Therapeutic ultrasound treatment system for opening the blood-brain barrier and ultrasound control method for the therapeutic ultrasound treatment system for opening the blood-brain barrier

Abstract

The ultrasound control method of the therapeutic ultrasound processing system for opening the blood-brain barrier of the present invention includes the steps of setting output conditions for outputting ultrasound energy to an acoustic cavitation-generating substance administered to a subject, outputting ultrasound energy to the subject according to the output conditions, receiving an acoustic signal generated by the acoustic cavitation phenomenon of the acoustic cavitation-generating substance, analyzing the acoustic signal to determine whether or not predetermined control conditions are satisfied, and outputting ultrasound energy by either stopping the output of ultrasound energy or adjusting at least one of the output conditions of ultrasound energy, namely, the duty cycle, the number of stimulation pulses per predetermined time, the pulse repetition frequency per predetermined time, and the applied voltage, depending on whether or not the predetermined control conditions are satisfied.

Description

[Technical Field]

[0001] The present invention relates to a therapeutic ultrasound processing system for opening the blood-brain barrier, and an ultrasound control method for the therapeutic ultrasound processing system.

[0002] This invention was funded by the Ministry of Health and Welfare's "Drug Delivery Therapeutic Technology Development Project" (Project ID: 1465040354, Project ID: HI23C0344000023, Research Project Title: Development of Technology for Brain Drug Delivery Using Extracorporeal Ultrasound and Drug Carriers, Project Management Agency: Korea Health Industry Development Agency, Project Executing Agency: Newmass Co., Ltd., Research Period: April 1, 2023 to December 31, 2027, Contribution Rate: 50%) and the Ministry of Small and Medium Enterprises' "Startup Growth Technology Development (Materials, Parts, and Equipment Accounting)" ) (Project ID: 1425179650, Project ID: 00261874, Research Project Title: Development of Patient-Customized Multi-Channel Focused Ultrasound Device for Blood-Brain Barrier Modulation, Project Management Agency: Small and Medium Business Technology Information Agency, Project Executing Agency: Newmass Co., Ltd., Research Period: June 1, 2023 - May 31, 2026, Contribution Rate: 50%). The Korean government has no proprietary interest in any aspect of this invention. [Background technology]

[0003] The blood-brain barrier (BBB) ​​is a physiological barrier present in the cerebral blood vessels that serves to isolate and protect the brain and central nervous system. This barrier serves to separate nerve cells in the brain from the blood.

[0004] On the other hand, the inability of brain disease therapeutic drugs to penetrate the brain due to the blood-brain barrier is a significant issue related to many neurological and medical problems. While the blood-brain barrier serves to separate blood from brain tissue to protect and keep the brain safe, it also makes it difficult to effectively deliver brain disease therapeutic drugs.

[0005] In recent years, various technologies have been developed and researched to deliver drugs to treat brain diseases across the blood-brain barrier. However, these technologies have various limitations, such as limited or temporary effects, safety issues, and difficulty in achieving precise delivery to the target site.

[0006] Therefore, there is a need for a technology that can efficiently and safely control the opening of the blood-brain barrier, overcome the above-mentioned problems, and effectively deliver therapeutic drugs for brain diseases into the brain. Summary of the Invention [Problem to be solved by the invention]

[0007] The technical problem to be solved by the present invention is to analyze in real time the acoustic signals generated from the movement activity of microbubbles injected into blood vessels to open the blood-brain barrier, which are generated by the interaction between the microbubbles and the ultrasound stimulus irradiated to the target brain region, and to control the ultrasound irradiation parameters.

[0008] This allows the degree of blood-brain barrier opening to be controlled in real time, making it possible to safely open the blood-brain barrier while minimizing damage to surrounding tissues. [Means for solving the problem]

[0009] An ultrasound control method for a therapeutic ultrasound processing system for opening the blood-brain barrier according to one embodiment of the present invention includes: (a) setting, by at least one processor, output conditions for outputting ultrasonic energy to an acoustic cavitation-generating substance administered to a subject; (b) outputting ultrasonic energy to the target object according to the output conditions by at least one processor; (c) receiving, by at least one processor, an acoustic signal generated by the acoustic cavitation phenomenon of the acoustic cavitation material; (d) analyzing, with at least one processor, the acoustic signal to determine whether it satisfies a predetermined control condition; and (e) outputting the ultrasonic energy by adjusting, by at least one processor, at least one of the output conditions of the ultrasonic energy, namely, the duty cycle, the number of stimulation pulses per predetermined time, the pulse repetition frequency per predetermined time, and the applied voltage, depending on whether the control condition is satisfied.

[0010] Furthermore, the step (a) according to this embodiment includes: a step (a-1) of setting an initial center frequency or an initial applied voltage among the output conditions; The method may include a step (a-2) of setting at least one of an initial duty cycle, an initial number of stimulation pulses per predetermined time, and an initial pulse repetition frequency per predetermined time among the output conditions.

[0011] Furthermore, the step (b) according to this embodiment includes: Outputting the ultrasonic energy having at least one of the set initial center frequency, initial duty cycle, initial stimulation pulse number, and initial pulse repetition frequency, or the ultrasonic energy generated by applying the set initial applied voltage, to the target body; Furthermore, the step (c) according to this embodiment includes: The method may include receiving the acoustic signal from the acoustic cavitation generating substance administered to the subject.

[0012] Furthermore, the step (d) according to this embodiment includes: a step (d-1) of frequency-analyzing the acoustic signal; (d-2) determining whether broadband noise is present in the frequency analysis; (d-3) analyzing the value of sub-harmonics or ultra-harmonics in the frequency analysis; and (d-4) analyzing the value of the subharmonic or the value of the ultraharmonic to determine whether a predetermined first threshold is reached.

[0013] Furthermore, the step (e) according to this embodiment includes: (e-1) stopping the output of the ultrasonic energy when the broadband noise is present; (e-2) stopping the output of the ultrasonic energy when the value of the subharmonic or the value of the ultraharmonic reaches a predetermined first threshold; The method may include a step (e-3) of analyzing the values ​​of harmonics in the frequency analysis when the broadband noise is not present and the values ​​of the subharmonics and the ultraharmonics do not reach the first threshold.

[0014] Furthermore, the step (e-3) according to this embodiment is (e-3-1) determining whether the value of the harmonics reaches a predetermined second threshold; If the second threshold is not reached, the step (e-3-2) of adjusting at least one of the duty cycle, the number of stimulation pulses per predetermined time, the pulse repetition frequency per predetermined time, and the applied voltage may be included.

[0015] Furthermore, the step (e-3-1) according to this embodiment is If the second threshold is not reached, increasing at least one of the duty cycle, the number of stimulation pulses per predetermined time, the pulse repetition frequency per predetermined time, and the applied voltage to increase the intensity of the ultrasonic energy and output it (e-3-1-1); When the second threshold is reached, the method may include a step (e-3-1-2) of determining whether the subharmonic or ultraharmonic is present, or whether the value of the subharmonic or the value of the ultraharmonic reaches a predetermined third threshold.

[0016] Furthermore, the step (e-3-1-2) according to this embodiment is When the subharmonic and the ultraharmonic do not exist or the value of the subharmonic and the value of the ultraharmonic do not reach the third threshold, increasing at least one of the duty cycle, the number of stimulation pulses per predetermined time, the pulse repetition frequency per predetermined time, and the applied voltage, and outputting the ultrasonic energy with an increased intensity (e-3-1-2-1); and (e-3-1-2-2) determining whether the subharmonic or ultraharmonic is present, or whether a predetermined treatment time or output time has been reached when the value of the subharmonic or the value of the ultraharmonic reaches the third threshold.

[0017] Furthermore, the step (e-3-1-2-2) according to this embodiment is When the treatment time is reached, a step (e-3-1-2-2-1) of stopping the output of the ultrasonic energy; If the treatment time is not reached, the step (e-3-1-2-2-2) of reducing the intensity of the ultrasonic energy by reducing at least one of the duty cycle, the number of stimulation pulses per predetermined time, the pulse repetition frequency, and the applied voltage is included.

[0018] Furthermore, the step (e-3-1-2-2) according to this embodiment is When the output time is reached, a step (e-3-1-2-2-3) of stopping the output of the ultrasonic energy; If the output time is not reached, the step (e-3-1-2-2-4) of reducing the ultrasonic energy by reducing at least one of the duty cycle, the number of stimulation pulses per predetermined time, the pulse repetition frequency, and the applied voltage may be included.

[0019] According to this embodiment, a computer-readable recording medium having a program recorded thereon for executing an ultrasound control method for a therapeutic ultrasound processing system for opening the blood-brain barrier may be included.

[0020] Furthermore, the therapeutic ultrasound processing system for opening the blood-brain barrier according to this embodiment may include a signal generating condition setting unit that sets output conditions for outputting ultrasonic energy to an acoustic cavitation generating substance administered to a subject; a signal generating unit that controls the output of ultrasonic energy to the subject according to the output conditions; a received signal collecting unit that receives an acoustic signal generated by the acoustic cavitation phenomenon of the acoustic cavitation generating substance; a frequency analyzing unit that analyzes the acoustic signal and determines whether or not predetermined control conditions are met; and a signal control unit that stops the output of the ultrasonic energy or adjusts at least one of the output conditions of the ultrasonic energy, namely, the duty cycle, the number of stimulation pulses per predetermined time, the pulse repetition frequency per predetermined time, and the applied voltage, depending on whether or not the control conditions are met. [Effects of the Invention]

[0021] The therapeutic ultrasound processing system for opening the blood-brain barrier and the method for controlling the therapeutic ultrasound processing system according to the present invention can minimize damage to the tissues surrounding the blood-brain barrier and safely open the blood-brain barrier by controlling the output of ultrasound energy based on acoustic signals received from microbubbles located near the blood-brain barrier. [Brief explanation of the drawings]

[0022] [Figure 1]FIG. 1 is a diagram illustrating a therapeutic ultrasound system for opening the blood-brain barrier according to one embodiment of the present invention. [Figure 2A] FIG. 2 is a flow chart of an ultrasound control method (or closed-loop control) of a therapeutic ultrasound processing system for opening the blood-brain barrier according to one embodiment of the present invention. [Figure 2B] FIG. 10 is a graph showing the relationship between frequency and received acoustic intensity. [Figure 3A] FIG. 3A is a diagram illustrating ultrasonic energy with varying duty cycle according to one embodiment of the present invention. [Figure 3B] FIG. 3B is a diagram illustrating ultrasonic energy with varying applied voltage according to one embodiment of the present invention. [Figure 3C] FIG. 3C is a diagram illustrating ultrasound energy with varying number of stimulation pulses per time period according to one embodiment of the present invention. [Figure 3D] FIG. 3D is a diagram illustrating ultrasound energy over time with varying pulse repetition frequency according to one embodiment of the present invention. [Figure 4] FIG. 4 is a diagram showing the analysis results of an acoustic signal according to a change in the number of cycles in accordance with an embodiment of the present invention. [Figure 5] FIG. 5 is a diagram showing the analysis results of an acoustic signal based on closed-loop control according to an embodiment of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0023] Hereinafter, with reference to the accompanying drawings, detailed descriptions will be given of embodiments of the present invention so that those skilled in the art can easily carry out the present invention. However, the present invention is not limited to the embodiments described below, and various modifications and alterations are possible.

[0024] In order to clearly explain the present invention, parts that are not relevant to the description will be omitted, and the same or similar components will be denoted by the same reference numerals throughout the specification. Therefore, the same reference numerals may be applied to other drawings.

[0025] Furthermore, the size and thickness of each component shown in the drawings are arbitrarily shown for the convenience of explanation, and the present invention is not necessarily limited to those shown in the drawings. In the drawings, thickness may be exaggerated to clearly show multiple layers and regions.

[0026] Furthermore, in the following description, when the term "identical" is used, it may also mean "substantially identical." In other words, it means an identity that can be recognized as identical by a person skilled in the art. In other expressions, "substantially" may also be omitted.

[0027] Furthermore, in the following description, when a configuration is described as "including" other components, it does not mean that the other components are excluded, but that the other components may further be included, unless otherwise specified. A "unit" as used in this specification is a unit that processes at least one function or operation, and may refer to, for example, a software, FPGA, or hardware component. The functions provided by a "unit" may be performed separately by multiple components or integrated with other additional components. The "unit" in this specification is not necessarily limited to software or hardware, and may be configured on an addressable recording medium or configured to be executed by one or more processors.

[0028] Hereinafter, embodiments of the present invention will be described in detail with reference to the drawings.

[0029] Fig. 1 is a diagram showing a therapeutic ultrasound processing system for opening the blood-brain barrier according to an embodiment of the present invention, and Fig. 2 is a flowchart showing an ultrasound control method for the therapeutic ultrasound processing system for opening the blood-brain barrier according to an embodiment of the present invention.

[0030] The following description will be given with reference to both FIG. 1 and FIG. 2A.

[0031] A therapeutic ultrasound processing system 1 for opening the blood-brain barrier according to one embodiment of the present invention may include a signal generation condition setting unit 10, a signal generating unit 11, a signal collecting unit 12, a frequency analysis unit 13, and a signal control unit 14.

[0032] However, it goes without saying that the therapeutic ultrasound processing system 1 for opening the blood-brain barrier may be configured with fewer or more components than those shown in Figure 1.

[0033] For example, the therapeutic ultrasound processing system 1 for opening the blood-brain barrier may further include a power supply unit (not shown) connected to the therapeutic ultrasound processing system 1 for opening the blood-brain barrier and supplying power, an output time or treatment time control unit (not shown) for setting or controlling the output time or treatment time of the ultrasound energy, a piezoelectric element (not shown) for receiving an electrical signal, converting it into ultrasound energy and outputting it, or receiving ultrasound energy and converting it into an electrical signal, a matching circuit (not shown) for adjusting the resonant (or center) frequency so that ultrasound energy is output at any resonant frequency set by the user, and a display unit (or display device, not shown) on which the results of the frequency analysis can be visually confirmed.

[0034] The condition setting unit 10, the signal generating unit 11, the signal collecting unit 12, the frequency analyzing unit 13, and the signal control unit 14 can each be driven by at least one processor.

[0035] In step (a), the signal generation condition setting unit 10 can set output conditions for outputting ultrasonic energy to the acoustic cavitation generating substance administered to the subject.

[0036] Specifically, an acoustic cavitation generating substance (for example, microbubbles) may be injected into the subject in advance.

[0037] At least one processor that drives the signal generation condition setting unit 10 can set the output conditions of the ultrasonic energy output by the piezoelectric element.

[0038] For example, the output conditions may be at least one of the duty cycle of the ultrasonic energy, the number of stimulation pulses per predetermined time, the pulse repetition frequency (PRF) per predetermined time, and the applied voltage applied to the piezoelectric element.

[0039] In step (a-1), the at least one processor can set an initial center frequency of the ultrasonic energy or an initial applied voltage to be applied to the piezoelectric element. In step (a-2), the at least one processor can set at least one of an initial duty cycle of the ultrasonic energy, a predetermined number of initial stimulation pulses, and an initial pulse repetition frequency per predetermined time.

[0040] In step (b), the signal generating unit 11 can be controlled so as to output ultrasonic energy that satisfies the output condition to the target object.

[0041] Specifically, at least one processor that drives the signal generating unit 11 can provide the electrical signal to the piezoelectric element so as to output ultrasonic energy having at least one of a set initial center frequency, an initial duty cycle, an initial stimulation pulse number, and an initial pulse repetition frequency to the acoustic cavitation generating substance administered to the subject.

[0042] In addition, at least one processor that drives the signal generating unit 11 can provide an electrical signal having a set initial applied voltage to the piezoelectric element, thereby controlling the piezoelectric element to output the ultrasonic energy to the acoustic cavitation generating material.

[0043] At this time, the microbubbles, which are the acoustic cavitation generating substance, can be located near the blood-brain barrier inside the subject, and by controlling the signal generating unit 11, the piezoelectric element can output ultrasonic energy to the microbubbles located near the blood-brain barrier (or a target site in the brain).

[0044] In step (c), the signal collecting unit 12 can receive an acoustic signal generated by the acoustic cavitation phenomenon of the acoustic cavitation substance.

[0045] Specifically, when ultrasonic energy is applied to an acoustic cavitation generating material, the material vibrates due to a resonance phenomenon, generating an acoustic signal. At this time, the received acoustic signal can be detected by a receiving ultrasonic piezoelectric element and converted into an electrical signal.

[0046] That is, the piezoelectric element that outputs ultrasonic energy (or the piezoelectric element for output) and the piezoelectric element that receives ultrasonic energy (or the piezoelectric element for reception) may be the same as or different from each other.

[0047] At least one processor driving the signal acquisition unit 12 can convert the signal into an electrical signal.

[0048] In step (d), the frequency analysis unit 13 can analyze the received acoustic signal to determine whether or not it satisfies a predetermined control condition.

[0049] In step (d), the frequency analysis unit 13 analyzes the received acoustic signal and can determine that the control condition is met even if at least one of the steps (d-2, d-3, d-4, e-3-1, e-3-1-2, e-3-1-2-2) described below is met.

[0050] Specifically, in step (d-1), at least one processor constituting the frequency analysis unit 13 can analyze (or frequency analyze) the received acoustic signal. At this time, a technique such as Fourier transform can be used, but the present invention is not limited to this. In other words, various techniques can be used to analyze the acoustic signal.

[0051] In step (d-2), the at least one processor may determine whether broadband noise is present in the frequency analysis.

[0052] Broadband noise refers to noise or noise occurring over a very wide frequency range. When broadband noise is present, it can be determined that microbubbles located near the blood-brain barrier have burst due to ultrasound irradiation, causing cavitation.

[0053] That is, the at least one processor can determine whether broadband noise is present, which maintains a constant level over a relatively wide frequency range in the frequency spectrum and exhibits a flat shape, or whether broadband noise is present in a form in which the intensity of the frequency spectrum generally increases while exhibiting a flat shape.

[0054] In step (d-3), the at least one processor may analyze subharmonic values ​​or ultraharmonic values ​​in the frequency analysis.

[0055] Specifically, the at least one processor can determine through frequency analysis whether subharmonics, i.e., a resonant frequency that is half the resonant frequency of the ultrasonic energy output from the piezoelectric element, are detected in the received acoustic signal due to the activity of the microbubbles.

[0056] The at least one processor can also determine through frequency analysis whether or not a received acoustic signal component generated by the activity of a microbubble is detected at an ultraharmonic, i.e., a frequency that is n / 2 times (but is a natural number other than 1) the resonant frequency of the ultrasonic energy output from the piezoelectric element.

[0057] In step (d-4), the at least one processor can determine whether the subharmonic value or the ultraharmonic value reaches a predetermined first threshold. If the subharmonic value or the ultraharmonic value exceeds the predetermined first threshold, it can be determined that a cavitation phenomenon is occurring in which microbubbles located near the blood-brain barrier are vibrating strongly due to ultrasound irradiation or are about to burst.

[0058] In this case, the first threshold value may be set in advance by the user, or may be set to any one of various values.

[0059] In step (e), the signal control unit 14 can stop the output of ultrasonic energy depending on whether or not predetermined control conditions are met, or can adjust at least one of the output conditions, namely, the duty cycle, the number of stimulation pulses per predetermined time, the pulse repetition frequency per predetermined time, and the applied voltage.

[0060] Specifically, in step (e-1), at least one processor that drives the signal control unit 14 can perform control to stop the output of ultrasonic energy when broadband noise is present in the frequency analysis.

[0061] In step (e-2), the at least one processor may be controlled to stop outputting ultrasonic energy when the value of the subharmonic or the value of the ultraharmonic reaches a predetermined first threshold.

[0062] That is, the at least one processor can determine that excessive acoustic cavitation (or violent bubble vibration) has occurred in the acoustic cavitation generating material if the frequency analysis reveals that broadband noise is present or that the subharmonic or ultraharmonic values ​​reach a predetermined first threshold.

[0063] The at least one processor can control the piezoelectric element to stop outputting ultrasonic energy, thereby minimizing damage to tissue surrounding the blood-brain barrier.

[0064] That is, the at least one processor stops outputting ultrasonic energy because the acoustic cavitation material (or microbubbles) may burst.

[0065] In step (e-3), the at least one processor may additionally analyze harmonic values ​​in the frequency analysis if broadband noise is not present and the subharmonic values ​​and ultraharmonic values ​​do not reach a predetermined first threshold.

[0066] That is, at least one processor can detect received acoustic signal components generated by the activity of microbubbles through frequency analysis at harmonics, frequencies n times (where n is a natural number) the resonant frequency of the ultrasonic energy output from the piezoelectric element, and analyze the values.

[0067] In step (e-3-1), the at least one processor may determine whether the value of the harmonics reaches a predetermined second threshold, which may be preset by a user or may be set to one of a variety of values.

[0068] In step (e-3-2), the at least one processor may adjust at least one of the output conditions, including the duty cycle, the number of stimulation pulses per predetermined time, the pulse repetition frequency per predetermined time, and the applied voltage, if the harmonic value does not reach a predetermined second threshold.

[0069] For example, in step (e-3-1-1), the at least one processor may increase the applied voltage to output ultrasonic energy at a higher intensity if the value of the harmonics does not reach a predetermined second threshold.

[0070] That is, if the frequency analysis results in the value of harmonics not reaching a predetermined second threshold, the at least one processor can determine that excessive acoustic cavitation is not occurring in the acoustic cavitation generating material (or that safe bubble vibrations or vigorous bubble vibrations are occurring).

[0071] The at least one processor may continuously or intermittently increase the applied voltage without decreasing it to output an increased intensity of ultrasound energy to open the blood-brain barrier.

[0072] Additionally, the at least one processor may increase the duty cycle, the number of stimulation pulses per predetermined time, and the pulse repetition frequency per predetermined time to output ultrasonic energy at a higher intensity if the harmonic value does not reach a predetermined second threshold.

[0073] The specific details are the same as or similar to the increase in applied voltage described above, so a duplicate description will be omitted.

[0074] This allows the blood-brain barrier to be safely opened.

[0075] In step (e-3-1-2), the at least one processor can determine through frequency analysis whether a subharmonic or ultraharmonic is present when the harmonic value reaches a predetermined second threshold, or whether the subharmonic value or ultraharmonic value reaches a predetermined third threshold.

[0076] In this case, the third threshold may be set in advance by the user, or may be set to any one of various values.

[0077] In step (e-3-1-2-1), the at least one processor can increase at least one of the duty cycle, the predetermined number of stimulation pulses, the predetermined pulse repetition frequency, and the applied voltage to output ultrasonic energy at an increased intensity when subharmonics and ultraharmonics are not present or the values ​​of the subharmonics and ultraharmonics do not reach a predetermined third threshold.

[0078] That is, the at least one processor can determine that excessive acoustic cavitation (or violent bubble vibrations) is not occurring in the acoustic cavitation generating material if the frequency analysis results in the absence of subharmonics and ultraharmonics or the values ​​of the subharmonics and ultraharmonics do not reach a predetermined third threshold.

[0079] The at least one processor can increase at least one or more of the duty cycle, the predetermined number of stimulation pulses, the predetermined pulse repetition frequency, and the applied voltage to output an increased intensity of the ultrasound energy in order to open the blood-brain barrier.

[0080] This allows the blood-brain barrier to be opened stably.

[0081] In step (e-3-1-2-2), the at least one processor may determine whether a subharmonic or ultraharmonic is present, or whether a predetermined treatment time or output time has been reached when the subharmonic value or ultraharmonic value reaches a predetermined third threshold.

[0082] In this case, the predetermined treatment time or output time may be preset by the user, or may be set to any one of a variety of times.

[0083] In step (e-3-1-2-2-1), the at least one processor can stop outputting ultrasonic energy when a predetermined treatment time is reached. Also, in step (e-3-1-2-2-3), the at least one processor can stop outputting ultrasonic energy when a predetermined output time is reached.

[0084] In step (e-3-1-2-2-2), if the predetermined treatment time is not reached, the at least one processor can reduce the intensity of the ultrasonic energy and output it by reducing at least one of the duty cycle, the number of stimulation pulses per predetermined time, the predetermined pulse repetition frequency, and the applied voltage.

[0085] In addition, in step (e-3-1-2-2-4), if the predetermined output time is not reached, the at least one processor can reduce the intensity of the ultrasonic energy and output it by reducing at least one of the duty cycle, the number of stimulation pulses per predetermined time, the predetermined pulse repetition frequency, and the applied voltage.

[0086] That is, if the predetermined treatment time has not been reached or if the predetermined output time has not been reached, the at least one processor can output the ultrasound energy at a reduced intensity to safely open the blood-brain barrier.

[0087] Referring to FIG. 2B, the first to third thresholds each have a predetermined value, and the magnitude (or intensity) of the third threshold is smaller than the magnitude (or intensity) of the first threshold, and the magnitude (or intensity) of the second threshold is smaller than the magnitude (or intensity) of the third threshold, but the present invention is not limited thereto.

[0088] That is, as described above, the first to third threshold magnitudes may be set to be different from each other or the same from each other depending on the user's settings, and the set first to third threshold magnitudes are compared and analyzed with the subharmonic value, ultraharmonic value, or harmonic value, and based on this, the intensity of the ultrasonic energy can be adjusted and output according to the closed-loop control of Figure 2A.

[0089] As described above, the therapeutic ultrasound processing system 1 for opening the blood-brain barrier according to one embodiment of the present invention can set the output conditions of ultrasound energy to open the blood-brain barrier and output the ultrasound energy to an acoustic cavitation generating substance located near the blood-brain barrier.

[0090] Additionally, acoustic signals generated by the acoustic cavitation phenomenon of the acoustic cavitation material can be received (or collected) in real time and compared with control conditions for adjusting the ultrasonic energy.

[0091] That is, based on the comparison result with the control condition, at least one of the duty cycle of the ultrasonic energy, the number of stimulation pulses per predetermined time, the predetermined pulse repetition frequency, or the applied voltage applied to the piezoelectric element can be adjusted.

[0092] This minimizes damage to the tissue surrounding the blood-brain barrier and enables the blood-brain barrier to be opened stably.

[0093] FIG. 3A is a diagram illustrating ultrasonic energy with varying duty cycle according to one embodiment of the present invention.

[0094] Duty cycle refers to the ratio of the total time that a pulse lasts for a specific time (t) that the pulse is continuously operating.

[0095] For example, in Figure 3A, if the duty cycle is 100%, the pulsed ultrasonic energy continues for the entire specified time (t), whereas if the duty cycle is 50%, the pulsed ultrasonic energy continues for only half (t / 2) of the specified time (t).

[0096] As the duty cycle increases, the ratio of the total duration of the pulse vibration within a specific time (t) increases, and the intensity of the ultrasonic energy can be increased. As the duty cycle decreases, the ratio of the total duration of the pulse vibration within a specific time (t) decreases, and the intensity of the ultrasonic energy can be decreased.

[0097] FIG. 3B is a diagram illustrating ultrasonic energy with varying applied voltage according to one embodiment of the present invention.

[0098] 3B, as the applied voltage increases (e.g., 10V, 20V, ... nV, where n is an integer), the amplitude of the ultrasonic energy output over a specific time (t) increases, and the intensity of the ultrasonic energy increases. Conversely, as the applied voltage decreases (e.g., nV, ... 20V, 10V), the amplitude of the ultrasonic energy output over a specific time (t) decreases, and the intensity of the ultrasonic energy decreases.

[0099] FIG. 3C is a diagram illustrating ultrasound energy with varying number of stimulation pulses per time period according to one embodiment of the present invention.

[0100] The number of stimulation pulses per time period refers to the number of pulses of ultrasonic energy vibrating over a particular time period (t).

[0101] As the number of stimulation pulses per given time increases, the number of pulses of ultrasonic energy vibrating over a specific time (t) increases, and the intensity of the ultrasonic energy can increase.

[0102] As the number of stimulation pulses per given time decreases, the number of pulses of ultrasonic energy vibrating over a specific time (t) decreases, and the intensity of the ultrasonic energy can decrease.

[0103] FIG. 3D is a diagram illustrating ultrasound energy over time with varying pulse repetition frequency according to one embodiment of the present invention.

[0104] The time-dependent pulse repetition frequency refers to the frequency at which ultrasonic energy is repeated over a particular time period (t).

[0105] As the pulse repetition frequency per given time increases, the frequency of the ultrasonic energy that is repeated at a particular time (t) increases. As the pulse repetition frequency per given time decreases, the frequency of the ultrasonic energy that is repeated at a particular time (t) decreases.

[0106] That is, as the pulse repetition frequency per given time increases, the number of periods (t1, t2, ..., t n ) becomes shorter. This means that the vibration period of the ultrasonic energy based on a specific time (t) becomes shorter, and the number of vibration repetitions of the ultrasonic energy increases.

[0107] On the other hand, the smaller the pulse repetition frequency per given time, the shorter the period (t n , ..., t2, t1) becomes longer. This means that the vibration period of the ultrasonic energy based on a specific time (t) becomes longer, and the number of vibration repetitions of the ultrasonic energy decreases.

[0108] As described above, at least one processor driving the signal generation condition setting unit 10 according to one embodiment of the present invention can receive a signal (or control signal) regarding whether or not the control conditions are met from at least one processor driving the signal control unit 14 in real time during the output of ultrasonic energy.

[0109] Based on the control signal, the signal generation condition setting unit 10 can generate a signal for adjusting the output conditions (duty cycle, number of stimulation pulses per predetermined time, pulse repetition frequency per predetermined time, and applied voltage) described above in Figures 3A to 3D and provide it to the signal generating unit 11.

[0110] The signal generating unit 11 controls the piezoelectric element based on the signal to output ultrasonic energy having the output conditions, thereby minimizing damage to the tissues surrounding the blood-brain barrier and enabling control to maximize the effect of opening the blood-brain barrier.

[0111] FIG. 4 is a diagram showing the analysis results of an acoustic signal according to an embodiment of the present invention, with the number of stimulation pulses being changed.

[0112] When outputting ultrasonic energy by adjusting the duty cycle or pulse repetition frequency per time among the output conditions, the output is the same as or similar to when outputting ultrasonic energy by adjusting the number of stimulation pulses (or the number of stimulation pulses per time) described below, and therefore duplicate descriptions will be omitted.

[0113] FIG. 4 shows the results of receiving and analyzing the acoustic signals generated by the acoustic cavitation phenomenon of the acoustic cavitation generating material when pulses of ultrasonic energy with specific stimulation pulse numbers (1500 cycles, 2000 cycles, 2500 cycles) are applied during a predetermined time.

[0114] When 1500 pulse cycles are output to an acoustic cavitation generating material within a specified time, analysis confirms that harmonic components (frequency: 500 kHz) of the resonant frequency (250 kHz) of the output ultrasonic energy are detected.

[0115] On the other hand, it can be seen that as the number of pulses increases (2000 cycles, 2500 cycles, ... in Figure 4), the amplitude of the electrical signal corresponding to the harmonic components increases (53db, 56db, 59db, ...).

[0116] In other words, if the electrical signal corresponding to the harmonic component does not reach a certain threshold, the acoustic cavitation generating substance located near the blood-brain barrier exhibits a stable vibration phenomenon due to ultrasonic energy, and at least one processor can determine that the blood-brain barrier is in an open state.

[0117] At this time, the at least one processor can increase the intensity of the ultrasonic energy output by gradually or temporarily increasing the voltage applied to the piezoelectric element, increasing the duty cycle, or decreasing the pulse repetition frequency, as described above with reference to Figures 1 and 2. This can stably open the blood-brain barrier.

[0118] On the other hand, when a pulse of 1500 cycles is output to an acoustic cavitation generating material during a specified time, the analysis results show that no subharmonic components (frequency: 125 kHz) or ultraharmonic components (frequency: 375 kHz) of the resonant frequency (250 kHz) of the output ultrasonic energy are detected.

[0119] As the number of pulses increases (2000 cycles, 2500 cycles, ... in Figure 4, or as the number of stimulation pulses per given time increases), the amplitude of the electrical signal corresponding to the subharmonic or ultraharmonic component increases (0db → 10db, 0db → 14db).

[0120] At this time, if the electrical signals corresponding to the subharmonic or ultraharmonic components do not reach a specific threshold, it can be determined that the acoustic cavitation-generating substance located near the blood-brain barrier is exhibiting an active vibration phenomenon due to ultrasonic energy, and that the blood-brain barrier is in an open state.

[0121] As described above with reference to Figures 1 and 2, at least one processor can increase the intensity of the ultrasonic energy by adjusting (or increasing) at least one of the output conditions of the ultrasonic energy output from the piezoelectric element, namely, the duty cycle, the number of stimulation pulses per time, the pulse repetition frequency per time, and the applied voltage, thereby enabling stable opening of the blood-brain barrier.

[0122] However, when the magnitude of the electrical signal corresponding to the subharmonic or ultraharmonic component reaches a certain threshold, the acoustic cavitation-generating substance located near the blood-brain barrier exhibits a violent vibration phenomenon due to the ultrasonic energy, which may damage the tissues surrounding the blood-brain barrier.

[0123] 1 and 2, the at least one processor can reduce the intensity of the ultrasonic energy by adjusting (or decreasing) at least one of the output conditions of the ultrasonic energy output from the piezoelectric element, namely, the duty cycle, the number of stimulation pulses per time, the pulse repetition frequency per time, and the applied voltage. This allows the blood-brain barrier to be stably opened without damaging the tissues surrounding the blood-brain barrier.

[0124] On the other hand, when broadband noise is detected, signal analysis shows a flat shape while maintaining a constant level (magnitude) in a relatively wide frequency range, and it can be confirmed that the level (magnitude) appears to be generally higher than that of 1500 cycles, 2000 cycles, and 2500 cycles.

[0125] In this case, microbubbles located near the blood-brain barrier burst, indicating the occurrence of a cavitation phenomenon, which may damage the tissues surrounding the blood-brain barrier.

[0126] In this case, as described above with reference to FIGS. 1 and 2, the at least one processor can perform control to stop the output of ultrasonic energy.

[0127] FIG. 5 is a diagram showing the analysis results of an acoustic signal based on closed-loop control according to an embodiment of the present invention.

[0128] 5, the graph line at the top represents the transition of the voltage applied to the piezoelectric element, and the solid line below it represents the analysis result of the acoustic signal generated by the acoustic cavitation phenomenon of the acoustic cavitation generating material.

[0129] It can be seen that the change in the graph of the acoustic signal analysis over time follows the change in the graph of the applied voltage. That is, as the applied voltage applied to the piezoelectric element increases, the strength of the received acoustic signal tends to increase, and as the applied voltage decreases, the strength of the received acoustic signal tends to decrease.

[0130] On the other hand, after a certain time (20 seconds) has elapsed since the voltage was applied, it can be seen that the graph obtained by analyzing the acoustic signal is located only between the thresholds Max and Min.

[0131] This means that the ultrasound control method of the therapeutic ultrasound processing system for opening the blood-brain barrier of the present invention controls the intensity of the ultrasound energy within a range (threshold Min to threshold Max) that allows stable opening of the blood-brain barrier without bursting the microbubbles.

[0132] In other words, the therapeutic ultrasound processing system for opening the blood-brain barrier and the control method of the therapeutic ultrasound processing system according to the present invention can minimize damage to the tissues surrounding the blood-brain barrier and stably open the blood-brain barrier by controlling the output of ultrasound energy based on acoustic signals received from microbubbles located near the blood-brain barrier.

[0133] The drawings and detailed description of the invention referred to above are merely illustrative of the present invention and are used for the purpose of explaining the present invention, not for limiting the scope of the present invention as defined in the claims. Therefore, a person skilled in the art will understand that various modifications and equivalent alternative embodiments are possible based on these. Therefore, the true technical scope of protection of the present invention should be determined by the technical spirit of the appended claims.

[0134] The embodiments described above may be realized by hardware components, software components, or a combination of hardware and software components. For example, the devices, methods, and components described in the embodiments may be realized using one or more general-purpose or special-purpose computers, such as a processor, a controller, an ALU (Arithmetic Logic Unit), a digital signal processor, a microcomputer, an FPGA (Field Programmable Gate Array), a PLU (Programmable Logic Unit), a microprocessor, or any other device capable of executing and responding to instructions.

[0135] A processing device may execute an operating system and one or more software applications that run on the operating system. The processing device may also access, store, manipulate, process, and generate data in response to the execution of software. For ease of understanding, a processing device may be described as a single processing element; however, those skilled in the art will appreciate that a processing device may include multiple processing elements and / or multiple types of processing elements.

[0136] For example, a processing device may include multiple processors or one processor and one controller. Other processing configurations, such as a parallel processor, are also possible. Software may include computer programs, code, instructions, or a combination of one or more of these, which may configure or instruct a processing device, alone or in combination, to perform desired operations.

[0137] The software and / or data may be embodied in any type of machine, component, physical device, virtual device, or computer storage medium or device to be interpreted by a processing device or to provide instructions or data to a processing device. The software may also be distributed across computer systems connected to a network so that it can be stored or executed in a distributed manner. The software and data may be stored on one or more computer-readable recording media.

[0138] The methods of the present invention may be implemented by various computer means and may be embodied in program instructions and stored on computer-readable media, which may include, alone or in combination with program instructions, data files, data structures, and the like. The program instructions stored on the media may be those specially designed and constructed for the present invention, or they may be well known and available to those skilled in the computer software arts.

[0139] Examples of computer-readable recording media include magnetic media such as hard disks, floppy disks, and magnetic tapes, optical media such as CD-ROMs and DVDs, and hardware devices specially configured to record and execute program instructions, such as ROMs, RAMs, and flash memories. Examples of program instructions include machine language codes generated by a compiler, as well as high-level language codes that can be executed by a computer using an interpreter or the like.

[0140] The hardware device may be configured to operate as one or more software modules to perform the operations of the present embodiment, and vice versa, software modules may be implemented as hardware devices.

[0141] While the examples have been described above with reference to limited embodiments and drawings, those skilled in the art will appreciate that various modifications and variations are possible from the above description. For example, the techniques described may be performed in an order other than that described, or the components of the described systems, structures, devices, circuits, etc. may be combined or combined in a manner other than that described, and other components or equivalents may be substituted or substituted and still obtain suitable results. Accordingly, other implementations, other embodiments, and equivalents of the claims are intended to be within the scope of the following claims.

Claims

1. 1. An ultrasound control method for a therapeutic ultrasound processing system for opening the blood-brain barrier driven by at least one processor, comprising: (a) setting, by at least one processor, output conditions for outputting ultrasonic energy to an acoustic cavitation-generating substance administered to a subject; (b) outputting, by at least one processor, ultrasonic energy to the target object according to the output conditions; (c) receiving, by at least one processor, an acoustic signal resulting from the acoustic cavitation phenomenon of the acoustic cavitation material; (d) analyzing, with at least one processor, the acoustic signal to determine whether it satisfies a predetermined control condition; (e) stopping the output of the ultrasonic energy by at least one processor, or adjusting at least one of the duty cycle, the number of stimulation pulses per predetermined time, the pulse repetition frequency per predetermined time, and the applied voltage among the output conditions of the ultrasonic energy, depending on whether the control condition is satisfied; 10. A method for controlling ultrasound in a therapeutic ultrasound treatment system for opening the blood-brain barrier, comprising:

2. The step (a) a step (a-1) of setting an initial center frequency or an initial applied voltage among the output conditions; Step (a-2) of setting at least one of an initial duty cycle, an initial stimulation pulse number per predetermined time, and an initial pulse repetition frequency per predetermined time among the output conditions; 2. The ultrasound control method of claim 1, comprising:

3. The step (b) Outputting the ultrasonic energy having at least one of the set initial center frequency, initial duty cycle, initial stimulation pulse number, and initial pulse repetition frequency, or the ultrasonic energy generated by applying the set initial applied voltage, to the target body; The step (c) receiving the acoustic signal from the acoustic cavitation-generating substance administered to the subject; 3. The ultrasound control method for a therapeutic ultrasound processing system for opening the blood-brain barrier according to claim 2.

4. The step (d) a step (d-1) of frequency-analyzing the acoustic signal; a step (d-2) of determining whether broadband noise is present in the frequency analysis; A step (d-3) of analyzing subharmonic values ​​or ultraharmonic values ​​in the frequency analysis; a step (d-4) of analyzing the value of the subharmonic or the value of the ultraharmonic to determine whether a predetermined first threshold is reached; 2. The ultrasound control method of claim 1, comprising:

5. The step (e) (e-1) stopping the output of the ultrasonic energy when the broadband noise is present; Step (e-2) of stopping the output of the ultrasonic energy when the value of the subharmonic or the value of the ultraharmonic reaches a predetermined first threshold; (e-3) analyzing the value of harmonics in the frequency analysis when the broadband noise is not present and the value of the subharmonics and the value of the ultraharmonics do not reach the first threshold; 5. The ultrasound control method of claim 4, comprising:

6. The step (e-3) a step (e-3-1) of determining whether the value of the harmonics reaches a predetermined second threshold; If the second threshold is not reached, adjusting at least one of the duty cycle, the number of stimulation pulses per predetermined time, the pulse repetition frequency per predetermined time, and the applied voltage (e-3-2); 6. The ultrasound control method of claim 5, comprising:

7. The step (e-3-1) If the second threshold is not reached, increasing at least one of the duty cycle, the number of stimulation pulses per predetermined time, the pulse repetition frequency per predetermined time, and the applied voltage to increase the intensity of the ultrasonic energy and output it (e-3-1-1); When the second threshold is reached, determining whether the subharmonic or ultraharmonic exists or whether the value of the subharmonic or the value of the ultraharmonic reaches a predetermined third threshold (e-3-1-2); 7. The ultrasound control method of claim 6, comprising:

8. The step (e-3-1-2) When the subharmonic and the ultraharmonic do not exist or the value of the subharmonic and the value of the ultraharmonic do not reach the third threshold, increasing at least one of the duty cycle, the number of stimulation pulses per predetermined time, the pulse repetition frequency per predetermined time, and the applied voltage, and outputting the ultrasonic energy with an increased intensity (e-3-1-2-1); (e-3-1-2-2) determining whether the subharmonic or ultraharmonic exists, or whether a predetermined treatment time or output time has been reached when the value of the subharmonic or the value of the ultraharmonic reaches the third threshold; 8. The ultrasound control method of claim 7, comprising:

9. The step (e-3-1-2-2) When the treatment time is reached, stopping the output of the ultrasonic energy (e-3-1-2-2-1); If the treatment time has not been reached, a step (e-3-1-2-2-2) of reducing the intensity of the ultrasonic energy by reducing at least one of the duty cycle, the number of stimulation pulses per predetermined time, the pulse repetition frequency, and the applied voltage; 9. The ultrasound control method of a therapeutic ultrasound processing system for opening the blood-brain barrier according to claim 8, comprising:

10. The step (e-3-1-2-2) a step (e-3-1-2-2-3) of stopping the output of the ultrasonic energy when the output time is reached; If the output time is not reached, a step (e-3-1-2-2-4) of reducing the ultrasonic energy by reducing at least one of the duty cycle, the number of stimulation pulses per predetermined time, the pulse repetition frequency, and the applied voltage; 9. The ultrasound control method of a therapeutic ultrasound processing system for opening the blood-brain barrier according to claim 8, comprising:

11. 10. A computer-readable recording medium having a program recorded thereon for executing the ultrasound control method of the therapeutic ultrasound processing system for opening the blood-brain barrier according to claim 1.

12. 1. A therapeutic ultrasound treatment system for opening the blood-brain barrier, comprising: a signal generation condition setting unit that sets output conditions for outputting ultrasonic energy to the acoustic cavitation generating substance administered to the subject; a signal generating unit that controls the output of ultrasonic energy to the target object according to the output conditions; a received signal collecting unit for receiving an acoustic signal generated by the acoustic cavitation phenomenon of the acoustic cavitation generating substance; a frequency analysis unit that analyzes the acoustic signal and determines whether a predetermined control condition is satisfied; a signal control unit that stops the output of the ultrasonic energy depending on whether the control condition is satisfied or not, or adjusts at least one of the duty cycle, the number of stimulation pulses per predetermined time, the pulse repetition frequency per predetermined time, and the applied voltage among the output conditions of the ultrasonic energy; 1. A therapeutic sonication system for opening the blood-brain barrier, comprising:

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