Ultrasonic ablation enhanced by bubbles formed from a cluster composition administered to the patient.

Abstract

The present invention provides a method for enhanced ultrasound ablation and compositions for use therewith, comprising: administering to a subject a cluster composition comprising a microbubble component and a microdroplet component; and creating at least one ablation-assist bubble proximate a target region by activating a phase-shift transition of the microdroplet component of the at least one cluster with ultrasound irradiation to create the at least one ablation-assist bubble, wherein the cluster composition comprises at least one cluster; and activating a phase-shift transition of the microdroplet component of the at least one cluster with ultrasound irradiation to create at least one ablation-assist bubble, wherein expansion from the transition of the at least one cluster into the at least one ablation-assist bubble provides a mechanical stress to the target region to assist in ablation on target tissue within the target region.

Description

[Background technology]

[0001] Tissue ablation therapy In tissue ablation therapy, layers of tissue are locally destroyed by exposure to a destructive environment. Ultrasound is well-suited for ablation therapy because it can produce both mechanical and thermal energy in the target area and deliver this energy via pressure waves.

[0002] HIFU High-intensity focused ultrasound (HIFU) induces a destructive effect, leading to direct or indirect cell death within a limited volume of target tissue. There are two mechanisms of action for HIFU: thermal ablation and mechanical tissue destruction. The thermal effect can be high heat, where the tissue temperature rises. Specifically, the thermal effect of HIFU is the heat generated by the absorption of acoustic energy due to a rapid increase in local tissue temperature, leading to instantaneous, irreversible cell death via coagulation necrosis. The mechanical effect is cavitation, where the HIFU sound field interacts with gas bubbles within the target tissue. Cavitation refers to a series of complex phenomena involving the generation, vibration, growth, and collapse of bubbles within a medium.

[0003] The efficacy of HIFU for tissue ablation depends on the frequency of the HIFU sound field and the depth of the target tissue region. For target tissues that are far from the HIFU source or are positioned so that a strong attenuation medium exists between the HIFU source and the target tissue, the HIFU needs to have a lower frequency to be effective, for example, a frequency below 1 MHz. Examples of such target tissues include target tissues inside the skull or target tissues in the central abdomen, such as certain areas of the pancreas or liver. For target tissues on the surface of the body or positioned closer to the HIFU source, the optimal frequency is a higher frequency, for example, a frequency above 10 MHz.

[0004] The length of the HIFU treatment volume can be approximated as being inversely proportional to the HIFU frequency and inversely proportional to the physical size of the HIFU source. Therefore, in order to achieve efficient thermal ablation by HIFU in thin target tissue, which is located far from the HIFU source or positioned so that a strong attenuation medium exists between the HIFU source and the target tissue, the HIFU source needs to be physically larger to reduce the risk of adverse effects associated with depositing excess energy into the volume of surrounding healthy tissue.

[0005] HIFU with microbubble technology Increasing acoustic intensity and / or extending the sonication time can alter treatment outcomes, such as more efficient destruction of larger volume target tumors. However, if the acoustic intensity is too high, there is a risk of excess energy accumulating in the volume of healthy tissue surrounding the target and / or proximal to the HIFU source. This can lead to adverse effects.

[0006] Thermal technologies such as HIFU have primarily been used in conjunction with microbubble technology to reduce damage to surrounding healthy tissue. An example of microbubble technology is pre-formed lipid-coated microbubbles, which have been developed mainly for ultrasound imaging. Lipid-coated microbubbles can be contrast agents for ultrasound imaging due to their compressible gas core, which gives the microbubbles echogenicity and strong absorptiveness in a specific frequency band depending on the microbubble diameter. When irradiated with ultrasound in a HIFU sound field in this frequency band, microbubbles absorb energy from the HIFU sound field more efficiently than the surrounding target tissue, thus lowering the acoustic intensity threshold for ablation, thereby minimizing heat accumulation in the surrounding tissue that can be associated with HIFU.

[0007] Microbubbles can induce additional heating of the target region through vibration and cavitation, and can also generate shock waves, thereby delivering additional thermal energy to the HIFU alone. Therefore, the ablation effect can be enhanced by adding microbubbles proximal to the HIFU target region.

[0008] Microbubbles are injected into the subject and can travel through the subject's circulatory system until they reach the proximal area of ​​the target site. This method can reduce the energy buildup required to achieve tissue ablation, thereby shortening and optimizing procedure time and the incidence of adverse events.

[0009] However, there are several limitations to using conventional microbubbles in combination with thermal ablation techniques. The first limitation is the short circulation time of microbubbles, which is approximately 2-3 minutes. HIFU takes considerably longer to set up and run. The microbubbles are likely to have dissolved and / or dissipated before the HIFU process is carried out. Another limitation is that these tiny microbubbles do not efficiently bind to low-frequency ultrasound, such as the low-frequency ultrasound used in transcranial applications. Yet another limitation is the low spatial selectivity of microbubbles, with their residence time in the target tissue being only a few seconds, which can cause unintended heating in areas far from the target site.

[0010] Therefore, due to the aforementioned limitations of HIFU, and HIFU combined with diagnostic microbubbles, the limitations of ultrasound ablation technology remain unresolved.

[0011] This application solves the above limitations by combining ultrasound technology with Acoustic cluster therapy (ACT) (registered trademark). [Overview of the Initiative]

[0012] According to one aspect of the present invention, a method of enhanced ultrasonic ablation is provided, the method comprising: administering a cluster composition comprising a microbubble component and a microdroplet component to a subject; and activating a phase shift transition of the microdroplet component of at least one cluster by ultrasonic irradiation to create at least one ablation-assisted bubble: a step of creating at least one ablation-assisted bubble proximal to a target region, wherein the cluster composition comprises at least one cluster; and a step of introducing mechanical stress to the target region by expansion from the transition of at least one cluster to at least one ablation-assisted bubble, thereby assisting ablation on target tissue within the target region.

[0013] At least one ablation-assisted bubble may have a diameter of at least 10 micrometers.

[0014] The method further comprises the steps of ultrasonically irradiating at least one ablation-assisted bubble with ultrasound of a predetermined intensity to induce at least one of the following phenomena: energy absorption, deposition, vibration, and cavitation of the ablation-assisted bubble, thereby bringing additional mechanical and / or thermal stress to the target region, thereby assisting ablation on the target tissue within the target region.

[0015] A predetermined ultrasound intensity for ultrasonically irradiating ablation-assisted bubbles can be equal to the intensity for ultrasound ablation without bubble assistance divided by a coefficient of 12 to 24.

[0016] Enhanced ultrasound ablation can be configured to result in a temperature of 30–70 degrees Celsius in the target area with a continuous irradiation time of at least 30 seconds.

[0017] The method further includes the step of using at least one ablation-assisted bubble for real-time imaging of a target region by ultrasonically irradiating at least one ablation-assisted bubble with imaging ultrasound, wherein at least one ablation-assisted bubble is induced as a high-echo spot.

[0018] The method is a step of using subject-specific and application-specific information to plan a particular ultrasound irradiation regime, which may further include a step of the ultrasound plan including at least one of a passive ultrasound plan and an active ultrasound plan.

[0019] Passive ultrasound planning can be based on one or more of the following: physiological information, anatomical structure of the ablation zone, cross-modality imaging and co-registration, and data defining the subject's anatomical structure obtained from the software.

[0020] Active ultrasound planning may include monitoring the ablation zone during the enhancement process for real-time feedback of the ablation zone, and adjusting a specific ultrasound irradiation regime to achieve predetermined parameters in the ablation zone, wherein the monitoring and adjustment processes are performed continuously over a predetermined period of time.

[0021] The steps for monitoring the ablation zone during the enhancement process for real-time feedback of the ablation zone may include at least one of the following: real-time temperature feedback, real-time mechanical feedback, cross-modality imaging and co-registration, real-time monitoring of cluster dynamics and concentration, and real-time monitoring of ablation-assisted bubble dynamics and concentration.

[0022] The step of monitoring a target region including an ablation zone may further include imaging via an image-guided modality, where the image-guided modality includes at least one of magnetic resonance guidance, ultrasonic guidance, computed tomography guidance, optical guidance, thermocouple guidance, and contrast-enhanced ultrasonic guidance.

[0023] The method may further include co-administering a therapeutic agent configured to assist ablation efficacy, where the therapeutic agent is administered pre, and / or simultaneously, and / or separately afterwards to the cluster composition.

[0024] According to a second aspect of the present invention, there is provided an intravenously administrable composition for use in a method of enhancing ablation in a target region, the composition comprising a microbubble / microdroplet cluster composition that forms at least one cluster via electrostatic force, where when the method includes the step of exposing at least one cluster to effective ultrasonic irradiation, each of the at least one cluster is configured to vibrate, expand, and fuse into a single entity to provide an ablation-assisting bubble.

[0025] When the method further includes the step of exposing the resulting ablation-assisting bubble to ultrasonic waves of a predetermined intensity, the ablation-assisting bubble may be configured to vibrate and / or cavitate to induce mechanical stress and / or thermal stress in the target region and increase the ablation efficiency in the target region.

[0026] The resulting ablation-assisting bubble may be configured to induce mechanical stress and / or thermal stress comparable to that induced by direct ultrasonic irradiation of the target region, where the predetermined intensity is equal to the intensity for ultrasonic ablation without bubble assistance divided by a factor of 12 to 24.

[0027] A microbubble / microdroplet cluster composition may be formed from a cluster dispersion of microdroplets having an average diameter of 2-3 μm and stabilized by a lipid membrane having a net positive surface charge, and microbubbles having an average diameter of 2-3 μm and stabilized by a lipid shell having a net negative surface charge.

[0028] The net surface positive charge of a microdroplet and the net surface negative charge of a microbubble can result in an electrostatic force that enables the formation of at least one microbubble / microdroplet cluster.

[0029] The resulting clusters may have a diameter in the range of 4–8 μm.

[0030] The gas in at least one microbubble / microdroplet cluster may contain sulfur hexafluoride, C3-6 perfluorocarbons, or a mixture thereof.

[0031] The oil phase of at least one microbubble / microdroplet cluster may contain partially or completely halogenated hydrocarbons or mixtures thereof.

[0032] A composition according to a second aspect of the present invention may be for use in the treatment of one or more of the following: tumors, space-occupying masses, thrombolysis, and neurological disorders. [Brief explanation of the drawing]

[0033] [Figure 1] A flowchart of the ACT®-enhanced ultrasound ablation method according to the present invention is shown. [Figure 2] This diagram shows the steps involved in the ACT® enhanced ultrasound ablation method. [Figure 3] This graph shows the number of ablation-assisted bubbles generated for different mechanical indices at different frequencies. [Figure 4a] This is a schematic diagram of a first exemplary transducer having a relatively low operating frequency and a relatively large aperture. [Figure 4b] This is a schematic diagram of a second exemplary transducer having a relatively high operating frequency and a relatively large aperture. [Figure 4c] This is a schematic diagram of a third exemplary transducer having a relatively low operating frequency and a relatively small aperture. [Figure 4d] This is a schematic diagram of a fourth exemplary transducer having a relatively high operating frequency and a relatively small aperture. [Figure 5a] Figures 4a to 4d are schematic diagrams of a first exemplary combination of transducers. [Figure 5b] Figures 4a to 4d are schematic diagrams of a second exemplary combination of transducers. [Figure 5c] Figures 4a to 4d are schematic diagrams of a third exemplary combination of transducers. [Figure 5d] Figures 4a-4d are schematic diagrams of a fourth exemplary combination of transducers. [Figure 6a] A schematic diagram of a further exemplary transducer configuration is shown. [Figure 6b] A schematic diagram of a further exemplary transducer configuration is shown. [Figure 7a] A schematic diagram of a further exemplary transducer configuration is shown. [Figure 7b] A schematic diagram of yet another exemplary transducer configuration is shown. [Figure 8a] This is a graphical representation of the calculation of the maximum differential volume of an ablation-assisted bubble oscillating in the first vibration mode in a free field with a mechanical index of 0.4. [Figure 8b] This is a graphical representation of the calculation of the maximum differential volume of an ablation-assisted bubble oscillating in the first vibration mode in a free field with a mechanical index of 0.6. [Figure 8c] This is a graphical representation of the calculation of the maximum differential volume of an ablation-assisted bubble oscillating in the first vibration mode in a free field with a mechanical index of 0.8. [Modes for carrying out the invention]

[0034] definition Unless otherwise defined, all technical terms, notations, and other scientific or technical terms used herein are intended to have meanings that are generally understood by those skilled in the art in which the invention relates. In some cases, terms that have a generally understood meaning are defined herein for clarity and / or for easy reference, and the inclusion of such definitions herein should not necessarily be construed as representing a substantial difference from the generally understood meaning in the art.

[0035] As used herein, “subject” means a human or non-human animal individual selected for treatment or therapy, and may include, but may not be limited to, patients, particularly human patients.

[0036] "Ultrasound insonation" is a term used to describe exposure to or treatment with ultrasound.

[0037] The term frequency is defined as the number of (ultrasonic) cycles per second (Hz). When used herein, the term specifies the center frequency of the sound field to which it applies.

[0038] The term "conventional medical imaging ultrasound" is used to describe ultrasound from commercially available ultrasound scanners and probes intended for medical imaging.

[0039] The term "high-intensity ultrasound" or "HIFU" is used to describe ultrasound with an intensity exceeding the diagnostic limits.

[0040] The term "microdroplet" is used to describe emulsion microdroplets with a diameter in the range of 0.2 to 10 μm.

[0041] The terms "microbubble" or "regular, contrast microbubble" are used to describe gas bubbles with or without a stabilizing shell, typically having a diameter in the range of 0.2–10 μm and an average diameter of 2–3 μm. "Regular, contrast microbubbles" include commercially available agents such as Sonazoid® (GE Healthcare), Optison® (GE Healthcare), Sonovue® (Bracco Spa.), Definity® (Lantheus Medical Imaging), Micromarker® (VisualSonics Inc.), and Polyson L® (Miltenyi Biotec GmbH).

[0042] The terms "microbubble / microdroplet cluster composition," "microbubble and microdroplet cluster composition," or "cluster composition" refer to a composition having a first component of microbubbles and a second component of microdroplets, particularly oil microdroplets.

[0043] The term "clustering" refers to the process by which microbubbles (the first component) and tiny droplets (the second component) form clusters.

[0044] The term "cluster" refers to a group of microbubbles and microdroplets within a cluster composition that are permanently held together by electrostatic attraction in a single aggregate.

[0045] The term "phase shift" is used to describe the phase transition of a substance from a liquid state to a gaseous state. Specifically, it refers to the transition (process) of the liquid-to-gas state change of the oil component in microdroplets within a cluster under ultrasonic irradiation.

[0046] The terms "activation" or "activation process" refer to the induction of a phase shift in microbubble / microdroplet clusters by ultrasonic irradiation.

[0047] In this document, the terms “ablation-assisted bubbles” or “AA bubbles” are used to describe the large (>10 μm) bubbles that form after ultrasonic activation of the cluster (i.e., bubbles resulting from the “activation process”).

[0048] The terms "enhancement" or "enhancement process" refer to ensuring the induction of volume oscillations and / or cavitation phenomena and biomechanical effects of ablation-assisted bubbles by ultrasonic irradiation.

[0049] "Acoustic Cluster Therapy (registered trademark)" or "ACT (registered trademark)" refers to a process in which a cluster composition is administered to a subject, the resulting phase shift of at least one cluster is activated by ultrasonic irradiation to generate an ablation-assisted bubble, and the ablation-assisted bubble is used in a further enhancement step. Detailed explanation

[0050] This invention provides a method for augmented ablation therapy (ACT® augmented ablation therapy), and more particularly a method for augmented ultrasound ablation (ACT® augmented ultrasound ablation therapy). Referring to Figure 1, Acoustic Cluster Therapy (ACT) (registered trademark) augmentation ablation therapy is (i) Step 10 of administering a cluster composition to a subject, wherein the cluster composition forms one or more clusters and the microbubbles and microdroplets are permanently held together by electrostatic attraction, (ii) optionally, step 20 of imaging one or more clusters using ultrasound imaging to identify a target area (target region) for treatment within the subject, (iii) Activation step 30, which includes activating the phase shift of the diffusible component of the cluster microdroplets from step (i) by ultrasonic irradiation at an activation frequency and optionally an activation mechanical index, in order to form at least one ablation-assisted (AA) bubble in the target region, (iv) an enhancement step 40 optionally including the step of irradiating at least one AA bubble with ultrasound to cause vibration and / or cavitation of at least one AA bubble, (v) A monitoring step which optionally includes monitoring the effect of ultrasonic irradiation during the enhancement step (iv) and adjusting at least one ultrasonic parameter according to an appropriate indicator, such as ablation efficiency, temperature of the target region, and / or bubble vibration dynamics of the target region, (vi) A repeating step which optionally repeats steps (iv) and (v) for a predetermined time.

[0051] Administration The cluster composition is administered to the subject parenterally, preferably intravenously. The cluster composition forms one or more aggregated clusters due to the electrostatic attraction of its constituent components. One or more clusters may be formed before or after administration to the subject. Preferably, one or more clusters are formed before administration to the subject.

[0052] In one example, a cluster composition of microbubbles and microdroplets is formed from a cluster dispersion of microdroplets (second component) stabilized with a lipid membrane having a net positive surface charge and microbubbles (first component) stabilized with a lipid shell having a net negative surface charge. In this example, the average diameter of both the microdroplets and microbubbles is 2-3 μm. The net positive surface charge of the microdroplets and the net negative surface charge of the microbubbles result in an electrostatic force that allows for the formation of at least one cluster.

[0053] In one example, the first component includes a dispersed gas selected from sulfur hexafluoride, perfluoropropane, perfluorobutane, perfluoropentane, and perfluorohexane, or a mixture thereof, stabilized by a first stabilizer selected from the group of phospholipids, proteins, and polymers. The second component includes a diffusible component selected from the group of perfluorocarbons, such as perfluorocycloalkanes, stabilized by a second stabilizer selected from the group of surfactants, such as phospholipids, polymers, and proteins. More specifically, one of the stabilizers is selected from phospholipids.

[0054] In a specific example, the first component consists of perfluorobutane (PFB) microbubbles embedded in lyophilized sucrose, stabilized by a hydrogenated egg phosphatidylserine-sodium (HEPS-Na) membrane. The HEPS-Na has a negatively charged head, which gives the microbubbles a negative surface charge. Each vial of the first component contains approximately 16 μL or 2-10⁹ microbubbles, with an average diameter of approximately 2.0 μm. The lyophilized formulation exhibits a long shelf life, more specifically 3 years, when stored at ambient room temperature. In this specific example, the second component consists of perfluoromethylcyclopentane (pFMCP) microdroplets stabilized by a 1,2-distearoyl-sn-glycerol-3-phosphocholine (DSPC) membrane, to which 3% mol / mol of stearylamine (SA) is added to provide a positive surface charge. The microdroplets in the second component are dispersed in 5 mM TRIS buffer. The standard formulation of the second component, in this specific example, contains approximately 0.8–10⁹ microdroplets per 4 μL or mL, with an average diameter of approximately 1.8 μm. The second component exhibits a long shelf life under refrigeration, more specifically 18 months or more. The cluster composition can be prepared aseptically by reconstituting a vial of the first component with 2 mL of the second component and then manually homogenizing it for 30 seconds. 2 mL can be drawn from the vial of the second component using a sterile, disposable syringe and needle. The contents of the syringe can be added through the stopper of the vial of the first component, and the resulting cluster composition can be homogenized to prepare the composition for administration.

[0055] imaging The method may include an optional step of imaging the microbubble components of clusters using a low mechanical index (MI) contrast imaging mode to identify lesion sites for treatment. In the low MI contrast imaging mode, the MI of the ultrasound irradiation is less than 0.1. Since clusters are not activated at low MI (below the activation threshold), standard medical ultrasound contrast imaging can be performed without triggering cluster activation. Therefore, clusters can be used for imaging, for example, to identify microvascular lesions of a tumor before subsequent steps in the ablation method of the present invention.

[0056] activation Following cluster formation and administration, the clusters are activated within, in, or near the target region by applying ultrasound energy directed towards the target region and / or target site. Alternatively, the clusters may be activated in nutrient arteries outside the target region, causing the activated bubbles to accumulate in the capillary bed downstream of the activation site, closest to the target region. Thus, the activated AA bubbles can be spatially localized within the target tissue or organ, such as proximal to a tumor, by spatially localized application of ultrasound energy to activate the clusters.

[0057] During the activation process 30, the cluster microbubbles vibrate and transfer energy to the cluster droplets. The vibrating microbubbles initiate the instantaneous evaporation (phase shift) of the attached droplets, resulting in the formation of AA bubbles. These AA bubbles temporarily accumulate (settle) in the microvascular system of the subject. In particular, the activated AA bubbles temporarily accumulate in the nearest capillary bed downstream of the activation site in amounts correlated with tissue blood perfusion.

[0058] Because the resonant frequencies of the microbubble components are typically in the 2–5 MHz range, clusters are readily activated by frequencies in the normal medical imaging range of 1–10 MHz, where Mis exceeds 0.1. However, the activation frequency of the clusters is application-dependent, and frequencies in the 50 kHz–20 MHz range are possible.

[0059] In one example, the cluster is activated by a standard diagnostic ultrasound imaging pulse (1-10 MHz) typically used in conventional medical ultrasound. Preferably, the MI of the ultrasound imaging pulse is 0.1-0.4, more preferably 0.15-0.3.

[0060] In one embodiment, referring to Figure 2, the activation step is initiated immediately after each administration of the cluster composition, such as within 20 seconds, and is preferably continued for approximately 60–120 seconds. Activation under medical ultrasound imaging control using imaging pulses allows for spatially targeted activation of clusters within the tissue region being examined by the ultrasound field. After activation, the produced AA bubbles 102 are temporarily confined within the microvascular system 106 of the target lesion due to their large size. The AA bubbles 102 are approximately 1000 times the volume of the existing emulsion microdroplets before evaporation. For example, a 2 μm diameter AA bubble may be generated from an existing 2 μm diameter oil microdroplet. The diameter of the activated bubbles (AA bubbles) is typically approximately 20 μm. The activated AA bubbles gradually shrink by intermittently settling and detaching, and after progressing further down the capillary tree, they typically disappear completely after 5–15 minutes.

[0061] Figure 3 shows graph 200 of the number of successfully activated AA bubbles per μL for MI at three different frequencies. These frequencies are 0.5 MHz, 1 MHz, and 2 MHz. The graph shows the peak number per μL of approximately 640 AA bubbles per μL when ultrasonically irradiated with an ultrasonic field having a frequency of 2 MHz and an MI of 0.5. Preferably, the number of AA bubbles generated per μL exceeds 300. Therefore, according to the graph in Figure 3, an ultrasonic field with a frequency of 2 MHz and an MI of 0.29 to 0.6 is suitable. An ultrasonic field with a frequency of 1 MHz is suitable when the MI is 0.65 or higher. An ultrasonic field with a frequency of 0.5 MHz is suitable when the MI is 0.7 or higher.

[0062] Enhancement The enhancement step 40 includes transferring ultrasonic energy to the AA bubbles to provide additional mechanical and / or thermal stress to the target region, in addition to the mechanical and / or thermal stress directly obtained from ultrasonic irradiation of the tissue, which has the effect of increasing the ablation efficiency of cells in the target region by inducing at least one of the energy absorption, deposition, vibration, and cavitation phenomena of the activated AA bubbles. The ablation frequency may be the same as or different from the ultrasonic frequency used in the activation step. In some examples, the pulse amplitude of the ultrasound associated with the enhancement step is different from the pulse amplitude of the activation step.

[0063] Referring further to Figure 2, ultrasound irradiation induces controlled volume oscillations 104 of the activated AA bubble, preferably until cavitation occurs, thereby exerting biomechanical forces on the tissue in the target area. Therefore, it has been found that the application of ultrasound at or near the cavitation frequency of the AA bubble can be used to enhance the effectiveness of ablation therapy by generating additional mechanical and / or thermal bioeffect mechanisms, in addition to the effects from ultrasound directly focused on the tissue in the target area. This increases the destruction of the target tissue.

[0064] Ultrasound irradiation depends on frequency, irradiation time, transducer characteristics such as geometric shape and configuration, total power delivered, sound pressure and intensity, and energy delivery mode. Specific ultrasound irradiation regimes are selected based on the tissue type of the target area, the desired ablation effect, and the ultrasound delivery path, as will be described in more detail below.

[0065] Preferably, the frequency of the irradiated ultrasound during the enhancement phase is less than 3 MHz, more preferably less than 1 MHz. However, the frequency may be outside this range depending on the location of the target therapeutic volume within the subject and the tissue characteristics of said volume. In the target volume, the target MI of the ultrasound field is preferably greater than 0.4, more preferably greater than 0.6, and even more preferably greater than 0.8.

[0066] The target time-averaged intensity of ultrasound used for ablation can range up to 5000 W / cm², depending on the specific application. 2 The range is as follows: If AA bubbles are present in the target tissue, the intensity required to achieve the same amount of ablation is reduced to more than 1 / 1, preferably more than 1 / 8, more preferably more than 1 / 16, even more preferably more than 1 / 24, even more preferably more than 1 / 50, and even more preferably more than 1 / 100.

[0067] The enhancement step 40 is performed non-invasively or invasively by a focused ultrasound array or a focused single-element ultrasound transducer, or by one or more surgically implanted ultrasound transducers.

[0068] The method may include two distinct steps: an activation step and an enhancement step involving ultrasound irradiation. After the completion of the activation step, ultrasound irradiation may be stopped before further ultrasound irradiation for the enhancement step is performed. The parameters of the ultrasound field may be modified for the further ultrasound irradiation described above. Alternatively, the ultrasound field provided for ultrasound irradiation in both the activation and enhancement steps may not be modified and may have the same parameters (i.e., frequency, intensity, MI) throughout the entire ACT enhancement ablation therapy process. This is possible because the use of AA bubbles reduces the ultrasound power required to achieve the desired ablation effect. This may have the advantage of simplifying the process, for example, requiring the transducer setup to be done only once.

[0069] The combination of ultrasound and AA bubbles has been shown to reduce the acoustic energy level required for ablation therapy by more than 1 / 100. The ultrasound field interacts with the AA bubbles in the form of an acoustic cavity phenomenon. This causes the AA bubbles to vibrate, grow, and collapse. The acoustically driven vibrations of the AA bubbles result in heat production, microstreams of fluid near the bubbles, and localized shear stress. The absorption of energy as ultrasound propagates through the medium also produces a heating effect. In tissue, the absorption rate increases with frequency. AA bubbles can generate higher harmonics of the excitation frequency, further enhancing the heating effect.

[0070] Ultrasound Planning The optional ultrasonic planning process may include a first passive ultrasonic planning process and a second active ultrasonic planning process.

[0071] In the first passive ultrasound planning step, subject- and application-specific information is collected and processed to plan a specific ultrasound irradiation regime. This information includes physiological information and anatomical structures in the ablation zone, and software may be used to determine the anatomical structures. Software defining the anatomical structures enables the treatment of various types of patients to deliver precise heat delivery.

[0072] Examples of the types of physiological information used in ultrasound planning include perfusion of various organs. Heat-sensitive organs such as the diaphragm, intestines, and spinal cord are anatomical structures that are particularly targeted in the ablation zone when planning ultrasound irradiation.

[0073] In the second active ultrasound planning step, real-time feedback of the ablation zone state is used to adjust ultrasound parameters in the iterative process, ensuring optimal conditions throughout the ACT-enhanced ultrasound ablation method. Real-time feedback may include real-time temperature feedback, real-time mechanical feedback, cross-modality imaging and co-registration, real-time monitoring of cluster dynamics and concentration, and real-time monitoring of AA bubble dynamics and concentration.

[0074] Real-time mechanical feedback can be obtained by detecting cavities using ultrasound. Because the generated AA bubbles are highly echogenic, the ultrasonic backscatter from the AA bubbles themselves can be used for imaging to detect cavities. Real-time mechanical feedback can also be obtained via shear wave monitoring (i.e., using elastography).

[0075] Real-time temperature feedback can be obtained using thermocouples, fiber optic temperature sensors, and magnetic resonance imaging (MRI).

[0076] During the ablation process, ultrasonic parameters may be modified based on real-time feedback evaluated against the desired ablation zone conditions. For example, ablation efficiency, target region temperature, and bubble vibration dynamics within the target region may be modified based on real-time feedback. The collection of real-time feedback (monitoring) and the corresponding readjustment of ultrasonic parameters can be carried out in a continuous feedback loop over the duration of the ablation procedure or over a predetermined period, such as the duration of the enhancement process.

[0077] The optimal selection of ultrasound frequency is application-specific and represents a compromise between treatment depth and desired heating rate. Frequencies around 1 MHz have been found to be most useful for heat deposition, lower frequencies around 0.5 MHz are used for deep treatments or in areas with large absorption in the propagation path (transcranial applications), and higher frequencies around 8 MHz are used for surface treatments (e.g., prostate and melanoma).

[0078] The threshold heating dose required to achieve the desired thermal effect, including irreversible damage and coagulation of key cellular proteins, tissue structural components, and the vascular system, resulting in immediate tissue destruction, varies depending on the type of tissue and irradiation time. For normal tissue, the temperature range is 30–77°C, while for tumor tissue, it is 41–64°C. In most applications, the threshold heating dose is in the range of 43–65°C with a continuous irradiation time of approximately 30 seconds.

[0079] monitoring The ablation zone benefits from careful monitoring, providing real-time feedback for the second active ultrasound planning step. As mentioned above, monitoring the ablation zone may include monitoring temperature, dynamics, clusters, and bubble dynamics and concentration. Various methods can be utilized to monitor the ablation zone.

[0080] A specific method for monitoring the ablation zone is the use of image-guided modalities. Examples of image-guided modalities include magnetic resonance (MR) guidance, ultrasound guidance, computed tomography (CT) guidance, optical guidance, thermocouple guidance, contrast-enhanced ultrasound guidance, or a combination of the above.

[0081] The scattering cross-section of AA bubbles is several orders of magnitude larger than that of micron-sized microbubbles in the cluster before activation. As a result, AA bubbles generate a large amount of backscatter signal, which is easily captured by diagnostic imaging systems in basic imaging mode. The resonant frequency of AA bubbles is also an order of magnitude lower than that of microbubbles in the cluster before activation (approximately 0.2–0.8 MHz).

[0082] MRI-guided ablation therapy offers superior anatomical resolution and high sensitivity, particularly for tumor detection, thereby allowing for precise planning of target tissue. Ultrasound transducers must be specifically designed for compatibility with the high magnetic field of MRI. MR-guided ultrasound offers additional benefits, including soft tissue contrast, quantitative temperature measurement, temperature feedback control, and diagnostics, although accessibility may be limited. MRI is highly sensitive to temperature changes, allowing for real-time feedback of temperature data throughout the procedure. MRI is particularly well-suited for ACT-enhanced ablation therapy, where biomechanical effects compensate for thermal effects, resulting in relatively low temperatures from an ablation perspective.

[0083] Ultrasound-guided ablation therapy is widely accessible, offers good temporal resolution, provides soft tissue contrast and diagnosis, and offers qualitative feedback. Typically, the processing head incorporates an ultrasound diagnostic transducer, enabling real-time imaging of the ablation process.

[0084] Magnetic resonance-guided focused ultrasound (MRgFUS) is a type of MRI-guided ablation therapy. During the MRgFUS procedure, the patient remains conscious, and the functional effect of the procedure is clinically evaluated throughout. The operator continuously controls and improves the target area and selects the attributes of the incident ultrasound field in terms of the level of MI and the number of ultrasound pulses.

[0085] The median duration of the MRgFUS procedure is approximately 1 hour, which includes acquisition of the planned sequence, targeting, and sonication. If necessary, the duration of the MRgFUS procedure can be covered by repeated injections or infusions of the ACT microcluster composition.

[0086] hardware ACT-enhanced ultrasound ablation may use one or more ultrasound transducers or transducer arrays to provide an ultrasound field for the activation step and optionally for the imaging, enhancement, and monitoring steps of the procedure.

[0087] The ultrasound probe provides an ultrasonic field for ultrasonic irradiation during the activation and enhancement steps. Since the use of AA bubbles may negate the need for HIFU, the ultrasound probe may be equipped with commercially available transducers that are not specifically designed for HIFU applications.

[0088] External ultrasound devices are typically used for targets within the breast, abdomen, brain, or limbs. For percutaneous procedures, a suitable acoustic window is required at the entry site to provide a propagation path for the focused ultrasound beam that is not interrupted by the intervention gas.

[0089] In one embodiment, an external (non-invasive) transducer is used. Such an external transducer provides an opportunity to combine ACT technology with MRI-guided focused ultrasound (MRgFUS).

[0090] In one example, the selected ultrasonic transducer emits ultrasound at a frequency in the focal intensity range of 1–5 MHz and a beam size of approximately -6 dB, where the -6 dB beam size is approximately 1–3 mm wide and 10 mm long, depending on the geometric size and acoustic parameters.

[0091] The ultrasound transducer may be a fixed transducer that provides a single irradiation and is suitable for small volume target areas. The volume of the target area that can be treated by a fixed transducer also depends on the specific frequency and shape of the transducer, as well as the position of the target area relative to the transducer. Since the treatable volume can be approximated as an ellipsoid with principal diameters A, B, and C, the treatable volume is approximately as follows:

[0092]

number

[0093] The example values ​​for principal diameters A and B are 1-3 mm, and the example value for principal diameter C is 10 mm. Therefore, the example treatment volume is 5-50 mm. 3 It falls within the range.

[0094] Ultrasonic probes may also feature ultrasonic transducers that provide the ability to direct the ultrasonic field to multiple target regions, either by physically rotating and / or translating the transducer array within the ultrasonic probe housing, or by electronically exciting specific transducer elements in a specific sequence. Therefore, the probes are suitable for target regions with larger volumes, for example, several times the volume range of a fixed transducer.

[0095] The probe may be combined with a catheter or placed in a sealed attachment to deliver ultrasound into the body, for example, if the target volume is in the prostate and the probe is inserted into the urinary tract or rectum. In other applications, such devices may need to be used in suitable openings such as the vaginal canal, nasal cavity, mouth, or esophagus.

[0096] The probe may feature a therapeutic transducer designed to deliver higher-power ultrasound and utilizing the same principles as conventional ultrasound transducers.

[0097] The probe may comprise two or more transducers or array transducers operating at independent frequencies, where a first set of transducers or transducer arrays provides ultrasonic irradiation in the activation step, and a second set of transducers or transducer arrays provides ultrasonic irradiation in the enhancement step.

[0098] Figure 4a is a schematic diagram of a first exemplary transducer 301 having a relatively low operating frequency, e.g., about 1.25 MHz, and a relatively large aperture, e.g., about 50 mm. Line 302 shows the range of the transmitted ultrasonic beam on the left, and a second line 303 shows the range of the transmitted ultrasonic beam on the right. The ellipse 304 shows the region where the intensity of the transmitted ultrasonic beam is highest.

[0099] Figure 4b is a schematic diagram of a second exemplary transducer 308 having a relatively high operating frequency, e.g., about 2.5 MHz, and a relatively large aperture, e.g., about 50 mm. The first line 309 shows the range of the transmitted ultrasonic beam on the left, and the second line 310 shows the range of the transmitted ultrasonic beam on the right. The ellipse 311 indicates the region where the intensity of the transmitted ultrasonic beam is highest.

[0100] Figure 4c is a schematic diagram of a third exemplary transducer 305 having a relatively low operating frequency, e.g., about 1.25 MHz, and a relatively small aperture, e.g., about 25 mm. The first line 306 shows the range of the transmitted ultrasonic beam on the left, and the second line 307 shows the range of the transmitted ultrasonic beam on the right.

[0101] Figure 4d is a schematic diagram of a fourth exemplary transducer 312 having a relatively high operating frequency, e.g., about 2.5 MHz, and a relatively small aperture, e.g., about 25 mm. The first line 313 shows the range of the transmitted ultrasonic beam on the left, and the second line 314 shows the range of the transmitted ultrasonic beam on the right. The ellipse 315 indicates the region where the intensity of the transmitted ultrasonic beam is highest.

[0102] Transducers 301, 305, 308, and 312 are depicted as planar, but may have a curved shape.

[0103] Figures 5a–5d are schematic diagrams illustrating examples of how transducers similar to those in Figures 4a–4d can be combined in a stacked or co-localized manner to achieve ablation suitable for specific applications.

[0104] In the first example shown in Figure 5a, a relatively high frequency (RHF) transducer 405 is colocalized with a relatively low frequency (RLF) transducer 401. The RHF transducer has a smaller active aperture than the RLF transducer such that the ranges 402, 403 of the low-frequency transmitted ultrasonic beam are wider than the ranges 406, 407 of the high-frequency transmitted ultrasonic beam. In this example, the high-frequency and low-frequency ultrasonic beams have overlapping and equal maximum intensity regions 404. This configuration is suitable for target treatment volumes of 10–500 mm³. 3 It is suitable for applications where the depth is approximately 3-7 cm and falls within that range.

[0105] In the second example shown in Figure 5b, the RHF transducer 411 is colocalized with the RLF transducer 408, and the RHF transducer 411 has a larger active aperture than the RLF transducer 408 such that the range 412, 413 of the high-frequency transmitted ultrasonic beam is wider than the range 409, 410 of the low-frequency transmitted ultrasonic beam. In this example, the high-frequency ultrasonic beam is approximately 1-50 mm deep at a depth of approximately 1-4 cm. 3 It has a region 414 with maximum intensity suitable for activation at the target volume within the region. In this example, the low-frequency beam is used for enhancement within the region 414 determined by the high-frequency beam, even if the range of the low-frequency beam is larger.

[0106] In the further examples shown in Figures 5c and 5d, RLF transducers 415 and 422 are stacked vertically with RHF transducers 419 and 423, respectively. The same principles for activation and enhancement apply as in the previous exemplary transducer setup.

[0107] Figures 6a and 6b are schematic diagrams of two further exemplary transducer configurations in which the RLF transducers 501 and 508 and the RHF transducers 504 and 512 are not colocalized or stacked.

[0108] The example in Figure 6a shows an RLF transducer with an out-of-focus ultrasonic beam 502 and an RHF transducer 504 that transmits an ultrasonic beam delimited by lines 505 and 506, with a region of maximum intensity 507. In this example, the target tissue is located in region 507.

[0109] In the example shown in Figure 6b, the RLF transducer 508 is configured to transmit a focused ultrasonic beam demarcated by lines 509 and 510, providing a region of maximum intensity 511. The RHF transducer 512 is configured to transmit an ultrasonic beam demarcated by lines 513 and 514, providing a region of maximum intensity 515. The target tissue is located in the overlapping region of 511 and 515, with activation brought about by either the RHF transducer 512 or the RLF transducer 508, and enhancement brought about by either the RHF transducer 512 or the RLF transducer 508.

[0110] Figures 7a and 7b are schematic diagrams of two more examples of transducer configurations.

[0111] In the first example in Figure 7a, two RHF transducers 604 and 608 are configured to transmit ultrasonic beams in ranges 605, 606, 609, and 610, respectively. The RHF transducers 604 and 608 provide maximum intensity regions 607 and 611, respectively, which overlap and combine to form a maximum intensity region 612. The arrangement of the RHF transducers 604 and 608 is such that the combined maximum intensity region 612 coincides with the transmitted ultrasonic beams delimited by lines 602 and 603 from the RLF transducer 601. The target volume is defined by the combined maximum intensity region 612. Activation is brought about by either the RHF transducers 604 and 608 or the RLF transducer 601. Enhancement is brought about by either the RHF transducers 604 and 608 or the RLF transducer 601.

[0112] In the second example according to Figure 7b, two RLF transducers 616, 619, configured to transmit ultrasonic beams in ranges 617, 618, 620, and 621 respectively, are positioned so that their beams coincide with the region of maximum intensity 615 within the ultrasonic beams 613, 614 transmitted by the RHF transducer 612. The target volume is defined by the region of maximum intensity 615. Activation is provided by both the RHF transducer 612 and the RLF transducers 616, 619, and enhancement is provided by both the RHF transducer 612 and the RLF transducers 616, 619.

[0113] A common system for performing ACT augmentation ablation is a computer-controlled system, which is suitable for generating ultrasound to achieve ultrasonic irradiation of AA bubbles within the target area, and for performing the activation step and the subsequent augmentation step. Computer-controlled ACT augmentation ablation systems may also utilize planning and procedure feedback.

[0114] A system for performing ACT-enhanced ablation may further include a power amplifier, a pulse generator, a 3D positioning system, and one or more imaging modalities such as the US, CT, or MRI imaging modalities described above.

[0115] advantage AA bubbles exhibit several properties that differ from conventional microbubbles, which allows ablation therapy to be performed at significantly lower ultrasound energies. The first property is that, compared to conventional microbubbles, which do not settle in place and pass through capillaries at a rate determined by perfusion velocity, AA bubbles that settle in place within capillaries have a residence time of approximately 5-15 minutes. This is typically only a few seconds, depending on tissue perfusion and volume. This increases the potential irradiation time of the target area for ACT-enhanced ablation therapy. Since ultrasound procedures usually take some time (typically, ultrasound ablation is performed over a range of hours), it is not possible for bubbles to flow freely, and having stationary bubbles is a significant advantage. The second property is that, compared to conventional contrast microbubbles, which are small and therefore limit the generation of thermal and mechanical effects, the larger size of AA bubbles allows for increased generation of thermal and mechanical effects using lower acoustic power.

[0116] AA bubbles also dissipate energy as heat through friction between the surface area of ​​the fixed AA bubble and the capillary wall, and through conduction during compression. Therefore, by combining ultrasound and AA bubbles, the required acoustic energy level can be effectively reduced.

[0117] AA bubbles are activated under imaging control and accumulate within the tissue's microvascular system. This allows for spatial targeting of AA bubbles within the tissue. Combined with the extended residence time of AA bubbles, this enables more efficient and controlled execution of ablation therapy.

[0118] Because the process is non-invasive and does not use implantable hardware, the technology poses no risk of infection. It also offers the added benefit of not using ionizing radiation. Furthermore, it can provide immediate results.

[0119] Furthermore, because AA bubbles are induced as high-echoic spots, real-time imaging can be provided. This allows for further information regarding the size and shape of lesions that are not visible in B-mode ultrasound imaging due to thermal ablation.

[0120] In many cases, it is useful to assess the perfusion of the organ to be treated before initiating the procedure. ACT techniques can be used to test the perfusion of various organs, thus providing a second utility alongside ablation enhancement and a third utility alongside imaging (i.e., the accumulation of AA bubbles in the target tissue can be used for control feedback).

[0121] ACT-enhanced ablation therapy may not reach as high temperatures as conventional thermal ablation, and the cooling time is also shortened. In many cases, a cooling period is required between ultrasound treatments to prevent unwanted heating of surrounding tissue. Therefore, a reduction in the time between ultrasound treatments is necessary, which shortens the overall ablation time.

[0122] All of the benefits outlined above can lead to the subsequent benefit of reducing the likelihood of side effects and bleeding.

[0123] Thermal activity is enhanced only at the acoustic focus where the pressure is sufficient for AA bubble activation. Focusing the ultrasound beam allows for high intensity only at specific locations within a small volume, minimizing the possibility of thermal damage to tissue outside the focal area. For example, the ultrasound beam may have a diameter of approximately 1 mm and a length of approximately 10 mm. At the boundaries of the thermal coagulation lesion, the tissue dies within 2-3 days and is taken up by the immune system. Ultrasound used in combination with ACT allows for lower intensities while achieving the same or better ablation and reducing the risk of damage to surrounding tissue.

[0124] usefulness ACT augmentation ablation has clinical implications in neurology / surgery, ophthalmology, urology, gynecology, and oncology. In neurology, ACT augmentation ablation may have clinical implications for brain tumors and space-occupying masses, neuromodulation, tremor, tremor-dominant Parkinson's disease (movement impairment symptoms), epilepsy, and stroke. In ophthalmology, ACT augmentation ablation may have clinical implications for glaucoma, intraocular tumors, retinal detachment, and trabeculotomy. In urology, ACT augmentation ablation may have clinical implications for kidney stones, precancerous lesions of the cervix, and the adrenal gland. In gynecology, ACT augmentation ablation may have clinical implications for uterine fibroids and ovarian cancer. In oncology, ACT augmentation ablation may have clinical implications primarily for the musculoskeletal system, lungs, breasts, brain, prostate, kidneys, liver, pancreas, brain tumors, renal tumors, and bladder. ACT augmentation ablation may have a clinical impact in the treatment of other malignancies, including adrenal tumors, thyroid cancer, skin cancer, large tumors (neck, nodules, bone), and superficial tumors (skin). In the field of cardiovascular disease (blocking irregular electrical signals and restoring a normal heartbeat), ACT augmentation ablation may have a clinical impact on atrial fibrillation, irregular heartbeat, arrhythmias, and normalization of vascular function. ACT augmentation ablation may also have a clinical impact on the treatment of symptomatic (metastatic) and chronic pain. Mental disorders can also be treated with ACT augmentation ablation. In the field of cosmetic surgery, ACT augmentation ablation may have a clinical impact on signs of aging and lifting. ACT augmentation ablation may also have a clinical impact on complete or partial vascular occlusion, such as deep vein thrombosis, pulmonary embolism, coronary artery occlusion, and arteriosclerosis.

[0125] The ultrasound settings (ultrasound irradiation regime) used in the enhancement process are application-specific. Specifically, "application-specific" refers to the type of tissue being ablated.

[0126] ACT-enhanced ultrasound ablation for tumor treatment Temperature changes are concentrated in the convergence zone within and around the tumor. The overall objective of thermal ablation of tumors is very similar to that of surgery: to remove the tumor and the seemingly normal tissue with a margin of 5-10 mm thickness. In contrast to surgical removal, which consists of physical excision, in thermal ablation, the tissue is killed at the insights and then absorbed by the body over several months.

[0127] In specific ultrasound settings for the enhancement step of ACT-enhanced ultrasound when the target region is a tumor, the MI is greater than 0.4, preferably greater than 0.6, and more preferably greater than 0.8, and the intensity is up to 5000 W / cm². 2 The frequency is less than 3 MHz, preferably less than 1 MHz, and the continuous or pulsed ultrasonic irradiation time is approximately 20 to 30 seconds.

[0128] ACT-enhanced ultrasound ablation is suitable for treating liver tumors and selectively destroying normal liver, bladder, muscle, and kidney tissue. Depending on the equipment and parameters used, the volume of focused ultrasound lesions can be as small as a grain of rice (approximately 10 cubic millimeters). This allows for extremely localized treatment and a clear boundary between the treated and untreated areas. For treating larger structures such as large tumors, multiple treatment volumes can be combined to encompass the entire volume.

[0129] Because tumors are metabolically active, they have high perfusion compared to the relatively low perfusion of surrounding tissues. The higher perfusion rate of the tumor compared to the surrounding tissue ultimately leads to a higher concentration of AA bubbles in the tumor tissue than in the surrounding area. As mentioned above, performing an enhancement step on AA bubbles destroys the proximal tissue. Therefore, ACT-enhanced ultrasound ablation is particularly suitable for removing tumor cells because its technique can take advantage of the higher perfusion rate within the tumor compared to normal tissue.

[0130] ACT-enhanced ultrasound ablation for signs of aging For target areas showing signs of aging, specific ultrasound settings for the enhancement step of ACT-enhanced ultrasound ablation are substantially similar to those for tumor ablation. However, the ultrasound field is preferably delivered in short bursts rather than continuous ultrasound irradiation.

[0131] Since the target area is normal tissue, the tissue must be exposed to a temperature range of 30–77°C.

[0132] ACT-enhanced ultrasound ablation using transrectal and interstitial ultrasound sources Transrectal and intertissue ultrasound sources can be positioned closer to the target volume to operate at lower power and higher frequencies while achieving the same ablation efficiency. A preferred ultrasound power range for transrectal / intertissue sources during the enhancement process is up to 5000 W / cm². 2 In the enhancement process, the preferred frequency is less than 4 MHz, and more preferably less than 1 MHz. For larger prostates with deeper lesions, the frequency selection is limited by the required penetration depth.

[0133] ACT-enhanced ultrasound ablation can be combined with chemotherapy, immunotherapy, and / or drug delivery to perform treatment more effectively and with fewer side effects. ACT-enhanced ultrasound ablation does not preclude other treatment options. There is no negative cell selection with antibody therapy or hormone therapy.

[0134] ACT-enhanced ultrasound ablation for brain treatment Without the use of AA bubbles, the usefulness of thermal ultrasound ablation for brain treatment is limited, mainly due to the barrier of ultrasound irradiation through bone structures.

[0135] ACT-enhanced ultrasound ablation has the advantage of overcoming the limitations of transcranial ultrasound, as it allows for shorter procedure times and lower temperature and frequency compared to non-ACT-enhanced ultrasound ablation.

[0136] Furthermore, because AA bubbles can remain stationary within the vascular system for up to 15 minutes, they can get closer to the endothelial wall, potentially enabling the generation of optimal thermal effects. This is in contrast to typical contrast microbubbles, which are small with an average diameter of approximately 1-3 μm, and therefore, depending on tissue perfusion and volume, can clear the vascular system in a significantly shorter time, for example, a few seconds.

[0137] Skull thickness varies with age, sex, and ethnicity. Ultrasound ablation is well-suited for procedures through the skull, which has a thick barrier. Furthermore, ultrasound ablation may be limited to treating target areas in the center of the brain. However, these problems can be overcome by combining the technique with an optimal AA bubble, achieving functionality with lower ultrasound energy. ACT offers the advantage of being temporarily confined to the microcirculation of the target area. This combination allows for the maximum utilization of MRgFUS technology for applications outside the central part of the brain, enabling it to work not only through thicker bone structures but also to open the blood-brain barrier.

[0138] ACT-enhanced ultrasound ablation for thrombolysis ACT-enhanced ablation and ACT-enhanced ultrasound ablation can also be used to treat the formation of thrombi in the vascular system. The method may include positioning at least one cluster proximal, preferably adjacent to, a target thrombus formed in a blood vessel of a subject. The cluster is then activated according to the method described above to produce at least one AA bubble. As a result of the activation process in which the cluster transitions to an AA bubble, the entity expands, creating mechanical stress on the proximal (adjacent) thrombus. This mechanical stress may be sufficient to cause the collapse (decomposition) of the thrombus. A method of treating thrombolysis by causing thrombus collapse may further include utilizing the enhancement step of ACT-enhanced ultrasound ablation, such as the enhancement step described above. A method of using ACT-enhanced ultrasound ablation to treat thrombolysis may further include an interleaved activation step, either alone or in combination with a thrombolytic agent or anticoagulant.

[0139] The generation of AA bubbles and ACT-enhanced ultrasound ablation can lead to thrombus fragmentation, reduction of thrombus size, promotion of thrombus movement, enhanced penetration of thrombolytic and anticoagulant agents into the thrombus, and / or removal of thrombus-degrading products by mechanical or thermal disruption.

[0140] ACT-enhanced ultrasound ablation can be used to treat myocardial infarction, stroke, and venous thromboembolism.

[0141] The ultrasound source used to provide the ultrasound field for achieving ACT-enhanced ultrasound ablation to treat thrombolysis may be an external ultrasound probe or a catheter-based probe.

[0142] ACT-enhanced ultrasound ablation for thrombolysis offers the advantage of a reduced risk of bleeding compared to thrombus breakdown using ultrasound alone or a combination of ultrasound and conventional microbubbles. Bleeding can also be reduced by the lower required ultrasound intensity. Bleeding can also be reduced because the use of thrombolytics and anticoagulants may be unnecessary or required in smaller doses in this method. A further advantage is that the procedure time can be shortened. [Examples]

[0143] Simulation of an augmented field on a bubble Figures 8a, 8b, and 8c show a graphical representation of the calculation of the maximum differential volume of an AA bubble oscillating in the first vibration mode, i.e., the difference between the volume at peak expansion and the volume at rest. The calculation is based on a simulation of the modified Rayleigh-Presset equations:

[0144]

number

[0145] Pre - clinical evidence To investigate the effect of MI variation in an enhanced ultrasonic field, the tumor - specific uptake of the fluorescent dye Evans Blue® was investigated in a SC PC3 mouse model.

[0146] Three mice were selected and subjected to enhanced ultrasound with a mechanical index of 0.8 (MI=0.8 group). Immediately after intravenous (IV) injection of Evans Blue®, a single IV dose of PS101 (5.1 mg PFMCP / kg [1000 μL PS101 / kg]) was administered, followed by 45 seconds of activated ultrasound (2.5 MHz, MI0.4) focused on the tumor, and then 5 minutes of enhanced ultrasound (0.5 MHz, MI0.8).

[0147] In the MI=0.8 group, tumors and non-ultrasonic control muscles were excised from the right leg, and the amount of Evans Blue® was measured by spectrophotometric analysis at 620 nm. The amount of Evans Blue® detected in the tumors of animals in the MI=0.8 group was less than the amount detected in other groups with lower enhanced ultrasound MI. This suggests either potential damage to cells within the tumor or damage to blood vessels, which would reduce blood supply and consequently decrease the concentration of Evans Blue within the target volume. Therefore, ACT bubbles appear to cause tissue ablation and significant bleeding when exposed to an enhanced MI of 0.8. In the MI=0.8 group, all animals died during or immediately after the procedure, and extensive bleeding was observed in the ultrasound-irradiated area (left thigh and leg). These animals likely died from high-intensity ultrasound irradiation of a significant portion of the mouse's body weight (approximately 10%, about 20 times the typical clinical situation) in combination with high doses of PS101 (20-40 times the expected clinical dose). By optimizing the PS101 dose and enhanced ultrasound MI, it is expected that ablation can be achieved without causing these effects.

[0148] While preferred examples of the present invention have been described, it will be apparent to those skilled in the art that other embodiments incorporating the present invention may also be used. These and other examples of the present invention illustrated above are for illustrative purposes only, and the actual scope of the invention is determined by the appended claims.

Claims

1. A method of enhanced ultrasound ablation, wherein the method is Administering a cluster composition to a subject that includes at least one cluster containing microbubble components and microdroplet components; and To create the at least one ablation-assisted bubble, the phase shift transition of the microdroplet component of the at least one cluster is activated by ultrasonic irradiation directed towards the target region of the cluster; by this: The process includes the step of creating at least one ablation-assisted bubble proximal to the target region, A method (excluding medical procedures on humans) in which mechanical stress is introduced to the target region by the expansion of the at least one cluster from the transition to the at least one ablation-assisted bubble, thereby assisting ablation on the target tissue within the target region.

2. The method according to claim 1, wherein the at least one ablation-assisted bubble has a diameter of at least 10 micrometers.

3. The method according to claim 1, further comprising the step of ultrasonically irradiating the at least one ablation-aided bubble with ultrasonic waves of a predetermined intensity to induce at least one of the energy absorption, deposition, vibration, and cavitation phenomena of the ablation-aided bubble to bring additional mechanical and / or thermal stress to the target region and to support ablation on the target tissue within the target region.

4. The method according to claim 3, wherein the predetermined intensity of the ultrasound for irradiating the ablation-assisting bubbles with ultrasound is equal to the value obtained by dividing the intensity for ultrasound ablation without bubble assistance by a coefficient of 12 to 24.

5. The method according to claim 1, wherein the enhanced ultrasonic ablation is configured to result in a temperature of 30 to 70 degrees Celsius in the target region over a continuous irradiation time of at least 30 seconds.

6. The method according to claim 1, further comprising the step of using the at least one ablation-assisted bubble for real-time imaging of the target region by ultrasonically irradiating the at least one ablation-assisted bubble with imaging ultrasound, wherein the at least one ablation-assisted bubble is induced as a high-echo spot.

7. The method according to claim 1, further comprising a step of ultrasound planning using subject-specific and application-specific information to plan a particular ultrasound irradiation regime, wherein the ultrasound planning includes at least one of passive ultrasound planning and active ultrasound planning.

8. The method according to claim 7, wherein the passive ultrasound planning is based on one or more of the following: physiological information, anatomical structure of the ablation zone, cross-modality imaging and co-registration, and data defining the anatomical structure of the subject obtained from the software.

9. Active ultrasound planning, A step of monitoring the ablation zone during the enhancement process for real-time feedback of the ablation zone, The step includes adjusting the specific ultrasonic irradiation regime to achieve predetermined parameters in the ablation zone, The method according to claim 7, wherein the monitoring step and the adjustment step are carried out continuously over a predetermined period of time.

10. The method according to claim 9, wherein the step of monitoring the ablation zone during the enhancement step for real-time feedback of the ablation zone includes at least one of real-time temperature feedback, real-time mechanical feedback, cross-modality imaging and co-registration, real-time monitoring of cluster dynamics and concentration, and real-time monitoring of ablation-assisted bubble dynamics and concentration.

11. The method according to claim 9, wherein the step of monitoring the target region including the ablation zone further includes imaging via an image-guided modality, the image-guided modality includes at least one of magnetic resonance guidance, ultrasound guidance, computed tomography guidance, optical guidance, thermocouple guidance, and contrast-enhanced ultrasound guidance.

12. The method according to claim 1, further comprising the simultaneous administration of a therapeutic agent configured to assist the ablation efficacy, wherein the therapeutic agent is administered separately to the cluster composition before and / or simultaneously and / or afterward.

13. A composition that can be administered intravenously for use in a method for enhancing ablation in a target region, wherein the intravenously administered composition is A microbubble-microdroplet cluster composition comprising a group of negatively charged microbubbles and positively charged microdroplets, wherein the negatively charged microbubbles and positively charged microdroplets are held together by their opposing electrostatic attraction to form a single aggregate, An intravenously administered composition comprising the step of exposing a target region of at least one cluster to effective ultrasonic irradiation, wherein each of the at least one cluster is configured to vibrate, expand, and fuse to form a single entity, providing ablation-assisted bubbles.

14. The intravenously administerable composition according to claim 13, wherein the method further includes the step of exposing the resulting ablation-assisted bubbles to ultrasound of a predetermined intensity, the ablation-assisted bubbles are configured to vibrate and / or form cavities to induce mechanical and / or thermal stress in the target region, thereby increasing the ablation efficiency in the target region.

15. The intravenously administerable composition according to claim 13, wherein the resulting ablation-assisted bubbles are configured to induce mechanical and / or thermal stress comparable to mechanical and / or thermal stress induced by direct ultrasonic irradiation of the target region, and the predetermined intensity is equal to the intensity for ultrasonic ablation without bubble assistance divided by a coefficient of 12 to 24.

16. The microbubble / microdroplet cluster composition is A cluster dispersion of microdroplets with an average diameter of 2-3 μm, stabilized by a lipid membrane having a net positive surface charge, The intravenously administerable composition according to claim 13, comprising microbubbles having an average diameter of 2 to 3 μm, stabilized by a lipid shell having a net surface negative charge.

17. The intravenously administerable composition according to claim 16, wherein the net surface positive charge of the microdroplets and the net surface negative charge of the microbubbles provide an electrostatic force that enables the formation of at least one microbubble / microdroplet cluster.

18. The intravenously administrable composition according to claim 13, wherein the resulting cluster diameter is in the range of 4 to 8 μm.

19. The intravenously administrable composition according to claim 17 for use according to any one of claims 1 to 9, wherein the gas of the microbubbles in at least one microbubble / microdroplet cluster comprises sulfur hexafluoride, C3-6 perfluorocarbon, or a mixture thereof.

20. The intravenously administrable composition according to claim 17 for use according to any one of claims 1 to 9, wherein the oil phase of the microdroplets of at least one microbubble / microdroplet cluster comprises a partially or completely halogenated hydrocarbon or a mixture thereof.

21. An intravenously administered composition according to claim 13 for use in the treatment of one or more of tumors, space-occupying masses, thrombolysis, and neurological disorders.

22. A composition that can be administered intravenously, comprising a microbubble-microdroplet cluster composition, The microbubble-microdroplet cluster composition comprises a group of negatively charged microbubbles and positively charged microdroplets, wherein the negatively charged microbubbles and positively charged microdroplets are permanently bound together as a single aggregate by their opposing electrostatic attraction. The composition is intended for use in a method of mechanical tissue ablation comprising the following steps: administering the cluster composition to a subject; and A step of activating the phase shift transition of the microdroplet component of at least one cluster by ultrasonic irradiation directed towards the target region of the cluster, thereby creating at least one ablation-assisted bubble within the target region; An intravenously administered composition wherein the expansion resulting from the transition from the at least one cluster to the at least one ablation-assisted bubble imparts mechanical stress to the target region, thereby supporting ablation on the target tissue within the target region.

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