Pre-treatment tissue sensitization for focused ultrasound procedures

Abstract

Systems and methods for treating target tissues include: a preparation sequence for generating acoustic processing pulses to deliver acoustic energy to the target tissue; pausing the generation of acoustic processing pulses after a delay interval; and a treatment sequence for generating a series of acoustic processing pulses to deliver acoustic energy to the target tissue, wherein the treatment sequences are spaced apart by acoustic processing intervals, and the delay intervals are larger than the maximum acoustic processing interval by a predetermined coefficient.

Description

[0001] Cross-references to related applications

[0002] This application claims priority and benefit to U.S. Provisional Patent Application No. 62 / 913,772, filed October 11, 2019, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention relates generally to ultrasound therapy, and more particularly to systems and methods for enhancing tissue response during ultrasound therapy. Background Technology

[0004] Tissues such as benign or malignant tumors, organs, or other body areas can be treated invasively by surgical removal of the tissue, or minimally invasively or entirely non-invasively using techniques such as thermal ablation. Both methods are effective in treating certain localized conditions, but involve complex procedures to avoid damaging or harming other healthy tissues.

[0005] Thermal ablation, which can be performed using focused ultrasound, is particularly attractive for treating lesions surrounded by or adjacent to healthy tissue or organs, as the effect of ultrasound energy can be confined to a well-defined target area. Due to the relatively short wavelength, ultrasound energy can be focused onto an area with a cross-section of only a few millimeters (e.g., at one megahertz (1 MHz), the cross-section can be as small as 1.5 millimeters (mm)). Furthermore, since acoustic energy typically penetrates soft tissue well, interventional anatomy usually does not pose an obstacle to defining the desired focal area. Therefore, ultrasound energy can be focused onto a small target to ablate lesions while minimizing damage to surrounding healthy tissue.

[0006] To focus ultrasonic energy at a desired target, a drive signal can be sent to an acoustic (preferably piezoelectric) transducer with multiple transducer elements, causing constructive interference at the focal region. At the target, sufficient acoustic energy can be delivered to heat the tissue until necrosis occurs, i.e., until the tissue is destroyed. Preferably, non-target tissue outside the focal region, through which the acoustic energy passes (“passage zone”), is heated only minimally (if any), thereby minimizing damage to the tissue outside the focal region.

[0007] Typically, ultrasound energy is delivered according to a treatment plan, usually based on a predefined model of the target and the patient's anatomy. During treatment, the temperature at the target site is monitored using equipment such as magnetic resonance imaging (MRI). If the measured temperature is below the target temperature required for necrosis, the ultrasound energy emitted from the transducer is increased. However, in some cases, the maximum acoustic energy that can be delivered to the target is limited—for example, due to the thermal sensitivity of surrounding tissues.

[0008] Therefore, there is a need for methods that provide effective ultrasound therapy without causing damage to non-target tissues by not exceeding the maximum permissible deposition of acoustic energy. Summary of the Invention

[0009] This invention provides systems and methods for allowing effective ultrasound therapy to target tissue while avoiding damage to non-target tissues by increasing tissue sensitivity in the target region prior to performing ultrasound therapy. In various embodiments, a "priming" phase, applying one or more acoustic treatment sequences to the target tissue, is performed before exposing the target tissue to a series of one or more therapeutic acoustic treatment sequences. The priming sequences of acoustic treatment can effectively enhance the sensitivity of various types of tissue in the target to acoustic energy at various frequencies. Because the tissue sensitivity at the target region is increased, the minimum acoustic energy required for tissue necrosis can be reduced. As a result, the acoustic energy emitted from the ultrasound transducer to provide effective targeted therapy can be reduced without exceeding the maximum permissible deposition of acoustic energy, thus avoiding damage to non-target tissues.

[0010] In one embodiment, after the preparation sequence of the acoustic treatment is completed and before the application of one or more therapeutic acoustic treatment sequences, the ultrasound transducer stops after a delay interval. Furthermore, the delay interval is preferably longer than the longest acoustic treatment interval between two consecutive therapeutic acoustic treatment sequences by a predetermined factor (e.g., 2x, 10x, 50x, or 100x). Additionally or alternatively, small gas / liquid bubbles (or “microbubbles”) may be introduced into the target region before and / or during the preparation phase; cavitation of the microbubbles can further enhance tissue sensitivity in the target region. In some embodiments, microbubbles are introduced into the target after the preparation sequence (e.g., during treatment) to aid in tissue destruction or necrosis and / or improve the focusing characteristics of the focused ultrasound beam.

[0011] Therefore, in one aspect, the present invention relates to a system for treating target tissue. In various embodiments, the system includes an ultrasonic transducer (e.g., a phased array transducer) for delivering acoustic energy to the target tissue; and a controller configured to (i) generate a acoustic processing pulse preparation sequence for driving the ultrasonic transducer to deliver acoustic energy to the target tissue according to the preparation sequence, (ii) pause driving the ultrasonic transducer through a delay interval, and (iii) generate a series of acoustic processing pulse treatment sequences for driving the ultrasonic transducer to deliver acoustic energy to the target tissue according to a series of treatment sequences. In one embodiment, there is an acoustic processing interval between treatment sequences, and the delay interval is larger than the maximum acoustic processing interval by a predetermined factor (e.g., 2 times or 10 times).

[0012] Furthermore, the system may further include an application device for applying an ultrasound contrast agent to a target tissue. For example, the controller may be further configured to operate the application device to apply the ultrasound contrast agent during a preparation sequence and / or a treatment sequence. In some embodiments, the preparation sequence has one or more fixed parameters selected from frequency, power, mechanical index in the target tissue, and beam shape. The controller may be further configured to determine a value for a fixed parameter used to maintain a target concentration of microbubbles at the target tissue. Additionally or alternatively, the controller may be further configured to determine a value for a fixed parameter used to maintain a target concentration of microbubbles at the target tissue.

[0013] In various embodiments, the preparation sequence has one or more varying parameters selected from frequency, power, mechanical index in the target tissue, and beam shape. The controller may be further configured to determine values ​​of said varying parameters for (i) inducing microbubble cavitation in the target tissue, (ii) maintaining a target range of microbubble cavitation at the target tissue, and / or (iii) avoiding the formation of microbubble clouds in the target tissue. In one embodiment, the controller is further configured to determine the target range of microbubble cavitation based at least in part on the acoustic response from the target tissue.

[0014] Furthermore, the system may further include one or more acoustic signal detectors; the controller may be further configured to adjust parameters associated with the preparation sequence based on the acoustic response from the target tissue detected by the acoustic signal detectors. In one embodiment, the preparation sequence has mixed frequencies. Additionally, the system may include one or more imaging devices (e.g., ultrasound, MRI, CT, X-ray, PET, SPECT, or infrared imaging devices) for guiding the preparation and / or treatment sequences. The imaging devices may generate 1D, 2D, 3D, and / or 4D images.

[0015] In another aspect, the present invention relates to a method for treating a target tissue. In various embodiments, the method includes generating a preparation sequence of acoustic processing pulses for delivering acoustic energy to the target tissue; pausing the generation of the acoustic processing pulses after a delay interval; and generating a treatment sequence of a series of acoustic processing pulses for delivering acoustic energy to the target tissue. In one embodiment, acoustic processing intervals are present between the treatment sequences, and the delay interval is larger than the maximum acoustic processing interval by a predetermined coefficient.

[0016] Another aspect of the invention relates to a system for treating target tissue. In various embodiments, the system includes an ultrasound transducer (e.g., a phased array transducer) for delivering acoustic energy to the target tissue; an application device for administering an ultrasound contrast agent to the target tissue; and a controller configured to (i) generate a preparation sequence of acoustic processing pulses for driving the ultrasound transducer to deliver acoustic energy to the target tissue according to the preparation sequence, (ii) operate the application device to administer the ultrasound contrast agent during the preparation sequence, and (iii) generate a treatment sequence of acoustic processing pulses for driving the ultrasound transducer to deliver acoustic energy to the target tissue according to the treatment sequence.

[0017] In various embodiments, the preparation sequence has one or more fixed parameters selected from frequency, power, mechanical index in the target tissue, and beam shape. Additionally, the controller may be further configured to determine values ​​of the fixed parameters for maintaining the target concentration of microbubbles at the target tissue. In one embodiment, the preparation sequence has one or more variable parameters selected from frequency, power, mechanical index in the target tissue, and beam shape. The controller is further configured to determine values ​​of the variable parameters for (i) inducing microbubble cavitation in the target tissue, (ii) maintaining a target range of microbubble cavitation at the target tissue, and / or (iii) avoiding the formation of microbubble clouds in the target tissue. Furthermore, the controller may be further configured to determine the target range of microbubble cavitation based at least in part on the acoustic response from the target tissue.

[0018] In some embodiments, the system further includes one or more acoustic signal detectors; the controller is further configured to adjust parameters associated with the preparation sequence based on the acoustic response from the target tissue detected by the acoustic signal detectors. In one embodiment, the preparation sequence has mixed frequencies. Furthermore, the system may further include one or more imaging devices (e.g., ultrasound, MRI, CT, X-ray, PET, SPECT, or infrared imaging devices) for guiding the preparation and / or treatment sequences. The imaging devices may generate 1D, 2D, 3D, and / or 4D images. In one embodiment, the controller is further configured to operate an application device to apply an ultrasound contrast agent during the treatment sequence.

[0019] On the other hand, the present invention relates to a method for treating a target tissue. In various embodiments, the method includes a preparation sequence for generating acoustic processing pulses for delivering acoustic energy to the target tissue according to the preparation sequence; administering an ultrasound contrast agent during the preparation sequence; and a treatment sequence for generating acoustic processing pulses for delivering acoustic energy to the target tissue according to the treatment sequence.

[0020] As used herein, the term "substantially" means ±10%, and in some embodiments, ±5%. Throughout the specification, references to "an example," "an example," "an embodiment," or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with that example is included in at least one example of the technical solution of the invention. Therefore, the phrases "an example," "an example," "an embodiment," or "an embodiment" appearing throughout the specification do not necessarily refer to the same example. Furthermore, specific features, structures, routines, steps, or characteristics may be combined in any suitable manner in one or more examples of the technical solution of the invention. The headings provided herein are for convenience only and are not intended to limit or interpret the scope or meaning of the claimed technology. Attached Figure Description

[0021] Figure 1A A focused ultrasound system according to various embodiments of the present invention is shown;

[0022] Figure 1B Exemplary MRI systems according to various embodiments of the present invention are illustrated schematically;

[0023] Figure 2A A single, continuous preparation sequence of acoustic processing pulses according to various embodiments of the present invention is shown;

[0024] Figure 2B A series of time-separated preparation sequences of acoustic processing pulses according to various embodiments of the present invention are shown;

[0025] Figure 3A-3I Various configurations of one or more preparation sequences of acoustic processing pulses according to various embodiments of the present invention are shown;

[0026] Figure 4 The illustration schematically depicts the injection and / or generation of microbubbles at the target region during the preparation phase, according to various embodiments of the invention.

[0027] Figure 5 The illustrations show various embodiments of the invention, followed by a preparatory acoustic processing sequence with a delay interval and a series of therapeutic acoustic processing sequences; and

[0028] Figure 6 A flowchart illustrating an exemplary method for treating target tissue according to various embodiments of the present invention. Detailed Implementation

[0029] Figure 1AAn exemplary ultrasound system 100 for focusing ultrasound onto a target region 101 within a patient's body is shown. The system 100 can shape ultrasound energy in various ways, such as producing point focusing, line focusing, ring focusing, or multiple focusing simultaneously. In various embodiments, the system 100 includes a phased array 102 of transducer elements 104, a beamformer 106 driving the phased array 102, a controller 108 communicating with the beamformer 106, and a frequency generator 110 providing input electronic signals to the beamformer 106.

[0030] Array 102 may have a curved (e.g., spherical or parabolic) shape suitable for placement on a surface of the skull or on a body part other than the skull, or may include one or more planar or other shaped portions. Its dimensions may vary between millimeters and tens of centimeters depending on the application. The transducer elements 104 of array 102 may be piezoelectric ceramic capacitive micromechanical ultrasonic transducers (CMUTs) or microelectromechanical systems (MEMS) elements, and may be mounted in silicone rubber or any other material suitable for mechanical coupling between damping elements 104. Piezoelectric composite materials or any material generally shaped in a manner conducive to the conversion of electrical energy into acoustic energy may also be used. To ensure maximum power transfer to transducer elements 104, elements 104 may be configured for electrical resonance, matching the input impedance.

[0031] Transducer array 102 is coupled to beamformer 106, which drives individual transducer elements 104 such that they collectively generate a focused ultrasonic beam or field. For n transducer elements, beamformer 106 may include n driver circuits, each circuit comprising an amplifier 118 and a phase shift circuit 120, or a combination of amplifier 118 and phase shift circuit 120; the driver circuits drive one of the transducer elements 104. Beamformer 106 receives radio frequency (RF) input signals from frequency generator 110, typically in the range of 0.1 MHz to 4.0 MHz, which may be, for example, a DS345 generator available from Stanford Research Systems. For the n amplifiers 118 and delay circuits 120 of beamformer 106, the input signal may be split into n channels. In some embodiments, frequency generator 110 is integrated with beamformer 106. The radio frequency generator 110 and the 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.

[0032] The amplification or attenuation factor α1-α applied by the beamformer 106 n and phase shift a1-a nThis is used to transmit and focus ultrasound energy through non-uniform tissue (e.g., the skull or different tissues of a patient, located along the acoustic path of the ultrasound beam from the transducer element to the target region or "path region") onto a target region (e.g., a region in the patient's brain). By adjusting the amplification factor and / or phase shift, the desired shape and intensity of the focused area can be formed at the target region.

[0033] The controller 108 can be used to calculate the amplification factor and phase shift, and the controller 108 can provide the relevant calculation functions through software, hardware, firmware, hardwiring, or any combination of the above. For example, the controller 108 can utilize a general-purpose or special-purpose digital data processor programmed with software in a conventional manner and without excessive experimentation to determine the frequency, phase shift, and / or amplification factor of the transducer element 104. In some embodiments, the controller calculations are based on detailed information about the characteristics (e.g., structure, thickness, density, etc.) of the interventional tissue located between the transducer 102 and the target 101 (e.g., through the region) and its effect on acoustic energy propagation. In various embodiments, such information is obtained from an imager 112 such as 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 examination device. Image acquisition can be three-dimensional (3D), or alternatively, imager 112 can provide a set of two-dimensional (2D) images suitable for reconstructing three-dimensional images of target region 101 and / or other regions (e.g., the region surrounding target 101, or the region located in the passage area between the transducer and the target, or other target regions). Image processing functions can be implemented in imager 112, controller 108, or a separate device.

[0034] Additionally, the ultrasound system 100 may include an application system 124 for introducing microbubbles into a patient. Examples of suitable application systems are described in PCT Publication WO 2019 / 116095, the entire contents of which are incorporated herein by reference. In some embodiments, the ultrasound system 100 and / or imager 112 may be used to detect signals from microbubbles located in or near a target region 101 (e.g., within 10 mm) to identify the amount, type, and / or location of microbubble cavitation. Additionally or alternatively, the system 100 may include an acoustic signal detector (such as a hydrophone or a suitable alternative) 126 to detect ultrasound emitted and / or reflected from the microbubbles and may provide the received signals to a controller 108 for further processing. For example, a method for identifying the amount, type, and / or location of microbubble cavitation using reflected signals from microbubbles is provided in U.S. Patent No. 10,575,816, the entire contents of which are incorporated herein by reference. The imager 112, application system 124, and / or acoustic signal detector 126 can be operated using the same controller 108 that manages the operation of the transducers; or they can be individually controlled by one or more dedicated controllers that communicate with each other.

[0035] Figure 1B An exemplary imager—namely, an MRI device 112—is shown. Device 112 may include a cylindrical electromagnet 134 that generates a necessary static magnetic field within an aperture 136 of the electromagnet 134. During a medical procedure, the patient is positioned within the aperture 136 on a movable support pedestal 138. A target region 140 within the patient's body (e.g., the patient's head) may be positioned within an imaging region 142, where the electromagnet 134 generates a substantially uniform field. A set of cylindrical magnetic field gradient coils 144 may also be disposed within the aperture 136 and surrounding the patient. The gradient coils 144 generate magnetic field gradients of predetermined amplitudes over predetermined times and in three mutually orthogonal directions. Using the field gradients, different spatial locations can be associated with different precession frequencies, thereby providing the MR image with its spatial resolution. An RF transmitter coil 146 surrounding the imaging region 142 transmits RF pulses into the imaging region 142, causing the patient's tissue to emit a magnetic resonance (MR) response signal. The raw MR response signal is sensed by RF coil 146 and transmitted to MR controller 148, which then calculates the MR image, which can be displayed to the user. Alternatively, separate MR transmitter and receiver coils can be used. Images acquired using MRI equipment 112 can provide radiologists and internists with visual contrasts between different tissues and detailed internal views of the patient's anatomy that cannot be visualized using conventional X-ray techniques.

[0036] The MRI controller 148 can control the pulse sequence, namely the relative timing and intensity of the magnetic field gradient and RF excitation pulse and response detection cycle. The MRI controller 148 can be combined with the transducer controller 108 to form an integrated system control facility.

[0037] The MR response signal is amplified, modulated, and digitized into raw data using a conventional image processing system, and further converted into an image data array using methods known to those skilled in the art. The image processing system may be part of an MRI controller 148, or a separate device (e.g., a general-purpose computer containing image processing software) communicating with the MRI controller 148 and / or transducer controller 108. Because the response signal is tissue- and temperature-dependent, it can be processed to identify the therapeutic target region 101 in the image and to calculate a temperature map from the image. Furthermore, the acoustic field generated by the ultrasound application can be monitored in real time using, for example, thermal MRI or MR-based acoustic radiation force imaging. Therefore, using MRI data, the ultrasound transducer 102 can be driven to focus ultrasound onto the target region 101 (or vicinity) while monitoring the temperature and / or acoustic field intensity of the target tissue and surrounding tissue.

[0038] In an exemplary procedure, an imager (e.g., an MRI device) 112 acquires information (such as location, size, and / or shape) of a target region and / or a non-target region before applying ultrasound processing. In one embodiment, the information includes a set of 3D voxels corresponding to the target / non-target regions, and in some cases, the voxels include attributes specifying tissue characteristics (e.g., type, properties, structure, thickness, density, etc.). Based on the acquired information, a transducer configuration (e.g., frequency, phase, and / or amplitude) can be determined to create a focal point at the target region 101 without overheating the non-target regions.

[0039] In various embodiments, once the target / non-target regions have been characterized, a preparation phase involving the application of at least one acoustic treatment sequence to the target tissue is performed before exposing the target tissue to a series of therapeutic acoustic treatments. (Refer to...) Figure 2A The preparation sequence may consist of a single, continuous sequence 202 of acoustic processing pulses 204 (at a frequency used during treatment). In one embodiment, the single, continuous pulse sequence 202 lasts from 0.01 to 10 seconds. Alternatively, see reference to... Figure 2B The preparation sequence may include a series of time-separated pulse sequences 214-218 of 212 (e.g., a 16ms pulse train repeated at a frequency of 10Hz, also at the same ultrasound frequency to be used during treatment). The series of time-separated pulse sequences 214-218 of 212 may last together from 1 to 600 seconds.

[0040] The various parameters of the ultrasound output in the preparation sequence can be fixed or can be varied. For example, refer again... Figure 2A The power and / or frequency of pulses 204 within the continuous pulse sequence 202 can be fixed; similarly, refer to Figure 2B In the time-separated pulse sequence of the acoustic processing series 212, the power and / or frequency of the pulses can be fixed, and the frequencies of sequences 214-218 in series 212 can be fixed. Alternatively, the power and / or frequency of the pulses within a continuous pulse sequence can vary. For example, Figure 3A and 3B The power and frequency of the changes in pulse 302 in the continuous pulse sequence 304 are shown respectively. Figure 3C The diagram shows the power and frequency of pulses 302 within a continuous pulse sequence 304 that varies during the preparation phase. Specifically, the power can vary from 1W to 1500W, and the frequency from 50kHz to 10MHz. Similarly, the power and / or frequency of pulses within a time-separated pulse sequence in a sound processing series can vary. For example, Figure 3D and 3E The power and frequency of the pulse 312 in the time-separated pulse sequence 314 of the acoustic processing series 316 are shown respectively. Figure 3F The diagram shows the power and frequency of pulse 312 in the time-separated pulse sequence 314, which varies during the preparation phase. Furthermore, different time-separated pulse sequences 314 and 318 in the acoustic processing series 316 can have different power levels. Figure 3G and 3I ) and / or frequency ( Figure 3H and 3I ).

[0041] Additionally, transducer 102 can be configured to generate ultrasonic pulses with multiple operating frequencies during the preparation phase; as a result, the preparation pulse sequence has a combination (or mixed frequency) of two or more ultrasonic frequencies. The mixed frequency can be fixed within the pulse sequence and / or between different time-separated pulse sequences in the acoustic processing series. For example, systems and methods for manufacturing and configuring transducers to provide multi-frequency and high-power output are described in U.S. Patent Publication No. 2016 / 0114193, the entire disclosure of which is incorporated herein by reference.

[0042] It should be noted that power and frequency are exemplary parameters that may be fixed or variable in the preparation of the pulse sequence; other parameters, such as sequence length, ultrasonic mechanical index in the target tissue and / or beam shape, may be fixed or variable and therefore fall within the scope of the invention.

[0043] Reference Figure 4In some embodiments, microbubbles 402 are injected and / or generated in the target region 101 during the preparation phase to enhance tissue sensitivity. For example, microbubbles can be generated by applying an ultrasound pulse with energy above a threshold. Microbubbles can also form due to negative pressure generated by the propagating ultrasound pulse or when a heated liquid ruptures and is filled with gas / vapor. Alternatively or additionally, microbubbles 402 can be introduced into the target region 101 using an application system 124. For example, microbubbles can be injected in the form of an ultrasound contrast agent such as SONOVUE, a suspension of sulfur hexafluoride gas microbubbles, etc. Methods for generating microbubbles and / or introducing microbubbles into target region 101 are provided, for example, in PCT Publications WO 2018 / 020315, WO 2019 / 116097, WO2019 / 058171, WO 2019 / 116097 and WO 2019 / 116095, U.S. Patent Publication 2019 / 0083065 and U.S. Patent No. 10,739,316, the contents of which are incorporated herein by reference.

[0044] Depending on the amplitude and frequency of the applied acoustic field, microbubbles 402 may oscillate or collapse (a mechanism known as "cavitation"). Cavitation of microbubbles can enhance tissue sensitivity at target region 101, resulting in faster heating and more efficient ablation of the tissue compared to the absence of microbubbles 402. Because cavitation typically involves the creation of voids or microbubbles in a liquid, these voids begin to collapse explosively with increasing applied acoustic energy; as the applied energy increases further, the explosion and the resulting shock wave (which can be detected as a measure of cavitation intensity) become more violent. Therefore, in various embodiments, one or more ultrasound parameters (such as power, frequency, mechanical index, beam shape, and sequence length) can be varied during the preparation pulse sequence to induce cavitation at a target range sufficient to enhance tissue sensitivity while avoiding extreme cavitation that produces significant clinical effects in the target region (i.e., significant temperature increases at the target and / or non-target regions). Once the target range for cavitation is reached, the ultrasound parameters can be fixed to maintain the cavitation level.

[0045] In various embodiments, the target range of cavitation is identified before or during the preparation phase by, for example, by tilting and increasing the power of the ultrasonic pulses and monitoring the response curves of the microbubbles. The microbubble response can be inferred from the temperature of the target / non-target tissue monitored by imager 112 and / or the acoustic response of the microbubbles detected by transducer 102 and / or acoustic signal detector 126. In one embodiment, the target range of cavitation is identified as having a power range between the pulse power that causes mild and stable cavitation and the pulse power that initiates the formation of a microbubble cloud. Further details regarding methods for identifying the target range of cavitation are provided, for example, in U.S. Patent Publication No. 2019 / 0175954; and methods for configuring transducer arrays for detecting microbubble responses are provided, for example, in PCT Publication No. WO / 2019 / 234497. The entire contents of these applications are incorporated herein by reference.

[0046] In addition to the applied acoustic energy, the degree of cavitation may also be affected by the microbubble concentration. Therefore, in some embodiments, one or more ultrasound parameters (e.g., power, frequency, mechanical index, beam shape, and sequence length) are optimized (and in some embodiments are fixed) to maintain the microbubble concentration within a fixed range; this range may in turn be based on the acoustic response of the microbubbles at the target / non-target region and / or the temperature of the target / non-target tissue as described above.

[0047] Reference Figure 5 After the preparation pulse sequence 502 ends, the ultrasound transducer 102 may stop passing through a delay interval 504 before generating a series of one or more treatment sequences 506-510 toward the target. As shown, there is an acoustic processing interval 512 between the treatment sequences; the acoustic processing interval 512 may be fixed or may vary throughout the treatment sequence. In one embodiment, the delay interval 504 is preferably longer than the longest acoustic processing interval by a predetermined factor (e.g., 2 times, 10 times, 50 times, or 100 times). For example, the acoustic processing interval 512 may last from 0.1 to 10 seconds, and the delay interval may range from 1 second (when the acoustic processing interval is 0.1 seconds) to 3 hours, such as 3 minutes (when the acoustic processing interval is 10 seconds).

[0048] Furthermore, microbubbles can be generated and / or introduced into the target region 101 after the preparation phase. For example, additional microbubbles can be applied during treatment to improve the focusing properties of the ultrasound focused beam and / or to aid in tissue rupture or necrosis. Methods using microbubbles to improve focusing properties are provided, for example, in U.S. Patent Publication No. 2019 / 0175954 and PCT Publication No. WO 2020 / 128615; and methods using microbubbles to aid in tissue destruction or necrosis are provided, for example, in U.S. Patent Publications Nos. 2019 / 0001154 and 2020 / 0139158 and PCT Publication No. WO 2019 / 002949. The entire contents of these applications are incorporated herein by reference.

[0049] Figure 6 A flowchart illustrating an exemplary method 600 for enhancing tissue sensitivity, thereby allowing effective ultrasound treatment of target tissue while avoiding damage to non-target tissues. In a first step 602, an imager (e.g., an MRI device) is activated to acquire information (such as location, size, and / or shape) of the target and / or non-target regions. In a second step 604, based on the acquired information, one or more sequences of acoustic processing pulses may be generated to apply acoustic energy to the target region to enhance tissue sensitivity therein. Additionally, microbubbles may optionally be generated and / or injected into the target region to further enhance tissue sensitivity (step 606). If microbubbles are used during the preparation phase, one or more ultrasound parameters (such as power, frequency, mechanical index, beam shape, and sequence length) may be adjusted to induce and / or maintain a target range of cavitation sufficient to enhance tissue sensitivity while avoiding extreme cavitation that produces significant clinical effects in the target region (i.e., significant temperature increases at the target and / or non-target regions) (step 608). Once the preparation phase is complete, the ultrasound transducer may be stopped after a predetermined delay interval (step 610). Subsequently, the ultrasound transducer can be activated to emit one or more treatment sequences for tissue rupture or necrosis in the target area (step 612). Again, microbubbles can optionally be introduced into the target during treatment to aid in tissue rupture or necrosis and / or improve the focusing characteristics of the ultrasound focused beam. Optionally, the preparation sequence and / or treatment sequence can be guided by the imager 112.

[0050] Therefore, various embodiments employ a preparatory sequence of acoustic treatment pulses before applying the therapeutic acoustic treatment pulses to the target tissue; this method can advantageously enhance the sensitivity of various types of target tissues to acoustic energy at various frequencies. As a result, the acoustic energy required for tissue destruction / necrosis in the target region can be reduced. Thus, various embodiments effectively reduce the acoustic energy required from the ultrasound transducer to provide effective targeted therapy while avoiding damage to non-target tissues.

[0051] Typically, the functions used to perform ultrasound therapy procedures, including, for example, generating one or more preparatory sequences of acoustic processing pulses, adjusting parameters of the preparatory acoustic processing sequences, generating microbubbles, applying acoustic processing to induce microbubble cavitation, and generating a treatment sequence of a series of acoustic processing pulses as described above, whether integrated into the imager's controller and / or ultrasound system or provided by a separate external controller, can be built into one or more modules implemented in hardware, software, or a combination of both. For embodiments where the functions are provided as one or more software programs, the programs can be written in any of many high-level languages, such as PYTHON, JAVA, C, C++, C#, BASIC, various scripting languages, and / or HTML. Alternatively, the software can be implemented in assembly language, pointing to a microprocessor residing on a target computer (e.g., the controller); for example, if the software is configured to run on an IBM PC or a PC clone, it can be implemented in Intel 80x86 assembly language. The software can be implemented on an article of art, including but not limited to floppy disks, flash drives, hard disks, optical disks, magnetic tapes, PROMs, EPROMs, EEPROMs, field-programmable gate arrays, or CD-ROMs. Implementations using hardware circuitry can be achieved using, for example, one or more FPGAs, CPLDs, or ASIC processors.

[0052] Furthermore, the term "controller" as used herein broadly includes all necessary hardware components and / or software modules for performing any of the functions described above; the controller may include multiple hardware components and / or software modules, and functionality may be propagated between different components and / or modules. Further, phased array operation is optional (a simple transducer is acceptable for some applications), as is image guidance. If imaging is employed, treatment sequences, preparation sequences, or both can be guided therefrom. As discussed, the imaging modality may be MRI, or computed tomography (CT), X-ray, positron emission tomography (PET), single-photon emission computed tomography (SPECT), or infrared imaging. The imaging device may produce 1D, 2D, 3D, and / or 4D images.

[0053] The terms and expressions used herein are descriptive and not restrictive, and their use is not intended to exclude any equivalents of the features shown and described or any part thereof. Furthermore, while certain embodiments of the invention have been described, it will be apparent to those skilled in the art that other embodiments incorporating the concepts disclosed herein may be used without departing from the spirit and scope of the invention. Therefore, the described embodiments should be considered merely illustrative and not limiting of the invention in all respects.

[0054] The claims are as follows:

Claims

1. A system for treating target tissue, the system comprising: An ultrasonic transducer used to transmit acoustic energy to target tissue; as well as The controller is configured to (i) generate a acoustic processing pulse preparation sequence to deliver acoustic energy to the target tissue by driving an ultrasonic transducer according to the preparation sequence, thereby enhancing the sensitivity of the target tissue to acoustic energy before initiating therapeutic acoustic processing of the target tissue; (ii) pause driving the ultrasonic transducer for a delay interval; and (iii) after the delay interval, initiate therapeutic acoustic processing of the target tissue by generating a series of acoustic processing pulse treatment sequences to deliver acoustic energy to the target tissue by driving an ultrasonic transducer according to a series of treatment sequences. The treatment sequences are spaced apart by acoustic processing intervals, and the delay interval is larger than the maximum acoustic processing interval by a predetermined coefficient.

2. The system of claim 1, further comprising an application device for applying an ultrasound contrast agent to a target tissue.

3. The system of claim 2, wherein, The controller is further configured to operate the application device to apply ultrasound contrast agent during the preparation sequence and / or treatment sequence.

4. The system of claim 1, wherein, The preparation sequence has at least one fixed parameter selected from frequency, power, mechanical index of the target tissue, and beam shape.

5. The system of claim 4, wherein, The controller is further configured to determine the value of the at least one fixed parameter for maintaining the microbubble target concentration at the target tissue.

6. The system of claim 1, wherein, The preparation sequence has at least one variation parameter selected from frequency, power, mechanical index of the target tissue, and beam shape.

7. The system according to claim 6, wherein, The controller is further configured to determine the value of the at least one variable parameter for (i) inducing microbubble cavitation in the target tissue, (ii) maintaining a target range of microbubble cavitation in the target tissue, and / or (iii) avoiding the formation of microbubble clouds in the target tissue.

8. The system according to claim 7, wherein, The controller is further configured to determine the target range of microbubble cavitation based at least in part on the acoustic response from the target tissue.

9. The system of claim 1, further comprising at least one acoustic signal detector, the controller further configured to adjust parameters associated with the preparation sequence based on acoustic responses from the target tissue detected by the at least one acoustic signal detector.

10. The system according to claim 1, wherein, The preparation sequence has a mixing frequency.

11. The system of claim 1, further comprising at least one imaging device for guiding at least one of the preparation sequence or the treatment sequence.

12. The system according to claim 11, wherein, The imaging device includes at least one of ultrasound, MRI, CT, X-ray, PET, SPECT, or infrared imaging devices.

13. The system according to claim 12, wherein, The imaging device produces at least one of 1D, 2D, 3D or 4D images.

14. The system according to claim 1, wherein, The predetermined coefficient is at least 10.

15. The system according to claim 1, wherein, The predetermined coefficient is at least 2.

16. The system according to claim 1, wherein, The transducer is a phased array transducer.

17. A system for treating target tissue, the system comprising: An ultrasonic transducer used to transmit acoustic energy to target tissue; An application device for administering ultrasound contrast agents to target tissues; as well as The controller is configured to (i) generate a preparation sequence of acoustic processing pulses to deliver acoustic energy to the target tissue by driving an ultrasound transducer according to the preparation sequence, thereby enhancing the sensitivity of the target tissue to acoustic energy before initiating therapeutic acoustic treatment of the target tissue; (ii) operate an application device to apply an ultrasound contrast agent during the preparation sequence; (iii) pause the generation of acoustic processing pulses after a delay interval; and (iv) after the delay interval, initiate therapeutic acoustic treatment of the target tissue by generating a treatment sequence of acoustic processing pulses to deliver acoustic energy to the target tissue by driving an ultrasound transducer according to the treatment sequence.

18. The system according to claim 17, wherein, The preparation sequence has at least one fixed parameter selected from frequency, power, mechanical index of the target tissue, and beam shape.

19. The system according to claim 18, wherein, The controller is further configured to determine the value of the at least one fixed parameter for maintaining the microbubble target concentration at the target tissue.

20. The system according to claim 17, wherein, The preparation sequence has at least one variation parameter selected from frequency, power, mechanical index of the target tissue, and beam shape.

21. The system according to claim 20, wherein, The controller is further configured to determine the value of the at least one variable parameter for (i) inducing microbubble cavitation in the target tissue, (ii) maintaining a target range of microbubble cavitation in the target tissue, and / or (iii) avoiding the formation of microbubble clouds in the target tissue.

22. The system according to claim 21, wherein, The controller is further configured to determine the target range of microbubble cavitation based at least in part on the acoustic response from the target tissue.

23. The system of claim 17, further comprising at least one acoustic signal detector, the controller being further configured to adjust parameters associated with the preparation sequence based on acoustic responses from the target tissue detected by the at least one acoustic signal detector.

24. The system according to claim 17, wherein, The preparation sequence has a mixing frequency.

25. The system of claim 17, further comprising at least one imaging device for guiding at least one of the preparation sequence or the treatment sequence.

26. The system according to claim 25, wherein, The imaging device includes at least one of ultrasound, MRI, CT, X-ray, PET, SPECT, or infrared imaging devices.

27. The system according to claim 25, wherein, The imaging device produces at least one of 1D, 2D, 3D or 4D images.

28. The system according to claim 17, wherein, The controller is further configured to operate the application device to apply an ultrasound contrast agent during a treatment sequence.

29. The system according to claim 17, wherein, The transducer is a phased array transducer.

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