Systems and methods for regulating microbubbles in ultrasound surgery

Abstract

Various methods for modulating microbubbles in targeted treatment procedures include: generating a tissue sensitivity map including a plurality of regions, at least one of the regions being outside a target region, the tissue sensitivity map assigning a sensitivity level to each of the regions indicating the sensitivity of the tissue to an interaction between microbubbles and an acoustic beam; selecting one or more interaction regions based at least in part on the tissue sensitivity map; and activating an ultrasonic transducer to generate an acoustic beam for interacting with microbubbles in the (plurality) selected interaction regions in the tissue sensitivity map, thereby indirectly changing a property of the microbubbles at the target region.

Description

Technical Field

[0001] The present invention relates generally to ultrasonic surgery, and more particularly to systems and methods for regulating microbubbles during such surgery to increase their effectiveness while avoiding damage to healthy tissue. Background Art

[0002] Focused ultrasound (i.e., sound waves with a frequency greater than about 20kHz) can be used to image or treat tissues in a patient's body. For example, ultrasound can be used for applications involving tumor ablation, targeted drug delivery, blood-brain barrier (BBB) ​​disruption, clot dissolution, and other surgical procedures. During tumor ablation, a piezoelectric ceramic transducer is placed outside the patient's body, but close to the tumor to be ablated (i.e., the target area). The transducer converts the electronic drive signal into mechanical vibrations, thereby emitting sound waves. The transducer can be geometrically shaped and positioned with other such transducers so that the ultrasonic energy they emit forms a focused beam together at a "focal area" corresponding to (or within) the target area. Alternatively or additionally, a single transducer can be formed by a plurality of individually driven transducer elements, each of which can be independently controlled. This "phased array" transducer facilitates turning the focal area to different positions by adjusting the relative phase between the transducers. As used herein, the term "element" refers to a single transducer in an array or an independently drivable portion of a single transducer. Magnetic resonance imaging (MRI) can be used to visualize the patient and the target to guide the ultrasound beam.

[0003] During focused ultrasound surgery, small bubbles (or "microbubbles") can be generated and / or introduced into a target area. Because the microbubbles encapsulate gas, the bubble surfaces can collectively form an ultrasound reflector. Therefore, by transmitting ultrasound to the microbubbles and receiving reflections from the microbubbles, the amplitude and / or phase associated with the reflected ultrasound can be determined; based on this, the transducer parameters (e.g., phase shift and / or amplitude) can be determined or adjusted to compensate for aberrations caused at least in part by the skull. Although this approach can effectively improve the focusing characteristics at the target, microbubbles remaining in the target and / or non-target tissues after the focused surgery may cause undesirable damage. For example, during the subsequent application of ultrasound energy for targeted treatment, the response of tissues containing a relatively high relative percentage of microbubbles is nonlinear and difficult to predict. In addition, depending on the amplitude and frequency of the applied acoustic field, the microbubbles may oscillate or collapse (a phenomenon known as "cavitation"), resulting in extensive tissue damage beyond the target range and may be difficult to control. As used herein, the response of microbubbles to applied ultrasound treatment is referred to as the "microbubble response," and the thermal or mechanical effects generated by ultrasound treatment and / or microbubble cavitation in target and / or non-target areas are referred to as the "therapeutic effect."

[0004] In order to minimize the undesirable effects caused by microbubbles during the treatment target, a conventional method suspends ultrasonic surgery until the microbubbles dissipate naturally. However, this method unnecessarily and undesirably prolongs the duration of ultrasonic surgery. Another conventional method for eliminating microbubbles is to apply low-energy ultrasound treatment to cavitate the microbubbles. However, this method may cause damage to non-target tissues caused by cavitation rather than avoidance. Therefore, it is necessary to effectively remove microbubbles during ultrasonic surgery to avoid damage to healthy tissues. Summary of the invention

[0005] The present invention relates to regulating the amount or concentration of microbubbles in a manner to maintain the efficiency of ultrasonic surgery while avoiding damage to healthy non-target tissues before and / or during a target treatment procedure (e.g., ultrasonic surgery). In various embodiments, a microbubble regulation method includes creating a tissue sensitivity map of one or more tissue regions outside a target region before a treatment procedure. In one implementation, the target region and / or the region outside the target is represented as a three-dimensional (3D) voxel group (i.e., volume pixels), and each voxel is associated with a sensitivity score indicating the tissue sensitivity to the interaction between the applied ultrasonic treatment and the microbubbles. For example, tissue sensitivity can be thermal sensitivity and / or sensitivity to microbubble cavitation. A relatively high sensitivity score indicates that the tissue corresponding to the voxel may be more sensitive to (e.g., relatively low tolerance to) temperature rise and / or microbubble cavitation events, and is therefore more susceptible to damage; while a relatively low sensitivity score indicates that the tissue is less sensitive to temperature rise and / or microbubble cavitation (e.g., has relatively large tolerance).

[0006] In some embodiments, before and / or during ultrasonic surgery (e.g., applying ultrasound to ablate target tissue), a small transient microbubble cloud is provided to the target area for automatically focusing the acoustic beam applied thereon. After determining the transducer parameters (e.g., frequency, phase shift and / or amplitude) of the focus at the optimized target area (e.g., via analyzing the acoustic reflection from microbubbles), the microbubbles in the target area and / or its vicinity can be eliminated (or at least reduced) using tissue sensitivity maps to avoid the undesirable damage caused thereby. The presence and / or quantity (or concentration) of microbubbles at the target area (and / or its vicinity) are measured based on the acoustic signal transmitted or reflected from the microbubble using an acoustic signal detection device and / or a transducer array. If there are microbubbles and / or its amount or concentration exceeds a predetermined threshold, the following measures can be taken. Thresholds can be set based on, for example, ultrasonic surgery that is effective and does not damage non-target tissues previously performed, in which case the affected non-target tissue area can be considered to be at least tolerant to the microbubbles at this level. Alternatively, the microbubble threshold may be estimated based on the known relationship (which may be approximate) between tissue temperature sensitivity (or tolerance) and the effect of microbubble cavitation (at a given applied power and microbubble concentration) on the tissue in question.

[0007] In various embodiments, based on the tissue sensitivity map, one or more regions that are relatively insensitive to the interaction of the acoustic beam and microbubbles in the tissue sensitivity map (e.g., having a lower sensitivity score) can be identified. The ultrasonic transducer can then be activated to generate one or more focal points at the identified region in order to clear the microbubbles therein (e.g., by cavitating them). Optionally, the acoustic signal detection device and / or the transducer array can be used again to monitor microbubble cavitation in real time. Based on this, the ultrasound parameters can be adjusted to ensure that the desired proportion of microbubbles can be destroyed without damaging the tissue even in relatively low sensitivity regions. Because this method may reduce the total amount of microbubbles in the bloodstream, the amount of microbubbles in the target region (and everywhere in the bloodstream) can be indirectly reduced. Therefore, undesirable damage caused by microbubbles at non-target regions near the target region and / or thereof during ablation of the target tissue can be avoided. In addition, because the microbubbles are destroyed in regions with relatively low sensitivity to temperature rise and / or microbubble cavitation, damage to low sensitivity regions may not be clinically significant. As used herein, "clinically insignificant" means having an undesirable (and sometimes lacking a desired) effect on tissue that is considered insignificant by a clinician, e.g., prior to causing damage to the tissue or other clinically adverse effects, whether temporary or permanent. Additionally, an "indirect" reduction of microbubbles in a region means that the ultrasound focus is not directed toward a region that could directly cause microbubble cavitation to occur and / or is not generated in that region.

[0008] In some embodiments, when determining the area to be cleared of microbubbles, the amount of microbubbles present in the area on the tissue sensitivity map can be considered. For example, applying an acoustic beam to an area with a relatively large number of microbubbles may cause more microbubble cavitation, thereby more effectively reducing the microbubble population in the target area (and everywhere in the blood flow). As described above, the amount of microbubbles in each area can be detected using acoustic reflections from microbubbles. Additionally or alternatively, one or more areas in which microbubbles are to be cleared can be selected based on the relative position of one or more areas relative to the target area. For example, destroying microbubbles in the upstream area of ​​the target area can quickly reduce the microbubble population in the target area; while destroying microbubbles in the downstream area of ​​the target area can reduce the microbubble population in the target, but due to the longer circulation path back to the target, the effect on the target may be delayed.

[0009] Although the main force for distributing microbubbles in the target area and the target external area is blood circulation, in some embodiments, the ultrasonic transducer can be configured to (e.g., by adjusting the phase, amplitude and / or frequency) produce a focus that can induce microbubble movement by applying acoustic force to it. Ultrasonic parameters (e.g., phase) can be adjusted to gradually move the focus (and microbubbles) from fragile areas (e.g., targets and / or relatively high sensitivity areas) to the identified relatively low sensitivity areas. Once the microbubbles move from fragile tissues to areas with lower sensitivity, the intensity of the acoustic beam can be increased to cause microbubble cavitation in order to clear the microbubbles. Furthermore, acoustic signal detection equipment and / or transducer arrays can be used to monitor microbubble movement and / or cavitation in real time. Based on this, the ultrasonic parameters can be adjusted to ensure that the desired part of the microbubbles is moved away from the relatively high sensitivity area without cavitation and without cavitation that may cause damage even in areas with relatively low sensitivity.

[0010] After the microbubbles are eliminated / reduced, an ultrasonic procedure for treating the target tissue may be started or continued. Thus, various embodiments utilize tissue sensitivity maps to identify one or more regions with lower sensitivity (or higher tolerance) to acoustic power and / or microbubble cavitation, and based thereon, configure the ultrasonic transducer to: induce microbubble cavitation in the identified lower sensitivity regions. This may advantageously avoid undesirable damage to healthy tissue caused by microbubble cavitation, while avoiding the need for prolonged ultrasonic procedures as required in conventional methods that pause before the microbubbles are naturally cleared.

[0011] Therefore, on the one hand, the present invention relates to a system for regulating microbubbles in a therapeutic procedure at a target area. In various embodiments, the system includes an ultrasonic transducer and a controller, which is configured to: (a) generate a tissue sensitivity map including multiple areas, one or more areas are outside the target area; (b) select one or more interaction areas based at least in part on the tissue sensitivity map; and (c) activate the ultrasonic transducer to generate an acoustic beam for interacting with microbubbles in the interaction area selected in the tissue sensitivity map, thereby indirectly changing the characteristics of the microbubbles at the target area (e.g., microbubble amount, concentration, size distribution and / or microbubble response to the acoustic beam). In one implementation, the tissue sensitivity map assigns a sensitivity level indicating tissue sensitivity to the interaction between the microbubble and the acoustic beam (e.g., thermal sensitivity and / or sensitivity to microbubble cavitation) to each area in the tissue sensitivity map.

[0012] The controller may also be configured to determine one or more parameters (e.g., frequency, amplitude, and / or phase) associated with one or more transducer elements of the ultrasonic transducer based at least in part on the selected interaction region in the tissue sensitivity map. In addition, the controller may also be configured to activate the ultrasonic transducer based at least in part on the determined parameters associated with the ultrasonic transducer. In some embodiments, the therapeutic procedure involves the use of microbubbles; the system also includes a device for providing microbubbles to the target area to initialize the therapeutic procedure. For example, the microbubbles may be administered to the target area using an administration system. Additionally or alternatively, the ultrasonic transducer may emit ultrasonic pulses to the target area to generate microbubbles. In addition, the controller may also be configured to perform step (c) only after the focusing characteristics of the acoustic beam at the target area are optimized.

[0013] In various embodiments, the system also includes a device for detecting microbubble characteristics in a target area, one of the areas in the tissue sensitivity map, and / or a dedicated monitoring area (e.g., an area that is continuously monitored throughout the treatment operation). The device for detecting microbubble characteristics may include an ultrasonic transducer, an acoustic signal detection device, and / or a second ultrasonic transducer that is different from the ultrasonic transducer activated in step (c). In addition, the controller may also be configured to: determine parameters associated with the ultrasonic transducer based at least in part on the detected microbubble characteristics. In one embodiment, the generated acoustic beam causes cavitation of at least some microbubbles in the interaction area selected in the tissue sensitivity map. The controller may also be configured to determine parameters associated with the ultrasonic transducer in order to select microbubbles for cavitation.

[0014] In addition, the system may also include an imaging device for acquiring a digital representation of a plurality of voxels including one or more portions of the region in the tissue sensitivity map; the controller may also be configured to: generate a tissue sensitivity map based at least in part on the digital representation. In some embodiments, the controller is further configured to: determine anatomical characteristics (e.g., tissue type, location, size, or function) of one or more portions of the region in the tissue sensitivity map based on the digital representation; and then generate the tissue sensitivity map based at least in part on the anatomical characteristics. In addition, the controller may also be configured to: generate the tissue sensitivity map by assigning sensitivity scores to the voxels of the one or more portions based at least in part on the anatomical characteristics associated with the one or more portions of the region in the tissue sensitivity map; the sensitivity score indicates the sensitivity level of the voxel to the interaction of the acoustic beam with the microbubble. The selected interaction region in the tissue sensitivity map may have a relatively low sensitivity score compared to other regions in the tissue sensitivity map. In addition, the controller may also be configured to: adjust parameters associated with the ultrasound transducer based at least in part on the sensitivity scores assigned to the regions in the tissue sensitivity map. In one embodiment, the controller is further configured to: adjust parameters associated with the ultrasound transducer so that at least some of the microbubbles move from the target region to the selected interaction region in the tissue sensitivity map.

[0015] On the other hand, the present invention relates to a method for regulating microbubbles in a therapeutic procedure of a target area. In various embodiments, the method includes (a) generating a tissue sensitivity map including a plurality of regions, one or more regions being outside the target area; (b) selecting one or more interaction regions based at least in part on the tissue sensitivity map; and (c) activating an ultrasonic transducer to generate an acoustic beam for interacting with microbubbles in the selected interaction region in the tissue sensitivity map, thereby indirectly changing the characteristics of the microbubbles at the target area (e.g., microbubble amount, concentration, size distribution, and / or microbubble response to the acoustic beam). In one implementation, the tissue sensitivity map assigns a sensitivity level indicating tissue sensitivity to the interaction between the microbubble and the acoustic beam (e.g., thermal sensitivity and / or sensitivity to microbubble cavitation) to each region in the tissue sensitivity map.

[0016] The method may also include determining one or more parameters (e.g., frequency, amplitude, and / or phase) associated with one or more transducer elements of the ultrasonic transducer based at least in part on the selected interaction region in the tissue sensitivity map. The ultrasonic transducer may then be activated based at least in part on the determined parameters. In addition, the therapeutic procedure may involve the use of microbubbles; the method may also include providing microbubbles to the target area to initialize the therapeutic procedure. In one embodiment, the microbubbles are administered using an administration system. Additionally or alternatively, the method may also include causing the ultrasonic transducer to emit ultrasonic pulses to the target area to generate microbubbles. In one embodiment, step (c) is performed only after the focusing characteristics of the acoustic beam at the target area are optimized.

[0017] In various embodiments, the method further includes detecting microbubble characteristics in a target area, one of the areas in a tissue sensitivity map, and / or a dedicated monitoring area (e.g., an area that is continuously monitored throughout a therapeutic operation). Microbubble characteristics can be detected using an ultrasonic transducer, an acoustic signal detection device, and / or a second ultrasonic transducer that is different from the ultrasonic transducer activated in step (c). In addition, the method may further include determining parameters associated with the ultrasonic transducer based at least in part on the detected microbubble characteristics. In one embodiment, the generated acoustic beam causes cavitation of at least some of the microbubbles in the selected interaction area in the tissue sensitivity map. The method may then further include determining parameters associated with the ultrasonic transducer in order to select microbubbles for cavitation.

[0018] In addition, the method may also include acquiring a digital representation of a plurality of voxels including one or more portions of the region in the tissue sensitivity map; generating a tissue sensitivity map based at least in part on the digital representation. In some embodiments, the method also includes determining anatomical characteristics (e.g., tissue type, location, size, or function) of one or more portions of the region in the tissue sensitivity map based on the digital representation; generating a tissue sensitivity map based at least in part on the anatomical characteristics. In addition, the method may also include assigning sensitivity scores to the voxels of the one or more portions based at least in part on the anatomical characteristics associated with the one or more portions of the region in the tissue sensitivity map; the sensitivity score indicates the sensitivity level of the voxel to the interaction of the acoustic beam with the microbubble. The selected interaction region in the tissue sensitivity map may have a relatively low sensitivity score compared to other regions in the tissue sensitivity map. In addition, the method may also include adjusting parameters associated with the ultrasound transducer based at least in part on the sensitivity score assigned to the region in the tissue sensitivity map. In one embodiment, the method also includes moving at least some of the microbubbles from the target region to the selected interaction region in the tissue sensitivity map.

[0019] References throughout this specification to "one example," "an example," "one embodiment," or "an embodiment" mean that a particular feature, structure, or characteristic described in conjunction with the example is included in at least one example of the present technology. Thus, the phrases "in one example," "in an example," "one embodiment," or "an embodiment" appearing in various places throughout this specification do not necessarily all refer to the same example. Furthermore, particular features, structures, routines, steps, or characteristics may be combined in any suitable manner in one or more examples of the present technology. The headings provided herein are for convenience only and are not intended to limit or interpret the scope or meaning of the claimed technology. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] In the accompanying drawings, the same reference numerals generally refer to the same parts in different views. In addition, the drawings are not necessarily drawn to scale, but emphasis is generally placed on illustrating the principles of the invention. In the following description, various embodiments of the invention are described with reference to the following drawings, in which:

[0021] Figure 1A schematically depicts an exemplary ultrasound system according to various embodiments of the present invention;

[0022] Figure 1B schematically depicts an exemplary MRI system according to various embodiments of the present invention;

[0023] Figure 2A depicts tissue volumes of target regions and non-target regions represented as groups of 3D voxels according to various embodiments of the present invention;

[0024] FIG. 2B to FIG. 2F depicts exemplary tissue sensitivity maps according to various embodiments of the present invention;

[0025] Figure 3 is a flow chart illustrating an exemplary method for generating a tissue sensitivity map according to various embodiments of the present invention;

[0026] FIG. 4A to FIG. 4C Depicted are various microvesicle modulation methods for indirectly eliminating / reducing the microvesicle population at a target area or a nearby non-target area according to various embodiments of the present invention;

[0027] Figure 5 Depicted is the implementation of a second ultrasound transducer for real-time monitoring of microbubble modulation methods and / or ultrasound surgery according to various embodiments of the present invention;

[0028] Fig. 6A is a flow chart illustrating a method of regulating a microbubble population in a target area and / or a non-target area before, during and / or after an ultrasound procedure according to various embodiments of the present invention; and

[0029] Figure 6B is a flow chart illustrating an exemplary microbubble modulation method according to various embodiments of the present invention. DETAILED DESCRIPTION

[0030] Figure 1A An exemplary ultrasound system 100 is shown for generating and delivering a focused acoustic energy beam to a target area to damage and / or ablate tissue therein. In various embodiments, the system 100 includes a phased array 102 of transducer elements 104, a beamformer 106 that drives the phased array 102, a controller 108 that communicates with the beamformer 106, and a frequency generator 110 that provides an input electronic signal to the beamformer 106.

[0031] The array 102 can have a curved (e.g., spherical or parabolic) shape suitable for placing it on the surface of the patient's body, or can include one or more flat or other shaped portions. Its size may vary from a few millimeters to tens of centimeters. The transducer elements 104 of the array 102 can be piezoelectric ceramic elements and can be mounted in silicone rubber or any other material suitable for mechanical coupling between the damping elements 104. Piezoelectric composites can also be used, or generally any material that can convert electrical energy into acoustic energy. In order to ensure maximum power transmission to the transducer elements 104, the elements 104 can be configured for electrical resonance of 50Ω, thereby matching the input connector impedance.

[0032] The transducer array 102 is coupled to a beamformer 106, which drives the individual transducer elements 104 so that they collectively produce a focused ultrasound beam or field. For n transducer elements, the beamformer 106 may include n driver circuits, each including or consisting of an amplifier 118 and a phase delay circuit 120; each driver circuit drives 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, such as a model DS345 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 integral with the beamformer 106. The 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 at different phases and / or different amplitudes.

[0033] The amplification or attenuation factor α1-α applied by the beamformer 106 n and phase shift a1-a nFor transmitting and focusing ultrasonic energy onto a target area, and taking into account the wave distortion caused in the tissue between the transducer element 104 and the target area. The amplification factor and phase shift are calculated using a controller 108, which can provide the calculation function through software, hardware, firmware, hard wiring or any combination thereof. For example, the controller 108 can utilize a general or dedicated digital data processor programmed with software in a conventional manner, and without excessive experimentation, in order to determine the phase shift and amplification factor required to obtain the desired focus or any other desired spatial field pattern in the target area. In some embodiments, the calculation is based on detailed information about the characteristics of the intervening tissue between the transducer element 104 and the target (e.g., structure, thickness, density, etc.) and its effect on the propagation of acoustic energy. This information can be obtained from an imager 122. The imager 122 can 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. The image acquisition may be three-dimensional (3D), or alternatively, the imager 122 may provide a set of two-dimensional (2D) images suitable for reconstructing a three-dimensional image of the target region and / or other regions (e.g., the region surrounding the target). In addition, the ultrasound system 100 and / or the imager 122 may be used to detect microbubble responses, presence, number, concentration, and / or size distribution, and / or the presence, type, and / or location associated with microbubble cavitation, as further described below. Additionally or alternatively, the system may include an acoustic signal detection device (such as a hydrophone or a suitable substitute) 124 that detects ultrasound emitted or reflected from the microbubbles to measure the presence, number, concentration, and / or size distribution of the microbubble responses and / or information associated with microbubble cavitation, and may provide its received signals to the controller 108 for further processing. In addition, the ultrasound system 100 may include an administration system 126 for introducing microbubbles and / or therapeutic agents into a patient's body from outside the gastrointestinal tract, as further described below. The imager 122, acoustic signal detection device 124, and / or management system 126 may be operated using the same controller 108 that facilitates transducer operation; alternatively, they may be separately controlled by one or more separate controllers that communicate with each other.

[0034] Figure 1BAn exemplary imager, namely an MRI device 122, is shown. The device 122 may include a cylindrical electromagnet 134 that generates a necessary static magnetic field within a bore 136 of the electromagnet 134. During a medical procedure, a patient is placed within 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 region 142, wherein the electromagnet 134 generates a substantially uniform field. A set of cylindrical magnetic field gradient coils 144 may also be disposed within the bore 136 and around the patient. The gradient coils 144 generate magnetic field gradients of predetermined amplitudes at predetermined times and in three mutually orthogonal directions. Through the field gradients, different spatial locations may 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 to cause the patient's tissue to emit magnetic resonance (MR) response signals. The raw MR response signals are sensed by the RF coils 146 and transmitted to the MR controller 148, which then calculates an MR image that may be displayed to a user. Alternatively, separate MR transmitter and receiver coils may be used.Images acquired using MRI device 122 may provide radiologists and physicians with visual contrast between different tissues and detailed internal views of the patient's anatomy that are not visible with conventional X-ray techniques.

[0035] The MRI controller 148 can control the pulse sequence, i.e., the relative timing and strength of the magnetic field gradients and the RF excitation pulses and response detection cycles. The MR response signals are amplified, conditioned, and digitized into raw data using a conventional image processing system, and further converted into an image data array by methods known to those of ordinary skill in the art. Based on the image data, a target area (e.g., a tumor or a target BBB) can be identified.

[0036] In order to perform targeted drug delivery or tumor ablation, the location of the target area needs to be determined with high precision. Therefore, in various embodiments, the imager 122 is first activated to acquire images of the target area and / or non-target area (e.g., healthy tissue around the target area, intervening tissue between the transducer array 102 and the target area and / or any area near the target), and based on this, the anatomical characteristics associated therewith (e.g., tissue type, location, size, thickness, density, structure, shape, vascularization) are determined. For example, a tissue volume can be represented as a set of 3D voxels based on a 3D image or a series of 2D image slices, and can include a target area and / or a non-target area.

[0037] In various embodiments, based on the acquired images and anatomical characteristics, an image, table, or "map" of the tissue's sensitivity level to the effects of the interaction between the acoustic beam and microbubbles at the target tissue and / or non-target tissue (e.g., temperature increase due to acoustic power and / or microbubble cavitation) can be generated as described below. For ease of reference, the following description only refers to tissue sensitivity maps; however, it should be understood that a table or other suitable data organization format can be used to indicate tissue sensitivity levels. Reference Figure 2A , the tissue sensitivity map 202 may include various regions outside the target region 204. For example, the target region 204 may be a brain tumor and the tissue sensitivity map 202 may include a region 206 surrounding the target tumor 204, an arteriole 208, a carotid artery 210, a facial vein 212, and a jugular vein 214; each region is represented by one or more voxels 216. In one implementation, the tissue sensitivity map 202 also includes the target region 204. The tissue sensitivity map 202 is generally useful for treatment planning so that ultrasound is effectively directed to one or more regions outside the target region 204 to clear microbubbles, but without damaging non-target tissues having different sensitivities. For this purpose, the tissue sensitivity map 202 identifies low-sensitivity non-target regions where microbubbles can be quickly "destroyed" (i.e., caused to undergo cavitation) or reduced by ultrasound treatment after being used for ultrasound autofocusing so as not to delay continued ultrasound treatment of the target 204 (e.g., ablation of target tumor tissue).

[0038] Tissue sensitivity maps may be created based on various tissue characteristics, such as tissue type. For example, brain tissue may have a lower thermal damage threshold than bone tissue. Therefore, in one embodiment, brain tissue is classified as a higher sensitivity category and / or assigned a higher sensitivity score; while bone tissue is classified as a lower sensitivity category and / or given a lower sensitivity score. Similarly, muscle tissue may have a lower thermal damage threshold than fat tissue; therefore, muscle tissue may be assigned a relatively higher sensitivity score and / or classified as a higher sensitivity category; while fat tissue is assigned a relatively lower sensitivity score and / or classified as a lower sensitivity category. Thermal and / or cavitation damage thresholds for various tissue types may be obtained based on retrospective studies of patients undergoing ultrasonic surgery and / or from known literature (e.g., see https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC3609720 / ). In some embodiments, the classification and / or assignment of sensitivity scores to various types of tissues is based on the thermal capacity of the tissue, which can also be obtained from known literature (e.g., see https: / / itis.swiss / virtual-population / tissue-properties / database / heat-capacity / ). Because tissues with relatively low thermal capacity may reach a threshold temperature (e.g., 43° C.) and experience damage in a relatively short period of time, tissues with relatively low thermal capacity can be classified into higher sensitivity categories and / or assigned higher sensitivity scores in terms of acoustic power and / or microbubble cavitation. In one embodiment, a sensitivity score is assigned to each voxel of target tissue and / or non-target tissue on the tissue sensitivity map 202.

[0039] Additionally or alternatively, tissue sensitivity map 202 can be based at least in part on tissue size and configuration. For example, the diameters of carotid artery 210 and jugular vein 214 are larger than the diameters of arteriole 208 and facial vein 212; therefore, microbubble cavitation in carotid artery 210 or jugular vein 214 can cause less undesirable tissue damage than arteriole 208 or facial vein 212. Therefore, carotid artery 210 and jugular vein 214 can be classified into a relatively less sensitive category and / or assigned a relatively lower sensitivity score to microbubble cavitation; while arteriole 208 and facial vein 212 are assigned a relatively higher sensitivity score and / or classified into a higher sensitivity category.

[0040] In various embodiments, the tissue sensitivity map can be further based on the importance of the function associated with the tissue; that is, a given absolute amount of tissue damage may be more acceptable in some tissues than in other tissues. For example, if damage to a tissue (e.g., cardiac tissue) poses a risk of lethality, then even a small amount of damage is unacceptable and the tissue is assigned a high sensitivity score and / or classified into a high sensitivity category. Conversely, if considerable damage to certain tissues (e.g., skin tissue) is unlikely to produce significant adverse clinical consequences, the tissue may be assigned a low sensitivity score and / or classified into a low sensitivity category. In addition, the tissue sensitivity map 202 is based on the location of the tissue. For example, tissue located near a vital organ may be assigned a higher sensitivity score and / or classified into a high sensitivity category; as the distance between the tissue and the vital organ increases, the corresponding sensitivity score / category may also decrease. For ease of reference, the following description relates to a tissue sensitivity map including a target area and / or a non-target area (e.g., an area outside the target area) having an assigned sensitivity score; however, it should be understood that the tissue sensitivity map 202 may also include tissues having a target area and / or a non-target area with a classification category.

[0041] In one embodiment, the sensitivity scores assigned to each voxel of target tissue and / or non-target tissue based on various tissue characteristics (e.g., type, size, function, location, etc.) are summed to create a tissue sensitivity map. FIG. 2B to FIG. 2D Tissue sensitivity maps are depicted, where the sensitivity score assigned to each voxel is based on tissue type, function, and size, respectively. Figure 2E The sum of the sensitivity scores assigned to voxels based on their corresponding tissue type, function, and size is depicted, e.g. FIG. 2B to FIG. 2D . For example, artery 210 and jugular vein 214 correspond to a lower overall sensitivity score (e.g., 12) than arteriole 208 and facial vein 212; and the overall sensitivity score (e.g., 15) of arteriole 208 and facial vein 212 is lower than the sensitivity score (e.g., 18) of target tumor region 204 and its surrounding region 206. Tissue sensitivity map 202 can be stored in system memory before, during, or after microbubble-mediated focused ultrasound surgery for adjusting the concentration and / or number of microbubbles in target tissue / non-target tissue, as further described below.

[0042] Alternatively, the sensitivity scores assigned to voxels based on their corresponding tissue characteristics (e.g., type, size and conformation, function, location, etc.) can be averaged, and the average can be weighted or otherwise adjusted to reflect the importance of the various tissue characteristics. For example, since brain tissue, arterioles, and arteries are all highly sensitive to the temperature increase caused by acoustic power and / or microbubble cavitation, and their functions are all equally important, the area to be destroyed by microbubbles may depend primarily on the size of the tissue. Therefore, based on tissue type (e.g., Figure 2B ) and functions (as shown in Figure 2C ) can all have a weighting factor of 25%; while sensitivity scores assigned based on size (such as Figure 2D ) may have a weighting factor of 50%. Figure 2F A sensitivity map with weighted tolerance scores is depicted. It should be noted that in this approach, the absolute value of the sensitivity score is not important, as long as at least one region outside the target region 204 on the tissue sensitivity map has a lower sensitivity score than the target region 204, indicating a lower sensitivity to applied acoustic power and / or microbubble cavitation; as further described below, a relatively low sensitivity score may be sufficient to facilitate treatment planning and / or indirectly reduce microbubbles at the target region 204.

[0043] Figure 3300 is a flow chart illustrating an exemplary method 300 for creating a tissue sensitivity map according to various embodiments. In a first step 302, an imaging device is activated to acquire an image of a patient's anatomical structure within a region of interest. The image may be a 3D image or a set of 2D image slices suitable for reconstructing a 3D image of the anatomical region of interest. In a second step 304, the image is processed by a controller associated with the imaging device to automatically identify the location of a target volume and / or a non-target volume therein using a suitable image processing technique. In one embodiment, the target and / or non-target tissue volume is represented as a set of 3D voxels. In a third step 306, the controller may further process the image to determine the anatomical characteristics (e.g., type, size, attributes, structure, thickness, density, etc.) of the target tissue / non-target tissue based on the anatomical map and specific attributes (e.g., density and hydration) of the tissue displayed in the image. In a fourth step 308, based on the determined location, anatomical characteristics, and physiological function (and, in some embodiments, known literature on tissue importance and vulnerability), the controller may assign a sensitivity score to each voxel of the target tissue / non-target tissue, the sensitivity score indicating the level of sensitivity of the tissue to the effects resulting from the interaction between the applied acoustic waves and the microbubbles (e.g., temperature increase caused by the applied acoustic power and / or microbubble cavitation). If multiple sensitivity scores are assigned to voxels based on different tissue characteristics (e.g., type, size, location, function, etc.), the sensitivity scores associated with the voxels may be summed or averaged, and the average may be weighted or otherwise adjusted to reflect the importance of the various tissue characteristics. In a fifth step 310, a tissue sensitivity map including voxels of non-target regions (such as regions outside the target region (and in some embodiments, the target region)) and their corresponding sensitivity scores may be generated.

[0044] In various embodiments, before and / or during an ultrasonic procedure for treating a target (e.g., applying ultrasound to ablate target tissue), a small transient cloud of microbubbles is provided to a target area for automatically focusing an acoustic beam therein. The microbubbles can be generated using ultrasound pulses and / or introduced intravenously using an administration system 126. Microbubble characteristics (e.g., presence, concentration, and / or amount) and / or behavior or response (e.g., cavitation) are monitored using an acoustic signal detection device 124 and / or a transducer array 102. For example, methods for automatically focusing an ultrasound beam at a target area are provided in International Application No. PCT / IB2017 / 000990 (filed on July 19, 2017) and U.S. Patent Application No. 62 / 781,258 (filed on December 18, 2018); methods for providing microbubbles to a target area are provided, for example, in International Application No. PCT / IB2019 / 001537 (filed on December 5, 2018); for example, in U.S. Patent Publication No. 2 Methods for measuring microbubble characteristics and / or activity are provided in International Application No. 018 / 0206816 and International Application No. PCT / IB2018 / 000841 (filed on June 29, 2018) and No. PCT / IB2018 / 000774 (filed on May 22, 2018); and methods for configuring the transducer array 102 to detect microbubble responses are provided, for example, in U.S. Patent Application No. 62 / 681,282 (filed on June 6, 2018). The entire contents of these applications are incorporated herein by reference.

[0045] In one embodiment, after determining the transducer parameters (e.g., frequency, phase shift, and / or amplitude) that optimize the focus at the target area during the autofocus process (e.g., via analysis of acoustic reflections from microbubbles), the amount of microbubbles at the target area (and / or nearby non-target areas) is preferably limited to avoid undesirable damage to non-target tissue during ablation of the target tissue. Therefore, after the autofocus process, the acoustic signal detection device 124 and / or the transducer array 102 can be used again to measure the presence, amount, concentration, and / or size distribution of microbubbles at the target area (and / or nearby non-target areas) based on the acoustic signals transmitted or reflected from the microbubbles. If microbubbles are present (or, in some embodiments, their amount exceeds a predetermined threshold that effectively excludes clinically significant damage to the target tissue and / or non-target tissue), a microbubble regulation method can be implemented to eliminate (or at least reduce) microbubbles at one or more selected non-target areas corresponding to low sensitivity levels on the tissue sensitivity map 202; this may then indirectly reduce the microbubble population in the target and / or its nearby areas. For example, referring to Figure 4A, when the presence or excess of microbubbles 402 is detected at the target area 204, the controller 108 can analyze the reflected signals from the microbubbles near the target 204 to identify other tissue areas that also have microbubbles. For example, microbubbles may be present in arterioles 208 and arteries 210. The controller 108 can then access the system memory to retrieve the stored tissue sensitivity map 202, compare the sensitivity levels associated with the areas where microbubbles are present, and select one or more areas to destroy the microbubbles therein. For example, because the artery 210 has a relatively low sensitivity score (such as 208) compared to the target area 204 and the arteriole 208, the controller 108 can then access the system memory to retrieve the stored tissue sensitivity map 202, compare the sensitivity levels associated with the areas where microbubbles are present, and select one or more areas to destroy the microbubbles therein. Figure 2E and Figure 2F ), the controller 108 may cause the beamformer 106 to provide a drive signal to the transducer element 104 to generate a focus (e.g., a point focus, a line focus, or a focus of any suitable shape) at the microbubbles 402 in the artery 210 to induce cavitation thereof, thereby reducing the concentration / amount of the microbubbles before they reach the target area 204. Because this approach can effectively reduce the total amount of microbubbles in the bloodstream, the amount / concentration of microbubbles in the target area 204 (and anywhere else in the bloodstream) can be indirectly reduced. Thus, undesirable damage caused by microbubbles at non-target tissue during subsequent ultrasound surgery (e.g., ablation of target tissue) can be avoided. Again, the ultrasound parameter values ​​(e.g., amplitude, phase, and / or frequency) used to generate a focus and induce microbubble cavitation at the selected area can be calculated by the controller 108 based on the anatomical characteristics acquired using the imager 122, as described above. In addition, the controller 108 can be configured to automatically create a focus and adjust the ultrasound intensity to start the microbubble adjustment process after completing the ultrasound autofocus process, when the presence of microbubbles in the target area 204 is detected and / or when the number of microbubbles 402 in the target area 204 exceeds a predetermined threshold during or after the autofocus process.

[0046] It should be noted that the selected area for microbubble cavitation may not necessarily correspond to the lowest sensitivity score on the tissue sensitivity map; as long as the sensitivity score of the selected area is lower than that of the target area 204, it may be sufficient to destroy the microbubbles at the selected area without damaging tissue in the target surrounding area and / or tissue in the selected non-target area. In addition, the ultrasonic parameter values ​​(e.g., amplitude, phase, and / or frequency) used to induce microbubble cavitation at the selected area can be adjusted based on the corresponding sensitivity scores. For example, the acoustic power of the light beam transmitted to the area corresponding to the lowest sensitivity score may be relatively large, resulting in a larger amount of microbubble cavitation. Conversely, when the sensitivity score of the selected area is slightly greater than the sensitivity score of the target area, the acoustic power can be reduced to allow mild microbubble cavitation, thereby avoiding damage to the selected area.

[0047] In various embodiments, the selection of the region where the microbubbles are to be destroyed can be based on the relative position of the region relative to the target region 204. For example, referring to Figure 4B Although both the carotid artery 210 and the jugular vein 214 have the lowest sensitivity scores on the tissue sensitivity map 202, it may be preferable to induce microbubble cavitation in the artery 210 rather than in the jugular vein 214. This is because the artery 210 is located upstream of the target region 204; destroying microbubbles therein can quickly reduce the microbubble population in the target 204, while the jugular vein 214 is downstream of the target region 204, so when destroying microbubbles in the jugular vein 214, it may take longer to reduce the microbubble concentration at the target.

[0048] Additionally or alternatively, the amount of microbubbles present in a region on the tissue sensitivity map 202 may be considered when selecting a region for microbubble destruction. Figure 4B , although regions 404 and 406 are both located in artery 210 and upstream of target 204, because there are more microbubbles in region 404 than in region 406, it is preferred to apply the focused acoustic beam to region 404, as this may cause more microbubble cavitation and thus more effectively reduce the microbubble population in the target region (and anywhere else in the blood). The amount of microbubbles in each region may be measured using the transducer array 102 and / or the acoustic signal detection device 124 based on acoustic reflections from the microbubbles as described above.

[0049] In various embodiments, the characteristics of the focused beam are optimized based on the characteristics of the microbubbles. Figure 4B , the size and / or shape of the focus 410 can be adjusted to match the size and / or shape of the microbubbles to be removed. In this way, the microbubble conditioning process can effectively destroy selected microbubbles at a time. Alternatively, the focus can be shaped / designed to destroy only a portion of the microbubbles. For example, referring to Figure 4C When some microbubbles are close to the arterial wall, their cavitation may cause damage to the arterial wall; therefore, the ultrasound controller 108 can shape and design the focus 410 to destroy only a portion of the microbubbles that are not close to the arterial wall. Adjustment of the focus size and / or shape can be achieved by adjusting the amplification factor and / or phase shift of the ultrasound beam emitted from the transducer element as described above.

[0050] Although the main force for distributing microbubbles in the target area and non-target areas outside the target is blood circulation, in some embodiments, the ultrasonic transducer can be configured to generate a focus (e.g., by adjusting the phase, amplitude, and / or frequency) that can induce microbubble motion by applying acoustic forces thereto. For example, the generated focus can sweep at least a portion of the microbubbles from the target area 204 (or an area with a relatively high sensitivity score) to a less sensitive area outside the target (e.g., the facial vein 212). In one embodiment, the generated focus has a sufficiently low acoustic power to sweep the microbubbles 402 without causing cavitation thereof.

[0051] In various embodiments, the focus causes the movement of the microbubble 402 by applying an acoustic force thereto. The acoustic force is generated by changes in the energy density and momentum of the propagating ultrasound wave caused by absorption, scattering or reflection from the intervening tissue between the transducer 102 and the target area 204. Typically, the amplitude of the acoustic force is proportional to the ultrasound intensity. Therefore, in one implementation, the intensity of the ultrasound beam directed to the microbubble 402 is gradually increased until the acoustic force generated is sufficient to manipulate and move the microbubble 402. In another embodiment, before manipulating the microbubble 402, the characteristics of the intervening tissue (e.g., absorption coefficient) are measured using the imager 122 as described above; the intensity of the ultrasound beam sufficient to move the microbubble 402 can be calculated based on this. Once the microbubble moves away from the target area and / or reaches an area with a relatively low sensitivity score, the controller 108 can increase the intensity of the ultrasound beam to cause microbubble cavitation in the low sensitivity area. Since cavitation now occurs in a low sensitivity area, any damage that may occur is clinically acceptable. Thus, the method can advantageously allow microbubbles to be removed from areas more susceptible to ultrasound-induced microbubble cavitation (e.g., areas of higher sensitivity) to areas less likely to be damaged by cavitation (e.g., areas of lower sensitivity). Thus, unintended damage to healthy tissue in target and / or non-target areas can be minimized.

[0052] It should be understood that the terms "point focus" and "line focus" used herein do not refer to points and lines in a strict mathematical sense, but refer to the focus shapes that approximate points or lines, respectively. Therefore, the intensity distribution of a point focus (for example, it can take the shape of a two-dimensional Gaussian distribution) can be characterized by a half-width of the order of several acoustic wavelengths in two dimensions of the focal plane, while the intensity distribution of a line focus (for example, it can have a one-dimensional Gaussian profile perpendicular to the line) extends in the direction of the line, but can have a half-width of the order of several acoustic wavelengths perpendicular thereto.

[0053] In various embodiments, the acoustic signal detection device 124 and / or the transducer array 102 are used as described above to monitor in real time the microbubble characteristics (e.g., amount, concentration, size distribution, and / or response) during ultrasound-induced microbubble cavitation at a selected one or more low sensitivity regions and / or during sweeping from a relatively high sensitivity region toward a relatively low sensitivity region. Figure 5 , a second transducer array 502 may be implemented to monitor cavitation and / or the sweeping process. For example, when the transducer array 102 is activated to cause microbubble cavitation at the artery 210, the second transducer array 502 may be placed on the skull closest to the artery 210 to monitor the cavitation process therein. In various embodiments, based on the acoustic signals measured by the acoustic signal detection device 124, the transducer array 102, and / or the second transducer array 502, the controller 108 may responsively adjust the ultrasound parameter values ​​(e.g., phase, amplitude, and / or frequency) to ensure that the desired number of microbubbles are destroyed without damaging the selected low sensitivity area. For example, if the detected signal indicates that the power of the generated focus is insufficient to cause microbubble cavitation, the controller 108 may increase the intensity of the ultrasound beam. In addition, the controller 108 may adjust the phase of the beam from the transducer element 104 so as to gradually move the focus to follow the movement of the microbubbles to be destroyed in the blood flow (e.g., generated by blood circulation).

[0054] In various embodiments, the above-described microbubble modulation process (by sweeping microbubbles from relatively high sensitivity areas to relatively low sensitivity areas and / or inducing microbubble cavitation in low sensitivity areas based on the tissue sensitivity map 202) can be repeated until the microbubble population at the target area 204 is completely eliminated or at least below a predetermined threshold; again, this can be verified using images acquired by the imager 112 and / or reflected signals detected by the acoustic signal detection device 124, the transducer array 102, and / or the second transducer array 502. After the desired amount of microbubbles is removed from the target area 204, the controller 108 can energize the transducer elements 104 to transmit ultrasound waves to the target area 204 using the treatment parameters (e.g., phase, frequency, amplitude, sonication duration, etc.) determined during the autofocus process to initiate or continue treatment.

[0055] Although the above-described microbubble regulation method adjusts the microbubble concentration / amount before applying ultrasound pulses / waves to treat a target (e.g., ablating a target tumor), the method can be used to eliminate / reduce microbubbles during and / or after an ultrasound procedure to avoid causing undesirable damage to target tissue / non-target tissue. For example, a targeted treatment procedure can be initiated after the microbubble population at the target is below a predetermined threshold; during the treatment procedure, the acoustic signal detection device 124, the transducer array 102, and / or the second transducer array 502 can again be used to monitor the microbubble concentration and / or response of the target area and / or non-target area in real time. If an excess of microbubbles is measured (e.g., carried by blood flow from another area), the above-described microbubble regulation method can be initiated to eliminate / reduce the excess microbubbles based on a tissue sensitivity map. For example, again referring to Figure 5 During treatment, the transducer array 102 can generate a focus at the target area 204 to ablate the tissue therein; the second transducer array 502 can monitor the amount / concentration of microbubbles in the artery 210 in real time. If too many microbubbles are detected in the artery 210, the second transducer array 502 can start a microbubble regulation method to destroy the microbubbles in the artery 210 before they enter the target 204. Therefore, the treatment of the target tissue can continue without any interruption. Therefore, various embodiments of the present invention provide methods for indirectly eliminating / reducing microbubbles at the target area before and / or during an ultrasound treatment procedure without prolonging the operation time while avoiding undesirable damage to healthy non-target tissues.

[0056] In addition, although the ultrasonic surgery described herein refers to thermal ablation for treating benign or malignant tumors in the skull of a patient, it should be understood that other ultrasonic surgeries can generally also apply the same microbubble regulation method to regulate the concentration / amount of microbubbles at the target area / non-target area. For example, ultrasonic surgery can be a microbubble-mediated BBB opening or thermal ablation for treating blood clots in the skull or other body areas of a patient. Implementation of the microbubble regulation method can again eliminate / reduce unwanted microbubbles at the target BBB area or target clot, thereby advantageously providing improved control of microbubble cavitation for ablation and avoiding damage to non-target tissues. In addition, the above description is only for ultrasonic therapeutic surgery for ease of reference; it should be understood that the same method is generally also applicable to ultrasonic imaging surgery.

[0057] Fig. 6A600 is a flowchart showing a representative method 600 for adjusting the concentration / amount of microbubbles before, during and / or after ultrasound surgery according to various embodiments herein. For example, the microbubble adjustment method can be implemented after performing ultrasound autofocusing but before ablating the target tissue. In a first step 602, the ultrasound controller 108 accesses a memory to retrieve a stored tissue sensitivity map established before or during ultrasound focusing surgery. In a second step 604, microbubbles are generated using the transducer array 102 and / or introduced via the administration system 126. In a third step 606, the acoustic signal detection device 124, the transducer array 102 and / or the second transducer array 502 are activated to detect signals from microbubbles; based on this, the amount, concentration and / or response of microbubbles at the target area and / or non-target area (e.g., an area outside the target area) can be determined. In an optional step 608, the detected microbubble amount / concentration can be compared with a predetermined threshold. If there are microbubbles at the target area (and / or nearby non-target areas) and / or the detected number / concentration of microbubbles exceeds a predetermined threshold, a microbubble regulation method is implemented to eliminate / reduce microbubbles (step 610). Steps 606 and 610 are iteratively performed until the amount / concentration of microbubbles in the target area / non-target area is lower than a predetermined threshold. Subsequently, the controller 108 can activate the ultrasonic transducer 102 to start or continue ultrasonic surgery (e.g., ablation of target tumors) (in step 612). Steps 606-612 can be iteratively performed throughout the ultrasonic surgery. In various embodiments, after achieving the therapeutic goal of ultrasonic surgery (e.g., ablation of target tissue), the microbubble regulation method is optionally used again to eliminate / reduce microbubbles in the target tissue / non-target tissue (in step 614). In one implementation, microbubbles are eliminated / reduced after ultrasonic surgery only when the measured amount / concentration of microbubbles exceeds a predetermined threshold.

[0058] Figure 6B650 is a flow chart showing a representative microbubble adjustment method according to the present invention. In various embodiments, when it is determined that microbubbles are present in a target area (and / or a nearby non-target area) and / or the amount / concentration of microbubbles detected exceeds a predetermined threshold, the controller 108 may identify one or more regions with relatively low sensitivity scores based on a tissue sensitivity map, which indicates low sensitivity to temperature rise caused by ultrasonic treatment and / or microbubble cavitation (in step 652). The identified low sensitivity region may have the lowest sensitivity score in the tissue sensitivity map. Alternatively, the identified low sensitivity region may only need to have a sensitivity score lower than the target area and / or the area where microbubbles or excess microbubbles are detected. In optional step 654, the controller 108 may cause the transducer array 102 to generate a focus that applies acoustic force to the microbubbles 402 at the target area (and / or a nearby non-target area), thereby causing it to move. In addition, the controller 108 can adjust the phase of the beam emitted from the transducer element 104 so that the focus (and therefore the microbubble) gradually moves from the target area toward the relatively low sensitivity area identified. Optionally, the acoustic signal detection device 124, the transducer array 102 and / or the second transducer array 502 can be used to monitor the movement of the microbubble in real time to ensure that the microbubble is fully moved without cavitation. In the third step 656, the controller 108 can generate a focus at the microbubble in the identified low sensitivity area to cause microbubble cavitation. Optionally, the acoustic signal detection device 124, the transducer array 102 and / or the second transducer array 502 are used again to monitor the microbubble cavitation event in real time to ensure that no (or at least limited) damage occurs at the relatively low sensitivity area (step 658). Steps 654-658 can be performed iteratively until the microbubble concentration / number at the target area (and / or nearby non-target area) is lower than a predetermined threshold. Once the microbubble concentration / amount is below a predetermined threshold, ultrasound surgery to treat the target (eg, ablate tissue therein) may be initiated (step 612).

[0059] In general, the functionality for facilitating microbubble-mediated ultrasound autofocus surgery and ultrasound targeted therapy surgery and / or using microbubble regulation methods to eliminate (or at least reduce) microbubbles in target and / or non-target areas can be constructed in one or more modules implemented in hardware, software, or a combination of both, whether integrated within the imager 122, the controller of the ultrasound system 100 and / or the management system 124, or provided by a separate external controller or other computing entity. Such functionality may include, for example: analyzing imaging data of the target area and / or non-target area acquired using the imager 112, determining a set of 3D voxels of target tissue and / or non-target tissue based on the imaging data, determining anatomical characteristics (e.g., tissue type, location, size, thickness, density, structure, shape, vascularization) associated with the target tissue / non-target tissue, assigning a tissue sensitivity score to each voxel of the target tissue / non-target tissue based on tissue type, location, size, function, etc., causing an acoustic signal detection device and / or a transducer array to detect acoustic signals emitted or reflected from microbubbles, determining the amount, concentration, size distribution of microbubbles based on the detected acoustic signals and / or response, comparing the measured microbubble amount / concentration with a predetermined threshold, identifying a tissue region outside the target having a relatively lower sensitivity score compared to the target region and / or other non-target regions, configuring the ultrasound transducer array to generate a focus at the identified tissue region to induce microbubble cavitation therein, adjusting ultrasound parameters to gradually sweep excess microbubbles from the target region (or a nearby non-target region) toward the identified relatively lower sensitivity region, monitoring microbubble movement and / or cavitation, causing the ultrasound transducer to transmit ultrasound treatment to the target region to initiate ultrasound surgery (e.g., ablate target tumor tissue), and / or monitoring microbubble response during ultrasound surgery, as described above.

[0060] In addition, the ultrasound controller 108, the MR controller 148, and / or the controller associated with the management system controller 126 may include one or more modules implemented in hardware, software, or a combination of both. For embodiments in which functionality is provided as one or more software programs, these programs may be written in any of a variety of high-level languages, such as PYTHON, FORTRAN, PASCAL, JAVA, C, C++, C#, BASIC, various scripting languages, and / or HTML. In addition, the software may be implemented in assembly language for a microprocessor resident on a 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 an article of manufacture, including, but not limited to, a floppy disk, a jump drive, a hard disk, an optical disk, a tape, a PROM, an EPROM, an EEPROM, a field programmable gate array, or a CD-ROM. Embodiments using hardware circuits may be implemented using, for example, one or more FPGA, CPLD, or ASIC processors.

[0061] The terms and expressions used herein are used as terms and expressions of description rather than limitation, and when such terms and expressions are used, it is not intended to exclude any equivalents of the features shown and described or parts thereof. In addition, having described certain embodiments of the present invention, it will be apparent to those of ordinary skill in the art that other embodiments incorporating the concepts disclosed herein may be used without departing from the spirit and scope of the present invention. Therefore, the described embodiments are to be considered in all respects to be illustrative only and not restrictive.

Claims

1. A system for regulating microbubbles in a therapeutic procedure at a target area, the system comprising: Ultrasonic transducer; as well as The controller is configured as: (a) generating a tissue sensitivity map comprising a plurality of regions, at least one of the regions being outside the target region, the tissue sensitivity map assigning to each of the regions a sensitivity level indicative of tissue sensitivity to interaction between microbubbles and an acoustic beam; (b) selecting at least one interaction region based at least in part on the tissue sensitivity map, wherein the sensitivity level of the at least one interaction region selected is lower than the sensitivity level of the target region; as well as (c) activating the ultrasound transducer to generate an acoustic beam for interacting with microbubbles in the selected at least one interaction region in the tissue sensitivity map, thereby indirectly changing the characteristics of the microbubbles at the target region.

2. The system of claim 1, wherein the controller is further configured to determine at least one parameter associated with the ultrasound transducer based at least in part on the selected at least one interaction region in the tissue sensitivity map.

3. The system of claim 2, wherein the controller is further configured to activate the ultrasonic transducer based at least in part on the determined parameter associated with the ultrasonic transducer.

4. The system of claim 1, wherein the therapeutic procedure involves the use of microbubbles, the system further comprising means for providing microbubbles to the target area to initiate the therapeutic procedure.

5. The system of claim 4, wherein the means for providing microbubbles comprises an administration system for administering the microbubbles to the target area.

6. The system of claim 4, wherein the means for providing microbubbles causes the ultrasound transducer to transmit ultrasound pulses toward the target area to generate microbubbles.

7. The system of claim 4, wherein the controller is further configured to perform step (c) only after a focusing property of the acoustic beam at the target area is optimized.

8. The system of claim 1, further comprising means for detecting microbubble characteristics in at least one of: the target area, one of the areas in the tissue sensitivity map, or a dedicated monitoring area.

9. The system of claim 8, wherein the means for detecting microbubble characteristics comprises the ultrasound transducer, an acoustic signal detection device, or a second ultrasound transducer.

10. The system of claim 8, wherein the controller is further configured to determine at least one parameter associated with the ultrasound transducer based at least in part on the detected microbubble characteristics.

11. The system of claim 1 , wherein the generated acoustic beam induces cavitation of at least some of the microbubbles in the selected at least one interaction region.

12. The system of claim 11, wherein the controller is further configured to determine at least one parameter associated with the ultrasonic transducer in order to select the at least some of the microbubbles for cavitation.

13. The system of claim 12, wherein the at least one parameter associated with the ultrasonic transducer comprises at least one of a frequency, an amplitude, or a phase associated with at least one transducer element of the ultrasonic transducer.

14. The system of claim 1, wherein the tissue sensitivity comprises at least one of thermal sensitivity or sensitivity to microbubble cavitation.

15. The system of claim 1, wherein the microbubble characteristic comprises at least one of an amount, a concentration, a size distribution, or a response to an acoustic beam of the microbubbles.

16. The system according to claim 1 further includes an imaging device for acquiring a digital representation of a plurality of voxels comprising at least a portion of the region in the tissue sensitivity map, and the controller is further configured to generate the tissue sensitivity map based at least in part on the digital representation.

17. The system of claim 16, wherein the controller is further configured to determine an anatomical characteristic of the at least a portion of the region in the tissue sensitivity map based on the digital representation, the tissue sensitivity map being generated at least in part based on the anatomical characteristic.

18. The system of claim 17, wherein the anatomical characteristic comprises at least one of tissue type, location, size, or function.

19. The system of claim 17, wherein the controller is further configured to generate the tissue sensitivity map by assigning sensitivity scores to voxels of at least a portion of the region in the tissue sensitivity map based at least in part on anatomical characteristics associated with the at least a portion of the region, the sensitivity scores indicating a level of sensitivity of the voxels to an interaction between an acoustic beam and microbubbles.

20. The system of claim 19, wherein the selected at least one interaction region in the tissue sensitivity map has a relatively lower sensitivity score compared to other regions in the tissue sensitivity map.

21. The system of claim 19, wherein the controller is further configured to adjust at least one parameter associated with the ultrasound transducer based at least in part on the sensitivity score assigned to the region in the tissue sensitivity map.

22. The system of claim 1, wherein the controller is further configured to adjust at least one parameter associated with the ultrasound transducer to cause at least some microbubbles to move from the target area to the selected at least one interaction area in the tissue sensitivity map.

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