HISTOTRIPSY

PRIORITY CLAIM

[0001] This patent application claims priority to U.S. provisional patent application no. 63/197,919, titled “ALL-IN-ONE ULTRASOUND SYSTEMS AND METHODS INCLUDING HISTOTRIPSY” and filed on June 7, 2021, which is herein incorporated by reference in its entirety.

INCORPORATION BY REFERENCE

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

STATEMENT AS TO FEDERALLY SPONSORED RESEARCH [0003] This invention was made with government support under EB028309 and NS 108042 awarded by the National Institutes of Health. The government has certain rights in the invention.

FIELD

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

BACKGROUND

[0005] Many medical conditions require invasive surgical interventions. Invasive procedures often involve incisions, trauma to muscles, nerves and tissues, bleeding, scarring, trauma to organs, pain, need for narcotics during and following procedures, hospital stays, and risks of infection. Non-invasive and minimally invasive procedures are often favored, if available, to avoid or reduce such issues. Unfortunately, non-invasive and minimally invasive procedures may lack the precision, efficacy or safety required for treatment of many types of diseases and conditions. Enhanced non-invasive and minimally invasive procedures are needed, preferably not requiring ionizing or thermal energy for therapeutic effect. [0006] Histotripsy, or pulsed ultrasound cavitation therapy, is a technology where extremely short, intense bursts of acoustic energy induce controlled cavitation (microbubble formation) within the focal volume. The vigorous expansion and collapse of these microbubbles mechanically homogenizes cells and tissue structures within the focal volume. This is a very different end result than the coagulative necrosis characteristic of thermal ablation. To operate within a non-thermal, Histotripsy realm; it is necessary to deliver acoustic energy in the form of high amplitude acoustic pulses with low duty cycle.

[0007] High intensity focused ultrasound (HIFU) delivers high intensity continuous ultrasound wave or long pulses from outside the body and focus to the target tissue inside the body to heat up the target tissue, resulting in thermal necrosis. The temperature increase generated by HIFU can be monitored by magnetic resonant imaging (MRI) thermometry during treatment. HIFU thermal ablation has been used clinically for treatment of benign and metastatic tumors, including tumor in pancreas, liver, prostate, breast, uterine fibroids, and essential tremor. [0008] Hyperthermia therapy (HT) can use ultrasound to induce low heating using continuous wave or ultrasound bursts at a high duty cycle (>10%). Hyperthermia is useful to induce low temperature increase (to -40-45 deg. C). Hyperthermia has been shown potentially to enhance radiation therapy. Hyperthermia can be visualized with MRI thermometry, thus has been used for targeting in MR-guide ultrasound treatment.

[0009] Ultrasound can also be used to aid with drug delivery. Low intensity ultrasound combined with microbubbles has been shown to generate cavitation in the blood vessels within target zones to open up the tight junction of the blood vessel to facilitate local drug delivery. In the brain, low intensity ultrasound combined with microbubbles has been shown to open up the blood brain barrier (BBB) temporarily to allow drug delivery into the brain. Microbubble- mediated ultrasound drug delivery has been investigated to treat many diseases, including various tumors, Parkinson’s disease, Alzheimer’s disease, etc.

[0010] HIFU and histotripsy have both shown the potential to stimulate immune response in the brain in mouse tumor models. Microbubble-mediated ultrasound drug delivery has also been used to deliver immune drugs in pre-clinical studies. Thus, HIFU, histotripsy, microbubble- mediated ultrasound drug delivery, or hyperthermia parameters may also be used to enhance immune therapy.

[0011] Sonodynamic therapy (SDT) has been broadly defined as a synergistic effect of low energy sonication applied in combination with substances referred to as "sonosensitizers". Sonodynamic therapy can be used for drug delivery. [0012] Low intensity focused ultrasound has shown neuromodulation effects on corticospinal and thalamocortical pathways related to movement, visual and cognitive processing, and brain connectivity related to mood change.

[0013] Compared with conventional focused ultrasound technologies, Histotripsy has important advantages: 1) the destructive process at the focus is mechanical, not thermal; 2) cavitation appears bright on ultrasound imaging thereby confirming correct targeting and localization of treatment; 3) treated tissue generally, but not always, appears darker (more hypoechoic) on ultrasound imaging, so that the operator knows what has been treated; and 4) Histotripsy produces lesions in a controlled and precise manner. It is important to emphasize that unlike thermal ablative technologies such as microwave, radiofrequency, and high-intensity focused ultrasound (HIFU), Histotripsy relies on the mechanical action of cavitation for tissue destruction. However, histotripsy therapy in combination with other ultrasound treatments opens the door for new and exciting combination treatments.

BRIEF DESCRIPTION OF THE DRAWINGS [0014] The novel features of the invention are set forth with particularity in the claims that follow. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0015] FIGS. 1A-1B illustrate an ultrasound imaging and therapy system.

[0016] FIG. 2A is a schematic illustration of transmit drive electronics for an all-in-one ultrasound system.

[0017] FIG. 2B is a schematic illustration of a power supply switching circuit for an all-in- one ultrasound system

[0018] FIG. 3 is a schematic illustration of receive drive electronics for an all-in-one ultrasound system.

[0019] FIG. 4 is a flowchart describing a method of treating tissue.

SUMMARY OF THE DISCLOSURE

[0020] Histotripsy produces tissue fractionation through dense energetic bubble clouds generated by short, high-pressure, ultrasound pulses. When using pulses shorter than 2 cycles, the generation of these energetic bubble clouds only depends on where the peak negative pressure (P-) exceeds an intrinsic threshold for inducing cavitation in a medium (typically 26 - 30 MPa in soft tissue with high water content). [0021] A method of delivering therapy to a target tissue, comprising the steps of providing an all-in-one ultrasound therapy system configured to provide a plurality of ultrasound therapy modalities to the target tissue, the all-in-one therapy system including a current driver and an ultrasound transducer array, positioning a therapy focus of the ultrasound transducer array on the target tissue, transmitting ultrasound therapy pulses of a first ultrasound therapy modality into the target tissue with a current driver and the ultrasound transducer array, selecting a second ultrasound therapy modality in the all-in-one ultrasound system, and transmitting ultrasound therapy pulses of the second ultrasound therapy modality into the target tissue with the current driver and the ultrasound transducer array.

[0022] In some embodiments, the first ultrasound therapy modality comprises histotripsy therapy. In other embodiments, the second ultrasound therapy modality is selected from the group consisting of hyperthermia/radio-sensitization, HIFU, microbubble-enhanced drug delivery, immunotherapy, sonodynamic therapy, and neuromodulation.

[0023] In one implementation, transmitting ultrasound therapy pulses further comprises turning on a transistor of the current driver to pull current through a primary winding of a transformer of the current driver, and turning off the transistor of the current driver to force the current to a secondary winding of the transformer and to the ultrasound transducer array.

[0024] In some embodiments, the secondary winding is configured to resonate with a capacitance of the ultrasound transducer array.

[0025] In one embodiment, transmitting ultrasound therapy pulses of the first ultrasound therapy modality further comprises coupling the current driver to a power supply switching circuit operating in a first operating mode, and wherein transmitting ultrasound therapy pulses of the second ultrasound therapy modality further comprises coupling the current driver to the power supply switching circuit operating in a second operating mode.

[0026] Also provided is an ultrasound system driving architecture configured to drive an ultrasound transducer array with a plurality of ultrasound modalities, the ultrasound system driving architecture comprising a power supply switching circuit configured to switch between a first power mode that provides a first voltage and a first current and a second power mode that provides a second voltage and a second current, wherein the second voltage is higher than the first voltage and the second current is lower than the first current, and a current driver circuit comprising a gate driver configured to receive a digital drive signal, a transformer electrically coupled to the ultrasound transducer array, and a transistor electrically coupled to the gate driver and the transformer, wherein the gate driver is configured to drive the transistor at a first pulse repetition frequency when the power supply switching circuit is operating in the first power mode to produce ultrasound pulses of a first ultrasound therapy modality, and wherein the gate driver is configured to drive the transistor at a second pulse repetition frequency when the power supply switching circuit is operating in the second power mode to produce ultrasound pulses of a second ultrasound therapy modality.

[0027] In one embodiment, the first ultrasound therapy modality is selected from the group consisting of hyperthermia/radio-sensitization, HIFU, microbubble-enhanced drug delivery, immunotherapy, sonodynamic therapy, and neuromodulation.

[0028] In another embodiment, the second ultrasound therapy modality comprises histotripsy.

[0029] In some embodiments, the ultrasound driving system architecture further comprises a first resistor and a first capacitor electrically coupled to the transistor and configured to slow down a turn-on and a turn off time of the transistor to reduce RF noise emissions.

[0030] In other embodiments, the ultrasound driving system architecture further comprises a blocking diode electrically connected to the transistor and configured to prevent the transistor from conducting when a polarity of the transistor is negative.

[0031] In some examples, a secondary winding of the transformer is configured to resonate with a capacitance of the ultrasound transducer array.

[0032] In some embodiments, the power supply switching circuit further comprises a first transistor configured to connect the power supply switching circuit to a first power supply, and a second transistor configured to connect the power supply switching circuit to a second power supply.

[0033] In some embodiments, the current driver circuit is further configured to enable the ultrasound transducer array to measure ultrasound signals.

[0034] In one example, the current driver circuit further comprises a current sensing resistor and a digitizer configured to measure a voltage across the current sensing resistor.

[0035] In some embodiments, the ultrasound driving system architecture further comprises a pair of MOSFETs in parallel with the current sensing resistor configured to block transmit currents.

[0036] In other embodiments, the ultrasound driving system architecture further comprises a second current sensing resistor configured to be switched into the current driver circuit in parallel with the current sensing resistor to reduce a gain in the circuit.

[0037] An ultrasound system driving architecture is also provided that is configured to drive an ultrasound transducer array with a plurality of ultrasound modalities, the ultrasound system driving architecture being configured to produce ultrasound pulses having microsecond-length and a peak negative pressure greater than 30MPa for histotripsy therapies and being further configured to produce continuous wave ultrasound pulses having a peak negative pressure below 5MPa for hyperthermia, hyperthermia/radio-sensitization, microbubble-enhanced drug delivery, blood brain barrier opening, immunotherapy, sonodynamic therapy, and neuromodulation therapies.

DETAILED DESCRIPTION

[0038] Provided herein are systems and methods that provide efficacious non-invasive and minimally invasive therapeutic, diagnostic and research procedures. In particular, provided herein are optimized systems and methods that provide targeted, efficacious ultrasound therapies in a variety of different regions and under a variety of different conditions without causing undesired tissue damage to intervening/non-target tissues or structures.

[0039] This disclosure further describes an All-In-One ultrasound (US) therapy system that can be used for a number of non-invasive ultrasound therapy modalities including Histotripsy, Hyperthermia/radio-sensitization, microbubble-enhanced drug delivery, immunotherapy, sonodynamic therapy, HIFU, and/or neuromodulation. This All-In-One US therapy system is capable of delivering different US modalities.

[0040] In some embodiments, the driving electronics described herein for an all-in-one ultrasound system includes transmit-receive driving electronics that are configured to deliver extremely high ultrasound pressure for histotripsy, ultrasound pulses for focal tissue thermal ablation (HIFU), lower pressure pulses at very high pulse repetition frequency (PRF) for hyperthermia, sonodynamic therapy, neuromodulation, and drug delivery, and receive the ultrasound signal for treatment monitoring and aberration correction. By changing the width of charge duration or the main power supply voltage, the output amplitude can be varied over large ranges for different therapeutic uses. In addition to short pulse histotripsy mode, the current driver is capable of quasi-CW operation by simply pulsing at very high rates and high duty cycle. The therapy transducer array elements can be used as receivers to detect cavitation emissions for treatment monitoring and/or aberration correction. The control system and receive data handling is performed by a set of FPGAs.

[0041] The system, methods and devices of the disclosure may be used for minimally or non- invasive acoustic cavitation and treatment of healthy, diseased and/or injured tissue, including in extracorporeal, percutaneous, endoscopic, laparoscopic, and/or as integrated into a robotically- enabled medical system and procedures. As will be described below, the histotripsy system may include various electrical, mechanical and software sub-systems, including a Cart, Therapy, Integrated Imaging, Robotics, Coupling and Software. The system also may comprise various Other Components, Ancillaries and Accessories, including but not limited to patient surfaces, tables or beds, computers, cables and connectors, networking devices, power supplies, displays, drawers/storage, doors, wheels, illumination and lighting and various simulation and training tools, etc. All systems, methods and means creating/controlling/delivering histotripsy are considered to be a part of this disclosure, including new related inventions disclosed herein. [0042] In one embodiment, the ultrasound system is configured as a mobile therapy cart, which further includes a touchscreen display with an integrated control panel with a set of physical controls, a robotic arm, a therapy head positioned on the distal end of the robot, a patient coupling system and software to operate and control the system.

[0043] The mobile therapy cart architecture can comprise internal components, housed in a standard rack mount frame, including a histotripsy therapy generator, high voltage power supply, transformer, power distribution, robot controller, computer, router and modem, and an ultrasound imaging engine. The front system interface panel can comprise input/output locations for connectors, including those specifically for two ultrasound imaging probes (handheld and probe coaxially mounted in the therapy transducer), a histotripsy therapy transducer, AC power and circuit breaker switches, network connections and a foot pedal. The rear panel of the cart can comprise air inlet vents to direct airflow to air exhaust vents located in the side, top and bottom panels. The side panels of the cart include a holster and support mechanism for holding the handheld imaging probe. The base of the cart can be comprised of a cast base interfacing with the rack mounted electronics and providing an interface to the side panels and top cover. The base also includes four recessed casters with a single total locking mechanism. The top cover of the therapy cart can comprise the robot arm base and interface, and a circumferential handle that follows the contour of the cart body. The cart can have inner mounting features that allow technician access to cart components through access panels.

[0044] The touchscreen display and control panel may include user input features including physical controls in the form of six dials, a space mouse and touchpad, an indicator light bar, and an emergency stop, together configured to control imaging and therapy parameters, and the robot. The touchscreen support arm is configured to allow standing and seated positions, and adjustment of the touchscreen orientation and viewing angle. The support arm further can comprise a system level power button and USB and ethernet connectors.

[0045] The robotic arm can be mounted to the mobile therapy cart on arm base of sufficient height to allow reach and ease of use positioning the arm in various drive modes into the patient/procedure work space from set up, through the procedure, and take down. The robotic arm can comprise six degrees of freedom with six rotating joints, a reach of 850 mm and a maximum payload of 5 kg. The arm may be controlled through the histotripsy system software as well as a 12 inch touchscreen polyscope with a graphical user interface. The robot can comprise force sensing and a tool flange, with force (x, y, z) with a range of 50 N, precision of 3.5 N and accuracy of 4.0 N, and torque (x, y, z) with a range of 10.0 Nm, precision of 0.2 Nm and accuracy of 0.3 Nm. The robot has a pose repeatability of +/- 0.03mm and a typical TCP speed of 1 m/s (39.4 in/s). In one embodiment, the robot control box has multiple I/O ports, including 16 digital in, 16 digital out, 2 analog in, 2 analog out and 4 quadrature digital inputs, and an I/O power supply of 24V/2A. The control box communication comprises 500 Hz control frequency, Modbus TCP, PROFINET, ethernet/IP and USB 2.0 and 3.0.

[0046] The therapy head can comprise one of a select group of ultrasound therapy transducers and an ultrasound imaging system/probe, coaxially located in the therapy transducer, with an encoded mechanism to rotate said imaging probe independent of the therapy transducer to known positions, and a handle to allow gross and fine positioning of the therapy head, including user inputs for activating the robot (e.g. for free drive positioning). In some examples, the therapy transducers may vary in size (22 x 17 cm to 28 x 17 cm or 30 cm diameter hemispherical shaped), focal lengths from 12 - 18 cm, number of elements, ranging from 48 to 1000 elements, comprised within 12-16 rings, and with frequencies that support a plurality of ultrasound modalities (200kHz - 5MHz). The therapy head subsystem has an interface to the robotic arm includes a quick release mechanism to allow removing and/or changing the therapy head to allow cleaning, replacement and/or selection of an alternative therapy transducer design (e.g., of different number of elements and geometry), and each therapy transducer is electronically keyed for auto-identification in the system software.

[0047] The patient coupling system can comprise a six degree of freedom, six joint, mechanical arm, configured with a mounting bracket designed to interface to a surgical/interventional table rail. The arm may have a maximum reach of approximately 850 mm and an average diameter of 50 mm. The distal end of the arm can be configured to interface with an ultrasound medium container, including a frame system and an upper and lower boot. The lower boot is configured to support either a patient contacting film, sealed to patient, or an elastic polymer membrane, both designed to contain ultrasound medium (e.g., degassed water or water mixture), either within the frame and boot and in direct contact with the patient, or within the membrane/boot construct. The lower boot provides, in one example, a top and bottom window of approximately 46 cm x 56 cm and 26 cm x 20 cm, respectively, for placing the therapy transducer with the ultrasound medium container and localized on the patient’ s abdomen. The upper boot may be configured to allow the distal end of the robot to interface to the therapy head and/or transducer, and to prevent water leakage/spillage. In preferred embodiments, the upper boot is a sealed system. The frame is also configured, in a sealed system, to allow two-way fluid communication between the ultrasound medium container and an ultrasound medium source (e.g., reservoir or fluidics management system), including, but not limited for filling and draining, as well as air venting for bubble management.

[0048] The system software and work-flow can be configured to allow users to control the system through touchscreen display and the physical controls, including but not limited to, ultrasound imaging parameters and therapy parameters. The graphical user interface of the system comprises a work-flow based flow, with the general procedure steps of 1) registering/selecting a patient, 2) planning, comprising imaging the patient (and target location/anatomy) with the freehand imaging probe, and robot assisted imaging with the transducer head for final gross and fine targeting, including contouring the target with a target and margin contour, of which are typically spherical and ellipsoidal in nature, and running a test protocol (e.g., test pulses) including a bubble cloud calibration step, and a series of predetermined locations in the volume to assess cavitation initiation threshold and other patient/target specific parameters (e.g., treatment depth), that together inform a treatment plan accounting for said target’s location and acoustic pathway, and any related blockage (e.g., tissue interfaces, bone, etc.) that may require varied levels of drive amplitude or frequency or phase/time delay to initiate and maintain the desired ultrasound modality. Said parameters, as measured as a part of a histotripsy test protocol, comprising calibration and multi-location test pulses, are configured in the system to provide input/feedback for updating bubble cloud location in space as needed/desired (e.g., appropriately calibrated to target cross-hairs), as well as determining/interpolating required amplitudes across all bubble cloud treatment locations in the treatment volume to ensure threshold is achieved throughout the volume. Further, said parameters, including but not limited to depth and drive voltage, may be also used as part of an embedded treatability matrix or look up table to determine if additional cooling is required (e.g., off-time in addition to time allocated to robot motions between treatment pattern movements) to ensure robust cavitation and intervening/collateral thermal effects are managed (e.g., staying below t43 curve for any known or calculated combination of sequence, pattern and pathway, and target depth/blockage). The work-flow and procedure steps associated with these facets of planning, as implemented in the system software may be automated, wherein the robot and controls system are configured to run through the test protocol and locations autonomously, or semi-autonomously. Following planning, the next phase of the procedure work-flow, 3) the treatment phase, is initiated following the user accepting the treatment plan and initiating the system for treatment. Following this command, the system is configured to deliver treatment autonomously, running the treatment protocol, until the prescribed volumetric treatment is complete. The status of the treatment (and location of the focal bubble cloud) is displayed in real-time, adjacent to various treatment parameters, including, but not limited to, of which may include total treatment time and remaining treatment time, drive voltage, treatment contours (target/margin) and bubble cloud/point locations, current location in treatment pattern (e.g., slice and column), imaging parameters, and other additional contextual data (e.g., optional DICOM data, force torque data from robot, etc.). Following treatment, the user may use the therapy head probe, and subsequently, the freehand ultrasound probe to review and verify treatment, as controlled/viewed through the system user interface. If additional target locations are desired, the user may plan/treat additional targets, or dock the robot to a home position on the cart if no further treatments are planned.

[0049] FIG. 1A generally illustrates an all-in-one ultrasound system 100 according to the present disclosure, comprising a therapy transducer 102, an imaging system 104, a display and control panel 106, a robotic positioning arm 108, and a cart 110. The cart can include circuitry including an electronic driver configured to drive the therapy transducer 102 to enable delivery of a plurality of ultrasound therapies or modalities, including Histotripsy, Hyperthermia/radio- sensitization, microbubble-enhanced drug delivery, immunotherapy, sonodynamic therapy, and/or neuromodulation. More specifically, the electronic drive can be configured to drive the single therapy transducer array to provide a plurality of ultrasound therapies. Previously, delivering multiple ultrasound therapies to a patient required separate therapy transducers for each patient and separate current drivers for each ultrasound modality. The electronic driver enables a plurality of ultrasound modalities with the same transducer array, from histotripsy requiring extremely high pressure and microsecond-length pulses at a very low duty to hyperthermia requiring ultrasound at low intensity and a very high duty cycle or continuous wave. The electronic driver also has transmit-and-receive capabilities to achieve aberration correction and cavitation detection during treatment. This allows the all-in-one ultrasound system described herein to be used outside a MRI scanner. The system can further include an ultrasound coupling interface and a source of coupling medium, not shown.

[0050] Table 1 is a listing of the various ultrasound modalities and typical parameters that the all-in-one ultrasound system is configured to support. [0051] Table 1:

[0052] FIG. IB is a bottom view of the therapy transducer 102 and the imaging system 104.

As shown, the imaging system can be positioned in the center of the therapy transducer. However, other embodiments can include the imaging system positioned in other locations within the therapy transducer, or even directly integrated into the therapy transducer. In some embodiments, the imaging system is configured to produce real-time imaging at a focal point of the therapy transducer. In some embodiments, a subset of the array elements can be configured to produce low pressure pulses, or pulses with a different frequency that other array elements. [0053] The histotripsy system may comprise one or more of various sub-systems, including a

Therapy sub-system that can create, apply, focus and deliver acoustic cavitation/histotripsy through one or more therapy transducers, Integrated Imaging sub-system (or connectivity to) allowing real-time visualization of the treatment site and histotrmsv effect through-out the procedure, a Robotics positioning sub-system to mechanically and/or electronically steer the therapy transducer, further enabled to connect/support or interact with a Coupling sub-system to allow acoustic coupling between the therapy transducer and the patient, and Software to communicate, control and interface with the system and computer-based control systems (and other external systems) and various Other Components, Ancillaries and Accessories, including one or more user interfaces and displays, and related guided work-flows, all working in part or together. The system may further comprise various fluidics and fluid management components, including but not limited to, pumps, valve and flow controls, temperature and degassing controls, and irrigation and aspiration capabilities, as well as providing and storing fluids. It may also contain various power supplies and protectors.

CART

[0054] The Cart 110 may be generally configured in a variety of ways and form factors based on the specific uses and procedures. In some cases, systems may comprise multiple Carts, configured with similar or different arrangements. In some embodiments, the cart may be configured and arranged to be used in a radiology environment and in some cases in concert with imaging (e.g., CT, cone beam CT and/or MRI scanning). In other embodiments, it may be arranged for use in an operating room and a sterile environment, or in a robotically enabled operating room, and used alone, or as part of a surgical robotics procedure wherein a surgical robot conducts specific tasks before, during or after use of the system and delivery of acoustic cavitation/histotripsy. As such and depending on the procedure environment based on the aforementioned embodiments, the cart may be positioned to provide sufficient work-space and access to various anatomical locations on the patient (e.g., torso, abdomen, flank, head and neck, etc.), as well as providing work-space for other systems (e.g., anesthesia cart, laparoscopic tower, surgical robot, endoscope tower, etc.).

[0055] The Cart may also work with a patient surface (e.g., table or bed) to allow the patient to be presented and repositioned in a plethora of positions, angles and orientations, including allowing changes to such to be made pre, peri and post-procedurally. It may further comprise the ability to interface and communicate with one or more external imaging or image data management and communication systems, not limited to ultrasound, CT, fluoroscopy, cone beam CT, PET, PET/CT, MRI, optical, ultrasound, and image fusion and or image flow, of one or more modalities, to support the procedures and/or environments of use, including physical/mechanical interoperability (e.g., compatible within cone beam CT work-space for collecting imaging data pre-, peri- and/or post-histotripsy).

[0056] In some embodiments one or more Carts may be configured to work together. As an example, one Cart may comprise a bedside mobile Cart equipped with one or more Robotic arms enabled with a Therapy transducer, and Therapy generator/amplifier, etc., while a companion cart working in concert and at a distance of the patient may comprise Integrated Imaging and a console/display for controlling the Robotic and Therapy facets, analogous to a surgical robot and master/slave configurations.

[0057] In some embodiments, the system may comprise a plurality of Carts, all slave to one master Cart, equipped to conduct acoustic cavitation procedures. In some arrangements and cases, one Cart configuration may allow for storage of specific sub-systems at a distance reducing operating room clutter, while another in concert Cart may comprise essentially bedside sub-systems and componentry (e.g., delivery system and therapy).

[0058] One can envision a plethora of permutations and configurations of Cart design, and these examples are in no way limiting the scope of the disclosure.

HISTOTRIPSY

[0059] Histotripsy comprises short, high amplitude, focused ultrasound pulses to generate a dense, energetic, “bubble cloud”, capable of the targeted fractionation and destruction of tissue. Histotripsy is capable of creating controlled tissue erosion when directed at a tissue interface, including tissue/fluid interfaces, as well as well-demarcated tissue fractionation and destruction, at sub-cellular levels, when it is targeted at bulk tissue. Unlike other forms of ablation, including thermal and radiation-based modalities, histotripsy does not rely on heat or ionizing (high) energy to treat tissue. Instead, histotripsy uses acoustic cavitation generated at the focus to mechanically effect tissue structure, and in some cases liquefy, suspend, solubilize and/or disrupt tissue into sub-cellular components.

[0060] Histotripsy can be applied in various forms, including: 1) Intrinsic-Threshold Histotripsy: Delivers pulses with at least a single negative/tensile phase sufficient to cause a cluster of bubble nuclei intrinsic to the medium to undergo inertial cavitation, 2) Shock- Scattering Histotripsy: Delivers typically pulses 3-20 cycles in duration. The amplitude of the tensile phases of the pulses is sufficient to cause bubble nuclei in the medium to undergo inertial cavitation within the focal zone throughout the duration of the pulse. These nuclei scatter the incident shockwaves, which invert and constructively interfere with the incident wave to exceed the threshold for intrinsic nucleation, and 3) Boiling Histotripsy: Employs pulses roughly 1-20 ms in duration. Absorption of the shocked pulse rapidly heats the medium, thereby reducing the threshold for intrinsic nuclei. Once this intrinsic threshold coincides with the peak negative pressure of the incident wave, boiling bubbles form at the focus. Alternatively, the 1- 20ms pulse can reach boiling temperature to form boiling bubbles.

[0061] The large pressure generated at the focus causes a cloud of acoustic cavitation bubbles to form above certain thresholds, which creates localized stress and strain in the tissue and mechanical breakdown without significant heat deposition. At pressure levels where cavitation is not generated, minimal effect is observed on the tissue at the focus. This cavitation effect is observed only at pressure levels significantly greater than those which define the inertial cavitation threshold in water for similar pulse durations, on the order of 10 to 30 MPa peak negative pressure.

[0062] Histotripsy may be performed in multiple ways and under different parameters. It may be performed totally non-invasively by acoustically coupling a focused ultrasound transducer over the skin of a patient and transmitting acoustic pulses transcutaneously through overlying (and intervening) tissue to the focal zone (treatment zone and site). It may be further targeted, planned, directed and observed under direct visualization, via ultrasound imaging, given the bubble clouds generated by histotripsy may be visible as highly dynamic, echogenic regions on, for example, B Mode ultrasound images, allowing continuous visualization through its use (and related procedures). Likewise, the treated and fractionated tissue shows a dynamic change in echogenicity (typically a reduction), which can be used to evaluate, plan, observe and monitor treatment.

[0063] Generally, in histotripsy treatments, ultrasound pulses with 3 or more acoustic cycles are applied, and the bubble cloud formation relies on the pressure release scattering of the positive shock fronts (sometimes exceeding 100 MPa, P+) from initially initiated, sparsely distributed bubbles (or a single bubble). This is referred to as the “shock scattering mechanism”. [0064] This mechanism depends on one (or a few sparsely distributed) bubble(s) initiated with the initial negative half cycle(s) of the pulse at the focus of the transducer. A cloud of microbubbles then forms due to the pressure release backscattering of the high peak positive shock fronts from these sparsely initiated bubbles. These back-scattered high-amplitude rarefactional waves exceed the intrinsic threshold thus producing a localized dense bubble cloud. Each of the following acoustic cycles then induces further cavitation by the backscattering from the bubble cloud surface, which grows towards the transducer. As a result, an elongated dense bubble cloud growing along the acoustic axis opposite the ultrasound propagation direction is observed with the shock scattering mechanism. This shock scattering process makes the bubble cloud generation not only dependent on the peak negative pressure, but also the number of acoustic cycles and the amplitudes of the positive shocks. Without at least one intense shock front developed by nonlinear propagation, no dense bubble clouds are generated when the peak negative half-cycles are below the intrinsic threshold.

[0065] When ultrasound pulses less than 2 cycles are applied, shock scattering can be minimized, and the generation of a dense bubble cloud depends on the negative half cycle(s) of the applied ultrasound pulses exceeding an “intrinsic threshold” of the medium. This is referred to as the “intrinsic threshold mechanism”.

[0066] This threshold can be in the range of 26 - 30 MPa for soft tissues with high water content, such as tissues in the human body. In some embodiments, using this intrinsic threshold mechanism, the spatial extent of the lesion may be well-defined and more predictable. With peak negative pressures (P-) not significantly higher than this threshold, sub-wavelength reproducible lesions as small as half of the -6dB beam width of a transducer may be generated. [0067] With high-frequency Histotripsy pulses, the size of the smallest reproducible lesion becomes smaller, which is beneficial in applications that require precise lesion generation. However, high-frequency pulses are more susceptible to attenuation and aberration, rendering problematical treatments at a larger penetration depth (e.g., ablation deep in the body) or through a highly aberrative medium (e.g., transcranial procedures, or procedures in which the pulses are transmitted through bone(s)). Histotripsy may further also be applied as a low-frequency “pump” pulse (typically < 2 cycles and having a frequency between 100 kHz and 1 MHz) can be applied together with a high-frequency “probe” pulse (typically < 2 cycles and having a frequency greater than 2 MHz, or ranging between 2 MHz and 10 MHz) wherein the peak negative pressures of the low and high-frequency pulses constructively interfere to exceed the intrinsic threshold in the target tissue or medium. The low-frequency pulse, which is more resistant to attenuation and aberration, can raise the peak negative pressure P- level for a region of interest (ROI), while the high-frequency pulse, which provides more precision, can pinpoint a targeted location within the ROI and raise the peak negative pressure P- above the intrinsic threshold. This approach may be referred to as “dual frequency”, “dual beam histotripsy” or “parametric histotripsy.”

[0068] Additional systems, methods and parameters to deliver optimized histotripsy, using shock scattering, intrinsic threshold, and various parameters enabling frequency compounding and bubble manipulation, are herein included as part of the system and methods disclosed herein, including additional means of controlling said histotripsy effect as pertains to steering and positioning the focus, and concurrently managing tissue effects (e.g., prefocal thermal collateral damage) at the treatment site or within intervening tissue. Further, it is disclosed that the various systems and methods, which may include a plurality of parameters, such as but not limited to, frequency, operating frequency, center frequency, pulse repetition frequency, pulses, bursts, number of pulses, cycles, length of pulses, amplitude of pulses, pulse period, delays, burst repetition frequency, sets of the former, loops of multiple sets, loops of multiple and/or different sets, sets of loops, and various combinations or permutations of, etc., are included as a part of this disclosure, including future envisioned embodiments of such. TECHNICAL CHALLENGES WITH HISTOTRIPSY

[0069] There are two technical challenges for using ultrasound therapy such as histotripsy to treat a deep tissue target (e.g., >8 cm) or through heterogenous tissue: 1) acoustic aberration and 2) real-time feedback of the ultrasound therapy.

[0070] Acoustic aberration is a problem that impacts ultrasound therapy and imaging, including histotripsy. Acoustic aberration can reduce the focal pressure and distort the focus due to ultrasound propagation through multi-layer heterogenous tissue. Reduction of the focal pressure can cause ineffective treatment or reduced treatment efficiency. For example, in histotripsy, focal pressures at the target tissue site are precisely controlled to generate cavitation at the target tissue site. Reduction of the focal pressures due to aberration can prevent cavitation from occurring. Distortion of the focus can also decrease treatment accuracy. Typically, a focused ultrasound transducer is shaped as a segment of a spherical surface, such that the sound wave emitted from all locations from the transducer surface go through the same distance to arrive at the focus at the same time. However, due to the variation of speed of sound across bones and heterogeneous soft tissue, the travel time from different elements of an ultrasound transducer array to arrive at the focus may be different. As a result, aberration can result in loss of focal pressure and defocusing, decreasing treatment efficacy and accuracy.

[0071] As ultrasound is a non-invasive therapy technique, real-time feedback is critical to achieve high treatment accuracy and minimizing any potential complications. Ultrasound imaging has been used to provide real-time feedback for histotripsy, as histotripsy-generated cavitation can be visualized on ultrasound images as a dynamic, bright zone. Typically, an ultrasound imaging probe is inserted in a central hole of the histotripsy transducer, thus the 2D ultrasound imaging plane contains the histotripsy focus. Ultrasound imaging can then be used to guide the targeting to place histotripsy focus to the correct target tissue and to monitor the treatment progression. However, there are two main limitations of using ultrasound imaging as the sole guidance for histotripsy. 1) When the ultrasound imaging probe is blocked by bone of the patient (e.g., ribs or skull), ultrasound images of the histotripsy focus cannot be obtained.

For example, histotripsy can be used to treat a tumor volume in the liver of a patient, which is partially behind the ribcage. When the histotripsy transducer is mechanically moved to scan the histotripsy focus to cover the tumor volume, the imaging probe can be blocked by the ribs for a certain duration of the therapy, at which point no real-time imaging of the therapy is available due to the rib blockage. Without any feedback during this duration, there is no way of knowing if cavitation is still generated at the target locations in the tumor (i.e., if the treatment is implemented over this duration). 2) Ultrasound imaging probes can only view the tissue and cavitation within the 2D image plane that contains the histotripsy focus. Thus, ultrasound imaging probes cannot view any potential unwanted cavitation occurring outside the image plane. Unwanted cavitation may generate undesired off-target damage.

[0072] The problems described above can be solved with a novel histotripsy ultrasound phased array transducer, as described herein, that is configured to transmit ultrasound signals to generate cavitation and deliver histotripsy as well as is configured to receive ultrasound signals (i.e., a transmit-receive histotripsy array).

[0073] For example, when the ultrasound therapy transducer comprises a phased array, phase correction techniques can be used to correct aberration to recover reduced focal pressure. This can be accomplished by adjusting the phase/time delay at transmission from each transducer element of the phased array to compensate for the travel time variation from each array element to the focus due to the speed of sound variation. In doing so, the aberration can be corrected to increase the focal pressure and improve the focusing.

[0074] An ultrasound phased array transducer that can delivery histotripsy and receive acoustic cavitation emission signals can further be configured to allow detection, localization, and mapping of cavitation. Currently, a typical histotripsy system only transmits ultrasound pulses to generate cavitation at the focus. A transmit-receive histotripsy system can not only be used to deliver ultrasound pulses to generate cavitation, but also can receive signals such as the acoustic cavitation emission (ACE) signals. Both the rapid expansion and rapid collapse of cavitating bubbles during histotripsy produce shockwaves that can be detected by an acoustic receiver. In some embodiments, received reflections of the main therapy pulse (if > 1-2 cycles long and not fully transformed to shockwave in cavitation generation event) or subsequent low amplitude therapy pulses could be used in various receive application listed below. By processing the ACE signals received from a histotripsy transducer array system with hundreds of elements and transmit-receive capability, cavitation can be detected and localized to provide a real-time, 3D cavitation map. The acoustic emission signals from the growth and/or collapse of histotripsy-induced cavitation microbubbles, received by the histotripsy array, can be used to localize and monitor the cavitation in 3D and real-time, even in situations where the ultrasound imaging probe is blocked by bone. 3D cavitation mapping can also allow real-time monitoring of any off-focus cavitation to increase safety and identify unwanted cavitation.

[0075] Transmit-receive driving electronics found in typical phased array systems cannot be directly adapted for a histotripsy phased array transducer because of the extremely high voltages (thousands of volts) necessary for generating high-pressure histotripsy pulses. A novel driving electronics, as described herein, is configured to safely block or significantly attenuate the transmit signal to the ultrasound transducer array while maintaining high sensitivity and high dynamic range for received ultrasound signals. This disclosure provides both hardware and software for a phased array histotripsy transducer array with transmit and receive capability.

This disclosure further describes the methods and signal processing algorithms that can be used with the transmit-receive histotripsy system for aberration correction and cavitation mapping.

ELECTRONIC DRIVER TRANSMIT ARCHITECTURE

[0076] FIG. 2A shows a simplified schematic of an electronic driver 200 with the key components for ultrasound transmission. This design is a type of “current driver” system producing very short half cycle drive pulses. A digital drive signal 202 (chan_drive) coming from a controller FPGA provides an input to an isolated transistor gate driver 204 (such as SI8261AAC). For histotripsy use, the gate signal can pulse the transistor Q1 at a pulse repetition frequency (PRF) ranging from 1 Hz to 1 kHz with a gate signal pulse width for typically set between 1 usee and 5 usee. This can cause the transistor to turn on for a brief period (~l-5 usee) pulling current through the primary of the transformer Tl. Q1 then turns off forcing the built up current out to secondary side of Tl to the therapy transducer of the all-in-one ultrasound system. Varying the duration of the transistor on-time adjusts the output linearly as the current will increase linearly in the transformer assuming ideal components (dl/dt = power supply /Inductance). The inductance of the secondary winding is chosen to resonate with the capacitance of the therapy transducer such that a damped sinusoidal output would be produced at the transducer operating frequency. Optional blocking diode D1 (e.g., 1200 V rated silicon carbide material) prevents the transistor Q1 from conducting when the polarity goes negative. Removing D1 from the schematic provides shorter pulses and a lower power output. Later cycles are significantly attenuated by the electrical and mechanical loss in the transducer as well as the radiated sound giving a very short output response. Components R1 and Cl combine to slow down the turn-on and turn-off of the transistor Q1 to reduce RF noise emissions. There is a tradeoff between power efficiency and electrical noise that can be optimized with component selection. For example, if the transistor is switched off too rapidly, high frequency cable resonances can be excited which don’t contribute to useful acoustic output. Typically, Q1 is a silicon carbide based transistor (such as UF3C120150B7S) capable of switching at high speed for high power efficiency. Cl also helps prevent an arc fault on the output or other failures from causing Q1 to turn on inappropriately due to feedback through the Miller capacitance. Alternatively, a transistor gate driver other than the SI8261AAC such as the 1ED3122MC12H could be used which has an integrated Miller clamp circuit to accomplish the same function. [0077] For histotripsy use, the current driver system has a driver transformer Tl. Use of a transformer allows a step up turns ratio (1:N turns ratio) such that the transistor Q1 is not required to have as high a breakdown voltage. Suitable transistors with a rating of 1200 V or less are readily available while higher voltage rating parts are very rare. Typical ultrasound therapy transducers may require as much as 3000 V or more to perform histotripsy. Type 3 or type 14 iron powder toroid cores work extremely well for this purpose. The inductance of the secondary winding (attached to transducer) determines the drive frequency.

[0078] Capacitor C2 stores energy for the high peak power output during a histotripsy pulse. Resistor R2 isolates different channels within a phased array system to minimize cross talk and to ensure a consistent output when only a single channel is pulsed versus the full array. This resistor also limits the peak energy available to the amount stored in C2 in case of a component failure or other circuit fault on the channel. A phased array system with hundreds of channels would be at risk of an electrical fire in case of a circuit fault from the large amount of stored energy in the capacitors C2 associated with each channel. An alternate strategy to reduce this risk is to use a fuse in place of resistor R2. 100 V is usually adequate for the main power supply (channel drive voltage) while still generating pulses up to several thousand volts on the output which is the principal advantage of the current driver circuit.

[0079] For the ultrasound modes other than histotripsy, when lower pressure ultrasound at a high PRF or continuous wave (CW) is used, quasi-CW operation is possible with this driving electronics design by setting very high PRFs for the channel drive signal at lower amplitude. For example, the gate signal can be pulsed at 1 MHz pulse repetition rate (PRF) with 500 ns wide pulses to generate a 1 MHz tone burst output. Optimization for this quasi-CW mode generally needs different components than optimization for histotripsy, but a compromise system may be sufficient for both. Changes include selecting gate drive components for higher efficiency and selection of the main transistor Ql. A circuit board layout designed for forced air cooling should greatly increase output capability. Higher current power supplies could also be required. The embodiment shown here is capable of running continuously at 1 MHz and 5 W/channel output electrical power without forced air cooling. In histotripsy mode, greater than 3kV and 20 A/channel is possible with the same circuit.

[0080] FIG. 2B is a power supply switching circuit configured to provide power for a plurality of operation modes, such as histotripsy, HIFU, etc. This power supply switching circuit feeds the current driver circuits shown on FIG. 2A allowing relatively rapid switching between operation modes. Turning on transistor Ql connects the drivers to a lower voltage (+48), high current power supply and system bypass capacitor Cl for operating in CW modes. Turning on transistor Q2 instead connects the driver to a higher voltage (+100), but lower current power supply suitable for histotripsy mode. This dual supply configuration has the potential to greatly reduce the cost of the system compared to a single supply which would need to be capable of providing high voltage, high current, and adjustability. Additionally, this may allow operation of the system with only single phase 120 VAC and not requiring 220 VAC. Not shown on the simplified schematic of FIG. 2B are standard gate drive components associated with the “high side” switch configurations for Q1 and Q2. These could be SI8261AAC isolated gate drivers, for example.

ELECTRONIC DRIVER RECEIVE ARCHITECTURE

[0081] In order to use the same transducer array for transmit and receive, the digitizer must be capable of rejecting large transmit voltages and currents. A traditional transmit/receive ultrasound switch is not practical because of the very large drive voltages for histotripsy therapy. One alternative is to attenuate the signals with a capacitive divider (as used by oscilloscope probes). The disadvantage of this method is that the sensitivity becomes very low and a very large dynamic range is required. Signal-to-noise-ratio (SNR) for weak receive signals is particularly low. A limiting circuit can be used to improve resolution for small signals or a non linear gain curve, but neither can achieve the same SNR as a transmit/receive switch or receive only channel.

[0082] Another alternative is a “current receive” electronic driver 300 shown in FIG. 3. The current receive electronic driver of FIG. 3 is configured to drive transmission of ultrasound pulses through the ultrasound therapy transducer array, and is also configured to enable sensing or receive functionality of ultrasound signals with the ultrasound therapy transducer array. A current sensing resistor R1 is placed in the ground side return path from the output transformer Tl. A digitizer 302 such as AFE5801 can measure the voltage across this resistor. Because ultrasound transducers are a capacitive load and the bandwidth is relatively narrow, the current is very similar to the voltage with merely a phase shift. Ultrasound imaging transducers have very small elements that produce extremely small charge/current as receivers so this would be impractical for a typical imager. Ultrasound therapy elements, on the other hand, have thousands of times larger surface area than imaging transducers, so they can produce large currents. On transmission, peak current can be 20 A or greater while desired receive signals can be as small as a fraction of a mA.

[0083] Transmit currents can be blocked with a pair of bypass diodes in parallel with the sensing resistor Rl. This is standard practice for current measuring devices. In the embodiment of FIG. 3, however, the driver 300 uses a pair of low threshold MOSFETs (CSD16301Q2, for example) for this function (Ql, Q2). They provide a larger sense range (in the “off’ state) that better matches the input to the ADC, and a higher “on” state conductivity and switching speed all in a smaller package than any diodes. A gate driver using a bipolar power supply such as the SI8261AAC shown can force these transistors fully on or off depending on transmit/receive state for optimal performance. [0084] To further extend the dynamic range for the current receive system, the driver 300 includes two sets of sense resistors. The default higher sensitivity setting is a large resistance (e.g., 200 ohm) resistor Rl. Turning on a pair of small signal MOSFETs (Q3, Q4) switches in a smaller resistance (e.g., 5 ohm) sense resistor R2 in parallel, which reduces the gain (e.g., by approximately 32 dB with the resistances described above). This is in addition to the variable gain amplifier within the digitizer. The large resistor Rl is still a relatively low impedance so there is no change in SNR between the two ranges. A single control line could set the current range for all channels or this could potentially be on a per channel basis. This setting can be changed and the output stabilized in less than a few microseconds so the current range can be changed in the middle of a receive acquisition to reduce strong reflections or amplify portions of the trace. The digitizer can be designed for a balanced input using an RF signal transformer T2 for the best SNR and dynamic range. The transformer allows electrical isolation to be maintained between the driver output and digital electronics, but is not capable of any high voltage isolation protection. R3 limits the current of any residual transient over-voltages from the bypass circuit to prevent harm to the ADC. Cl and C2 are specified for the digitizer as the input is meant to be capacitively coupled. All the power supplies interfacing to the receive section should be low noise to achieve the best SNR (the +/- 9V supply for the gain switch and the digitizer).

MRI COMPATABILITY AND IMAGING

[0085] Other than the electronic driver, all components of the all-in-one ultrasound system are MRI compatible. Long cables can be used to connect the ultrasound array and the electronic driver, such that the ultrasound array can be placed inside an MRI scanner, and the electronic driver can be placed outside the scanner room in the control room. As such, this all-in-one ultrasound system can be used with MRI to guide and monitor the treatment.

[0086] Targeting

[0087] The all-in-one system can be guided by ultrasound imaging, MRI, or surgical navigation system.

[0088] When using MR guidance, MR thermometry and low heating can be used for targeting. For targeting, the all-in-one ultrasound system can function at the hyperthermia mode to increase the temperature in the US focal zone by 1-2°C. The MR thermometry can be used to identify and mark the focal location on the MR image.

[0089] Aberration Correction

[0090] Aberration correction can be necessary for brain treatment, due to the aberration induced by ultrasound propagation through the skull with varying thickness and different speed of sound from soft tissue. The ultrasound array can include fiducial markers that can be imaged on MRI. The MR images containing the patient’s head and the ultrasound array can then be co registered with pre-treatment imaging (e.g., CT scan of the patient head) by aligning the skull. The ultrasound array location with regard to the skull can be identified based on the MR fiducial markers on the array. Aberration correction can be performed using a ray-tracing approach based on the skull location, thickness, speed of sound, and relative location to the ultrasound array. It is also possible to use MR images to measure the skull thickness for aberration correction, without requiring pre-treatment CT head scan.

[0091] Monitoring

[0092] To monitor temperature increases in the tissue, MR thermometry can be used. To monitor cavitation, diffusion- weighted MRI can be synchronized with the ultrasound delivery to image the local movement induced by cavitation.

[0093] When using surgical navigation system to guide the treatment, the ultrasound array has transmit-and-receive capabilities, such that the cavitation emission signals can be received by each of the array element and processed to detect and map the cavitation during treatment using the computer that controls the ultrasound array. The cavitation map can be overlaid on the pre treatment 3D MR image on the surgical navigation system of the target tissue.

[0094] When using ultrasound imaging to guide the treatment, cavitation can be directly visualized on real-time ultrasound images.

METHODS OF USE

[0095] Many novel and inventive therapy methods can be implemented with the all-in-one ultrasound system described herein. Prior to this disclosure, delivery of a plurality of different ultrasound therapies and/or modalities was not possible with a single ultrasound system. The novel electronic driver and transducer arrays described herein enable this new functionality. [0096] Referring to FIG. 4, a flowchart is illustrated that includes applying a plurality of different ultrasound modalities to treat a target tissue. For example, referring to step 402 of the flowchart of FIG. 4, a target tissue can be identified. The target tissue can comprise, for example, a liver, a brain, a tumor, a prostate, etc. In some embodiments, the target tissue can be identified with real-time imaging, which can be integrated within an all-in-one ultrasound system or separate from the system.

[0097] At step 404, the method can comprise applying a first or primary ultrasound therapy modality, such as histotripsy therapy, to the target tissue with a current driver and a therapy transducer array of the all-in-one ultrasound system. As described above, the electronics driver of the all-in-one system can be configured to deliver a plurality of user- selectable ultrasound modalities to a target tissue with a single or the same ultrasound therapy transducer array. The modalities can include, in addition to histotripsy, HIFU, Hyperthermia/radio-sensitization, microbubble-enhanced drug delivery, immunotherapy, sonodynamic therapy, and/or neuromodulation. While method step 404 is described and illustrated as providing histotripsy as the primary ultrasound therapy modality, it is merely optional that the primary ultrasound modality provided by the all-in-one system be histotripsy. In other embodiments, the primary ultrasound therapy modality can comprise any other ultrasound modality supported by the current driver, including, for example, HIFU, Hyperthermia/radio-sensitization, microbubble- enhanced drug delivery, immunotherapy, sonodynamic therapy, and/or neuromodulation.

[0098] Next, at step 406, the method can include selecting a second or different ultrasound modality in the all-in-one ultrasound system. As described above, if the first or primary ultrasound therapy modality comprises histotripsy, the second or different ultrasound modality can include Hyperthermia/radio-sensitization, microbubble-enhanced drug delivery, immunotherapy, sonodynamic therapy, and/or neuromodulation. In embodiments where the first ultrasound therapy modality is not histotripsy, then the second or different ultrasound therapy modality can comprise histotripsy.

[0099] Finally, at step 408, the method can comprise applying the different ultrasound modality to the target tissue with the current driver and the ultrasound therapy transducer array of the all-in-one ultrasound system.

[0100] For example, histotripsy can be used with drug delivery or sonodynamic therapy, such that histotripsy is used debulk the core tumor, while ultrasound drug delivery or sonodynamic therapy is used at the tumor periphery to treat the diffused tumor cells. Histotripsy or ultrasound drug delivery can also be combined with ultrasound immunotherapy, such that histotripsy or ultrasound drug delivery is used to treat the local tumor, while ultrasound immunotherapy is used to treat distant tumors.

[0101] As for additional details pertinent to the present invention, materials and manufacturing techniques may be employed as within the level of those with skill in the relevant art. The same may hold true with respect to method-based aspects of the invention in terms of additional acts commonly or logically employed. Also, it is contemplated that any optional feature of the inventive variations described may be set forth and claimed independently, or in combination with any one or more of the features described herein. Likewise, reference to a singular item, includes the possibility that there are plural of the same items present. More specifically, as used herein and in the appended claims, the singular forms "a," "and," "said," and "the" include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely," "only" and the like in connection with the recitation of claim elements, or use of a "negative" limitation. Unless defined otherwise herein, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The breadth of the present invention is not to be limited by the subject specification, but rather only by the plain meaning of the claim terms employed.