dedicated "apps" or user training materials and applications (software or paper), virtual supervisors or trainers and / or other features, devices, systems or applications, and / or methods of using the foregoing.

[0202] System variants and methods / applications

[0203] In addition to performing a range of procedures, the system may also provide additional benefits such as enhanced planning, imaging, and guidance to assist the user. In one embodiment, the system may allow a user to create a patient, goal, and application-specific treatment plan, wherein the system may be configured to optimize treatment parameters based on feedback to the system during planning, and wherein planning may further include the ability to run various test protocols to gather specific input to the system and plan.

[0204] Feedback may include various energy, power, orientation, location, organization, and / or other parameters.

[0205] The system and the feedback described above can also be further configured and used to autonomously (and automatically) perform test plans and delivery of optimized treatment plans and plans, which are visualized through real-time imaging during surgery, allowing the user to directly observe the local treatment tissue effects as the treatment progresses during the treatment process and decide to start / stop / modify the treatment at their own discretion. Under the guidance of the user, or in some embodiments based on the logic embedded in the system, the test and treatment plans can be updated during the process.

[0206] It can also be appreciated that many of these benefits can further improve other forms of acoustic therapy, including thermal ablation using high intensity focused ultrasound (HIFU), high intensity therapeutic ultrasound (HITU) including boiling tissue destruction (thermal cavitation), and are considered part of the present disclosure.

[0207] In another aspect, a treatment subsystem includes, in part, one or more amplifiers, transducers, and power supplies, and can be configured to allow for a variety of acoustic cavitation and tissue destruction drive capabilities to provide specific benefits based on application, method, and / or patient specific use. These benefits may include, but are not limited to, the ability to better optimize and control treatment parameters, which may allow for more energy to be delivered, with more ideal thermal performance, increased treatment speed and reduced procedure time, enabling electron beam steering, and / or other features.

[0208] The present disclosure also includes novel systems and concepts related to systems and subsystems including new and "universal" amplifiers that can allow for multiple drive regimes (e.g., single-cycle and multi-cycle pulses). In some embodiments, this can include various novel features to further protect the system and user from electrical safety or other hazards (e.g., damage to the transducer and / or amplifier circuitry).

[0209] In another aspect, the system and treatment subsystem may include a number of treatment transducers, wherein the treatment transducers are configured for specific applications and uses and may be adapted to perform treatment over a wide range of operating parameters (target size, depth, location, etc.) and may include a wide range of operating instructions (described in detail below). The transducers may be further adapted, coupled and connected to the robotic automation system and the coupling subsystem to allow the transducers to be positioned within or with the acoustic coupling device, allowing, in many embodiments, simultaneous imaging and tissue destruction through an acceptable acoustic window. The treatment transducer may also include an integrated imaging probe or positioning sensor that is capable of displaying and determining the transducer position within the treatment site and providing a direct view (or representation) of the treatment site, and throughout the treatment, the appearance and intensity of the acoustic cavitation / tissue destruction effect and bubble cloud may or may not change as a function of the location in the treatment (e.g., tumor, surrounding healthy tissue, critical structures, adipose tissue, etc.).

[0210] The systems, methods, and uses of the systems disclosed herein can be beneficial in addressing significant unmet needs in the fields of soft tissue resection, oncology, immuno-oncology, advanced image-guided surgery, surgical procedures (including but not limited to open surgery, laparoscopic surgery, single incision surgery, natural orifice surgery, endoscopic surgery, non-invasive surgery, various combinations of the above), catheter-based surgery in various interventional spaces (for vascular, cardiovascular and / or neural related spaces, cosmetic / aesthetics, metabolic (e.g., type 2 diabetes), plastic and reshaping, eye and ophthalmology, gynecology, and men's health), and systems, devices, and methods for treating diseased, injured, unwanted, or healthy tissues, organs, or cells.

[0211] Treatment Mode

[0212] The present invention also provides systems and methods for improving treatment patterns within tissue, which can reduce treatment time, improve efficacy, and reduce energy delivered to the patient and local tissue heating. In some embodiments, the treatment pattern describes the manner in which the bubble cloud is moved or manipulated within the target tissue volume to ablate the tissue volume.

[0213] The "Standard Z" (SZ) mode is a treatment path through a spherical volume in a series of axial slices (parallel to the imaging plane) starting at the center slice and proceeding outward in the positive x-dimension until the entire +x hemisphere is treated. Treatment then moves to an untreated slice adjacent to the center, and the remaining half of the spherical volume is treated in a similar manner, in this case proceeding outward in the negative x-dimension. In each slice, treatment starts at the center point and moves outward in a spiral.

[0214] The "Top-Down" and "Bottom-Up" modes differ from the SZ mode in that they do not traverse the volume in axial slices; instead, they proceed through the sphere in a series of transverse slices (i.e., slices perpendicular to the acoustic axis of the treatment transducer). In each slice, treatment begins at the center point and moves outward in a spiral fashion (the same way that the SZ mode traverses the axial slices). As the names imply, the "Top-Down" and "Bottom-Up" modes traverse the sides of the sphere from the uppermost part of the sphere (closest to the transducer) to the most distal part (farthest from the transducer) or from the most distal part to the uppermost part, respectively.

[0215] Figure 7A-7B An illustration of the "DZ" mode is provided. The target tissue volume is divided into multiple slices (e.g., Fig. 7A In the example shown, 13 slices are treated in alternating order starting from the middle of the volume (the number below each slice indicates the treatment order). Figure 7B As shown, the columns are processed in an alternating manner (the numbers below each column indicate the order of processing). The columns themselves can be traversed from top to bottom or bottom to top, depending on the treatment type, tissue, type, and tissue location.

[0216] The "Standard Z Side-to-Side" and "Scrambled Standard Z" modes represent variations of the SZ mode. The spherical volume is still traversed in a set of axial slices parallel to the imaging plane, and the treatment progression within each slice remains the same. In both schemes, only the treatment order of the axial slices changes. Specifically, the "Standard Z Side-to-Side" mode treats axial slices starting from one lateral extreme of the volume (e.g., the slice farthest in the +x dimension) and traverses one slice at a time until the other lateral extreme of the volume (the slice farthest in the -x dimension) is reached. The "Scrambled Standard Z" mode increments in the slices according to the selected strategic order to maximize the spatial distribution of consecutive treatment slices. If the central axial slice of the sphere is defined as slice 0, the farthest slice in the +x dimension is defined as 6, and the farthest slice in the -x dimension is defined as -6, then "Scrambled Standard Z" is performed in the following order in the 13 slices comprising a 3 cm sphere: 0, 4, -2, -5, -1, 6, -3, 5, 1, -6, 3, -4, 2.

[0217] The "spiral in and out" pattern traverses the spherical volume from the center of the sphere outward in a series of radial layers. Within each layer, and when transitioning between layers, the points are treated in order of proximity (i.e., the next point to be treated is the nearest untreated point in the current radial layer, or when transitioning between layers, the next point to be treated is the nearest point in the next radial layer).

[0218] In one example, tissue destruction can be applied in a "bubble knife" or cylindrical shape. The "bubble knife" or cylindrical shape can be implemented by rapidly electronically steering the bubble cloud focus in the z direction through a column of treatment points and repeating the column of treatments multiple times, eliminating the need to mechanically move the bubble cloud in the z direction. The "bubble knife" technology can provide a huge thermal benefit by electronically directing the bubble cloud to a position closer than the geometric focus to ablate shallow targets. The main thermal benefit of the "bubble knife" technology comes from the electronic steering itself (utilizing the lowest possible effective f-number). Another benefit of the "bubble knife" is the reduced impact of motion on local dose, as well as the potential therapeutic benefits of a more parallel treatment strategy (preventing intact "bulks" of tissue from moving into previously treated areas and escaping further treatment). Figure 8-9 Shown by Figure 8 The laser irradiation in Fig. 9 An example of a columnar bubble cloud shown under real-time ultrasound imaging in Fig. 9 , but it will be appreciated that real-time imaging, such as ultrasound, may also be used).

[0219] In another embodiment, tissue destruction can be applied in a "radial spiral" pattern that minimizes the distance between treatment columns while keeping the damage progressing "from the inside out" in the tissue. Rather than columns of treatment points arranged in a Cartesian grid, the treatment points in this technique are arranged in radial layers. The layers are then treated from the inside out, with the columns in each layer being treated sequentially around each ring in the spiral (or alternating from side to side if necessary to maintain the thermal benefits of sequentially treating columns as far apart as possible). This is similar to a linear treatment pattern (such as Fig.10 Compared with Fig.11A This mode, shown in , provides a more coherent 3D cloud overlap and minimizes the distance between consecutive treatment trains, resulting in a planned ablation volume that more closely matches the ellipsoidal planning contour.

[0220] The radial spiral technique has the flexibility to reduce treatment time by eliminating de facto cool down time when moving between spatially distant treatment trains. It is important to note that while this paradigm does not eliminate the need for cool down time, it only allows the flexibility to include or exclude cool down time as required by the expected heat load, i.e., a faster approach may be chosen if heat is tolerated.

[0221] Fig. 11B and Fig. 11CAdditional side and top views of the radial spiral pattern are shown, showing how each individual planned bubble cloud treatment fills the target tissue volume. As can be seen from these images, the radial spiral pattern covers almost the entire tissue volume. In some embodiments, the radial spiral pattern can be implemented to cover 90-100% of the target tissue volume. The ablation center points of each bubble cloud are distributed at discrete intervals in the X and Y directions, and any points outside the tissue volume boundary are discarded. The position of the points in the Z direction is dynamically adjusted to match the tissue volume boundary contour.

[0222] Figures 11D-11E Another embodiment of the radial spiral pattern is shown. In this example, the ablation center point of each bubble cloud is distributed in radial layers in the X and Y directions, and its radius is dynamically adjusted to match the target tissue volume boundary. The position of the point in the Z direction is also dynamically adjusted to match the target tissue volume boundary contour. The column treatment strategy is retained, and there is no obvious gap between the treatment ellipsoid and the target tissue volume contour in any dimension. In some embodiments, the radial spiral pattern can be implemented to cover 95-100% of the target tissue volume.

[0223] Threshold test

[0224] As described above, the system described herein includes the ability to evaluate and test acoustic cavitation / tissue destruction thresholds at different locations in a user-selected area of ​​interest or a defined treatment area / volume to determine the minimum cavitation threshold throughout the area or area / volume to ensure that treatment parameters are optimized to achieve, maintain, and dynamically control acoustic cavitation / tissue destruction. During treatment planning or during treatment, cavitation threshold test pulses can be transmitted to multiple locations of interest. The number of test locations of interest can be selected based on the size and / or shape of the treatment area. For example, a spherical treatment area benefits from at least seven test locations to detect the extremes of the spherical volume. Fig.12 is an illustration of an example of using seven test pulse positions within a spherical treatment volume. In this illustrated example, the test scheme and test pulses can be positioned at 1) the center of the treatment volume, 2) the most proximal aspect of the treatment volume (top), 3) the most distal aspect of the treatment volume, 4) the most left aspect of the treatment volume, 5) the most right aspect of the treatment volume, 6) the most cranial aspect of the treatment volume (cephalic), and 7) the most caudal aspect of the treatment volume (tail).

[0225] During treatment, the cavitation threshold of each position of interest can be evaluated with a single treatment pulse repetition frequency to determine whether cavitation has been formed before increasing to the next pulse repetition frequency. For example, the formation (or non-formation) of cavitation can be observed in real time by imaging such as ultrasound imaging. In general, the driving voltage required to induce a violent bubble cloud in the tissue decreases with the increase of the treatment pulse repetition frequency. As the treatment process proceeds, the cavitation threshold in the tissue can also change. Therefore, testing various points of interest within the treatment volume during treatment can be a useful tool for real-time evaluation of the cavitation threshold and adjusting the pulse repetition frequency and / or driving voltage of the treatment pulse to optimize the treatment at each test position. Then, the treatment plan itself can be adjusted based on the test pulse to ensure that the optimal amount of energy is delivered to each position in the tissue for tissue destruction using a variable amplitude / pulse repetition frequency based on the test results. In addition, the depth of each test position can be measured or determined (manually or automatically by the system) to provide additional information to the system to determine the optimal treatment parameters.

[0226] In some embodiments, the test location can be used to determine the maximum energy that can be applied without causing undesirable damage to the test location or surrounding or intermediate tissue. For example, when determining the cavitation threshold for each test location, the drive voltage and / or pulse repetition frequency of the system can be increased until cavitation can be observed under real-time imaging. In some embodiments, the drive voltage and / or pulse repetition frequency can be increased until undesirable damage to the test location or cavitation / thermal damage to locations other than the test location is observed. This can be used to determine the maximum energy that can be applied to a given test location.

[0227] Based on the test protocol and the tested cavitation threshold, an appropriate drive voltage can be selected for each point in the treatment grid. Using the desired voltages at the center and six extreme ends of the target volume as input, the voltages for the remaining points that make up the treatment volume can be interpolated. The drive voltage can then be automatically adjusted by the software as the treatment progresses in the automated treatment volume. In this way, each point is ablated with an amplitude sufficient to maintain a valid bubble cloud, but not over-ablated to minimize heat deposition in the acoustic path.

[0228] For example, a method of delivering tissue destruction to tissue may include delivering tissue destruction pulses to the tissue at multiple target test locations and imaging the test locations in real time to assess whether cavitation has been formed at the test locations. If cavitation has not been formed at the test location, the drive voltage and / or pulse repetition frequency of the tissue destruction pulses may be adjusted, and the tissue destruction pulses with the adjusted parameters may be delivered to the tissue at the test location. Real-time imaging may be used again to assess whether cavitation has been formed at each test location. This process may be repeated until a cavitation threshold at each test location is determined, and a high-density map may be created based on various algorithms to extrapolate the thresholds over the target area / treatment volume of interest, particularly over the acoustic path and target depth. For example, if the cavitation thresholds at the first test location and the second test location are known, the cavitation threshold at the third test location may be extrapolated based on the cavitation thresholds at the first test location and the second test location. Further, this extrapolation may be based on the tissue type, target tissue depth, and acoustic path at the third test location.

[0229] In one example, a method of treating tissue may include transmitting an ultrasonic pulse to a first test location using at least one ultrasonic transducer, determining a first cavitation threshold at the first test location, transmitting an ultrasonic pulse to a second test location using at least one ultrasonic transducer, determining a second cavitation threshold at the second test location, adjusting a first drive voltage and / or pulse repetition frequency of at least one ultrasonic transducer based on the first cavitation threshold, transmitting an ultrasonic pulse to the first test location using the at least one ultrasonic transducer at the first adjusted drive voltage and / or pulse repetition frequency to produce cavitation at the first test location, adjusting the second drive voltage and / or pulse repetition frequency of the at least one ultrasonic transducer based on the second cavitation threshold, and transmitting an ultrasonic pulse to the second test location using the at least one ultrasonic transducer at the second adjusted drive voltage and / or pulse repetition frequency to produce cavitation at the second test location.

[0230] Therapeutic pulse sequences and thermal management

[0231] A given tissue destruction treatment or course of treatment can be defined in terms of a set number of pulses N that need to be delivered within a set total treatment time T. The number of pulses delivered per second by the systems described herein is defined by the pulse repetition frequency (PRF) of the system, which can be adjusted during treatment based on cavitation threshold, tissue type, depth, etc. Therefore, the total number of pulses N delivered within the total treatment time T (in seconds) is equal to the total treatment time T multiplied by the pulse repetition frequency of the system. For example, a system running at a constant 200 Hz pulse repetition frequency for a total treatment time of 10 minutes (600 seconds) will have a total number of pulses equal to 120,000. The systems and methods described herein may include pulse repetition frequencies of 400 Hz or higher to produce acoustic cavitation, including pulse repetition frequencies in the range of 400 to 900 Hz.

[0232] The systems and methods provided herein implement tissue blasting pulse sequences with frequent short cooling periods, which advantageously improves the heat distribution produced by tissue blasting, wherein in limited cases, N pulses are evenly distributed over a treatment time T to produce a minimal temperature rise. These pulse sequences can be further characterized by the amount of time that treatment is actively delivered to the tissue relative to the amount of cooling time when no treatment pulses are delivered to the tissue. For example, a system that delivers treatment pulses for 5 minutes at a pulse repetition frequency of 400 Hz, followed by a 5-minute cooling period when no treatment pulses are delivered (total treatment time of 10 minutes), has a 1:1 ratio of treatment (5 minutes) to cooling (5 minutes).

[0233] Fig.13A The temperature curves produced by the six pulse schemes are shown, and the corresponding t43 curves are Fig. 13B The illustrated pulse protocol includes the following within a total treatment time of 10 minutes:

[0234] Protocol 1301: 200 Hz pulse repetition frequency for 10 minutes.

[0235] Protocol 1302: 400 Hz pulse repetition frequency for 5 minutes, followed by 5 minutes of cool down

[0236] Protocol 1303: 400 Hz pulse repetition frequency for 2.5 minutes, followed by 2.5 minutes of cool down, and treatment and cool down were repeated until a total treatment time of 10 minutes was reached.

[0237] Protocol 1304: 400 Hz pulse repetition frequency for 1.25 minutes, followed by 1.25 minutes of cool down, and treatment and cool down were repeated until a total treatment time of 10 minutes was reached.

[0238] Protocol 1305: 800 Hz for 1.25 minutes, followed by cool down for 3.75 minutes, and repeat treatment and cool down until a total treatment time of 10 minutes is reached.

[0239] Protocol 1306: 266.67 Hz for 3.75 minutes, followed by 1.25 minutes of cool down, and repeat treatment and cool down until a total treatment time of 10 minutes is reached.

[0240] like Fig.13A As shown, when 120,000 tissue destruction pulses are evenly distributed within the total treatment time window of 10 minutes, a minimum temperature rise is produced (scheme 1301).

[0241] When the treatment pulse repetition frequency is doubled and cooling steps are implemented (schemes 1302-1304), the extent of the temperature increase depends on the distribution of the cooling steps. A single, longer cooling step (scheme 1302) produces the largest temperature rise that can be observed using this strategy. Conversely, shorter / more frequent cooling steps (scheme 1304) are closer to the case of uniformly distributed pulses and produce the smallest temperature rise that can be observed using this strategy.

[0242] Finally, scenarios 1305 and 1306 show that for a fixed number of tissue blasting pulses delivered within a given total treatment time window, a higher treatment:cooling time ratio (e.g., 3:1) is superior to a lower treatment:cooling time ratio (e.g., 1:3). In essence, for a fixed number of tissue blasting pulses delivered within a given time window, a lower pulse repetition frequency is thermodynamically beneficial. This is consistent with the results of scenario 1301, which showed that the lowest possible pulse repetition frequency (achieved by evenly distributing tissue blasting pulses within a given time window) produces the lowest temperature rise.

[0243] When using tissue blasting to ablate a target volume that is larger than the cavitation bubble cloud produced by the system, the cavitation focus of the tissue blasting treatment system is moved (mechanically or electronically) within the target volume to ablate the entire target volume. The present disclosure provides methods and techniques that can improve the heat distribution of tissue blasting therapy when ablating a target tissue volume that is larger than the cavitation bubble cloud.

[0244] Table 1:

[0245]

[0246]

[0247] Table 1 describes a series of pulse sequence strategies, including the pulse repetition frequency of the treatment pulses and the pulse repetition frequency of the bubble manipulation pulses, as well as the total treatment time. In addition, sequences 1401, 1402, 1304, and 1405 ablate the entire target volume in a single "pass" of the bubble cloud through the target volume, while sequence 1403 requires two "passes" of the bubble cloud to ablate the target volume. Comparing sequences 1404 and 1405, both sequences have a treatment pulse repetition frequency of 150 Hz, a bubble manipulation pulse repetition frequency of 600 Hz, and a total treatment time of 48 minutes, however, sequence 1403 completes two "passes" of the bubble cloud through the target tissue volume with 24 minutes per "pass" compared to a single 48-minute "pass" in sequence 1404.

[0248] Fig.14A The temperature curves of the sequence strategies shown in Table 1 are shown. Fig. 14B The t43 curves produced during treatment are shown. The lowest temperature rise is observed in the sequences using the lowest treatment pulse repetition frequencies (1403 and 1404). In both sequences, there are some thermodynamic advantages to making multiple faster passes through the volume (sequence 1403 using two 24 minute passes) compared to a single slower pass (sequence 1404 using a single 48 minute pass). The former strategy may provide benefits because it allows for efficient distribution of the incident acoustic energy in time and space. The enhanced movement of the transducer allows one area of ​​the volume to cool while another area is heated, rather than staying in any given position for an extended period of time.

[0249] Sequences 1401 and 1402 have been observed to produce localized anterior wall damage during in vivo liver treatment. As expected, these sequences produced the largest temperature rises shown.

[0250] The type of volumetric treatment path used by the tissue destruction system described herein may also have an impact on the thermal effect in the tissue. As described above, some possible treatment modes include a "standard Z" (SZ) mode, a "top-down" mode, a "bottom-up" mode, a "standard Z side-to-side" mode, a "scrambled standard Z" mode, and a "spiral-in-out" mode.

[0251] Table 2:

[0252]

[0253] Table 2 illustrates various cooling techniques performed using the SZ pattern. The SZ pattern without a cooling step was used as a control group. Both Cooling Protocol 1 and Cooling Protocol 2 included a total cooling time of 24 minutes. In Protocol 1, the cooling time was divided into 24 1-minute cooling steps, which were evenly distributed after a fixed number of treatment points throughout the treatment process. In contrast, in Protocol 2, the 24-minute cooling time was evenly distributed after each treatment point. In these cases, the protocol with 24 minutes of cooling produced a treatment run time of 51.8%. Protocols 3 and 4 studied the effect of the ratio of treatment run time to cooling time, with treatment run time percentages of 66.7% and 33.3%, respectively. In both cases, the cooling steps were evenly distributed after each treatment point.

[0254] An advantageous feature of the "DZ" processing mode is that it provides logical points for implementing cooling steps, such as cooling time periods. The method of alternating columns (and similarly, alternating slices) allows cooling steps to be performed between columns (and slices) during the movement time. In effect, this mode has inefficiencies intentionally built into it to accommodate strategic cooling times.

[0255] Table 3:

[0256]

[0257]

[0258] Treatment Schemes 3 and 4 in Table 3 above describe two variations of implementing the cooling step in the DZ mode. In Scheme 3, treatment is stopped only when moving between columns, which is expected to be the minimum cooling time implemented in a DZ sequence. In Scheme 4, additional cooling time is provided, which exceeds the time required for motor movement; this scheme was chosen to give initial insights into the relationship between the temperature profile and the percentage of operating time for volumetric treatment. It should be noted that in Scheme 2, treatment is performed over the entire movement path (including movement between columns), which is not an intended implementation of the DZ mode. Instead, this scheme is used only to compare the thermal characteristics of this path and the SZ path.

[0259] Figures 15A-15B, thermal curves resulting from five treatment protocols used to investigate the implementation of a cooling step during volumetric treatment are shown. Cooling is not shown in curve 1501, and cooling protocols 1-4 in Table 2 are shown as curves 1502-1505, respectively. As expected, treatments performed without cooling (i.e., 100% treatment run time) produced the highest temperature rise (Δt=12.7°C). When cooling was implemented after each treatment point, a decrease in temperature rise was observed, with the percentage of volumetric treatment run time being 66.7% (cooling protocol 1504), 51.8% (cooling protocol 1503), and 33.3% (cooling protocol 1505), respectively, which produced temperature rises of 10.5°C, 8.3°C, and 6.2°C, respectively.

[0260] While an increase in pulse delivery rate is generally associated with an increase in heat deposition, the reduction in cavitation threshold associated with high pulse repetition frequencies may offset this, resulting in a lower overall temperature rise. Thus, the present disclosure also provides pulse sequences with relatively high pulse repetition frequencies that can be used to reduce heat deposition in tissue.

[0261] Table 4:

[0262]

[0263] Figures 16A-16B The thermal effect of the high pulse repetition frequency sequence as a function of cooling time is illustrated. The 1601 sequence using the SZ mode produces a temperature rise of 21.2°C, while the 1602 sequence with the top-down variation of the DZ mode produces a temperature rise of 12.9°C. The corresponding t43 curves are at 1.43×10 5 and 1.21×10 3 The peak value is reached at the equivalent minute.

[0264] Executing sequence 1603 in the top-down variation of the DZC mode further reduced heat deposition, with a temperature rise of only 6.2°C and a peak t43 at 9.6 minutes. Thus, it can be seen that the high pulse repetition frequency strategy is very promising for reducing focal heating effects. On the first pass, it seems counterintuitive to increase the pulse rate as a means of reducing heat deposition because, at a given amplitude, the temperature rise is linearly proportional to the pulse application rate. However, the reduction in the bubble cloud initiation threshold associated with the higher pulse repetition frequency appears to clearly outweigh this effect. This is a result of the temperature rise being proportional to the square of the pulse amplitude; therefore, if the threshold amplitude difference is large enough, the thermal advantage of the lower pressure will outweigh the thermal disadvantage of the increased pulse rate.

[0265] In addition to the obvious thermal advantages, the increased treatment pulse repetition frequency has a second major advantage: reduced treatment time. This is illustrated by Schemes 2 and 3, both of which use the same pattern with (essentially) the same amount of cool-down time (cooling only occurs during inter-sequence motion). In this case, delivering a dose of 947 pulses / point requires a total treatment time of 43:30 with sequence 1602; delivering the same dose with sequence 1603 requires only 32:00.

[0266] Treatment plan

[0267] Further described herein are systems and methods including a graphical user interface (GUI) for planning and implementing ablation therapy. Figures 17A-17E , a graphical user interface of the present disclosure may include one or more internal views of a patient, including a target tissue volume. An operator (e.g., a physician) may identify the target tissue volume in real-time imaging and mark the target tissue volume and a desired margin around the target tissue volume in the system. The system may automatically calculate / determine the size of the target tissue volume upon selection, as well as calculate a planned treatment time for a specific set of treatment parameters for a user-defined target and area of ​​interest. Reference Fig. 17B , a graphical user interface can overlay a selected treatment plan and mode over the target tissue volume, including a configurable view of treatment and bubble cloud positions and spacing, which treatment plan and mode can be pre-selected from any of the above-mentioned treatment modes (e.g., SZ mode, DZ mode, etc.) or selected by the user.

[0268] In some embodiments, the depth of the target tissue volume can be a factor in determining which pulse sequence parameters and / or treatment mode to use, and / or part of a treatment algorithm, including as part of an input to an embedded treatability matrix or lookup table. Thus, the graphical user interface can further enable a user to measure the depth of the target treatment volume, such as Fig. 17C shown.

[0269] Fig.17D An example of a treatment subsystem is shown: a cooling treatability matrix or lookup table that can be used during treatment to determine appropriate treatment and cooling parameters to prevent or reduce thermal damage to non-target tissue sites. In some examples, the tissue destruction system can automatically use the depth of the target tissue and the selected drive voltage % to determine optimal pulse parameters, including the ratio of treatment pulse to cooling time, that will avoid tissue damage to non-target tissue. Therefore, such embodiments advantageously eliminate or reduce the risk of damage or heating, for example, to pre-focused tissue located between the target tissue and the treatment transducer.

[0270] Therapy Subsystem: Cooling Therapeutic Availability Matrix uses the selected drive voltage (%) and target tissue depth (cm) to automatically determine the ratio of treatment time to cooling time for a given treatment period. As described above, during a treatment period with a 1:1 treatment to cooling time ratio, the same amount of time is allocated to treatment pulse delivery and to cooling (no treatment period). For example, if the total treatment time for a treatment is 30 minutes and the treatment:cooling ratio is 1:1, 15 minutes of the total treatment time will be used to deliver treatment pulses to tissue and 15 minutes of the total treatment time will not deliver treatment pulses to tissue (e.g., to reposition the treatment transducer to deliver a subsequent bubble cloud).

[0271] Return reference Fig.17D The treatability matrix in , the driving voltage and target tissue depth are used to determine the ratio of treatment to cooling to avoid non-target tissue damage. For the lines 1701 and Fig.17DFor a drive voltage and target tissue depth combination in the area between the x-axis of , a first cooling ratio can be applied to the treatment pulse sequence to avoid unwanted tissue damage. In one example, the first cooling ratio can include a 1:1 ratio of treatment to cooling ratio (e.g., for a given treatment time, treatment is performed during 50% of the treatment time, and cooling or no treatment is performed during 50% of the treatment time). For a drive voltage and target tissue depth combination in the area between line 1701 and line 1702, a second cooling ratio can be applied to the treatment pulse sequence to avoid unwanted tissue damage. In one example, the second cooling ratio can include a 1:2 ratio of treatment to cooling ratio (e.g., for a given treatment time, treatment is performed during 33% of the treatment time, and cooling or no treatment is performed during 67% of the treatment time). For a drive voltage and target tissue depth combination in the area between line 1702 and line 1703, a third cooling ratio can be applied to the treatment pulse sequence to avoid unwanted tissue damage. In one example, the third cooling ratio may include a ratio of 1:3 treatment to cooling (e.g., for a given treatment time, treatment is performed during 25% of the treatment time, and cooling or no treatment is performed during 75% of the treatment time). For the drive voltage and target tissue depth combinations in the area between line 1703 and line 1704, a fourth cooling ratio may be applied to the treatment pulse sequence to avoid unwanted tissue damage. In one example, the fourth cooling ratio may include a ratio of 1:4 treatment to cooling (e.g., for a given treatment time, treatment is performed during 20% ​​of the treatment time, and cooling or no treatment is performed during 80% of the treatment time). For the drive voltage and target tissue depth combinations in the area between line 1704 and line 1705, a fifth cooling ratio may be applied to the treatment pulse sequence to avoid unwanted tissue damage. In one example, the fifth cooling ratio may include a ratio of 1:5 treatment to cooling (e.g., for a given treatment time, treatment is performed during 16% of the treatment time, and cooling or no treatment is performed during 84% of the treatment time). It should be understood that the exact cooling rates described herein as examples may be adjusted depending on target tissue type, total treatment time, transducer type, drive amplifier, target tissue size, depth, etc.

[0272] refer to Fig.17E, real-time imaging can be used to guide the user during the treatment itself. For example, in one embodiment, the user can be instructed to increase the drive voltage of the treatment transducer until a bubble cloud appears in the real-time imaging. When the drive voltage reaches the desired cavitation threshold for the selected target tissue location, a bubble cloud or cavitation will appear in the tissue. This can further include guiding the user through a test pulse protocol to report a patient / target specific treatment plan that takes into account, but is not limited to, a combination of sequence, pattern, path, and any intervening tissue / obstructions to ensure optimal tissue effect and minimal and / or no collateral damage to adjacent or intervening tissue.

[0273] Usage Environment

[0274] The systems, methods of use, and use of the systems disclosed herein can be performed in a variety of environments and locations, with or without various support systems such as anesthesia, including but not limited to surgical suites, operating rooms, hybrid rooms, inpatient and outpatient settings, mobile settings, imaging centers, radiation, radiation therapy, oncology, surgery, and / or any medical center, as well as physician offices, mobile health centers or systems, cars and related vehicles (e.g., vans), and / or any structure capable of providing temporary surgical support (e.g., tents). In some cases, the systems and / or subsystems disclosed herein can also be provided as integrated features into other environments, for example, integrating the tissue ablation subsystem directly into an MRI scanner or patient surface / bed, where at least the treatment generator and transducer are such an integral unit, and in other cases where the tissue ablation configuration also includes a robotic positioning system, the system can also be integrated into the scanner or bed-centric design.

Claims

1. A tissue destruction system configured to treat tissue, the system comprising: Pulse generator; a therapeutic probe comprising at least one ultrasonic transducer electrically coupled to the pulse generator and configured to deliver tissue blasting energy to tissue, the therapeutic probe further comprising an imaging system configured to provide real-time imaging of the tissue; a robotic positioning arm coupled to the treatment probe and configured to position a focus of the at least one ultrasound transducer at tissue during treatment; as well as at least one processor electrically coupled to the at least one ultrasound transducer and the imaging system of the treatment probe and to the robotic positioning arm, the processor configured to implement a program comprising: directing the robotic positioning arm to move the at least one ultrasonic transducer to a first testing position; directing the at least one ultrasonic transducer to transmit a first tissue destruction test pulse to the first test location; determining a first cavitation threshold at the first test location based on the first tissue destruction test pulse; directing the robotic positioning arm to move the at least one ultrasonic transducer to a second testing position; directing the at least one ultrasonic transducer to transmit a second tissue destruction test pulse to the second test location; determining a second cavitation threshold at the second test location based on the second tissue destruction test pulse; extrapolating a third cavitation threshold at a third test position between the first test position and the second test position based on the first cavitation threshold and the second cavitation threshold; adjusting a first driving voltage and / or a pulse repetition frequency of the pulse generator based on the first cavitation threshold; directing the robotic positioning arm to move the at least one ultrasonic transducer to the first testing position; directing the at least one ultrasonic transducer so that tissue destruction pulses are transmitted to the first test location with the at least one ultrasonic transducer at the adjusted first drive voltage and / or pulse repetition frequency to generate cavitation at the first test location; adjusting a second driving voltage and / or a pulse repetition frequency of the pulse generator based on the second cavitation threshold; directing the robotic positioning arm to move the at least one ultrasonic transducer to the second testing position; and The at least one ultrasonic transducer is directed such that tissue destruction test pulses are transmitted to the second test location by the at least one ultrasonic transducer at the adjusted second drive voltage and / or pulse repetition frequency to generate cavitation at the second test location.

2. The tissue destruction system of claim 1, wherein the at least one processor is further configured to repeat the procedure at three or more test locations in the tissue.

3. The tissue destruction system of claim 1, wherein the at least one processor is further configured to repeat the procedure at six or more test locations in the tissue.

4. The tissue destruction system of claim 3, wherein the six or more test locations are positioned in cubic coordinates around the center of the tissue.

5. The tissue destruction system of claim 1, wherein the at least one processor is further configured to interpolate the drive amplitudes required at the first test position, the second test position, and the third test position to ensure that each cavitation threshold is met.

6. The tissue destruction system of claim 1, wherein the first test location and the second test location are positioned near an outer boundary of the tissue.

7. The tissue destruction system of claim 1, wherein the tissue comprises a tumor volume.

8. The tissue destruction system of claim 7, wherein the tissue comprises a tumor volume and a margin surrounding the tumor volume.

9. The tissue destruction system of claim 1, wherein the first test location and the second test location are two or more tumors.

10. The tissue destruction system of claim 1, wherein the at least one processor is further configured to perform depth measurements at the first test location and the second test location.

11. The tissue destruction system of claim 1 , wherein the at least one processor is further configured to determine a maximum energy that can be applied to the first test location without causing undesirable damage to the first test location or surrounding intervening tissue.

12. The tissue destruction system of claim 1, wherein the imaging system comprises an ultrasound imaging system.

13. The tissue destruction system of claim 12, wherein the at least one processor is configured to determine the first cavitation threshold and the second cavitation threshold based on real-time imaging from the ultrasound imaging system.

14. The tissue destruction system of claim 1, wherein the at least one processor is further configured to: adjusting a third drive voltage and / or a pulse repetition frequency of the at least one ultrasonic transducer based on the third cavitation threshold; directing the robotic positioning arm to move the at least one ultrasonic transducer to the third testing position; The at least one ultrasonic transducer is guided so that tissue destruction test pulses are transmitted to the third test location by the at least one ultrasonic transducer at the adjusted third drive voltage and / or pulse repetition frequency to generate cavitation at the third test location.

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