Method and system for calculating point estimates of ultrasonic dose

Abstract

A method for creating a media characteristics map of a subject's region of interest, wherein the media characteristics map provides multiple different media characteristics values ​​in different segments of the region of interest, each dependent on the medium within the range of each segment, the method comprising: obtaining an image of the region of interest including a target treatment area and the surrounding area of ​​the target treatment area; processing the image to identify different components of the region of interest; dividing and classifying the different components into predetermined media categories; obtaining media characteristics values ​​associated with each media category; and assigning the above media characteristics values ​​to each respective component of the divided region of interest.

Description

[Background technology]

[0001] Ultrasound has long been used for diagnostic imaging. More recently, there has been growing interest in and development of using ultrasound in combination with microbubbles for drug delivery, immunotherapy, blood-brain barrier opening, and other applications.

[0002] As ultrasound waves propagate through tissue, their energy is attenuated by several mechanisms, including scattering and absorption. Absorption mechanisms transfer energy from the ultrasound to the tissue, where it is dissipated as heat. Excessive heating of tissue can lead to tissue damage and other undesirable biological effects. Such effects should be avoided when using ultrasound for diagnostic purposes. The thermal index (TI) is a dimensionless parameter intended to indicate the level of tissue heating during an ultrasound scan. This index is displayed on diagnostic ultrasound equipment, and there is a defined upper limit that must not be exceeded in the diagnostic settings.

[0003] The combination of high rarefactional pressure and low frequency in ultrasound can result in a mechanical effect called cavitation. In cavitation, bubbles form, vibrate, and collapse with varying degrees of intensity, potentially causing undesirable biological effects. The mechanical index (MI) is a dimensionless parameter indicating the likelihood of cavitation and is often displayed on diagnostic ultrasound instruments. Regulatory requirements for medical ultrasound imaging stipulate the use of an MI of less than 1.9. In ultrasound imaging with microbubble contrast agents, an MI of less than 0.7 is recommended to avoid adverse biological effects such as microbleeding and irreversible vascular damage. Using an MI of less than 0.4 in ultrasound imaging with microbubble contrast agents is considered "best practice." MI is defined as the peak (rarefactional) negative pressure in the ultrasound field (PNP), degraded by an attenuation factor that accounts for intratissue acoustic attention, and divided by the square root of the center frequency (Fc) of the ultrasound field in MHz according to the following formula:

[0004]

number

[0005] The ultrasonic pressure amplitude of the ultrasonic field generated by a medical ultrasound scanner with a connected ultrasonic probe is characterized by immersing the probe surface of the ultrasonic probe in water and measuring the pressure wave radiated from the probe with a hydrophone. From these measurements, the amplitude of the pressure wave that the probe can generate in tissue is estimated. A conservative value of the ultrasonic attenuation of the tissue is used in this estimate to calculate the upper safe operating limit of MI or TI. 0.3 dBcm -1 MHz -1 This conservative value helps avoid undesirable biological effects during diagnostic ultrasound examinations of subjects. However, this is a very simplified calculation of MI, assuming a homogeneous tissue pathway from the ultrasound source to the target area, and is not suitable for ultrasound implementations that require more precise delivery of ultrasound energy.

[0006] These current recommendations are not suited or optimized for ultrasound-mediated therapy. For the effective deployment of the mechanical and thermal action mechanisms involved when applying ultrasound irradiation in therapy, it is crucial to make the best estimate of the ultrasound dose delivered to the volume of tissue being treated. This invention provides a method for real-time ultrasound dosimetry in ultrasound-mediated therapy. European Patent Application Publication No. 2468191 discloses an ultrasonic diagnostic apparatus that provides a map of indices of interest. The ultrasonic diagnostic apparatus includes a calculation unit for calculating mechanical indices (MIs) corresponding to depth values ​​in the direction in which ultrasound propagates from the ultrasonic output section of a transmission transducer; a visualization unit for generating an MI map in which the relationship between the calculated MIs and the depth values ​​is visualized in graph form; and a display unit for displaying the MI map. European Patent Application Publication No. 2521593 discloses a system for applying focused ultrasonic energy to nerves around a patient's blood vessels, the system comprising: a platform for supporting a patient; one or more piezoelectric arrays coupled to the platform, each comprising a plurality of piezoelectric elements; a controller configured to control the piezoelectric elements; a programmable generator configured to produce output power to one or more of the piezoelectric elements; and a programmable processor configured to process signals sensed by at least one of the piezoelectric elements, wherein the platform comprises a table having recesses for the one or more piezoelectric arrays, and one or more of the piezoelectric elements are configured to deliver energy to treat areas around blood vessels. International Publication No. 2021 / 118783 discloses a technique for neuromodulation of tissue, comprising the step of simultaneously or sequentially applying energy (e.g., ultrasonic energy) to tissue in multiple regions of interest. As a result of neuromodulation, observable tissue displacement may occur through changes in one or more molecules of interest. Acoustic Cluster Therapy (ACT) – A Novel Concept for Targeted Drug Delivery via Ultrasound, Sontum et al [September 25, 2015] discloses a novel approach for drug delivery via ultrasound (US), Acoustic Cluster Therapy (ACT), and the basic features of the ACT formulation are described. The above concept involves the administration of free-flowing clusters of negatively charged microbubbles and positively charged microdroplets. These clusters are activated within the scope of the target pathology by diagnostic US, subsequently undergoing a liquid-to-gas phase change, transiently depositing large bubbles of 20–30 μm in the microvascular system, blocking blood flow for 5–10 minutes. Further applications of US would include biomechanical effects that increase vascular permeability, resulting in locally enhanced extravasation of components (e.g., released or concomitantly administered drugs) from vascular compartments. Methodologies for determining the crucial in vitro characteristics of ACT compounds, cluster concentration, and size distribution are described in detail. The study demonstrates how these properties are designed through various formulation parameters, and their importance as a predictor of biological behaviors such as depositional properties is demonstrated by US imaging in a canine model. Furthermore, the in vivo properties of activated ACT foam are investigated by in vivo microscopy in a rat model to confirm the assumed behavior of the above concepts. [Means for solving the problem]

[0007] According to a first aspect of the present invention, a method for calculating a point estimate of ultrasonic dose in a target treatment area, comprising the steps of calculating a unique ultrasonic propagation correction coefficient for a specific ultrasonic propagation path passing through a particular region of interest by obtaining a media characteristic map of the region of interest, wherein the media characteristic map provides a plurality of different media characteristic values ​​in different segments of the region of interest, which are media-dependent within each range of the segment, and obtaining the media characteristic map of the region of interest comprises the substep of obtaining an image of the region of interest including the target treatment area and the surrounding region of the target treatment area, the substep of processing the image to identify different components of the region of interest, the substep of dividing and classifying the different components into predetermined media categories, and the substep of obtaining media characteristic values ​​associated with each media category, A method is provided which includes a substep of estimating a category-specific ultrasonic coupling bubble element correction for a medium characteristic value resulting from the presence of at least one ultrasonic coupling bubble element in at least one component, adjusting the medium characteristic value of at least one component to take into account the respective category-specific ultrasonic coupling bubble element correction, and assigning the above medium characteristic value to each respective component of a divided region of interest; a substep of drawing a propagation path from an ultrasonic source to the above target therapeutic site; and a substep of compiling a medium characteristic value for each segment across the propagation path to calculate a unique propagation correction factor; and a step of using a unique propagation correction coefficient to indicate the ultrasonic dose delivered to the target therapeutic area.

[0008] The media category may include at least one of the following: different types of tissue, different types of tissue afflicted with one or more specific diseases, fluids, and gases.

[0009] Different types of tissue include one or more of the following: soft tissues, which include fat, muscle, parenchyma, tendons, and ligaments, and hard tissues, which include bone.

[0010] The substep of obtaining an image of the region of interest may include at least one of the following: obtaining a pre-scanned scan of the region of interest, performing a pre-scan of the region of interest, and using real-time diagnostic imaging system images.

[0011] The scan may include one or more of the following: computed tomography images and magnetic resonance images.

[0012] Category-specific media characteristics can be obtained from the database.

[0013] At least one ultrasonic coupling bubble element may include one or more of the following: contrast agent microbubbles, cavitation seeds, large microbubbles, and ACT® bubble technology ultrasonic coupling bubble elements, the ACT® bubble technology ultrasonic coupling bubble elements may include ACT® microbubble clusters and activated ACT® bubbles.

[0014] At least one ultrasonic coupling bubble element may contain contrast agent microbubbles, and the step of estimating contrast agent microbubble correction includes a substep of obtaining or estimating one or more contrast agent microbubble parameters, the one or more contrast agent microbubble parameters including a value relative to the dose of administered contrast agent microbubbles, contrast agent properties per unit concentration, subject blood volume, subject cardiac output, blood volume values ​​associated with each category, time to reach after intravenous administration of the contrast agent for each category, and a time-concentration curve; and a substep of using the contrast agent parameters to calculate the contrast agent correction for each category.

[0015] At least one ultrasonic coupling bubble element can include an ACT (registered trademark) bubble technology ultrasonic coupling bubble element, and the step of calculating an additional ACT (registered trademark) bubble correction includes sub-steps of estimating an additional correction resulting from an ACT (registered trademark) microbubble cluster in the presence of a high-frequency activated ultrasound, estimating an additional correction resulting from ACT (registered trademark) bubbles generated in the presence of a high-frequency activated ultrasound, and estimating an additional correction resulting from ACT (registered trademark) bubbles in the presence of a low-frequency enhanced ultrasound.

[0016] The step of calculating an additional ACT (registered trademark) bubble correction can further include sub-steps of obtaining or estimating one or more ACT (registered trademark) bubble parameters, where the ACT (registered trademark) bubble parameters include the blood volume of the subject, the cardiac output of the subject, the perfusion of each category of components, and the time-concentration curve, and calculating the number of ACT (registered trademark) bubbles delivered to each component by multiplying the fraction of cardiac output considering the perfusion of each category of components by the yield of activation of the ACT (registered trademark) bubble cluster, thereby estimating the number of ACT (registered trademark) bubbles in the category associated with each component.

[0017] The estimation of the number of ACT (registered trademark) bubbles in the category associated with each segment can include time-dependence by obtaining a value for the lifetime of ACT (registered trademark) bubbles in each category to model the decrease in the number of ACT (registered trademark) bubbles in each category over time.

[0018] The step of calculating the correction due to the presence of the contrast agent in each category can be based on contrast mode imaging ultrasound.

[0019] The step of calculating additional corrections due to the presence of ACT(registered trademark) bubbles in each category can be based on basic B-mode imaging ultrasound.

[0020] The method may further include the step of using a unique propagation correction coefficient to calculate an indication of the delivered ultrasonic dose, which is at least one of the resulting pressure, mechanical index, intensity, power, and thermal index.

[0021] According to a second aspect of the present invention, a non-temporary computer-readable storage medium is provided which stores instructions that, when executed on a processor, perform the method of the first aspect of the present invention.

[0022] According to a third aspect of the present invention, a system for providing point estimation of ultrasound dose in a region of interest in a subject comprises an ultrasound source, an image processor module for processing images to identify different components of the region of interest, a computer processor, a database module having media characteristic values ​​associated with a plurality of categories of components within the region of interest, and a data storage module having computer-readable instructions, wherein the data storage module, when executed on the above processor, performs the following tasks: acquiring an image of the region of interest including a target treatment area and the surrounding area of ​​the target treatment area; processing the image to identify different components of the region of interest; dividing and classifying the different components into predetermined media categories; and acquiring media characteristic values ​​associated with each media category, for at least one component. A system is provided that performs the tasks of: estimating a category-specific ultrasonic coupling bubble element correction for a medium characteristic value due to the presence of at least one ultrasonic coupling bubble element; adjusting the medium characteristic value of at least one component taking into account the category-specific ultrasonic coupling bubble element correction for each category; assigning the above medium characteristic value to each component of a divided region of interest; drawing an ultrasonic propagation path from the ultrasonic source to the above target treatment area; compiling the medium characteristic value for each component along the propagation path to calculate an ultrasonic propagation correction coefficient specific to the ultrasonic propagation path through the region of interest; calculating a point estimate of the ultrasonic dose in the region of interest based on the specific propagation correction coefficient; and adjusting the ultrasonic source according to the calculated point estimate of the ultrasonic dose when it is outside a given ultrasonic dose range.

[0023] A fourth aspect of the present invention provides a system for providing a point estimate of an ultrasonic dose in a region of interest in a subject, comprising: an ultrasonic source; an image processor module for processing images to identify different components of the region of interest; a computer processor; a database module having media characteristic values ​​associated with a plurality of categories for components within the region of interest; and a data storage module having computer-readable instructions that, when executed on the processor, perform the following tasks: drawing an ultrasonic propagation path from the ultrasonic source to the target treatment area; compiling media characteristic values ​​for each component along the propagation path to calculate an ultrasonic propagation correction coefficient specific to the ultrasonic propagation path through the region of interest; calculating a point estimate of the ultrasonic dose in the region of interest based on the specific propagation correction coefficient; and adjusting the ultrasonic source according to the calculated point estimate of the ultrasonic dose when it is outside a predetermined ultrasonic dose range.

[0024] The above image processor can be configured to divide and classify different components of a region of interest by identifying boundaries between different patterns in an image, analyzing patterns within those boundaries, and comparing each pattern to an image pattern of a known tissue type in order to find a match.

[0025] The above system can be a machine learning system, where each processed image is stored as training data along with the associated image data so that the image processor can provide more accurate segmentation and classification over time.

[0026] The above system can be further configured to track the probe's position, re-evaluate one or more propagation correction factors for changes in the probe's position, and store one or more propagation correction factors for each probe position to reduce the computational load.

[0027] The above system can be further configured to track the rhythmic in-plane and out-of-plane motion of the medium of interest, to re-evaluate one or more propagation correction factors for each of the in-plane and out-of-plane positions of the moving medium, and to store one or more propagation correction factors for each of the in-plane and out-of-plane positions of the moving medium.

[0028] The above system can be configured to track the rhythmic motion of a medium in and out of a plane through speckle tracking or machine learning algorithms.

[0029] In the method of the first or second embodiment, or the system of the fourth embodiment, the media characteristics may include at least one of attenuation, sound velocity, shear wave velocity, acoustic impedance, nonlinear compressibility coefficient, and dispersion coefficient.

[0030] The media characteristics may further include one or more acquisition characteristics that can be obtained from any one or any combination of the media characteristics listed above. [Brief explanation of the drawing]

[0031] [Figure 1] This is a flowchart of a method for calculating point estimates of ultrasound dose. [Figure 2] This is a flowchart of a method for calculating a media characteristics map of a region of interest. [Figure 3a] This figure shows an exemplary image of the subject's region of interest. [Figure 3b] This figure shows an example image of the region of interest in Figure 3a, with different components identified. [Figure 3c] This figure shows a representation of the region of interest composed of identified components. [Figure 4a] This is a graph of the normalized backscatter intensity curve of bubbles in the human liver. [Figure 4b] Figure 5a is a graph of the actual concentration as a function of time, using the backscattering intensity curve. [Figure 5] This diagram shows a system for calculating point estimates of ultrasonic dose. [Figure 6a] This is a diagram of a method carried out according to a first embodiment of the present invention. [Figure 6b] This graph shows the relationship between tissue layer and depth according to the method of the first embodiment. [Figure 6c] This is a graph showing the relationship between MI and depth according to the first embodiment. [Figure 7a] This is a diagram of a method carried out according to a second embodiment of the present invention. [Figure 7b] This is a graph showing the relationship between tissue layer and depth, according to the second example. [Figure 7c] This is a graph showing the relationship between MI and depth according to the second embodiment. [Figure 8] This figure shows the results of tumor-specific uptake of fluorescent dyes by ACT® treatment using an enhanced step ultrasound irradiation field. [Modes for carrying out the invention]

[0032] Unless otherwise defined, all technical terms, notations, and other scientific or specialized terms used herein are intended to have meanings that are generally understood by those skilled in the art to which this invention relates. In some cases, terms that have generally understood meanings are defined herein for clarity and / or for quick reference, and the inclusion of such definitions herein should not necessarily be interpreted as representing a significant difference beyond what is generally understood in the art.

[0033] The term "ultrasonic dosimetry," as used herein in the field of medical ultrasound technology, describes determining, including measuring, calculating, and evaluating the amount of ultrasound radiation delivered to a target tissue in order to achieve the desired biological effect.

[0034] The terms "ultrasound irradiation" or "insonation" as used herein refer to exposure to or treatment with ultrasound.

[0035] As used here, the term "speed of sound" refers to the group velocity and / or phase velocity and / or signal velocity of a longitudinal pressure wave.

[0036] The terms "ultrasound dose" or "ultrasound dosage" as used herein refer to instantaneous, time-averaged, spatially averaged, time-integrated, and spatially integrated ultrasound parameters at a point or region, as defined, for example, in the international standards for medical diagnostic ultrasound, IEC62127-1, IEC62359, and IEC60601-2-37.

[0037] The terms "ACT bubble" or "ACT® bubble" as used herein are interchangeable and refer to large, activated bubbles derived from ACT microbubble clusters after ultrasonic irradiation with activated ultrasound.

[0038] In diagnostic imaging applications, numerous acoustic parameters are used to quantify various aspects of the applied ultrasound dose, including the mechanical index (MI), thermal index (TI), and intensity spatial peak temporal index (Ispta). Generally, in therapeutic and diagnostic ultrasound procedures, ultrasound is applied to the subject's region of interest. This ultrasound is delivered by a transducer positioned in or toward the region of interest, with a predetermined ultrasound dose.

[0039] In diagnostic applications, the use of ultrasound technology alone or in combination with contrast agents such as microbubble compositions is well established. Currently, there is growing interest in and development of ultrasound use in therapeutic applications. Ultrasound dose measurement is necessary for drug delivery via ultrasound and microbubbles, ultrasound and microbubble-mediated therapy, and ultrasound-mediated therapy. To effectively develop the mechanical and thermal action mechanisms when applying ultrasound irradiation in therapy, it is important to make the best estimate of the ultrasound dose delivered to the volume of tissue being treated.

[0040] The actual ultrasound dose delivered to a target region by an ultrasound source (point estimate of ultrasound dose) depends on the configuration of the ultrasound source, the ultrasound transmission parameters, and the characteristics of the medium through which the ultrasound propagates from the ultrasound source to the target region. Therefore, the ultrasound parameters, such as frequency, wavefront phase, and amplitude, may change due to propagation through various tissue types and the presence of an ultrasound coupling bubble element. This thus strongly influences the actual ultrasound dose in the target region.

[0041] The present invention includes the steps of identifying and segmenting various tissue types in a region of interest, estimating the presence of at least one ultrasonic coupling bubble element (e.g., microbubbles and / or ACT® bubbles) in each of the various tissue types and calculating at least one propagation correction coefficient for use in calculating a more accurate ultrasonic dose, and optionally including the step of reconstructing an ultrasonic source that provides the ultrasonic dose.

[0042] The ultrasonic coupling bubble element can be contrast agent microbubbles, ACT® microbubble clusters, cavitation seed-type drugs, large bubbles, and / or activated ACT® bubbles. In other words, the ultrasonic coupling bubble element is microbubble technology. The large bubbles in microbubble technology have a diameter greater than 8 μm and can be trapped in the capillary bed of the subject.

[0043] Acoustic Cluster Therapy (ACT®) is a technique for localized drug delivery via ultrasound. ACT® comprises microbubbles consisting of negatively charged microbubbles containing perfluorobutane (PFB) stabilized by a monophospholipid membrane, combined with positively charged microdroplets stabilized by a monophospholipid membrane containing perfluoromethylcyclopentane (PFMCP). When these microbubbles and microdroplets are mixed, small clusters are formed, bound together by electrostatic forces. ACT® microclusters can be administered in combination with therapeutic drugs. When irradiated with pulsed ultrasound (typically at frequencies of 2-5 MHz in clinical diagnostic settings), these clusters undergo an activation phase, causing the vibrating microbubbles to transfer energy to the microdroplets, resulting in the instantaneous evaporation of the microdroplets, which form larger bubbles hereafter referred to as ACT® bubbles.

[0044] The spatially varying properties of a medium in the region through which ultrasound propagates include attenuation, sound velocity, shear wave velocity, acoustic impedance, nonlinear compressibility, and dispersion coefficient. At least one propagation correction coefficient can be calculated based on one or more of the above properties or their derivatives.

[0045] Ultrasonic dose is determined based on one or more of the established ultrasonic parameters, such as peak negative pressure, peak positive pressure, mechanical index (MI), thermal index (TI), spatial peak time-averaged intensity (Ispta), spatial peak pulse-averaged intensity (Ipa), spatial mean time-averaged intensity (Isata), and total acoustic power, as defined in IEC62127-1, IEC62359, and IEC60601-2-37.

[0046] Figure 1 is a flowchart of Method 100 for calculating point estimation of ultrasonic dose.

[0047] This method begins in step 102, in which a media properties (MP) map of the subject's region of interest is acquired, and the MP map provides specific different MP values ​​across the region of interest. The MP map is based on the unique composition and anatomical structures and / or other components of the region of interest. An example of the MP map and the method for acquiring it is described below in more detail with reference to Figure 2.

[0048] One exemplary MP map is an attenuation map. This attenuation map provides distinct attenuation values ​​specific to the region of interest. The attenuation values ​​are based on the specific composition and anatomical structure of the region of interest, as well as the presence of other components, particularly the presence of one or more ultrasonic coupling bubble elements. Another example of an MP map is a velocity map, in which changes in the mass density and bulk modulus of the changing medium through which the ultrasound propagates affect the velocity of the ultrasound. The velocity map provides distinct velocity values ​​specific to the region of interest. The velocity values ​​are based on the specific composition and anatomical structure of the region of interest, as well as the presence of other components. A further example is a phase map, which can be combined with a velocity map and an attenuation map. In a preferred embodiment, two or more individual MP maps for attenuation, velocity, nonlinear coefficients, and phase are combined to provide a composite medium properties (CMP) map of the region of interest.

[0049] In step 104, the propagation path (PP) that defines the dose is approximated (projected). In the first embodiment, this is achieved by drawing a line-of-sight from the ultrasound source to the target tissue. Alternatively, this is achieved by drawing multiple line-of-sights, each starting from each element in the transducer array. In the preferred embodiment, the PP is an acoustic model of the conducted ultrasound field. Ultrasound is typically applied to the external or internal surface of the body, or generated inside the body by inserting a transducer, for example, via a laparoscope. As the ultrasound passes through each component along the above path, it undergoes various absorptions, scatterings, refractions, and aberrations.

[0050] In step 106, it is possible to calculate (i.e., integrate) the MP value across the PP in order to calculate the intrinsic propagation correction factor (PCF) of the PP through a particular region of interest (step 108). In some embodiments, the PCF takes a complex value.

[0051] In step 110, the resulting MI or TI from the ultrasonic field along the PP is estimated based on a pre-selected set of ultrasonic parameters and the PCF.

[0052] A pre-selected set of ultrasound parameters can be modified based on the initial MI or TI estimate to provide an improved / refined MI / TI estimate, and can be used in conjunction with PCF.

[0053] Furthermore, the optimized set of parameters can be iteratively used with the PCF to converge to the optimal estimate of MI / TI. Attenuated temporal peak dilute pressure P γ、α At any point in the ultrasonic field transmitted by the ultrasonic source, it can be defined as follows:

[0054]

number

[0055] The optimal MI can be calculated using a modified version of Equation 1 where α is replaced with the attenuation correction factor (α CF ).

[0056] TIFF0007878789000003.tif1023 and

Number

[0057]

Number

[0058] Thus, in embodiments where the PCF is the attenuation correction factor, the attenuation correction factor can be used in an adjusted equation that relates the above attenuation coefficient, ultrasonic operating frequency, and mechanical index.

[0059]

Number

[0060] In step 112, the calculated M1 can be sent to the ultrasound source to automatically adjust the output settings of the ultrasound source in order to deliver the specialized ultrasound dose to the volume of tissue to be treated. Alternatively, the MI can be displayed, and the user can manually adjust the settings of the ultrasound source, in which case the displayed MI value is calculated and updated in real time via method 100.

[0061] Steps 104–110 can be performed in real time in a continuous loop 103 during ultrasound imaging and / or ultrasound therapy. For example, if the ultrasound source / transducer is moved, the PP changes and the PCF is recalculated. The movement of the ultrasound source can be detected using hardware and software to spatially track one or more of the ultrasound source's movement, orientation, and posture. Such tracking can also be combined with co-registered images from other imaging modalities, including CT and MRI. In further embodiments, the PCF is recalculated when the region of interest is moved by other external factors such as subject movement or respiratory motion.

[0062] In one embodiment, the PCF is determined by an attenuation correction coefficient and a phase shift correction coefficient. In this case, steps 104-110 can be performed in real time in a continuous loop between ultrasound imaging and / or ultrasound treatment. For each loop iteration, one of the above factors is recalculated based on an image-specific metric, such as the point spread function of a single-point scatterer in the region of interest. An example of such a point scatterer is an activated ACT® cluster.

[0063] Figure 2 is a flowchart of Method 200 for creating a (C)MP map specific to a particular region of interest. Method 200 provides step 102 of Method 100. A (C)MP map consists of segments of known volume / area, each having an associated MP value. An MP map can be an attenuation map, a sound velocity map, a shear wave velocity map, an acoustic impedance map, a dispersion coefficient map, a nonlinear coefficient map, or a map of parameters derived from these properties. An MP map can be a CMP, which is a combination of two or more of the above maps.

[0064] In step 202, images of the region of interest in the subject are obtained. The region of interest consists of the target region and the surrounding region relative to the target region. The target region is the area to which the ultrasound dose is delivered. For example, the target region may be a metastasis in the subject's liver, and the surrounding region may be a healthy liver, muscle, fat, and other adjacent organs. Images of the region of interest can be obtained in a variety of different ways. For example, many images of the region of interest may have already been taken during the health status assessment phase of the subject. It is preferable to use 3D image data for images of the region of interest, but 2D image data can also be used.

[0065] Method 100 may provide images of the region of interest if scans of the region of interest, particularly volume scans, such as magnetic resonance imaging (MRI), computed tomography (CT), or earlier ultrasound scans already exist. Alternatively, new scans of the region of interest, such as MRI or CT scans, can be performed to provide images of the region of interest. Another method for obtaining images of the region of interest is to utilize an ultrasound source. The ultrasound source used in Method 100 can be used first to obtain an ultrasound scan of the region of interest by irradiating the region with ultrasound. The ultrasound pressure amplitude for the purpose of obtaining images of the region of interest is 0.3 dBcm to avoid overexposure before a method is calculated to find an accurate estimate of the radiation dose. -1 MHz -1This may be determined by a lower derating factor. In some embodiments, the ultrasound scan is obtained in real time. In yet another embodiment, the real-time ultrasound scan is superimposed on a pre-scanned image to enhance information about the region of interest. Imaging may include a step of identifying the volume of the target if it is not yet known. Imaging may also include a further step of identifying a tumor or metastasis within the target region.

[0066] Referring to Figure 3a, an exemplary image 300 of the subject's region of interest 301 is shown. Image 300 is an example of an image that will be processed by an image processor. The example image in Figure 3a was obtained by an ultrasound scan.

[0067] In step 204, image processing is performed on the image of the region of interest to identify different components and divide the image into different categories based on the identified components (step 206). The components to be identified and classified may be different types of tissue in both healthy and diseased states. Different types of tissue may include, but are not limited to, soft tissues such as fat, muscle, tendons, and ligaments, and hard tissues such as bone. Metastases may also be identified and classified in a different way from other components. The region of interest is divided in this way because each component may have a different effect on ultrasound.

[0068] Figure 3b is an exemplary image 300 of the region of interest 301 of Figure 3a, divided into different components by an image processor. In the example of Figure 3b, the identified components are muscle 304, metastasis 306, healthy liver 302, and aorta 308.

[0069] In step 208, for each component in the region of interest, at least one MP value specific to the component's associated category, such as attenuation and / or sound velocity, is retrieved from the database and assigned to that component. An example database is shown below in Table 1.

[0070] [Table 1]

[0071] Figure 3c shows an exemplary MP map in the form of an exemplary attenuation map 500 of the region of interest 301, composed only of its constituent components. The attenuation map 500 is a graphical representation of the collection of data points, including the 3D / 2D coordinates of each segment along with the respective attenuation values ​​within these segment coordinates. The attenuation map 500 is divided into segments 502 representing the region of healthy liver, segments 504 representing the region of muscle, several segments 506 representing the region of metastasis, and segment 508 representing the region of the aorta. The attenuation map 500 can be stored in a database for access by ultrasound scanner software. The attenuation map can be stored in data storage memory for long-term or short-term use for later retrieval.

[0072] This method incorporates a correction 210 into the unique PCF based on the presence of one or more ultrasonic coupling bubble elements in at least some of the tissue layers.

[0073] In a specific embodiment shown in Figure 2, in step 210a, the correction for the PCF is calculated based on the presence of microbubbles, such as contrast agent microbubbles, in at least one of the components in the region of interest.

[0074] Because contrast agents are often added during the pre-ultrasound imaging stage, contrast agent microbubbles are frequently present in the tissue of the region of interest when treating metastases with ultrasound. Adding a contrast agent to this region alters its acoustic properties. Depending on the ultrasound frequency, the scattering, absorption, reflection, and refraction properties of the region may change. For example, a decrease in density at the interface between the contrast agent and surrounding tissue causes strong scattering and reflection of ultrasound, returning it to the ultrasound probe. This acoustic property is known as backscattering, resulting in higher contrast in various areas of the acquired ultrasound image. Because contrast agents alter the acoustic properties of the region, they can significantly affect the derating coefficient applied to the ultrasound pulse delivered to the target region. Therefore, refining the estimation of the ultrasound dose delivered to the target region requires additional corrections for the contrast agent and their additional amounts. At least four commercially available diagnostic ultrasound imaging (contrast) agents exist on the market: Sonazoid®, Definity®, Optison®, and SonoVue®, which are also used in clinical research for therapeutic applications. These drugs are “free-flow” tracers because they are small enough to circulate in the bloodstream and are not trapped in capillaries. The terms “microbubble” or “regular, contrast-enhanced microbubble” are used herein to describe microbubbles having a diameter in the range of 0.2–10 μm, generally with an average diameter between 2–3 μm. Other microbubble technologies are also being adopted in clinical practice, such as Acoustic Cluster Therapy® (Exact Therapeutics®) and SonoTrans® (Oxsonics®).

[0075] In certain embodiments where the correction factor is an attenuation correction factor, the properties of the contrast agent can be calculated or obtained from in vivo experiments in order to calculate the additional attenuation due to the presence of the contrast agent in terms of attenuation per unit concentration. For example, the in vivo environment may be whole blood or 5% human serum albumin at 37°C and 85% gas saturation. Next, ultrasound of a predetermined frequency is applied to the environment containing the contrast agent. The MI (micro-intensity) affected by the environment can be measured. The measured MI and the applied ultrasound frequency can be used to calculate the attenuation per unit concentration of contrast agent microbubbles.

[0076] Next, the subject's blood volume is approximated; for example, a 70 kg subject has approximately 5 liters of blood. Then, the subject's cardiac output is estimated; for example, for a 70 kg subject, this would be 5 liters of blood per minute. Estimates of general values ​​for blood volume not contained in large compliant tubes are also required for each of the segmented tissue types. For example, the liver accounts for approximately 15% of blood volume, while the blood volume of skeletal muscle, skin, and adipose tissue at rest is only a fraction of that of the liver. Next, a table of general arrival times after intravenous administration of contrast agent for each component category is required. Further tables of concentration-time curves for intravenously administered free-flowing contrast agents are required for each component category. Tables providing values ​​for concentration-time curves of intravenously administered free-flowing contrast agents can be found in the prior art.

[0077] The dynamics of bubble inflow and washout from various organs are well-known for free-flowing microbubbles and have been similarly studied for activated ACT® bubbles. For example, in a canine model, the half-life of ACT® bubbles, measured by backscatter intensity of ultrasound imaging, was 70 seconds. Figure 4a shows typical normalized backscatter intensity curves for free-flowing microbubble sonazoid and ACT® bubbles in the human liver. Once activated, ACT® bubbles accumulate in the liver over time. Sonazoid inflow is more rapid and decreases rapidly due to partial washout of bubbles from the liver. Some bubbles are absorbed by Kupffer cells in the liver, leaving residual concentrations after the washout is complete. Similar curves can be created for other organs, in which case, in the absence of Kupffer cells, the free-flowing component of ACT® injection follows the dashed line 402. Figure 4b shows the actual concentration as a function of time, using the backscatter intensity curve from Figure 4a. The decay in each tissue type will depend on these time-varying curves. These curves can be predetermined or calculated for each patient by parameterizing a tissue-specific function in the following way, for example, using the infusion time T and the tissue-specific washout time θ.

[0078]

number

[0079]

number

[0080] These models can also be used as parameterized models in model-based estimation schemes. The model-based approach estimates parameters based on backscatter information collected from each segment during the processing procedure and a prior model for concentration. The calculated concentration is used to calculate the attenuation the ultrasound pulse experiences as it traverses the tissue structure between the probe and the target tissue for each time point. For each time point, the ultrasound source configuration is updated, for example, by adjusting the amplitude or frequency of the ultrasound source excitation, to achieve the desired situ mechanical index at the target lesion.

[0081] Therefore, additional attenuation due to the presence of the contrast agent can be calculated from the attenuation value per unit concentration, the blood volume value, the time to reach the target after administration, and the concentration value over time in each component category, and this can be added to at least one category attenuation value, which is preferably associated with the components and concentrations of the contrast agent.

[0082] The peak attenuation of ultrasound pulses generated from contrast agent microbubbles is calculated from data provided in the database. Peak attenuation due to freely flowing contrast agent microbubbles can be approximated by using formulas to calculate the concentration of freely flowing bubbles for each tissue type. (Patient weight M, contrast agent injection volume D per body weight, cardiac output Q, organ blood volume fraction R) B Using the injection time T and activation efficiency η, the peak dose can be calculated as follows.

[0083]

number

[0084] After calculating the correction as a result of the presence of the contrast agent, the method can then proceed to step 214, in which an MP map of the region of interest is generated.

[0085] Alternatively or additionally, the method may proceed to step 210b so that (further) additional corrections due to the presence of acoustic cluster therapy (ACT®) bubbles in at least one category are taken into consideration.

[0086] In ACT®, small clusters of charged microbubbles attached to conversely charged oil droplets are injected into the bloodstream. Ultrasound is applied to vibrate the microbubbles and transfer energy from the microbubbles to the clusters, fusing the particles within the clusters into single particles. Subsequently, the oil evaporates into gas contributed by the microbubbles, generating enlarged microbubbles (ACT® bubbles). The ultrasonic pulses applied to the ACT® bubbles vibrate the larger gas ACT® bubbles.

[0087] More specifically, the above formulation is a cluster dispersion of microdroplets. This cluster dispersion is stabilized by a lipid membrane with a positive net surface charge and a median diameter of 2-3 μm, forming clusters of microbubbles with a median diameter of 2-3 μm, and by a lipid shell with a negative surface charge. These are opposite charges on the oil droplet and microbubble surfaces, respectively, and electrostatic interactions allow them to form small clusters. These clusters are approximately 5 μm in diameter and flow freely within the vascular system. When exposed to medical diagnostic ultrasound frequencies, the (multiple) microbubbles within the clusters vibrate, the particles fuse into a single entity, the oil evaporates, and the expanded microbubbles (ACT® bubbles) are generated.

[0088] The frequency of medical diagnostic ultrasound is in the range of 1 to 15 MHz, preferably 2 to 10 MHz, more preferably 5 MHz. The oil droplet-microbubble fusion process can also be generated by short imaging pulses, low MI, e.g., less than 0.1 MI, and low duty cycles, which are commonly used in medical imaging systems. Once fused, the oil droplets evaporate into gas that forms the core of the bubble, forming a bubble with a median diameter of 20 to 30 μm. Because the oil has low water solubility and a short diffusion distance, the bubbles can persist for several minutes before dissolving. When administered intravenously, clusters flow through the bloodstream, and large ACT® bubbles are formed (activated) from the clusters to which the ultrasound field is applied (activated ultrasound), spatially localizing their generation only in the tissue irradiated with ultrasound. The ACT® bubbles are large enough to become lodged in the first capillary bed into which they flow and remain there for several minutes. During this time, a lower frequency ultrasound field (enhanced ultrasound) is applied at a low MI to drive mechanical vibrations that drive a biomechanical action mechanism capable of producing a therapeutic effect and / or enhancing extravasation and delivery of the drug. The lower frequency of the applied ultrasound field is between 0.1 and 1 MHz, preferably 0.3 and 0.6 MHz, and more preferably 0.5 MHz.

[0089] The MI is preferably in the range of 0.1 to 0.4. Therefore, for treatment using ACT® technology, both the ultrasonic field that generates ACT® bubbles from clusters at high frequencies (activated ultrasound) and the ultrasonic field that generates ACT® bubbles from clusters at low frequencies that drives the mechanical effect for treatment (enhanced ultrasound) must be appropriately controlled in order to achieve the optimal therapeutic effect.

[0090] Accurate ultrasound dose estimation is particularly important for ACT® therapy because the ultrasound dose applied requires a specific lower limit of energy, and undesirable biological effects and tissue damage must still be controlled. For example, the conservative, lower derating coefficients in current ultrasound control standards may not yield sufficient outcomes for ACT® therapy, and the need for region-specific PCF is particularly useful for ACT® therapy.

[0091] Since activated ultrasound is high-frequency and enhanced ultrasound is low-frequency, there are three elements to the ACT® treatment process. These can separately affect the medium properties (i.e., attenuation of the segment of interest, sound velocity, shear wave velocity, acoustic impedance, nonlinear compressibility, and dispersion coefficient). Therefore, it is preferable that MP corrections be calculated for each element. The first element is microbubbles in the presence of high-frequency activated ultrasound. The second element is ACT® bubbles generated in the presence of high-frequency activated ultrasound. The third element is ACT® bubbles in the presence of low-frequency enhanced ultrasound. It is preferable that MP corrections for each component category be calculated for each of the three elements described above. Therefore, for ACT® treatment, the type of tissue, the number of free-flowing microbubbles, and treatment corrections for both the generation and lifetime of ACT® bubbles can all potentially be corrected to modify the ultrasound dosimetry parameters in both the high-frequency ultrasound activation step and the low-frequency ultrasound treatment enhancement step.

[0092] An optional intermediate step in the process of calculating additional MP correction by ACT® bubbles is to destroy the free-flowing microbubbles with high-amplitude and high-power diagnostic imaging pulses. These high-amplitude and high-power diagnostic imaging pulses can be incorporated into a diagnostic scanner as a “flash” sequence or as part of an “uncorrelated” imaging mode. Such pulses typically have an MI of 0.7 or higher. Such pulses can be used to more effectively image the free-flowing microbubble components or to remove free-flowing microbubbles within a scan plane or tissue volume. However, such high-intensity pulses do not destroy ACT® bubbles. Therefore, these imaging pulses can be used to remove free-flowing microbubble components while leaving the ACT® bubble components unaffected. Thus, the need for MP correction due to the presence of contrast agents can be reduced or even eliminated. For example, by substantially destroying all free-flowing microbubbles before the irradiation of a therapeutic ultrasound dose to the treatment area, the attenuation component from the free-flowing microbubbles can be completely removed.

[0093] To calculate MP corrections related to ACT® bubbles, first, the number of ACT® bubbles trapped in capillaries is estimated. The values ​​of the subject's total blood volume and cardiac output are estimated or obtained. Next, estimates of perfusion velocity for each component category are calculated. Then, the number of ACT® bubbles delivered to the tissue can be calculated by multiplying the fraction of cardiac output accounted for by the cluster activation yield. The activation yield has been quantitatively calculated to be 24% in a large animal dog model. Furthermore, the decrease in the number of ACT® bubbles present as a function of time in each category component is estimated or retrieved from a database. The decrease in ACT® bubbles over time can be estimated by measuring the lifetime of ACT® bubbles in different tissue types.

[0094] Table 2 shows an example database that provides information specific to the components. For simplicity, only two frequencies are shown here.

[0095] [Table 2]

[0096] Here, MP is attenuation. Contrast-enhanced mode imaging ultrasound is suitable for estimating the attenuation of free-flowing contrast agents. Basic B-mode imaging is suitable for estimating attenuation by ACT® bubbles. This is for the following reasons:

[0097] Contrast imaging modes are likely to be more specific due to the backscatter signals generated from the free-flowing microbubble components of commercially available microbubble contrast agents. These imaging modes utilize the nonlinear behavior of the bubbles to extract nonlinear vibrational signatures, selectively suppressing backscatter signals from tissue components, in order to form images where the microbubble components are more dominant. The frequencies of these pulses are approximately 2–10 MHz, close to the mechanical resonance of the bubble system, resulting in a strong coupling between these microbubbles and the diagnostic imaging pulses. Therefore, bubble vibration is significantly increased compared to ultrasound irradiation with off-resonance pulses. In contrast, the resonance frequency of ACT® bubbles is approximately 300 kHz. This resonance frequency is significantly lower than the range of diagnostic imaging frequencies. Ultrasound irradiation is applied to ACT® bubbles beyond resonance at the diagnostic imaging frequency. In this situation, the scattering efficiency of the bubbles is much higher than that of the contrast agent. Here, scattering efficiency is defined as the ratio of scattering to absorption plane. As the size of the ACT® bubbles increases, they generate significantly more backscatter (increased scattering plane compared to free-flowing drugs). Therefore, they are easily visualized in basic B-mode. In this imaging mode, the enhancement of tissue contrast between basic B-mode imaging is dominated by the ACT® bubble components compared to the contrast agent. Thus, contrast-mode imaging ultrasound is preferably used for estimating the attenuation of the free-flowing contrast agent, and basic B-mode imaging is preferably used for estimating the attenuation by the ACT® bubble.

[0098] Alternatively, further ACT®-specific imaging modes may be suitable for use in estimating decay by ACT® bubbles.

[0099] Attenuation values ​​across a frequency range are obtained for activated ACT® clusters and the microbubble components of the clusters. An example of such a database is given in Table 3. For simplicity, only two frequencies are shown here. The attenuation values ​​are proportional to the concentration.

[0100] [Table 3]

[0101] The peak attenuation of the ultrasound pulse caused by the injection of ACT® clusters is calculated from data provided to the database. For example, the peak attenuation from free-flowing ACT® microbubble clusters can be approximated by using a formula to calculate the concentration of free-flowing bubbles for each tissue type. (Patient weight M, ACT® injection dose per unit of body weight D, cardiac output Q, organ blood volume fraction R) B Using the infusion time T, the percentage of free-flowing bubbles r in the injected formulation, and the activation efficiency η, the peak dose can be calculated as follows:

[0102]

number

[0103] Similarly, the peak concentration of the ACT® bubble can be calculated for each tissue type using the following formula, where V is the total blood volume.

[0104]

number

[0105] By using additional information and assigning values ​​to different segments of the identified tissue types, the predicted maximum attenuation for a given dose can be calculated as shown in Table 4. Here, a dose of 40 μL / kg is used to calculate the attenuation from the microbubble and ACT® bubble components based on the given formula and the table above.

[0106] [Table 4]

[0107] Once the MP values ​​specific to each category have been adjusted to take into account up to three additional category-specific elements of the ACT® treatment process correction and assigned to their respective components, the method can then proceed to step 214, where the (C)MP map is generated.

[0108] The presence of microbubbles and ACT® bubbles can affect changes in sound velocity and phase. In a manner similar to adding additional attenuation to each component of a divided region of interest, components in an MP map, such as the sound velocity map or the phase change map, can also be tuned by the presence of microbubbles and ACT® bubbles, and in a manner similar to additional attenuation.

[0109] If the ultrasound dose falls significantly below the effective dose range, the bubbles described above will not vibrate sufficiently; therefore, precisely controlling the ultrasound dose intended to target and vibrate the ACT® bubbles is particularly important. Insufficient bubble vibration will prevent the desired ACT® therapeutic effect from being achieved. However, if the ultrasound dose is too high, exceeding the effective dose range, the ACT® bubbles may vibrate too strongly, potentially causing undesirable biological effects. These undesirable biological effects may include vascular damage and capillary wall destruction. This can lead to blood flow obstruction, potentially resulting in less chemotherapy being delivered to the tissue site than with chemotherapy without ACT® treatment. Therefore, there is an acceptable range of ultrasound energy (window) for driving drug delivery and achieving the desired ACT® therapeutic effect. Using the method of the present invention described herein, this range of ultrasound energy (ultrasound dose) can be controlled more easily and reliably, despite the anatomical structure and composition of the subject and the presence of additional components for imaging and / or ACT® treatment.

[0110] Once (C)MP is generated, method 200 is terminated, and the method according to method 100 can proceed to step 104. Here, the calculation of the attenuation value across PP for calculating PCF includes additional contrast agent correction for bubbles. For example, the attenuation correction coefficient includes the attenuation of additional contrast agent and / or the attenuation of ACT® bubbles.

[0111] Figure 5 is a schematic diagram of system 500 for both generating a (C)MP map of a subject's region of interest (Method 200) and calculating a point estimate of the ultrasound dose (Method 100). System 500 comprises a computer processor 205, an ultrasound source 504, an image processor 506, a database module 508, and a data storage module 510. As indicated by the dashed lines 502a-h, each module of system 500 communicates data with each of the other modules, either directly or through one of the other modules. The data storage module 510 contains computer-readable instructions 502 that, when executed on the computer processor 205, perform the tasks described below. Hereafter, computer-readable instructions when executed on the computer processor will be referred to as “programs” for simplicity.

[0112] First, the program instructs the image processor module 506 to process images of the subject's region of interest, divide the region of interest into its different constituent parts, and classify those constituent parts. The image processor 506 is able to divide and classify the different constituent parts of the region of interest by identifying boundaries between different patterns in the image and analyzing the patterns within the boundaries by comparing them to patterns of known tissue types to find the closest match. Over time, each of the processed images, and the associated decay map data, can be used as historical data in the system 500 to accumulate the image processor's more accurate division and classification capabilities in the form of machine learning.

[0113] Next, the program instructs access to the MP value database 508, retrieves MP values ​​for each identified category, and assigns appropriate values ​​to each identified component. An example of a database containing ultrasound parameter (MP) values ​​for each identified category (e.g., tissue type) is shown in Table 1. In this illustrative table, attenuation values ​​for skin, muscle, fat, parenchyma, and pancreas are given at a first frequency of 0.5 MHz and a second frequency of 2 MHz. Preferably, the MP value database contains ultrasound parameter values ​​across a frequency range. Such data is publicly available in the art.

[0114] Preferably, the database module 508 further comprises a contrast agent microbubble (or other ultrasound coupling bubble element) database 516 containing values ​​for additional corrections, for example, values ​​for decay per unit concentration of different contrast agents. The database 516 may further contain extractable values ​​for the following: Blood volume relative to different subject body weights, Estimation of cardiac output for different subject body weights Typical values ​​of blood volume for each component category, Typical arrival times after intravenous administration of different contrast agents for each component category, Concentration-time curves for intravenously administered free-flow contrast agents for each component category.

[0115] The program can obtain the necessary values ​​from an additional database 516 to estimate additional corrections, such as additional attenuation, for the presence of contrast agents in each category. Then, before the program performs the step of calculating the PCF across PP, the additional corrections can be added to the MP values ​​of each respective component, such as the attenuation values.

[0116] As described above, the peak attenuation of ultrasound pulses generated from contrast agent microbubbles can be calculated from the data provided in the database. The peak attenuation from free-flowing contrast agent microbubbles can be approximated by using Equation 8 to calculate the concentration of free-flowing bubbles for each tissue type.

[0117] If ACT® treatment is available, the database module 508 may include a database 518 containing values ​​for estimating additional corrections resulting from the three elements of the ACT® treatment process.

[0118] Database 518 may also contain additional retrieveable values ​​for the following: Total blood volume of subjects with different body weights Cardiac output of subjects with different body weights, Perfusion rates for each component category (Table 2, row 4), Activation yield of ACT® microbubble clusters (Table 2, row 8), The decrease in the number of ACT(registered trademark) bubbles existing as a function of time in each category component (Table 2, row 7), and Lifespan of ACT® bubbles in different types of tissues (Table 2, row 6).

[0119] Instead of obtaining this information from a database, it is possible to determine a patient's total blood volume and cardiac output through patient examinations or by using approximations. For example, blood volume and cardiac output can be estimated from the patient's body weight.

[0120] The program can calculate the peak attenuation of ultrasonic pulses caused by the injection of ACT® clusters from data provided to the database. For example, the peak attenuation from free-flowing ACT® microbubble clusters can be approximated by using Equation 9 to calculate the concentration of free-flowing bubbles for each tissue type. The peak attenuation from activated ACT® bubbles can be approximated using Equation 10.

[0121] The program can retrieve the necessary values ​​from an additional database 518 to estimate additional adjustments due to the presence of ACT® treatment in each category. Next, the estimated additional corrections are added to the MP values ​​of each respective component before the program performs the step of calculating the PCF over the PP.

[0122] A C(MP) map, which depends on the geometry and tissue type, the presence of contrast agent, and / or the presence of ACT® bubbles, is thus generated and stored in the data storage module 510.

[0123] Values ​​in database module 516 can also be acquired and used to estimate corrections for the presence of microbubbles on media properties or derived properties such as sound velocity, shear wave velocity, acoustic impedance, nonlinear compression coefficient, and dispersion coefficient, depending on the desired MP map. Further values ​​in database module 518 can also be acquired and used to estimate additional corrections for the presence of ACT® bubbles on the above media properties. Thus, each sound velocity map, shear wave velocity map, acoustic impedance map, nonlinear compression coefficient map, and dispersion coefficient map (as well as any derived property maps) can be generated and stored in data storage module 510, depending on the geometry and tissue type, the presence of contrast agent, and / or the presence of ACT® bubbles.

[0124] The database 508 and data storage module 510 can be housed on the same or different hardware devices. Alternatively, the database 508 and / or data storage module 510 can be housed on a cloud-based platform.

[0125] Once the MP (e.g., attenuation) map is generated, the program then draws the PP from the ultrasound source 504 to the target therapeutic area. The location of the ultrasound source 504 and the location of the therapeutic target area are identified by the program or manually entered by the user. The program then compiles the MP (e.g., attenuation) values ​​for each component across the PP to generate, for example, a PCF for attenuation.

[0126] The program uses a PCF (e.g., attenuation) to calculate the relevant MI resulting from a specific PP to indicate the ultrasound dose irradiated to the target region. When the program generates a CMP map, several media properties are used to calculate one or more PCFs for calculating the relevant MI and ultrasound dose.

[0127] The MI / ultrasonic dose specific to the calculated path is sent to the ultrasound source 504 (i.e., the ultrasound scanner). The ultrasound source is adjustable to take into account the calculated MI / ultrasonic dose and the desired US dose to the target area.

[0128] In some embodiments of the present invention, the system 500 is configured to continuously perform the process of calculating a specific PCF, and therefore M1 / ultrasonic dose value, for a specific path. In this way, the ultrasonic dose can be tracked by moving the ultrasonic source 504 relative to the target region and / or adjusting the ultrasonic frequency. If the ultrasonic source remains within the region of interest, the system 500 does not need to generate a new (C)MP (e.g., attenuation) map. Thus, time and processing power can be saved.

[0129] As described above, this definition of MI is unsuitable for some ultrasound applications due to the significant discrepancy (decrease) between the actual tissue peak negative pressure and that given in the standard definition of MI. In particular, it is sub-optimal when point estimation of peak dilution is required for therapeutic applications. This is due to the simplified definition of MI, which includes a simple power law dependence on attenuation and a single lower value for tissue (for a safe upper limit). Therefore, the MI output recommended for diagnostic imaging may not be best for therapeutic use. Accordingly, the method of the present invention rather takes into account the components of the propagation medium in order to estimate the ultrasound dose to be delivered for therapeutic use. Thus, a more accurate method according to the present invention involves the step of classifying the type of tissue present between the ultrasound transducer and the volume of tissue to be treated, and recognizing the effect of bubbles (contrast agents, ACT® microbubble clusters and / or ACT®) in each type of tissue and to identify and define the ultrasound dose for use in therapeutic applications.

[0130] PCF is required to adapt to the specific environment in which the ultrasound field traverses from the ultrasound source to the target area. As mentioned above, the specific environment depends on the subject's anatomical structure and composition, as well as the presence of additional components for imaging and / or ACT® treatment.

[0131] In certain embodiments where MP is attenuated, there are specific challenges to effective ACT® treatment with the current conservative, lower derating coefficients for obese subjects. This is because the excess fat volume in the ultrasound path can cause greater-than-average attenuation of the irradiated ultrasound field, and therefore, the ultrasound dose delivered to the target treatment area may be insufficient. The method described herein is particularly useful for ultrasound treatment in obese patients because it can be adapted to specific compositions with respect to tissue type and geometry. [Examples]

[0132] A first embodiment of the method of the present invention described above is shown in Figures 6a to 6c.

[0133] Figure 6a shows a cross-section of the abdomen 610 of a human subject. The cross-section above includes muscle 603, liver 604, blood vessels 605, kidney 606, bone 607, spleen 608, intestine 609, stomach 610, and pancreas 611. An ultrasonic transducer 600 is brought into contact with the external skin surface of the abdomen 610 of the human subject. The ultrasonic transducer 600 delivers an ultrasonic field along the acoustic path 601 toward the target depth indicated by the cross symbol 602. As shown in the figure, the acoustic path 601 passes through several different types of organs between the ultrasonic transducer 600 and the target 602, namely, skin, muscle 603, fat, liver 604, intestine 609, and pancreas 311.

[0134] In the example in Figure 6a, the acoustic path 601 is shown as a single linear path from the discrete point of the transducer 600 to the target 602. However, the acoustic path may be composed of multiple ultrasonic rays, each having its own path, as described above.

[0135] Figure 6b shows a graph of the attenuation coefficient with respect to depth along the acoustic path 601 in Figure 6a, where the attenuation coefficient depends on the type of tissue traversed at that depth. In the example of Figure 6b, the attenuation coefficient at depths between 0 cm and approximately 0.5 cm is 0.4, i.e., the attenuation coefficient of skin. The attenuation coefficient at depths between approximately 0.5 cm and 1.0 cm and between 2.0 cm and 2.5 cm is 0.3, i.e., the attenuation coefficient of fat. The attenuation coefficient at depths between approximately 1.0 cm and 2.0 cm is 0.5, i.e., the attenuation coefficient of muscle. The attenuation coefficient at depths between approximately 2.5 cm and 5.5 cm is the attenuation coefficient of liver, approximately 0.35. At depths of 5.5 to 6.5, the acoustic path traverses the intestine, and intestinal tissue has an attenuation coefficient of approximately 1.5. The last type of tissue traversed by the ultrasound field before reaching the target is the organ tissue of the pancreas 608, which has an attenuation coefficient of approximately 0.25 dB / cm.

[0136] Figure 6c shows a graph of the resulting mechanical index (Equation 5) with respect to depth along the acoustic path 602. The solid line represents the mechanical index adjusted for a standard derating of 0.3 dB / cm / MHz, and the dotted thick solid line represents the mechanical index adjusted for the attenuation specific to the medium in the example 6b in Figure 6c. Therefore, the dotted thick solid line represents α → α CF This represents the pressure according to Equation 5 in this case. At the target, the mechanical index is approximately 0.15.

[0137] A second embodiment of the method of the present invention described above is shown in Figures 7a to 7c.

[0138] Figure 7a shows a cross-section of the abdomen 710 of a human subject. The cross-section above shows tissue from muscle 703, liver 704, fat 705, and skin 706. An ultrasonic transducer 700 is brought into contact with the external skin surface of the abdomen 710 of the human subject. The ultrasonic transducer 700 delivers an ultrasonic field along the acoustic path 701 toward a target depth indicated by the cross symbol 702. As shown in the figure, the acoustic path 701 passes through several different types of organs between the ultrasonic transducer 700 and the target 702, all of which contain microbubbles and ACT® bubbles, namely, skin 706, fat 705, muscle 703, fat 705, and liver.

[0139] Similar to Example 6a, in the embodiment of Figure 7a, the acoustic path 701 is shown as a single linear path from a discrete point of the transducer 700 to the target 702. However, the acoustic path may be composed of multiple ultrasonic rays, each having its own path, as described above.

[0140] Figure 7b shows a graph of the attenuation coefficient with respect to depth along the acoustic path 701 in Figure 7a, where the attenuation coefficient depends on the type of tissue traversed at that depth. In the example in Figure 7b, the attenuation coefficient at depths between 0 cm and approximately 0.5 cm is 0.96 dB / cm, i.e., the attenuation coefficient for skin where microbubbles and ACT® bubbles are present. The attenuation coefficient at depths between approximately 0.5 cm and 1.0 cm and between 2.0 cm and 2.5 cm is 0.37 dB / cm, i.e., the attenuation coefficient for fat where microbubbles and ACT® bubbles are present. The attenuation coefficient at depths between approximately 1.0 cm and 2.0 cm is 0.41 dB / cm, i.e., the attenuation coefficient for muscle where microbubbles and ACT® bubbles are present. The attenuation coefficient at depths between approximately 2.5 cm and target 502 located at a depth of approximately 5.0 cm is 0.71 dB, i.e., the attenuation coefficient for liver tissue where microbubbles and ACT® bubbles are present.

[0141] Figure 7c shows a graph of the resulting mechanical index with respect to depth along the acoustic path 702. The dotted thick solid line represents the mechanical index resulting from adjustment for attenuation specific to the medium, while the solid line represents the mechanical index resulting from adjustment for standard attenuation (0.3 dB / cm / MHz) in the medium of the embodiment 7b in Figure 7c. At the target depth, the mechanical index is approximately 0.15.

[0142] Examples of the method, as shown in Example 1 according to Figures 6a-6c and Example 2 according to Figures 7a-7c, demonstrate the dependence of pressure on the type of tissue, and on the presence and absence of bubbles within the tissue.

[0143] As an example, the target area is a metastatic lesion located in the patient's liver. The patient receives treatment consisting of chemotherapy drugs administered intravenously, and the treatment is enhanced by administering doses of ACT® clusters and performing activated and enhanced ultrasound on the target lesion. Therapeutic ultrasound is provided from an ultrasound scanner connected to an ultrasound probe positioned in contact with the patient's abdominal skin, as shown in Figures 6a and 7a. Prior to treatment, the preferred placement of the probe is determined based on the patient's ultrasound imaging. Once the preferred placement is determined, the types of tissue present between the probe and the target lesion are identified. This process can be performed by a segmentation algorithm using trained artificial intelligence that has access to ultrasound scanner data. One or more line-of-sight lines are drawn from the probe plane to the target lesion, and the thickness of each segment along these line-of-sight lines is calculated. Typically, in this situation, the ultrasound field emitted by the probe traverses layers of skin, fat, muscle, and liver parenchyma before reaching the target lesion. A media characteristics map is created by an ultrasonic scanner by retrieving data from a database for each tissue type, including tissue perfusion values, ACT® bubble lifetime values, ACT® bubble half-life values, ACT® bubble activation yield values, and ultrasonic attenuation values ​​across a frequency range. An example of such a database is given in Table 2.

[0144] Furthermore, attenuation values ​​across a frequency range are extracted for activated ACT® clusters and the microbubble components of the clusters. An example of such a database is given in Table 3, where, for simplicity, only two frequencies are shown. The attenuation values ​​are proportional to the concentration.

[0145] The total blood volume and cardiac output of a patient can be determined through patient examination or by utilizing approximations. For example, blood volume and cardiac output can be estimated from the patient's weight. In this example, the patient's weight is 70 kg, and this patient's weight is provided as input to the ultrasound scanner. This value is used by the algorithm to calculate a blood volume of 4.6 L and a cardiac output of 5 L / min. The ACT® cluster is infused over a period of 30 seconds, so that the dose is mixed within a limited blood pool as it first passes through the circulatory system.

[0146] The peak attenuation of ultrasonic pulses resulting from the injection of ACT® clusters is calculated from data provided to the database. For example, the peak attenuation from free-flowing microbubbles can be approximated using Equation 9.

[0147] Similarly, the peak concentration of the ACT® bubble can be calculated for each tissue type using the following formula 10.

[0148] By using additional information and assigning values ​​to different segments of the identified tissue type, the algorithm can calculate the expected maximum attenuation for a given dose, as shown in Table 4. Here, a dose of 40 uL / kg is used to calculate the attenuation from the microbubble and ACT® bubble components.

[0149] In the above example, which uses a discrete integral along a specified line of sight, and is described using values ​​given along that line of sight, the total attenuation at 0.5 and 2 MHz is 5.0 and 15.2 dB, respectively, compared to the standard deratings of 1.4 and 5.5 dB obtained by using standard deratings.

[0150] As mentioned above, if the ultrasound dose is too low compared to the effective dose range, the ACT® bubble will not vibrate sufficiently. Therefore, it is particularly important to precisely control the ultrasound dose intended to target and vibrate the ACT® bubble. This is shown in Figure 8. Figure 8 gives results for tumor-specific uptake of a fluorescent dye (Evans Blue) in ACT® treatment with an enhanced step ultrasound field at 500 kHz using mechanical indicators (MI) of 0, 0.1, 0.2, 0.3, and 0.4 (bottom panel). The Y-axis shows tumor-specific uptake in units of mg of Evans Blue / mg of tumor tissue. The X-axis shows the mechanical indicator. The top four panels show results from modeling the response of the activated bubble to the incident US field at different MIs investigated. The Y-axis shows the radius of the activated bubble in μm. The X-axis shows time in μs.

[0151] To investigate the effect of mismatched MI in US-enhanced fields, tumor-specific uptake of Evans Blue (EB, a fluorescent dye) was investigated in a mouse subcutaneous prostate cancer model (PC3). Five groups with enhanced ultrasound-irradiated MI of 0, 0.1, 0.2, 0.3, and 0.4 were investigated (N=3 animals per group). Immediately after IV injection of EB, a single dose of the cluster composition (2 mL / kg, (iv)) was administered, followed by 45 seconds of activated US (2.25 MHz, MI 0.4) and 5 minutes of enhanced US (0.5 MHz, variable MI) focused on tumor volume. Thirty minutes after treatment, the tumor was resected, and the amount of EB was measured by spectrophotometric analysis at 620 nm.

[0152] The results of tissue uptake of Evans Blue and bubble oscillation as a function of MI are visualized in Figure 8. As noted, tissue uptake increases from no ultrasound (MI=0) to MI=0.1, further increases for MI=0.2, but decreases again at MI=0.3 and further decreases for MI=0.4. At MI=0.2, tumor-specific uptake is observed to increase by approximately 60% compared to MI=0 (no ultrasound). Simultaneously, the maximum radial oscillation from the implanted bubble oscillation panel increases from approximately 3 μm at MI=0.1 to approximately 6 μm at MI=0.2, approximately 10 μm at MI=0.3, and over 20 μm at MI=0.4. Importantly, the beginning of the decrease in tissue uptake (from MI=0.2 to MI=0.3) coincides with the beginning of significant nonlinear behavior in which inertial cavitation begins to occur.

[0153] The present invention is not limited to the embodiments and examples shown. While various embodiments of the disclosure are described herein, it will be apparent to those skilled in the art that such embodiments are provided only as examples. Numerous modifications and changes to the embodiments described herein, as well as variations and substitutions of these embodiments, will be obvious to those skilled in the art without departing from the disclosure. It should be understood that various alternative examples of the embodiments described herein can be used when carrying out the disclosure.

[0154] It should be understood that all embodiments of this disclosure may be arbitrarily combined with any one or more of the other embodiments described herein.

[0155] It should be understood that each component, compound, particle, or parameter disclosed herein is disclosed for use alone or in combination with one or more of the other components, compounds, or parameters disclosed herein. Each quantity / value or range of quantity / value for each component, compound, or parameter disclosed herein is similarly disclosed in combination with each quantity / value or range of quantity / value disclosed for any other(multiple) components,(multiple) compounds, or(multiple) parameters disclosed herein, and therefore it should be further understood that any combination of quantities / values ​​or ranges of quantity / value for two or more(multiple) components,(multiple) compounds, or(multiple) parameters disclosed herein is similarly disclosed in combination with each other for the purposes of this description. Any and all features described herein, and combinations of such features, are included within the scope of the invention, provided that the features do not conflict with each other.

[0156] It should be understood that each lower limit of each range disclosed herein should be interpreted as being disclosed in combination with each upper limit of each range disclosed herein for the same component, compound, or parameter. Thus, a disclosure of two ranges should be interpreted as a disclosure of four ranges derived by combining each lower limit of each range with each upper limit of each range. A disclosure of three ranges should be interpreted as a disclosure of nine ranges derived by combining each lower limit of each range with each upper limit of each range, and so on. Furthermore, any specific amount / value of a component, compound, or parameter disclosed in the description or examples should be interpreted as a disclosure of either a lower or upper limit of a range, and can therefore be combined with any other lower or upper limit, range, or specific amount / value for the same component, compound, or parameter disclosed elsewhere in this application to form a range for that component, compound, or parameter.

[0157] While preferred embodiments of the present invention have been described, it will be apparent to those skilled in the art that other embodiments incorporating the present invention can be used. These and other embodiments of the present invention described above are intended merely as examples, and the actual scope of the invention should be determined from the appended claims.

Claims

1. A method for calculating a point estimate of the ultrasonic dose in a target treatment area, A step of calculating a unique ultrasonic propagation correction coefficient for a specific ultrasonic propagation path passing through a particular region of interest by obtaining a media characteristics map of the region of interest, The media characteristics map provides a plurality of different media characteristics values ​​for different components of the region of interest, depending on the medium within each component of the region of interest. Obtaining the media characteristics map of the region of interest is: A substep of obtaining an image of the region of interest, which includes the target treatment area and the surrounding area of ​​the target treatment area, A substep of processing the image to identify different components of the region of interest, A substep of dividing and classifying the aforementioned different components into predetermined media categories, A substep to obtain media characteristic values ​​associated with each media category, To estimate a media category-specific ultrasonic coupling bubble element correction for the media characteristic value resulting from the presence of at least one ultrasonic coupling bubble element in at least one component, Adjusting the media characteristic value of at least one component, taking into account ultrasonic coupling bubble element correction specific to each media category, Assigning the media characteristic value to each component of the divided region of interest, Substeps including, A substep that depicts the propagation path from the ultrasonic source to the target treatment area, A substep of compiling the media characteristic values ​​for each component along the propagation path in order to calculate the intrinsic ultrasonic propagation correction coefficient, Steps including, The steps include using the specific ultrasound propagation correction coefficient to indicate the ultrasound dose delivered to the target treatment area, The steps include: calculating a point estimate of the ultrasonic dose in the target treatment area based on the aforementioned unique ultrasonic propagation correction coefficient; Includes, The steps of calculating the unique ultrasonic wave propagation correction coefficient, using the unique ultrasonic wave propagation correction coefficient, and calculating the point estimate of the ultrasonic dose in the target treatment area are performed by a computer. method.

2. The aforementioned media categories are: Different types of organizations, Different types of tissue affected by one or more specific diseases, fluids, and gas, The method according to claim 1, comprising at least one of the following.

3. The different types of the aforementioned organizations are, Soft tissues including fat, muscle, parenchyma, tendons, and ligaments, as well as hard tissues including bone. The method according to claim 2, comprising one or more of the above.

4. The substep of obtaining an image of the region of interest is: To obtain a pre-scanned scan of the region of interest, and Perform a pre-scan of the region of interest. Includes at least one of the following: The method according to claim 1, wherein the scan includes one or more computed tomography images and magnetic resonance images.

5. The method according to claim 1, wherein the media characteristic values ​​specific to the media category are obtained from a database.

6. The at least one ultrasonic coupling bubble element is Contrast agent microbubbles, Cavitation Seed, Large microbubbles, Acoustic cluster therapy (ACT) bubble technology, ultrasonic coupling bubble element, Includes one or more of the following: The aforementioned Acoustic Cluster Therapy (ACT) bubble technology ultrasonic coupling bubble element is, Acoustic cluster therapy (ACT), microbubble clusters, and Activated acoustic cluster therapy (ACT) bubbles, Includes, The aforementioned large microbubbles are microbubbles larger than 8 μm. The method according to claim 1.

7. The at least one ultrasonic coupling bubble element includes contrast agent microbubbles, Estimating the ultrasonic coupling bubble element correction includes the step of estimating the contrast agent microbubble correction. The step of estimating the contrast agent microbubble correction is as follows: A substep for obtaining or estimating contrast agent microbubble parameters, The contrast agent microbubble parameters are, The value relative to the amount of contrast agent microbubbles administered, Contrast agent attenuation per unit concentration, The subject's blood volume and The cardiac output of the aforementioned subject and The blood volume values ​​associated with each media category, The time to reach the target of contrast agent after intravenous administration for each media category, Time-concentration curve and, Substeps including, A substep that uses contrast agent microbubble parameters to calculate contrast agent correction for each media category, including, The method according to claim 6.

8. The at least one ultrasonic coupling bubble element includes an acoustic cluster therapy (ACT) bubble technology ultrasonic coupling bubble element, Estimating the ultrasonic coupling bubble element correction includes the step of calculating the acoustic cluster therapy (ACT) bubble correction, The step of calculating the aforementioned acoustic cluster therapy (ACT) bubble correction is: A substep to estimate the correction arising from the microbubble cluster in the presence of high-frequency activated ultrasound, A substep to estimate the correction arising from acoustic cluster therapy (ACT) bubbles generated in the presence of high-frequency activated ultrasound, A substep to estimate the correction arising from acoustic cluster therapy (ACT) bubbles in the presence of low-frequency enhanced ultrasound, The method according to claim 6, including the method described in claim 6.

9. The step of calculating the acoustic cluster therapy (ACT) bubble correction is: A substep of obtaining or estimating one or more acoustic cluster therapy (ACT) bubble parameters, wherein the acoustic cluster therapy (ACT) bubble parameters are The subject's blood volume, The cardiac output of the aforementioned subject, Perfusion of each medium category of the components, and Substeps including time-concentration curves, A substep of calculating the number of acoustic cluster therapy (ACT) bubbles delivered to each of the components by multiplying the fraction of cardiac output considering the perfusion of each medium category of the components by the yield of activation of acoustic cluster therapy (ACT) bubble clusters, By doing so, the number of acoustic cluster therapy (ACT) bubbles in the media category associated with each component is estimated. To calculate the acoustic cluster therapy (ACT) bubble correction based on the number of acoustic cluster therapy (ACT) bubbles delivered to each of the aforementioned components and estimated, The method according to claim 8, further comprising:

10. The estimate of the number of acoustic cluster therapy (ACT) bubbles in the media category associated with each segment is: To model the decrease in the number of acoustic cluster therapy (ACT) bubbles in each medium category over time, we obtain a value for the lifetime of acoustic cluster therapy (ACT) bubbles in each medium category. The method according to claim 9, which includes a time dependency.

11. The method according to claim 7, wherein the step of estimating the contrast agent microbubble correction is based on contrast-mode imaging ultrasound.

12. The method according to claim 9, wherein the substeps of estimating corrections arising from acoustic cluster therapy (ACT) microbubble clusters in the presence of high-frequency activated ultrasound, estimating corrections arising from acoustic cluster therapy (ACT) bubbles generated in the presence of high-frequency activated ultrasound, and estimating corrections arising from acoustic cluster therapy (ACT) bubbles in the presence of low-frequency enhanced ultrasound are based on basic B-mode imaging ultrasound.

13. The method according to claim 1, comprising the step of using the specific ultrasonic propagation correction coefficient to calculate at least one of pressure, mechanical index, intensity, power, and thermal index, which are indicators of the delivered ultrasonic dose.

14. A non-temporary computer-readable storage medium storing instructions for performing the method described in claim 1, which are executed on a processor.

15. A system for providing point estimation of ultrasound dose in a region of interest in a subject, Ultrasonic source and An image processor module for processing an image to identify different components of the region of interest, Computer processor and A database module comprising media characteristic values ​​associated with multiple media categories of components within the aforementioned region of interest, A data storage module equipped with computer-readable instructions, Equipped with, The aforementioned image processor module performs the following tasks: A task of acquiring an image of the region of interest, which includes the target treatment area and the surrounding area of ​​the target treatment area; A task of processing the image to identify different components of the region of interest; A task of dividing and classifying the aforementioned different components into predetermined media categories; Execute, The computer processor, by means of the instruction, performs the following tasks: A task to obtain media characteristic values ​​associated with each media category, To estimate a media category-specific ultrasonic coupling bubble element correction for the media characteristic value resulting from the presence of at least one ultrasonic coupling bubble element in at least one component, Adjusting the media characteristic value of at least one component, taking into account ultrasonic coupling bubble element correction specific to each of the aforementioned media categories, Tasks including; A task of assigning the media characteristic values ​​to each component of the divided region of interest, A task of drawing the ultrasonic propagation path from the ultrasonic source to the target treatment area; The task of compiling the media characteristic values ​​for each component along the propagation path in order to calculate an ultrasonic propagation correction coefficient specific to the ultrasonic propagation path passing through the region of interest; A task of calculating a point estimate of the ultrasonic dose in the region of interest based on the intrinsic ultrasonic propagation correction coefficient; and A task of adjusting the ultrasonic source according to the calculated point estimate of the ultrasonic dose when it is outside the range of a predetermined ultrasonic dose range, Execute system.

16. The image processor is Identifying the boundary between different patterns in the aforementioned image, Analyzing the pattern within the said boundary, and To find a match, compare each of the aforementioned patterns with image patterns of known tissue types. The region of interest is configured to divide and classify the different components thereof. The system according to claim 15.

17. The system is a machine learning system, and each processed image is stored as training data along with the associated image data by the image processor to provide more accurate segmentation and classification. The system accumulates the ability to divide and classify different components of the domain of interest based on the accumulated training data. The system according to claim 16.

18. The system according to claim 15, further configured to track the position of an ultrasonic probe.

19. The system according to claim 15, further configured to track the rhythmic movement of a medium in the region of interest.

20. The system is configured to track the rhythmic motion of the medium through speckle tracking or machine learning algorithms. The system according to claim 19.

21. The media characteristics include at least one of the following: ultrasonic attenuation, sound velocity, shear wave velocity, acoustic impedance, and nonlinear compression coefficient. The method according to claim 1.

22. The media characteristics include at least one of ultrasonic attenuation, sound velocity, shear wave velocity, acoustic impedance, and nonlinear compression coefficient. The system according to claim 15.

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