Monitoring and control of histotripsy treatment

Abstract

Histotripsy treatment involves sonicating a target region with a series of acoustic pulses, detecting ultrasonic reflected signals from the target region, controlling an ultrasonic transducer to deliver a sequence of acoustic pulses to the target region with sufficient amplitude to induce cavitation sufficient to mechanically rupture the tissue within the target region, receiving data characterizing the detected reflected signals, computationally estimating the level or location of acoustic activity or acoustic field distribution in the target region based on the data, and controlling the delivery of acoustic pulses by stopping, continuing, increasing, or decreasing the output level for acoustic pulse delivery based on multiple acoustic activity level estimates or acoustic field distribution estimates, thereby controlling tissue destruction in a target internal anatomical region.

Description

Technical Field

[0001] The present disclosure relates to systems and methods for monitoring and controlling histotripsy procedures in focused ultrasound therapy.

Background Art

[0002] Histotripsy involves delivering acoustic energy in the form of short (generally less than 50 μsec), high-amplitude acoustic pulses that deliver relatively low total energy at high peak pressures. This induces short-lived cavitation that mechanically ruptures the target tissue. Cavitation occurs when sufficiently negative pressure is applied to the tissue to form microbubbles from fluid evaporation and the release of dissolved gas. Once formed, the microbubbles exhibit a very dynamic pattern of vibration and inertial collapse that causes cell and tissue destruction. Lesion applications, such as those involving high-intensity focused ultrasound, are sensitive to the amount of energy reaching the target, but histotripsy is more sensitive to negative peak pressure. The pulse intensity required to induce cavitation is very high (>20 MPa).

[0003] Of course, all treatments involving tissue ablation must be monitored and managed to ensure patient safety and treatment effectiveness. The initiation of histotripsy is primarily (not cumulative) a threshold effect, which means that the manifestation of the effect is sudden as the treatment parameter, which is typically the delivered output, increases. As the output level increases beyond the threshold, the degree of the histotripsy effect increases significantly with the output and / or the number of repetitions. Thus, any increase in the delivered output can trigger the effect without warning signs. At the high output levels required to induce cavitation, the risk of injury due to excessive energy accumulation (i.e., exceeding the amount required to induce cavitation at the level required for treatment) is significant. Therefore, rapid feedback is essential to enable histotripsy-based treatments to be efficient and safe.

[0004] Achieving accurate, real-time in-vivo imaging to detect the onset and extent of cavitation remains a challenge. Standard active ultrasound imaging is fast but has limited resolution, particularly in transcranial procedures where the skull exhibits patient-to-patient aberrations. An alternative is magnetic resonance imaging (MRI), which provides better images and is less susceptible to interference from bone structures. However, MRI is a relatively slow technique, making it difficult to update images at sufficiently short intervals to allow for fine-grained control of histotripsy procedures. Furthermore, even when cavitation onset can be detected rapidly and reliably, the optimal post-detection control sequence is not obvious. If the output is reduced or cut off too quickly, the desired therapeutic effect will not be achieved; if the output is maintained at the current level, cavitation may shrink below therapeutically useful levels; and if the output is increased, there is a risk of patient injury. [Overview of the project] [Means for solving the problem]

[0005] This disclosure provides a system and method for monitoring and controlling histotripsy treatment in focused ultrasound therapy.

[0006] In one embodiment, a system for controllably inducing tissue destruction in a target internal anatomical region is described. The system includes an ultrasonic transducer for sonicating a target region with a series of acoustic pulses, an acoustic detection system having at least one detector for detecting ultrasonic reflected signals from the target region, which tracks at least a portion of the acoustic pulses, and a controller. The controller is configured to control the ultrasonic transducer to deliver a sequence of acoustic pulses to the target region, each having a duration of 100 μsec or less and an amplitude sufficient to induce cavitation within the target region sufficient to mechanically rupture the tissue in the target region, and to receive data characterizing the detected reflected signals from the acoustic detection system. Based at least on the data characterizing the detected reflected signals, the controller is configured to estimate the level or location of acoustic activity or the acoustic field distribution in the target region. Based on a plurality of acoustic activity level estimates or acoustic field distribution estimates, the controller is configured to stop the delivery of acoustic pulses, continue the delivery of acoustic pulses at a constant output level, increase the output level for the delivery of acoustic pulses, or decrease the output level for the delivery of acoustic pulses.

[0007] In another embodiment, a method for controllingly inducing tissue destruction in a target internal anatomical region is described. The method includes sonicating a target region with a series of acoustic pulses; detecting ultrasonic reflected signals from the target region that follow at least some of the acoustic pulses; controlling an ultrasonic transducer to deliver a sequence of acoustic pulses to the target region, each having a duration of 100 μsec or less and an amplitude sufficient to induce cavitation within the target region that is sufficient to mechanically rupture the tissue within the target region; and receiving data characterizing the detected reflected signals. Based at least on the data characterizing the detected reflected signals, the method further includes computationally estimating the level or location of acoustic activity or the acoustic field distribution in the target region. Based on a plurality of acoustic activity level estimates or acoustic field distribution estimates, the method further includes stopping the delivery of acoustic pulses, continuing the delivery of acoustic pulses at a constant output level, increasing the output level for the delivery of acoustic pulses, or decreasing the output level for the delivery of acoustic pulses.

[0008] In the drawings, similar reference letters generally refer to the same part throughout different drawings. Furthermore, the drawings are not necessarily to scale, and instead, the emphasis is generally on illustrating the principles of the present disclosure. In the following description, various embodiments of the present disclosure are described with reference to the following drawings. [Brief explanation of the drawing]

[0009] [Figure 1A] An exemplary ultrasonic system according to various embodiments of this disclosure is schematically shown. [Figure 1B] An exemplary MRI system according to various embodiments of this disclosure is schematically shown. [Figure 2] Several embodiments of acoustic reflectors that are substantially close to the target area are shown. [Figure 3] This graph shows exemplary ultrasonic processing events in which the applied acoustic output level is selected according to the reflected signal caused by a histotripsy event, according to several embodiments. [Figure 4] This flowchart shows exemplary approaches for monitoring and controlling histotripsy treatment in focused ultrasound therapy, according to several embodiments. [Modes for carrying out the invention]

[0010] Figure 1A shows an exemplary ultrasound system 100 for generating a focused acoustic energy beam and delivering it to a target region 101 within a patient's body. The illustrated system 100 includes a phase array 102 of transducer elements 104, a beamformer 106 that drives the phase array 102, a controller 108 that communicates with the beamformer 106, and a frequency generator 110 that provides input electronic signals to the beamformer 106.

[0011] The array 102 may have a curved (e.g., spherical or parabolic) or other contoured shape suitable for placement on the surface of a patient's body, or it may include one or more planar or other shaped sections. Its dimensions may vary between a few millimeters and several tens of centimeters. The transducer elements 104 of the array 102 may be piezoelectric ceramic elements and may be mounted on silicone rubber or any other material suitable for attenuating the mechanical coupling between the elements 104. Piezoelectric composite materials, or any material in general that can convert electrical energy into acoustic energy, may also be used. To ensure maximum power transmission to the transducer elements 104, the elements 104 may be configured to resonate electrically at 50 Ω, matching the input connector impedance.

[0012] The transducer array 102 is coupled to a beamformer 106, which drives individual transducer elements 104 so that they collectively generate a focused ultrasonic beam or field. For n transducer elements, the beamformer 106 may include n drive circuits, each including or consisting of an amplifier 118 and a phase delay circuit 120, each drive circuit driving one of the transducer elements 104. The beamformer 106 receives a radio frequency (RF) input signal, typically in the range of 0.1 MHz to 10 MHz, from a frequency generator 110, which may be, for example, a Model DS345 generator available from Stanford Research Systems. The input signal may be split into n channels for the n amplifiers 118 and delay circuits 120 of the beamformer 106. In some embodiments, the frequency generator 110 is integrated with the beamformer 106. The radio frequency generator 110 and beamformer 106 are configured to drive the individual transducer elements 104 of the transducer array 102 at the same frequency, but with different phases and / or different amplitudes.

[0013] The amplification or attenuation coefficients α1 to αn, and the phase shifts a1 to an imposed by the beamformer 106, help to explain the transmission of ultrasonic energy through intervening tissue located between the transducer element 104 and the target region, focusing it onto the target region 101, and the distortion of waves induced in the intervening tissue. The amplification coefficients and phase shifts are calculated using a controller 108, which may provide computational capabilities through software, hardware, firmware, wiring, or any combination thereof. In various embodiments, the controller 108 uses a software-programmed general-purpose or dedicated digital data processor to determine the frequency, phase shift, and / or amplification coefficients required to obtain a desired focus or any other desired spatial field pattern in the target region 101, without the need for unnecessary experiments, using conventional methods. In certain embodiments, the calculations are based on detailed information about the characteristics of the intervening tissue located between the transducer element 104 and the target (e.g., type, size, location, nature, structure, thickness, density, etc.) and their effect on the propagation of acoustic energy. Such information may be obtained from an imaging device 112. The imaging device 112 may be, for example, a magnetic resonance imaging (MRI) device, a computed tomography (CT) device, a positron emission tomography (PET) device, a single-photon emission computed tomography (SPECT) device, or an ultrasound device. Image acquisition may be three-dimensional (3D), or alternatively, the imaging device 112 may provide a set of two-dimensional (2D) images suitable for reconstructing a three-dimensional image of the target region 101 and / or other regions (e.g., a region surrounding target 101 or another target region). Image manipulation functions may be implemented in the imaging device 112, in the controller 108, or in a separate device. Additionally, the ultrasound system 100 and / or the imaging device 112 may be used to detect signals from an acoustic reflector (e.g., a microbubble 202, see Figure 2) positioned substantially close to the target region 101, as further described below.Additionally or alternatively, the system 100 may include an acoustic signal detection device (such as a hydrophone or a preferred alternative) 124 that detects ultrasonic waves transmitted or reflected from the acoustic reflector and provides the received signal to the controller 108 for further processing. Additionally, the ultrasound system 100 may include a delivery system 126 for parenterally introducing the acoustic reflector into the patient's body. The imaging device 112, the acoustic signal detection device 124, and / or the delivery system 126 may be operated using the same controller 108 to facilitate transducer operation, or alternatively, they may be controlled separately by one or more separate controllers communicating with each other.

[0014] Figure 1B shows an exemplary imaging apparatus, namely an MRI apparatus 112. The apparatus 112 may include a cylindrical electromagnet 134 that generates the required static magnetic field within a bore 136 of the electromagnet 134. During the medical procedure, the patient is positioned inside the bore 136 on a movable support table 138. A region of interest 140 within the patient (e.g., the patient's head) may be positioned within an imaging area 142 where the electromagnet 134 generates a substantially uniform field. A pair of cylindrical magnetic field gradient coils 144 may also be provided within the bore 136 and surrounding the patient. The gradient coils 144 generate a magnetic field gradient of a predetermined magnitude in three mutually orthogonal directions over a given time. The magnetic field gradient can be used to associate different spatial locations with different precession frequencies, thereby giving the magnetic resonance (MR) image its spatial resolution. RF transmitter coils 146 surrounding the imaging area 142 radiate RF pulses into the imaging area 142, causing the patient's tissues to radiate MR response signals. The raw MR response signal is sensed by the RF coil 146 and passed to the MR controller 148, which then calculates an MR image, which may be displayed to the user. Alternatively, separate MR transmitter and receiver coils may be used. Images acquired using the MRI apparatus 112 may provide radiologists and physicians with visual contrasts between different tissues and detailed internal diagrams of the patient's anatomical structures that cannot be visualized with conventional X-ray techniques.

[0015] The MRI controller 148 may control the pulse sequence, i.e., the relative timing and intensity of the magnetic field gradient, as well as the RF excitation pulse and response detection period. The MR response signal is amplified, regulated, digitized into raw data using a conventional image processing system, and further converted into an array of image data by methods known to those skilled in the art. Based on the image data, a target region (e.g., a tumor or a targeted blood-brain barrier) can be identified.

[0016] To perform targeted drug delivery or tumor ablation, the location of the target region 101 must be determined with high precision. Therefore, in various embodiments, the imaging device 112 is operated to first acquire images of the target region 101 and / or non-target regions (e.g., healthy tissue surrounding the target region, intervening tissue located between the transducer array 102 and the target region 101, and / or any region located near the target), and based on these images, determine the associated anatomical properties (e.g., tissue type, location, size, thickness, density, structure, shape, angiogenesis). For example, tissue volume may be represented as a 3D set of voxels based on a 3D image or a series of 2D image slices, and may include the target region 101 and / or non-target regions.

[0017] To create a high-quality focus in the target region 101, it may be necessary to calibrate the transducer element 104 and take into account the transducer's geometric imperfections, for example, due to the movement, shift, and / or deformation of the transducer element 104 from its expected position. Additionally, since ultrasound may scatter, absorb, reflect, and / or refract as it travels through heterogeneous intervening tissue located between the transducer element 104 and the target region 101, it may also be necessary to account for the distortion of these waves in order to improve the focusing characteristics in the target region 101.

[0018] Referring to Figure 2, the ultrasound transmitted from all (or at least some) of the transducer elements 104 is reflected by the acoustic reflector 202. The acoustic reflector 202 may essentially consist of microbubbles generated by the ultrasound and / or microbubbles introduced parenterally by the administration system. In some embodiments, the administration system 126 introduces seed microbubbles into the target region 101 and then activates the transducer 102 to transmit ultrasound to the seed microbubbles to generate a cloud of microbubbles. Strategies for generating microbubbles and / or introducing microbubbles into the target region 101 include, for example, PCT Publication 2018 / 020315, PCT Application PCT / US2018 / 064058 (filed December 5, 2018), PCT / IB2018 / 001103 (filed August 14, 2018), and PCT / US2018 / 064892 (filed December 1, 2018). This is provided in PCT / IB2018 / 000841 (filed June 29, 2018), PCT / US2018 / 064066 (filed December 5, 2018), U.S. Patent Publication No. 2019 / 0083065, and U.S. Patent Application No. 15 / 837,392 (filed December 11, 2017), the contents of which are incorporated herein by reference.

[0019] According to various embodiments, control of the histotripsy treatment is based on spatial acoustic imaging of the target region 101. This essentially provides a 3D image of the acoustic energy distribution, enabling the detection of high-energy events such as cavitation that stand out from the background. The acoustic energy is generated by histotripsy events (e.g., sound waves emitted by cavitation bubbles) or by propagation by transducers and reflected during or after the histotripsy events by the products of the events (e.g., sound waves propagated from transducers and reflected by cavitation bubbles). As used herein, the acoustic imaging terms “reflected signals” and “reflection signals” refer to signals generated by acoustic energy, regardless of the source of this energy. Control of the applied acoustic output may be based on a series of consecutive cavitation level estimates, resulting in either complete cessation of acoustic pulse delivery, continuation of pulse sequences at a constant output level, or an increase in delivered output at a rate at least partially determined by the consecutive cavitation level estimates. For example, the delivery power may be increased until an observed acoustic event (i.e., a significant, limited reflected signal) that is likely to indicate cavitation is observed in the focal region within the target area. At this point, the power may be increased slowly, typically by 2–5 percent relative to the previous acoustic power. After several events are observed in the focal region, typically 1–4 events per focal point, the treatment power may be kept constant until several more events (e.g., 1–10) are observed, at which point treatment with respect to the focal region is complete. The power may then be increased or decreased by a coefficient (e.g., 40%), the focal region shifting to a new portion of the target area, and the procedure described above is repeated. If no events are detected after increasing the power to the maximum safe level, the focus may be shifted to another target area, or treatment may be stopped completely. Reflected signals received from the current focal region may also be used to improve focusing on nearby points.

[0020] In various embodiments, a specific frequency or frequency band of the reflected signal is selected for analysis. The reflected signal may be analyzed using the first harmonic of the transmitted signal (i.e., the same frequency as the transmitted signal). Additionally or alternatively, the reflected signal may be analyzed using any other frequency band (e.g., second harmonic frequencies, subharmonic frequencies, and / or superharmonic frequencies). In some embodiments, a broadband signal is used for analysis. A single hydrophone or an array of hydrophones may be used for the measurement itself. Without loss of generality, the following description assumes that the reflected signal is detected using a hydrophone array. Since the difference between two reflected signals through the skull is monitored, the effects of aberrations and attenuations are eliminated, and system calibration is generally not required to obtain quantitative results.

[0021] Using short pulses, a characteristic of histotripsy with hydrophone arrays, enables the generation of a 3D acoustic activity map of a target area, a procedure also known as passive acoustic mapping or PAM. This may be achieved by constructing a 3D image of the spatial acoustic field using reflected signals from spatially distributed transducer elements. The distance between each transducer element and each voxel in the spatial region of interest is known, as is the speed of sound through the relevant tissue. Therefore, the response to an event at each voxel of interest can be calculated based on time-of-flight and / or phase delay, and by aggregating measurements from multiple sensing transducer elements to obtain a degenerate solution. As a result, the above analysis method can be implemented on a voxel-by-voxel basis within the region of interest, providing spatial information relevant to the progression, effectiveness, and safety of the treatment. For example, excessive activity may be identified at undesirable locations (e.g., unintended shifts in the main beam effect from the target area).

[0022] Typically, signals reflected from histotripsy events are mixed with signals from other reflectors within the body, such as bone. In some embodiments, generating a cavitation activity map for each pulse in a sequence facilitates comparison between two pulses (e.g., the first and second pulses in the sequence), and thus facilitates generation of a 3D map of the acoustic field generated as a response to the transmitted pulses within the region of interest. These maps can be overlaid on MRI maps to estimate treatment outcomes with respect to both efficacy and safety.

[0023] In some embodiments, a general pipeline for generating an acoustic map for a controller includes: (a) generating a histotripsy event (e.g., a cavitation bubble); (b) receiving signals (e.g., emitted or reflected from the cavitation bubble); (c) optionally, removing unwanted portions of the signals (e.g., reflections of transmitted treatment signals reflected by static anatomical structures such as the skull); (d) correcting signal deviations; and (e) adding the signals (e.g., field reconstruction).

[0024] To generate histotripsy in the treatment area, pulses each containing only a single cycle may be required. Even so, in some scenarios, the pulses used to generate the acoustic map may be longer (e.g., longer than 3 cycles), thereby reducing resolution. To overcome this issue, the reflected signals may be processed as follows.

[0025] First, for each receiver, two consecutive received signals are subtracted to remove the background. Then, a significant portion of the signal (on the order of the pulse length) is filtered with respect to a specific frequency (usually the transmission frequency or other frequencies mentioned above), and the phase and amplitude of this signal portion are obtained at the selected frequency. Using a relatively long signal portion allows more energy to be utilized in the measurement, improving the SNR by sacrificing resolution (assuming the sparsity effect). This generates the complex signal values (including phase, amplitude, or both) of the selected frequency for each receiver.

[0026] To correct for wave propagation time and / or aberration, phase delay correction is applied to the complex signal based on (i) the distance from the receiver to each reconstructed spatial point and / or (ii) the anatomical - related aberration.

[0027] The wave propagation time is the flight time of the acoustic wave from the histotripsy event to each receiver, based on the speed of sound in water and watery tissues. The correction from the wave propagation time is achieved by a simple calculation based on length and speed.

[0028] The correction of aberration is for the aberration caused by more complex tissues such as the skull. The correction of aberration can be performed using (i) a physical model as described in U.S. Patent No. 10,765,892, the entire disclosure of which is incorporated herein by reference, (ii) intraoperative measurements as described in U.S. Patent Publication No. 2019 / 0308038, the entire disclosure of which is incorporated herein by reference, and / or (iii) other models such as those described in U.S. Patent No. 11,291,430, the entire disclosure of which is incorporated herein by reference.

[0029] The corrected complex signal values from all receivers are summed to obtain the amplitude (corresponding to the magnitude of the acoustic field) at each reconstructed point. The phase is also obtained for each point. The phase values and amplitude values over all reconstructed points construct the 3D PAM.

[0030] Another approach to 3D spatial reconstruction involves reconstructing a single 2D plane within the target point by point and using the angular spectral method to create a map of adjacent planes, and thus a 3D spatial map. Specifically, the angular spectral method may include extending the complex wave field to the sum of plane waves of the same frequency and different directions. This technique can predict the acoustic pressure field distribution across planes based on knowledge of the pressure field distribution in parallel planes.

[0031] The following paragraphs present the results of a typical histotripsy experiment using a histotripsy controller. At each trigger initiated by the controller, the transducer sonicates a sequence of two consecutive pulses, each approximately 50 us or less in length. All sonication sequences trigger the acquisition system to acquire an acoustic signal from the treatment area of ​​interest. The acoustic signal is then analyzed (with reference to the reflected signal) as described above, and a 3D acoustic map is delivered to the histotripsy controller to determine the next trigger parameter. For this treatment, histotripsy activity was monitored via the maximum intensity of the reconstructed acoustic map.

[0032] The left axis of Figure 3 plots the maximum intensity within the therapeutic area, measured in arbitrary units, marked as "signal." Previous experiments have identified signals greater than 0.015 as evidence of histotripsy, and therefore, signal = 0.015 was set as the histotripsy treatment threshold.

[0033] The spatial distribution of the field in a 3D acoustic map can be analyzed. When the output is below the histotripsy event generation threshold, the measured acoustic field distribution is broad. When the output lever exceeds the histotripsy threshold level, localized histotripsy events generate a strong field with a narrow distribution (e.g., more than 50% of the energy within a radius of 3 mm). Additionally, when the output level exceeds the safety threshold, the histotripsy effect may be greater or affect a larger area, and therefore the reconstructed acoustic field may have a broader distribution. In some embodiments, the acoustic field distribution is used to determine the treatment threshold and / or safety threshold.

[0034] In this experiment, the treatment was managed using basic tools. Specifically, the measured maximum acoustic intensity (signal in Figure 3) was the input, and the output voltage (RPout in Figure 3) was controlled as the output, thereby increasing the FUS output. The starting output voltage was 30% of the maximum voltage allowed by the user. If the signal was higher than the threshold, the "histological tripsy event" counter was incremented by 1, i.e., event = event + 1. If the number of "events" was 0, the next trigger was set to increase the voltage by 5%. If the number of "events" was greater than 0 and less than 3, the next trigger was set to increase the voltage by 2%. If the number of "events" was greater than 2 but less than 20, the next trigger was set to the previous voltage until the desired cumulative event was reached, which in this experiment was set to an "event" equal to 20. If the number of "events" was greater than 20, the next trigger was set to zero, in other words, the treatment was terminated. The right axis in Figure 3 plots the voltage applied (corresponding to the delivery output) according to the controller algorithm described above.

[0035] In addition to, or as an alternative to, the hardware platform described above with reference to Figures 1A-2, a representative hardware platform for embodiments of the present invention is described in U.S. Patent No. 11,918,832, the full disclosure of which is incorporated herein by reference. The hardware system may include an imaging device (e.g., a magnetic resonance imaging (MRI) device) that characterizes the tissue type and / or properties of a target region and / or surrounding tissue, each tissue type and location may have corresponding tolerances to histotripsy depending on its properties, and therefore the imaging device may be used to spatially characterize the tissue tolerances, and this spatial representation may be used for comparison with a spatial acoustic map. Patent No. 832 also describes a preferred ultrasonic transducer configuration and driver circuit (similar to those described above with reference to Figures 1A-2).

[0036] A controlled histotripsy treatment at a single point may cover a volume of 0.001–1 cubic centimeter (cc), with a typical cauterization volume being approximately 0.1 cc. Targets to be treated by histotripsy treatment are typically 0.5 cc–125 cc (but not limited to this). A careful treatment control (as described above, see Figure 3), starting with an output below the treatment threshold and gradually increasing, is a good starting point for volumetric treatment. Additionally, this careful threshold detection provides a high safety margin. However, repeating this process for each point to be cauterized within the target can be too time-consuming, as the target may consist of thousands of points that need to be cauterized.

[0037] Therefore, a strategy is needed for rapid ablation of each target point while maintaining the efficacy and safety of the treatment. Experiments have shown that the variability of histotripsy thresholds is very large, but the thresholds of two approaching points within a single tissue type do not differ significantly (up to 50% difference). Therefore, in some embodiments, once the threshold of a particular point is measured by the controller, the controller can set the working output level for the area and process the entire area at the same output level. The working output for a given area may be slightly higher (10% to 100%) than the threshold found for a point in that area. In some embodiments, an area is defined as all points within a distance of a predetermined radius from the point where the threshold was measured. A typical predefined radius may be 10 to 20 mm. In some embodiments, a medical image of the treated area is used to segment the area by tissue type, and the selection of working output may be limited to tissues of the same type. In some embodiments, histotripsy events in the treatment area are used for progressive correction of focus. In some embodiments, treatment of points around the point where the threshold was measured is monitored by the controller in the same manner as the treatment of the first point was monitored to ensure efficacy and safety. If the signal for a cavitation event is lost, the controller may initiate an increase in the treatment output. If a reflection from a histotripsy event raises safety concerns, the controller may reduce the output. In some embodiments, the treatment area to which the working output is applicable is not limited to a specific radius. Treatment may be continued as long as efficacy and safety are acceptable, and the output level may be adjusted as needed.

[0038] In some embodiments, the system also includes an imaging device used to induce targeting. In some embodiments, the imaging device is an MRI, CT, and / or ultrasound scanner. To ensure treatment at the desired location, images may be taken, and the location of the actual interaction between the acoustic beam and the tissue (the actual location of treatment) may be positioned on the image. Images can be taken before, during, and / or between histotripsy activity. In some embodiments, the image is a thermal image of acoustic heating by the acoustic beam. The thermal image can be created using MRI thermometry or ultrasound thermometry. The heating is typically mild and transient, with no significant clinical effect. In some embodiments, the image shows minute extracellular blood leakage caused by an explosion of the acoustic contrast agent or (usually a few weak) histotripsy events. Extracellular blood leakage can be imaged by MRI (e.g., T2*) or CT imaging. In some embodiments, ultrasound imaging is used to detect bubbles generated by histotripsy. In some embodiments, the controller automatically positions the actual location of treatment on the image. In some embodiments, the controller adjusts treatment parameters to shift the actual location of treatment toward the desired location of treatment. In some embodiments, the controller configures or triggers imaging at the correct location and / or time.

[0039] Figure 4 is a flowchart illustrating an exemplary process 400 for controllingly inducing tissue destruction in a targeted internal anatomical region, according to several embodiments. The process may be managed by instructions stored in computer memory or a non-temporary computer-readable storage medium. The instructions may be contained in one or more programs stored in the non-temporary computer-readable storage medium. When executed by one or more processors (e.g., 108 and / or 148), the instructions cause the system to carry out the process. The non-temporary computer-readable storage medium may include one or more solid storage devices (e.g., flash memory), magnetic disk or optical disk storage devices, or other non-volatile memory devices. The instructions may include source code, assembly language code, object code, or any other instruction format that can be interpreted by one or more processors. Some operations of the process may be combined, and the order of some operations may be changed.

[0040] In operation 402, the ultrasonic system (e.g., 100) ultrasonically treats a target area (e.g., 101) with a series of acoustic pulses.

[0041] In operation 404, the system detects an ultrasonic reflected signal from the target region by following at least a portion of the acoustic pulse (e.g., 112).

[0042] In operation 406, the system controls an ultrasonic transducer (e.g., 102) to deliver a sequence of acoustic pulses to the target region having an amplitude sufficient to induce cavitation within the target region that is sufficient to mechanically rupture the tissue within the target region, and having a duration of 70 μsec or less, or 100 μsec or less, respectively (or having a duration outside these ranges depending on the application).

[0043] In operation 408, the system receives data (e.g., 124) characterizing the detected reflected signal.

[0044] In operation 410, based at least on data characterizing the detected reflected signals, the system computationally estimates the level or location of acoustic activity or the acoustic field distribution in the target region.

[0045] In operation 412, based on multiple acoustic activity level estimates or acoustic field distribution estimates, the system either stops delivering acoustic pulses (e.g., after pulse 39 in Figure 3), continues delivering acoustic pulses at a constant output level (e.g., between pulses 21 and 39 in Figure 3), increases the output level for delivering acoustic pulses (e.g., between pulses 1 and 20 in Figure 3), or decreases the output level for delivering acoustic pulses. In some embodiments, the multiple acoustic activity level estimates or acoustic field distribution estimates include multiple consecutive acoustic activity level estimates or acoustic field distribution estimates.

[0046] In some embodiments, detecting ultrasonic reflected signals involves the use of multiple spatially distributed acoustic detectors.

[0047] In some embodiments, the level of acoustic activity or acoustic field distribution is determined at least partially based on the position of the acoustic detector relative to the target region.

[0048] In some embodiments, the level of acoustic activity or acoustic field distribution is determined at multiple spatially distributed locations.

[0049] In some embodiments, the process further includes calculating the volume acoustic field within a target region by field reconstruction.

[0050] In some embodiments, the acoustic pulse has a duration in the range of 10 μs to 100 μs.

[0051] In some embodiments, the process further includes estimating the acoustic field distribution of the transmission frequency field, the second harmonic field, the subharmonic field, and / or the superharmonic field.

[0052] In some embodiments, the process further includes determining a treatment threshold and / or a safety threshold based at least partially on the acoustic field distribution.

[0053] In some embodiments, the process further includes increasing the output level for delivering acoustic pulses, including increasing the output level at a rate at least partially determined by the acoustic activity level estimates, based on a plurality of acoustic activity level estimates.

[0054] In some embodiments, the process further includes setting a constant output level, an increased output level, or a decreased output level as the working output level for multiple points within a target area, and continuing to deliver acoustic pulses at the working output level to the multiple points within the target area without reestimating the level of acoustic activity or the acoustic field distribution.

[0055] In some embodiments, the process further includes defining an area comprising multiple points as all points within a segment of a target region that are less than a predetermined radius from an initial point where the level of acoustic activity or acoustic field distribution was estimated, or all points within a segment of a target region having a tissue type corresponding to the tissue type at the initial point where the level of acoustic activity or acoustic field distribution was estimated.

[0056] In some embodiments, the process further includes acquiring an image using an imaging device including a magnetic resonance imaging (MRI) device, a computed tomography (CT) device, or an ultrasound device; using the image acquired by the imaging device to determine the location of the acoustic pulse interaction; and adjusting one or more therapeutic parameters to shift the location of the interaction to a desired location within the target region.

[0057] In some embodiments, the image is a thermal image of acoustic heating caused by an acoustic pulse, or the image is sensitive to extravasation of blood cells.

[0058] In some embodiments, determining the location of an interaction includes locating extravasation of blood cells in an image, or otherwise determining the location of an interaction in an image.

[0059] More generally, the functionality for performing controlled histotripsy in a target region may consist of one or more modules implemented in hardware, software, or a combination of both. In embodiments where the functionality is provided as one or more software programs, the programs may be written in one of several high-level languages, such as PYTHON®, FORTRAN, PASCAL, JAVA®, C, C++, C#, BASIC, various scripting languages, and / or HTML. Additionally, the software may be implemented in assembly language directed to a microprocessor residing on the target computer; for example, if the software is configured to run on an IBM PC or PC clone, the software may be implemented in Intel 80x86 assembly language. The software may be embodied on products including, but not limited to, floppy disks, jump drives, hard disks, optical disks, magnetic tapes, PROMs, EPROMs, EEPROMs, field-programmable gate arrays, or CD-ROMs. Embodiments using hardware circuitry may be implemented, for example, using one or more FPGAs, CPLDs, or ASIC processors.

[0060] Various embodiments have been referenced in detail, examples of which are illustrated in the accompanying drawings. The above detailed description provides many specific details in order to give a complete understanding of the present invention and the embodiments described. However, the present invention may be practiced without these specific details. In other instances, well-known methods, procedures, components, and circuits are not described in detail so as not to unnecessarily obscure the aspects of the embodiments.

[0061] Terms such as "first" and "second" may be used herein to describe various elements, but it should be understood that these elements should not be limited by these terms. These terms are used solely to distinguish one element from another. For example, a first device can be referred to as a second device, and similarly, a second device can be referred to as a first device, without changing the meaning of the description, as long as all occurrences of the first device are consistently renamed and all occurrences of the second device are consistently renamed. Both the first device and the second device are devices, but they are not the same device.

[0062] The terminology used herein is intended solely to describe specific embodiments and is not intended to limit the scope of the claims. Where used in the descriptions of embodiments and the accompanying claims, the singular forms “a,” “an,” and “the” are also intended to include plural forms unless the context clearly indicates otherwise. Where used herein, the term “and / or” is also understood to refer to and encompass any and all possible combinations of one or more of the enumerated items relating to the description. For example, “A, B, and / or C” means A only, B only, C only, A and B, A and C, B and C, or A, B, and C. Where used herein, the terms “comprises” and / or “comprising” specify the presence of the described features, components, steps, actions, elements, and / or components, but are not intended to exclude the presence or addition of one or more other features, components, steps, actions, elements, components, and / or groups thereof.

[0063] As used herein, the term “if” may, depending on the context, be interpreted as “when” or “upon,” or “in response to a determination,” “according to a determination,” or “in response to detection,” that the preceding stated condition is true. Similarly, depending on the context, the phrases “if it is determined (that the preceding stated condition is true),” “when (the preceding stated condition is true),” or “when (the preceding stated condition is true)” may be interpreted as “at the time of determination,” “in response to determination,” “according to determination,” or “at the time of detection,” or “in response to detection,” that the preceding stated condition is true.

[0064] The above description is provided for illustrative purposes with reference to specific embodiments. However, the above illustrative considerations are not intended to be exhaustive or to limit the invention to the exact form disclosed. Many modifications and variations are possible in light of the above teachings. The embodiments are selected and described to best illustrate the principles of the invention and its practical applications, thereby enabling those skilled in the art to best utilize the invention and various embodiments with various modifications suitable for the specific use intended.

Claims

1. A system for controllingly inducing tissue destruction in a targeted internal anatomical region, An ultrasonic transducer for ultrasonically treating a target area with a series of acoustic pulses, An acoustic detection system comprising at least one detector for detecting ultrasonic reflected signals from the target region that track at least a portion of the acoustic pulses, A controller is provided, and the controller is The ultrasonic transducer is controlled to deliver a sequence of acoustic pulses to the target region, each having a duration of 100 μsec or less, with an amplitude sufficient to induce cavitation within the target region that is sufficient to mechanically rupture the tissue within the target region. The acoustic detection system receives data characterizing the detected reflected signal. Based at least on the data characterizing the detected reflected signal, the level or location of acoustic activity or the acoustic field distribution in the target region is estimated. Based on multiple acoustic activity level estimates or acoustic field distribution estimates, To stop the delivery of the aforementioned acoustic pulse, Continue delivering the acoustic pulse at a constant output level, To increase the output level for delivering the acoustic pulse, or A system configured to reduce the output level for the delivery of the aforementioned acoustic pulses.

2. The aforementioned acoustic detection system comprises a plurality of spatially distributed acoustic detectors, The system according to claim 1, wherein the level of acoustic activity or the acoustic field distribution is determined at least partially based on the position of the acoustic detector relative to the target region.

3. The system according to claim 1, wherein the level of acoustic activity or the acoustic field distribution is determined at a plurality of spatially distributed locations.

4. The controller is configured to calculate the volume acoustic field within the target region by field reconstruction, The system according to claim 1, wherein the acoustic pulse has a duration in the range of 10 μs to 100 μs.

5. The aforementioned controller The acoustic field distribution of the transmission frequency field, second harmonic field, subharmonic field, and / or superharmonic field is estimated, The system according to claim 1, configured to determine a therapeutic threshold and / or a safety threshold based at least partially on the acoustic field distribution.

6. The system according to claim 1, wherein the controller is configured to increase the output level for delivery of the acoustic pulse, including increasing the output level based on the plurality of acoustic activity level estimates at a rate at least partially determined by the acoustic activity level estimates.

7. The aforementioned controller The aforementioned constant output level, increased output level, or decreased output level is set as the working output level for multiple points within the target area. The system according to claim 1, configured to continue delivering the acoustic pulses to the plurality of points in the target area at the working output level without reestimating the level of acoustic activity or the acoustic field distribution.

8. The controller controls the area including the plurality of points, All points located at a distance less than a predetermined radius from the initial point where the level of acoustic activity or the acoustic field distribution was estimated, or The system according to claim 7, wherein the level of acoustic activity or the acoustic field distribution is defined as all points within the segment of the target region having the tissue type corresponding to the tissue type at the initial point from which the acoustic activity level or acoustic field distribution was estimated.

9. The system further includes imaging equipment including a magnetic resonance imaging (MRI) device, a computed tomography (CT) device, or an ultrasound device. The aforementioned controller Using the image acquired by the imaging device, the location of the interaction of the acoustic pulses is determined. The system according to claim 1, further configured to adjust one or more therapeutic parameters to shift the location of the interaction to a desired location within the target region.

10. The image is either a thermal image of acoustic heating caused by the acoustic pulse, or an image sensitive to extravasation of blood cells. The system according to claim 9, wherein the controller is configured to determine the position of the interaction in the image.

11. A method for controllingly inducing tissue destruction in a targeted internal anatomical region, The process involves ultrasonically treating a target area with a series of acoustic pulses, To detect ultrasonic reflected signals from the target region that follow at least a portion of the aforementioned acoustic pulses, Controlling an ultrasonic transducer to deliver a sequence of acoustic pulses to the target region, each having a duration of 100 μsec or less, with an amplitude sufficient to induce cavitation within the target region that is sufficient to mechanically rupture the tissue within the target region. Receiving data characterizing the detected reflected signal, Computationally estimating the level or location of acoustic activity or the acoustic field distribution in the target region based at least on the data characterizing the detected reflected signal, Based on multiple acoustic activity level estimates or acoustic field distribution estimates, To stop the delivery of the aforementioned acoustic pulse, Continue delivering the acoustic pulse at a constant output level, To increase the output level for delivering the acoustic pulse, or A method comprising reducing the output level for the delivery of the acoustic pulse.

12. Detecting the aforementioned ultrasonic reflection signal involves the use of multiple spatially distributed acoustic detectors. The method according to claim 11, wherein the level of acoustic activity or the acoustic field distribution is determined at least partially based on the position of the acoustic detector relative to the target region.

13. The method according to claim 11, wherein the level of acoustic activity or the acoustic field distribution is determined at a plurality of spatially distributed locations.

14. The method further includes calculating the volume acoustic field within the target region by field reconstruction, The method according to claim 11, wherein the acoustic pulse has a duration in the range of 10 μs to 100 μs.

15. To estimate the acoustic field distribution of the transmission frequency field, second harmonic field, subharmonic field, and / or superharmonic field, The method according to claim 11, further comprising determining a therapeutic threshold and / or a safety threshold based at least partially on the acoustic field distribution.

16. The method according to claim 11, further comprising increasing the output level for delivery of the acoustic pulse, including increasing the output level at a rate determined at least partially by the acoustic activity level estimates based on the plurality of acoustic activity level estimates.

17. Setting the aforementioned constant output level, increased output level, or decreased output level as the working output level for multiple points within the target area, The method according to claim 11, further comprising: continuing to deliver the acoustic pulses to the plurality of points in the target area at the working output level without reestimating the level of acoustic activity or the acoustic field distribution.

18. The area including the aforementioned multiple points All points located at a distance less than a predetermined radius from the initial point where the level of acoustic activity or the acoustic field distribution was estimated, or The method according to claim 17, further comprising defining all points within the segment of the target region having the tissue type corresponding to the tissue type at the initial point where the level of acoustic activity or the acoustic field distribution was estimated.

19. Acquiring images using imaging devices including magnetic resonance imaging (MRI), computed tomography (CT), or ultrasound equipment, Using the image acquired by the imaging device, the location of the interaction of the acoustic pulses is determined. The method according to claim 11, further comprising adjusting one or more therapeutic parameters to shift the location of the interaction to a desired location within the target region.

20. The image is either a thermal image of acoustic heating caused by the acoustic pulse, or an image sensitive to extravasation of blood cells. The method according to claim 19, wherein determining the position of the interaction includes determining the position of the interaction in the image.

Images