Patent ID: 12246195

DETAILED DESCRIPTION

FIG.1Aillustrates an exemplary ultrasound system100for focusing ultrasound onto a target region101in a patient. The system100can shape the ultrasonic energy in various ways, producing, for example, a point focus, a line focus, a ring-shaped focus, or multiple foci simultaneously. In various embodiments, the system100includes a phased array102of transducer elements104, a beamformer106driving the phased array102, a controller108in communication with the beamformer106, and a frequency generator110providing an input electronic signal to the beamformer106.

The array102may have a curved (e.g., spherical or parabolic) shape suitable for placing it on the surface of a skull or a body part other than the skull, or may include one or more planar or otherwise shaped sections. Its dimensions may vary, depending on the application, between millimeters and tens of centimeters. The transducer elements104of the array102may be piezoelectric ceramic, capacitive micromachined ultrasonic transducer (CMUT) or microelectromechanical systems (MEMS) elements, and may be mounted in silicone rubber or any other material suitable for damping the mechanical coupling between the elements104. Piezo-composite materials, or generally any materials shaped in a manner facilitating conversion of electrical energy to acoustic energy, may also be used. To assure maximum power transfer to the transducer elements104, the elements104may be configured for electrical resonance, matching input impedance.

The transducer array102is coupled to the beamformer106, which drives the individual transducer elements104so that they collectively produce a focused ultrasonic beam or field. For n transducer elements, the beamformer106may contain n driver circuits, each circuit including or consisting of an amplifier118and a phase shift circuit120; drive circuit drives one of the transducer elements104. The beamformer106receives a radio frequency (RF) input signal, typically in the range from 0.1 MHz to 4.0 MHz, from the frequency generator110, which may, for example, be a Model DS345 generator available from Stanford Research Systems. The input signal may be split into n channels for the n amplifiers118and delay circuits120of the beamformer106. In some embodiments, the frequency generator110is integrated with the beamformer106. The radio frequency generator110and the beamformer106are configured to drive the individual transducer elements104of the transducer array102at the same frequency, but at different phases and/or different amplitudes.

The amplification or attenuation factors α1-αnand the phase shifts a1-animposed by the beamformer106serve to transmit and focus ultrasonic energy through inhomogeneous tissue (e.g., the patient's skull or different tissues located in the acoustic paths of ultrasound beams from the transducer elements to the target region or “path zones”) onto the target region (e.g., a region in the patient's brain). Via adjustments of the amplification factors and/or the phase shifts, a desired shape and intensity of a focal zone may be created at the target region.

The amplification factors and phase shifts may be computed using the controller108, which may provide the relevant computational functions through software, hardware, firmware, hardwiring, or any combination thereof. For example, the controller108may utilize a general-purpose or special-purpose digital data processor programmed with software in a conventional manner, and without undue experimentation, to determine the frequency, phase shifts and/or amplification factors of the transducer elements104. In certain embodiments, the controller computation is based on information about the characteristics (e.g., structure, thickness, density, etc.) of intervening tissues located between the transducer102and the target101(e.g., the pass zone) and their effects on propagation of acoustic energy. In various embodiments, such information is obtained from an imager112, such as a magnetic resonance imaging (MRI) device, a computer tomography (CT) device, a positron emission tomography (PET) device, a single-photon emission computed tomography (SPECT) device, or an ultrasonography device. Image acquisition may be three-dimensional (3D) or, alternatively, the imager112may provide a set of two-dimensional (2D) images suitable for reconstructing a three-dimensional image of the target region101and/or other regions (e.g., the region surrounding the target101, the region in the pass zone located between the transducer and the target, or another target region). Image-manipulation functionality may be implemented in the imager112, in the controller108, or in a separate device.

In addition, the ultrasound system100may include an administration system124for introducing microbubbles into the patient's body. Examples of suitable administration systems are described in PCT Publication No. WO 2019/116095, the entire contents of which are incorporated herein by reference. In some embodiments, the ultrasound system100and/or imager112can be utilized to detect signals from the microbubbles located at or close to (e.g., within 10 mm of) the target region101so as to identify the amount, type and/or location of the microbubble cavitation. Additionally or alternatively, the system100may include an acoustic-signal detector (such as a hydrophone or suitable alternative)126that detects transmitted and/or reflected ultrasound from the microbubbles, and which may provide the signals it receives to the controller108for further processing. Approaches to utilizing reflection signals from the microbubbles for identifying the amount, type and/or location of the microbubble cavitation are provided, for example, in U.S. Pat. No. 10,575,816, the entire content of which is incorporated herein by reference. The imager112, the administration system124, and/or the acoustic-signal detector126may be operated using the same controller108that governs the transducer operation; alternatively, they may be separately controlled by one or more dedicated controllers intercommunicating with one another.

FIG.1Billustrates an exemplary imager—namely, an MRI apparatus112. The apparatus112may include a cylindrical electromagnet134, which generates the requisite static magnetic field within a bore136of the electromagnet134. During medical procedures, a patient is placed inside the bore136on a movable support table138. A region of interest140within the patient (e.g., the patient's head) may be positioned within an imaging region142wherein the electromagnet134generates a substantially homogeneous field. A set of cylindrical magnetic field gradient coils144may also be provided within the bore136and surrounding the patient. The gradient coils144generate magnetic field gradients of predetermined magnitudes, at predetermined times, and in three mutually orthogonal directions. With the field gradients, different spatial locations can be associated with different precession frequencies, thereby giving an MR image its spatial resolution. An RF transmitter coil146surrounding the imaging region142emits RF pulses into the imaging region142to cause the patient's tissues to emit magnetic-resonance (MR) response signals. Raw MR response signals are sensed by the RF coil146and passed to an MR controller148that then computes an MR image, which may be displayed to the user. Alternatively, separate MR transmitter and receiver coils may be used. Images acquired using the MRI apparatus112may provide radiologists and physicians with a visual contrast between different tissues and detailed internal views of a patient's anatomy that cannot be visualized with conventional x-ray technology.

The MRI controller148may control the pulse sequence, i.e., the relative timing and strengths of the magnetic field gradients and the RF excitation pulses and response detection periods. The MRI controller148may be combined with the transducer controller108into an integrated system control facility.

The MR response signals are amplified, conditioned, and digitized into raw data using a conventional image-processing system, and further transformed into arrays of image data by methods known to those of ordinary skill in the art. The image-processing system may be part of the MRI controller148, or may be a separate device (e.g., a general-purpose computer containing image-processing software) in communication with the MRI controller148and/or the transducer controller108. Because the response signal is tissue- and temperature-dependent, it can be processed to identify the treatment target region (e.g., a tumor to be destroyed by heat)101in the image, as well as to compute a temperature map from the image. Further, the acoustic field resulting from ultrasound application may be monitored in real time, using, e.g., thermal MRI or MR-based acoustic radiation force imaging. Thus, using MRI data, the ultrasound transducer102may be driven so as to focus ultrasound into (or near) the target region101, while the temperature of the target and surrounding tissues and/or the acoustic field intensity are being monitored.

In an exemplary procedure, the imager (e.g., MRI device)112acquires information (such as the location, size and/or shape) of the target region and/or non-target region prior to applying ultrasound sonications. In one embodiment, the information includes a 3D set of voxels corresponding to the target/non-target regions, and in some cases, the voxels include attributes specifying tissue characteristics (e.g., the type, property, structure, thickness, density, etc.). Based on the acquired information, the transducer configurations (e.g., frequency, phase and/or amplitude) can be determined to create a focus at the target region101without overheating the non-target region.

In various embodiments, once the target/non-target region is characterized, a priming stage involving application of at least one sequence of sonications to the target tissue is performed prior to exposure of the target tissue to a series of therapeutic sonications. Referring toFIG.2A, the priming sequence may consist of a single continuous sequence202of sonication pulses204(at the frequency to be used during treatment). In one embodiment, the single continuous pulse sequence202lasts from 0.01 to 10 sec. Alternatively, referring toFIG.2B, the priming sequence may include a series212of time-separated pulse sequences214-218(e.g., a 16 ms burst repeated at a frequency of 10 Hz, also at the same ultrasound frequency as will be used during treatment). The series212of time-separated pulse sequences214-218may collectively last from 1 to 600 sec.

Various parameters of the ultrasound output in the priming sequence(s) may be fixed or may vary. For example, referring again toFIG.2A, the power and/or frequency of the pulses204within the continuous pulse sequence202may be fixed; similarly, referring toFIG.2B, the power and/or frequency of the pulses in a time-separated pulse sequence of the sonication series212may be fixed, and the frequency of the sequences214-218in the series212may be fixed. Alternatively, the power and/or frequency of the pulses within the continuous pulse sequence may vary. For example,FIGS.3A and3Bdepict a varying power and a varying frequency, respectively, of the pulses302in a continuous pulse sequence304.FIG.3Cdepicts both power and frequency of the pulses302in a continuous pulse sequence304vary in the priming stage. In particular, the power may vary from 1 W to 1500 W and the frequency may vary from 50 kHz to 10 MHz. Similarly, the power and/or frequency of the pulses within one time-separated pulse sequence of a sonication series may vary. For example,FIGS.3D and3Edepict a varying power and frequency, respectively, of the pulses312in a time-separated pulse sequence314of a sonication series316.FIG.3Fdepicts both power and frequency of the pulses312in a time-separated pulse sequence314varying in the priming stage. Further, different time-separated pulse sequences314,318of the sonication series316may have different power levels (FIGS.3G and3I) and/or frequencies (FIGS.3H and3I).

Additionally, the transducer102may be configured to generate ultrasound pulses having multiple working frequencies in the priming stage; as a result, the priming pulse sequence has a combination (or a mixed frequency) of two or more ultrasound frequencies. The mixed frequency may be fixed within a pulse sequence and/or among different time-separated pulse sequences of a sonication series. Systems and methods for manufacturing and configuring the transducer to provide multiple frequencies and high-power output are described, for example, in U.S. Patent Publ. No. 2016/0114193, the entire disclosure of which is hereby incorporated by reference.

It should be noted that the power and frequency are exemplary parameters that may be fixed or may vary in the priming pulse sequence(s); other parameters such as the sequence length, the ultrasound mechanical index in the target tissue and/or the acoustic beam shape may be fixed or may vary as well and thus are within the scope of the present invention.

Referring toFIG.4, in some embodiments, microbubbles402are injected and/or generated in the target region101in the priming stage to promote tissue sensitivity. For example, the microbubbles may be generated by applying ultrasound pulses having an energy above a threshold. The microbubbles can be formed due to the negative pressure produced by the propagating ultrasonic pulses or when the heated liquid ruptures and is filled with gas/vapor. Additionally or alternatively, the microbubbles402may be introduced into the target region101using an administration system124. For example, the microbubbles may be injected in the form of an ultrasound contrast agent such as SONOVUE, a suspension of sulfur hexafluoride gas microbubbles. Approaches to generating the microbubbles and/or introducing the microbubbles to the target region101are provided, for example, in PCT Publication Nos. WO 2018/020315, WO 2019/116097, WO 2019/058171, WO 2019/116097, and WO 2019/116095, U.S. Patent Publication No. 2019/0083065, and U.S. Pat. No. 10,739,316, the contents of which are incorporated herein by reference.

Depending upon the amplitude and frequency of the applied acoustic field, the microbubbles402may oscillate or collapse (this mechanism is called “cavitation”). Cavitation of microbubbles may enhance tissue sensitivity at the target region101, thereby causing the tissue therein to be heated faster and be ablated more efficiently than would occur in the absence of microbubbles402. Because cavitation typically involves the production of voids or microbubbles in a liquid, these voids begin to collapse explosively with increasing applied acoustic energy; as the applied energy increases further, the explosions and resulting shock waves (which may be detected as a measure of cavitation intensity) become more violent. Thus, in various embodiments, one or more ultrasound parameters (such as the power, frequency, mechanical index, acoustic beam shape, and sequence length(s)) can be varied in the priming pulse sequence(s) to induce a target range of cavitation that is sufficient to enhance tissue sensitivity while avoiding extreme cavitation that creates significant clinical effects (i.e., a significant temperature increase at the target and/or non-target regions) in the target region. Once the target range of cavitation is achieved, the ultrasound parameter(s) may be fixed to maintain the cavitation level.

In various embodiments, the target range of cavitation is identified prior to or during the priming stage by, for example, ramping up the power of the ultrasound pulses and monitoring the response profile of the microbubbles. The microbubble response can be inferred from the temperature of the target/non-target tissue monitored by the imager112and/or the acoustic response of the microbubbles detected by the transducer102and/or acoustic-signal detector126. In one embodiment, the target range of cavitation is identified as having a power range between the power of the pulses that causes gentle and stable cavitation and the power of the pulses that commences formation of a microbubble cloud. Further details about approaches to identifying the target range of cavitation are provided, for example, in U.S. Patent Publication No. 2019/0175954); and approaches to configuring the transducer array for detecting the microbubble response are provided, for example, in PCT Publication No. WO/2019/234497. The entire contents of these applications are incorporated herein by reference.

Besides the applied acoustic energy, the degree of cavitation may also be influenced by the concentration of microbubbles. Thus, in some embodiments, one or more ultrasound parameters (e.g., the power, frequency, mechanical index, acoustic beam shape, and sequence length(s) are optimized (and, in some embodiments, fixed) to maintain the concentration of microbubbles within a fixed range; that range, in turn, may, again, be based on the acoustic response of the microbubbles at the target/non-target regions and/or the temperature of the target/non-target tissue as described above.

Referring toFIG.5, after the priming pulse sequence(s)502ends, the ultrasound transducer102may be halted for a delay interval504prior to generating a series of one or more treatment sequences506-510to the target. As depicted, the treatment sequences have a sonication interval512therebetween; the sonication interval512may be fixed or may vary throughout the treatment sequences. In one embodiment, the delay interval504is preferably longer than the maximal sonication interval512by a predetermined factor (e.g., 2 times, 10 times, 50 times or 100 times). For example, the sonication interval512may last from 0.1 to 10 sec. and the delay interval may range from 1 sec (when the sonication interval is 0.1 sec) to 3 hours, e.g., 3 min (when the sonication interval is 10 sec).

Additionally, the microbubbles may be generated and/or introduced to the target region101after the priming stage. For example, additional microbubbles may be administered during treatment for improving focusing properties of the ultrasound focused beam and/or assisting tissue disruption or necrosis. Approaches to utilizing microbubbles for improving focusing properties are provided, for example, in U.S. Patent Publication No. 2019/0175954 and PCT Publication No. WO 2020/128615; and approaches to utilizing microbubbles for assisting tissue disruption or necrosis are provided, for example, in U.S. Patent Publication Nos. 2019/0001154 and 2020/0139158 and PCT Publication No. WO 2019/002949. The entire contents of these applications are incorporated herein by reference.

FIG.6is a flow chart illustrating an exemplary approach600for enhancing tissue sensitivity, thereby permitting effective ultrasound therapy of the target tissue while avoiding damage to the non-target tissue in accordance herewith. In a first step602, an imager (e.g., MRI device) is activated to acquire information (such as the location, size and/or shape) of the target region and/or non-target region. In a second step604, based on the acquired information, one or more sequences of priming sonication pulses can be generated to apply acoustic energy to the target region for enhancing tissue sensitivity therein. In addition, microbubbles may be optionally generated and/or injected into the target region to further enhance tissue sensitivity (step606). If the microbubbles are used in the priming stage, one or more ultrasound parameters (such as the power, frequency, mechanical index, acoustic beam shape, and sequence length(s)) may be adjusted so as to induce and/or maintain a target range of cavitation that is sufficient to enhance tissue sensitivity while avoiding extreme cavitation that creates significant clinical effects (i.e., a significant temperature increase at the target and/or non-target regions) in the target region (step608). Once the priming stage is complete, the ultrasound transducer may be halted for a predetermined delay interval (step610). Thereafter, the ultrasound transducer may be activated to transmit a series of one or more treatment sequences for tissue disruption or necrosis in the target region (step612). Again, the microbubbles may be optionally introduced to the target during treatment for assisting tissue disruption or necrosis and/or improving focusing properties of the ultrasound focused beam. Optionally, the priming sequence and/or the treatment sequence may be guided by the imager112.

Accordingly, various embodiments apply the priming sequence of sonication pulses prior to application of the therapeutic sonication pulses to the target tissue; this approach may advantageously enhance sensitivity of various types of target tissue to acoustic energy at various frequencies. As a result, the acoustic energy required for tissue disruption/necrosis in the target region can be reduced. Accordingly, various embodiments effectively reduce the required acoustic energy from the ultrasound transducer to provide effective target therapy while avoiding damage to the non-target tissue.

In general, functionality for performing an ultrasound treatment procedure, including, for example, generating one or more priming sequences of sonication pulses, adjust parameters of the priming sonication sequence(s), generating microbubbles, applying sonications to cause microbubble cavitation, and generating a series of therapeutic sequences of sonication pulses as described above, whether integrated within a controller of the imager, and/or an ultrasound system, or provided by a separate external controller, may be structured in one or more modules implemented in hardware, software, or a combination of both. For embodiments in which the functions are provided as one or more software programs, the programs may be written in any of a number of high level languages such as PYTHON, JAVA, C, C++, C#, BASIC, various scripting languages, and/or HTML. Additionally, the software can be implemented in an assembly language directed to the microprocessor resident on a target computer (e.g., the controller); for example, the software may be implemented in Intel 80x86 assembly language if it is configured to run on an IBM PC or PC clone. 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 magnetic tape, a PROM, an EPROM, EEPROM, field-programmable gate array, or CD-ROM. Embodiments using hardware circuitry may be implemented using, for example, one or more FPGA, CPLD or ASIC processors.

In addition, the term “controller” used herein broadly includes all necessary hardware components and/or software modules utilized to perform any functionality as described above; the controller may include multiple hardware components and/or software modules and the functionality can be spread among different components and/or modules. Further, the phased-array operation is optional (simple transducers are acceptable for some applications), as is image guidance. If imaging is employed, the treatment sequence, the priming sequence or both may be guided thereby. The image modality may be Mill, as discussed, or computed tomography (CT), X-ray, positron-emission tomography (PET), single-photon emission computed tomography (SPECT), or infrared imaging. The imaging device may produce 1D, 2D, 3D and/or 4D images.

The terms and expressions 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. Accordingly, the described embodiments are to be considered in all respects as only illustrative and not restrictive.