Spatial and temporal real-time monitoring of histotripsy dose delivery damage

Abstract

A histotripsy therapy system configured for tissue treatment, which may include any number of features, is provided. Systems and methods providing effective, non-invasive and minimally invasive therapeutic, diagnostic, and research procedures are provided herein. Systems and methods are provided to facilitate real-time monitoring of delivered dose and tissue dissection. Techniques may include monitoring received acoustic cavitation emission signals or using dMRI.

Description

[Technical Field]

[0001] Priority Claim

[0001] This patent application claims priority to U.S. Provisional Patent Application No. 63 / 493,886, filed on April 3, 2023, entitled "REAL-TIME MONITORING OF HISTOTRIPSY DOSE DELIVERY DAMAGE SPATIALLY AND TEMPORALLY", U.S. Provisional Patent Application No. 63 / 493,889, filed on April 3, 2023, entitled "HISTOTRIPSY SYSTEMS AND METHODS FOR SELECTIVE ABLATION OF WHITE MATTER IN THE BRAIN", and U.S. Provisional Patent Application No. 63 / 493,891, filed on April 3, 2023, entitled "HISTOTRIPSY SYSTEMS AND METHODS FOR FAT REDUCTION", each of which is incorporated herein by reference as a whole.

[0002] Embedding by reference

[0002] All publications and patent applications referenced herein are incorporated herein by reference to the same extent as each individual publication or patent application is specifically and individually indicated to be incorporated by reference.

[0003] Description of research funded by the federal government.

[0003] The present invention was made with government support under grant numbers R01-EB032772, R01-EB028309, and R01-CA211217, awarded by the National Institutes of Health, USA. The government has specific rights to the present invention.

[0004]

[0004] This disclosure details novel high-intensity therapeutic ultrasound (HITU) systems configured to produce acoustic cavitation, methods, devices, and procedures for minimally invasive and non-invasive treatment of healthy, diseased, and / or injured tissue. The acoustic cavitation systems and methods described herein, also known as histotripsy, may include transducers, drive electronics, positioning robotics, imaging systems, and integrated treatment planning and control software for performing comprehensive treatment and therapy of a patient's soft tissue. [Background technology]

[0005]

[0005] Histotripsy or pulsed ultrasonic cavitation therapy is a technique in which extremely short, powerful bursts of acoustic energy induce controlled cavitation (microbubble formation) within a focal volume. The violent expansion and collapse of these microbubbles mechanically homogenize the cellular and tissue structures within the focal volume. This is a very different end result from the coagulation necrosis characteristics of thermal delamination. To operate within the non-thermal histotripsy region, it is necessary to deliver the acoustic energy in the form of high-amplitude acoustic pulses with a low duty cycle.

[0006]

[0006] Compared to conventional focused ultrasound techniques, histotripsy has several key advantages: 1) the destructive process at the focus is mechanical and not thermal; 2) cavitation appears bright on ultrasound imaging, thereby confirming correct targeting and localization of treatment; 3) the treated tissue appears darker (less echogenic) on ultrasound imaging, not always but generally, so that the operator can see what has been treated; and 4) histotripsy presents lesions in a controlled and precise manner. It is important to emphasize that, unlike thermal dissection techniques such as microwave, radio frequency, high-intensity focused ultrasound (HIFU), cryo, or radiation, histotripsy relies on the mechanical action of cavitation for tissue destruction and does not rely on heat, cold, or ionizing energy. [Overview of the Initiative] [Problems that the invention aims to solve]

[0007]

[0007] A method is provided for using a transmission-receiving histotripsy system for histotripsy therapy monitoring, comprising the steps of: transmitting a high-voltage histotripsy therapy pulse to a focal location in target tissue using a transmission electronic device and a histotripsy therapy transducer array to generate cavitation at a focal location; receiving a low-voltage acoustic cavitation emission (ACE) signal from the cavitation using a reception electronic device and a histotripsy therapy transducer array; processing the received ACE signal to identify the cavitation lifespan of the cavitation at the focal location; and identifying a stagnation period in the cavitation lifespan to determine that complete cellular unsustainability has occurred at the focal location. [Means for solving the problem]

[0008] In one aspect, the method further includes generating in real time a 3D map of the cavitation created by the transmitted pulse.

[0009] In one aspect, identifying a quiescent period includes identifying the time until the cavitation life span enters the quiescent period.

[0009]

[0010] In other aspects, identifying a quiescent period includes identifying the number of pulses until the cavitation life span enters the quiescent period.

[0011] In one aspect, identifying a quiescent period includes identifying when the cavitation life span stops increasing.

[0010]

[0012] In one aspect, the method includes automatically stopping transmission of the high voltage histotripsy therapy pulse when it is determined that complete cell viability loss has occurred at the focal location.

[0013] In one aspect, the method includes providing an indication to the user that complete cell viability loss has occurred at the focal location.

[0011]

[0014] In one aspect, the indication includes an audible warning.

[0015] In other aspects, the indication includes a visual warning.

[0016] An ultrasonic transducer array, a transmission electronic device connected to the ultrasonic transducer array and configured to transmit one or more histotripsy pulses to one or more focal locations to generate cavitation in a target tissue, a reception electronic device configured to receive acoustic cavitation emissions (ACE) from the cavitation, and one or more processors operatively connected to the transmission and reception electronic devices, the one or more processors being configured to process the received ACE signal to identify the cavitation life span of the cavitation at the focal location and further configured to identify a stagnation period during the cavitation life span to determine that complete cell non-viability has occurred at the focal location, a histotripsy system is provided.

[0012]

[0017] In some embodiments, the one or more processors are further configured to generate in real time a 3D map of the cavitation created by the transmitted pulses.

[0018] In one embodiment, the system includes a display configured to display the 3D map.

[0013]

[0019] In some embodiments, the one or more processors are configured to identify the stagnation period by identifying the time until the cavitation life span enters the stagnation period.

[0014]

[0020] In other embodiments, the one or more processors are configured to identify the stagnation period by identifying the number of pulses until the cavitation life span enters the stagnation period.

[0015]

[0021] In some embodiments, the one or more processors are configured to identify the stagnation period by identifying when the cavitation life span stops increasing.

[0022] In one embodiment, one or more processors are configured to stop delivering high-voltage histotripsy therapy pulses when they determine that complete cellular unsustainability has occurred at a focal location.

[0016]

[0023] In some embodiments, one or more processors are configured to provide an instruction to the user that complete cellular unsustainability has occurred at a focus location.

[0024] In one aspect, the instructions include an audible warning.

[0017]

[0025] In other embodiments, instructions include visual warnings.

[0026] A method for monitoring histotripsy therapy is provided, comprising the steps of: delivering high-voltage histotripsy therapy pulses to focal locations in target tissue using a transmission electronic device and a histotripsy therapy transducer array to generate cavitation at one or more focal locations; acquiring periodic diffusion-weighted magnetic resonance imaging (dMRI) images of one or more focal locations in the target tissue; processing the dMRI images to identify apparent diffusion coefficients (ADCs) at one or more focal locations in the target tissue; and generating an ADC map that conveys the dose of histotripsy therapy received at each of the one or more focal locations in the target tissue.

[0018]

[0027] In one embodiment, the method includes displaying an ADC map.

[0028] In other embodiments, the method includes indicating that the increased ADC in the target tissue has received an increased histotripsy dose.

[0019]

[0029] In some embodiments, the method includes identifying complete cellular instability at one or more focal locations in the target tissue.

[0030] A histotripsy system is provided, comprising: an ultrasound transducer array; a transmission electronic device connected to the ultrasound transducer array and configured to deliver one or more histotripsy pulses to one or more focal locations to generate cavitation in target tissue; a magnetic resonance imaging (MRI) system configured to periodically acquire diffusion-weighted magnetic resonance imaging (dMRI) images of one or more focal locations in target tissue; and one or more processors operationally coupled to the transmission electronic device and the MRI system, configured to process the dMRI images to identify apparent diffusion coefficients (ADCs) at one or more focal locations in target tissue, and further configured to generate ADC maps that convey the dose of histotripsy therapy received at each of the one or more focal locations in target tissue.

[0020]

[0031] In some embodiments, the system includes a display configured to show an ADC map.

[0032] In one aspect, increased ADC in the target tissue indicates that it received an increased histotripsy dose.

[0021]

[0033] In another embodiment, the system is configured to identify complete cellular instability at one or more focal locations in the target tissue.

[0034] A method is provided for using a transmission-receive histotripsy system for tissue type detection, comprising the steps of: transmitting a high-voltage histotripsy therapy pulse to one or more focal locations within a target tissue using a transmission electronic device and a histotripsy therapy transducer array to generate cavitation in the target tissue; receiving a low-voltage acoustic cavitation emission (ACE) signal from the cavitation using a reception electronic device and a histotripsy therapy transducer array; processing the received acoustic cavitation emission signal to identify features relating to the tissue type; and determining, based on the identified features, that a first tissue at a first focal location has a different tissue type from a second tissue at a second focal location.

[0022]

[0035] In one embodiment, the method includes generating a 3D map of the cavitation produced by the transmitted pulse in real time.

[0036] In some embodiments, the identified features include the maximum cavitation lifespan at each of one or more focal locations.

[0023]

[0037] In one aspect, the identified features include the time until the cavitation lifespan enters a plateau phase.

[0038] In some embodiments, the identified features include the number of pulses until the cavitation lifespan enters a plateau phase.

[0024]

[0039] In other embodiments, the maximum cavitation lifespan at the first focal location is considerably smaller than the maximum cavitation lifespan at the second focal location.

[0025]

[0040] In one embodiment, the maximum cavitation lifespan at the first focal location is 2 to 3 times smaller than the maximum cavitation lifespan at the second focal location.

[0026]

[0041] In some embodiments, the method includes determining that the first tissue includes fibrous tissue and the second tissue includes cellular tissue.

[0042] A histotripsy method is provided, comprising: transmitting a histotripsy pulse to a first focal location using a transmission-receiving histotripsy transducer array to generate cavitation; receiving an ACE signal from the first focal location using a transmission-receiving histotripsy transducer; identifying a first maximum cavitation lifespan at the first focal location; mechanically or electronically steering a histotripsy therapy transducer array from the first focal location to a second focal location; transmitting a histotripsy pulse to a second focal location using a transmission-receiving histotripsy transducer array to generate cavitation; receiving an ACE signal from the second focal location using a transmission-receiving histotripsy transducer; identifying a second maximum cavitation lifespan at the second focal location; and comparing the first maximum cavitation lifespan to the second maximum cavitation lifespan to determine whether the second focal location is located in a different tissue type than the first focal location.

[0027]

[0043] In some embodiments, the method includes determining that the second focal location is in a different tissue type if the second maximum cavitation lifespan is considerably different from the first maximum cavitation lifespan.

[0028]

[0044] In one embodiment, the method includes determining that the second focal location is of a different tissue type if the maximum cavitation lifespan at the first focal location is 2 to 3 times smaller than the maximum cavitation lifespan at the second focal location.

[0029]

[0045] In some embodiments, the method includes determining that the second focal location is of a different tissue type if the maximum cavitation lifespan at the first focal location is 2 to 3 times greater than the maximum cavitation lifespan at the second focal location.

[0030]

[0046] The present invention provides a histotripsy method comprising: transmitting a histotripsy test pulse to one or more test locations within a target tissue using a transmission electronic device and a histotripsy therapy transducer array to generate cavitation in the target tissue; receiving low-voltage acoustic cavitation emission (ACE) signals from the cavitation at each of the one or more test locations using a reception electronic device and a histotripsy therapy transducer array; processing the received acoustic cavitation emission signals to determine the tissue type at one or more test locations; and modifying the histotripsy treatment plan based on the tissue type determination to deliver histotripsy therapy to one or more focal locations within the tissue type to be treated and to avoid delivering histotripsy pulses to any locations within the tissue type not to be treated.

[0031]

[0047] The present invention provides a histotripsy system transmission-receiver drive electronics comprising: an ultrasonic transducer array; a transmission electronics unit connected to the ultrasonic transducer array and configured to transmit one or more histotripsy pulses to one or more focal locations to generate cavitation in target tissue; a receiving electronics unit configured to receive acoustic cavitation emissions (ACE) from the cavitation; and one or more processors operationally coupled to the transmission and receive electronics unit, each processor configured to process the received ACE signals to identify tissue type features and determine the tissue type at one or more focal locations based on the identified features.

[0032]

[0048] The present invention provides a histotripsy method comprising acoustically coupling a histotripsy therapy transducer to the skin of a subject, positioning the focus of the histotripsy therapy transducer within the subcutaneous fat layer, and delivering histotripsy pulses at a peak negative pressure greater than 14 MPa and less than 26 MPa to non-invasively and selectively liquefy the fat rather than the surrounding tissue.

[0033]

[0049] The novel features of the present invention are described in detail in the claims that follow. A better understanding of the features and advantages of the present invention will be obtained from the following detailed description and reference to the accompanying drawings, which illustrate exemplary embodiments in which the principles of the present invention are utilized. [Brief explanation of the drawing]

[0034] [Figure 1A]

[0050] This is a diagram of an ultrasound imaging and therapy system. [Figure 1B] This is a diagram of an ultrasound imaging and therapy system. [Figure 2]

[0051] This is a system diagram showing a histotripsy therapy system including a therapy cart, a fluid mechanics cart, and a coupling system. [Figure 3A]

[0052] This is a diagram of various drive and receive electronic components to enable a transmit-receive transducer array. [Figure 3B] This is a diagram of various drive and receive electronic components to enable a transmit-receive transducer array. [Figure 3C] This is a diagram of various drive and receive electronic components to enable a transmit-receive transducer array. [Figure 3D] This is a diagram of various drive and receive electronic components to enable a transmit-receive transducer array. [Figure 4A] This is a diagram of various drive and receive electronic components to enable a transmit-receive transducer array. [Figure 4B]This is a diagram of various drive and receive electronic components to enable a transmit-receive transducer array. [Figure 4C] This is a diagram of various drive and receive electronic components to enable a transmit-receive transducer array. [Figure 5]

[0053] Figure 5A shows the cavitation lifespan measured from ACE in brain tissue against the number of histotripsi pulses and their location within the tissue. Figure 5B shows the cavitation lifespan measured from ACE in brain tissue against the number of histotripsi pulses and their location within the tissue. [Figure 6]

[0054] Figure 6A shows an example of measuring the ACE signal generated from cavitation in brain tissue. Figure 6B shows an example of measuring the ACE signal generated from cavitation in brain tissue. [Figure 7]

[0055] This diagram illustrates a method for determining the tissue type at a focal location using ACE signals. [Figure 8]

[0056] Figure 8A shows the probability data and fitted curves for cavitation generation with various sample types. Figure 8B shows the probability data and fitted curves for cavitation generation with various sample types. Figure 8C shows the probability data and fitted curves for cavitation generation with various sample types. Figure 8D shows the probability data and fitted curves for cavitation generation with various sample types. Figure 8E shows the probability data and fitted curves for cavitation generation with various sample types. Figure 8F shows the probability data and fitted curves for cavitation generation with various sample types. [Figure 9]

[0057] This is a diagram illustrating a technique for selectively dissecting adipose tissue using histotripsy. [Figure 10]

[0058] This is a flowchart for selectively dissecting adipose tissue using histotripsy. [Figure 11]

[0059] Figure 11A shows dMRI images of histotripsy lesions in tissues using different doses, and the resulting increase in ΔADC values ​​as the histotripsy dose increases. Figure 11B shows dMRI images of histotripsy lesions in tissues using different doses, and the resulting increase in ΔADC values ​​as the histotripsy dose increases. [Figure 12]

[0060] This is a flowchart for generating an ADC map of tissue treated with histotripsy. [Figure 13]

[0061] This is a diagram of a fluid engineering system for delivering a connecting medium to a connecting container. [Modes for carrying out the invention]

[0035]

[0062] The systems, methods, and devices of this disclosure may be used for non-invasive acoustic cavitation in extracorporeal, endoscopic, or fully percutaneous, surgical, minimally invasive (laparoscopic and percutaneous), robotic surgery (integrated into robotically capable medical systems), endoscopic, or fully percutaneous, for the treatment of healthy, diseased, and / or damaged tissue, including but not limited to tissue destruction, cutting, skeletonizing, and dissection. Furthermore, due to its tissue selectivity, histotripsy may be used to create a cytoskeleton that enables subsequent tissue regeneration through the application of new or stem cells and other auxiliary means. Finally, histotripsy may be used to induce the release of delivered agents, such as chemotherapy and immunotherapy, by locally inducing the release of these agents by applying acoustic energy to a target. As described below, acoustic cavitation systems may include a variety of subsystems, including carts, therapy, integrated imaging, robotics, coupling, and software. The system may also comprise a variety of other components, auxiliary devices, and accessories, including but not limited to computers, cables and connectors, networking devices, power supplies, displays, drawers / storage, doors, wheels, and various simulation and training tools. All systems, methods, and means for producing / controlling / implementing histotripsy, including any new related inventions disclosed herein, are considered part of this disclosure.

[0036]

[0063] Figure 1A illustrates the histotripsy system 100 according to this disclosure as a whole, comprising a therapeutic transducer 102, an imaging system 104, a display and control panel 106, a robotic positioning arm 108, and a cart 110. The system may further include an ultrasonic coupling interface and a source of coupling medium, which are not shown.

[0037]

[0064] Figure 1B is a bottom view of the therapy transducer 102 and the imaging system 104. As shown, the imaging system can be positioned at the center of the therapy transducer. Nevertheless, other embodiments may include imaging systems positioned at other locations within the therapy transducer, or possibly directly integrated with the therapy transducer. In some embodiments, the imaging system is configured to produce real-time imaging at the focus of the therapy transducer. The system also allows multiple imaging transducers to be placed within the therapy transducer to provide multiple views of the target tissue simultaneously and integrate these images into a single 3D image.

[0038]

[0065] The histotripsy system may comprise one or more of various subsystems, including a therapeutic subsystem capable of generating, applying, focusing, and performing acoustic cavitation / histtripsy through one or more therapeutic transducers; an integrated imaging subsystem (or connection thereto) enabling real-time visualization of the treatment site and histotripsy effect throughout the procedure; a robotics positioning subsystem for mechanically and / or electronically steering the therapeutic transducers, which may further be capable of connecting to / supporting or interacting with a coupling subsystem to enable acoustic linkage between the therapeutic transducers and the patient; a system and computer-based control system (and other external systems); and software for communicating with, controlling, and interfaceing with various other components, assistive devices and accessories, including one or more user interfaces and displays and associated induction workflows, all of which function partially or together. The system may further comprise various fluid engineering and fluid management components, including pumps, valves and flow control, temperature and degassing control, and without limitation, water injection and suction capabilities, as well as supplying and storing fluids. The system may also comprise various power supplies and protective devices.

[0039]

[0066] As described above, the histotripsy system may include integrated imaging. However, in other embodiments, the histotripsy system may be configured to interface with a separate imaging system such as a C-arm, fluoroscope, cone-beam CT, or MRI to provide real-time imaging during histotripsy therapy. In some embodiments, the histotripsy system may be made to be sized to fit inside a C-arm, fluoroscope, cone-beam CT, or MRI, and may be configured to fit inside such a system.

[0040] cart

[0067] The cart 110 can be configured as a whole in various schemes and form factors based on specific intended use and procedures. In some cases, the system may comprise a number of carts configured in similar or different arrangements. In some embodiments, the carts may be configured and arranged for use in a radiological environment, and optionally in conjunction with imaging (e.g., CT, cone-beam CT and / or MRI scans). In other embodiments, the carts may be arranged for use in operating rooms and sterile environments for invasive or laparoscopic and endoscopic applications, or in robot-enabled operating rooms, and may be used alone or as part of a surgical robot procedure in which the surgical robot performs specific tasks before, during, or after the use of the system and the implementation of acoustic cavitation / histotomy. Accordingly, and depending on the procedure environment based on the embodiments described above, the carts may be positioned to provide ample workspace and access to various anatomical locations of the patient (e.g., torso, abdomen, flanks, head and neck, etc.), as well as to provide workspace for other systems (e.g., anesthesia carts, laparoscopic towers, surgical robots, endoscopic towers, etc.).

[0041]

[0068] The cart may also work with the patient's surface (e.g., a table or bed) to allow the patient to be presented and repositioned in a great many positions, angles, and orientations, including allowing changes to be made pre-operative, perioperative, and post-operative. The cart may further have 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, optics, ultrasound, and image fusion and / or image flow of one or more modalities, and to support a procedure and / or usage environment, including physical / mechanical interoperability (e.g., compatibility within a cone-beam CT workspace for collecting pre-histotripsy, pre- and post-histotripsy, and / or post-histotripsy imaging data), and to provide access to and display of patient medical data, including but not limited to laboratory and historical medical record data.

[0042]

[0069] In some embodiments, one or more carts may be configured to operate together. For example, one cart may comprise a bedside mobile cart equipped with one or more robotic arms corresponding to a therapy transducer and a therapy generator / amplifier, while companion carts operating with and away from the patient may comprise integrated imaging and console / display for controlling robots and therapy facets similar to surgical robots and master / slave configurations.

[0043]

[0070] In some embodiments, the system may comprise multiple carts, all slaves to one master cart, each equipped to perform acoustic cavitation procedures. In some arrangements and in some cases, one cart configuration may allow for the storage of specific subsystems at a distance that reduces the disruption of the operating room, while another cooperating cart may essentially house bedside subsystems and components (e.g., implementation systems and therapies).

[0044]

[0071] A great many sorting and configurations of cart designs can be envisioned, and these examples do not limit the scope of this disclosure. histotripsy

[0072] Histotripsy employs short, high-amplitude, focused ultrasonic pulses to generate a dense, active “bubble cloud” capable of targeted tissue division and destruction. Histotripsy has the ability to produce controlled tissue erosion when directed at tissue interfaces, including tissue / fluid interfaces, as well as well-bounded tissue division and destruction at subcellular levels when histotripsy targets large amounts of tissue. Unlike other forms of dissection, including thermal and radiation-based modalities, histotripsy does not rely on heat, cold, or ionizing (high) energy to treat tissue. Instead, histotripsy uses acoustic cavitation generated at the focus to mechanically influence tissue structure, potentially causing the tissue to liquefy, float, dissolve, and / or break down into subcellular components.

[0045]

[0073] Histotripsy can be applied in various forms, including: 1) Intrinsic threshold histotripsy: A pulse is delivered with a high amplitude inverse / extension phase pressure of 1-2 periods that exceeds the intrinsic threshold for cavitation in the medium (e.g., approximately 24-28 MPa for aqueous soft tissue). 2) Shock scattering histotripsy: A pulse of 3-20 periods is typically delivered within the duration. The shock waves (positive / compression phase) scattered from the initial individual microbubbles generated form inverse shock waves that structurally interfere with the incoming inverse / extension phase, forming a high amplitude inverse / dilute phase that exceeds the intrinsic threshold. In this way, a cluster of cavitating microbubbles is generated. The amplitude of the extension phase of the pulse 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 invert the incident wave and scatter the incident shock wave that structurally interferes with the incident wave, exceeding the threshold for intrinsic nucleation. 3) Boiling histotripsy: A pulse of approximately 1–20 ms is employed during the duration. The absorption of the impacted pulse rapidly heats the medium, thereby lowering the threshold of the intrinsic nucleus. When this intrinsic threshold coincides with the peak negative pressure of the incident wave, boiling bubbles are generated at the focus.

[0046]

[0074] The high pressure generated at the focus creates a cloud of acoustic cavitation bubbles exceeding a certain threshold, causing localized stress and tension within the tissue, as well as mechanical collapse without significant heat accumulation. At pressure levels where cavitation is not generated, minimal effects are observed in the tissue at the focus. This cavitation effect is only observed at pressure levels significantly higher than those defining the inertial cavitation threshold in water for similar pulse durations, with peak negative pressures of approximately 10 to 30 MPa.

[0047]

[0075] Histotripsy can be performed in numerous ways and under different parameters. Histotripsy can be performed entirely non-invasively by acoustically coupling a focused ultrasound transducer to the patient's skin and delivering acoustic pulses through the skin to the focal zone (treatment zone and site) through the tissues above (and intervening) it. While the application of histotripsy is not limited to percutaneous approaches, it can be applied through any means that allows contact of the transducer with tissue, including percutaneous and robotically bridging surgical procedures between open surgery and laparoscopic surgery. Assuming that the bubble cloud generated by histotripsy can be visible as a highly dynamic echo region on B-mode ultrasound images, for example, enabling continuous visualization through its use (and associated procedures), it can be further targeted, planned, directed and observed under direct visualization via ultrasound imaging. Similarly, treated and dissected tissues exhibit dynamic changes (typically reductions) in echoes that can be used to evaluate, plan, observe and monitor the treatment.

[0048]

[0076] Generally, in histotripsy therapy, an ultrasonic pulse with one or more acoustic periods is applied, and bubble cloud formation depends on the pressure-release scattering (sometimes exceeding 100 MPa, P+) of the positive shock wavefront from the initially initiated, slightly dispersed bubbles (or a single bubble). This is called the "shock scattering mechanism."

[0049]

[0077] This mechanism relies on one (or several slightly dispersed) bubbles initiated in the initial negative half-period of the pulse at the transducer's focus. Then, a cloud of microbubbles is generated by the pressure-releasing backscattering of the high-peak positive shock wavefront from these slightly initiated bubbles. These backscattered high-amplitude tenuous waves exceed the intrinsic threshold, thus creating a localized, high-density bubble cloud. Each subsequent acoustic period then induces further cavitation through backscattering from the surface of the bubble cloud, which grows toward the transducer. As a result, a stretched, high-density bubble cloud, growing along the acoustic axis opposite to the direction of ultrasonic propagation, is observed in the shock scattering mechanism. This shock scattering process makes bubble cloud generation dependent not only on the peak negative pressure but also on the number of acoustic periods and the amplitude of the positive shock. Without at least one strong shock wavefront induced by nonlinear propagation, a high-density bubble cloud would not be generated when the negative half-period of the peak falls below the intrinsic threshold.

[0050]

[0078] When ultrasonic pulses of less than two cycles are applied, shock scattering can be minimized, and the formation of high-density bubble clouds depends on the negative half-cycle of the applied ultrasonic pulse that exceeds the "intrinsic threshold" of the medium. This is called the "intrinsic threshold mechanism."

[0051]

[0079] This threshold can be in the range of 26-30 MPa for soft tissues with high water content, such as human tissue. In some embodiments, using this intrinsic threshold mechanism can make the spatial extent of lesions well-defined and more predictable. At peak negative pressures (P-) not significantly higher than this threshold, subwavelength reproducible lesions can be generated that are only about half the size of the transducer's -6 dB beamwidth.

[0052]

[0080] Using high-frequency histotripsi pulses results in smaller minimum reproducible lesion sizes, which is beneficial for applications requiring precise lesion generation. However, high-frequency pulses are more susceptible to attenuation and aberrations, making treatment at greater penetration depths (e.g., deep tissue dissection) or through highly aberration-prone media (e.g., transcranial procedures or procedures where pulses are transmitted through bone) uncertain. Furthermore, histotripsi can be applied in conjunction with low-frequency "pump" pulses (typically <2 periods and having frequencies between 100 kHz and 1 MHz) and high-frequency "probe" pulses (typically <2 periods and having frequencies greater than 2 MHz or extending between 2 MHz and 10 MHz), and the peak negative pressures of the low and high-frequency pulses structurally interfere to exceed the intrinsic threshold of the target tissue or medium. Low-frequency pulses, which are tolerant of attenuation and aberrations, can raise the peak negative pressure (P-) level in a region of interest (ROI), while high-frequency pulses, which offer higher precision, can precisely pinpoint target locations within the ROI and raise the peak negative pressure (P-) above the intrinsic threshold. This approach is sometimes called "dual-frequency," "dual-beam histotripsy," or "parametric histotripsy."

[0053]

[0081] Additional systems, methods, and parameters for performing optimized histotripsy using various parameters enabling impact scattering, intrinsic thresholds, and frequency compounding and bubble manipulation are included herein as part of the systems and methods disclosed herein, including additional means for controlling the histotripsy effect such as those relating to steering and positioning the focus and simultaneously managing tissue effects (e.g., constant-focus thermal incidental injury) at or within the treatment site. Furthermore, various systems and methods that may include multiple parameters such as, but not limited to, frequency, operating frequency, center frequency, pulse repetition frequency, pulse, burst, number of pulses, period, pulse length, pulse amplitude, pulse duration, delay, burst repetition frequency, set of the former, loops of many sets, loops of many and / or different sets, sets of loops, and various combinations or arrangements thereof are included herein as part of the disclosure, including future conceivable embodiments thereof.

[0054] Therapeutic components

[0082] The therapeutic subsystem can operate in conjunction with other subsystems to produce, optimize, deliver, visualize, monitor, and control acoustic cavitation, also referred herein and hereafter as “histtripsy” and its derivatives, including boiling histotripsy and other high-frequency ultrasonic approaches to heat. It is noted that the inventions of the disclosure may also further benefit from other acoustic therapies that do not involve cavitation, mechanical, or histotripsy components. Among other features, the therapeutic subsystem may include an ultrasonic therapeutic transducer and pulse generator system configured to deliver ultrasonic pulses to tissue. The pulse generator can be incorporated into a therapeutic cart, for example, within cart 110 in Figure 1A.

[0055]

[0083] To produce and deliver histotripsy and histotripsy derivatives, the therapeutic subsystem may also include components including, but not limited to, one or more function generators, amplifiers, therapeutic transducers, and power supplies.

[0056]

[0084] Therapeutic transducers can comprise a single or multiple elements configured to be excited by high-amplitude electrical pulses (>1000V, or any other voltage that may be harmful to the body). The amplitude required to drive the therapeutic transducer for histotripsy varies depending on the transducer design, the material used (e.g., solid or polymer / piezoelectric composites including ceramic or single crystals), and the transducer center frequency, which is directly proportional to the thickness of the piezoelectric material. Thus, a transducer operating at high frequencies requires a lower voltage to produce a given surface pressure than a low-frequency therapeutic transducer. In some embodiments, the transducer elements are formed using piezoelectric polymer composite materials or solid piezoelectric materials. Furthermore, the piezoelectric material can be of polycrystalline / ceramic or single-crystal components. In some embodiments, the transducer elements can be formed using silicon using MEM techniques, including CMUT and PMUT designs.

[0057]

[0085] In some embodiments, the function generator may include a field-programmable gate array (FPGA) or other suitable function generator. The FPGA may consist of parameters previously disclosed herein, including but not limited to frequency, pulse repetition frequency, burst, and number of bursts, where a burst may include pulses, number of pulses, pulse length, pulse duration, delay, burst repetition frequency, or duration; a set of bursts may include a parameter set; a loop set may include various parameter sets with or without delays, and various time delays, and independently controlled, and a number of loop sets of various combinations and sorts of such as, and throughout, may be repeated and / or new loop sets may be introduced.

[0058]

[0086] In some embodiments, the generator or amplifier may be a general-purpose single-period or multi-period pulse generator and may be configured to support driving via Class D or inductive drive and across all conceivable clinical applications and operating environments, which will be discussed in part later in this disclosure. In other embodiments, the Class D or inductive current driver may be configured to further provide step-up / down components and, optionally, preferably, enable amplitude step-up, a transducer and / or automatic transducer drive circuit. These may also have inherent protective features to further support the system and provide the ability to protect other components of the system (e.g., therapeutic transducers and / or amplifier circuit components) and / or the user from a variety of threats, including but not limited to electrical safety threats that may potentially lead to the operating environment, the system and the therapeutic system, and harm, adverse effects or problems to the user.

[0059]

[0087] The disclosed generator may enable and support the ability of the system to select, vary, and control a variety of parameters (through an effective software tool), including but not limited to those previously disclosed, as well as the ability to start / stop therapy, set and read voltage levels, pulse and / or burst repetition frequencies, number of cycles, duty cycle, effective channels and delays, modulate pulse amplitude on a fast time scale independent of the high voltage source, and / or perform other services, diagnostic or therapeutic features.

[0060]

[0088] In some embodiments, the therapeutic subsystem and / or its components, such as amplifiers, may have further integrated computer processing capabilities and may be networked, connected, accessible, and / or removable / portable, modular, and / or interchangeable between systems, and / or driven / commanded by / by other systems, or in various combinations. Other systems may include other acoustic cavitation / histtripsy, HIFU, HITU, radiotherapy, radio frequency, microwave, and cryoablation systems, navigation and positioning systems, invasive surgery, laparoscopy, single-incision / single-port, endoscopic and non-invasive surgical robots, laparoscopy or surgical towers with other energy-based or vision systems, surgical system racks or booms, imaging carts, and the like.

[0061]

[0089] In some embodiments, one or more amplifiers may comprise a Class D amplifier and associated drive circuit equipment including a matching network component. Depending on the electrical impedance of the transducer element and the selection of the matching network component (e.g., an LC circuit made from a series inductor L1 and a parallel capacitor C1), the combined impedance can be set aggressively low 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 transistor, the matching network component or inductor, and the transducer or autotransformer, and may typically be in the low kV range (e.g., 1–3kV).

[0062]

[0090] Therapeutic transducer elements are excited with an electrical waveform having an amplitude (voltage) sufficient to produce a pressure output for histotripsy therapy. The excitation field can be defined as the required waveform voltage per unit thickness of the piezoelectric element. For example, a piezoelectric element operating at 1 MHz is half the thickness of an equivalent 500 kHz element, so it will require half the voltage to achieve the same electric field and surface pressure.

[0063]

[0091] The therapy subsystem may also include therapy transducers of various designs and working parameters to support use in various procedures (and procedures in various settings). The system may consist of one or more therapy transducers, one or more of which may be further interchangeable and can operate with various aspects of the system in similar or different ways (for example, they may interface with a robotic arm using common interfaces and interchangeable features, or conversely, be adapted to operate with application-specific imaging probes, each of which may interface with and integrate with therapy transducers in a specifically different way).

[0064]

[0092] Therapeutic transducers can consist of various parameters, including size, shape (e.g., rectangular or circular, anatomically curved housing, etc.), geometric shape, focal length, number of elements, size of elements, distribution of elements (e.g., number of rings and ring size in annular pattern transducers), frequency, and electron beam steering that enables them. Transducers can be made from various materials (e.g., piezoelectric, silicon, etc.), form factors and types (e.g., machined elements, chip-based, etc.), and / or by various methods of their manufacture.

[0065]

[0093] Transducers can be designed and optimized for clinical applications (e.g., abdominal tumors, peripheral vascular diseases, fat removal, etc.) and desired outcomes (e.g., acoustic cavitation / histotolypse without burns to interstitial tissues), as well as to provide a broad range of applications including relatively shallow and superficial targets (e.g., thyroid or mammary nodules) and deeper or more difficult-to-reach targets such as central liver or brain tumors. They can be configured to enable acoustic cavitation / histotolypse under various parameters and sets, such as those enabled by the aforementioned 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 duration, delay, repetition, synchronization delay, synchronization duration, synchronization pulse, synchronization pulse delay, various loop sets, and others, and their sortings. Transducers can also be designed to enable activation of drug payloads accumulated in tissues through various means, including injection, replacement, or delivery in micelles or nanostructures.

[0066] Integrated imaging

[0094] The disclosed system may include various imaging techniques that enable the user to visualize, monitor, and collect / use feedback on the patient's anatomical structure, areas of interest and treatment / procedure sites, and surrounding and intervening tissues in order to evaluate, plan, and perform procedures, and to adjust treatment parameters as necessary. The imaging techniques may include various ultrasound, X-ray, CT, MRI, PET, fluoroscopy, optical, contrast or agent-enhanced versions, and / or various combinations thereof. It is further disclosed that various image processing and characterization techniques may also be utilized to provide enhanced visualization and user decision-making. These may be selected or commanded manually by the user or automatically by the system. The system may be configured to enable the user to identify, define, and be informed of various modes of using imaging during a procedure, such as side-by-side, toggling, overlay, 3D reconstruction, segmentation, registration, multimodal image fusion, image flow, and / or displayed on various system user interfaces and displays. Examples, without limitation, may include identifying one or more significant structures (e.g., tumor drainage lymphatic vessels or vascular structures, or tumors near organ encapsulation or underlying organs) in the context of each other, such as blood vessels, tubes, nerves, ureters, fissures, encapsulations, tumors, tissue trauma / injury / disease, other organs, connective tissues, and / or identifying potential therapeutic sites within, on, and / or surrounding areas, organ systems, organs or tissues of interest.

[0067]

[0095] The system may be configured to include onboard integrated imaging hardware, software, sensors, probes, and wetware, and / or to communicate and interface with external imaging and image processing systems. Furthermore, the aforementioned components may be integrated into a therapeutic subsystem component of the system, including probes, imaging arrays, or similar, and may be electrically, mechanically, or electromechanically integrated into a therapeutic transducer. This can partially provide the ability to perform geometrically aligned imaging and therapy, where the therapy is directly in the field of view and, in some cases, aligned with the imaging. In some embodiments, this integration can constitute a fixed orientation of context-adapted imaging capability (e.g., imaging probe) to the therapeutic transducer. In other embodiments, the imaging solution may have the ability to move or adjust its position, including modifying other parameters such as angle, range (e.g., distance from the therapeutic transducer or patient), rotation (e.g., imaging plane in the case of an ultrasound probe), and / or dynamically moving / adjusting while actively imaging. The imaging component or probe may be encoded in such a way that its orientation and position relative to another aspect of the system, such as a therapeutic transducer and / or a robot-compatible positioning component, can be determined.

[0068]

[0096] In one embodiment, the system may further include an onboard ultrasound system configured to allow the user to visualize, monitor, and receive feedback about the treatment site through a system display and software, including enabling ultrasound imaging and characterization (and various forms thereof), ultrasound-guided planning, and ultrasound-guided treatment, all in real time. The system may be configured to allow the user to image the patient manually (e.g., by hand or using a robot-enabled imager), semi-automated, or fully automated means.

[0069]

[0097] In some embodiments, imaging feedback and monitoring may include monitoring changes in various combinations thereof, including backscattering from bubble clouds, backscatter speckle reduction, backscatter speckle statistics, mechanical properties of tissue (i.e., elastography), tissue perfusion (i.e., ultrasound contrast), shear wave propagation, acoustic emission, electrical impedance tomography, and / or other forms of imaging (e.g., CT or MRI) that are displayed or integrated with these.

[0070]

[0098] In some embodiments, imaging including feedback and monitoring from backscatter from bubble clouds can be used as a method to immediately determine whether a histotripsy process has been initiated, properly maintained, or possibly extinguished. For example, this method allows for the continuous monitoring of drug delivery, tissue erosion, and similar processes in real time. The method can also provide feedback that allows the histotripsy process to be initiated at a high intensity and maintained at a much lower intensity. For example, backscatter feedback can be monitored by any transducer or ultrasound imager. By measuring feedback from a therapeutic transducer, an accessory transducer can be configured to emit interrogation pulses or passively detect cavitation. Furthermore, the nature of the feedback received can be used to adjust acoustic parameters (and associated system parameters) to optimize drug delivery and / or tissue erosion processes.

[0071]

[0099] In some embodiments, imaging, including feedback and monitoring from backscatter, and speckle reduction may be configured in the system.

[0100] In systems with feedback and monitoring via backscattering, and as a background means, when the tissue is gradually mechanically subdivided, in other words, homogenized, rendered unviable, or corroded, this process results in changes in the size and distribution of acoustic scattering. At some point in the process, the size and density of scattered particles are reduced to a level where ultrasound is hardly scattered, or the amount scattered is significantly reduced. This results in a significant reduction of speckle, which is a coherent constructive and destructive interference pattern of bright and dark areas seen in an image when a coherent illumination source, in this case ultrasound, is used. After some treatment time, the speckle reduction results in dark areas within the treatment volume. The amount of speckle reduction is related to the amount of tissue subdivision and therefore may be related to the size of the remaining tissue fragments. When this size is reduced to a level smaller than cells, it is not assumed that cells are surviving. Thus, treatment can proceed until the desired level of speckle reduction is achieved. Speckle is readily visible and evaluated on standard ultrasound imaging systems. Specialized transducers and systems, including those disclosed herein, may also be used to evaluate backscattering changes.

[0072]

[0101] Furthermore, in systems with speckle-mediated feedback and monitoring, as well as as a background means, the image persists and changes little from frame to frame, provided that the scattering distribution does not change and there is no movement of the object being imaged. Nevertheless, the scattering can change enough to be detected by signal processing and other means well before it is reduced to a size sufficient to cause speckle reduction. This group of techniques can act as detectors of speckle statistical changes. For example, the size and location of one or more specks in an image begin to decorrelate before observable speckle reduction occurs. Speckle decorrelation, after appropriate motion compensation, can be a highly sensitive measure of the mechanical unviability of tissue and therefore a measure of the efficacy of therapy. This feedback and monitoring technique can enable early observation of changes resulting from acoustic cavitation / histotopsis processes and can identify tissue changes (e.g., the occurrence of erosion) before substantial or complete tissue effects. In one embodiment, this method may be used to monitor acoustic cavitation / histtripsy processes for enhanced drug delivery when the treatment site / tissue is to be temporarily rendered unsustainable and tissue damage / erosion is undesirable. In other embodiments, this may include speckle decorrelation by the movement of scattering in an increasingly fluidized therapeutic volume, for example, when partial or complete tissue erosion is desired.

[0073]

[0102] In systems with feedback and monitoring via elastography, and as a background measure, when the treatment site / tissue is further subdivided (homogenized, rendered unsustainable, or corroded) for each acoustic cavitation / histotomy effect, its mechanical properties change from a soft but interconnected solid to a mucus or paste with little long-range interaction. These changes in mechanical properties can be measured by various imaging techniques, including MRI and ultrasound imaging systems. For example, ultrasound pulses can be used to generate forces (i.e., radiant forces) on localized volumes of tissue. Tissue responses (displacement, tension, and velocity) can be significantly altered during histotripsy treatment, allowing the state of tissue unsustainability to be determined by imaging or other quantitative means.

[0074]

[0103] The system can also incorporate feedback and monitoring via changes in shear wave propagation. As a background measure, tissue repartitioning makes the tissue more fluid and less solid, and fluid systems generally do not propagate shear waves. Thus, the degree of tissue fluidization provides an opportunity for feedback and monitoring of the histotripsy process. For example, ultrasound and MRI imaging systems can be used to observe shear wave propagation. The disappearance of such waves in the volume being treated can be used as a measure of tissue destruction or inviolability. In one system embodiment, the system and support subsystems can be used to generate and measure interacting shear waves. For example, two adjacent ultrasound foci may affect tissue by pushing the tissue in a particular manner. If the adjacent foci are in a fluid, the shear waves will not propagate to interact with each other. If the tissue is not fluidized, the interaction should be detected by external means, for example, by the difference frequency which is detected only when two shear waves interact nonlinearly, and the disappearance of the wave correlates with tissue damage. Therefore, the system can be configured to use this modality to enhance feedback and monitoring of acoustic cavitation / histopexy procedures.

[0075]

[0104] In systems with feedback and monitoring via acoustic emission, as well as as a background means, when tissue volume is subdivided, its effect on acoustic cavitation / histtripsy (e.g., bubble cloud here) changes. For example, bubbles may grow larger, have different lifetimes, and disrupt the changing properties of intact and fluidized tissue. Bubbles may also migrate and interact after tissue subdivision, creating larger bubbles or synergistic interactions between bubbles, all of which can produce changes in acoustic emission. These emissions can be heard during treatment and change during treatment. Analysis of these changes, and their correlation with the efficacy of the therapy, can enable monitoring of the progress of the therapy and may be configured as a feature of the system.

[0076]

[0105] In systems with feedback and monitoring via electrical impedance tomography, and as a background means, it is possible to generate an impedance map of the therapy site based on the spatial electrical properties throughout the therapy site. Imaging of the conductivity or dielectric constant of the patient's therapy site can be inferred from performing surface electrometry. 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 several 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 employed. A measure of the electrical properties of the therapy site within the skin surface can be obtained from the impedance map, and changes in acoustic cavitation / histtripsy (e.g., specifically bubble clouds) and their location, as well as the histotripsy process, can be monitored using this as configured in the system and support subsystems.

[0077]

[0106] Through the system software, user interface, and display, users may be able to further select, annotate, mark, highlight, and / or outline various areas of interest or treatment sites, as well as predefined treatment targets (on images) that can be used to instruct and direct the system to image, test, and / or treat the areas to be treated. In some configurations, users may perform procedures using manual ultrasound probes (e.g., diagnostic handheld probes). In other configurations, the system may perform procedures as directed and / or automated by the system using robotic and / or electromechanical positioning systems, or conversely, the system may allow a combination of manual and automated use.

[0078]

[0107] The system may further include the ability to perform image registration, including the registration of imaging and image datasets to enable the system's navigation and localization to a patient, including treatment sites (e.g., tumors, serious structures, anatomical structures of bone, anatomical structures and their distinguishing features). In one embodiment, the system enables a user to image and identify an area of ​​interest, such as the liver, using integrated ultrasound, and to select and mark a tumor (or its surrogate marker) contained within the liver through / displayed in the system software, the system registers the image data in a coordinate system defined by the system, and the system's therapy and robotics subsystems further enable the delivery of synchronized acoustic cavitation / histotopsy to the marked tumor. The system may have the ability to register various image sets, including those previously disclosed, with respect to each other and to provide navigation and localization (e.g., therapy transducers to the images and therapy transducers to CT or MRI / ultrasound fusion images with robotics subsystem tracking).

[0079]

[0108] The system may also be capable of operating in a variety of interventional endoscopic and surgical environments, including independently, and in conjunction with or equipped with various optical imaging capabilities (e.g., fiber and / or digital) and other systems (surgical / laparoscopic towers, vision systems, endoscopic systems and towers, ultrasound-enabled endoscopic ultrasound (flexible and rigid), percutaneous / endoscopic / laparoscopic and minimally invasive navigation systems (e.g., optical, electromagnetic, shape-sensing, ultrasound-enabled, etc.)). The disclosed system may be configured to operate with these systems, and in some embodiments, it may operate together with them, or in other embodiments, all or part of the system may be integrated into the above systems / platforms (e.g., acoustic cavitation / histtripsy-enabled endoscopic systems or laparoscopic surgical robots). In many of these environments, the therapeutic transducer may operate, for example, during or around the time of use of optically guided endoscopes / bronchoscopes, or, as another example, with laparoscopic robots (e.g., Intuitive Da The Vinci*Xi system may be used when browsing / manipulating a tissue / treatment site. Furthermore, these embodiments and examples may include cases where the other systems / platforms described above are used to deliver fluid (locally) to enable the creation of an artificial acoustic window that would not normally exist (e.g., fluidizing a segment or lobe of the lung in preparation for acoustic cavitation / histotolipssis via non-invasive transthoracic treatment (e.g., with the transducer placed externally on / around the patient)). The systems disclosed herein may also comprise all or part of these subsystem hardware packaged within the other system carts / consoles / systems described herein (e.g., acoustic cavitation / histotolipssis systems and / or subsystems integrated and operated from the navigation or laparoscopic systems described above).

[0080]

[0109] The system may also be configured through various aforementioned parameters and other parameters to spatiotemporally display real-time visualization of the bubble cloud, including tissue effects resulting from the treatment phase / post-treatment from tissue / bubble cloud interactions, and the system can dynamically image, visualize, and display the bubble cloud and any changes to the bubble cloud (e.g., decreasing or increasing echogenicity), which may include intensity, shape, size, location, morphology, persistence, etc. These features can enable the user to track and follow the treatment in real time and continuously within a single integrated procedure and interface / system, and to verify the safety and efficacy of the treatment in operation (for other interventions or surgical modalities that require numerous steps to achieve the same thing, or when the treatment effect is not visible in real time (e.g., radiotherapy), or when such as (e.g., real-time visualization of local tissue during thermal dissection) is not achievable, and / or when other procedures further require invasive approaches (e.g., incisions or holes) and repeated imaging in a scanner between procedure steps (e.g., CT or MRI scans)). The systems, subsystems, components, modalities, features, and usage workflows / methods of the above disclosure may be implemented without limitation through hardware, software, user interfaces, and usage environments, and any resulting data, as well as any means of using such data for analytics, artificial intelligence, or digital health applications and systems, as well as any future improvements, enhancements, and inventions in this area, are also considered to be within the scope of this disclosure.

[0081] Robotics

[0110] The system may comprise a variety of robotic subsystems and components, including, but not limited to, one or more robotic arms and controllers, which may further operate in conjunction with other subsystems or components of the system for delivering and monitoring acoustic cavitation / histtripsy. As previously discussed herein, the robotic arms and control systems may be integrated into one or more cart configurations.

[0082]

[0111] For example, one system embodiment may include an integrated robotic arm and control system, as well as a cart with therapy, integrated imaging, and software, where the robotic arm and other mentioned subsystems are controlled by the user through a single bedside cart form factor.

[0083]

[0112] In other embodiments, the robot subsystem may consist of one or more separate carts that can be driven in a master / slave configuration from a separate master cart, the robot-enabled cart being located on the bed / patient side and the master being located away from the cart.

[0084]

[0113] The disclosed robotic arm may include multiple joints, segments, and degrees of freedom, and may also include various integrated sensor types and encoders implemented for various uses and safety features. Sensing techniques and data may include, for example, vision, potentiometers, position / localization, kinematics, force, torque, speed, acceleration, dynamic loading, and / or others. In some cases, sensors may be used for a user to direct robot commands (e.g., to gesture to the robot to a preferred setup position or to dock at home). Further details regarding the robotic arm can be found in U.S. Patent Publication No. 2013 / 0255426 to Kassow et al., which is disclosed herein by reference in whole.

[0085]

[0114] The robotic arm receives control signals and commands from a robotic control system that may be housed in a cart. The system may be configured to provide a variety of functions, including but not limited to position, tracking, pattern, triggering, and event / action.

[0086]

[0115] The positions may be configured to include fixed positions, pallet positions, time-controlled positions, distance-controlled positions, variable time-controlled positions, and variable distance-controlled positions.

[0116] Tracking may be configured to include time-controlled tracking and / or distance-controlled tracking.

[0087]

[0117] The movement pattern may be configured to include intermediate positions or points, and a sequence of positions along a predefined path in space.

[0118] The trigger may be configured to include a variety of sensory means, including distance measuring means, time, and / or those disclosed herein, but not limited to visual / imaging-based force, torque, localization, energy / power feedback, and / or others.

[0088]

[0119] Events / actions may be configured to include a variety of examples, such as proximity-based events (approaching / moving away from a target object), activation or deactivation of various end-effectors (e.g., therapeutic transducers), starting / stopping / pausing sequences of the above events, triggering or switching between triggers of events / actions, starting and changing / toggle movement patterns, and / or time-based and transient events spanning defined tasks and spatiotemporal space.

[0089]

[0120] In one embodiment, the system includes a three-degree-of-freedom robot positioning system that allows the user to microscopically position the therapeutic transducer through the X, Y, and Z coordinate system (through the system's software and associated user interface), and the overall macroscopic positioning of the transducer (e.g., aligning the transducer over the patient's body) is completed manually. In some embodiments, the robot may have six degrees of freedom, including X, Y, Z, as well as pitch, roll, and yaw. In other embodiments, the robot subsystem may have further degrees of freedom, allowing the robot arm support base to be positioned along a linear axis running parallel to the overall direction of the patient surface, and / or the support base height to be adjusted up and down, and allowing the position of the robot arm to be corrected relative to the patient, patient surface, cart, linking subsystem, additional robot / robot arm, and / or additional surgical systems, including but not limited to surgical towers, imaging systems, endoscopy / laparoscopic systems, and / or others.

[0090]

[0121] One or more robotic arms may also be equipped with various features to assist in manually or semi-manually manipulating and correcting the arm position, and these features may interface on or between the therapeutic transducer and the most distal joint of the robotic arm. In some embodiments, the features are configured to include a handle that enables manipulation and manual control by one or more hands. The handle may also be configured to include user input and electronic control features of the robotic arm (e.g., activating or deactivating a free-drive mode) for commanding various drive capabilities or modes to actuate the robot to assist in the overall or fine positioning of the arm. The workflow for the initial positioning of the robotic arm and therapeutic head can be configured to allow the therapeutic transducer / head to be positioned first in the coupling solution, with the therapeutic transducer interfaced directly with the arm, or, in a different workflow, to allow the user to set up the coupling solution first, with the robotic arm interfaced with the therapeutic transducer / coupling solution as a later / final setup step.

[0091]

[0122] In some embodiments, one or more robot arms or other features of the robot subsystem may include sensors or other features configured to measure, determine, or predict forces acting on the robot arm and / or a therapy transducer array coupled to the robot arm. These sensors may include force sensors or force transducers, not limited to load cells, pneumatic load cells, capacitive load cells, strain gauge load cells, hydraulic load cells, etc. In some implementations, the force sensors may be located on or within the robot arm, on or within the transducer array or therapy probe, on or within the coupling linkage between the transducer array and the robot arm, or at any other location within the system including the robot subsystem, and one or more force sensors should be adapted and configured to measure forces applied to the robot arm or transducer array. Furthermore, these force sensors may be electronically or motion-coupled to any of the control systems described herein, including an electronic controller, robot positioning system, navigation system, or any other CPU, processor, or controller configured to control the operation of the transducer array, robot subsystem, or any other subsystem during therapy.

[0092]

[0123] In some embodiments, the robotic arm may comprise a robotic arm on a laparoscope, single-port, endoscope, a hybrid or combination thereof, and / or other robot, and the robot in the system may also be a slave to a master controlling the arm and potentially multiple other arms, equipped to simultaneously perform other tasks (such as visualizing, imaging, grasping, cutting, tying, sealing, closing, stapling, dissecting, suturing, marking, etc.) including operating one or more laparoscopic arms (and instruments) and various histotripsy system components. For example, the laparoscopic robot may be used to prepare the surgical site, including manipulating the position of the organ to provide more ideal acoustic access and, optionally, further stabilizing the organ to minimize respiratory movement. In conjunction with and in parallel with this, a second robotic arm may be used to deliver non-invasive acoustic cavitation through body cavities, such as observed under real-time imaging from a therapeutic transducer (e.g., ultrasound) and by simultaneously occurring visualization via a laparoscopic camera. In other related embodiments, similar approaches combining endoscopy and non-invasive approaches, as well as further combining endoscopy, laparoscopy, and non-invasive approaches, may be used.

[0093] software

[0124] The system may feature a variety of software applications, features, and components that enable users to interact with, control, and use the system for a wide range of clinical applications. The software may communicate with and work with one or more subsystems, including but not limited to therapeutic, integrated imaging, robotics, and other components, as well as assistive devices and accessories for the system.

[0094]

[0125] Overall, in no particular order of importance, the software is responsible for initializing and setting up the system, servicing the system, communicating and importing / exporting / storing data, modifying / operating / configuring / controlling / commanding various settings and parameters by the user, mitigating safety and usage-related risks, planning procedures, supporting various transducer configurations, robotic arm and drive systems, function generator and amplifier circuits / slaves, test and therapeutic ultrasound sequences, transducer steering and positioning (electromechanical and electron beam steering, etc.), treatment patterns, imaging and imaging probe support, their manual and electromechanical / robot-responsive movement, imaging support for measuring / characterizing various dimensions within or around the procedure and treatment site (e.g., depth from one anatomical location to another), in It can provide features and support for performing pre-procedure assessments and protocols to measure / characterize the nature and state of situ treatment sites (e.g., acoustic cavitation / histotolypse threshold and its heterogeneity), target setting and target alignment, calibration, marking / annotating, localizing / navigating, registering, guiding, providing and guiding, providing communication tools (video, audio, sharing, etc.), troubleshooting, instructions, warnings, alerts, and / or enabling communication through various networking devices and protocols, under direct observation and viewing with real-time imaging such as displayed through software that includes various views and viewports for autonomous, autonomous but browsing.The software user interface and support display may include a variety of buttons, commands, icons, graphics, text, etc., that enable the user to interact with the system in a user-friendly and effective manner, and these may be presented in an unlimited number of arrangements, layouts, and designs, and may include two or more displays (e.g., a touchscreen monitor and a touchpad), and / or may be networked to one or more external displays or systems (e.g., another robot, navigation system, system tower, console, monitor, touch display, mobile device, tablet, etc.), and may be displayed in a similar or different style or set of features of the system.

[0095]

[0126] The software, as part of a typical system including one or more computer processors, can support various aforementioned function generators (e.g., FPGAs), amplifiers, power supplies, and therapeutic transducers. The software may be configured to allow the user to select, determine, and monitor various parameters and settings of acoustic cavitation / histtripsy, and to allow the user to stop / start / modify the above parameters and settings upon observing / receiving feedback on performance and status.

[0096]

[0127] The software may be configured to allow the user to select from a list or menu of numerous transducers and to support automatic detection of the transducers upon connection to the system (and verification of appropriate sequence and parameter settings based on the selected application). In other embodiments, the software may update target and amplifier settings (e.g., channels) based on the specific transducer selection. The software may also provide transducer recommendations based on pre-treatment and planning inputs. Conversely, the software may provide the user with error messages or warnings if the selection or parameters of the therapeutic transducers, amplifiers, and / or function generators are incorrect or result in errors or failures. This may further include reporting details and locations of such errors.

[0097]

[0128] In addition to the above, the software may be configured to allow users to select treatment sequences and protocols from a list or menu and store selected and / or previously selected sequences and protocols so as to be associated with specific clinical use or patient profiles. Associated profiles may include any associated patient, procedure, clinical and / or engineering data, which may be used to inform, modify and / or guide current or future treatments or procedures / interventions, whether as decision support (e.g., using sequential datasets to build and guide new treatments) or as an active part of the procedure itself.

[0098]

[0129] As part of the plan or during treatment, the software (and working with other components of the system) can enable the user to evaluate and test acoustic cavitation / histtripsy thresholds at various locations within a user-selected region of interest or a predefined treatment area / volume to determine a minimum cavitation threshold throughout the region or area / volume, ensuring that treatment parameters are optimized to achieve, maintain, and dynamically control acoustic cavitation / histtripsy. In one embodiment, the system allows the user to manually evaluate and test threshold parameters at various points. These points may include points at the predefined boundaries of the selected region of interest and treatment area / volume, within the boundaries, and at central locations / positions, and the resulting threshold measurements may be reported / displayed to the user and used to update treatment parameters before treatment. In another embodiment, the system may be configured to enable automated threshold measurement and updating, such as enabled by the robotics subsystem described above, where the user can instruct a robot or the robot may be commanded to perform measurements autonomously.

[0099]

[0130] The software may also be configured to enable various sortings of delivering and positioning optimized acoustic cavitation / histtripsy in and through a selected area / volume by working with a computer processor, as well as one or more function generators, amplifiers, and therapeutic transducers. This may include, but is not limited to, systems comprising various combinations including fixed / natural focus placement using pure electromechanical positioning configurations, electron beam steering (with or without electromechanical positioning), electron beam steering to a new selected fixed focus with further electromechanical positioning, axial (Z-axis) electron beam steering with lateral (X and Y) electromechanical positioning, high-speed axial electron beam steering with lateral electromechanical positioning, high-speed beam steering in 3D space, and dynamically varying one or more acoustic cavitation / histtripsy parameters based on the aforementioned ability to update therapeutic parameters based on threshold measurements (e.g., dynamically adjusting amplitude across a therapeutic area / volume).

[0100] Other components, auxiliary devices, and accessories

[0131] The system may comprise a variety of other components, auxiliary equipment and accessories, including but not limited to computers, computer processors, power supplies including high-voltage power supplies, controllers, cables, connectors, networking devices, security, communications, software applications for integration into information systems including hospital information systems, cellular communication devices and modems, handheld wired or wireless controllers, goggles or glasses for advanced visualization, augmented or virtual reality applications, cameras, sensors, tablets, smart devices, telephones, Internet of Things capabilities, special use "apps" or user training materials and applications (software or paper-based), virtual proctors or trainees and / or other enabling features, devices, systems or applications, and / or methods of using the foregoing.

[0101] System variations and methods / applications

[0132] In addition to performing a wide range of procedures, the system can enable users to benefit from additional advantages such as enhanced planning, imaging, and guidance. In one embodiment, the system can enable users to create patient, target, and specific-use treatment plans, and the system may be configured to optimize treatment parameters based on feedback to the system during planning, and planning may further include the ability to perform various test protocols to gather unique inputs to the system and the plan.

[0102]

[0133] The feedback can include various parameters such as energy, power, location, position, organization, and / or other parameters.

[0134] The system and the feedback described above may also be further configured and used to autonomously (and robotically) deliver optimized treatment plans and protocols, such as those visualized under real-time imaging during the procedure, allowing the user to directly observe the local therapeutic tissue effects as the treatment progresses, and to start / stop / modify the treatment at the user's discretion. Both test and treatment protocols may be updated during the procedure at the user's direction, or based on logic built into the system in some embodiments.

[0103]

[0135] Many of these benefits can further improve other forms of acoustic therapy, including thermal dissection by high-intensity focused ultrasound (HIFU) and high-intensity therapeutic ultrasound (HITU), including boiling histotripsy (thermal cavitation), and are also recognized as part of this disclosure. This disclosure also considers the application of histotripsy as a means of activating previously delivered active drug payloads that are inactive, either by protection in micelles, nanostructures or similar protective structures, or through molecular arrangements that enable activation only when acoustic energy is applied.

[0104]

[0136] In another embodiment, a therapeutic subsystem comprising one or more amplifiers, transducers, and power supplies may be configured to enable numerous acoustic cavitation and histotripsy driving capabilities, resulting in unique 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 therapeutic parameters that enable electron beam steering and / or other features, along with the delivery of more energy, along with a more desirable thermal profile, increased treatment speed, and reduced treatment time.

[0105]

[0137] This disclosure also includes novel systems and concepts such as systems and subsystems comprising a new and "general-purpose" amplifier capable of enabling a number of drive approaches (e.g., single and multi-period pulse generation). In some embodiments, this may include a variety of novel features to further protect the system and user in terms of electrical safety or other threats (e.g., adverse effects on transducers and / or amplifier circuit equipment).

[0106]

[0138] In another embodiment, the system and therapy subsystem may include a very large number of therapy transducers, which may be configured for specific applications and uses, adaptable to therapies across a wide range of working parameters (such as target size, depth, and location), and may include a wide range of working specifications (detailed below). The transducers may be further adapted, interfaced, and connected to robot-enabled systems, as well as to coupling subsystems that allow the transducer to be positioned in or with an acoustic coupling device that enables simultaneous imaging and histotripsy therapy through an acceptable acoustic window in many embodiments. The therapy transducer may also be equipped with an integrated imaging probe or localization sensor that has the ability to display and determine the transducer position within the therapy site and provide a direct view (or representation) of the therapy site, as well as such that the appearance and intensity of acoustic cavitation / histotopsis tissue effects and bubble clouds may or may not change throughout the therapy, and depending on its location within the therapy (e.g., tumor, around healthy tissue, severe structure, fatty tissue, etc.).

[0107]

[0139] The systems, methods, and uses of the systems disclosed herein may be beneficial in overcoming important yet unaddressed needs in the areas of surgical procedures including, but not limited to, soft tissue dissection, oncology, cancer immunology, advanced image-guided procedures, laparotomy, laparoscopy, single incision, transluminal, endoscopic, non-invasive, and various combinations thereof; various intervention spaces for catheter-based procedures in vascular, cardiovascular, pulmonary, and / or neuroscience-related spaces; cosmetic / aesthetics, metabolism (e.g., type 2 diabetes), plastic surgery and reconstruction, vision and ophthalmology, orthopedics, gynecology, and human health conditions, as well as other systems, devices, and methods for treating diseased, injured, undesirable, or healthy tissues, organs, or cells.

[0108]

[0140] Systems and methods are also provided for improving the treatment pattern within tissue, which can reduce treatment time, improve efficacy, and reduce the amount of energy and constant-focus tissue heating delivered to the patient.

[0109] Usage environment

[0141] The disclosed systems, methods of use, and methods of using the systems can be performed in a great many environments and settings, with or without various support systems such as anesthesia, including but not limited to physician's offices, mobile healthcare centers or systems, automobiles and related vehicles (e.g., vans), aircraft and ships and other aerospace and maritime transport vehicles, and / or any structure capable of providing temporary procedural support (e.g., tents). In some cases, the systems and / or subsystems disclosed herein may also be provided as features integrated into other environments, such as direct integration of the histotripsy therapy subsystem into an MRI scanner or patient surface / bed, where at least the therapy generator and transducer are integrated into such a system, and in other cases, the histotripsy configuration further includes a robotic positioning system which may be further integrated into a scanner or bed-centered design.

[0110] Link

[0142] The system may comprise various coupling subsystem embodiments enabled and configured to allow acoustic coupling to the patient to provide effective acoustic access for ultrasound visualization and acoustic cavitation / histopepsis (e.g., providing an acoustic window and medium between the transducer and the patient, and supporting it). These may include different form factors of such as open and closed device solutions, as well as several arrangements that may be configured to allow dynamic control over the acoustic medium (e.g., temperature, oil-soluble gas contents, particulate filtration level, sterility, volume, components, etc.). Such dynamic control components may be directly integrated into the system (in the cart) or may be located in separate devices and / or outside the cart, but in transient / intermittent or continuous communication with the system.

[0111]

[0143] The coupling subsystem typically comprises at least a coupling medium (e.g., degassed water or aqueous solution), a reservoir / container for holding the coupling medium, and a support structure (including interface to other surfaces or devices). In most embodiments, the coupling medium is water, which may be conditioned before or during treatment (e.g., cooled, degassed, filtered, etc.). Various conditioning parameters may be employed depending on the system configuration and its intended use / application.

[0112]

[0144] Reservoirs or media containers can be formed and shaped in various sizes and shapes to fit / conform to a patient, allowing therapy transducers to engage / access and work within the acoustic media for each defined and required working space (such as the minimum volume of media to allow therapy transducers to be positioned and / or move through one or more therapy positions or patterns and at various standoffs or depths from the patient), and the reservoir or media container may also mechanically support the load and load distribution through the use of mechanical and / or electromechanical support structures. Typical examples include support frames. Containers may also be of various shapes, sizes, curvatures, and dimensions and may include various material components (single, multiple, composite, etc.) which may vary throughout. In some embodiments, the container may have insertable and removable features such as films, drapes, thin films, blowers, etc., which can be used to conform to the patient and assist in confining / filling the medium within the container. The container can also accommodate various sensors (e.g., volume / fill level), drainage (e.g., inlet / outlet), lighting (e.g., LED), markings (e.g., filling line, setup orientation, etc.), text (e.g., labeling), and more.

[0113]

[0145] In one embodiment, the reservoir or medium container includes a sealable frame in which a thin film and / or film may be placed to provide a comfortable means of contact with the reservoir (later comprising a treatment head / therapy transducer) as an interface to the patient, further providing a barrier to the medium (e.g., water) between the patient and the therapy transducer. In other embodiments, the thin film and / or film may have an opening, the edge in which the patient contacts, which provides a fluid / mechanical seal to the patient, but in contrast, directly allows for medium communication with the patient (e.g., a direct degassed water interface with the patient). The superstructure of the reservoir or medium container in both of these examples may further provide a proximal portion (e.g., top) of the structure that will be open or enclosed (e.g., to prevent spillage or to give additional features).

[0114]

[0146] The thin films of disclosure may include various elastic materials, viscoelastic polymers, thermoplastics, thermoplastic elastic materials, thermosetting polymers, silicon, urethane, rigid / flexible copolymers, block copolymers, random block copolymers, etc. The materials may be hydrophilic, hydrophobic, surface-modified, coated, extracted, etc., and may further contain various additives to enhance performance, appearance, or stability. In some embodiments, the thermoplastic elastic material may be styrene-ethylene-butylene-styrene (SEBS) or other similar strong, flexible elastic materials. The thin film form factor can be flat or pre-formed before use. In other embodiments, the thin film can be inelastic (i.e., convex) and can be pressed against the patient's skin to acoustically couple a transducer to tissue. Systems and methods for controlling the level of contaminants (e.g., particulate matter) on the thin film to maintain an appropriate level of ultrasonic coupling are further disclosed. Too much particulate matter or contaminants may cause ultrasonic scattering. This can be achieved with a removable film or coating on the outer surface of the thin film to protect from contamination.

[0115]

[0147] The above materials may be formed into useful thin films through molding, casting, spraying, ultrasonic spraying, extrusion, and / or any other processing method that produces useful embodiments. The above materials may be single-use or reposable / reusable. The above materials may be non-sterile, antiseptically clean, or sterile, and sterilization may include any known method, including but not limited to ethylene oxide, gamma, e-beam, autoclavation, steam, hydrogen peroxide, plasma, chemicals, etc. The thin film may be further configured with an externally molded or overmolded frame to provide mechanical stability to the thin film during handling, including assembly, setup, and disassembly of linked subsystems. Various parameters of the thin film, including thickness, thickness profile, density, and manufacturing method (e.g., polymer molecular weight and copolymer ratio, additives, plasticizers, etc.), can be optimized for this use, including optimizing in particular to maximize acoustic transmission properties, including minimizing ultrasonic imaging artifacts, including but not limited to impact on the cavitation onset threshold and / or thin film reflections, as a typical example.

[0116]

[0148] An open reservoir or media container may include various methods of filling, including using a pre-prepared media or water that can be delivered to the container to a predefined specification (such as temperature and gas saturation levels), or it may include additional features integrated into the design that enable filling and draining (e.g., ports, valves, hoses, tubes, fittings, bags, pumps, etc.). These features may be further configured to interface with, or into, other devices, such as a fluid engineering system. In some cases, the fluid engineering system may be an in-hospital media preparation system in a hospital or medical environment room, or conversely, a mobile cart-based system capable of preparing and transporting media from a cart to a media container.

[0117]

[0149] Enclosed iterations of a reservoir or media container may include various features for sealing, in some embodiments sealing to the proximal / top part or structure of the reservoir / container, or in other cases, the sealing may include embodiments sealing features on the transducer or transducer housing. Furthermore, some embodiments may include dynamic capabilities to control the volume of fluid within these designs, minimize the possibility of air bubbles or turbulence in the fluid, and allow changes in the focal length to a target area without moving the transducer. Thus, integrated features and controls enabling fluid communication may be provided, some of which include the ability to monitor and control the various fluid parameters disclosed above (the ability to supply / remove fluid on demand). To provide this functionality, the entire system, and as a part thereof, the linked subsystem may include a fluid conditioning system which may include various electromechanical devices, systems, power, sensing, computing, pumping, filtering, and control systems. The reservoir may also be configured to receive signals that deform or change its shape in a specific and controlled manner to allow the target point to be adjusted without moving the transducer.

[0118]

[0150] The linked support system may include various mechanical support devices for interface the reservoir / container and medium to the patient and workspace (e.g., bed, floor, etc.). In some embodiments, the support system comprises a mechanical arm with three or more degrees of freedom. The arm may have a proximal interface to one or more locations (and features) of the bed, including but not limited to frames, rails, customized rails or inserts, as well as one or more distal locations of the reservoir or container. The arm may also be a feature realized on one or more carts, the carts may consist of various unrestricted arrangements, and in some cases the carts may have only the role of supporting and providing the disclosed support structure.

[0119]

[0151] In some embodiments, the support structure and arm may be implemented as a standalone cart or as a robot-enabled arm integrated into a cart further comprising two or more system subsystems, or the robot-enabled arm may be the arm of another robot of an interventional, surgical, or other type, further comprising various user input features and / or coupling solution features (e.g., filling, draining, etc.) for operating / controlling the robot arm (e.g., located in / within a coupling medium). In some examples, the support structure robot arm position encoder may be used to coordinate the operation of a second arm (e.g., comprising a therapy transducer / treatment head), such as by positioning the therapy transducer at a desired / known location and placing it within the coupling support structure.

[0120]

[0152] Overall, significant unaddressed needs exist today within interventional and surgical medical procedures across a variety of procedures, including those that utilize minimally invasive devices and approaches to treat disease and / or injury, where unaddressed needs may be resolved entirely by novel medical procedures. The capabilities of today's medical systems are often limited by access, making less invasive or non-invasive approaches preferable, or the tools of today lack the ability to deliver preferred / requested tissue effects (e.g., working around / through severe structures without serious injury), or the physical setup of the system makes certain procedural approaches less desirable or impossible, and combinations of approaches, along with treatments affecting enhanced tissue, can enable entirely novel procedures and approaches that are not possible today.

[0121]

[0153] In addition, there is a unique need to enable histotripsy delivery, including robotic histotripsy delivery, and one or more histotripsy therapy transducers may be configured to acoustically couple to a patient using a completely sealed approach (e.g., no acoustic media communication with the patient's skin), and to allow one or more histotripsy transducers to be moved within the coupling solution without interfering with the movement / route of the robotic arm or interfering with / disrupting the coupling interface, which could affect the intended treatment and / or target location.

[0122]

[0154] As a non-limiting example, histotripsy acoustic and patient-connected systems and methods for enabling histotripsy therapy / treatment in any setting, such as intervention suites, operating rooms, hybrid suites, imaging centers, medical centers, office environments, mobile treatment centers, and / or others, are disclosed herein. The following disclosures further describe novel systems used to create, control, maintain, modify / enhance, monitor, and set up / deconstruct acoustic and patient-connected systems in a variety of approaches, methods, environments, architectures, and workflows. Generally, the novel systems of the disclosure can enable a coupling medium, in some cases degassed water, to interface between a histotripsy therapy transducer and a patient, the acoustic medium providing sufficient acoustic coupling to the patient to enable delivery of histotripsy pulses through a user-desired therapeutic location (and volume), the delivery may require the physical movement of the histotripsy therapy transducer within a defined workspace including the coupling medium, and the coupling system is configured to allow the above movement of the therapy transducer (and the positioning of the system, e.g., a robot) to be free and unhindered by a coupling support system (e.g., a frame or manifold holding the coupling medium).

[0123] Connecting systems and subsystems / components

[0155] The disclosed histotripsy acoustic and patient coupling system may generally comprise one or more subsystems and components, including but not limited to: 1) a thin film / barrier film for providing an enclosed, sealed, and equiangled patient coupling and histotripsy system interface; 2) a frame and assembly for holding the thin film and providing the histotripsy therapy transducer with sufficient work and headspace required for the range of motion (x, y, and z, longitudinal, transverse, and eccentric); 3) a volume of ultrasonic medium sufficient to provide acoustic coupling and interface to the histotripsy therapy transducer and robotic arm; 4) one or more mechanical support arms for enabling the installation, positioning, and load-bearing of the frame, assembly, and medium; and 5) a fluid engineering system for preparing, supplying, and removing the ultrasonic medium from the frame and assembly.

[0124]

[0156] In some embodiments, the coupling system can be completely sealed, while in other embodiments and configurations, it can be partially open to provide immediate access (physical and / or visual).

[0125]

[0157] Acoustic and patient coupling systems and subsystems can further incorporate various features and functions, as well as associated workflows, and can be configured in various ways to enable histotripsy procedures, as detailed below.

[0126]

[0158] The disclosed histotripsy acoustic and patient coupling system may generally comprise one or more subsystems and components, including but not limited to: 1) a thin film / barrier film for providing an enclosed, sealed, and equiangled patient coupling and histotripsy system interface; 2) a frame and assembly for holding the thin film and providing the histotripsy therapy transducer with sufficient work and headspace required for the range of motion (x, y, and z, longitudinal, transverse, and eccentric); 3) a volume of ultrasonic medium sufficient to provide acoustic coupling and interface to the histotripsy therapy transducer and robotic arm; 4) one or more mechanical support arms for enabling the installation, positioning, and load-bearing of the frame, assembly, and medium; and 5) a fluid engineering system for preparing, supplying, and removing the ultrasonic medium from the frame and assembly, an example of which is depicted in at least Figure 10.

[0127]

[0159] In some embodiments, the coupling system may be completely sealed, while in other embodiments and configurations, the coupling system may be partially open to provide immediate access (physical and / or visual).

[0128]

[0160] Acoustic and patient coupling systems and subsystems may further feature a variety of characteristics and functions, as well as associated workflows, and may be further configured in various ways to enable histotripsy procedures as detailed below.

[0129]

[0161] Figure 2 illustrates one embodiment of the histotripsy therapy and imaging system 200, including a coupling assembly 201. As described above, the histotripsy therapy and imaging system may include a therapy transducer 202, an imaging system, a robotic positioning arm 208, and a fluid mechanics cart 210. The robotic positioning arm can be mounted on a therapy cart such as cart 209.

[0130]

[0162] Therapeutic and / or imaging transducers can be placed within a coupling assembly 201, which may further include a coupling thin film 214 and a thin film constraint 216 configured to prevent the thin film from expanding too far from the transducer. The coupling thin film can be filled with an acoustic coupling medium such as a fluid or gel. The thin film constraint may be, for example, a semi-rigid or rigid material compared to the thin film and may be configured to limit the expansion / movement of the thin film. In some embodiments, the thin film constraint is not used, and the stretch and tensile strength of the thin film prevents expansion. The coupling thin film may be a mineral oil-injected SEBS thin film to prevent direct fluid contact with the patient's skin. In the exemplary embodiment, the coupling assembly 201 is supported by a mechanical support arm 218 that is load-bearing in the xy plane but capable of allowing manual or automated z-axis adjustment. The mechanical support arm may be attached to the floor, a patient table, or a fluid engineering cart 210. The mechanical support is designed and configured to align and hold the connecting thin film 214 in appropriate position relative to the patient's skin, while still allowing the movement of the therapy / imaging transducer relative to the patient and further relative to the connecting thin film 214 by the robotic positioning arm 208.

[0131]

[0163] The fluid engineering cart 210 may include additional features, including a fluid tank 220, a cooling and degassing system, and a programmable control system. The fluid engineering cart is configured for external loading of linked thin films with automatic control of the fluid sequence. Further details about the fluid engineering cart are provided below.

[0132]

[0164] Therapeutic and / or imaging transducers can be housed in a coupling assembly, which may further include a coupling film and a film constraint configured to prevent the film from expanding too far from the transducer. The coupling film can be filled with an acoustic coupling medium such as a fluid or gel. The film constraint may be, for example, a semi-rigid or rigid material and configured to limit the expansion / movement of the film. In some embodiments, no film constraint is used, and the elastic and tensile strength of the film prevents expansion. The coupling film can be a SEBS film injected with mineral oil to prevent direct fluid contact with the patient's skin. In the illustrated embodiment, the coupling assembly is supported by a mechanical support arm that can withstand loads in the xy plane but allows for manual or automatic z-axis adjustment. The mechanical support arm can be mounted on the floor, a patient table, or a cart. The mechanical support is designed and configured to fit and hold the coupling film in place against the patient's skin while still allowing movement of the therapy / imaging transducer relative to the patient and also relative to the coupling film on a robotic positioning arm.

[0133]

[0165] The system may further include a fluid engineering system that may include a fluid source, cooling and degassing systems, and a programmable control system. The fluid engineering system is configured for the external loading of the linked thin film with automatic control of the fluid sequence. Further details about the fluid engineering system are provided below.

[0134] Thin films / barrier films and related architectures

[0166] Thin films and barrier films may consist of a variety of biocompatible materials capable of enabling conformal linkage to the patient's anatomical structures with minimal or no trapped bubbles that could interfere with ultrasound imaging and histotripsy therapy, and providing a sealed barrier layer between the aforementioned patient's anatomical structures and the ultrasound medium, contained within the working space provided by the frame and assembly.

[0135]

[0167] Thin film and barrier film materials can comprise flexible and elastic biocompatible materials / polymers, such as various thermoplastics and thermosetting materials, as well as permanent or bioabsorbable polymers. Additionally, UMC frames can also comprise the same materials. In some examples, the thin film may be a pre-formed or flat rigid or semi-rigid polymer.

[0136] ultrasonic medium

[0168] As described above, the ultrasonic medium may comprise any applicable medium capable of providing sufficient and useful acoustic coupling to enable histotripsy therapy and adequate clinical imaging (e.g., ultrasound). The ultrasonic medium may include, but is not limited to, a variety of aqueous solutions / mediums, including mixtures with other soluble fluids that may have preferred or more preferred acoustic qualities, including the ability to match the speed of sound, as part of this disclosure and system. Examples of media may include defasted water, and / or mixtures / cosolutions of defasted water with various alcohols such as ethanol.

[0137]

[0169] Nevertheless, because the speed of sound in water is slower than the speed of sound in tissue, sound waves can encounter aberrations as they travel along the water-tissue path. There are two sources of these aberrations. Firstly, when sound waves travel from a medium with a lower speed of sound to a medium with a higher speed of sound, the angle of transmission becomes greater than the angle of incidence—that is, the sound wave bends away from the normal and away from the surface (Snell's Law). Secondly, the paths traversed by sound waves originating from different regions of the transducer aperture consist of different relative distances through each medium—that is, the ratio of the connecting medium path length to the tissue path length is variable throughout the transducer. As a result of these effects, sound waves reach the transducer's geometric focus in a phase-shifted state, reducing the amplitude of the sound produced via constructive interference at the intended target. Furthermore, these phase aberrations can cause a spatial shift (i.e., a shift in focus) at the point of maximum constructive interference in the sound field, resulting in therapeutic effects occurring at unexpected locations.

[0138]

[0170] This disclosure provides advantages to coupling media compared to existing solutions. These aberration effects are minimized when the sound velocity of the coupling medium is designed to match the sound velocity of the tissue pathways it covers. Using a Medium for Enhanced Acoustic Coupling (MEAC) such as the one provided herein, waves originating from different regions of the transducer arrive in phase at the intended focal location. Thus, the advantages of MEAC include 1) maximizing the amplitude of the signal at the focal point, and 2) minimizing spatial deviation from the intended target location. These improvements contribute to both maximizing therapeutic effect and improving the predictability of treatment location—the latter of which provides significant benefits with regard to therapeutic ultrasound treatment planning.

[0139]

[0171] The MEAC as provided herein includes a unique recipe of a coupling liquid medium for matching the speed of sound of the coupling liquid medium to human tissue. Instead of glycerin and salts, only glycerin at various concentrations is added to water, and the concentration depends on the temperature of the water. Using Formulas 1 and 2 described below, the speed of sound in the MEAC can be matched to human soft tissue.

[0140]

[0172] Specific examples of these improvements have been observed for in vivo targeting of porcine muscle with histotripsy. When a histotripsy therapy transducer was coupled to an animal via traditional means - a degassed water bolus, it was observed that the resulting bubble cloud formed a prefocal at the intended geometric focus of the transducer. Still, when targeting the same location using a MEAC designed to match the speed of sound of the porcine tissue path, a bubble cloud was formed at the intended geometric focus of the transducer. Additionally, the transducer drive voltage required for bubble cloud initiation decreased compared to that required when using traditional water coupling. The reduced drive voltage is due to the reduced aberration by using the MEAC.

[0141]

[0173] Equation for the speed of sound

[0174] 1. Speed of sound c in water according to temperature T (°C) W (m / s) - Marczak equation [1]:

[0175] c W (T) = 1.402385×10 3 +5.038813×T - 5.799136×10 -2 ×T 2 +3.287156×10 -4 ×T 3 -1.398845×10 -6 ×T 4 +2.787860×10 -9 ×T 5

[0176] 2. Speed of sound c in glycerin according to temperature T (°C) G (m / s):

[0177] c G (T) = -2.2 × (T - 25) + 1904

[0178] 3. The speed of sound c in saltwater according to temperature T (°C) and salt concentration C (g / L) SW (m / s)[2]:

[0179] c SW (C,T) = S1(C) + S2(C) × In(T)

[0180] S1(C)=1285.9+1.7661×C-0.0015×C 2

[0181] S2(C)=62.268-0.2197×C+0.0002×C 2

[0182] Formula 1: Water + Glycerin

[0183] 1. Volume percentage γ of glycerin in the final mixture:

[0184] c W (T)×(1-γ)+c G (T) × γ = c T ,

[0185] Here, c T The speed of sound in human tissue is 1560 m / s.

[0142]

[0186]

[0143]

number

[0144]

[0187]

[0145] [Table 1]

[0146]

[0188] *Assumes that the speed of sound in human tissue is 1560 m / s.

[0189] Formula 2: Saltwater + Glycerin

[0190] 1. Volume percentage γ of glycerin in the final mixture:

[0191] c SW (C,T)×(1-γ)+c G (T) × γ = c T ,

[0192] Here, c T The speed of sound in human tissue is 1560 m / s.

[0147]

[0193]

[0148]

number

[0149]

[0194] 2. Volume chart of a real-world example

[0150] [Table 2]

[0151] [Table 3]

[0152]

[0195] *Assumes that the speed of sound in human tissue is 1560 m / s.

[0196] Note: There is no significant difference in the speed of sound between water and saltwater; therefore, the volume ratios are similar in both cases.

[0153]

[0197] Figure 13 provides a system including a fluid engineering system 1309 configured to deliver MEAC 1301, according to the concept described above, to a linked container 1302 of a histotripsy system. A circulating tube 1303 allows the medium to pass from a fluid engineering system reservoir 1304 to the linked container. A degassing pump 1306 can remove a selected volume or percentage of gas or air from the fluid. The fluid engineering system 1309 may include a heating coil 1305 or other temperature control system for managing the temperature of the fluid. Once the linked container is filled with MEAC, a therapeutic transducer 1307 can be submerged in the medium to acoustically link to a subject 1308.

[0154] Mechanical support arms and arm architectures

[0198] Various designs and configurations of mechanical support arms (and arm architectures) may be employed to support acoustic and patient linkage systems, including providing users with an efficient and ergonomic workflow. Support arms may be configured with a range of degrees of freedom that include, but are not limited to, x, y, z, pitch, roll, and yaw, as well as additional interface features that may allow for additional height adjustment or translation.

[0155]

[0199] Arms can have a variety of joints and segments of different numbers and types. Typically, an arm can have at least two segments. In some configurations, an arm can have three to five segments.

[0156]

[0200] The arm is also configured to interface proximal to the main support base or base interface (e.g., robot, table, table / bed rail, cart, floor mount, etc.) and distally to the frame / assembly and the overall "UMC" or "connection solution". This specific distal interface may further include features for controlling the position / orientation of the frame / assembly within the frame / assembly interface.

[0157]

[0201] For example, in some embodiments, the arm / frame interface may include a ball-jointed wrist. In another example, the interface may include the use of a gimbal wrist or a wrist with adjustable pitch and roll control. These interfaces may further employ unique user interfaces and inputs to assist interaction with various wrists, which may include additional handles or knobs (as an unrestricted example) to further allow for the placement of UMC / coupling solutions. For example, a gimbal wrist can benefit from allowing the frame / assembly to have three degrees of freedom (independent of arm degrees of freedom), including pitch, roll, and yaw adjustments.

[0158]

[0202] The support arm, comprising a frame / assembly and an arm wrist further interfaced with it, may feature brakes, including cable-operated or electronically actuated brakes, and quick-release mechanisms that can interact with one or more axes individually or in groups. The support arm may also include an electronic lift system and base support. In some embodiments, these lift systems / base supports are located in the same place as the robot arm base, and the robot arm is equipped with a histotripsy therapy transducer configured to fit / function within an enclosed coupling solution. In other embodiments, the support arm is placed on a separate cart. In some cases, the separate cart may include a fluid mechanics system or a user console. In other embodiments, the separate cart is interfaced to a bed / table, including but not limited to rails, sides, and / or a bed / table base. In other examples / embodiments, the separate cart is interfaced to a floor base structure / foundation capable of managing weight and tipping requirements.

[0159] Fluid dynamics systems, control systems, and system architectures

[0203] As part of the overall fluid engineering management, the histotripsy system, including the acoustic / patient coupling system, may be configured to include an automated fluid engineering system, which is primarily responsible for providing a reservoir for the preparation and use of the coupling medium, and preparation may include the ability to degas, cool, monitor, regulate, supply / fill, and remove / drain the coupling medium from the frame / assembly. The fluid engineering system may include an emergency high-flow system for rapid drainage of the coupling medium from the UMC. In some embodiments, the fluid engineering system may be configured for single use of the coupling medium or for reuse of the medium as an alternative. In some embodiments, the fluid engineering system may achieve positive pressure or vacuum to perform leak tests of the UMC and thin film before filling with the coupling medium. Vacuum assistance may also be used for the removal of air from the UMC during the filling process. The fluid engineering system may further include filters configured to prevent particulate contamination from reaching the UMC.

[0160]

[0204] The fluid engineering system may be implemented in the form of a mobile fluid engineering cart. The cart may include an input tank, a drain tank, a degassing module, a filling pump, a drain pump, an inert gas tank, an air compressor, tubing / connectors / lines, electronic and manual control systems and input devices, a power supply and one or more batteries. The cart may also optionally include a system check container / reservoir for evaluating histotripsy system performance and relational system diagnostics (configured to accommodate the required water volume and working space for therapeutic transducers).

[0161] Transmission-receiving electric drive system

[0205] The electrical transmission signal to a histotripsy transducer is typically around a few kilovolts, while the received ultrasonic signal typically ranges from a few millivolts to tens of volts. Therefore, the transmission-receiver electrically driven circuit equipment described herein is designed and configured to have sufficient sensitivity and dynamic range to receive low-amplitude signals of about tens of volts, while blocking or greatly attenuating high-amplitude transmission waveform signals of about several thousand volts.

[0162]

[0206] Numerous drive circuit equipment embodiments and implementation configurations for achieving the functions / objectives described above are described herein. In some examples, the drive circuit equipment can be modified or added on to an existing transmission-only histotripsy system to provide transmission-reception capability. In other embodiments, the drive circuit equipment is integrated into a completely new transmission-reception histotripsy system. Any of the drive circuit equipment embodiments described herein can be incorporated into or configured to operate together with any of the pulse generators and / or amplifiers described herein. The drive circuit equipment can be placed or housed in a therapeutic cart of a system such as cart 110 in Figure 1A.

[0163]

[0207] Figure 3A shows one embodiment of a receiver drive circuit device 300 configured to modify an existing transmit-only histotripsy system to enable transmit-receive functionality. In the illustrated schematic diagram, the nonlinear compressor can attenuate all signals connected to each of the histotripsy elements, but with greater attenuation for high-amplitude signals and less for low-amplitude signals. For example, a capacitive voltage divider 302, as indicated by C1 and C2, can first be configured to attenuate all incoming / received voltage signals from transducer element TX1 to approximately 1-10% (or 90-99% of the signal). Then, a diode resistor voltage divider 304, as indicated by D1, D2, and C3, is configured to provide nonlinear attenuation to compress all signals above approximately 1 volt, and the alternating current (AC) connects the signal to an analog-to-digital converter (ADC) for ADC conversion. The final component before the ADC is a voltage level shifter 306, as indicated by R2 and R3, which places the signal to the ADC within an appropriate voltage range (e.g., typically between + / -0.5V and + / -2V). As described above, this circuit is configured to modify an existing transmission-only histotripsy drive system. For example, a separate circuit board can be added and connected to the existing transmission circuit to add receiving functionality. In one embodiment, the receiving circuit is added in parallel to the transmission electronics and passively receives the signal without affecting the transmission electronics.

[0164]

[0208] Figure 3B shows one embodiment of a drive circuit device 300a integrated into a high-voltage histotripsy drive electronic device. In the embodiment of Figure 3B, a bank of capacitors (not shown) in series with the primary coil 20 of the transducer is charged with a high-voltage supply. The driver chip U1 then triggers an n-channel MOSFET transistor Q1, which sends a high-voltage AC pulse through the primary coil of the transducer, thereby generating an AC pulse in the secondary coil 22 of the transducer at a voltage proportional to the turns ratio between the coils. The secondary coil can be electrically coupled to each of the transducer elements (transducer element TX1 in this example). In one implementation, a turns ratio of approximately 1:3 is used between the primary and secondary coils. This receiver drive circuit device can thereby generate a single-period pulse at a transducer center frequency of approximately 3kV. It should be understood that other turns ratios are possible.

[0165]

[0209] Referring to Figure 3C, another embodiment of the receiver drive electronics for a histotripsy system is shown. As illustrated, the receiver drive electronics may include a secondary transducer coil 22 coupled to the transducer element TX1. Since the driver for this system already includes transducers at the output of each channel, a third coil 24 can be added to each transducer that will be used for the receiver electronics, thereby providing complete isolation between the driver (e.g., primary coil 20) and the receiver (e.g., third coil 24). In one implementation, the receiver or third coil can be wound with approximately 10 times fewer turns than the secondary transducer coil 22, thereby resulting in a 10-fold reduction in voltage between the secondary and third coils. The number of turns of the tertiary or third coil can be adjusted for specific applications and does not necessarily have to be 10 times less than the secondary. The ratio depends on the received signal amplitude and can be adjusted based on the desired voltage. In one embodiment, the receiving winding (third coil 24) from Figure 3C can be coupled to a second converter designed for small-signal use with a specifically selected core material and size, which should be configured to saturate the transmitted pulses to protect the analog-to-digital circuit equipment (ADC) behind the receiving winding. When receiving a signal, however, the second small-signal converter should still be configured not to saturate, thereby allowing appropriate gain and sensitivity for the received signal.

[0166]

[0210] Figure 3D shows a schematic design of the receiving circuit equipment for an integrated receiving-enabled histotripsy system. The main difference between the embodiment shown in Figure 3D and the embodiment shown in Figure 3A is the converter, which will be described in the embodiment shown in Figure 3C. The embodiment in Figure 3D adds a VGA circuit and provides a digitizer with a "balanced" input by two capacitors C3 and C4 in series, rather than a level shifter as shown in Figure 3A.

[0167]

[0211] In another embodiment, the transmit-receive drive circuit equipment may include a transmit-receive switch. An integrated drive-receive circuit equipment having both transmit and receive circuit equipment on the same board can use a switch to separate the transmit signal from the receive signal. For example, a traditional TR switch with a diode blocks high-voltage transmit signals without attenuating the receive signal. Circuits with different linear gains can, according to the switch, appropriately amplify or attenuate a selected portion of the receive signal based on the amplitude of the received signal, thereby maximizing sensitivity. However, this design would waste a lot of power and would be large and expensive.

[0168]

[0212] Figure 4A illustrates another embodiment of a drive-receive circuit device configured to measure the current flowing back from transducer TX1 through drive converter T1 (rather than measuring the voltage generated by the transducer during reception as discussed above). The relatively large surface area of ​​the therapeutic transducer array element compared to conventional imaging transducers means that the transducer array generates a relatively large current, which enables high sensitivity during reception, whereas in the case of imaging transducers, only measuring the voltage induced by the acoustic signal is practical. Conventional ultrasonic imaging elements are too small to generate a usable received current. Therapeutic elements such as those described herein have a surface area hundreds to thousands of times larger than conventional imaging elements, and therefore the current is considerably larger and easier to measure (in the milliampere range rather than microamperes). In the illustrated circuit device, the current can be measured by a sensing resistor in the electrical path (R1). The drive-receive circuit device is configured to pass excess current from large reflections or in transmission pulses through a set of bypass diodes (D1 and D2). The transmitted current can be as large as 40A. While the drive-receiving circuit equipment receives reflections such as ultrasonic reflected signals and / or acoustic cavitation emissions, the sensing resistor is configured to measure the current induced in the circuit equipment by these reflections. The voltage generated across the current sensing resistor is connected to the ADC through a balun (T2) and capacitors C1 and C2. This balanced input configuration is the manufacturer's preferred circuit for the AFE5801 digitizer. Single-ended operation should also be possible for this or other digitizers by directly measuring the voltage on R1 relative to the ground.

[0169]

[0213] The drive-receive circuit device in Figure 4A can be configured to operate in low-gain and high-gain modes. Still referring to Figure 4A, the circuit device may have two current-sensing resistors R1 and R2 so that the overall sensitivity of the circuit can be greatly varied. As shown, this can provide a pair of transistors Q2 and Q3 configured to switch on / off simultaneously with the larger value resistor R1 (high sensitivity) and the smaller value resistor R2 (low sensitivity). The resistance of the circuit can be changed very quickly with these transistors to allow the use of both a low setting for a portion of the sudden increase in received data (e.g., higher amplitude received signals such as ultrasonic reflection signals from bone) and a high setting a few microseconds later (e.g., lower amplitude received signals such as acoustic cavitation emission signals from cavitation collapse). Since the sensor is changed directly, both scales have a very high SNR, unlike variable-gain amplifiers where the SNR is usually poor at higher gains. In some embodiments, additional sensing resistors can be provided in the same manner for an even wider dynamic range. In the circuit shown in Figure 4A, the high-gain mode is configured to measure a maximum current of 5mA in the ADC connected to the circuit equipment via the converter T2, while the low-gain mode is configured to measure a maximum current of 200mA in the ADC.

[0170]

[0214] Figure 4B shows an alternative embodiment that can be provided to pass large transfer currents using low gate threshold MOSFET transistors Q4 and Q5 instead of bypass diodes. With advances in transistors, there are now transistors that are smaller, cheaper, and more powerful than any diode for this bypass task. These transistors can have a higher turn-on voltage than a single diode, making it easier to use the full dynamic range of the ADC.

[0171]

[0215] Figure 4C shows a third embodiment in which bypass transistors Q4 and Q5 are explicitly controlled as active transmit-receive switches. The transistor gates are connected to a gate drive signal to fully turn the transistors on (in transmit mode) or fully off (in receive mode), and the gate drive signal can be + / - 5V, for example, depending on the transistor drive requirements. This configuration can reduce the RF noise generated during transmit, but instead, the passively switched bypass components must turn on and off rapidly at the ultrasonic frequency. This design has the trade-off of a small increase in complexity.

[0172]

[0216] The analog received signals described above can be converted to digital signals and then collected and processed. Signals received from the histotripsi transducer array can be, for example, reflections from bone or soft tissue, or acoustic emission signals from cavitation. These signals are typically received within a specific time window after the histotripsi pulse (e.g., tens to hundreds of microseconds after the transmission of the therapeutic pulse). Therefore, the hardware and software described herein are configured to synchronize the transmission, reception, and ADC conversion and sampling time clocks to obtain an appropriate time window after each histotripsi pulse containing the desired received signal. Once the synchronization and time window are properly set, the desired received signal can be collected and processed.

[0173]

[0217] To achieve proper synchronization and windowing, any of the transmit-receive drive electronics described herein may include embodiments capable of controlling both the transmit and receive operations of the transducers, as well as the ADC for several subsets or all channels of a histotripsy system, using a single field-programmable gate array (FPGA) device connected to an ADC. Synchronization between subsystems can be ensured, particularly when controlling various subsets of histotripsy transducer elements using multiple FPGAs, by providing the FPGA with a single clock on which the timing of operations to be performed in separate subsystems is based. Thus, receiving signals with a proper time window can be achieved through the proper allocation of timing for each operation during FPGA programming. When multiple FPGAs are required, for example, in arrays with too many transducer elements to be controlled from a single device, a single clock line can be spread to all transducer elements for synchronization, and a centralized "master" FPGA can be used to trigger the execution of the transducer elements' operations within the proper time window.

[0174]

[0218] Alternatively, any of the transmit-receive drive electronics described herein may include a multi-FPGA system that can be set up to run in “headless” mode, in which a centralized “master” FPGA is not required to generate / extend a single shared clock line or to trigger the execution of individual board operations. In such a mode, each FPGA should be set to operate independently of its own individual clock, as well as to monitor and update two common “program execution states” and one common “execution operation,” which are open-drain hardware I / O lines shared by the entire system. The open-drain lines should operate such that if any single FPGA applies a low signal to the line, any signal measured anywhere on the line should record the lowest value, and if all FPGAs apply a high signal to the line, and only in that case, any signal measured anywhere on the line should record the highest value. Two "Program Execution Status" lines are to be used by FPGAs to issue 1) "Ready to Execute" and 2) "Complete Execution" signals throughout the system. By default, each FPGA should apply a low signal to each of these lines, and each FPGA should apply a high signal to the "Operation Execution" line. When a new executable instruction is reached in the program while it is running, each FPGA should update the "Ready to Execute" line to apply a high signal to each FPGA and enter a standby state, in which state each FPGA should monitor signals on both the "Ready to Execute" and "Operation Execution" lines. When all FPGAs reach the "Ready to Execute" state, the signal recorded on the "Ready to Execute" line should reach its highest value, and the first FPGA in the system to detect the high state on the "Ready to Execute" line should issue a low signal on the "Program Execution" line, causing the first FPGA to record a lowest value everywhere. When a low signal is detected on the "Program Execution" line, each FPGA should set its own terminal on the "Program Execution" line to the lowest possible value and execute its stored command.Each FPGA should apply a high signal to both the "Execution Complete" and "Program Execution" lines after it has finished executing its respective command. When both the "Execution Complete" and "Program Execution" lines reach their highest values, the FPGA should reset all shared open drain line values ​​to their defaults, load the next instruction in the program, and repeat the process for each instruction until the program is complete.

[0175]

[0219] A fully connected set of receiving elements can generate large amounts of data; therefore, to meet the need for monitoring during therapy, we propose strategies to reduce the data load so that acquired signals can be transmitted and processed in real time. These strategies can be applied to any of the transmit-receive drive electronics described herein. Such strategies include, for example, artificially downsampling the data coming from the ADC in firmware running on an FPGA (for example, by storing only every other data point generated by the ADC, or the average of data points generated over many acquisition cycles). This effectively reduces the sampling frequency and therefore the data load without sacrificing time accuracy or dynamic range or increasing noise in the system. A differential compression scheme can also be applied in which all data captured after a first time point is stored as the difference between values ​​captured at adjacent time points. For example, for the values ​​of X at time 1 and Y at time 2, the difference between Y and X at time 2, D=YX, is stored directly instead of the value of Y, and then the actual value of Y can be calculated during processing as Y=X+D. In this way, very small values, such as X=64000 and Y=63900, which together represent 4 bytes of data, can be stored as X=64000 and D=-100, which together represent 3 bytes of data, allowing for the complete recovery of the Y value. As the length of the data record increases, this compression strategy results in data reduction proportional to the ratio of the size of the variable required to store the difference value to the size of the variable required to store the actual value. Generally, this can reduce the data load in current systems by 30% to 50%, although the reduction can be considerably larger in systems where the size of individual data elements is larger. For applications that do not require real-time processing / compression, further reduction in data size can be achieved through frequency domain conversion using methods similar to those employed to compress audio files.

[0176]

[0220] While some events that need to be monitored during histotripsy therapy require very high temporal precision (e.g., signals from individual cavitation events), others require little precision (e.g., signal reflections from large boundaries such as the skull, ribs, and tissue interfaces). Therefore, strategies for dynamically changing the compression ratio can be implemented to fully utilize incoming data for real-time applications. To this end, firmware and software controlling data acquisition have been configured to allow the sampling frequency and compression strategy used during acquisition to be set per channel in the array and to be independently updated in real time, even in the middle of individual acquisition events. This allows setting up different sub-apertures in the array to monitor different features of the therapy with required sampling frequencies and compression settings, as well as setting the receiving system to the maximum sampling frequency / minimum compression setting across all elements of the array as needed to monitor potentially weak, short-lived events, and then resetting to a lower sampling frequency with a higher compression setting outside the window requiring maximum monitoring. This allows for complete monitoring of this type of short-lived event without requiring acquisition cutoffs to reduce the data load, which would otherwise potentially result in a reduction in the physical size of the active monitoring field or a dramatic decrease in the monitoring speed during therapy.

[0177]

[0221] In some situations, the received signal amplitude may be low and the noise may be high, resulting in a low signal-to-noise ratio (SNR). One way to reduce noise and increase SNR is to oversample and average the data in firmware (e.g., FPGA firmware) before storing it. This also helps to increase the dynamic range and reduce memory requirements. Another technique is to provide a dynamically variable sample rate. For example, an ADC can be configured to always run at 50 MHz, but only high time precision may be required for certain parts of the data record. For parts of the signal that do not require such a high frame rate, the samples can be drastically reduced or averaged to greatly reduce storage requirements.

[0178]

[0222] While the bandwidth of therapeutic transducer elements is typically small, high sampling rates can be used to sample with excellent timing accuracy. The received data should be exceptionally well compressed in the Fourier domain (at least 10 times, and sometimes more). FPGAs can be configured to perform this compression for storage or transmission in firmware or software. Data compression is crucial for performing real-time monitoring, as the system will be overwhelmed by the volume of received data being collected.

[0179]

[0223] In applications where real-time monitoring is not essential, or where the treatment rate needs to remain higher than possible while simultaneously transferring fully acquired signals to the user's computer after each pulse, the system can be configured to transfer only partial signals and / or store the acquired signals directly within the FPGA device itself for later transfer to a control computer. This should allow for uninterrupted acquisition of signals from all delivery pulses without limiting the treatment rate. Such capability is useful for monitoring long-term changes in acquired signals. For example, there are inherent fluctuations in acoustic cavitation emission (ACE) signal characteristics related to the detachment state of target tissue, which makes it difficult to track tissue state pulse by pulse, but the changes in ACE signal characteristics exist over longer treatment timescales (e.g., >20 applied pulses) that allow for evaluation of the detachment state of the tissue. Partial signals can be transferred in real time to allow for localization and mapping of cavitation events pulse by pulse, while longer record-length signals, which will be transferred intermittently to evaluate the detachment state at the therapeutic target, can be stored in the FPGA.

[0180]

[0224] In some situations, it is possible to generate focal pressures far exceeding twice the nominally required to generate cavitation during therapy, and in such cases, it may be possible to generate cavitation using less than half the number of histotripsi transducer array elements. The software controlling the histotripsi array allows for easy partitioning of the array's elements into independently controllable sub-apertures, effectively enabling a single physical histotripsi transducer array to operate as numerous separate histotripsi arrays. Thus, multiple locations within the focal volume can be targeted simultaneously for therapy using separate sub-apertures of the array, allowing for increased therapy speed without requiring an increase in the rate at which pulses are delivered.

[0181] Ultrasound-based real-time histotripsy dose monitoring

[0225] Different tissue types / components require different histotripsy doses to completely render them inoperable. For example, tissues with high mechanical strength (e.g., blood vessels, nerves) require higher histotripsy doses to destroy. Tissues that are primarily cellular and collagen may require different doses to destroy. Disrupting the extracellular material in tissues requires much higher doses compared to the cellular components. Tissues can be heterogeneous, and therefore, even within a target tissue, treating one location of the target tissue (e.g., gray matter versus white matter in the brain) may require different doses than treating another location within the target tissue. Furthermore, histotripsy doses have an impact on the immune response, as different tumors require different histotripsy doses for complete dissection or maximization of the immune response. Even within a tumor, it is possible to have different tissue (cellular vs. extracellular) components. According to one aspect of this disclosure, a system and method for administering histotripsy and for real-time monitoring of tissue damage or treatment, both spatially and temporally, is provided to enable tracking of treatment progress and desired damage (e.g., homogeneous dissection of the target tissue or dissection of one tissue type while preserving another tissue type within the target tissue). In one aspect, spatial and temporal monitoring of histotripsy treatment progress is performed together with real-time monitoring of ultrasound signals generated during therapy. In other aspects, other imaging techniques, such as MRI, can be used to monitor histotripsy treatment progress. Alternatively, ultrasound monitoring recorded together with an MRI scan showing the target tumor can be used to monitor histotripsy treatment progress.

[0182]

[0226] According to aspects of this disclosure, real-time histotripsy dose monitoring can be used to 1) identify and locate cavitation formation within a target tissue volume, 2) identify when cavitation becomes completely cellularly unsustainable, 3) identify various tissue types and their locations within the target tissue volume, and 4) perform the following actions. In some aspects, real-time histotripsy dose monitoring is performed not by real-time imaging, but instead by monitoring and analyzing acoustic cavitation emission (ACE) signals received by a transfer-receiver histotripsy array. Note that these signals are non-imaging data, but instead convey features regarding the formation and collapse of cavitation within the tissue volume, which can then be used to determine the tissue type and / or the extent of tissue damage caused by the cavitation (e.g., the degree of cellular unsustainability).

[0183]

[0227] Real-time ultrasound feedback received from a transmission-receiving histotripsy array allows for spatial and temporal monitoring of dose delivery and damage. After transmitting a histotripsy pulse to a focal location within the target tissue region in the transmission-receiving histotripsy array to generate cavitation, cavitation nucleation, expansion, and collapse signals can be detected via the acoustic cavitation emission (ACE) signal received in the transmission-receiving histotripsy array. The received ACE signal can then be processed by the system to quantitatively monitor cavitation nucleation, expansion, and collapse, as well as the progress and completion of tissue treatment. Many different parameters or characteristics of the ACE signal can be used for this purpose, including but not limited to the timing and amplitude of the cavitation bubble expansion signal, collapse signal, rebound signal, cavitation collapse time (i.e., the time between the expansion signal and the collapse signal), peak amplitude of the expansion signal, peak amplitude of the collapse signal, amplitude ratio of the growth and collapse ACE signals, or decay rate of the rebound-related ACE signal amplitude.

[0184]

[0228] In some embodiments, ACE signals can be evaluated or processed to determine or identify the tissue type at the cavitation focus. Different tissue types respond to cavitation in different ways, and the ACE signals resulting from this cavitation reflect the differences between these tissue types. For example, soft tissues such as white matter, cellular tumors, or adipose tissue may have cavitation with a longer cavitation lifespan compared to hard or fibrous tissues such as neurovascular bundles or fibromas, which may have a relatively much shorter cavitation lifespan. Similarly, the histotripsy dose required to completely render fibrous tissue unsustainable is higher than that required to completely render a cellular tumor or a normal liver unsustainable. The histotripsy dose required to completely render the gray matter of the brain unsustainable is slightly higher than that required to completely render the white matter unsustainable.

[0185]

[0229] In some embodiments, these ACE signals can be used to determine whether cavitation is forming in a target tissue type within a target tissue volume (e.g., in fibrous tissue growing in the white matter of the brain) or in a non-target tissue type within a target tissue volume (e.g., in the gray matter of the brain). For example, the brain typically consists of gray matter containing a high density of nerve cell bodies, and white matter containing myelin, which is an insulating layer or sheath around the nerves. Brain tumor growth can occur in the white matter, in the gray matter, or at the point where the white and gray matter meet. Regardless of the tumor's location, treatment of brain tumors can be guided by monitoring ACE signals to determine the tissue type at the focal location and to induce therapy so as to result in complete cellular instability only in the desired tissue type (e.g., tumor tissue and / or white matter), and to avoid damaging undesirable tissue types (e.g., gray matter).

[0186]

[0230] Knowledge of tissue types at focal locations derived from ACE signals can be used to spatially map tissue types within a target tissue volume. Furthermore, this mapping or spatial recognition of locations where different tissue types are localized can be used to adjust or modify treatment plans, including adjusting or modifying histotripsi pulse waveforms, amplitudes, and pulse repetition frequencies (PRFs) based on tissue type. For example, when treating brain tissue, test or sample pulses can be directed to various locations within the tissue volume, and the resulting ACE signals can be evaluated to determine the tissue type (e.g., by monitoring the cavitation lifespan of the resulting cavitation). The system can be configured to identify the tissue type for each focal location using knowledge of various cavitation lifespans for a collection of tissue types. Since different tissue types also have different cavitation thresholds (e.g., the pressure required to generate cavitation), the amplitude or pulse sequence for each treatment location within the tissue volume can be adjusted to generate cavitation within the desired tissue type and not within other tissue types (or to generate cavitation lifespans below the threshold). For example, when treating a tumor that affects or is near both white matter and gray matter tissue, the amplitude of the histotripsi pulse can be adjusted or modified to generate cavitation in both the tumor and white matter tissue while avoiding cavitation in the gray matter tissue (assuming, for example, that gray matter tissue requires a higher cavitation threshold than white matter tissue and tumor), or while generating a cavitation lifespan below the threshold to minimize damage in the gray matter (our preliminary data show that the cavitation lifespan is shorter in gray matter than in white matter even with the same histotripsi parameters).

[0187]

[0231] Figures 5A–5B illustrate one example of monitoring ACE features with a transmit-receive transducer array to spatially and temporally quantify histotripsy-induced tissue damage. In Figure 5A, the target tissue volume 50 can include brain tissue containing both white and gray matter. White matter is typically found near the center of the brain, while gray matter is typically found in the outer cortex. Distinguishing between white and gray matter during real-time imaging can be challenging, especially because ultrasound imaging through the skull is difficult or impossible. In Figure 5A, the target tissue volume 50 was treated individually at treatment locations 55–65 along the X-axis (relative to the transducer) as shown. In this example, the treatment locations are positioned in 1 mm increments from -5 mm to 5 mm along the X-axis. Each treatment location 55–65 represents a location within the target tissue volume 50 that receives a dose of histotripsy energy to mechanically dissolve the tissue at this treatment location, causing cavitation. In some embodiments, the transmit-receive transducer array can be mechanically moved between each of the treatment locations, for example, by a robotic arm or robotic positioning system. In other embodiments, the transmit-receive transducer array can be electronically steered between locations (e.g., phased array steering). In additional embodiments, movement between treatment locations can be a combination of mechanical movement and electronic focus steering. Since histotripsi pulses are delivered to each of the treatment locations in Figure 5A, the transmit-receive transducer array can be configured to detect ACE signals from cavitation to monitor treatment both spatially and temporally.

[0188]

[0232] In some embodiments, the precise location of the transmit-receive transducer array can be determined from the position and orientation of the robotic arm and robotic navigation system. The focal position for each focal location can also be determined from the natural focal distance (or electronically steered focal location) relative to the transducer. Thus, each focal location can be spatially mapped by the system and associated with the received ACE signal for each focal location. This information can be presented to the user and can also be overlaid on other images of the target tissue volume, including ultrasound, CT, or MRI imaging. When using the ACE signal to determine the tissue type at a particular focal location, this information can also be presented to the user.

[0189]

[0233] Figure 5B shows plots of cavitation lifespan (x-positional - spatial) and applied histotripsi pulse (dose-temporal) for each of the treatment locations 55–65, with 50 pulses applied to each location. As shown in each individual plot, the cavitation lifespan (time between cavitation nucleation and decay), as derived from the ACE signal, is given by pulse P 1,65 From increasing, plateau pulse P P,65 In this case, a plateau phase is entered as the number (or duration) of applied histotripsi pulses increases. As shown in the figure, the cavitation lifespan is plateau pulse P P,65 and pulse P 50,65 It remains relatively constant or stable between these two points. The cavitation lifespan plot associated with treatment location 65 contrasts with the cavitation lifespan plot for treatment location 55. As shown in Figure 5B, the cavitation lifespan for treatment location 55 is P 1,55 and plateau pulse P P,55 It increases between the plateau and pulse phases. As shown in the figure, the cavitation lifespan is as follows: P,55 and pulse P 50,55It remains relatively constant or stable between these two points. Complete cell survival is related to a plateau in the cavitation lifespan, and therefore, in the case of treatment locations 55 and 65, complete cell survival is related to the plateau pulse P P,55 and P P,65 These are achieved in each respective location. The greatest difference between the plot associated with treatment location 55 and the plot associated with treatment location 65 is that the cavitation lifespan enters a plateau phase at treatment location 55 later than at treatment location 65.

[0190]

[0234] To provide additional context, when the treatment locations in Figures 5A–5B are spatially mapped to brain tissue, treatment locations 55–59 are located within the gray matter tissue of the brain, and treatment locations 60–65 are located within the white matter tissue of the brain. In summary, referring to Figure 5B, it is found that all treatment locations within the gray matter of the brain (e.g., treatment locations 55–59) require more histotripsi pulses for cavitation lifespan to enter a plateau phase compared to treatment locations in the white matter (e.g., treatment locations 60–65), while white matter requires fewer histotripsi pulses before cavitation lifespan enters a plateau phase. Therefore, ACE-induced cavitation lifespan can be used by the system to monitor histotripsi therapy both spatially and temporally, and furthermore, to quantify and localize tissue type-specific damage (e.g., gray matter vs. white matter). Although gray matter and white matter tissues are similar, gray matter is slightly harder than white matter tissue. In the context of the ACE map in Figure 5B, it can be seen that gray matter tissue has a slightly smaller maximum cavitation lifespan compared to white matter tissue and should require more treatment before entering a plateau phase (before indicating complete cellular unsustainability).

[0191]

[0235] In some embodiments, the system can be configured to deliver histotripsi pulses to a target tissue volume to form cavitation at treatment locations within the target tissue and to receive ACE signals from the cavitation. Features derived from the ACE signals, such as the maximum cavitation lifespan or the time / pulse until the cavitation lifespan enters a plateau phase, can then be used by the system to determine the tissue type and / or the progress or completion of treatment. In some embodiments, histotripsi pulse delivery can be stopped immediately and automatically when the system identifies a plateau phase and therefore treatment completion or cell instability to avoid delivering excessive ultrasound pulses to the tissue location. In some embodiments, treatment completion or complete cell instability can be indicated to the user in the form of a visual indicator (e.g., a warning or message on the system console or GUI) or as an audible sound or warning. In some embodiments, tissue type determination is based on the amount of pulses delivered to a given treatment location (or time) before the cavitation lifespan enters a plateau phase or stops increasing, as derived from the received ACE signals. Alternatively, the plateau phase can be defined as a change in the rate of increase of the cavitation lifespan. For example, histotripsy therapy can induce cavitation with a cavitation lifespan that increases at a first cavitation lifespan rate until a plateau occurs, after which pulses either stop increasing or increase at a second cavitation lifespan rate that is lower (or significantly smaller) than the first cavitation lifespan rate.

[0192]

[0236] Referring again to Figure 5B and focus location 65, P 1,65 and P P,65 The pulse delivered between the two results in an increased cavitation lifespan at the first cavitation lifespan rate, and P P,65 and P 50,65The pulses delivered between the two points may increase or not increase at all after a plateau period at the second cavitation lifespan rate. Furthermore, tissue type determination can be based solely on the maximum value of the cavitation lifespan. A large maximum cavitation lifespan within the first cavitation lifespan range may indicate fatty or healthy cellular tissue such as white matter, while a lower maximum cavitation lifespan within the first cavitation lifespan range may indicate fibrous material such as pancreatic tumors. In other words, a maximum cavitation lifespan above the threshold may indicate cellular tissue, while a maximum cavitation lifespan below the threshold may indicate hard or fibrous tumors. Note that not all healthy tissue is softer than tumors, as many tumors are not hard or fibrous. To give a specific example, the maximum cavitation lifespan of white matter and gray matter are quite similar, typically ranging from 30–50 μs in the first cavitation event (gray matter is slightly harder and therefore has a smaller maximum cavitation lifespan), and then extending to 100–120 μs during the stagnation phase, with gray matter having a slightly smaller maximum cavitation lifespan. Fibromas, on the other hand, can have a maximum cavitation lifespan 2–3 times greater. To create a greater difference in cavitation lifespan between different tissue types, higher peak negative pressure or a slightly longer pulse duration can be used.

[0193]

[0237] In some embodiments, the system can be configured to automatically determine the tissue type at the focus or treatment location based on ACE features and / or thresholds associated with the received ACE features. In further embodiments, the system can be configured to determine whether the focus or treatment location is located within fibrous tissue or within cellular or adipose tissue. In some embodiments, the system may access or include a database or lookup table that correlates various ACE features with specific tissue types in order to perform tissue type determination. For example, the system may classify fibrous tissue (or other fibrous tissue) as being associated with ACE signals that generally result in a smaller maximum cavitation lifespan or higher dose / time required for cavitation lifespan stagnation, rather than ACE signals from surrounding cellular tissue that generally have a larger maximum cavitation lifespan or lower dose / time required for cavitation lifespan stagnation. To give a concrete example, in the case of a given histotripsipulse sequence, if it is determined that complete cellular failure of a tumor occurs when the cavitation lifespan enters a stagnation phase within a first threshold range, complete cellular failure of the gray matter of the brain occurs when the cavitation lifespan enters a stagnation phase within a second threshold range, and complete cellular failure of white matter tissue occurs when the cavitation lifespan enters a stagnation phase within a third threshold range, the system can monitor the cavitation lifespan from the received ACE signal, determine when the cavitation lifespan entered a stagnation phase, and perform tissue type determination.

[0194]

[0238] Furthermore, as explained above, the maximum cavitation lifespan itself can provide indication of the tissue type. Generally, fibrous tissues such as fibromas will have a smaller maximum cavitation lifespan than healthy surrounding tissue. Therefore, the system can be configured to automatically detect, based on the maximum cavitation lifespan, when the focal location or cavitation is located within a tissue type not intended for treatment and when it is located within a tissue type intended for treatment (e.g., tumor tissue). In addition, if the system is moving the transducer's focal zone through a tissue volume and the received ACE signal indicates a large decrease in cavitation lifespan, the system can determine that the focal zone has moved from a tissue intended for treatment (e.g., a tumor with a relatively large maximum cavitation lifespan) to a tissue not intended for treatment (e.g., healthy surrounding tissue with a much smaller maximum cavitation lifespan). In some embodiments, the system can be automatically configured to stop or pause treatment or histotripsi pulse delivery (e.g., in a pulse generator), or alternatively, to refocus the transducer's focus back to its previous location (e.g., back into tumor tissue in a robotic positioning system).

[0195] Selective treatment of brain tissue

[0239] Figure 6A shows a cross-section of a subject's brain containing white matter, gray matter, and fibroma, which are slated for treatment with histotripsy therapy. Figure 6B is a magnified view of the tumor, including the surrounding white and gray matter regions. In Figure 6B, histotripsy pulses can be delivered to various test points TP1 through TP5 in the tissue. The ACE signals resulting from cavitation formed at each test point can be used to determine the tissue type at each test point. For example, the number of pulses or time to reach the maximum cavitation lifespan, or cavitation lifespan stagnation at TP3, can be evaluated by the system to determine whether the tissue at TP3 is white matter or potentially white matter. Similarly, the number of pulses or time to reach the maximum cavitation lifespan, or cavitation lifespan stagnation at TP5, can be evaluated by the system to determine whether the tissue at TP5 is gray matter or potentially gray matter. Furthermore, the number of pulses or time until the maximum cavitation lifespan, or the cavitation lifespan stagnation phase in TP1, TP2, and TP4, can be evaluated by the system to determine whether the tissue in TP1, TP2, and TP4 is or potentially fibrotic tissue.

[0196]

[0240] As described above, tissue types at various focal locations (or test points) can be spatially mapped and presented to the system user. Knowledge of the locations of various tissue types can also be used to adjust or modify the treatment plan for the target tissue volume. For example, a robotic positioning system can be controlled to avoid delivery of therapy to tissue locations including non-target tissues (e.g., gray matter and white matter). Furthermore, knowledge of tissue types can be used to adjust or modify pulse parameters or amplitude to ensure that the cavitation threshold required for complete cellular instability is achieved. In addition, sensitive tissues such as gray matter can be protected by adjusting the amplitude or pulse sequence to generate cavitation in tissues such as tumors or white matter without generating cavitation in gray matter. Thus, knowledge of tissue types, such as that derived from ACE signals, can be used to selectively treat target tissues without damaging non-target or undesirable tissues.

[0197]

[0241] In the case of ACE-based tissue detection, the specific methods and algorithms illustrated in the flowchart of Figure 7 can be performed in the histotripsy system of this disclosure. The method can be a computer-executed method or one or more algorithms performed by the processor of the histotripsy system to cause the histotripsy system to perform the following operations. In step 702, the method may include delivering histotripsy therapy pulses to focal locations in the target tissue using an ultrasonic transducer array to generate cavitation at the focal locations. In some embodiments, the delivery of histotripsy therapy pulses may be for testing a cavitation response at a particular focal location. In other embodiments, the pulses are delivered to treat the focal location to cause complete cellular instability. As described above, multiple transducer elements of the array can each deliver histotripsy pulses to the tissue. The ultrasonic transducers may be mounted on a robotic arm and configured to deliver histotripsy pulses to one or more therapeutic or focal locations in the target tissue to generate cavitation at each focal location.

[0198]

[0242] Next, in operation 704, the method may include receiving acoustic cavitation emission (ACE signal) resulting from histotripsy-induced cavitation. Receiving the ACE signal may utilize, for example, one of the systems or drive electronics described above. The histotripsy system may process or analyze the ACE signal to extract or identify features of the ACE signal, including but not limited to the timing and amplitude of the cavitation bubble expansion signal, collapse signal, rebound signal, cavitation collapse time (i.e., the time between the expansion signal and the collapse signal), peak amplitude of the expansion signal, peak amplitude of the collapse signal, amplitude ratio of the growth-to-collapse ACE signal, or decay rate of the rebound-related ACE signal amplitude.

[0199]

[0243] Next, in operation 706, the method can use the information or features encoded in these ACE signals (e.g., maximum cavitation lifespan, time / pulse to reach cavitation lifespan stagnation) to determine the tissue type at the focal location. In some embodiments, the system may have access to or know features that associate features or feature ranges / values ​​with specific tissue types. For example, the system may access a database or lookup table of ACE features for adipose tissue, healthy tissue, fibrous tissue, tumor tissue, etc., and compare the received ACE features with the database or lookup table to determine the tissue type. For example, a relatively large maximum cavitation lifespan (e.g., 90-100 μs or more) may indicate fibrous tissue such as a tumor, while a smaller cavitation lifespan (e.g., approximately 30-50 μs) may indicate healthy or non-target tissue such as gray matter or white matter.

[0200]

[0244] Finally, in operation 708, the method may optionally include adjusting one or more parameters of the drive electrical signal to each array element to take into account the tissue type detected at this focal location. For example, the treatment plan may be modified to avoid shifting the transducer focus to tissues not intended for treatment (such as white / gray matter), or alternatively, to adjust the pulse amplitude so as not to generate cavitation in these tissues (e.g., the pressure is below the cavitation threshold).

[0201] Selective treatment of fat (fat removal)

[0245] The principles described above can also provide systems and methods for using histotripsy for rapid fat reduction without damaging surrounding tissues (including tubes, nerves, and muscles). Obesity is a major health problem, increasing the risk of many diseases, including cardiovascular disease and cancer. Millions of Americans suffer from health problems associated with high levels of body fat. Current standard surgical treatments for subcutaneous fat reduction are invasive. Other alternatives include laser or ultrasound-based approaches limited to low treatment speed and small treatment volume.

[0202]

[0246] Histotripsy uses microsecond ultrasonic pulses to liquefy target tissue into cell-free debris by controlling acoustic cavitation, a mechanism entirely different from current approaches. Cavitation generation in histotripsy is achieved when a microsecond pulse reaches a negative pressure exceeding an intrinsic threshold, overcoming the surface tension of existing nanometer gas pockets within the tissue. This threshold has been measured to be 26–30 MPa for water-based tissues (nerves, tubes, liver, kidneys, heart, brain, etc.) and 14 MPa for fat when using a single period pulse. Figures 8A–8F show the probability data and fitted curves for each sample type tested. Each data point is a fraction of 100 pulses in which cavitation was detected. The curves were fitted to each dataset by nonlinear least-squares regression.

[0203]

[0247] Histotripsy can be used to non-invasively and selectively liquefy fat that can be absorbed by the body via metabolism or removed with a small catheter, while preserving the surrounding tissues, including nerves, tubes, and muscles, in their original state.

[0204]

[0248] Histotrips have the potential to reduce large volumes of subcutaneous or visceral fat (e.g., in the abdomen, legs, and arms) and for precise fat reduction for facial or body sculpting. To accelerate fat reduction treatment, histotrips transducers with a large focal volume (>5 mm) can be used. By leveraging the differential cavitation threshold between fat and water-based tissue, large focal zone transducers can perform fat reduction treatment very quickly (>10 mL / min) while preserving other tissues. While imaging guidance can be used to induce targeting by leveraging the differential threshold, it is not required and simplifies the setup. For precise fat reduction for facial or body sculpting, histotrips with a small focal zone and shallow depth of focus can be used to treat subcutaneous fat near the skin.

[0205]

[0249] Figure 9 is a cross-sectional view of human tissue, including the skin, adipose tissue, and muscle layers. Vascular structures, including blood vessels, are also shown. As described above, histotripsi pulses can be delivered to a subject to selectively detach or liquefy adipose tissue without damaging surrounding tissues such as skin, muscle, or tubules. In some embodiments, the period may be configured to generate a negative pressure with a peak greater than 14 MPa and less than 26 MPa to liquefy adipose tissue without damaging or rendering the skin, muscle, or tubules unsustainable.

[0206]

[0250] Alternatively, the transmitted pulses and the ACE signals measured in response to cavitation can be processed or analyzed to determine the tissue type at the focal location. For example, it may not be precisely known how deep or thick the fat layer is. In one embodiment, a test pulse can be transmitted at increased depth within the tissue, and the cavitation response can be monitored to determine the tissue type (e.g., skin, fat, muscle). The test point or focal location can be mapped to determine the thickness or depth for each tissue type. After this mapping, a treatment plan can be generated or adjusted to direct the histotripsi pulse only within the fat region, including along the skin / fat boundary and fat / muscle boundary. In this way, a personalized treatment plan can be generated that more efficiently targets adipose tissue without targeting other sensitive tissues that are not intended for treatment.

[0207]

[0251] Figure 10 shows a flowchart of a method for removing or reducing fat in a patient, which involves delivering a histotripsi pulse to the target tissue with a peak negative pressure sufficient to liquefy the fat-based tissue rather than the water-based tissue (step 1002). As described above, the pulse can have a peak negative pressure between 14 MPa and less than 26 MPa (step 1004). The pulse can be one cycle (step 1006). In some cases, the transducer can have a large focal volume (e.g., >5 mm) to reduce treatment time (step 1008).

[0208] MRI-based real-time histotripsy dose monitoring

[0252] Periodic diffusion-weighted MRI (dMRI) therapy can also be used to spatially and temporally monitor the histotripsy dose. In some embodiments, the MRI imaging system can be positioned around or near the patient so that MRI imaging can be applied periodically during therapy. In some embodiments, the entire histotripsy system is MRI compatible. In other embodiments, the system (e.g., transducer array) can be moved out of the imaging field when taking dMRI images, while other embodiments of the system can be MRI compatible (e.g., linked containers).

[0209]

[0253] dMRI images can be evaluated to identify tissue changes within a target tissue volume in response to cavitation, as reflected by changes in the apparent diffusion coefficient (ADC) in the dMRI image. In some embodiments, ADC changes reflect the total dose delivered to the tissue, and increasing the ADC indicates receiving a higher dose. ADC changes, and therefore histotripsy doses delivered to the tissue, can be presented to the user. In some embodiments, the system can be configured to generate an ADC map with this data, which can be presented to the user or, optionally, overlaid on other high-quality medical imaging of the target tissue volume (e.g., ultrasound, CT, MRI, etc.).

[0210]

[0254] Figures 11A and 11B show examples of histotripsy-generating injury in the brain in vitro, as observable by dMRI. In Figure 11A, the focus is electronically steered to cover the target volume with various pulse counts (1, 5, 10, 30, 50, and 100) for each focal location of the histotripsy dose, resulting in a 1 cm² dose. 3Cube-shaped lesions were induced in the brains of ex vivo bovine animals. Because histotripsy mechanically disrupts cellular members and extracellular intercellular material, the apparent diffusion coefficient (ADC) in the tissue changes, as shown in dMRI immediately after treatment. As shown in Figure 11B, ΔADC tends to increase as the histotripsy dose increases. Therefore, ADC maps collected periodically during histotripsy treatment (e.g., at any predetermined interval, such as every 6 seconds) can be overlaid on T1 or T2-weighted MRI to indicate histotripsy-induced injury both spatially and temporally. The ADC maps can be used to identify one or more focal locations where complete cellular non-viability occurs. In some embodiments, a warning or indication can be provided to the user when complete cellular non-viability occurs at one or more focal locations in the target tissue.

[0211]

[0255] Pre-treatment measurements (e.g., ultrasound or MRI elastography) can provide spatial tissue property measurements. These measurements can then be used to plan spatial dose delivery.

[0212]

[0256] Figure 12 is a flowchart showing methods and algorithms that can be performed with the histotripsy system of the present disclosure. A method can be a computer-executed method or one or more algorithms performed by the processor of the histotripsy system to cause the histotripsy system to perform the following operations. In step 1202, the method may include delivering histotripsy therapy pulses to focal locations in target tissue using an ultrasonic transducer array to generate cavitation at the focal locations. In some embodiments, the delivery of histotripsy therapy pulses may be for testing a cavitation response at a particular focal location. In other embodiments, the pulses are delivered to treat the focal location to cause complete cellular instability. As described above, multiple transducer elements of the array can each deliver histotripsy pulses to the tissue. The ultrasonic transducers may be mounted on a robotic arm and configured to deliver histotripsy pulses to one or more therapeutic or focal locations in target tissue to generate cavitation at each focal location.

[0213]

[0257] In step 1204, the system can periodically acquire diffusion-weighted MRI (dMRI) images of the target tissue, such as on an MRI system connected to or separate from the histotripsy system, and located near the patient. The system can acquire dMRI images according to a preset interval (e.g., every 1 second, every 2 seconds, every 3 seconds). In some embodiments, the interval is less than 10 seconds between subsequent dMRI images.

[0214]

[0258] In operation 1206, the system can identify a change in the apparent diffusion coefficient (ADC) in the dMRI image. In some embodiments, an increased ADC indicates an increased dose delivered to the target tissue volume.

[0215]

[0259] In operation 1208, an optional ADC map can be generated that maps the delivered histotripsy dose at the focal location within each target tissue volume. In operation 1208, the ADC map can optionally be overlaid on other medical imaging of the target tissue volume, such as ultrasound imaging, MRI imaging, or CT imaging of the target tissue volume.

[0216]

[0260] The present invention provides a histotripsy system that allows for spatial and temporal prediction and control of dose delivery and damage by using ultrasound or MRI spatial and temporal feedback during histotripsy treatment combined with pre-treatment tissue measurements, in order to treat a specific tissue (e.g., white matter) while preserving another specific adjacent tissue within the target, or to homogeneously dislodge the target tissue.

[0217]

[0261] Regarding additional details relating to the present invention, materials and manufacturing techniques may be adopted as being within the level of those skilled in the art. The same may apply to method-based embodiments of the present invention in terms of additional actions that are generally or logically adopted. Furthermore, it is assumed that any optional feature of any variant of the described invention may be described and claimed independently or in combination with any one or more of the features described herein. Similarly, references to singular items include the possibility that a plural form of the same item exists. More specifically, as used herein and in the appended claims, the singular “a,” “and,” “said,” and “the” include plural referents unless the context otherwise explicitly states. It should be further noted that the claims may be drafted to exclude any optional element. Thus, this statement is intended to serve as an antecedent for the use of exclusive technical terms such as “solely,” “only,” and similar ones in relation to the enumeration of claim elements or the use of “negative” limitations. Unless otherwise defined herein, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art in which the invention pertains. The scope of the invention should not be limited by the specification of the subject matter, but rather by the plain meaning of the claims adopted.

Claims

1. A method using a transmission-receiving histotripsy system for histotripsy treatment monitoring, The steps include: transmitting a high-voltage histotripsy therapy pulse to the focal location in target tissue using a transmission electronic device and a histotripsy therapy transducer array to generate cavitation at the focal location; The steps include receiving a low-voltage acoustic cavitation emission (ACE) signal from the cavitation with a receiving electronic device and the histotripsy therapy transducer array, The steps include processing the received ACE signal to identify the cavitation lifespan of the cavitation at the focal location, In order to determine that complete cellular failure has occurred at the aforementioned focal location, the steps include identifying a stagnation period during the cavitation lifespan. Methods that include...

2. The method according to claim 1, further comprising the step of generating a 3D map of the cavitation generated by the transmitted pulse in real time.

3. The method according to claim 1, wherein the step of identifying the plateau includes the step of identifying the time until the cavitation lifespan enters the plateau.

4. The method according to claim 1, wherein the step of identifying the plateau includes the step of identifying the number of pulses until the cavitation lifespan enters the plateau.

5. The method according to claim 1, wherein the step of identifying the stagnation period includes the step of identifying when the cavitation lifespan stopped increasing.

6. The method according to claim 1, further comprising the step of automatically stopping the delivery of a high-voltage histotripsy therapy pulse when it is determined that complete cell survival has occurred at the aforementioned focal location.

7. The method according to claim 1, further comprising the step of providing an instruction to the user that complete cellular failure has occurred at the aforementioned focal location.

8. The method according to claim 1, wherein the instruction includes an audible warning.

9. The method according to claim 1, wherein the instruction includes a visual warning.

10. Ultrasonic transducer array and A transmission electronic device connected to the ultrasonic transducer array and configured to transmit one or more histotripsi pulses to one or more focal locations to generate cavitation in target tissue, A receiving electronic device configured to receive acoustic cavitation emissions (ACE) from the aforementioned cavitation, One or more processors operationally coupled to the aforementioned transmission and reception electronic equipment, configured to process the received ACE signal to identify the cavitation lifespan of the cavitation at the focal location, and further configured to identify a stagnation period in the cavitation lifespan to determine that complete cellular unsustainability has occurred at the focal location, and A histotripsy system equipped with this feature.

11. The system according to claim 10, wherein one or more processors are further configured to generate a 3D map of the cavitation produced by the transmitted pulses in real time.

12. The system according to claim 11, further comprising a display configured to display the 3D map.

13. The method according to claim 10, wherein one or more processors are configured to identify the stagnation period by identifying the time until the cavitation lifespan enters a stagnation period.

14. The method according to claim 10, wherein one or more processors are configured to identify the stagnation period by identifying the number of pulses until the cavitation lifespan enters a stagnation period.

15. The method according to claim 10, wherein one or more processors are configured to identify the stagnation period by identifying when the cavitation lifespan stopped increasing.

16. The method according to claim 10, wherein one or more processors are configured to stop delivering a high-voltage histotripsy therapy pulse when they determine that complete cell survival has occurred at the focal location.

17. The method according to claim 10, wherein one or more processors are configured to provide an instruction to the user that complete cellular unsustainability has occurred at the focus location.

18. The method according to claim 10, wherein the instruction includes an audible warning.

19. The method according to claim 10, wherein the instruction includes a visual warning.

20. A method for monitoring histotripsy treatment, The steps include: transmitting high-voltage histotripsy therapy pulses to one or more focal locations in target tissue using a transmission electronic device and a histotripsy therapy transducer array to generate cavitation at the focal locations; The steps include acquiring periodic diffusion-weighted magnetic resonance imaging (dMRI) images of one or more focal locations in the target tissue, The steps of processing the dMRI images to identify the apparent diffusion coefficient (ADC) at one or more focal locations in the target tissue, A step of generating an ADC map that conveys the dose of histotripsy therapy received at each of the one or more focal locations in the target tissue. Methods that include...

21. The method according to claim 20, further comprising the step of displaying the ADC map.

22. The method according to claim 20, wherein the increased ADC in the target tissue indicates that it has received an increased histotripsy dose.

23. The method according to claim 20, further comprising the step of identifying complete cellular instability at one or more focal locations in the target tissue.

24. Ultrasonic transducer array and A transmission electronic device connected to the ultrasonic transducer array and configured to transmit one or more histotripsi pulses to one or more focal locations to generate cavitation in target tissue, A magnetic resonance imaging (MRI) system configured to periodically acquire diffusion-weighted magnetic resonance imaging (dMRI) images of one or more focal locations in the target tissue, One or more processors operationally coupled to the transmission electronic equipment and the MRI system, configured to process the dMRI images to identify the apparent diffusion coefficient (ADC) at one or more focal locations in the target tissue, and further configured to generate an ADC map that conveys the dose of histotripsy therapy received at each of the one or more focal locations in the target tissue. A histotripsy system equipped with this feature.

25. The system according to claim 24, further comprising a display configured to display the aforementioned ADC map.

26. The system according to claim 24, wherein the increased ADC in the target tissue indicates that it has received an increased histotripsy dose.

27. The method according to claim 24, wherein the system is configured to identify complete cellular instability at one or more focal locations in the target tissue.

28. A method for tissue type detection using a transmission-receiving histotripsy system, The steps include: transmitting high-voltage histotripsy therapy pulses to one or more focal locations within the target tissue using a transmission electronic device and a histotripsy therapy transducer array to generate cavitation in the target tissue; The steps include receiving a low-voltage acoustic cavitation emission (ACE) signal from the cavitation with a receiving electronic device and the histotripsy therapy transducer array, The steps include processing the received acoustic cavitation emission signal to identify characteristics related to the tissue type, The steps include determining, based on the identified features, that the first tissue at the first focus location has a different tissue type from the second tissue at the second focus location. Methods that include...

29. The method according to claim 28, further comprising the step of generating a 3D map of the cavitation generated by the transmitted pulse in real time.

30. The method according to claim 28, wherein the identified features include the maximum cavitation lifespan at each of the one or more focal locations.

31. The method according to claim 28, wherein the identified features include the time until the cavitation lifespan enters a plateau phase.

32. The method according to claim 28, wherein the identified features include the number of pulses until the cavitation lifespan enters a plateau phase.

33. The method according to claim 30, wherein the maximum cavitation lifespan at the first focal location is considerably smaller than the maximum cavitation lifespan at the second focal location.

34. The method according to claim 33, wherein the maximum cavitation lifespan at the first focal location is 2 to 3 times smaller than the maximum cavitation lifespan at the second focal location.

35. The method according to claim 28, further comprising the step of determining that the first tissue includes fibrous tissue and the second tissue includes cellular tissue.

36. The steps include: transmitting a histotripsy pulse to a first focal location in a transmission-receiving histotripsy transducer array to generate cavitation; The steps include receiving the ACE signal from the first focal location with the transmission-receive histotripsy transducer, The steps include identifying a first maximum cavitation lifespan at the first focal location, The steps include mechanically moving or electronically steering the histotripsy therapy transducer array from the first focal location to the second focal location, The steps include transmitting a histotripsy pulse to the second focal location in the transmission-receiving histotripsy transducer array to generate cavitation, The steps include receiving the ACE signal from the second focal location with the transmission-receive histotripsy transducer, The steps include identifying a second maximum cavitation lifespan at the second focal location, The steps include: comparing the first maximum cavitation lifespan with the second maximum cavitation lifespan in order to determine whether the second focal location is located in a different tissue type than the first focal location; A histotripsy method, including the above.

37. The method according to claim 36, further comprising the step of determining that the second focal location is in a different tissue type if the second maximum cavitation lifespan is considerably different from the first maximum cavitation lifespan.

38. The method according to claim 37, further comprising the step of determining that the second focal location is in a different tissue type if the maximum cavitation lifespan at the first focal location is 2 to 3 times smaller than the maximum cavitation lifespan at the second focal location.

39. The method according to claim 37, further comprising the step of determining that the second focal location is in a different tissue type if the maximum cavitation lifespan at the first focal location is 2 to 3 times greater than the maximum cavitation lifespan at the second focal location.

40. The steps include: transmitting a histotripsy test pulse to one or more test locations within the target tissue using a transmission electronic device and a histotripsy therapy transducer array to generate cavitation in the target tissue; The steps include receiving low-voltage acoustic cavitation emission (ACE) signals from the cavitation at each of the one or more test locations using a receiving electronic device and the histotripsy therapy transducer array, The steps include processing the received acoustic cavitation emission signal to determine the tissue type in one or more test locations, The steps include modifying the histotripsy treatment plan based on the tissue type determination in order to deliver histotripsy therapy to one or more focal locations within the tissue type to be treated, and to avoid delivering histotripsy pulses to any locations within the tissue type not to be treated. A histotripsy method, including the above.

41. Ultrasonic transducer array and A transmission electronic device connected to the ultrasonic transducer array and configured to transmit one or more histotripsi pulses to one or more focal locations to generate cavitation in target tissue, A receiving electronic device configured to receive acoustic cavitation emissions (ACE) from the aforementioned cavitation, One or more processors operationally coupled to the transmission and reception electronic equipment, configured to process the received ACE signal in order to identify features relating to tissue type and to determine the tissue type at one or more focus locations based on the identified features, and A transmission-receiving drive electronic device for a histotripsy system.

42. The steps include acoustically linking a histotripsy therapy transducer to the subject's skin, The steps include positioning the focus of the histotripsy therapy transducer within the layer of fat beneath the skin, The steps involve delivering a histotripsi pulse with a negative pressure peak greater than 14 MPa and less than 26 MPa in order to non-invasively and selectively liquefy the fat rather than the surrounding tissue, and A histotripsy method, including the above.

Images