阅读说明：本技术 用于调节超声手术中的微泡的系统和方法 (System and method for modulating microbubbles in ultrasound surgery ) 是由 约阿夫·莱维 于 2020-04-08 设计创作，主要内容包括：用于在目标治疗手术中调节微泡的各种方法包括：生成包括多个区域的组织敏感性图,区域中的至少一个在目标区域之外,组织敏感性图为区域中的每一个分配指示组织对微泡与声束之间的相互作用的敏感性的敏感性水平；至少部分地基于组织敏感性图选择一个或多个相互作用区域；以及激活超声换能器以生成声束以用于与组织敏感性图中的(多个)选择相互作用区域中的微泡相互作用,从而间接改变目标区域处微泡的特性。(Various methods for modulating microvesicles in targeted therapeutic procedures include: 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 a sensitivity level to each of the regions indicative of the sensitivity of the tissue to the interaction between the microbubbles and the acoustic beam; selecting one or more interaction regions based at least in part on the tissue sensitivity map; and activating the ultrasound transducer to generate an acoustic beam for interacting with the microbubbles in the selected interaction region(s) in the tissue sensitivity map, thereby indirectly changing the properties of the microbubbles at the target region.)

1. A system for modulating microbubbles in a therapeutic procedure in a target region, the system comprising:

an ultrasonic transducer; and

a controller configured to:

(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 a sensitivity level to each of the regions indicative of tissue sensitivity to an interaction between a microbubble and an acoustic beam;

(b) selecting at least one interaction region based at least in part on the tissue sensitivity map; and

(c) activating the ultrasound transducer so as 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 properties of microbubbles at the target region.

2. The system of claim 1, wherein the controller is further configured to: determining 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: activating the ultrasound transducer based at least in part on the determined parameter associated with the ultrasound 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 region to initiate the therapeutic procedure.

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

7. The system of claim 4, wherein the controller is further configured to: step (c) is performed only after the focal properties of the acoustic beam at the target region are optimized.

8. The system of claim 1, further comprising means for detecting microbubble characteristics in at least one of the target region, one of the regions in the tissue sensitivity map, or a dedicated monitored region.

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: determining 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 causes cavitation of at least some microbubbles in the selected at least one interaction region.

12. The system of claim 11, wherein the controller is further configured to: determining at least one parameter associated with the ultrasound transducer for selecting the at least some microbubbles to cavitate.

13. The system of claim 12, wherein the at least one parameter associated with the ultrasound transducer comprises at least one of a frequency, an amplitude, or a phase associated with at least one transducer element of the ultrasound 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, concentration, size distribution, or response to the acoustic beam of microbubbles.

16. The system of claim 1, further comprising an imaging device for acquiring a digital representation of a plurality of voxels comprising at least a portion of a region in the tissue sensitivity map, the controller 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: determining an anatomical property of the at least a portion of the region in the tissue sensitivity map based on the digital representation, the tissue sensitivity map generated based at least in part on the anatomical property.

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

19. The system of claim 17, wherein the controller is further configured to: generating the tissue sensitivity map by assigning a sensitivity score to voxels of the at least a portion of the region based at least in part on anatomical characteristics associated with the at least a portion of the region in the tissue sensitivity map, the sensitivity score indicating a level of sensitivity of the voxels to beam-microbubble interactions.

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 than other regions in the tissue sensitivity map.

21. The system of claim 19, wherein the controller is further configured to: adjusting 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: adjusting at least one parameter associated with the ultrasound transducer to cause at least some microbubbles to move from the target region to the selected at least one interaction region in the tissue sensitivity map.

Technical Field

The present invention relates generally to ultrasound surgery and, more particularly, to systems and methods for modulating microbubbles during such surgery to increase their efficiency while avoiding damage to healthy tissue.

Background

Focused ultrasound (i.e., sound waves having a frequency greater than about 20 kHz) may be used to image or treat tissue within a patient. For example, ultrasound may be used for applications involving tumor ablation, targeted drug delivery, Blood Brain Barrier (BBB) disruption, clot lysis, and other surgical procedures. During tumor ablation, a piezoceramic transducer is placed outside the patient's body, but close to the tumor to be ablated (i.e., the target region). The transducer converts the electronic drive signal into mechanical vibrations, thereby emitting sound waves. The transducers may be geometrically shaped and positioned with other such transducers such that their emitted ultrasound energy collectively forms a focused beam at a "focal zone" corresponding to (or within) a target area. Alternatively or additionally, a single transducer may be formed from a plurality of individually driven transducer elements, each phase of which may be independently controlled. Such "phased array" transducers facilitate steering the focal zone to different positions by adjusting the relative phase between the transducers. As used herein, the term "element" refers to a single transducer or independently drivable portions of a single transducer in an array. Magnetic Resonance Imaging (MRI) can be used to visualize a patient and a target, thereby guiding an ultrasound beam.

During focused ultrasound surgery, small gas bubbles (or "microbubbles") may be generated in and/or introduced into the target region. Because the microbubbles encapsulate the gas, the bubble surfaces can collectively form an ultrasonic reflector. Thus, by transmitting ultrasound waves to the microbubbles and receiving reflections from the microbubbles, the amplitude and/or phase associated with the reflected ultrasound waves can be determined; based thereon, transducer parameters (e.g., phase shift and/or amplitude) may be determined or adjusted to compensate for aberrations caused at least in part by the skull. While this approach may be effective in improving the focusing characteristics at the target, microbubbles remaining in the target and/or non-target tissue after the focusing procedure may cause undesirable damage. For example, during subsequent application of ultrasound energy for target treatment, the response of tissue containing a relatively high relative percentage of microbubbles is nonlinear and difficult to predict. Furthermore, 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 "microbubble response" and the thermal or mechanical effects generated by ultrasound treatment and/or microbubble cavitation in the target and/or non-target regions are referred to as "therapeutic effects".

To minimize the undesirable effects caused by microbubbles during treatment of a target, one conventional method suspends ultrasound surgery until the microbubbles naturally dissipate. However, this approach unnecessarily and undesirably extends the duration of the ultrasound procedure. Another conventional method of eliminating microbubbles is to apply low energy ultrasound treatment to cavitate the microbubbles. However, this approach may result in, rather than avoid, cavitation-induced damage to non-target tissue. Therefore, there is a need for methods to effectively remove microbubbles during ultrasound surgery to avoid damage to healthy tissue.

Disclosure of Invention

The present invention relates to adjusting the amount or concentration of microbubbles prior to and/or during a targeted therapeutic procedure (e.g., ultrasound procedure) in a manner that maintains the efficiency of the ultrasound procedure while avoiding damage to healthy, non-targeted tissue. In various embodiments, the microbubble modulation method comprises creating a tissue sensitivity map of one or more tissue regions outside the target region prior to the treatment procedure. In one implementation, the target region and/or regions outside the target are represented as a three-dimensional (3D) group of voxels (i.e., volume pixels), and each voxel is associated with a sensitivity score indicative of tissue sensitivity to the interaction between the applied ultrasound treatment and the microbubbles. For example, the tissue sensitivity may be thermal sensitivity and/or sensitivity to microbubble cavitation. A relatively higher sensitivity score indicates that the tissue corresponding to the voxel may be more sensitive to (e.g., tolerate a relatively lower) temperature increase and/or microbubble cavitation events, and thus more vulnerable to damage; while a relatively lower sensitivity score indicates that the tissue is less sensitive (e.g., has relatively greater tolerance) to elevated temperatures and/or cavitation of the microbubbles.

In some embodiments, a small transient microbubble cloud is provided to the target region for autofocusing the acoustic beam applied thereto prior to and/or during ultrasound surgery (e.g., applying sonication to ablate the target tissue). After determining transducer parameters (e.g., frequency, phase shift, and/or amplitude) that optimize the focus at the target region (e.g., via analyzing acoustic reflections from the microbubbles), the tissue sensitivity map can be utilized to eliminate (or at least reduce) the microbubbles at the target region and/or regions in the vicinity thereof to avoid undesirable damage caused thereby. The presence and/or quantity (or concentration) of microbubbles at a target region (and/or a non-target region in the vicinity thereof) is measured based on acoustic signals transmitted or reflected from the microbubbles using an acoustic signal detection device and/or a transducer array. If microbubbles are present and/or the amount or concentration thereof exceeds a predetermined threshold, the following measures may be taken. The threshold may be set based on, for example, previously performed ultrasound procedures that are effective without damaging non-target tissue, in which case the affected non-target tissue region may be deemed to be resistant to at least that level of microbubbles. Alternatively, the microbubble threshold may be estimated based on a 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.

In various embodiments, based on the tissue sensitivity map, one or more regions that are relatively less sensitive (e.g., have a lower sensitivity score) to the interaction of the acoustic beam and the microbubbles in the tissue sensitivity map may be identified. The ultrasound transducer may then be activated to generate one or more focal points at the identified region in order to clear the microbubbles therein (e.g., by cavitation thereof). Optionally, microbubble cavitation may be monitored in real time, again using an acoustic signal detection device and/or transducer array. Based on this, the ultrasound parameters can be adjusted to ensure that a desired proportion of microbubbles are destroyed without damaging the tissue, even in regions of relatively low sensitivity. Because this approach may reduce the total amount of microbubbles in the blood stream, the amount of microbubbles in the target region (and everywhere in the blood stream) may be indirectly reduced. Thus, undesired damage caused by microbubbles at the target region and/or non-target regions in the vicinity thereof during ablation of the target tissue may be avoided. Furthermore, because the microbubbles are destroyed in regions of relatively low sensitivity to temperature increase and/or microbubble cavitation, damage to the hyposensitive regions may not be clinically significant. As used herein, "clinically insignificant" means that tissue that is deemed insignificant by a clinician, whether temporary or permanent, has an undesirable (and sometimes undesirable) effect, for example, before causing damage or other clinically adverse effects to the tissue. Furthermore, the "indirect" reduction of microbubbles in a region means that the ultrasound focus is not directed to and/or generated in a region where microbubble cavitation may directly result.

In some embodiments, the amount of microbubbles present in the region on the tissue sensitivity map may be considered when determining the region from which the microbubbles are to be eliminated. For example, applying an acoustic beam to a region with a relatively large number of microbubbles may result in more microbubble cavitation, thereby more effectively reducing the population of microbubbles in the target region (and everywhere in the blood stream). As described above, the amount of microbubbles in each region can be detected using acoustic reflections from the microbubbles. Additionally or alternatively, the one or more regions in which microbubbles are to be removed may be selected based on the relative position of the one or more regions with respect to the target region. For example, disrupting microbubbles in a region upstream of the target region can rapidly reduce the population of microbubbles in the target region; while destroying microbubbles in regions downstream of the target region may reduce the population of microbubbles in the target, the effect on the target may be delayed due to the longer circulation path back to the target.

While the primary force for distributing the microbubbles at and outside the target region is blood circulation, in some embodiments, the ultrasound transducer may be configured (e.g., by adjusting phase, amplitude, and/or frequency) to create a focal point to which microbubble motion may be induced by applying acoustic forces. The ultrasound parameters (e.g., phase) may be adjusted to gradually move the focal point (and microbubbles) from the region of weakness (e.g., target and/or relatively higher sensitivity region) toward the identified relatively lower sensitivity region. Once the microbubbles move from the fragile tissue to the less sensitive region, the intensity of the acoustic beam may be increased to cause cavitation of the microbubbles to clear the microbubbles. Again, microbubble motion and/or cavitation may be monitored in real time using an acoustic signal detection device and/or transducer array. Based on this, the ultrasound parameters can be adjusted to ensure that the desired portion of the microbubbles are removed from the relatively more sensitive region in the absence of cavitation and in the absence of cavitation that may cause damage even in the relatively less sensitive region.

After the microbubbles are eliminated/reduced, ultrasound surgery to treat the target tissue may begin or continue. Accordingly, various embodiments utilize a tissue sensitivity map to identify one or more regions of lower sensitivity (or higher tolerance) to acoustic power and/or microbubble cavitation, and based thereon, configure an ultrasound transducer to: causing cavitation of the microbubbles in the identified less sensitive region. This can advantageously avoid undesirable damage to healthy tissue caused by microbubble cavitation, while avoiding the need for prolonged ultrasound surgery as required in conventional methods that pause before microbubbles clear naturally.

Accordingly, in one aspect, the present invention is directed to a system for modulating microbubbles in a therapeutic procedure in a target region. In various embodiments, the system includes an ultrasound transducer and a controller configured to: (a) generating a tissue sensitivity map comprising a plurality of regions, one or more regions being outside of a target region; (b) selecting one or more interaction regions based at least in part on the tissue sensitivity map; and (c) activating the ultrasound transducer to generate an acoustic beam for interacting with the microbubbles in the selected interaction region in the tissue sensitivity map, thereby indirectly changing a characteristic of the microbubbles at the target region (e.g., microbubble amount, concentration, size distribution, and/or response of the microbubbles to the acoustic beam). In one implementation, the tissue sensitivity map assigns a sensitivity level to each region in the tissue sensitivity map that is indicative of tissue sensitivity (e.g., thermal sensitivity and/or sensitivity to microbubble cavitation) to the interaction between the microbubbles and the acoustic beam.

The controller may be further configured to: one or more parameters (e.g., frequency, amplitude, and/or phase) associated with one or more transducer elements of an ultrasound transducer are determined based at least in part on the selected interaction region in the tissue sensitivity map. Further, the controller may be further configured to: activating the ultrasound transducer based at least in part on the determined parameter associated with the ultrasound transducer. In some embodiments, the therapeutic procedure involves the use of microbubbles; the system also includes means for providing microbubbles to the target region to initiate the therapeutic procedure. For example, administration systems can be employed to administer microbubbles to a target area. Additionally or alternatively, the ultrasound transducer may transmit ultrasound pulses to the target region to generate microbubbles. Furthermore, the controller may be further configured to perform step (c) only after the focal properties of the acoustic beam at the target region are optimized.

In various embodiments, the system further includes means for detecting microbubble characteristics in the target region, one of the regions in the tissue sensitivity map, and/or a dedicated monitoring region (e.g., a region that is continuously monitored throughout the treatment procedure). The means for detecting the microbubble characteristics may comprise an ultrasound transducer, an acoustic signal detection device, and/or a second ultrasound transducer different from the ultrasound transducer activated in step (c). Further, the controller may be further configured to: a parameter associated with the ultrasound transducer is determined based at least in part on the detected microbubble characteristic. In one embodiment, the generated acoustic beam causes cavitation of at least some of the microbubbles in the selected interaction region in the tissue sensitivity map. The controller may also be configured to determine parameters associated with the ultrasound transducer in order to select microbubbles for cavitation.

In addition, the system may further include an imaging device for acquiring a digital representation of a plurality of voxels comprising one or more portions of a region in the tissue sensitivity map; the controller may be further configured to: a tissue sensitivity map is generated based at least in part on the digital representation. In some embodiments, the controller is further configured to: 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; a tissue sensitivity map is then generated based at least in part on the anatomical feature. Further, the controller may be further configured to: generating a tissue sensitivity map by assigning sensitivity scores to voxels of one or more portions of a region in the tissue sensitivity map based at least in part on anatomical characteristics associated with the one or more portions; the sensitivity score indicates the level of sensitivity 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 lower sensitivity score than other regions in the tissue sensitivity map. Further, the controller may be further configured to: a parameter associated with the ultrasound transducer is adjusted based at least in part on the sensitivity score assigned to the region in the tissue sensitivity map. In one embodiment, the controller is further configured to: parameters associated with the ultrasound transducer are adjusted such that at least some of the microbubbles move from the target region to a selected interaction region in the tissue sensitivity map.

In another aspect, the invention relates to a method of modulating microbubbles in a surgical procedure for treating a target region. In various embodiments, the method includes (a) generating a tissue sensitivity map including a plurality of regions, one or more regions outside of a target region; (b) selecting one or more interaction regions based at least in part on the tissue sensitivity map; and (c) activating the ultrasound transducer to generate an acoustic beam for interacting with the microbubbles in the selected interaction region in the tissue sensitivity map, thereby indirectly changing a characteristic of the microbubbles at the target region (e.g., microbubble amount, concentration, size distribution, and/or response of the microbubbles to the acoustic beam). In one implementation, the tissue sensitivity map assigns a sensitivity level to each region in the tissue sensitivity map that is indicative of tissue sensitivity (e.g., thermal sensitivity and/or sensitivity to microbubble cavitation) to the interaction between the microbubbles and the acoustic beam.

The method may further include determining one or more parameters (e.g., frequency, amplitude, and/or phase) associated with one or more transducer elements of the ultrasound transducer based at least in part on the selected interaction region in the tissue sensitivity map. The ultrasound transducer may then be activated based at least in part on the determined parameter. In addition, therapeutic surgery may involve the use of microbubbles; the method may further include providing microbubbles to the target region to initiate a therapeutic procedure. In one embodiment, the microvesicles are administered using an administration system. Additionally or alternatively, the method may further comprise causing the ultrasound transducer to transmit ultrasound pulses to the target region to generate microbubbles. In one embodiment, step (c) is performed only after the focal properties of the acoustic beam at the target region are optimized.

In various embodiments, the method further comprises detecting microbubble characteristics in the target region, one of the regions in the tissue sensitivity map, and/or a dedicated monitoring region (e.g., a region that is continuously monitored throughout the treatment procedure). The microbubble characteristic may be detected using an ultrasound transducer, an acoustic signal detection device, and/or a second ultrasound transducer different from the ultrasound transducer activated in step (c). Further, the method may further comprise determining a parameter associated with the ultrasound transducer based at least in part on the detected microbubble characteristic. In one embodiment, the generated acoustic beam causes cavitation of at least some of the microbubbles in the selected interaction region in the tissue sensitivity map. The method may then further comprise determining parameters associated with the ultrasound transducer in order to select microbubbles for cavitation.

Additionally, the method may further include acquiring a digital representation of a plurality of voxels comprising one or more portions of the region in the tissue sensitivity map; a tissue sensitivity map is generated based at least in part on the digital representation. In some embodiments, the method further comprises determining an anatomical characteristic (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; a tissue sensitivity map is generated based at least in part on the anatomical characteristic. Further, the method may further include assigning a sensitivity score to voxels of the one or more portions based at least in part on anatomical characteristics associated with the one or more portions of the region in the tissue sensitivity map; the sensitivity score indicates the level of sensitivity 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 lower sensitivity score than other regions in the tissue sensitivity map. Further, the method may further include adjusting a parameter 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 further comprises moving at least some of the microbubbles from the target region to a selected interaction region in the tissue sensitivity map.

Reference throughout this specification to "one example," "an example," "one embodiment," or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the example is included in at least one example of the present technology. Thus, the appearances of the phrases "in one example," "in an example," "one embodiment," or "an embodiment" in various places throughout this specification are not necessarily all referring to the same example. Furthermore, the particular features, structures, routines, steps, or characteristics may be combined in any suitable manner in one or more examples of the 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.

Drawings

In the drawings, like reference numerals generally refer to like parts throughout the different views. In addition, the drawings are not necessarily to scale, emphasis instead generally being placed upon illustrating the principles of the invention. In the following description, various embodiments of the present invention are described with reference to the following drawings, in which:

FIG. 1A schematically depicts an exemplary ultrasound system according to various embodiments of the present invention;

FIG. 1B schematically depicts an exemplary MRI system according to various embodiments of the present invention;

FIG. 2A depicts tissue volumes of a target region and a non-target region represented as a 3D voxel group according to various embodiments of the invention;

2B-2F depict exemplary tissue sensitivity maps according to various embodiments of the present invention;

FIG. 3 is a flow diagram illustrating an exemplary method for generating a tissue sensitivity map according to various embodiments of the invention;

4A-4C depict various microbubble modulation methods for indirectly eliminating/reducing a microbubble population at or near a target region and a non-target region in accordance with various embodiments of the present invention;

figure 5 depicts an implementation of a second ultrasound transducer for real-time monitoring of microbubble modulation methods and/or ultrasound procedures in accordance with various embodiments of the present invention;

figure 6A is a flow diagram illustrating a method of adjusting a population of microbubbles in a target region and/or a non-target region before, during, and/or after an ultrasound procedure according to various embodiments of the invention; and

figure 6B is a flow chart illustrating an exemplary microbubble adjustment method according to various embodiments of the present invention.

Detailed Description

Fig. 1A illustrates an exemplary ultrasound system 100 for generating and delivering a focused beam of acoustic energy to a target region to destroy and/or ablate tissue therein. 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 in communication with the beamformer 106, and a frequency generator 110 providing input electronic signals to the beamformer 106.

The array 102 may have a curved (e.g., spherical or parabolic) shape suitable for placement on a patient's body surface, or may include one or more planar or otherwise shaped portions. The dimensions of which may vary from a few millimeters to a few tens of centimeters. The transducer elements 104 of the array 102 may be piezo-ceramic elements and may be mounted in silicone rubber or any other material suitable for mechanical coupling between the damping elements 104. Piezoelectric composites, or generally any material capable of converting electrical energy to acoustic energy, may also be used. To ensure maximum power transfer to the transducer element 104, the element 104 may be configured for 50 Ω electrical resonance, matching the input connector impedance.

The transducer array 102 is coupled to a beamformer 106, which drives the individual transducer elements 104 such that they collectively produce a focused ultrasound beam or field. For n transducer elements, the beamformer 106 may contain n driver circuits, each including or consisting of an amplifier 118 and a phase delay circuit 120; each driving circuit drives one of the transducer elements 104. The beamformer 106 receives a Radio Frequency (RF) input signal, typically in the range of 0.1MHz to 10MHz, from a frequency generator 110, which may be, for example, model DS345, available from the stanford research system. The input signal may be split into n channels for n amplifiers 118 and delay circuits 120 of the beamformer 106. In some embodiments, the frequency generator 110 is integrated with the beamformer 106. The frequency generator 110 and beamformer 106 are configured to: the individual transducer elements 104 of the transducer array 102 are driven at the same frequency but with different phases and/or different amplitudes.

Amplification or attenuation factor a applied by the beamformer 106₁-α_nAnd phase shift a₁-a_nFor transmitting and focusing ultrasound energy onto a target region and accounting for wave distortion induced in tissue located between the transducer elements 104 and the target region. The amplification factor and phase shift are calculated using a controller 108, which may provide the calculation function by software, hardware, firmware, hardwiring, or any combination thereof. For example, the controller 108 may utilize a general or special purpose digital data processor programmed with software in a conventional manner and without undue experimentation in order to determine the phase shift and amplification factors required to achieve the desired focus or any other desired spatial field pattern at the target region. In certain embodiments, the calculations are based on detailed information about the properties (e.g., structure, thickness, density, etc.) of intervening tissue located between the transducer elements 104 and the target and its effect on acoustic energy propagation. Such information may be obtained from the imager 122. The imager 122 may be, for example, a Magnetic Resonance Imaging (MRI) device, a Computed Tomography (CT) device, a Positron Emission (PET) deviceA 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 region of interest and/or other regions (e.g., the region surrounding the object). In addition, the ultrasound system 100 and/or the imager 122 may be used to detect microbubble response, presence, quantity, concentration, and/or size distribution, and/or presence, type, and/or location associated with microbubble cavitation, as described further below. Additionally or alternatively, the system may include an acoustic signal detection device (such as a hydrophone or suitable substitute) 124 that detects ultrasound emitted or reflected from the microbubbles to measure the presence, quantity, concentration, and/or size distribution of the microbubble responses and/or information related to cavitation of the microbubbles, and may provide signals received thereby 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 parenterally into the patient, as described further below. The imager 122, acoustic signal detection device 124, and/or management system 126 may operate using the same controller 108 that facilitates transducer operation; alternatively, they may be individually controlled by one or more individual controllers in communication with each other.

FIG. 1B shows an exemplary imager, namely an MRI device 122. The device 122 may include a cylindrical electromagnet 134 that generates the necessary static magnetic field within a bore 136 of the electromagnet 134. During a medical procedure, a patient is placed within the aperture 136 on the movable support 138. A region of interest 140 within the patient (e.g., the patient's head) may be positioned within the imaging region 142, with the electromagnet 134 generating 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 magnitude at predetermined times and in three mutually orthogonal directions. By means of the field gradients, different spatial positions can be associated with different precession frequencies, thus 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 transmit Magnetic Resonance (MR) response signals. The raw MR response signals are sensed by the RF coil 146 and passed to the MR controller 148, which then computes an MR image that can be displayed to the user. Alternatively, separate MR transmitter and receiver coils may be used. The images acquired using the MRI apparatus 122 may provide a radiologist and physician with a visual contrast between different tissues and detailed internal views of the patient's anatomy that are not visible with conventional X-ray techniques.

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

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

In various embodiments, based on the acquired images and anatomical characteristics, an image, table or "map" of the sensitivity level of the tissue to the effects produced by the interaction between the acoustic beam and the microbubbles at the target tissue and/or non-target tissue (e.g., temperature rise caused by acoustic power and/or microbubble cavitation) may be generated as described below. For ease of reference, the following description refers only to tissue sensitivity maps; however, it should be understood that a table or other suitable data organization format may be used to indicate the tissue sensitivity level. Referring to fig. 2A, a tissue sensitivity map 202 may include various regions outside of a 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, arterioles 208, carotid arteries 210, facial veins 212, and jugular veins 214; each region is represented by one or more voxels 216. In one implementation, the tissue sensitivity map 202 also includes a target region 204. The tissue sensitivity map 202 generally facilitates treatment planning such that ultrasound is effectively directed to one or more regions outside of the target region 204 to clear microbubbles, but without damaging non-target tissue with different sensitivities. For this purpose, the tissue sensitivity map 202 identifies low-sensitivity non-target regions where microbubbles, after being used for ultrasound autofocus, can be "destroyed" (i.e., caused to undergo cavitation) or reduced quickly by sonication so as not to delay continued ultrasound therapy (e.g., ablation of target tumor tissue) of the target 204.

Tissue sensitivity maps may be created based on various tissue characteristics, such as tissue type. For example, the threshold for thermal damage to brain tissue may be lower than that of bone tissue. Thus, in one embodiment, brain tissue is classified into a higher sensitivity class and/or assigned a higher sensitivity score; while bone tissue is classified into a less sensitive category and/or given a lower sensitivity score. Similarly, the thermal injury threshold of muscle tissue may be lower than that of adipose tissue; thus, muscle tissue may be assigned a relatively higher sensitivity score and/or classified as a higher sensitivity category; while adipose tissue is assigned a relatively lower sensitivity score and/or classified as a lower sensitivity class. Thermal and/or cavitation damage thresholds for various tissue types can be obtained based on retrospective studies of patients undergoing ultrasound surgery and/or from known literature (see, e.g., 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 tissues, which can likewise be obtained from the known literature (see, e.g., https:// is. swiss/visual-publication/tissue-properties/database/heat-capacity /). Because tissue with relatively low heat capacity may reach a threshold temperature (e.g., 43 ℃) and experience damage in a relatively short period of time, tissue with relatively low heat capacity may be classified into a higher sensitivity class and/or assigned a higher sensitivity score 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.

Additionally or alternatively, the tissue sensitivity map 202 may be based at least in part on tissue size and configuration. For example, the diameter of the carotid artery 210 and jugular vein 214 is larger than the diameter of the arteriole 208 and facial vein 212; thus, cavitation of microbubbles in carotid artery 210 or jugular vein 214 may cause less undesirable tissue damage than in arteriole 208 or facial vein 212. Thus, the carotid artery 210 and jugular vein 214 may be classified into a relatively less sensitive category and/or assigned a relatively less sensitive score to microbubble cavitation; while arterioles 208 and facial veins 212 are assigned relatively higher sensitivity scores and/or classified into higher sensitivity categories.

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

In one embodiment, 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. For example, fig. 2B-2D depict tissue sensitivity maps in which the sensitivity score assigned to each voxel is based on tissue type, function, and size, respectively. Fig. 2E depicts the sum of sensitivity scores assigned to voxels based on their corresponding tissue type, function, and size, as shown in fig. 2B-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 the arteriole 208 and facial vein 212 is lower than the sensitivity score (e.g., 18) of the target tumor region 204 and its surrounding region 206. The tissue sensitivity map 202 may be stored in system memory before, during, or after microbubble-mediated ultrasound focusing procedures for adjusting the concentration and/or amount of microbubbles in target/non-target tissue, as described further below.

Alternatively, the sensitivity scores assigned to voxels based on their corresponding tissue characteristics (e.g., type, size and conformation, function, location, etc.) may be averaged, and the average may be weighted or otherwise adjusted to reflect the degree of importance of the various tissue characteristics. For example, since brain tissue, arterioles and arteries are highly sensitive to temperature increases caused by acoustic power and/or cavitation of microbubbles, and their function is equally important, the area in which the microbubbles are to be destroyed may depend primarily on the size of the tissue. Thus, sensitivity scores assigned based on tissue type (as shown in FIG. 2B) and function (as shown in FIG. 2C) may both have a weight factor of 25%; while a sensitivity score based on size assignment (as shown in fig. 2D) may have a weight factor of 50%. FIG. 2F depicts a sensitivity map with a weighted tolerance score. 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 on the tissue sensitivity map outside of the target region 204 has a sensitivity score lower than the target region 204, indicating a lower sensitivity to applied acoustic power and/or microbubble cavitation; as described further below, a relatively low sensitivity score may be sufficient to facilitate treatment planning and/or indirectly reduce microbubbles at the target region 204.

Fig. 3 is a flow diagram illustrating an exemplary method 300 for creating a tissue sensitivity map, in accordance with various embodiments. In a first step 302, an imaging device is activated to acquire images of the patient's anatomy 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 an 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 the target volume and/or non-target volume therein using suitable image processing techniques. In one embodiment, a targeted and/or non-targeted tissue volume is represented as a set of 3D voxels. In a third step 306, the controller may further process the image to determine anatomical characteristics (e.g., type, size, properties, structure, thickness, density, etc.) of the target/non-target tissue and specific properties (e.g., density and hydration) of the tissue displayed in the image based on the anatomical map. 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/non-target tissue that indicates the level of sensitivity of the tissue to the effects produced by the interaction between the applied acoustic waves and the microbubbles (e.g., temperature rise caused by 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.

In various embodiments, a small transient cloud of microbubbles is provided to a target region for autofocusing an acoustic beam therein prior to and/or during an ultrasound procedure for treating the target (e.g., applying ultrasound treatment to ablate target tissue). The microbubbles can be generated using ultrasound pulses and/or introduced intravenously using the administration system 126. Microbubble characteristics (e.g., presence, concentration, and/or quantity) and/or behavior or response (e.g., cavitation) are monitored using the acoustic signal detection device 124 and/or the transducer array 102. Methods for automatically focusing an ultrasound beam at a target area are provided, for example, in international application No. PCT/IB2017/000990 (filed 7/19/2017) and U.S. patent application No. 62/781,258 (filed 12/18/2018); for example, international application No. PCT/IB2019/001537 (filed 12/5/2018) provides a method for providing microvesicles to a target region; methods for measuring microbubble properties and/or activity are provided, for example, in U.S. patent publication No. 2018/0206816 and international application nos. PCT/IB2018/000841 (filed 6/29/2018) and PCT/IB2018/000774 (filed 5/22/2018); and, for example, in U.S. patent application No. 62/681,282 (filed 6/2018), a method of configuring the transducer array 102 to detect microbubble responses is provided. The entire contents of these applications are incorporated herein by reference.

In one embodiment, after determining transducer parameters (e.g., frequency, phase shift, and/or amplitude) that optimize focusing at a target region in an auto-focusing process (e.g., via analysis of acoustic reflections from microbubbles), the amount of microbubbles at the target region (and/or nearby non-target regions) is preferably limited to avoid undesirable damage to non-target tissue during ablation of the target tissue. Thus, after the auto-focusing process, the acoustic signal detection device 124 and/or transducer array 102 may be used again to measure the presence, amount, concentration, and/or size distribution of microbubbles at the target region (and/or nearby non-target regions) based on acoustic signals transmitted or reflected from the microbubbles. If microbubbles are present (or, in some embodiments, in an amount exceeding a predetermined threshold effective to preclude clinically significant damage to the target tissue and/or non-target tissue), a microbubble modulation method can be implemented to eliminate (or at least reduce) microbubbles at one or more selected non-target regions corresponding to a low sensitivity level on the tissue sensitivity map 202; this may then indirectly reduce the microbubble population at the target and/or its vicinity. For example, referring to fig. 4A, when the presence or excess of microbubbles 402 at the target region 204 is detected, the controller 108 can analyze the reflected signals from microbubbles near the target 204 to identify other tissue regions that also have microbubbles therein. For example, microbubbles may be present in arterioles 208 and arteries 210. The controller 108 may then access the system memory to retrieve the stored tissue sensitivity map 202, compare the sensitivity levels associated with the regions where microbubbles are present, and select one or more regions to destroy microbubbles therein. For example, because the artery 210 has a relatively lower sensitivity score (as depicted in fig. 2E and 2F) than the target region 204 and the arteriole 208, the controller 108 can cause the beamformer 106 to provide drive signals to the transducer elements 104 to generate a focal point (e.g., a point focal point, a line focal point, or a focal point of any suitable shape) at the microbubbles 402 in the artery 210 to cause cavitation thereof, thereby reducing the concentration/amount of microbubbles before they reach the target region 204. Because this approach can effectively reduce the total amount of microbubbles in the blood stream, the amount/concentration of microbubbles in the target region 204 (and anywhere else in the blood stream) can be indirectly reduced. Thus, undesired damage caused by microbubbles at non-target tissue during subsequent ultrasound procedures (e.g., ablation of target tissue) may be avoided. Again, the ultrasound parameter values (e.g., amplitude, phase, and/or frequency) used to generate the focal point and cause cavitation of the microbubbles at the selected region may be calculated by the controller 108 based on the anatomical characteristics acquired using the imager 122, as described above. Further, the controller 108 may be configured to: upon completion of the ultrasound autofocus process, when the presence of microbubbles in the target region 204 is detected and/or when the number of microbubbles 402 in the target region 204 exceeds a predetermined threshold during or after the autofocus process, a focal point is automatically created and the ultrasound intensity is adjusted to begin the microbubble adjustment process.

It should be noted that the selected region of 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 region is below the target region 204, it may be sufficient to destroy microbubbles at the selected region without damaging tissue in the region surrounding the target and/or tissue in the selected non-target region. Further, ultrasound parameter values (e.g., amplitude, phase, and/or frequency) for causing cavitation of the microbubbles at the selected region may be adjusted based on the corresponding sensitivity scores. For example, the acoustic power of the beam delivered to the region corresponding to the lowest sensitivity score may be relatively large, resulting in a greater amount of microbubble cavitation. Conversely, when the sensitivity score of the selected region is slightly greater than the sensitivity score of the target region, the acoustic power may be reduced to cavitate the mild microbubbles, thereby avoiding damage to the selected region.

In various embodiments, the selection of the region in which the microbubbles will be destroyed may be based on the relative location of the region with respect to the target region 204. For example, referring to fig. 4B, while 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 cause 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 the microbubbles therein can rapidly reduce the population of microbubbles in the target 204 while the jugular vein 214 is downstream of the target region 204, and thus, when the microbubbles are destroyed in the jugular vein 214, it may take longer to reduce the concentration of microbubbles at the target.

Additionally or alternatively, the amount of microbubbles present in the region on the tissue sensitivity map 202 may be considered in selecting the region for microbubble destruction. For example, referring again to FIG. 4B, although both regions 404, 406 are located in the artery 210 and upstream of the target 204, because there are more microbubbles present in region 404 than region 406, it is preferable to apply a focused acoustic beam to region 404, as this may result in more microbubble cavitation, thus more effectively reducing the population of microbubbles in the target region (and anywhere else in the blood). The amount of microbubbles in the various regions can 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.

In various embodiments, the characteristics of the focused beam are optimized based on the characteristics of the microbubbles. For example, referring again to FIG. 4B, the size and/or shape of focal spot 410 may be adjusted to conform to the size and/or shape of the microbubbles to be removed. In this manner, the microbubble modulation process can effectively destroy selected microbubbles at once. Alternatively, the focal spot may be shaped/sized to destroy only a portion of the microbubbles. For example, referring to fig. 4C, when some microbubbles are near the artery wall, their cavitation may cause damage to the artery wall; thus, the ultrasound controller 108 may shape and size the focal point 410 to destroy only a portion of the microbubbles that are not proximate to the arterial wall. Adjustment of the focal spot size and/or shape may be achieved by adjusting the amplification factor and/or phase shift of the ultrasound beam emitted from the transducer element, as described above.

While the primary force for distributing microbubbles in the target region and non-target regions outside the target is blood circulation, in some embodiments, the ultrasound transducer may be configured (e.g., by adjusting phase, amplitude, and/or frequency) to create a focal point to which microbubble motion may be induced by applying acoustic force. For example, the generated focal point may sweep at least a portion of the microbubbles from the target region 204 (or a region with a relatively higher sensitivity score) to a less sensitive region outside of the target (e.g., facial vein 212). In one embodiment, the generated focal point has a sufficiently low acoustic power to sweep the microbubble 402 without causing cavitation thereof.

In various embodiments, the focal point induces motion of the microbubbles 402 by applying an acoustic force thereto. The acoustic force is generated by changes in the energy density and momentum of the propagating ultrasonic waves caused by absorption, scattering, or reflection from intervening tissue located between the transducer 102 and the target region 204. Generally, the magnitude of the acoustic force is proportional to the ultrasound intensity. Thus, in one implementation, the intensity of the ultrasound beam directed at the microbubble 402 is gradually increased until the generated acoustic force is sufficient to manipulate and move the microbubble 402. In another embodiment, prior to manipulation of the microbubbles 402, a property of intervening tissue (e.g., absorption coefficient) is measured using the imager 122 as described above; the intensity of the ultrasound beam sufficient to move the microbubbles 402 can be calculated based thereon. Once the microbubbles are removed from the target region and/or reach a region with a relatively low sensitivity fraction, the controller 108 may increase the intensity of the ultrasound beam to cause cavitation of the microbubbles in the low sensitivity region. Since cavitation now occurs in the hypo-sensitive region, any damage that may occur is clinically acceptable. Thus, the method may advantageously allow microbubbles to be removed from regions more susceptible to ultrasound-induced microbubble cavitation (e.g., regions of higher sensitivity) to regions less likely to be damaged by cavitation (e.g., regions of lower sensitivity). Thus, accidental damage to healthy tissue in the target area and/or non-target areas may be minimized.

It should be understood that the terms "point focus" and "line focus" as used herein do not refer to points and lines in the strict mathematical sense, but rather to the shape of the focus that approximates a point or line, respectively. Thus, the intensity distribution of a point focus (which may take the shape of a two-dimensional gaussian distribution, for example) may be characterized by a half-width in two dimensions of the focal plane of the order of about several acoustic wavelengths, while the intensity distribution of a line focus (which may have a one-dimensional gaussian profile perpendicular to the line, for example) extends in the direction of the line but may have a half-width perpendicular thereto of the order of about several acoustic wavelengths.

In various embodiments, the acoustic signal detection device 124 and/or transducer array 102 are used to monitor microbubble characteristics (e.g., amount, concentration, size distribution, and/or response) in real-time during ultrasound-induced microbubble cavitation at a selected one or more regions of low sensitivity and/or during sweeping from a region of relatively higher sensitivity toward a region of relatively lower sensitivity, as described above. Additionally, referring to FIG. 5, a second transducer array 502 may be implemented to monitor the cavitation and/or 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 region of low sensitivity. For example, if the detected signal indicates that the power of the generated focal spot is insufficient to cause cavitation of microbubbles, the controller 108 may increase the intensity of the ultrasound beam. In addition, the controller 108 may adjust the phase of the beams from the transducer elements 104 in order to gradually move the focal point to follow the movement of microbubbles in the blood stream (e.g., resulting from blood circulation) to be destroyed.

In various embodiments, the above-described microbubble modulation process (by sweeping microbubbles from a region of relatively higher sensitivity to a region of relatively lower sensitivity and/or inducing microbubble cavitation in a region of low sensitivity based on the tissue sensitivity map 202) may be repeated until the population of microbubbles at the target region 204 is completely eliminated or at least below a predetermined threshold; again, this may 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 removing the desired amount of microbubbles from the target region 204, the controller 108 may excite the transducer elements 104 with the treatment parameters (e.g., phase, frequency, amplitude, sonication duration, etc.) determined during the auto-focusing process to transmit ultrasound waves into the target region 204 to begin or continue treatment.

Although the above-described microbubble modulation method modulates microbubble concentration/amount prior to applying ultrasound pulses/waves to treat a target (e.g., ablate a target tumor), the method may be used to eliminate/reduce microbubbles during and/or after ultrasound surgery to avoid causing undesirable damage to target/non-target tissue. For example, a target treatment procedure may be initiated after the population of microbubbles at the target is below a predetermined threshold; during the therapeutic procedure, the acoustic signal detection device 124, transducer array 102, and/or second transducer array 502 may again be used to monitor the microbubble concentration and/or response in real-time in the target region and/or non-target region. If excess microbubbles are measured (e.g., carried by blood flow from another region), the above-described microbubble modulation method can be initiated to eliminate/reduce excess microbubbles based on the tissue sensitivity map. For example, referring again to fig. 5, during treatment, the transducer array 102 may generate a focal spot at the target region 204 to ablate tissue therein; the second transducer array 502 may 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 may begin a microbubble modulation method to destroy the microbubbles in the artery 210 before they enter the target 204. Thus, treatment of the target tissue can continue without any interruption. Accordingly, various embodiments of the present invention provide methods of indirectly eliminating/reducing microbubbles at a target region prior to and/or during an ultrasound therapy procedure without extending the procedure time while avoiding undesirable damage to healthy, non-target tissue.

Furthermore, although the ultrasound surgery described herein refers to thermal ablation for the treatment of benign or malignant tumors within the skull of a patient, it should be understood that other ultrasound surgeries may generally apply the same microbubble modulation methods to modulate the microbubble concentration/amount at the target/non-target regions. For example, ultrasound surgery may be microbubble-mediated BBB opening or thermal ablation for the treatment of blood clots in the skull or other body regions of a patient. Implementing the microbubble modulation method can again eliminate/reduce undesired microbubbles at the target BBB region or target clot, advantageously providing improved control of microbubble cavitation for ablation and avoiding damage to non-target tissue. In addition, the above description is of an ultrasound treatment procedure for ease of reference only; it should be understood that the same method is generally applicable to ultrasound imaging procedures as well.

Fig. 6A is a flow chart illustrating a representative method 600 for adjusting microbubble concentration/quantity before, during, and/or after an ultrasound procedure according to various embodiments, in accordance with the present disclosure. For example, the microbubble modulation method can be implemented after performing ultrasound autofocus 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 prior to or during an ultrasound focusing procedure. 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 the microbubbles; based on this, the amount, concentration and/or response of microbubbles at the target region and/or non-target region (e.g., region outside of the target region) can be determined. In optional step 608, the detected amount/concentration of microbubbles may be compared to a predetermined threshold. If microbubbles are present at the target region (and/or nearby non-target regions) and/or the number/concentration of detected microbubbles exceeds a predetermined threshold, a microbubble adjustment 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/non-target region is below a predetermined threshold. Subsequently, the controller 108 may activate the ultrasound transducer 102 to begin or continue ultrasound surgery (e.g., to ablate a target tumor) (in step 612). Step 606-612 may be performed iteratively throughout the ultrasound procedure. In various embodiments, after achieving a therapeutic target for the ultrasound procedure (e.g., ablating the target tissue), the microbubble modulation method is optionally again used to eliminate/reduce the microbubbles in the target/non-target tissue (in step 614). In one implementation, the microbubbles are eliminated/reduced after the ultrasound procedure only if the measured amount/concentration of microbubbles exceeds a predetermined threshold.

Fig. 6B is a flow chart illustrating a representative microbubble adjustment method 650 according to the present disclosure. In various embodiments, upon determining that microbubbles are present in the target region (and/or nearby non-target regions) and/or that the detected amount/concentration of microbubbles exceeds a predetermined threshold, the controller 108 may identify one or more regions with a relatively low sensitivity score indicative of low sensitivity to temperature increase caused by sonication and/or cavitation of microbubbles based on the tissue sensitivity map (in step 652). The identified hyposensitivity region may have the lowest sensitivity score in the tissue sensitivity map. Alternatively, the identified regions of low sensitivity may only need to have a lower sensitivity score than the target region and/or the region where the presence or excess of microbubbles is detected. In optional step 654, the controller 108 may cause the transducer array 102 to generate a focal point that applies an acoustic force to the microbubbles 402 at the target region (and/or nearby non-target regions) causing them to move. In addition, the controller 108 may adjust the phase of the beams transmitted from the transducer elements 104 in order to gradually move the focal point (and thus the microbubbles) from the target region toward the identified relatively less sensitive region. Optionally, the motion of the microbubbles may be monitored in real time using the acoustic signal detection device 124, the transducer array 102, and/or the second transducer array 502 to ensure sufficient motion of the microbubbles without cavitation. In a third step 656, the controller 108 may generate a focal point at the microbubbles in the identified region of low sensitivity to cause cavitation of the microbubbles. Optionally, the microbubble cavitation events are monitored in real-time, again using the acoustic signal detection device 124, the transducer array 102, and/or the second transducer array 502, to ensure that no (or at least limited) damage occurs at the relatively less sensitive region (step 658). Step 654-658 may be performed iteratively until the concentration/quantity of microbubbles at the target region (and/or nearby non-target regions) is below a predetermined threshold. Once the microbubble concentration/amount is below a predetermined threshold, ultrasound surgery for treating a target (e.g., ablating tissue therein) may be initiated (step 612).

In general, the functionality for facilitating microbubble-mediated ultrasound autofocus procedures and ultrasound target treatment procedures and/or using microbubble modulation methods to eliminate (or at least reduce) microbubbles in target and/or non-target regions may be configured in one or more modules implemented in hardware, software, or a combination of both, whether integrated within the controller of the imager 122, ultrasound system 100, and/or management system 124, or provided by a separate external controller or other computing entity. Such functions may include, for example: analyzing imaging data of a target region and/or non-target region acquired using imager 112, determining a set of 3D voxels of the 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 transducer array to detect acoustic signals emitted or reflected from microbubbles, determining an amount, concentration, size distribution, and/or response of the microbubbles based on the detected acoustic signals, comparing the measured amount/concentration of microbubbles to a predetermined threshold, identifying tissue regions outside of the target having a relatively lower sensitivity score than the target region and/or other non-target regions, configuring an ultrasound transducer array to generate a focal point at an identified tissue region to induce microbubble cavitation therein, adjusting ultrasound parameters to gradually sweep excess microbubbles from a target region (or nearby non-target regions) toward the identified relatively less sensitive region, monitoring microbubble motion and/or cavitation, causing an ultrasound transducer to transmit ultrasound treatment to the target region to begin ultrasound surgery (e.g., to ablate target tumor tissue), and/or monitoring microbubble response during ultrasound surgery, as described above.

Further, the ultrasound controller 108, the MR controller 148, and/or the controllers 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, the programs may be written in any of a number of high-level languages, such as PYTHON, FORTRAN, PASCAL, JAVA, C + +, C #, BASIC, various scripting languages, and/or HTML. Further, the software may be implemented in assembly language for a microprocessor residing on the target computer; for example, if the software is configured to run on an IBM PC or PC clone, the software may be implemented in Intel 80x86 assembly language. 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, magnetic tape, a PROM, an EPROM, an EEPROM, a field programmable gate array, or a CD-ROM. Embodiments using hardware circuitry may be implemented using, for example, one or more FPGA, CPLD, or ASIC processors.

The terms and expressions which have been employed herein are used as terms and expressions of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof. In addition, having described certain embodiments of the 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 invention. The described embodiments are, therefore, to be considered in all respects only as illustrative and not restrictive.